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Chapter 14 The Alkaloids of Aspidosperma, Diplorrhyncus, Kopsia, Ochrosia, Pleiocarpa, and Related Genera
THE ALKALOIDS OF ASPIDOSPERMA. DIPL ORRHYNC US. KOPSIA. OCHROSIA. PLEIOCARPA. AND RELATED GENERA B . GILBERT Centro de Pesquisas de Produtos Naturais. Fuculdade Nucional de FarmCicia. Rio de Janeiro. Brazil
1. Introduction ......................................................
I1. The Aspidospermine Group ......................................... A. Introduction ................................................... B. Quebrachamine ................................................ C. Aspidospermine ................................................ D. NMR- and Mass Spectra of the Aspidospermine-Type Alkaloids . . . . . E. Some Minor Alkaloids of Aspidasperma quebrachoblancoand Rhazya strictu F. Demethoxyvallesine, Demethoxyaspidospermine, and Demethoxypalosine ....................................................... G. Demethylaspidospermine ........................................ H . Vallesine and Palosine ........................................... I. Aspidocarpine and Demethylaspidocarpine ......................... J. Aspidolimine ................................................... K . Pyrifolidme and Deacetylpyrifolidme .............................. L . Spegazzinine and Spegazzinidine .................................. M. Cylindrocaxpine and Cylindrocarpidine ............................ N . Limaspermine and Related Alkaloids .............................. 0. Tabersonine ................................................... P. Vinca Alkaloids of the Aspidospermine Group ......................
336 337 337 337 361 367 395 398 399 400 400 403 404 405 410 414 416 419
I11. The Aspidofractinine Group ......................................... A. Introduction ................................................... B . Intercorrelations and Skeletal Structure ........................... C. Aspidofractinine ................................................ D. Pyrifoline. Refractidine. and Refractalam .......................... E. Aspidofiline .................................................... F. Some Alkaloids of Aspidosperm populifolitm ...................... G. Kopsinine. Aspidofractine. Pleiocarpine. Pleiocarpinine. and Refractine H. Kopsinilam and Pleiocarpinilam .................................. I. Kopsiflorine. Kopsilongine. and Kopsamine ........................ J. Kopsine and Related Alkaloids ................................... K . K o p s k Alkaloids of Unknown Structure ...........................
420 420 421 429 429 432 433 434 439 439 441 444
IV. The Aspidoalbine Group ............................................ A. Aspidoalbine and Its N-Acetyl Analog ............................. B Aspidolimidine ................................................. 336
445 445 448
.
B . GILBERT
336 C. D. E. F. G.
Dichotamine and 1-Acetylaspidoalbidine . . . . . . . . . . . . . . . . . . . . . . . . . . . Haplocine and Haplocidine . . . . .... Cimicine and Cimicidine . . ................... Other Alkaloids of the Asp bine Group ......................... Obscurinervine and Related Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449 450 451 451 452
453 V . The Condylocarpine Group .......................................... A. Iiitroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453 B . Aspidospermatine, Aspidospermatidine, and Related Alkaloids . . . . . . . . 453 C. Condylocarpine and Stemmadenine . . . . . . . . . . . . 457 I). Tubotaiwine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 E. 11.Methoxy.14,19.dihydroeondylocarpin e . . . . . . . . . . . . . . . . 462
VI . Alkaloids Related t o Akuammicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . il. Introduction . . . . . . . ......................................... B. Mossambine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Norfluorocurarine D . Compactinervine .
463 463 463 466 466
................. V I I . The Uleine Group . . . A. Introduction . . . . ................. B. Uleine and Relate C . Olivacine, Dihydroolivacine, and Guatambuine . . . . . . . . . . . . . . . . . . . . . D . Ellipticine, Dihydroellipticine, and N-Methyltetrahydroellipticine. . . . .
469 469 469 474 477
V I I I . Tetrahydro /3-Carbolineand Related Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . A . Yohimbine and Tetrahydroalstonine Derivatives . . . . . . . . . . B. Normacusine.B, Polyneuridine, and Akuammidine . . . . . . . . . . . . . . . . . . C. Quebrachidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Harman-3-carboxylicAcid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Eburnamine and Related Alkaloids ............................... F. TuboAavine ............................... . . . . . . . . . . . . . . . . . . . . . G. Flavocarpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Carapanaubine ...................... ........... ...... I. Isoreserpiline.+.indoxyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J . Ochropamine and Ochropine ......................................
482 482 485 491 495 495 497 498 502 503 503
1X . Alkaloids of Unknown Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Alkaloids of Pleiocarpa Species ................ B. Alkaloids of Ochrosia Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Alkaloids of Aspidosperma, Rhnzya, and Sternmadeniu . . . . . . . . . . . . . . .
504 504 504 505
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
..........
505
.
I Introduction
The great advance in our knowledge of the chemistry of this group during the past few years is indicated by the fact that a t the time of completion of the previous review (Volume VII. Chapter 10)no structure was known. whereas a t the time of the present writing. the structures of more than 100 alkaloids from these genera have been elucidated . A list
14. Aspidosperma AND RELATED ALKALOIDS
337
of the alkaloids at present known with their plant sources and physical properties is given in Table I. These bases may conveniently be divided into eight groups, each of these groups ranging over two or more of the seven genera under discussion.
11. The Aspidospermine Group
A. INTRODUCTION This group of alkaloids, whose basic carbon skeleton wtts not readily explained by the earlier biosynthetic hypotheses (1, a), appears to be relatively restricted in nature, occurring principally in the genera Aspidosperma, Kopsia, Pleiocarpa, and Stemmadenia of the family Apocynaceae. Similar alkaloids, for example, vindolinine (CVI, 3), vindoline (CIII, 4,5 ) , and vincadifformine (XCIII, 6), occur in Vinca or Catharanthus species and tabersonine (XCII, 7) is found in the genus Amsonia as well as in Stemmadenia (Section 11, 0 and P). The parent alkaloid of the group, quebrachamine (I),is also one of the most widely distributed. Although as an indole it is distinct from all the other members of the group, which are dihydroindoles, its obvious relation to the others justifies its inclusion here.
B. QUEBRACHAMINE The earlier literature on quebrachamine has been dealt with in previous volumes, and its occurrence in some new sources is recorded in Table I. Most important from the biogenetic point of view is the existence in nature of both optical enantiomers. The common levorotatory form corresponds in absolute configuration t o aspidospermine (11,vide infra), while the dextrorotatory form found in Stemmadenia donnell-smithii (8) is related to (+)-pyrifolidine (XLVI, 9, 10) and to (-)-tabersonine (XCII, 7). The Vinca minor alkaloids vincadine (11-A) and vincaminoreine (11-B)are the 3-carbomethoxy- and 3-carbomethoxy-Na-methyl derivatives, respectively, of ( + )-quebrachamine (10a). The same plant (lob). also contains ( k )-indolic-N-methylquebrachamine The determination of the structure of quebrachamine (I)followed on that of aspidospermine (11),and was indeed suggested at the time that this latter structure was published (11, 12, 13, 14). In work prior to this, Witkop and his co-workers were able to show that the two alkaloids were related, since both gave on zinc dust distillation a mixture from which
TABLE I
w w ca
PHYSICAL CONSTANTSAND PLANT SOURCES PART1. Quebrachamine and its derivatives
Compound'
Formula
mP ("C)
Quebrachamine, 1, a 38, 59; b 23, 63; c 34; d 5 2 ; e 51, 62; f Volume VII, 60, 61; E 38b
ClgHzeNz
146-147
Dextrorotatory, g 8 Racemic Salts (see Volume 11)
147-149 114-1 16
[uID2
-108 (c) -91 (e) - 110 (a) - 100 (d) +111 (c)
Reference 23, 34 55 8 6, 8
PART 2. Aspidospermidine and its derivatives Formula
Aspidospermidine(282A), XXXI, C ~ ~ H Z a ~ 28,51a; N Z , e,51 1,2-Dehydroaspidospermidine,IX, C ~ ~ H Z ~ e 51b NZ, Demethoxyvallesine, XXXII, CzoHz~Nz0,h 37 Demethoxyaspidospermine, XXXIII, C21HZsN20, h 40a; i 48; mm 48 Demethoxypalosine, XXXIV, Cz~H30Nz0,j 40; h 408 A',-methylaspidospermidine, XXXV, CzoHzsNz, a 28, 51a Aapidosine, XXXVI, C1gHzeNzO
w
0
16
17
Ne.
H
H
H
H H
H H
CHO
H H H
H H OH
mP (" C)
[elD
120-121 amorph.
+ 243(e)
+17(e)
Ac
amorph.
- 15 (c)
EtCO Me H
115-120
- 17 (c)
265.5-257.5
- 16 (e)
Reference
28, 51b 28, 51a, b 37 40a 40 28 38, 25, 26
Demethylaspidospermine, XXXVII, C21H2sN202, h 40e; i 48 Deacetylaspidospermine, VI, CzoHzsNzO, a 28, 51a; b 38a
H
OH
Ac
amorph.
H
OMe
H
109-111
11-Hydroxy-10-0xoaspidospermine(A),XII,
CzzHzsNz04. CsHs 11-Acetoxy-10-oxoaspidospermine(A), XV, C24H30Nz05 11-Hydroxy-10-oxoaspidosperrnine(B), XVI, CzzHzgN204 10,11-Dioxoaspidospermine, XIII, CzzHzsNz04. CeHa oxime, C22H27N304. CaHs 11-Chloro-10-oxoaspidospermine, XIV, CzzH27ClNz03 Vallesine, XXXVIII, Cz1H2sN202, k 41 ; 1 39 Aspidospermine, 11, CzzH30Nz02, a 38; b 23; m Volume 11; k 41,41a; 139 10-Oxoaspidospermine, XI, CzzHzsNz03. CeH6 8-Oxoaspidospermine, XX, CzzHzsNzOa Apoaspidospermine, LI, C15HzzNz02 Palosine, XXXIX, C23H32N202, b 23 N,-Isobutyryldeacetylaspidospermine, XL, Cz4H34Nz02 N,-Benzoyldeacetylaspidospermine, Cz7H32N202 N,-Carbethoxydeacetylaspidospermine,C23H3zN203 N,-Methyldeacetylaspidospermine,XLI, CzlH3oNzO N-Ethyldeacetylaspidospermine, XVII, CzzH32NzO N,-Benzyldeacetylaspidospermine,C27H34N20 0,N-Diacetylaspidosine, C23H3oN203 Demethylaspidocarpine, L, C21HzsNz03, d 42 Aspidocarpine, XLIV, C22H3oN203, n 30; j 31, 40; ii 48; p 113 i; d 42 Aspidolimine, LIII, C23H32N203, j 31, 40; q 47; p 113 i Deacetylpyrifolidine, XLVII, C21H30N202, r 37 Pyrifolidine, XLVI, C23H32N203, Dextrorotatory, r 10
H
H
OMe OMe
CHO Ac
40a, 25
228-230
25, 26, 28, 38, 38a 24
211 247 249 261 294-296 154-1 56 208-209
24 24 24 24 24 41, 39 23, 26, 38
115 174-176 224-225
H H H H H H H H OH OMe
OMe OMe OMe OMe OMe OMe OMe OAc OH OH
EtCO iPrC0 PhCO CO2Et CH3 Et PhCHz Ac Ac Ac
149-152 162-164 187-190 125.5-128 amorph. 111-112 119.5-120.5 158-1 58.5 156-158 168.5-169.5
OMe OMe
OH OMe
EtCO
OMe
OMe
Ac
150-1 51 153-154 148-150.5 152-154 147.5-150
H
+ 119 (c) +3
(0)
-92 (c) -93 (c) -99 ( 0 )
- 132 (c) - 128 (c) - 86 (0)
+ 125 (c) + 140 (c) + 133 (c) - 5 (c) + 7 (0) - 94 ( 0 ) 90 (c)
+
24 24 30 30 23,43 43 25,39 25 25, 28, 51s 25 25 25 30,42 30, 31 31 30 9 30,28 10
TABLE I-Continued Formula
Compound
W
[elD
N,
16
17
N,-Ethyldeacetylpyrifolidine, LVII, Cz3H3sNz02
OMe
OMe
Et
0-Acetylaspidocarpine, XLV, Cz4H32N204 0-Acetylaspidolimine, LIV, C25H34Nz04 Picrate, B .C~H3N307 0-Propionylaspidolimine,L v , C26H36N204 Picrate, B. CsH3N307 0,O-Diacetyldemethylaspidocarpine, XLIX, C25H32N205
OMe OMe
OAc OAc
Ac EtCO
OMe
EtCOO
EtCO
OAc
OAc
Ac
-
-~
Reference
amorph. amorph.
-21
(c)
165-167
-8
(c)
semi-cryst.
+ 20 ( c )
193-195.5 179-181 144-145
+ 10 (c)
254-257 104.5-106
+ 63 ( c ) + 176 (c)
36 36 30,31 31 31 31 31 30
PART3. Aspidospermine-type alkaloids oxygenated a t C-3and their derivatives Formula
Compound
Deacetylspegazzinine, LXII, C I ~ H Z ~ N Z O ~ Spegazzinine, LXIV, C21H28N203, c 34 0-Methyldeacetylspegazzinine, LXIII, CaoHzsNzOz 0-Methylspegazzinine, LXV, CzzH30NzOa 0-Methyl-0-acetylspegazzinine, LXVI, C24H32N204 0-Methyl-0-benzoylspegazzinine, LXVII, CzgH34N204 0,O-Diacetylspegazzinine,LXVIII, Cz5H32N205 Spegazzinidine, LXIX, C Z ~ H Z ~ N cZ 35, O ~36 , 0,O-Dimethylspegazzinidine, LXX, C23H32N204 0,O-Dimethyl-0-tosylspegazzinidine, LXXIV, C30H38Nz06S O,O-Dimethyl-3-dehydrospegazzinidine, LXXI, C23H3oN204
16
17
H
OH OH
H H H H H H OH OMe OM0 OMe
N,
3
H
OH OH OH OH OAc PhCOO OAc OH OH OTs
OMe
Ac H Ac Ac Ac Ac Ac Ac Ac
OMe
Ac
OMe
OMe
OMe OMe OAc OH OMe
=O
amorph. amorph. amorph.
192-194
amorph.
237-238 167-169 158-160 185-187 or
155-160
- 64 ( c )
- 136
-23 ( c )
+ 97 + 123 ( c ) + 186
- 156 (c) +42 (c) - 53
34 34 34 34 34 34 34 35,36 35,36 36 35,36
b P
0
PART 4. Aspidospermine-type aIkaloids oxygenated at C-21 and their derivatives Compound
Formula mp ("C)
[c(ID
Reference
- 122 (c)
10 29, 10 10 10
COzH
11,s-118.5 168-169 146-147 236-238 and 245-248 265 (dec.)
DHC
CO2H
203-217
DHC Ac EtCO
H H
OMe OH OH OMe OMe OMe
H DHC Et
CHO CHaOH CH2OH CHzOH CHaOH CHzOH
H
OMe
CnHii
CHzOH
48-49
29, 10
H H
OMe OAc
Ac EtCO
CHzOAc CHzOAc
OMe
OH
Ac
CHzOH
148-150 amorph. 122-123 220
+ 131 (c)
52 33 33 120
OMe
OH
EtCO
CHzOH
174- 175
+118(c)
33,120
H
CHeOH
175-1 77
~
16
17
Cylindrocarpidine, LXXVI, C Z ~ H ~ O Ns 49, ~ O10 ~, Cylindrocarpine, LXXV, C30H34Nz04, s 49, 10 Dihydrocylindrocarpine, LXXVII, C30H36N~04 Cylindrocarpinic acid dihydrochloride, LXXX, CzoHz8ClzNz03. E t O H
H H H H
Cylindrocarpic acid hydrochloride, LXXVIII, CzsH33CINzO4 Dihydrocylindrocarpic acid hydrochloride, LXXIX, CzsH35ClNz04 Dihydrocylindrocarpal, L X X X I I I , CzgH34Nz03 Limapodine, L X X X I X , Cz~HzsNnOs,j 120 Limaspermine, LXXXVII, CzzH30N203, j 33 Decinnamoylcylindrocarpol, LXXXIV, CzoHz8NzOz Dihydrocylindrocarpol, LXXXII, CznH36Nz03 N,-Ethyldecinnamoylcylindroca.rpo1,LXXXVI, CzzH3zNzOz N,-y-phenylpropyldecinnamoylcylindrocarpol, LXXXI, CznH3sNzOz 21-Acetoxyaspidospermine, LXXXV, C z 4 H 3 ~ N ~ 0 4 0,O-Diacetyllimaspermine, LXXXVIII, Cz~H3.gN205 Picrate, B. C~H3N307 21-Hydroxyaspidocarpine( 16-methoxylimapodine), XC, C ~ ~ H ~ O Nj 120 ZO~, 21-Hydroxyaspidolimine( 16-methoxylimaspermine), XCI, C Z ~ H ~ Z N jZ120 O~,
N,
21
OMe OMe OMe OMe
Ac Cin DHC H
COzMe COzMe
H
OMe
Cin
H
OMe
H H H H
-
COzMe
COzH
amorph. 177-178 175-175.5 145-147 amorph. amorph.
- 181 (c) - 126 (c) - 3 (w)
10 10
+ 110 (c) f 108 (c)
+2 -98 (c)
10 120 33 52 10 52
.
N-Deacyl-0-methylaspidoalbinol, CXCIII, C2&€82N2O6
52
TABLE I-Continued PART 5. Aspidospermine-type alkaloids bearing a carbon substituent at C-3 and their derivatives -
~~~
~~
~~~~
Compound Tabersonine, XCII, C Z I H Z ~ N Z Ot Z65; , g 66a; u 66a; v 66a; w 66a Hydrochloride, B .HCI Vincadifformine, ( = 6,7-dihydrotabersonine),XCIII, CziHzsNz0z Minovine (N,-methylvincadifformine), CVIII, CZZHZENZOZ Minovincinine, CVII, CziHzaNz03 Minovincine, CIX, CzlHzsNz03 16-Methoxyminovincine, CX, C2zHzeNz04 2,3-DihydrotabersonoI, XCVII, CzoHzsNzO N,,O-diacetate, C, Cz4H30Nz03
Formula mP
2,3
6,7
3
20
(" C)
A
A
COzMe
H
amorph.
A
COzMe
H
A
COzMe
H
A A A
COzMe COzMe COzMe CHzOH CHzOAc
OH =O =O
A A
H H
196 (dec.) 124-125 amorph. 79-81 amorph. amorph. amorph. 186 196
[.ID
Reference 7, 64, 65
- 310 ( m )
rac. - 540 (e) 0 (e) -418 (e) - 504 (e) -414 (0) 82 ( e )
+
64, 65 6, 74 7, 32 74a 32, 76 32 32 32 7, 64 64
a,
8 W
M
3
PART6. Miscellaneous alkaloids with t h e aspidospermine skeleton a n d their derivatives
-
Vindoline Deacetylvindoline Dih ydrovindoline
__
Compound
16-Methoxy-N,-methyl-4-oxoaspidospermidine Vindolinine CVI dihydrochloride, B .2HC1 Other derivatives (see Ref. 3)
Formula CIII CXIII CXI CV CVI
CzsH3zNzOs Cz3Hm~Nz05 CzsHdzOs CZIHZENZOZ CziHz4NzOz
mP
Reference
(" C)
154-1 55 156-157 121-1 24 and 164-166 130-1 32 250-252 210-212 214-2 18
+42 (c) i-52 ( c )
+ 12 (c) - 72 (w) - 8 (w)
- 18 (w)
72 72 4 4 3, 72, 71 71 72 3
PART 7. Aspidofractinine-type alkaloids unsubstituted in position 3 Formula Compound
Aspidofractinine, CXVII, C I ~ H ~ x~ 102 N, Aspidofiline, CXXXVI, CzlHz6NzO~,r79 0-Methyldeacetylaspidofiline, CXXXIX, CzoHzaNzO, y 48
N-Formyl-0-methyldeacetylaspidofiline, CXLI-B, CzlHz6NzOz, Y 48 0-Methylaspidofiline, CXXXVIII, CzzHzaNzOz 0-Acetylaspidofiline, CXXXVII, Cz3HzsNz03 16,17-Dimethoxyaspidofractinine,CXLI-A, CzlHzaNzOz, y 48 N-Formyl-16,17-dimethoxyaspidofractinine, CXLI-C, CzzHzaNz03, Y 48 Deformylrefractidine, CXXII, CeoHzaNzO Dihydrochloride, B .2HC1 Methiodide, B.MeI Z, Refractidine, CXX, C Z ~ H Z ~ N ZxO81 N-Methyldeformylrefractidine, CXXIII, CziHzaNzO 6-Demethyldeformylrefractidine, CXXVII, C19H~4N20 N-Aretyl-6-demethyldeformylrefractidine, CXXX, C z l H ~ 6 N z 0 ~ N,-Methyl-6-demethyldeformylrefractidine, CXXXI, CzoHz6NzO N,O-~iacetyl-6-demethyldeformylrefractidine, CXXIX,
Cz3HzsNz03 6-Dehydrodemethyldeformylrefractidine,CXXXV, C19HZzN20 Deacetylpyrifoline, CXXI, CzlHzsNzOz Perchlorate, B .HC104
Pyrifoline, CXIX, C Z ~ H ~ ~ Nr Z 81,O49 ~, 6-Demethyldeacetylpyrifoline, CXXV, CzoHz6NzOz 6-Acetyldemethylpyrifoline, CXXVIII, C Z ~ H ~ ~ N ~ O ~ 6-Dehydrodemethylpyrifoline, CXXXIII, CzoH24NzOz
N,
6
(" C)
H OH
Ac
H
H H H
amorph. 190-1 9 1 129-131
OMe
H
OMe
CHO
H
amorph.
OMe OAc 16,17 (0Me)z 16,17(0Me)z H
Ac Ac
H
H
H
amorph. 179-181 140- 142
CHO
H
amorph.
H
OMe
H
CHO Me
OMe OMe
H H H
Ac
amorph. 189-193 258.5-259.5 158-160 104-106 163-164 2 18-2 19 160-161 193-194
H H
H
H
Me
OH OH OH
Ac
OAc
H
H H
OMe
OMe OMe OMe OMe
Ac
OMe
Ac
OAc
OMe
H
H
=O
OH
=O
[.ID
mP
17
132-136 amorph. 2 70-2 7 5 (dec.) 142-144 202-203 197-199 158-160
- 174 (c) -8 (c)
or
+ 3 (c)
+ 53 (c)
- 141 (c)
Reference
102 80, 79 80 48
80 80 48 48
- 53 (c) -31 (e)
- 140 (c) - 86 (c)
-24 (c) 4-39 (c) - 44 (c) +44 (c)
+ 10 (c)
- 14 (c)
+ 102 (c) - 20 (c) + 170 (c)
+ 24 (c)
81 37 37 81 37 81 81 81,102 81 81,37 81 37 49, 81 81 81 81
TABLE I-Continued ~
~~
W rp
PART 8. Aspidofractinine-type alkaloids substituted in position 3
rp
Compound
[aID
Reference
- 62 t o - 77 (c)
91, 82,87
~
Kopsinine, CXLII-A, CzlHz6NzOz, z 87, && 91; b b 96; o 48
H
H
COzM0
105
Aspidofractine, CXLIII-A, CzzHzeNz03, x 82 N-Acetylkopsinine, CXLIV-A, Cz3HzsNz03 Pleiocarpine, CXLV-A, Cz3HzsNz04, &a 91; b b 93, 96; cc 94 Pleiocarpinine, CXLVI-A, CzzHzsNzOz, tm 91; b b 96; cc 94
H
CHO Ac COzMe Me
COzMe COzMe COzMe COzMe
197 184-1 85 141-142 135-136
H CHO
COzMe COzMe
amorph. 157.5-159 and 191-192 amorph. 109-110 155-156 190-1 9 1 144-145 210-211
Doformylrefractine, CXLIX-A, CzzHzsNz03 Refractine, CL-A, Cz3HzsNz04, x 49; y 48 Deformylieoaspidofractine, CXLII-C, Cz1Hz6NzOz Isoaspidofractine, CXLIII-C, CzzHz6Nz03 Deformylisorofractine, CXLIX-C, CzzHzsNz03 Isorefractine, CL-C, Cz3HzsNz04 KopsiAorine, CLVI, Cz3HzsNz05, z 87 Kopsilongine, CLVII, Cz4H3oNz06, z 87
H
H H OM0
OM0 H
H
OMe OMe
H
OMe
H CHO
CO~MO COzMe H COzM0 CHO COzMe COzMe OH,COzMe COzMe OH,COzMe
- 142 (c)
-116 ( m ) - 56 (c) -23 (c)
82, 91 96 91, 92 91 94 82 49, 82
+7 (c) + 3 (c) 34 (0) 76 (c) -67 (c) -18 (c)
37 82 82 82 87 87, 89
-48 (c)
87, 88, 85 89
- 145 (c) - 124 (c)
+
+
16.17
Kopsamine, CLVIII, Cz4HzsNz07, z 87 Kopsaminic acid, CLX, Cz3HzeNz07.+HzO
OzCHz
OzCHz
COzMe COzH
OH, C O ~ M O OH,COzMe
205-206 131
OH,COzMe OH,COzMe OH,COzMe
148-149 148-149 119-120
17
KopsiAoreine CLXI, CziHz6Nz03 Nitroso-, CLXIV, CziHz5N304 Kopsilongeine, CLXII, CzzHzsNz04
H
H OMe
H NO
H
89 89 89
W
W M
E
16,17
H NO
OH, COzMe OH, COzMe
145-146 185-186
89 89
H H
H H
COzH COzH
OM0
H
COzH
209-21 1 280-281 273-274
89 37 37
H
H H
OH, COzH OH, COzH
242-250 198 199
H
OH, COzH
220-221
H
H
COzMe
254-254.5
H H
COzMe
COzMe
190 249-250
H H H H
H
COzMe COzMe
205-207 201-202 131-132 162
OzCHz OzCHz 17
Kopsinic acid, CXLII-B, CzoHz4NzOz Deformylisoaspidofractic acid, CXLII-B, CzoHz4NzOz Dihydrochloride, B. 2HC1 Deformylisorefractic acid, CXLIX-B, C Z I H Z ~ N Z O ~ Dihydrochloride, B .2HC1 Kopsifloric acid, CLXVII, CzoH34Nz03. HzO Kopsilongic acid, CLXVIII, CziHz6N~O4.3HzO
OMe
+20(m)
37 89 89
16,17
O~. Kopsamic acid, C L X I X , C Z I H Z ~ N Z 3HzO
OzCHz
89
17
Kopsinilam ( l o - o s o ) , CXLII-D, CziHz4NzO3, aa 96; bb 96; cc 96 Pleiocarpine lactam A( 10-oxo),CXLV-D, Cz3Hz+$"05 Pleiocarpinilam (lo-oxo), CXLVI-D, CzzHzsNzO3, aa 96; bb 96; cc 96 Kopsinine-8-lactait1, CXLII-E, CziHz4NzO3 Pleiocarpine lactam B (8-oxo),CXLV-E, Cz3HzfiNzOj N-Methylkopsinal, CLV, C Z ~ H Z ~ N ~ O Kopsinyl alcohol, CXLII-F, CzoHzfiNzO N-Methylkopsinyl alcohol, CXLVI-F, CZiHzsNzO 0-AcetaLe, CXLV1-K, Cz3HmNzOz Deformylrefractinol, C X L I X - F , CziHzsNzOz Deformylisorefractinol, CXLIX-T, CzlHzsNzOz .MeOH 0-Acetate, C~3H3oNzO3 Kopsinyl tosylate, C X L I I - H , C Z ~ H ~ ~ N Z O ~ S Deformylrefractinol tosylate, C X L I X - H , C Z E H ~ ~ N Z O ~ S Deformylisorefractinol tosylate, CXLIX-W, CzsH34Nz04S Kopsinyl iodide, C X L I I - J , CzoHzsINz
H
H OMe OMe OMe
H
OMe OMe
H
CH3
COzMe Me
H
Me Me
H H H
H H
H H
COZMe
CHO CHzOH CHzOH CHzOAc CHzOH CHzOH CHzOAc
CHzOTs CHzOTs CHzOTs CHzI
136-137 124-125 153-154 101-103 amorph. amorph. 147-148 amorph. I62 (dec.)
- 13 ( c )
96
-53 (c)
95 96
- 82 (c)
-47 (c) -3 (c) + 6 (c) -57 (c) - 50 ( c ) - 17 (c)
96 95 95 82, 89, 91, 92 91, 92 91 82 37 37 82 82 37 95
+Z
U
*e
M
ti b
c
'F1 c3 @ 01
TABLE I-Continued
Compound
N,O-Methylenekopsinyl ether, CLIII, CzlHzeNzO Kopsinyl N,-carboxylate, CLIV, CzlH24NzOz Kopsinylene, CXLII-M, CzoHz4Nz Picrate, B. CeH3N307 N-Methylkopsinylene, CXLVI-M, CzlHzeNz Deformylrefract-3-ene, CXLIX-M, CzlHzeNzO N-Methylisokopsinylene, CXLVI-N, CzlHzeNz Kopsinane, CXLII-0, CzoHzeNz N-Methylkopsinane, CXLVI-0, CzlHzsNz Deformylrefractane, CXLIX-0, CzlHzsNzO Noraspidofractone, CXLIII-P, CzoHzzNzOz Deformylnorrefractone, CXLIX-P, CzoHz4NzOz Norrefractone, CL-P, C Z ~ H ~ ~ N Z O ~
w
Formula
mP
~
17
N,
H H H
CHzOCHz CO-Q-CHz H =CHz
H
Me
H H H OMe H OMe
H Me H Me H CHO H
=CHz =CHz =C(CH3) CH3 CH3 CH3 =O =O
OMe
CHO
=O
OM0
[aID
Reference
(" C)
3
101-103 200-201 amorph. 183-187 68-70 amorph. 124-126 118 112-1 14 amorph. 140-142 202-209 (dec.) 184-189
-85 (c)
- 102 (c)
- 10 (0) - 240 (c)
95 95 82, 37 95 95 82 95 95 95 82 37 82
-51 (c)
37,102
[alD
Reference
PART 9. Kopsine and derivatives Formula
Compound
mP
N,
3
3'
(" C)
Kopsine, CLXX, C2zHz4Nz04, dd 100, 103, 109
COzMe
OH
=O
218
Dihydrokopsine-A (NaBH4), CLXXII, CzzHzeNz04
COzMe
OH
OH
256-257 (dec.)
+ 16 (e)4 - 18 (c)
104, 55 109, 112 100, 109, 112
W
8 W
M
E
0-Acetate, CzlHzsNzOs
COzMe
OH
OAc
COzMe
OH
OH
COzMe
OH
OAc
Kopsine Lactam A (10-OXO), CLXXV, CzzHzzNz05
COzMe
OH
=O
CLXXVII, CzzHz4NzOs Dihydrokopsine Lactam R ( 10-OXO),
COzMe
OH
OH
170-1 7 1 (dec.) 223-225 (dec.) 214-215 (dec.) 234-235 (dec.) 222-224
Decarbomethoxykopsine, CLXXI, C~OHZZNZOZ, dd 113
H
OH
=O
240-242
Ethyl carbonate, Cz3HzeN204 Dihydrodecarbomethoxykopsine (NaBH4),CLXXIII, CzoHz4NzOz Dihydrodecarbomethoxykopsine (Hz/Pt),CzoHz4NzOz
H H
OCOzEt OH
=O OH
H
OH
OH
=O
217 266-268 and 276 178-180 and 190-1 9 1 190-192 160.5-162.5 238-240 248-250 and 260-261 278-280
H H H
252-254 244 (dec.) 163-1 64.5 162-163 155 154-155 174-1 75
Dihydrokopsine-B (Hz/Pt),CLXXIV, CzzHzsNzO4 0-Acetate, Cz4HzsNz05
Isokopsine, CLXXXVII, CzzHz4Nz04 Dihydroisokopsine, CLXXXVII-B, CzzHz6Nz04 Decarbomethoxyisokopsine, CLXXXVII-A, CzoHzzNzOz, dd 113 Dihydrodecarbomethoxyisokopsine,CLXXXVII-C, CzoHz4NzOz Decarboinethoxykopsine lactam (10-oxo), CLXXVI, CzaHzoNz03 Kopsine methine, CLXXX, Cz3HzsNz04 Dihydro, Cz3HzsNz04 Tetrahydro, Cz3H30N204 Carbethoxytetrrthydro, C Z ~ H ~ Z N Z O ~ Kopsane, CLXXXIV, CzoH24Nz N-Acetyl, CLXXXV, C2zHzsNzO 10-Lactam, CLXXXVI, CzoHz2NzO
H
H Ac H
OH
H H H
100,112 100,101 100,112
+30 (e)
100, 101, 109,112 100, 101, 112 100, 109, 104 100 100,109 111
-82(~)
111 111 111 111 100,101 101,112 101,112 101,112 101,112 101,112 101 101
TABLE I-Continued W
rp
m
PART10. Compounds related t o aspidoalbine Formula
Compound 15, 16, 17 Fendleridine, CCI-L, C ~ ~ H ~ ~ G N 113f ZO, 1-Acetylaspidoalbidine, CCI-K, CzlHzsNzOz, 1~1130 Deacylhaplocine, CCI-F, ClgH24N202 Haplocidine, CCI-C, C21H26N203, F 113b, k 1138 Haplocine, CCI-D, CzzHzsN203, F 113b 0-Methylhaplocidine, CCI-B, CzzHzsNz03 0-Methylhaplocine, CCI-G, CzaH30Nz03 0-Acetylhaplocine, CCI-E, C24H3oN204 Dichotamine, CCI-A, C21Hz4Nz04, k 41, 113e Aspidolimidine, CCI, j 40, d 113h Fendlerine, CCI-0, G 113f N,-Acetyldepropionylaspidoalbine,CLXXXIX, CzaH30Nz05, d 42, 52; H 48 Aspidoalbine, CLXXXVIII, Cz4H32N205, d 42, 52 ; H 48 0-Methyldepropionylaspidoalbine, CXCII, CzzHaoN204 N,-Acetyl-0-methyldepropionylaspidoalbine, CXCI, C24H3zNz05 10-0x0, C24H30NzOs 0-Methylaspidoalbine, CXC, C25H34Nz05 CXCI-21-lactone, C24H3oNzOe CXC-21-lactone, Cz5H3zNzO6, CXCIX-A, ee 113g
mP
N,
21
H
H
17-OH 17-OH 17-OH 17-OMe 17-OMe 17-OAc 17-OMe 16-OMe,17-OH 16-OMe,17-OH 15, 16-(OMe)z,17-OH
Ac EtCO Ac EtCO EtCO CHO Ac EtCO Ac
15, 16-(OMe)2, 17-OH
EtCO
15, 16, 17-(OMe)3
15, 16, 17-(OMe)3 15, 16, 17-(OMe)3 15, 16, 17-(OMe)3
185-1 86 173-174 250 (dec.) 183-184 186-187 237-239 240-241 194-195 263-265 196- 199 185-186 175-179 or 194-1 95 174-177
Ac
H
148-149
Ac
177-178
EtCO Ac EtCO
CH2
co
CO
[O L ] ~
Reference
(" C)
2 14-2 18 128-131 225-226 180-182
+ 239 (c) + 174 (c)
113f 1130 113b 113b 113b 113e 113c 113b 113e 40, 113h 113f 42, 48
+ 164 (c)
42
+ 46
(0)
- 116 (c)
-36 (m)
52 52
+22 (m) + 9 (c) - 114 (m)
52 42, 52 52 113g
ej W M
2
PART11. Compounds with t h e aspidospermatidine or strychane skeleton
Compound
Formula
16
[.In
Reference
20
mP ("C)
=CHMe
H
184-1 86
28. 51a
=CHMe
€1
149-152
118
=CHMe
H
amorph.
28. 51a
=CHMe
H
amorph.
28, 51a
=CHMe
H
amorph.
28. 51a
=CHMe
H
157-159
Et
H
amorph.
Et
H
amorph.
+213 (c)
48
=CHMe
H
167-168
+900 (c) 870 (e) +584 (c)
116, 117, 75 120, 118a
~
N,
14 ~~
Aspidospermatidine, CCIV, ClsHzzNz, H H a 28, 51a 1,2-DihydrodecarbomethoxycondyloH H carpine, CCXXII, C18HzzNz N-Acetylaspidospermatidine, CCVIII, Ac H C Z O H Z ~ N ZaO28, , 51a H N-Methylaspidospermatidine, CCVI, Me C ~ ~ H Z ~a N28,Z 51a , Deacetylaspidospermatine, CCVII, H(12-OMe) H C ~ ~ H Z ~ NaZ28, O ,51a H Aspidospermatine, CCIX, CzlHz,jNzOz, Ac( 12-OMe) a 28, 51a Dihydroaspidospermatine, CCX, Ac( 12-OMe) H C21HZsNzOz, a 28, 51a 1l-Methoxy-14,19-dihydrocondylocarpine, H( 11-OMe) A , COzMe CCXXIV-A, CziHz1jNzO3, y 48 H Condylocarpine, CCXV, CzoHzzNzOz, ff 116 A, COzMe Tubotaiwine, CCXXIV, CzoHz4NzOz, bb 119; j 120 Picrate Tetrahydrocondylocarpine, CCXX, CzoHz~jNzOz Decarbomethoxyakuammicine, ClsHzoNz 19,2O-Dihydrodecarbomethoxyakuammicine, C C X X X I X , ClsHzzNz, bb 119 Tubifoline picrate5
H
A,COzMe
a-Et
H
amorph.
H
COzMe
Et
H
171-1 72 145-147
A A
H H
H H
=CHMe a-Et
80-84 amorph. 194-196
-73 (e)
28, 59, 51a 28, 51a
+
119,120 118 -361 (ea)
19 67, 118a 119
TABLE I-Continued
Compound
Formula
Na
16
14
20
[aID
Reference
- 298 (c)
122
mP (" C)
0 01
o
-
H
OH
=CHMe
190
H
H
=CHMe
187-189
19
H
H
8-Et
176-177
119, 19
A , COzMe
H
=CHMe
181-182.5
H
A , COzMe
H
P-Et
173-175
H
A , COzMe
OH
=CHMe
240
H H
A , COzMe A , COzMe
OAc OH
=CHMe Et
111
H
A , COzMe
H
CHOHMe
H
A , COzMe
H
135 (hydr.) -515 244 (anhydr.) 220 211-214 607 (dec.)
H
A , COzMe
H
19-Dehydr0, CCXLI-G, CzoHzzNz04
H
A , COzMe
H
19,20-Diacetate, CCXLI-A, Cz4HzeNzOa
H
A , COzMe
H
Decarbomethoxymossambine, CCXXXI, A CisHzoNzO 1,2-Dihydrodecarbornethoxyakuammicine, H CCIL CiBHzzNz Tetrahydrodecarbomethoxyakuammicine = H Tubifolidine, CCXXXIX-A, C I ~ H Z ~ N bbZ 119 , Akuammicine, CCXXV, CzoHzzNzOz H 19,20-Dihydroakuammicine,CCXXXVII, CzoHz4NzOz Mossambine, CCXXVI, CzoHzzNz03, ff 121, 116 0-Acetate, CCXXVII, CzzH24Nz04 19,20-Dihydromossambine,CCXXVIII, CzoHz4Nz03 Echitamidine, CCXLII, CzoHz4Nz03 0-Acetate, CzzHzaNzOa Lochneridine, CCXLIII, CzoH~4Nz03 Compactinervine, CCXLI, CzoHz4Nz04, gg 127
+
- 470 (c) - 498 (c)
-523 (c)
+
OH (Et C L M e M e:{
1(;:
-745 (0) - 727 (m) 720 (m) - 673 (m)
AcMe
19, 77, 69,131 125, 69, 19,1378 116, 122
Pj 0
p W
122 121 130, 126 126 129, 127, 75
110-120 235 (dec.)
- 640 (PI
125a
224-226 (dec.)
- 607 (c)
125a
208
- 623 (c)
125a
M
T:
Dihydro, CCXLI-B, CzoHzaNz04
H
COzMe
H
19-Epi, CCXLI-H, CzoHz4Nz04
H
A, COzMe
H
H
A, CHO
H
C:OHMe =CHMe
H
a-COzMe
H
=CHMe
Norfluorocurarine, CCXL, C19HzoNz0, ff 116 Methochloride, B HCl 2,16-Dihydroakuammicine,CCXXXVIII, CzoHz4NzOz Tetrilhydroakuammicine, CCXXXV, CzoHz6NzOz 2,16-Dihydromossambine, CCXXIX, CzoHz4Nz03 Tetrahydromossambine, CCXXX, CzoHzaNz03 2,16-Dihydrocompactinervine, CCXLI-B, CZOH26"204
.
H
H
m-COzMe
H
COzMe
OH
H
COzMe
OH
H
COzMe
H
CzOHMe
,5-Et =CHMe
cr
265-270 (dec.)
-44 (c)
12th
222-224 (dec.)
-680 (p)
125a
184-186 270 (dec.) 140
-1230(~)
- 18
135-137 197-198
+24(c)
Et
OHMe
116 133-1 37 68, 6% 137a, 75 137a 122 122
265-270 (dec.)
-44
(0)
48
Stemmadenine, CCXIII, Cz1Hz6Nz03, g 8 ; u 66a; v 66a Degradation product (KBH4) ex akuammicine, CigHzeNz Degradation product (KBH4) ex mossambine, CCXXXII, CisHzsNzO Degradation product (KBH4) ex compactinervine
01
m
[a]=
Reference
20
mP (" C)
+329(p)
116
N,
16
H
CHzOH, COzMe
=CHMe
H
189-191
H
H
=CHMe
H
H
OH
=CHMe
125-150 and 160-1 62 2 15-2 16
H
H
H
b
5 8 2
r-
Formula 14
+
b
PART12. Indoles related to stemmadenine Compound
~
/OH \CHOHMe
230-232
19 -62 (c)
M U
m
122 48
w m c
TABLE I-Continued
W
01 E3
PART 13. Compounds related t o uleine and the pyridocarhazole bases
Compound
Formula
[aID
Reference
+ 18 (c)
138, 147
~
Uleine, CCXLV, hh 138; ii 140; j j 49; kk 141, 147; 11 143h; i 48; mm 48; nn 48; o 48; K 37 Dihydrouleine, CCXLVI Olivacine, CCLVIII, ii 140; kk 141, 147; 00 158; pp 145; nn 48; i 48; qq 148; J 48 1,2-Dihydroolivacine, CCLXXIV, hh 139 1,2,3,4-Tetrahydroolivacine N-Acetyltetrahydroolivacine Guatambuine, CCLX, dextrorotatory, hh 139; kk 141, 147; pp 145, 146;'ll 143b; J 48 Levorotatory, kk 147 Racemic, kk 147 Methiodide Ellipticine, CCLXXXIV, rr 156; ss 156; tt 161; uu 161; vv 161; 00 157, 158 Methonitrate, 00 158 1,2,-Dihydroellipticine,CCXCIII, hh 139, 00 158 Methonitrate, 00 158 1,2,3,4-Tetrahydroellipticine, CCXCIV N-Acetyltetrahydroelipticine N-Methyltetrahydroellipticine,CCLXXXV, h h 139; 00 158; C 163; I1 143b
ClsHZzNz, methanolate C18Hz4N2 Ci7Hi4N2
76-118 118-120 (cap.) 75-1 15 318-324 (dec.) 307-318 290-295 238-244 249-252
(dec.) (dec.) (dec.) (dec. )
232-234 (dec.) 299-301 (dec.) 311-315 (dec.)
C18H2oNz
293-304 (dec.) 296-300 301-303 (dec.) 160-165 (dec.) 272.5-273 224.5-225
-llO(c)
+112(p)
- 106 (PI
138 140, 141, 147 150 150 150 139, 141, 147, 146 147 147, 150 144, 147 156 158 158 158 158 158 139, 158
W W
PART14. Indole and oxindole alkaloids related to /?-carboline and their derivatives
Compound
Formula
mP
(" C)
3-Carbomethoxyharman, CCCXXXIX, b 180 11-Methoxyyohimbine stereoisomer, ww 162 Deacetylpoweridine, CCXCVIII Isodeacetylpoweridine /?-Lactone, CCCII Poweridine, CCXCVII, x x 161 LiAlH4 diol Dihydrocorynantheol, CCCVI, y y 163; zz 48
252-253 148-149 222 (dec.) 197 (dec.) 277 (dec.) 226 (dec.) 215 (dec.) 181-183
Methochloride, cc 164 10-Methoxydihydrocorynantheol, CCCVI-A, h 113d; ee 48; ww 164a 19,20-Dehydro, CCCVI-B, h 113d; ee 37; ww 48 Ajmalicine, CCCXVII, v 66a
272-273 165-166
Aricine, CCCIII, y y 163
186-187 (dec.)
Reserpinine, CCCIV, zz 48 Reserpiline, CCCLVI, h 113d
243-244 (dec.) amorph.
Isoreserpiline, CCCV, k 41; h 171; 113d; rr 156; tt 161; uu 161 ; vv 161 Methochloride, rr 182 Isoreserpiline-4-indoxyl, CCCLVII-A, h 113d Isoreserpiline oxindole (see Carapanaubine below)
210-212 (dec.)
184-185 253-254 (dec.)
283-985 (dec.) 250-253 (dec.)
[.ID
Reference 180 162 161 161 161 161 161 198, 163
-5(a)
- 19 (c)
- 37 (P)
+ 6 3 (w-m)
- 16 (p)
198 113d, 48
-65 (p) 113d, 48 - 61 (c) 66a, 55, -48 (p) 192b -89 (c) 55, 192b, -66(p) 192~ -59 (0) -131 (c) 65, 192b - 69 (m) 113d, 192b - 14 (P) -82 (p) 55, 192b -134(m)
182 113d, 192a
w
TABLE I-Continued
01
ip
Compound
Formula
Norrnacusine-B, CCCXX, ff 116, 121; b 165
Reference 245 and 275
172, 165, 116, 121
Methochloride 0-Acetate, CCCXXVIII
248-249 223
Dihydro, ZOor-Et
189-190 or 159-160 192 and 219-220 279
173 165, 121, 116, 177 172, 165
Dihydro-0-acetate, 2Oa-Et Methiodide (macusine-B iodide), b 173a
172 173, 121, 116 174, 176 165 174, 175
Dehydroxymethylpolyneuridine, CCCXXX t-Butyl ester, CCCXXXI Akuammidine, CCCXXII, k 113e; D (Volume V I I )
231 246-247 2 34-2 36
Polyneuridine, CCCXXI, b 165
245-247.5
165, 178, 176 173, 165 173 165, 176 174, 165
Methiodide = macusine-A iodide Methochloride 0-Acetate Akuainmidinol, CCCXXVI
B.Me1
274 (dec.) 252 (dec.) 278 260-265
0,O-Diacetate 17-Dehydropolyneuridine(aldehyde), CCCXXIX-A
C24H28NZO4 CziHzzNz03
224-227 285-286
165 165
td
z r ?:
Polyneuridinic acid, CCCXXIV Hydrochloride Quebrachidine, CCCXXXVIII-D, a 179b 0,N-Diacetate, CCCXXXVIII-E N-Methylquebrachidinol, CCCXXXVIII-G Hydrochloride Monoacetate, CCCXXXVIII-H N-Methylquebrachidinal, CCCXXXVIII-I Eburnamenine, CCCXLIII, cc 183; aa 91; a 28, 51a, 51; e 51 Picrate Eburnamine, CCCXL, cc 183; aa 53, 91; e 51; F 113b Isoeburnamine, CCCXLI, F 113b 0-Methyleburnamine, CCCXL-A, F 113b Eburnamonine, CCCXLII, cc 183; e 51 Tuboflavine, CCCXLVIII, bb 186 Carapanaubine, CCCLIV, A 171
CzoHz3ClNz03 CziHz4NzOa CzsHzsNz05 CziHz6NzOz Cz3HzsNz03 CziHz4NzOz C1gHzzNz CigHdzO CigHz4NzO CzoHzaNzO CigHzzNzO CiaHizNzO Cz3HzsNzOs
255-265 276-278 amorph. 255-260 199-201 212-215 amorph. 196 181 217 181 183 207-208 221-223
+54 (c)
+183 (c)
- 93 (0) +111 (c)
+ 89 (0) -101
(0)
165 179b 179b 179b 179b, 179c 179b Chapter11 Chapter 11 Chapter11 113b Chapter 11 186 171
~
3 %
i! b-
w
U
z
5
-
Pleiocarpamine, a a 91 Pleiomutine, aa 91 Dipicrate Distyphnate Pleiomutinine, a& 91 Lactam 3 (P.tubicina)
b
Q
F
PART15. Alkaloids of unknown structure and their derivatives
Compound
w rp
Formula ___ CzoHzzNzOz C4z-43Hsz-tieN402 B. 2C6H3N307 B. 2C~H3N308 C40H46-48N402
mP (" C) 159 amorph. 230 230 220 287-290 (dec.)
U b-
[@ID
Reference
+123(c) -97 (c)
91.53 91 91 91 91 96 - u 1
k
s
0
u1
TABLE I-Continued
0
01 Q,
Compound
Formula
mP (" C)
[a]=
Reference
108, 89, 56 .108, 89, 56 108, 89 109, 113, cf. 100 109, 113
Kopsingine, B 108, 89, 56
270-274 (dec.)
+75 ( c )
Kopsaporine, B 108, 89, 56 Kopsingarine, B 108, 89 Fruticosine, dd 53, 100, 109
224 (dec.) 230 (dec.) 225-226
+48 (c)'
0-Acetylfruticosine Decarbomethoxyfruticosine Isodecarbomethoxyfruticosine 0-Acetyldecarbomethox yfruticosine Fruticosamine, dd 109, 113 Elliptinine, rr 156 Unnamed, 0. sandwicensis Hydriodide Unnamed, 0. oppositifolin Methoxyellipticine, rr 156; ss 156; tt 161; uu 161; vv 161 Elliptamine Picrate Powerine LiAIH4 product, picrate Poweramine, xx 161 Ochropine, xx 192d Unnamed, A. australe
115-118 or 132-134 292-293 290-294 211-212 177-181 231-233 215 (dec.) 282-284 270-272 (dec.) 170 188-189 (dec.) 212 (dec.) 241-242 146 186-1 88
- 19 (c)
+43 (c) - 255 -I-27 0
-216 (a)
- 229 (a)
109 109 109 109, 113 156 156 194 156, 55 161 161 161 161 161 55, l92d 147
td
B
W M
E
Quebrachacidine, a 195 Aglycone Rhazinine, e 62, 197 Tosylate ~~
Cz6Hz8Nz011 Ci9Hz4NzO ~
~~~
234-238 315-32 1 115-1 16 280 (dec.)
- 250 + 4 (e)
195 195 197 197
~
Plant sources: a, Aspidosperma quebrachoblanco Schlecht; b, A. polyneuron Mull.-Arg. ; c, A. chakensis Speg. ; d, A. album (Vahl) R. Benth. ; e, R h z y a stricta Decaisne; f, G o n i o m k a m s s i E. May; g, Stemmadenia donnell-srnithii (Rose) Woodson; h, Aspidosperrna discolor A.DC. ;i, A . eburneum Fr. All. ;j, A. limae Woodson; k, Vallesia dichotoma Ruiz et Pav. ; 1, V . glabra (Cav.) Link; m, Aspidosperma quirandy Hassler (57, 58); n, A . megalocarpon Mull.-Arg.; 0,A . multijlorunz A.DC.; p, A . obscurinervium Azambuja; q, A . triternatum Rojas Acosta; r, A . pyrifolium Mart. ; s, A . cylindrocarpon Mull.-Arg.; t, Amsonia tabernaemontana Walt.; u, Stemrnadenia tomentosa Greenman var. palmeri; v, S. pubescens Benth. (S. obovata K. Schum.); w, Tabernaemontana citrifolia L. ( T. alba Mill. or Nicholson); x, Aspidosperma refracturn Mart. ; y . A. populifolium A.DC. ; z, Kopsia longifiora Merrill; aa, Pleiocarpa mutica Benth. ; bb, P. tubicina Stapf; cc, Hunteria eburnea Pichon ;dd, Kopsia fruticosa A.DC. ;ee, Adspidosperma spp. ;ff, Diplorrhyncus condylocarpon (Mull.-Arg.) Pichon spp. nzossambicensis (Benth.) Duvign. ( D . mossambicensis Benth.); gg, Aspidosperma compactinerviurn Kuhlm. ; hh, A. ulei Mgf. ; ii, A. olivaceum Mull.-Arg,; jj, A. pyricollum Mull.-Arg. ; kk, A. australe Mull.-Arg. ;11, A. dasycarpon A.DC. ; mm, A. gomezianum A.DC. ; nn, A. subincanum Mart. (Brazil)-see 0 0 3 ; 00, A. subincanum Mart. (Peru)-see nn3; pp, A. longipetiolatum Kuhlm. ; qq, Tabernaemontana psychotrzfolia H.B.K. ; rr, Oehrosia elliptica Labill. ; ss, 0. sandwicensis A.DC. ; tt, 0. moorei F. Muell. ; uu, 0. glomerata Valeton; vv, 0. coccinea Mgf. (Ezcavatia coccinea Mig. T. and B.); ww, Aspidosperma oblongum A.DC. ; xx, Ochrosia poweri Bail. ; yy, Aspidosperma marcgravianum Woodson; zz, A. auriculatum Mgf. ; A, A. carapanauba Pichon; B, Kopsia singapurensis Ridley; C, A. parvifolium A.DC. ; D, Picralima nitida (Stapf) Th. and H. Durand ( P . klaineanu Pierre); E, A . sandwithianurn Mgf.; F, Haplophyton cimicidum A.DC.; G, A . fendleri Woodson; H, A . spruceanum Benth.; J, A . nigricans Handro; K , A . hilurianurn Mull.-Arg. 2 Rotation in: c, chloroform; a, acetone; d, dioxane; e, ethanol; m, methanol; w, water; ea, ethyl acetate. 3 Two specimens of Aspidosperma subincanum Mart. have been studied, one collected in Peru and the other in Brazil. The alkaloids isolated, although chemically related, were different with the exception of olivacine, which occurs in both. 4 Whether this difference is due to solvent or to the existence of two enantiomeric forms of kopsine is not clear. 5 Cornpare strychene picrate, mp 150-153" and 178-184" (67). 1
? b
' 2
%
8
2U
2G
kL
Ei
z1
358
B. GILBERT
3,ij-diethyl- and 3-ethyl-5-methylpyridinecould be isolated as the mixed picrate (15, 16, 12). Other dehydrogenation products which were not identified consisted of /3-alkylindoles, methylcarbazoles, and a substituted ci- or /3-carboline. Oxidation of quebrachamine under a variety of
11-A; R = H 11-B; R = Me
XCII
conditions gives products which are probably indolenines. For example, ozone and peracids give a hydroxy base, C19HzsNzO (probably 111, 13); catalytic oxidation gives C19HzGNzOZ (probably IV) which is readily converted to I11 (15). A tribromide, C19HZ3NzBr3, probably of similar
111;R = O H I V ; R = OOH V; R = C N
structure, is obtained by treatment of quebrachamine with N-bromosuccinimide (13). The hydroxy base (111)is reconverted to quebrachamine (I)by lithium aluminum hydride, whereas alkali converts it to a mixture of an oxindole and an indoxyl. Yet another indolenine, of probable structure V, was obtained by the action of cyanogen bromide on ( + )-quebrachamine (8). Hydrolysis with alcoholic alkali gave back ( + )-quebrachamine.
14. Aspidosperrna
359
AND RELATED ALKALOIDS
An examination of the NMR-spectrum of quebrachamine (I) (17) showed the absence of an a-hydrogen on the indole nucleus and confirmed the absence of an N-methyl group. The real confirmation that quebrachamine had structure I came with the use of mass spectrometry by Biemann and Spiteller (18, 18a). First, the zinc dust distillation was examined and its products, separated by vapor phase chromatography (VPC), were shown to be 3-ethylpyridine (75y0),3-methyl-5-ethylpyridine ( l a % ) , 3-ethyl-4-methylpyridine( 5 % ) , and 3,5-diethylpyridine (5%) together with 3-methylindole, 2-ethylindole, 2,3-dimethylindole, 2,3-diethylindole, and a methylethylindole. It will be seen that the major pyridine fragment does not require rearrangement for its formation and, together with 2,3-diethylindole, contains all the carbon atoms of structure I . I n order to provide a model with identical aliphatic structure, aspidospermine (11)was converted to 17-methoxyquebrachamine (VIII). Deacetylaspidospermine (VI) was oxidized with iodine and alkali to the indolenine VII, which although contaminated by unchanged VI was recognized by its UV-spectrum and its conversion by lithium aluminum deuteride to monodeuterio-VI. Compound VII was susceptible t o a reverse Mannich condensation (19, see arrows in VII but note that reaction may not proceed in two stages as indicated) and, on reduction with sodium borohydride, it gave 17-methoxyquebrachamine (VIII) which was separated from the accompanying unchanged deacetylaspidospermine (VI) by alumina chromatography. A comparison of the mass spectra of I and VIII left no doubt as to the complete identity of the aliphatic portions of the two molecules as can be seen from Table I1 in which the main peaks are given. The fragments expected from the breakdown of I (20, 21) are in fact TABLE I1 MASSSPECTRA OF QUEBRACHAMINE (I),17-METHOXYQUEBRACHAMINE(VIII), AND ~ ~ - D E U T E R 17-METHOXYQUEBR IOACHAMINE (19d-VIII) Molecular weight of fragment/charge = m/e Indoles Alkaloid Quebrachamine VIII 19d-VIII
M+ M-Me M-Et 282 312 313
267 297
253 283 284
Piperidines 157 187 187
143 173 173
138 138 139
125 125 126
110 110 111
96 96 97
360
B. GILBERT
observed. In the spectrum of V I I I those that contain the indole nucleus are shifted to molecular weights 30 units higher, corresponding to the addition of the 17-methoxyl group, whereas those containing the aliphatic piperidine portion appear a t identical m/e values. Confirmation that the m/e 124 peak in fact represents the piperidinic ring was obtained by preparation of 19-deuterio-17-methoxy-quebrachamine(19d-VIII) by using sodium borodeuteride, and in its spectrum this peak was partly
I JICO
H
I
Meo
\'I
ii TI1
i
19d-VIII; R = D
I
\ iiijc
1Ji
inje 110
injc 125
mie 96
i
inje 124; R = H mje 125; R = D
14.
d S p ~ d O S p ~ ? W % AND Cl RELATED ALKALOIDS
361
shifted to m/e 125 (two-thirds), part remaining a t m/e 124 (note preferential loss of C-19 H over C-19 D). Both the transitions m/e 138t o m/e 110 and m/e 125 to m/e 96 were confirmed by observed metastable peaks (see Section 11,D). 17-Methoxyquebrachamine (VIII) has the rotation, - 103" in dioxane, compared with - 111" found for quebrachamine (I)in the same solvent, and the optical rotatory dispersion (ORD) curves are very similar. It may therefore be deduced that ( - )-quebrachamine has the same absolute configuration a t position 5 as does aspidospermine. The closure of a bond between positions 12 and 19, presumably involved in the natural synthesis of aspidospermine-type alkaloids from quebrachamine, has been shown (18) to occur during the zinc dust distillation of the latter when a compound I X was isolated whose mass spectrum was exactly comparable with that of the indolenine VII, except for the 30-unit shift in the indole-containing fragments (Table V). Substance I X has subsequently been found in nature (Section 11,E). The total synthesis of ( f )-quebrachamine has been achieved by a modification of the route used for the synthesis of aspidospermine (Section 11,C; ref. 27a). Condensation of the intermediate X X X - J with phenyl hydrazine gave dl-IX which on borohydride reduction yielded ( f )-quebrachamine (I). C. ASPIDOSPERMINE The structure of aspidospermine (11) was practically solved by chemical degradative methods (see formula CCCCXXXIII, Volume VII, p. 131) but the final location of the ethyl side chain and the relative stereochemistry only became known after the single crystal X-ray study of its methiodide (22, 11) which was shown to have structure X.l Extensive degradative work, the results of which appeared side by side with those of the X-ray determination, had shown the nature of the structure around both nitrogen atoms and established the size of rings D and E (24, 12). Chromic acid oxidation of aspidospermine gave three lactams (XI, XII, and XIII, 24). The IR-carbonyl frequency (1680 cm-1) of the new amide group in lactam X I shows it to be in a five-membered ring, while the presence in the NMR-spectrum of a nonequivalence quartet a t 2.37 6 1 Stereochemical formulas show relative but not absolute configuration throughout Sections 11-IV.
362
B. GILBERT
(J = 16 cisec), attributable to the two protons at C-11, showed by the absence of further splitting that there is no hydrogen atom at position 12. This is supported by the fact that the single hydrogen atom at C-11 in the hydroxylactam XI1 shows only a singlet at 3.83 8 shifted to 5.10 8 in the acetate, XV, where it is well clear of other absorption. That no rearrangement had taken place during the formation of these two lactams was established by conversion of XI1 t o X I using phosphorus oxychloride to give XIV and then zinc dust followed by reduction of XI to the known N,-deacetyl-N,-ethylaspidospermine (XVII, 25). These results establish R3C. CHzCHzN in the five-membered ring E. Following this, other experiments elucidated the nature of ring D. Mild dehydrogenation of aspidospermine (11) with mercuric acetate gave 7,8-dehydroaspidospermine(XVIII),whose perchlorate (XIX)has the double bond in the expected 8,9 position showing C=N+ absorption at 1698 em-1. Sodium borohydride reduction of this salt to aspidospermine showed that no skeletal change had occurred, while silver oxide oxidation in aqueous dioxane gave the six-membered lactam (XX, vc0, 1625 em-1) in which the carbonyl group is in ring D. The characteristic 8-lactam absorption was clearer in the deacetyl derivative (XXI). IR-evidence and, particularly, coupling of 7,s-dehydroaspidospermine (XVIII) with phenyl diazonium chloride, which from its mechanism must take place at position 7 to give XXII, established the presence of a hydrogen atom in this position in XVIII and hence excluded structure CCCCXXXIII (Volume VII) for aspidospermine. The formation of 3,5diethyl- and 3-methyl-5-ethylpyridine during the dehydrogenation of aspidospermine under vigorous conditions (25) thus involves a rearrangement of the ethyl side chain. These results establish the series N-CHzCHZ in the six-membered ring D. The presence of a third adjacent methylene group was shown in another series of degradative steps. Aspidospermine N,-methiodide (X, 26, 2 7 ) which is reconverted t o aspidospermine under Hofmann degradation conditions, suffered the Emde degration (26, 24) to give the dihydromethine (XXIII) whose methiodide underwent Hofmann degradation to give the methine XXIV in which rings D and E have been opened and which has a terminal methylene group (IR-,910,995 em-1; NMR-, two one-proton quartets at 5.01 and 5.05 6 in the vinyl region). In addition, it has a vinyl hydrogen atom flanked by four vicinal protons (NMR-complexmultiplet at 4.24 6). As we know that position 12 is quaternary, this vinyl proton cannot be in position 11, and it must therefore be in position 7, the nitrogen having remained attached to carbon 10. From the aforementioned NMRabsorption, we may deduce that there is a methylene group in position 6.
XII; R = OH X I V ; R = C1 X V ; K = OAc X V I ; H. = O H (epimer of XII)
XX
I
i
0
J 363
PIIS*(’I
364
B. GILBERT
This result was confirmed by cleavage of the double bond in XXIV to give the aldehyde XXV, in which the aldehydic hydrogen atom shows a 1: 2 : 1 triplet a t 9.83 6 and therefore lies adjacent t o a methylene group in position 6. Furthermore, isomerization of the methine XXIV with hydrochloric acid moves the double bond to the 6,7 position (XXVI) as shown by the appearance of an allylic methyl group in the NMRspectrum (1.68 6, doublet, J = 2.6 cisec), and in this compound (XXVI) there are two vinyl protons (multiplet a t 5.47 6). The transformation of XXIV t o XXVI does not involve rearrangement because both compounds on reduction yield the same dihydro derivative, XXVII.
1
1. HCI-Hs0
z,3lcI
I
1. JleI 2. KOt-Uu
Me0
SSVIII
SSIS
XXIV
XSX
Ac XXVI
XXVII
No real evidence was adduced for the quaternary center a t position 5 in aspidospermine (11),but the formation of lactams and compounds containing C=N,, in which the nitrogen has necessarily the planar configuration excludes any bridging of the two rings D and E.
14. Aspidosperma
AND RELATED ALKALOIDS
365
Evidence for the six-membered ring C was lacking, and an attempt to clarify this portion of the molecule was made starting with the N,dimethiodide of deacetylaspidospermine (XXVIII, 12). Emde degradation gave X X I X in which the aryl-nitrogen bond has been cleaved. This underwent Hofmann elimination of N, on prolonged heating with methyl iodide to give a base containing only one nitrogen atom which could be XXX, which contains a hydrogenable double bond. Unfortunately, no quinoline derivative or other recognizable product could be isolated from the dehydrogenation of this compound, probably because of the two resistant quaternary centers in ring C. The synthesis of aspidospermine (11)has been achieved (27a).Starting with n-butyraldehyde in which the a-methylene group represents the eventual quaternary carbon atom a t position 5, acrylic ester was added by way of the enamine synthesis (27b) to give XXX-A. A second enamine synthesis using methyl vinyl ketone furnished the aldehyde XXX-B which by spontaneous condensation gave the isolable cyclohexenone, XXX-C, in which the final ring C is present and the propionic side chain provides the carbon atoms of ring D. A Mannich-type addition of ammonia to XXX-C led to the bicyclic amides XXX-D containing rings C and D. Reaction of XXX-D in the Fischer indole synthesis with o-methoxyphenylhydrazine led to the two isomeric indoles XXX-E and XXX-F, showing that enolization of XXX-D occurs away from, rather than toward, the ring junction. To induce enolization in the desired direction, it was necessary to build on ring E, which was achieved by lithium aluminum hydride reduction o f the amide carbonyl group of XXX-D (the ketonic carbonyl was protected as the ethylene ketal) to give the amine, XXX-G, which furnished the tricyclic amide, XXX-I in two steps. A slow acetic acid-catalyzed Fischer indole synthesis using this amide still gave only indolic material showing that enolization, even under these equilibrating conditions, proceeded away from the ring junction, due to the fact that enolization in the desired direction would have resulted in a strained five-membered ring containing three trigonal atoms. Reduction of the keto-amide, XXX-I to the keto-amine X x x - J removed two of these atoms, and the Fischer synthesis with this compound yielded an indolenine which was the dl-form of 1,2-dehydrodeacetylaspidosperniine (VII). The fact that this product, had the correct stereochemistry derives from the equilibration of the asymmetric centers a t positions 12 and 19 by the reversible conversion to dl-XXX-K (see Section 11, B) during the Fischer synthesis (note too that the intermediate phenylhydrazone could similarly equilibrate), VII being the most stable stereoisomer. Lithium aluminum hydride introduced hydrogen on the desired side of the molecule (see Section 11,B, Refs. 18,
366
B. GILBERT
xxx-I
XXX-H
XXX-J
\/+/U I H
I Me0
I Me0
dl-VII
Ac
dl-I1
14. Aspiclosperma
AND RELATED ALKALOIDS
367
18a) at position 2, and acetylation of the product furnished dl-aspidospermine whose IR- and mass spectra were identical with those of the natural alkaloid (27a).
D. NMR- AND MASS SPECTRA OF THE ASPIDOSPERMINE-TYPE ALKALOIDS Although NMR was only partly responsible for the structure determination of aspidospermine (11)and the mass spectrum of the alkaloid was only measured after its structure was known, these two physical methods have had immense application in subsequent investigations of related alkaloids. For this reason, the more important data have been collected in Tables I V and V. Considering first the NMR-spectra, the nature of the aromatic substitution pattern may often be deduced from the absorption between 7.3 and 6.6 6 [see pyrifolidine (XLVI), aspidocarpine (XLIV), and aspidoalbine (CLXXXVIII), for example], especially when the data are taken in conjunction with the UV-absorption spectrum (Table 111). Of the nonaromatic protons, the one found furthest downfield is the C-2 hydrogen atom, which appears as a quartet centered at 4.0-4.5 6 (29,45). The absence of this peak is indicative of substitution at this point and is an important means of recognizing alkaloids of the aspidofractinine group (Section 111) in which the sixth ring terminates at position 2 . Alkaloids which lack the C-2 proton but which bear a carbomethoxy group on C-3, e.g., refractine (CL-A),exhibit a quartet at about 3.8 8 due to the C-3 proton. The four protons next to nitrogen in positions 8 and 10 absorb in the region 3.3 to 2.9 6 and in all the alkaloids based on the aspidospermine skeleton form a characteristic pattern which is not obscured by other absorption (9, 29) and which is profoundly altered in the spectra of the related hexacyclic bases (Sections I11 and IV). The single proton on C-19, not having any neighbor, produces a singlet from 2.2-2.5 6 which is sometimes hidden by absorption due to the N-COCH3 where this group is present, though in these cases, its presence may be deduced from the integration curve. In addition to these absorptions, there are usually easily recognized three proton singlets due to aromatic methoxyl groups a t 3.75-3.90 8 and to the methyl group of an N-acetyl at 2.2 6. I n the case of N,-propionyl compounds a quartet may be observed at 2.3-2.8 6 due to the COCHz protons, though in a 60-mc spectrum, slight overlapping occurs with the N,-C( 19)H absorption in some cases. The methyl group of such a propionyl group exhibits a triplet centered a t approximately 1.25 8. The terminal methyl group of
TABLE 111
W
% --
UV-DATA Wavelength, mp
Chromophorel
Reference
log € 2 ~
Dihydroindoles (N,H) Unsubstituted, XCVI Unsubstituted, CXXII-Me1 16-Methoxy-, CXVI 17-Methoxy-, C X L I X - F
16,17-Dimethoxy-,X L V I I
n3
ac
n n
ac n aC
15,16,17-Trimethoxy-, CXCII 17-Hydroxy-,X X X V I N-Alkyldihydroindoles N,-Methyl, CXLVI-A 16-Methoxy-,C I I I 17-Methoxy-, X L I
16,17-Dimethoxy-,L V I I N -Acyldihydroindoles N-Formyl, C X X N-Acetyl, CXLIV-A N-Carbomethoxy-, CXLV-A 17-Methoxy, -11 16,17-Dimethoxy-,X L V I
alk n
n
n
n n ac n
n
n n
n n
245, 2984 226, 260(sh),5 268(sh) 225, 250(sh), 300 212, 245, 288 215, 268, 275 215, 293 230, 279 as neutral 212, 240(sh), 305 245, 292
3.86, 3.48 3.58 3.98, 3.65, 3.52 4.56, 3.88, 3.41 4.36, 3.22, 3.23 4.40, 3.50 3.97, 3.30
206, 254, 211, 251, 220, 266, 218, 272, 218, 263,
4.42, 3.97, 3.52 4.52, 3.85, 3.71 4.42, 3.87, 3.40 3.47, 2.86, 2.86 4.36, 3.80, 3.48
300 304 305 278 305
208,253, 278,288 210, 257, 286, 294 206.5, 246, 282.5, 289.5 220, 257, 280-290(sh) 223, 252,286
~-
7 37 32 37
9, 10
4.48, 3.85, 3.63 3.66, 3.24
4.36,4.16, 4.33,4.15, 4.49, 4.20, 4.56, 4.09 4.55, 3.99,
3.72, 3.67 3.77, 3.74 3.51, 3.48 3.37
91 55, 72 25 36
81 96 91 25 10
n
16,17-Dimethoxy-,L X X 15,16,17-Trimethoxy-, CXC 17-Hydroxy-, L X X X V I I 16,17-Dihydroxy-,L X I X 16-Methoxy-17-hydroxy-,LIII 15,lR-Dimethoxy-17-hydroxy-, CLXXXVIII Indolenines Decarbomethoxymossambine, CCXXXI 1,2-Dehydrodeacetylaspidosperinine, VII
a-Methyleneindolines Vincadifformine, X C I I I Condylocarpine, CCXV Norfluorocurarine, CCXL 16-Methoxyrninovincine, CX 11-Methoxy-14,19-dihydrocondylocarpine, CCXXIV - A
n alk n alk n alk n alk
222, 250, 290(sh) 218,258, 295 221, 261, 292 230, 258(sh), 311 225, 260, 295(sh) 216, 237, 304 228, 264 224, 307 227, 267 308
4.48, 3.85, 3.27 4.51, 4.15, 3.58 4.40, 3.92, 3.55 4.39, 3.80, 3.74 4.30, 3.89 4.29, 4.24, 3.44 4.43, 3.94 4.42, 3.73 4.16, 3.88 3.64
n n
220, 262 228, 236(sh), 255, 307
4.32, 3.84 4.22,4.14, 3.69, 3.65
121
n
225, 300, 328 228, 295, 328 242, 299, 360 230, 250, 325 255, 286, 327
3.97, 4.03, 4.19 4.04, 4.01, 4.17 3.98, 3.57, 4.25 4.05, 4.03, 4.14 4.17, 4.04, 4.05
6 116 116 32
n n
n n n n
36 52 33 36 31 52
18
48
w t+
b
9. 3 % 3 -3
z U
P d
Fr3 M
tl P
t-
x
Extended indole Uleine, CCXLV
n
209, 309
4.38, 4.30
138
Py.ridociirbazoles Olivacine, CCLVIIl6
n
224, 239, 269, 277, 288, 293, 315, 330, 345, 377 242, 307, 351, 412
4.32,4.22, 4.54,4.71, 4.89,4.8S, 3.61, 3.73, 3.52, 3.58 4.45,4.92, 3.78, 3.59
160
ac
t. 5 F:
u
TABLE 111-Continued
Chromophorel
Ellipticine methonitrate Anhydronium base from olivacine methiodide, CCLIX 1,2-Dihydroellipticine, CCXCIII 1,2-Dihydroolivacine, CCLXXlV Guatambuine, CCLX7 Oxindole Carapanaubine, CCCLIV $-Indoxy1 Isoreserpiline-~-indoxyl,CCCLVII-A
Wavelength, mp
4 0
Reference
log €2
n n
241, 249, 307, 356, 423 270, 336, 373,400, 510
4.38, 4.36, 4.86, 3.72, 3.68 3.58,4.69, 3.88, 3.78,3.60
158 149
n
236, 244, 271(sh), 281, 302, 313,382 235, 270(sh), 279, 301, 312, 378 239, 248,275, 330, 344 235, 283, 314, 377 241, 250(sh), 263, 300, 330, 344
4.45,4.30,4.46,4.64, 4.18,4.30,4.43
158
ac n ac n
4.42, 4.45, 4.63, 4.48,4.46,4.59, 4.43, 4.63, 4.33, 4.64, 4.51, 4.38,
4.15, 4.28, 4.36 3.94, 3.63 4.32 4.30, 3.60, 3.52
W
139, 150
B z
W M
n ac
215, 244, 278(sh), 300(sh) 222, 246(sh), 278, 300(sh)
4.57, 4.23,3.80, 3.66 4.56, 3.79, 3.61,4.15
171
n
226, 251, 282, 402
4.36, 4.46,4.07, 3.74
113d
1 Many examples of the chromophores recorded are found in other alkaloid groups, especially that of the curare alkaloids (see Chapter 15). An excellent collection of spectra is found in refs. 55 and 56. 2 Log E rather than E values have been given for uniformity, as most literature values are so recorded. 3 Abbreviations: n = neutral, ac = acid, alk = alkaline. 4 Kopsinine shows peaks a t 205, 246, and 295 mp. 5 sh = shoulder. 6 Ellipticine (CCLXXXIV) has a similar spectrum (156, 55). 7 N-Methyltetrahydroellipticine(CCLXXXV) has a similar spectrum (158, 55).
TABLE IV
NMR- DATA^ PART1. Simple derivatives of aspidospermidine Position of protons; 6 , ppm; no. of peaks; J, cjsec
-
Compound
Demethoxyaspidospermine, X X X I I I
Aromatic2
Na
19
8,lO
213
H
substitution
acyl
H
CHz
CH3
2.93-3.35
0.73
40a
2.3s
2.9-3.3
0.72
40
2.28s
2.9-3.3
0.72
40a
3 5U
2.9-3.3 2.8-3.3
0.67 0.69
29 30,45
$
2.23s
ca. 3.0
0.62
31
2.17s
2.9-3.3
0.67
9, 30
0.75
36
4.08q, J = 6,lO 4.08q, J = 6.5,lO
Demethylaspidospermine, XXXVII
6.9m
Aspidospermine, I1 Aspidocarpine, XLIV
7.0m 6.53t. J = 9
Aspidolimine, L I I I
6.65q, J = 8
4.07q, J = 6,lO 4.50q 3.95q, J = 5.5,lO 4.12q, J = 6.5, 10.5 4.50q, J = 6,lO 4.05d, J=8 4.5q 4.4% J = 6.5,lO 4.12q
Demethoxypalosine, XXXIV
Pyrifolidine, XLVI Spegazzinidine, LXIX
6.6%
J = 8.2 6.57q
Cylindrocarpidine, LXXVI Cylindrocarpine, LXXV
7.0m 7.17m
Limaspermine, LXXXVII
6.92m
w
16,17
8.13m( 17-H) 7.16m(3H) 8.13m(17-H) 7.07m(3H)
2.27s
10.83s 3.89s 3.80s 10.77s 3.88s 11.0s 3.77, 3.84 5.84m, 11.1s 3.88s 3.84s 10.88s
2.38q 1.24t J = 6.5 2.32s 2.20s 2.27s 2.57q 1.25t J=7 2.22s 2.48s 2.22s -5
2.57q J = 7.5
2.45s 2.48s
2.9-3.35 2.9-3.3 ca. 3.0
-4 -4
3.52t6, J=7
Reference
.”
2
b
6
& Y
Eti
U
bw b 5 F1
29 29 33
0
4
w
TABLE IV-Continued
PART2. Aspidospermidine derivatives bearing a carbomethoxyl group at C-3
Compound
Aromatic
6,7 vinyl
19 H
COzMe
~-
~
8 CHz
21 CH3
Reference
~~
Tabersonine, XCII Vincadifformine, XCIII Minovine, CVIII Mmovmcine, CIX Vindolinine,* CVI
7. O m 7.0m 6.95 6-7 lines 6 08d, 6 30% 6 91d, J = 2 5,s
Vindoline, CIII
5.75s
3.64s 3.75s
-
5.6-6.3 12 lines 5.23, 5.88, ,,J = 10
3.78s 3.68s 3.80~9
8.98 8.88 3.25 8.8 4.5 approx. 2.68
0.77
2.65
3.4
1.85 0.95d 5=7 0.487
7,66a 6,66a 32 32
3 4
~
PART3. Aspidofractinine and kopsine-type alkaloids and their derivatives
Compound ~
~~
Aromatic .
Aspidofiline, CXXXVI Refractidine, CXX Pyrifolme, CXIX Deacetylpyrifoline, CXXI 6-Acety1-6-demethylpyrifoline, CXXVIII
Pleiocarpine, CXLV-A Refractine, CL-A
6 or 3 substitution
N*
17
substitution
-
19 H ~~
7.0m 6.93m 6.75m 7.0m
7.72d( 17-H), 7.17m 6.9m
3.35s 3.33s 3.33s 2.02s, 4.63q, J = 5, 10.5 3.72s 3.68s
10.02s 3.81s 3.78s 3.80s
2.32s 8.37s 2.12s
-
11 H
_____________~
3.0m
2.12s
-3.0m -3.15m
9.47s
-
3.82s 3.85s
8,lO CH2
Reference -~
80,37 81 81,37 37 81,37
3.0m
91
3.0m
82, 37
Isorefractine, CL-C Deformylrefractine, CXLIX -A Deformylisorefractine, CXLIX-C N-Methyldeformylrefractinol, CLI-F
6.9m G.73m 6.8m 6.8m
N-Methylkopsinylene, CXLVI-M N-Methylkopsinane, CXLVI-0
A'-Methylisokopsinylene, CXLVI-N X-Methylenekopsinyl ether, CLIII
3.78s 3.75s 3.80s 3.95oct J = 2.5, 6.5,12 5.0 2 x 6 lines 1.3d J = 6.5 2.03d J = 1.5
Kopsine, CLXX
7.4m
7.2S'U
Fruticosamine11 Fruticosinell
7.251~1 7.70(17-H) 7.2m
5.52br10 3.1710 4.79q'Z
Kopsine-l0-lactam,11CLXXV
3.83s 3.80s 3.82s 3.77s
--
9.20s
N
2.90s
3.0m 2.9m 3.1 3.0m
37 37 37 37
95 95 95 4.48q
95
3.93s
100, 101, 109 109 109
J=7
3.90s 3.88s 3.75d J=1 3.5d J = -1 3.57s
Dihydrokopsine- 10-lartam, CLXXVlI Kopsane- 10-lactam,ll CLXXXVl
2.82s
101
2.63d J = -1
101 101
PART4. Aspidoalbine-type alkaloids and their derivatives Compound
Aromatic
l5,16,17 N, substltutlorl substitution
21 CHz
-~ ~
Aspidolimidine, CCI
Aspidoalbine, CLXXXVIII
6.73d 7.09d J=8 6.82s
0-Methyl-depropionylaspidoalbine, CXCII
6.89
3.88s 0.78s 3.86s 3.85s
2.32s
4.05m
-4.3m
8,10 CHz _ _ -2.85m
-
Reference 40
52
3. O m
4.02q _ _ _ _ ~
52 ~~
w 4 w
TABLE IV-Continued
W
4
ip
PART5. Alkaloids related to condylocarpine and mossambine and their derivatives ~~~
N,
Aromatic
Compound
16 substitution
3,15
H
19
18
Reference
~
3.78s
Condylocarpine, CCXV 2,16-Dihydromossambine, CCXXIX
6.8m
Decarbomethoxymossambine, CCXXXI Echitamidine, CCXLII
7.05m
8.68
3.89s
Lochneridine, CCXLIII Stemmadenine, CCXIII
7.35111
9.3
3.77s 3.79s 4.38
3.92m 4.12d J=2
5.32q
1.58d
117
5.55
1.66d J=6
122
5.33
122 126
1.16d J=6 0.77m 1.7d
5.4q
td
127 117
PART6. Indole and oxindole alkaloids and their derivatives ~~
~
Compound Uleine, CCXLV 3-Carbomethoxy-1-methyl-P-carboline, CCCXXXIX
Aromatic 7.34m 7.0-8.7m
N,
COzMe
8.38s 9.40s
3.95s
17 __ 5.27s 4.98s (vinyl)
18
19 -~
0.83m
Reference -
~
142
(Et) 180
Yohimbine, CCXCV 8-Yohimbine, CCXCVI Dihydrocorynantheol, CCCVI
7.25m 7.17m 7.2m
7.90s 7.87s 8.80s
0Acetyldihydrocorynantheol
7.15m
8.12s
Isoreserpiline, CCCV
6.77s, 6.90s 6.55s, 6.74s
7.95s
3.72s
8.73s
3.61s
Carapanaubine, CCCLIV 0,O-Diacetylakuammidinol, CCCXXVII
6.25m
8.43s
0-Acetylnormacusine-B, CCCXXVIII
6.25m
8.57s
3.77s 3.88s 4.05q (CH20Ac) 7.37s (vinyl) 7.44s (vinyl) 4.0m (CH20Ac) 3.93m (CH20Ac)
0.88 (Et) 0.87 (Et) 1.37d
(J = 6) 1.40d
(J = 6) 1.59d
(J = 6.5) 1.57d ( J =7)
37 37 63, 37 63, 37 4.44 oct 4.56 oct (J = 6, 5.7) 5.35q (J = 6.5) 5.38q ( J =7)
171
171 165 165
1 For model compounds, see refs. 45,17,101,66a. Abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, oct = octet, m = multiplet, br = broad. 2 CHCl3 proton appears at 7.28 6. 3 Position of principal peak. 4 C02CH3; cylindrocarpidine, 3.58 6 ; cylindrocarpine, 3.56 6. 5 Trans-cinnamoyl vinyl protons show two doublets at 6.75 and 7.72 6 (J = 16). 6 Shifted to 4.0 6 in the acetate. 7 The high field position of the aliphatic proton absorption in tabersonine and vindoline may be due to increased shielding by ring currents from the aromatic ring (7, 51b). 8 c-2proton absorbs a t 3.85 6, doublet, J = 4.5 c/sec in N-methylvindolinol acetate (3). 9 Aromatic OCHs coincident. 10 Eliminated after replacement of active hydrogen by deuterium. 11 Absorption in 4.0-4.5 6 region attributed in the kopsine lactams to a C-8 proton. 12 Due to CH-CH(OH), converted to a doublet by treatment with D2O.
TABLE V
W
4 Q,
MASS SPECTRAL DATA PART1. Alkaloids which fragment as aspidospermine
Compound
Mol. wt. of fragmentlcharge = m/el
Reference
-
Mf2
a2
282 312 313 342 324 338 296 326 354 412
254 284 285 314 296 310 268 298 326 384
b3
c4
130 160 1615 190 130 130 144 174 160
124 124 1246 124 124 124 124 124 124 182 182 124 124 124 124 124 124 1408 140 140 141 14P
Other peaks -
Aspidospermidine, X X X I Deacetylaspidospermine, VI 2-d Deacetylpyrifolidine, XLVII Demethoxyaspidospermine, X X X I I I Demethoxypalosine, X X X I V N-Methylaspidospermidine, X X X V N-Methyldeacetylaspidospermine, X L I Aspidospermine, I1 21-Acetoxyaspidospermine, LXXXV 0,N-Diacetyl-0-methyldeacylaspidoalbinol, CXCV Pyrifolidine, XLVI Aspidocarpine, XLIV Aspidolimine, L I I I Spegazzinine, LXIV Spegazzinidine, L X I X Demethylaspidospermine, XXXVII Limaspermine, L X X X V I I N-Decinnamoylcylindrocarpol, L X X X I V 0-Methyldeacylaspidoalbinol,CXCIII 19-d, CXCIV N-Et.hyldecinnamoylcylindrocarpo1, LXXXVI
-7
384 370 3842 356 372 340 370 328 388
356 342 3562 312 328
356
328
220 190 176 176
3428 300
146
-7
220 220
.-
28, 21 9, 21 21
339, 311, 1099
9 40a 40 28,21 28 28,21 52 52 28, 37 40 40 36 36 40a 33 52 52 52 52
m
2 EM
N-Ethyl-0-methyldeacylaspidoalbinol, CXCVI N-CD3CH3, CXCVII 2,3-Dihydrotabersonine, XCVI Dihydrovincadifformine, CI 2,3-Dihydrotabersonol, XCVII Dihydrovincadifforminol, XCIX ( = tetrahydrotabersonol) 20-Hydroxydihydrovincadifforminol, CXIV 2,3-Dihydrotabersonane, XCVIII Dihydrovincadifforminane, CII 20-Hydroxydihydrovincadiff orminane, CXV Vindoline, CIII Dihydrovindoline, CXI 16-Methoxy-N,-methyl-4-oxoaspidospermidine, CV 20-Hydroxy- 16-methoxy-2,3-dihydrovincadifforminol, CXVI
416
7
338 340 310 312
252 254 252 254
328 294 296 312 45610 45810 340 358
270 252 254 270 296 298 298 300
248 250
140 122 124
121
124 140
174 174 174 160
124 140 122 124 124 140
309, 282, 135 311, 28410.11 166"
52 52 7 6 7 6, 7 32 7 32 32 21 4,21 4, 21 32
"
PART2. Aspidospermine-type compounds with a 2,3-double bond
Compound
Tabersonine, XCII Vincadifformine (6,7-dihydrotabersonine),XCIII Minovincinine, CVII 0-Acetylminovincinine Minovine, CVIII Minovincine, CIX 16-Methoxyminovincine, CX
Mol. wt. of fragment/charge = m/e
M+ 336 338 3548 39610 352 35214 382
g12
228 214 244
c
124 1408 18210 124 138 138
Other peaks 135, 107, 9213
Reference
7
6, 7 32 32 32 32 32
w
4
4
W 41 06
TABLE V-Continued
PART3. Aspidospermine-type compounds with a l,2-double lbond (indolenines) Mol. wt. of fragmentlcharge = m/e Compound
1,2-Dehydroaspidospermidine,I X 1,2-Dehydroaspidospermine, VII
PART4. Aspidofractinine-type compounds
Reference
~-
M+
M-29
M-70
C
280 310
251 281
210 240
124
28 21
G)
E
b
~_
M
Mol. wt. of fragment/charge = m/e Compound
Reference M+
Aspidofractinine, CXVII 0-Methyldeacetylaspidofiline, CXXXIX 6,7-Dehydro-CXXXIX,CXLI N-Ethyldeacetylaspidofiline, CXL Aspidofiline, CXXXVI 0-Methylaspidofiline, CXXXVIII 0-Acetylaspidofiline, CXXXVII Deformylrefractidine, CXXII N-Methyldeformylrefractidine, CXXIII
280 310 308 324 3382 3522 3802 310 32419.20
h 252 282 280 296 3102 3242 3522 282 296
Indole 14415 17415 18816 18815 188 14415 15815
C
124 124 124 124 124 124 154 154
i 109 109 107 109 109 109 109 139 139
Other peaks
29517 130, 10918 10918
102 80 80 37 80 80 80 81 81,37
E
N-CD2H analog, CXXIV Deacetylpyrifoline, CXXI Refractidine, CXX Pyrifoline, CXIX Deformyldemethylrefractidine, CXXVII N -Acetyldeformyldemethylrefractidine,CXXX N-Methyldeformyldemethylrefractidine,CXXXI N-CDzH analog, CXXXII Deacetyl-6-demethylpyrifoline,CXXV 6-Deuterio analog, CXXVI N,O-Diacetyldeformyldemethylrefractidine, CXXIX 6-Acetyl-6-demethylpyrifoline, CXXVIII 6-Dehydrodeformyldemethylrefractidine,CXXXV 6-Dehydrodeacetyldemethylpyrifolhe,CXXXIII 1,7,7-Trideuterio analog, CXXXIV Kopsinine, CXLII-A Aspidofractine, CXLIII-A Pleiocarpine, CXLV-A Deformylrefraatine, CXLIX-A Refractine, CL-A Isorefractine, CL-C 3-Deuterio analog, CL-S Pleiocarpine lactam A, CXLV-D
326 340 33819 3822 2968 3388 3108 312 326 327 3802 410 294 324 327 338 36620 396 368 39620 396 397
298 312 31019 3542 2688 310 282 284 298 299 35229 10 382 266 296 299 310 338 368 340 368
Pleiocarpinilam, CXLVI-D Kopsinyl alcohol, CXLII-F N-Methylkopsinyl alcohol, CXLVI-F N-Trideuteriomethyl-3’,3’, 10,lO-tetradeuteriokopsinyl alcohol, CXLVIII-G Deformylrefractinol, CXLIX-F
3108 324
282 296
3408
312
16015 17415 14415 17415 14415 14415 15815 16015
17415 174 14415 174 14415 17415 17515 157
259 27212 215 22812
12424
81 81 81 81 81 81 81 81 81 81 81 81 81 81 81 82, 37 82, 37 95 82,37 82,37 102 102 102
12424
102
124 124 126
10922 109 111
82, 37 95 102
124
109
154 154 154 154 140 140 140 140 140 141 182 182 138 138 140 12422 124 124 124 124 absent23 absent23
139 139 139 139 125 125 125 125 125 126 16710 167 123 123 125 10922 109 109 109 109
109 10918 307,21 10918 130
130
154 154
37
TABLE V-Continued
W W
3
~
._
~
Mol. wt. of fragment/charge = m/e
Compound
~
M+
h
__
Indole
C
i
Other peaks
Reference
~-
0 -Acetyldeformylisorefractinol
38225
35425
109
3’,3’-Dideuterio analog, CXLIX-V
384
35625
109
Kopsinylene, CXLII-M
292
264
109
220,207,182, 168,129,12226
37,102
Aspidofract-3-ene, CXLIII-M
320
2922827
10922
213,164,130, 12226
37
Deformylrefract-3-ene, CXLIX-M
32228
109
250,16226
350
29428 3222.27
124
Refract-3-ene, CL-M
124
109
250, 243, 12226
37 37
Deformylnoraspidofractone, CXLII-P
294
266
124
10922
238,209,156, 130, 122,11526
37
Noraspidofractone, CXLIII-P
3222
2942
124
10922
238,209,156, 143,130,12226
37
Deformylnorrefractone, CXLIX-P
324
296
124
10922
268,239,201, 12226
37
Norrefractone, CL-P
352
3242927
124
281,268,12226
Deformylnorrefractol, CXLIX-Q
326
10922
96
37 37,102
1243
82 82
M
z *
H
62
z
M
PART5. Kopsine-like compounds Mol. wt. of fragment/charge = m/e
Compound
-
-
Mf
Reference
-~
Other peaks
M-28
__
-
-
Kopsine, CLXX
38027
Decarbomethoxykopslne, CLXXI ,V,-Methyldecarbomethoxydlhydrokopslne, CLXXVIII 3'-Deuter1odecarbomethoxyd1hydrokopsine, CLXXLX Fruticosamine Fruticosine
35227
28225
254(w)
322 338
224 238
210(W)
325
224
196(w)
380 380
35227 35227
282 282
107,106, 109 107 107 107 243 321,230
109 109
PART6. Aspidoalbine-type compounds
Mol. wt. of fragment/charge = m/e
Compound
~~~
M+
n'
M-44
b3
c'
310 326 340 356 400 414 400 358
294 310 324 3402 384 398 3842 342
130 146 160
138 138 138 138 138 138 138 138
Other peaks
Reference
~ _ _ _ _ _
1-Acetylaspidoalbidine, CCI-K Haplocidine, CCI-C 0-Methylhaplocidine, CCI-B Aspidolimidine, CCI Aspidoalbine, CLXXXVIII 0 -Methylaspidoalbine, CXC CXCI 0 .Methyl-N,-acetyldepropionylaspidoalbine, CXCII 0-Methyldepropionylaspidoalbine,
338 354 368 3842 428 442 42S2 386
176
220
160 149,310,311 110,160
110,160
113e 113e 113e 40 52 52 52 52
TABLE V-Continued
W 00 t.3
PART7. Aspidospermatidine- and strychane-like compounds Mol. wt. of fragmentlcharge = m/e Compound
Reference Mf
Dihydroaspidospermatidine, CCV Dihydroaspidospermatine, CCX Tetrahydrocondylocarpine,C C X X Aspidospermatidine, CCIV N-Acetylaspidospermatidine, CCVIII N-Methylaspidospermatidine, CCVI Deacetylaspidospermatine, CCVII Aspidospermatine, CCIX Tetrahydrodecarbomethoxyakuammicine,CCIII Tetrahydroakuammicine, C C X X X V Tetrahydromossambine, C C X X X 2,16-Dihydroechitamidine 16-Methyl-16-decarbomethoxytetrahydroakuammicine, C C X X X V I 16-Methyl-16-decarbomethoxytetrahydromossambine, C C X X X I V Spermostrychnine, C C X I Deacetylspermostrychnine, C C X I I 2,16-Dihydrodecarbomethoxyakuammicine, CCII 2,16-Dihydroakuammicine,C C X X X V I I I 2,16-Dihydromossambine, C C X X I X
r
8
227
268 340 326 266 308 280 296 338 268 326 342 342 282
138 138 196 136 136 136 136 136 138 196 212 212 152
298
168
215
368 326 266 324 340
166 166 136 194 210
271 229
227
199 199 215 199 199
b3
U
Other peaks
130 160 130 130 130 144 160 160 130 130 130 130
28,21 28,21 118 28,21 28,21 28,21 28,21 28,21 28,21 122 122 126 I22 122
160 160 130 130 130
139 139
25129 25129 26729
21 21 28, 21 122 122
td
8 W
2
PART 8. Yohimbine- and ajmalicine-like compounds Mol. wt. of frctgment/charge = m/e Compound
Reference Mf 3548,25,27
V
W
2
Y
Other peaks
170
169
184
156
165, 162
17.Deoxy-a-yohimbine, CCCX
170
169
184
156
165
Alloyohimbone, CCCXI
170
169
184
156
165
16-Ketoyohimbane, CCCXII
170
169
184
156
165
Yohimbinone, CCCXIII
170
169
184
156
165
Seredone, CCCXIV
230
229
244
216
165
200
199
214
186
162
N-Methylyohimbane, CCCXV
184
183
198
170
165
3-Deuterioyohimbine, CCCVII
171
170
185
157
165 165
Yohimbine (and stereoisomers)
11-Methoxyyohimbine, CCXCVIII
38427.25
Tetrahydroalstonine, CCCXVIII
35227
170
169
184
156
Ajmalicine, CCCXVII
35227
170
169
184
156
225
165
3,5,6-Trideuterioajmalicine, CCCIX
35530
173
172, 171
187
158
228
165
3,14-Dideuterioajmalicine,CCCVIII
35430
171
170
185
158, 157
171
Tetraphylline, CCCXIX
38227
200
199
214
186
165
Aricine, CCCIII
38227
200
199
214
186
Tetramethylenetetrahydr0-/3-~arboline
22627
170
169
184(w)
156
165 197
165
w
TABLE V-Continued
PART9. Sarpagine-like compounds Mol. wt. of fragment/charge = m/e
Compound
M+ Bisdeoxyajmalol-B, CCCXXXIV 0-Methyl-17-deoxydihydrosarpagine, CCCXXXV Dih ydronormacusine - B Normacusine-B, CCCXX 0-Acetylnormacusine-B, CCCXXVIII Polyneuridine, CCCXXI 0-Acetylpolyneuridine, CCCXXV Akuammidine, CCCXXII 0,O-Diacetylakuammidinol, CCCXXVII 17,17-Dideuterio-CCCXXVII
cc
29420,27,32 328 2968.27 29419,20,27 33620,25,27 3528,19.20,25,27 3941%2 0 , 2 5 , 2 7 . 3 3 35219.20.25.27 40810.25.27.33 41010,25,27,33
dd31
W
237 253 249 249 249 249 249 249(w) 249(w)
223
Other peaks __~ _ _ _ _ _
bb
167 167
1823 1983 16915 169 169 169 169 169 169 169
168 1683 1683 1683 1683 1683 1683 1683
Reference
259,267 275,207 275,261 275 275 282, 275, 208 282, 275, 208
165 165 37 165 165a 165, 165a 165, 37 165, 37
PART10. Eburnamine-like compounds
Mol. wt. of fragment/charge = m/e
Compound
E burnamenine, CCCXLII I (eburnamine, isoeburnamine) 14-Deuterioeburnamenine, CCCXLIV
ff
ee
99
278
249
208
193
279
250
209
194
Mf
hh
____Other peaks
206
Reference
51, 170 51
W
E
W M
Apovincamine( 14-carbomethoxyeburnamenine) 11-Methoxyapovincamine Dihydroeburnamenine, CCCXLV 14-Deuteriodihydroeburnamenine, CCXLVI Eburnamonine, CCCXLIl 14-018-Eburnamonine Vincamine( 14-carbomethoxyisoeburnamine) 11-Methoxyvincamine
336
307
266
251
264
170
366 28027 281
337 251 252
296 210 211
281 195 196
294
170 51 51
224 226 284 22434 314 25434
209(w)
265 267 3258(w) 26534 3558(w) 29534
29427 296 3548.20.25.27 29434 3848,20,25.27 32434
81, 170
237 237
20934
23734
23934
26334
267, 252
51 170
297, 282
170
PART11. Oxindoles __ Mol. wt. of fragmentlcharge = m/e
Compound
22
kk
11
Reference mm
nn
M
___ Yohimbine oxindole A Yohimbine oxindole B Mitraphylline, CCCXLIX 3-Deuteriomitraphylline, CCCL 3,5,6-Trideuteriomitraphylline, CCCLI
37089 25 37089 25 3688.19,25 36930 37 1 3 O
2258 2258 22320
3,14-Dideuteriomitraphylline, CCCLII Aricine oxindole, CCCLIII Carapanaubine, CCCLIV Rhyncophylline
37030 39883 1 9 42882 19 38419.20.32
22520 22320 22320 23919.20.32
22520
1303 1303 1303 1303 132, 131 1303 1603 1903 1303
14522 14522 14522 14522927
159 159 159 159 161
171 171
17522 20522 14522
159 189 219 159
171 171 171 171
C
37 171 171
~
b
Fr
2C m
__
W 00
u1
TABLE V-Continued
w
00 5 2
PART12. Quebrachidine-like compounds Mol. wt. of fragmentlcharge = m/e Compound
Reference M+
Quebrachidine, CCCXXXVIII-D 0,N-Diacetylquebrachidine, CCCXXXVIII-E Vincamedine, CCCXXXII
352 43625 408
b 13035 13035 14435
PP
QP
rr
122 264 264
222 222
190 190 190
179b 179b 179b
m
PART13. Miscellaneous compounds
B
_- __ Compound
3-Carbomethoxyharman, CCCXXXIX Tetrahydroharman
Mol. wt. of fragmentlcharge = m/e
M+
Other peaks
240 186
182 171
Reference
180 165
1 Only principal peaks are recorded. Blanks in the table do not signify that a peak is missing but rather that it is not recorded in the literature. 2 In compounds bearing a n acyl substituent, RCO, on N,, the molecular ion is accompanied by peaks at M-RCO and M-RCO +H. Similar peaks may often be detected accompanying a. An RCO peak may usually be found in the lower mass range. 3 Accompanied by a peak 14 units higher. 4 Accompanied by peaks 1 ( c f H), 14 (cfCH2, weak) and 28 (c+ 2CH2, strong) units higher, except in CV whero c+COCHz appeers a t m/e 166. 5 Homologs show identical shift.
W M
Homologs show no shift. Weak or negligible M-28 peaks due perhaps to inverted stereochemistry at ‘2-19. 8 Accompanied by peaks 17 or 18 units lower due to loss of OH or water. 9 Due to loss of CHzOH (31 units) from Mf, a,and c. 10 Accompanied by peaks 60 units lower due to loss of acetic acid. 11 These peaks are due to fragment c plus atoms C-4 and C-3 with their substituents (see footnote 4). 1 2 Represents the indole fragment b carrying also atoms C-3 and C-4 with the carbomethoxyl [C(C02Me)=CHz]. 13 These fragments come from the piperidine or D ring and are seen in the spectrum of vindolinine, which also exhibits the following principal peaks: Mf, M-CH3, M-OCH3, m/e 277, 249, 230, 229, 216, 170, 156, 134, 122, 121, 120(3). 14 Accompanied by M-43 (loss of COCH3, side chain). 15 Accompanied by peaks 1 unit lower and 12, 13, and 14 units higher. 16 Base peak. 1 7 M-85 = M-(2CH3CO)+H. 18 Loss of CHzO from i. 10 Accompanied by a peak 31 units lower (loss of CH30 or CH20H). 20 Accompanied by a peak 15 units lower (loss of CH3). 21 M-75 = M-(CH3CO+MeOH). 22 Accompanied by a peak 1 unit higher. 23 Presence of m/e 124 has been shown to be due to refractine. 24i+H. 25 Accompanied by a peak 59 units lower (loss of CH3COO or COz CH3). 26 Cleaves abnormally due to extra double bond or ketone group. 27 Accompanied by a peak 1 unit lower. 28 Accompanied by a peak 30 units lower. 29 This fragment is due to an ion in which (2-16 aRd its substituent (where present) have been expelled from the molecular ion (115a). 30 Accompanied by a peak 2 units lower. 31 Structure dd (Section VIII, B formulas) has been ascribed to this fragment. 32 Accompanied by a peak 29 units lower (loss of CzH5). 33 Accompanied by a peak 119 units lower, M - ~ C H ~ C O Z H H or M-(CH3C02H+ C02CHa). 34 These are eburnamonine or methoxyeburnamonine peaks resulting from the loss of H .C02Me from vincamine or 11-methoxyvincamine, respectively. 35 Accompanied by peak 13 units higher. 6
7
F b P
b
*U
P
.
+
w
00
l
388
B. GILBERT
TABLE VI pK DATA Alkaloid
PK',
Solvent
Reference ~~
Aspidospermine, I1 Deacetylaspidospermine, VI N,-Benzoyldeacet ylaspidospermine Aspidocarpine, XLIV Pyrifolidine, XLVI Deacetylpyrifolidine, XLVII Spegazzinidine, LXIX 0,O-Dimethylspegazzinidine, LXX 3-Dehydro-O,O-dimethylspegazzinidine, LXXI Cylindrocarpine, LXXV Vindoline, C I I I Dihydrovindoline, CXI 16-Methoxy-A~~-methyl-4-oxoaspidospermidine, CV Vindolinine, CVI Refractidine, CXX Deformylrefractidine, CXXII Deformyldemethylrefractidine, CXXVII Pyrifoline, CXIX Deacetyldemethylpyrifoline, CXXV 6-Dehydrodeacetyldemethylpyrifoline, CXXXIII Kopsinine, CXLII-A Aspidofractine, CXLIII-A Pleiocarpine, CXLV-A Pleiocarpinine, CXLVI-A Refractine, CL-A Deformylrefractinol, CXLIX-F Kopsiflorine, CLVI Kopsilongine, CLVII Kopsamine, CLVIII Kopsine, CLXX Dihydrokopsine-A, CLXXII Decarbomethoxykopsine, CLXXI Dihydrodecarbomethoxykopsine-A, CLXXIII Fruticosamine Fruticosine 0-Methyldepropionylaspidoalbine,CXCIl
50% aq. EtOH 50% aq. EtOH 50% aq. EtOH
7.30 7.36 6.98 6.55 6.85 7.8 2.9,6.4,10.7 2.76,6.45 3.0,5.48
66% 50% 33% 33% 33%
DMFl aq. EtOH DMF DMF DMF
25 25 25 30 10,49 30 36 36 36
5.9 5.5 5.9 5.35
66% 66% 66% 66%
DMF DMF DMF DMF
10,49 72 4 4
66% DMF
72 92 81, 37 37 37 49 81 81
3.3,7.1 6.26 6.25 7.15 2.9,7.5 6.40 7.25 5.90
80% MCS1
DMF DMF DMF DMF aq. DMF aq. DMF
33% 33% 33% 66%
70% MeOH ttq. DMF aq. MCS aq. MCS aq. DMF aq. DMF 70% MeOH 70% MeOH 70% MeOH 800/, MCS
7.50 6.85 6.19 6.94 6.64 3.2,8.0 6.38 6.80 6.58 4.28 6.1 5.4 6.1
80% MCS
4.04 4.62 8.5
807; MCS
33% DMF ~
DMF =dimethylformamide; MCS = methyl cellosolve.
87 37 91 91 49 37 87 87 87 109 100 100 100 109 109
52
14. Aspidosperma
389
AND RELATED ALKALOIDS
TABLE VI-Continued
pK DATA
-
Alkaloid
PK:
~-
Solvent ~
~-
Uleine, CCXLV Dihydrouleine, CCXLVI Olivacine, CCLVIII
8.23 8.87 6.05-6.13
800/, MCS 80% MCS 80% MCS
Ellipticine, CCLXXXIV 1,2-Dihydro?livacine, CCLXXIV 1,2-Dihydroellipticine, CCXCIII Cuatambuine, CCLX N-Methyltetrahydroellipticirle, CCLXXXV 11-Methoxyyohimbine, CCXCVIII Polyneuridine, CCCXXI Akusmmidine, CCCXXII
5.78 8.09 7.53 7.87 7.49
80% MCS 80% MCS 80% MCS 80% MCY 800,6 MCS
7.1 6.60 6.30
66% U M F
Reference ~ _ _ _ _ 138 138 140, 149, 150 140 150 155 139 139 161 165 62
the C-ethyl side chain is easily distinguished from this, since its absorption is centered at 0.65 6 and contains two principal peaks separated by 5 4 clsec. The absence of this absorption shows that the side chain is substituted on its terminal carbon atom and this may either indicate the presence of a C-21 oxygen function as in cylindrocarpine (LXXV, 10, 29) or limaspermine (LXXXVII, 31), or that the carbon atoms 20 and 21 are involved in a sixth ring as in the aspidofractinine (Section 111) and aspidoalbine (Section IV) groups. Other functions which may be recognized from the NMR-spectrum include a phenolic hydroxyl whose presence is also seen by the change in the UV-spectrum in an alkaline medium (Table 111). Phenolic hydroxyls usually occur in this series in position 17 where hydrogen bonding with the carbonyl group of the N,-acyl is possible, and in these cases the OH proton peak is found a t 10.7-11.2 8. When the hydroxyl group is not in position 17 it is not found so far downfield, for example, the 16-OH of spegazzinidine absorbs at 5.84 6. Another downfield singlet found in the spectra of some alkaloids derives from the proton of an N,-formyl group which appears around 9.5 6. The three-proton singlet due t o the methyl group of a carbomethoxy function appears slightly upfield with respect to the aromatic methoxyl absorptions, occurring at 3.55-3.7 6. Other, less general deductions which may be made from NMR-absorption will be dealt with under specific cases in later sections. The use of NMR-spectroscopy mainly to determine the nature of peripheral groups has as its ideal complement mass spectrometry which
390
B. GILBERT
gives direct information about skeletal structure. I n some cases complete elucidation. of a structure has been possible by determining the mass spectrum by use of less than 1 mg of material ; it has therefore become possible to investigate successfully the minor Aspidosperma bases which were present in quantities too small to permit even elementary analysis (28, 51, 51a). I n the mass spectrometer, the alkaloid molecule is split by electron impact and those fragments which are sufficiently stable and which carry a positive charge are collected in order of their molecular weights. Ions carrying a double positive charge appear a t mi2 where m is their molecular weight. The information which may be derived from the pattern of relative intensity plotted against m/e (e representing the charge on the ion) can be divided into three parts (28a). First, the highest molecular weight peak is usually that of the molecular ion2, that is, the whole molecule singly charged. This peak is referred to as Mi- and is accompanied by minor peaks one and two units higher corresponding t o molecular ions containing heavier isotopes of nitrogen, hydrogen, carbon, and other elements (20, 21). From the molecular weight thus precisely determined, the molecular formula is derived, leaving no doubt as t o the correct number of hydrogen atoms. Although this was already possible by integration of the NMR-spectrum, the amount of material required for the mass spectral method is minute in comparison. Second, it is possible to classify an unknown alkaloid into a structural class provided that other alkaloids with the same carbon skeleton are known. The cleavage of the molecule is independent of many superficial substituents. I n the aspidospermine group, these have been found to include a hydroxyl or methoxyl substituent on the aromatic ring (18, lo), an oxygen function on the ethyl side chain, whether a t C-20 (32) or a t C-21 (33, 5 2 ) , a carbomethoxy or other one-carbon group or a hydroxyl group a t C-3 (6, 7 , 35,36), and a carbonyl group a t C-4 ( 3 6 ,4 ) . [Note that a 3-ketone fragments differently (361.1 Thus the characteristic pattern of aspidospermine (11)may be recognized in all related alkaloids and derivatives containing the same skeleton, the only difference being that those peaks which correspond t o fragments containing an extra substituent are shifted to higher molecular weight by a number of units equal to the molecular weight of the substituent, while alkaloids that do not contain the aromatic methoxyl group of aspidospermine exhibit a pattern due to the aromatic fragments a t correspondingly lower molecular weight. 2
For an exception see ref. 28b where peaks higher than the molecular ion were observed.
14. Aspidosperma
391
AND RELATED ALKALOIDS
Third, and most important, direct structural information may be obtained. It is often possible, especially when the method is used in conjunction with NMR and with deuteration, to determine the exact position of substituents and also to establish the nature of new skeletons without in many cases having to make any extensive degradations. The importance of this will be seen particularly in the sections on aspidofractinine-, aspidoalbine-, and condylocarpine-type alkaloids (Sections 111, IV, and V), whose structures do not lend themselves to easy degradation by classical methods, owing to the presence of quaternary centers.
b m/e 160
c m/e
124
The breakdown of deacetylaspidospermine (VI) is represented by the formulas a-c (9, 28, 21). That of aspidospermine itself (11) is similar, except that the group R which is acetyl in the parent alkaloid is either acetyl or hydrogen in fragment a, both peaks appearing in the spectrum, while in b the indole nitrogen atom bears a hydrogen atom. The evidence for the structures assigned t o fragments a , b, and c is threefold. First, these fragments may be predicted from the known breakdown patterns of simpler molecules (20, 21). It is known, for example, that bonds /3 to
392
B. GILBERT
nitrogen such as C-19 to C-12 and C-2 t o C-3 in V I are readily broken since the carbonium ion or radical produced, at C-19 or C-2, respectively, in the case under consideration, can be stabilized by the donation of electrons from the lone pair on the nitrogen atom. A similar stabilization, by delocalization, favors the production of allylic, benzylic, or similar radicals and ions, rendering the allylic and benzylic bonds subject t o facile cleavage. Stable ions are favored, especially those in which there are conjugated double bonds or enhanced aromatic character. I n addition, there is a tendency t o cleave bonds at a highly substituted carbon atom. In many cases a number of bonds are broken simultaneously by a concerted movement of electrons within a ring, and in deacetylaspidospermine (VI) the movement indicated by the arrows in the formula represents one of the principal manners of cleavage observed. The fact that the calculated molecular weights of the fragments a, b, and c so predicted are in accordance with the principal observed peaks is adduced as evidence in favor of these structures. It will be noted that C-3 and C-4 are expelled as ethylene producing the a peak at M-28, and this M-28 a fragment together with the c fragment at mje 124 are the characteristics of the aspidospermine group alkaloids (Table V). [Strychanone (CCXLIV) also shows these two peaks, although it does not have the aspidospermine skeleton (36).]It should be emphasized that the breakdown illustrated by the formulas is not the only one to take place. There is a strong peak at c + 28 t o which a structure such as d may be assigned, the C-4 to C-5 bond having resisted cleavage. Weaker peaks appear at c + 14 (e) and b + 14 (f).
CCXLIV
\
CI
U
m/e 254
I
COzMe
J. c m/e 124
Second, evidence for the structures of the fragments responsible for the peaks observed has been obtained by the detection of metastable peaks (20). Such a peak proves that a certain fragment, say x of mass m,, was formed by decomposition of another fragment, y, of mass my, the
14. Aspidosperma
AND RELATED ALKALOIDS
393
position of the metastable peak, m*, being given by the approximate equation :
As an example may be cited the case of dihydrovincadifformine (CI) in which the decomposition of the molecular ion (m/e 340) to fragment a (m/e 254) with expulsion of the elements of acrylic ester is documented not only by the presence in the spectrum of those two peaks but also by the appearance of a metastable peak a t 191. The further breakdown of a to give c (m/e 124) was recognized by a metastable peak a t 61 (6). Similarly, in deacetylaspidospermine the loss of ethylene from the molecular ion (m/e 312 to m/e 284) is accompanied by a metastable peak a t m/e 259 (21). Third, as mentioned previously, peaks a, b, and c have been found to occur in the spectra of alkaloids and derivatives substituted in various positions. I n many cases the location of these substituents has been established by independent evidence, and the substituted molecule has been converted into the unsubstituted by chemical methods establishing the identity of the skeleton. The variation of molecular weight found for fragments such as a, b, and c in such a series can be used to decide with certainty some of the constituent atoms of those fragments. For example, fragment a contains all the atoms in the original molecule with the exception of C-3 and C-4 and any substituents that these atoms carried. This is shown by the fact that no increase in the mass of fragment a is observed in the mass spectra of molecules substituted in these positions. Thus, for example, 2,3-dihydrovincadifformine(CI) and dihydrovincadifforminol (XCIX) both show fragment a a t m/e 254 (6) in the same position in which it is found in the spectrum of aspidospermidine (XXXI), the parent alkaloid of the aspidospermine series. I n aspidospermidine this peak lies a t M-28 (loss of CHzCHz), whereas in CI i t corresponds to M-86 (loss of CHz=CHCOzCH3) and in XCIX to M-58 (loss of CHz=CHCHzOH). The position of the carboxylic ester group in vincadifformine (XCIII) and hence of the corresponding substituents in C I and XCIX is established by the UV-spectrum as C-3 (6), so that the lost atoms are necessarily C-3 and C-4. A similar result is encountered in the mass spectrum of spegazzinidine (LXIX) where the a peak is found a t m/e 328 or M-44 (loss of CHOHCHz) and independent evidence has established that the hydroxyl group which is lost is located on (2-3. Independent chemical proof has also been obtained for the aspidospermine-type skeletons of vincadifformine and spegazzinidine.
394
B. GILBERT
A t the same time, substituents in positions 17 and 16 [series aspidospermidine (XXXI), deacetylaspidospermine (VI), and deacetylpyrifolidine (XLVII) in Table V] ; position 1 [series aspidospermidine (XXXI), demethoxyaspidospermine (XXXIII), demethoxypalosine (XXXIV), and N-methylaspidospermidine (XXXV)]; position 20 [pair dihydrovincadifforminane (tetrahydrotabersonane, CII) and 20hydroxydihydrovincadifforminane(CXV)]; and position 2 1 [pair aspidospermine (11) and 2 1-acetoxyaspidospermine (LXXXV)] result in corresponding changes in the molecular weight of a, demonstrating that a incorporates these carbon atoms.
R3
Rz ~~~
XXXI VI XLVII XXXIII XXXIV XXXV
Ri
H H Me0
H H
H
1L
Rz K3 H H Me0 H Me0 H H Ac H EtCO H Me
Ji
HO
Ac
OH
CI; R = COzMe LXIX XCIX; R = CHzOH XCIII; R = COzMe 2,3-douhle bond
CH3
CII;
R =H CXV; R = O H
Me0
Ac
11; R = H LXXXV; R = OAc
The same type of evidence supports the structures assigned to fragments b and c. Variations in the aromatic substitution produce in all cases the corresponding variation in the molecular weight of b while c is not affected by these changes. The hydrogen atom on C-2 is retained in fragment b , for when it is replaced by deuterium (1S), the b peak, found at m/e 160 in deacetylaspidospermine (VI), is shifted to m/e 161 (21). On the other hand, alterations in ring D or in the ethyl side chain are reflected in the molecular weight of c which is altered appropriately. For example, limaspermine (LXXXVII), which has a primary alcoholic group at C-21, exhibits peaks at m/e 140 (strongest peak in the spectrum), 122, and 109 which may be interpreted as due t o c (16 mass units higher than in the aspidospermine spectrum due to the C-21 oxygen), c-HzO, and c-CH20H (33). In contrast, the highly substituted dihydrovindoline
14. Aspidosperma
AND RELATED ALKALOIDS
395
(CXI) has a normal c peak at m/e 124 because none of the substituents is located on ring D or the ethyl side chain (4). The molecular weight of fragment d , the structure assigned (21) to the c + 28 peak which occurs at mje 152 in VI, is shifted to m/e 166 in the spectrum of the ketone (CV); whereas in its 3,3-dideuterio derivative, a further shift to m/e 168 is observed. This is strong evidence that d retains atoms 3 and 4, since the shifts are those calculated for the substitution of CO for CH2 in
cv position 4 and of CD2 for CH2 in position 3. The position of the carbonyl at C-4 is independently based on NMR-evidence. Similarly, in dihydrovindoline (CXI) the d peak is shifted t o mje 284, the shift of 132 mass units corresponding to the substitution of hydrogen atoms on C-3 and C-4 by COzCHz(+ 58), OH( + 16), and OAc( + 58). Returning to the spectrum of the ketone (CV), fragment b and its homolog fragment f,at mje 174 and 188 respectively, do not change their positions when the ketone is deuterated (excluding structures which contain C-3, for these fragments).
E. SOMEMINORALKALOIDS OF Aspidosperma quebrachoblanco AND
Rhazya stricta
In a reinvestigation of the minor alkaloids of A . quebrachoblanco,whose presence had already been indicated by Kesse (59) in 1882 (Vol. 11), Biemann et al. (28, 51a) were able t o isolate by a combination of alumina and gas chromatography about twenty compounds. The identification or structure determination of fifteen of these by mass spectrometry was described. Six belonged t o the aspidospermine group and four of these were the known compounds, aspidospermine (11), deacetylaspidospermine (VI), N,-methyldeacetylaspidospermine (XLI),and ( - )-pyrifolidine (XLVI). The three last-named had not previously been encountered in nature, V I and XLI having been prepared from aspidospermine (11)and vallesine (XXXVIII) (38, 39, 25). (-)-Pyrifolidine is identical with 0-methylaspidocarpine (XLVI) which has been prepared
396
B . GILBERT
from aspidocarpine (XLIV) (30). 0-Methylaspidocarpine (XLVI) has been shown (9) t o be the enantiomer of the alkaloid (+)-pyrifolidine which occurs in A . pyrifolium.
XXXI XXXV VI XLI
rr
(-)-XLVI
Ri H
H H H H OMe
Rz H
H OMe OMe OMe OMe
R3 H Me H Me Ae Ac
The two previously unknown compounds in the series were designated “Alkaloid 2 8 2 8 ” [later (51) named aspidospermidine] and “Alkaloid 296A” (or N-methylaspidospermidine), the numbers referring to their mass spectrometrically determined molecular weights. The first has also been found in Rhazya stricta (51). The mass spectrum of aspidospermidine differed from that of aspidospermine only in the shift of the mie values of all those peaks containing the benzene nucleus and N,, corresponding to the absence of substituents in these positions. Thus the &I+ and fragment a peaks appear 7 2 units lower down on the mass scale, corresponding to the absence of methoxyl (30) and acetyl (42) (see Table V). I n a similar manner, the spectrum of N-methylaspidospermidine parallels exactly that of N,-methyldeacetylaspidospermine (XLI), showing only a lowering of the mie values for the same two ions by 30 mass units that corresponds t o the absence of the nuclear methoxyl group. The structures of aspidospermidine and N,-methylaspidospermidme were thus shown t o be XXXI and XXXV, respectively, and aspidospermidine may be recognized as the parent of the aspidospermine group. The indolenine corresponding t o aspidospermidine was also isolated (28,51a).It was denominated “Alkaloid 280A” [later named 1,2-dehydroaspidospermidine (51)] and has structure IX. This compound had previously been obtained by the zinc dust distillation of quebrachamine (18, Section 11, B) and was subsequently found in R. stricta (51). It is
14. Aspidosperma
AND RELATED ALKALOIDS
397
noteworthy that the 21-methyl group of I X absorbs a t unusually high field in the NMR-spectrum, due t o shielding by the benzene ring not observed in compounds lacking the 1,2-double bond (51b). A compound with apparently the same structure (IX)has also been obtained both in the racemic and the levorotatory form ([aJI, - 225" in ethanol) by the degradation respectively of racemic vincadifformine (XCIII, 6, see Chapter 12) and (-)-tabersonine (XCII, 7 , Section 11, 0). As the levorotatory form of I X is converted by alkaline borohydride to ( + )-quebrachamine (I),it is probably the optical antipode of the product isolated from 8.stricta. The latter gives ( - )-quebrachamine and the configurationally related ( + )-aspidospermidhe (XXXI)on borohydride reduction (51b).
XCIII XCII 6,7-double bond 2N HC1
I
105"
IX
1
I
Hz cat
XXXI
The structure (IX) of 1,2-dehydroaspidospermidinerests on comparison of its UV- (Table 111)and mass spectra (characteristic peaks a t mje 280, 251, and 210) with that of l,%dehydroaspidosperniine ( V I l , Section 11,B). Lithium aluminum hydride reduction also gave aspidospermidine (XXXI, 28, 18, 51a, b). Nine other minor alkaloids of A . quebrachoblanco are dealt with in Sections V and VIII.
398
B. GILBERT
F. DEMETHOXYVALLESINE, DEMETHOXYASPIDOSPERMINE, AND DEMETHOXYPALOSINE The three alkaloids named in the title (XXXII, XXXIII, and XXXIV) are respectively the N,-formyl, -acetyl, and -propionyl derivatives of aspidospermidine (Section 11, E). Demethoxypalosine (XXXIV) has been isolated from Aspidosperma limae (40) and A . discolor (40a) and was characterized as an N,-acyldihydroindole by its UV-spectrum (Table 111)and IR-absorption a t 5.89 p. A strong band in the IR-spectrum a t 13.1 p indicated an unsubstituted benzene ring. The foregoing information was confirmed and the substance was shown to belong to the aspidospermine group by NMR- and mass spectrometry. I n the NMR-spectrum (Table IV) the 17-proton absorption is found a t 8.13 6 well downfield from the three-proton multiplet due t o the other aromatic protons which is centered a t 7.07 6. This shift is due t o the proximity of the carbonyl group of the N,-propionyl group. In the aliphatic part of the spectrum, absorptions which are characteristic of the
(X)/" H
o=c,
COR
R
a M-28
b m/e 130
XXXII; R = H XXXIII; R = Me XXXIV; R = Et
c m/e 124
aspidospermine skeleton (see Section 11, D) were found a t 4.08 6 (C-2 proton), 3.3-2.9 6 (CH2-Nb-CH2), 2.60-2.17 6 (quartet) and 1.401.08 6 (triplet, propionyl CH2, and CH3, respectively), and 0.75-0.45 (triplet, CH3 of a C-ethyl group). The mass spectrum (Table V) shows the molecular ion peak a t 338, confirming the molecular formula, C22H30N20 ; the other principal peaks are those characteristic of alkaloids of the aspidospermine group, that is, M-28 (m/e 310, fragment a ) , m/e 130 (fragment b accompanied by a homolog a t m/e 144), and mje 124 (fragment c, base peak of much higher intensity than any other and
14. Aspidosperma AND RELATED ALKALOIDS
399
accompanied by homologs at m/e 138 and 152). A strong peak at m/e 57 is due to the propionyl group on N,. From A . discolor has also been isolated the N,-acetyl analog, demethoxyaspidospermine (XXXIII, 40a). The alkaloid, which was separated chromatographically from the accompanying demethylaspidospermine (XXXVII, Section 11,G), was not obtained crystalline but was identified as demethoxyaspidospermine (XXXIII) by examination of its NMR- and mass spectra. The former resembled in all respects that of demethoxypalosine (XXXIV) with the exception of a threeproton singlet at 2 . 2 2 6 due to the N,-acetyl group which replaced the propionyl absorptions observed in the spectrum of XXXIV. The mass spectrum (Table V ) shows the molecular ion and M-28 (fragment a ) peaks 14 mass units lower than in the spectrum of XXXIV, while the b and c fragments and their homologs do not suffer this shift. Demethoxyvallesine (XXXII)has also been detected in the same plant (37).
G. DEMETHYLASPIDOSPERMINE The simplest of the phenolic members of the aspidospermine group, demethylaspidospermine (XXXVII),has been found in A . discolor (40a). It was isolated as its crystalline perchlorate ( 2 5 ) from which the oily free
XXXVI XXXVII XLII
Ri Rz H H
H Ac
Ac Ac
VI
XXXVIII; R I1; R XXXIX; R XL: R
=H = Me = Et = n-Pr
base was obtained. From the NMR- and mass spectra (Tables I V and V), the compound was recognized as the known aspidospermine derivative (XXXVII) which had previously been obtained by demethylation of aspidospermine (11) with aluminum chloride in nitrobenzene ( 2 5 ) . Confirmation of its identity was obtained by methylation with dimethyl sulfate and potassium carbonate in dry acetone t o give aspidospermine (11).It is noteworthy that the phenolic hydroxyl group in position 17 is strongly hydrogen-bonded to the carboayl group of the N,-acetyl (OH
400
B . GILBERT
shows NMR-singlet a t 10.83 6) and XXXVII does not suffer ready air oxidation as do phenolic bases in this series which lack the ilr-acyl group, e.g., aspidosine (XXXVI). As a result of the hydrogen bonding, the foregoing relatively vigorous conditions are necessary for inethylation but in spite of this the strong steric hindrance of N, (1 1, 12, 27) enables the direct isolation of the tertiary base aspidospermine, with little or no methylation of Nb having occurred (40a).
H. VALLESINE AND PALOSINE Vallesine (XXXVIII) and palosine (XXXIX) are respectively the N,-formyl and N,-propionyl analogs of aspidospermine (11).Vallesine which occurs in Vallesia glabra and V . dichotoma (Volume I1 and Ref. 41) has been related to aspidospermine (39, 2 5 ) and has therefore structure XXXVIII. Palosine (XXXIX) has been isolated from Aspidosperma polyneuron (23), where it occurs in admixture with aspidospermine and a ketonic base (43) in addition to other alkaloids (Table I). The separation of palosine from the mixture was very difficult but was finally achieved by chromatography on paper using formamide containing 10% of pure formic acid and 8% of ammonium formate as a buffered stationary phase with benzene: chloroform (4: 1) saturated with formamide as the mobile phase. Acid hydrolysis of palosine gave deacetylaspidospermine (VI) and propionic acid (43),the latter being identified by paper chromatography (44). Propionylation of deacetylaspidospermine gave palosine to which, therefore, the structure XXXIX may be given. I . ASPIDOCARPINE AND DEMETHYLASPIDOCARPINE Aspidocarpine (XLIV) was isolated by direct crystallization from the light petroleum extract of Aspidosperma megalocarpon (30), and was characterized as the perchlorate, hydrochloride, hydrobromide, and hydriodide. Its empirical formula is CZ2H30N203 and it contains one methoxyl group. Aspidocarpine represents an important chemical link between aspidospermine (11)and its relatives with one oxygen substituent in the benzene nucleus, on the one hand, and the related alkaloids with two oxygen substituents on the other, since it has been related directly with aspidospermine. The UV-spectrum of aspidocarpine, which is somewhat similar to that of aspidospermine, exhibits a large bathochromic shift on passing from
14. Aspidosperma
AND RELATED ALKALOIDS
40 1
neutral to alkaline solution (Table III),indicative of the presence of a phenolic hydroxyl group in the molecule. A carbonyl peak in the IRspectrum at 1632 em-1 indicated an amide group, and acid hydrolysis followed by steam distillation gave acetic acid, showing that this amide was present as an N-acetyl group. The low frequency of the amide carbonyl absorption and the absence of a hydroxyl peak in the IRspectrum, coupled with the olive-green ferric reaction of aspidocarpine and the fact that the phenolic hydroxyl group resists methylation with diazomethane, were indicative of strong hydrogen bonding between the O H and C=O groups. Evidence confirming these functional groups was obtained by acetylation to 0-acetylaspidocarpine (XLV) and methylation with dimethylsulfate in alkali (note that Nb resists methylation) to 0-methylaspidocarpine (XLVI) ([.Iu - 94" in chloroform, later shown t o be antipodal to ( + )-pyrifolidine, ["ID + 90" in chloroform; Refs. 9, 10) and in both XLV and XLVI the amide carbonyl absorption appeared a t higher frequencies (1666 and 1656 em-1, respectively) indicating that hydrogen bonding no longer occurred. 0-Methylaspidocarpine hydrolyzed with 10% hydrochloric acid gave 0-methyldeacetylaspidocarpine(XLVII) ( [aID- 4.9" antipodal to ( + )-deacetylpyrifolidine, [a]=+ 7" ; Refs. 9, lo), which could be reacetylated to XLVI. On these grounds, it was reasonable to propose the partial structure XLIII. The NMR-spectrum of aspidocarpine (XLIV) (30, 45) fully confirmed the foregoing, a hydrogen-bonded phenolic proton being found a t 10.83 6 and the N-acetyl methyl singlet a t 2.20 6. In addition, the methoxyl group exhibited a three-proton singlet at 3.73 6, and that it is an aromatic methoxyl is demonstrated by the presence of absorption due t o only two aromatic protons. These form a triplet with a large central peak a t 6.5 6, the small side peaks being separated by J = 9 cjsec which shows that these two protons are almost equivalent and are disposed ortho to one another. Most importantly, the aliphatic part of the spectrum closely resembles that of aspidospermine (II),showing the C-2 proton, CHz-N-CHz and C-ethyl absorptions (Table IV). The foregoing information really suffices t o place the methoxyl in position 16, but chemical evidence was also adduced to show that it was ortho to the phenolic hydroxyl. Demethylation of aspidocarpine (XLIV) with hydrobromic acid gave the unstable catechol XLVIII (ferric reaction, blood-red) which was acetylated to the triacetate (XLIX) in which the two 0-acetate absorptions in the IR-spectrum (1777 and 1767 em-1) showed them to be phenolic acetates. Alkaline hydrolysis of this triacetate gave demethylaspidocarpine (L), which was shown to be a catechol by the ferric reaction (blue-green passing t o deep-red in the
XLIII
Ri
__ LII Me LIII Me X L V I I Me XLVI Me XLV Me LIV Me LV Me
THB*
XLVIII
XLIV It2
It3
H H
H EtCO H
Me
Me
Ac Ac
EtCO
Ac Ac
EtCO EtCO
14. Aspidosperma
AND RELATED ALKALOIDS
403
presence of sodium carbonate), and by the strong bathochromic shift of the UV-spectrum in the presence of boric acid buffered with sodium acetate (30, 46). Aspidocarpine derivatives were found to couple with diazotized sulfanilic acid when either the C-17 OH or N, was unsubstituted but not when they were both substituted; this was used as evidence that positions 14 and 15, para t o these groupings, were unsubstituted. Finally, proof was obtained that the aliphatic portion of the aspidocarpine molecule was identical with the correspondingportion of aspidospermine by oxidation of the two compounds with chromic acid in dilute sulfuric acid. In both cases, the aromatic ring was destroyed and there was isolated the a-keto amide (LI), mp 224"-225", [ C L ]-~ 132" (chloroform). The identity of this oxidation product shows not only that aspidocarpine (XLIV) and aspidospermine (11) have an identical skeleton but also that they have the same absolute configuration at all four centers. Aspidocarpine has also been found in other Aspidosperma species (Table I) while demethylaspidocarpine (L) has been isolated from A . album (42).
J. ASPIDOLIMINE Aspidolimine (LIII) is one of the main constituents of the bark of A . limae, where it occurs together with a number pf other alkaloids (Sections11, F, I and IV, B ;Refs. 31,40). It is also foundin A. triternatum (47). The IR- and UV-spectra are practically identical with those of aspidocarpine (XLIV), although elementary analysis and the mass spectrum (molecular ion peak at m/e 384) show it to contain one CH2 group more than that alkaloid. Examination of the NMR-spectrum (31) shows that there is an N,-propionyl group present (N-COCHzCH3 quartet at 2.57 6, J = 7 c/sec; N-COCHZCH~ triplet at 1.25 6 , J = 7 cjsec) while the N,-acetyl three-proton singlet shown by aspidocarpine (Section 11,I) is absent. It was reasonable to suppose that aspidolimine (LIII) was the N,-propionyl analog of aspidocarpine, and this was readily shown t o be true both chemically (31) and by examination of the mass spectrum (40). Vigorous acid hydrolysis of the alkaloid gave depropionylaspidolimine (LII), which without isolation was acetylated to give 0-acetylaspidocarpine (XLV). Similar hydrolysis of aspidocarpine (XLIV) and propionylation of the product gave 0-propionylaspidolimine (LV). The mass spectrum of aspidolimine shows all of the characteristic peaks of the aspidospermine group alkaloids (Section 11, D, Table V). In addition to M+ and M-28, peaks are found at M-56 (loss
404
B. GILBERT
of the propionyl group and pick-up of one hydrogen) and at M-84 [M-(56+28)]. The strongest peak of the spectrum is found at m/e 124 (fragment c ) ,and the peaks due to fragment b and homologs are found at m/e values 16 mass units higher than in the spectrum of aspidospermine, corresponding to the extra oxygen atom in the aromatic ring.
K. PYRIFOLIDINE AND DEACETYLPYRIFOLIDINE ( - )-Pyrifolidine (XLVI) has already been mentioned as a constituent of A. quebrachoblanco (Section 11,E) and as the product of methylation of aspidocarpine (Section 11, I). Dextrorotatory pyrifolidine and its ( + )-deacetyl derivative (XLVII) occur in Aspidosperma pyrifolium (49,56).At the time of isolation, the levorotatory compound (XLVI)was not known. The UV-spectrum (Table 111) is somewhat different from those of known N-acyldihydroindoles. The NMR-spectrum, however, not only confirmed the presence of two methoxyl groups and an N-acetyl function already detected by functional group analysis, but showed that the compound belonged to the aspidospermine group (9, 10). The C-2 proton quartet at 4.50 6, CHzN-CHz multiplet at 3.31-2.90 6, and the side chain terminal methyl absorption at 0.67 6 were all placed exactly as found in the spectrum of aspidospermine. Elementary analysis and the integrated proton count showed that the empirical formula was C23H32N203, differing from aspidospermine by CH20, equivalent to the addition of the extra methoxyl group known t o be present. The presence of only two aromatic protons occupying adjacent positions on the benzene ring was shown by a two-proton quartet with J = 8.2 c/sec, and this shows that both methoxyl groups are aromatic and must be in one of the three orientations, LVIII, LIX, or LX. Biogenetically, LVIII and LIX with a methoxyl at C-17 were attractive. Of these, LVIII with the other methoxyl at C-14 was the less likely, as this group would be expected t o alter the NMR aliphatic “fingerprint” region which is in fact almost superimposable upon that of aspidospermine (11). Conclusive evidence that the aliphatic portion of the pyrifolidine molecule was in fact identical with that of aspidospermine (11)was obtained from the mass spectra of their deacetyl derivatives (XLVII and VI, Table V). These proved to be identical, save only in the shift of 30 units observed in the peaks attributable to fragments containing the aromatic nucleus, this shift being due to the extra aromatic methoxyl group. Finally, direct comparison of ( + )-pyrifolidine with ( - )-@methylaspidocarpine (XLVI) and of their respective deacetyl derivatives
14. Aspidosperma
AND RELATED ALKALOIDS
405
(XLVII) showed complete identity by IR-spectra and by chromatography, while the rotatory dispersion curves of ( + )-XLVI and ( - )XLVI were mirror images of one another, demonstrating that the two compounds were enantiomeric at all four centers. Pyrifolidine is thus one of a small group of indole alkaloids which exist in both enantiomeric
+ )-XLVII;R = H (+)-XLVI; R = AC (
VI; R = H 11; H. = AC
forms ; others are quebrachamine (I),vincadifformine (XCIII, 6, 74), akuammicine (CCXXV, 7 7 ) , guatambuine (CCLX, 147), and vincanorine (CCCXLII, 78). It is noteworthy that these alkaloids either contain only one asymmetric center or could have been formed from a precursor with only one center by a concerted reaction in which the configuration of the remaining centers might depend on that of the original. AND SPEGAZZINIDINE L. SPEGAZZININE
Evidence presented earlier (Volume VII, p. 132) led to the proposal of partial structure LXI (34) for spegazzinine and the suggestion was made that the molecule had the aspidospermine skeleton. This has subsequently been shown to be correct, but the evidence was obtained by a study of the related alkaloid spegazzinidine (LXIX). Both alkaloids occur in Aspidosperma chalensis, the proportion of each present having been found to vary with different specimens of the plant (35, 36). Spegazzinidine (LXIX) was shown by elementary analysis to be CzlHzsNz04, the number of hydrogens being confirmed by the mass spectral molecular weight determination. Its UV-spectrum resembles
406
B. GILBERT
that of spegazzinine (LXIV) and is of the aspidospermine type (Table 111).A bathochromic shift in alkaline solution similar to that shown by spegazzinine showed that it was also a phenolic base, and a carbonyl peak a t 6.13 p indicated the presence of the usual N-acyl function. The NMRspectrum of spegazzinidine (LXIX) confirmed the expected similarity to aspidospermine (11),exhibiting the characteristic CHz-N-CHz pattern, the N,-COCH3 methyl singlet, and the side chain terminal methyl absorption at 0.75 6. I n the aromatic region, a quartet due to two ortho protons, similar t o that of pyrifolidine (Section 11,K) was observed, while absorptions due t o two phenolic hydroxyl protons appeared, one a sharp singlet at 11.1 6 characteristic of a hydrogen-bonded hydroxyl in position 17, the other a broader band a t 5.84 6 due to a non-hydrogenbonded OH. Methylation of spegazzinidine (LXIX) with dimethyl sulfate (cf. aspidocarpine, Section II, I ; note that the alcoholic hydroxyl as well as N,, are unaffected) gave spegazzinidine dimethyl ether (LXX) whose NMR-spectrum now closely resembled that of pyrifolidine (XLVI). One striking difference existed between the NMR-spectra of spegazzinidine and its methyl ether on the one hand and aspidospermine and pyrifolidine on the other. This lay in the absorption due t o the C-2 proton which in the latter two alkaloids appears as a quartet, while with spegazzinidine and its methyl ether only a doublet is observed. This indicated that there was only one hydrogen atom a t C-3 and, as spegazzinidine dimethyl ether (LXX) still showed hydroxyl absorption in the IR-spectrum, it was reasonable to suppose that C-3 carried an alcoholic hydroxyl group. To confirm this, LXX was oxidized with chromium trioxide (50) to the ketone, 3-dehydrospegazzinidine (LXXI),in whose NMR-spectrum the doublet previously observed had disappeared and been replaced by a singlet a t 5.11 6. This observation is only consistent with a secondary alcoholic group having been present at C-3,and the further downfield shift of the C-2 proton peak in LXXI is caused by the adjacent carbonyl group (36). Independent evidence for the position of the carbonyl group in this ketone was obtained by exhaustive deuteration with sodium deuteroxide in DzO-CH~OD, when mass spectrometry showed that six deuterium atoms had entered the molecule (molecular ion raised from m/e 398 t o m/e 404). Three of these were in the acetyl group, since the m/e 4 3 peak (CH&O+) was shifted t o m/e 46 (CD&O+), and therefore three had entered a to the ketonic carbonyl (LXXII ; note that LXXIII is a by-product of the deuteration reaction). Only two positions in an aspidospermine skeleton have three a-hydrogen atoms-positions 3 and 20. The latter position is excluded by the NMRspectrum, and the carbonyl group is therefore at (2-3. Detailed study of the mass spectra of LXXI and its hexadeuterio derivative confirmed
14. Aspidosperma
AND RELATED ALKALOIDS
407
these findings (35, 36), although it should be noted that the 3-ketone does not, in contrast t o a 4-ketone (36, 4), fragment in the manner characteristic of aspidospermine (11) and its derivatives. Rather, it loses first the carbonyl group as CO, a behavior observed in other cyclic ketones (20, 21). The foregoing arguments have been based on the assumption that spegazzinidine has in fact the same skeleton as aspidospermine (11).That this is true was established in two ways. First, in the mass spectrum of spegazzinidine (LXIX) and of its dimethyl ether (LXX) the principal peaks are observed a t m/e values exactly coinciding with the calculated molecular weights of the fragments a, b, and c and their homologs that would be expected for a molecule with the aspidospermine skeleton but carrying two hydroxyl or, respectively methoxyl groups on the aromatic ring (Table V). It will be noted that the C-3 and C-4 atoms are not present in any of the aforementioned fragments. The nonappearance of the alcoholic oxygen, whose position has been proved, in these fragments has been cited (Section 11, D) as evidence that the C-3 and C-4 atoms are those initially lost in the breakdown of aspidospermine-type molecules under electron bombardment. This breakdown, which normally results in the loss of ethylene and the formation of the M-28 peak common to the spectra of most alkaloids of this group, results in the loss of vinyl alcohol, CHOH=CHz, or its equivalent, and the formation of an M-44 peak in the spectra of LXIX and LXX, which is raised t o M-45 when the alcoholic proton is replaced by deuterium. Second, direct chemical proof of the aspidospermine skeleton was obtained by conversion of spegazzinidine dimethyl ether (LXX) to its tosylate (LXXIV) which on reduction with lithium aluminum hydride gave ( - )-N,-deacetyl-N,-ethylpyrifolidine(LVII) identical, except for direction of rotation, with the product, ( + )-N,-deacetyl-N,-ethylpyrifolidine (LVII),obtained by a similar reduction of ( + )-pyrifolidine (XLVI). Since ( + )-pyrifolidine is antipodal to aspidospermine (Section 11, K), spegazzinidine has the same absolute configuration as aspidospermine (36). Finally, the coupling constant (J = 8 cjsec) observed €or the C-2 proton doublet in the NMR-spectrum of spegazzinidine shows that the C-2 and C-3 hydrogens are situated trans-diaxial with respect to one another. The C-3 hydroxyl group is therefore a-equatorial. A comparison of the NMR- and mass spectra of spegazzinine (LXIV) and it methyl ether (LXV) with those of spegazzinidine (LXIX) and its dimethyl ether (LXX)showed that the parent alkaloids differed only by the absence of the C-16 hydroxyl group in spegazzinine and of the C-16 methoxyl group in its methyl ether. In particular, the 5.84 6 signal due
!+
0 00
LXI
LXII LXIII LXIV LXV LXVI LXVII LXVIII
H H H Ac Me Ac Me Ac Me Ac Ac Ac
H Me
H
H H H Ac PhCO Ac
,/ RO LXIX
/
Ac a (M-44)
from LXIX; R = H fromLXX; R = Me
from LXIX; R = H from1,XX; R = Me
14. Aspidosperma AND RELATED ALKALOIDS
409
410
B. GILBERT
to the non-hydrogen-bonded phenolic grouping in LXIX is absent from the NMR-spectrum of spegazzinine, which shows absorption due to three aromatic protons, while in its mass spectrum the fragments a and b and relatives containing the aromatic ring appear a t m/e values 16 mass units lower (i.e., less one oxygen atom) than in the spectrum of spegazzinidine (LXIX). Similarly, a corresponding lowering of 30 mass units (CHzO) is observed when the spectra of spegazzinine methyl ether (LXV) and spegazzinidine dimethyl ether (LXX) are compared, all other peaks appearing at identical m/e values. I n accordance with previous experience (Section 11, D), therefore, spegazzinine may be allocated structure LXIV.
M. CYLINDROCARPINEA N D CYLINDROCARPIDINE Cylindrocarpine (LXXV) and cylindrocarpidine (LXXVI) occur in the trunk bark of Aspidosperma cylindrocarpon, and the former was first isolated by way of its crystalline perchlorate (49). The IR-spectrum of cylindrocarpine showed the presence of an ester (Aco, 5.79 p ) as well as an amide (A,,,, 6.06 p ) grouping, while the UV-spectrum showed the presence of a chromophore different from that of aspidospermine (11) and its relatives (Table 111).The integrated NMR-spectrum supported the empirical formula, C ~ O H ~ ~ Nand ZO confirmed ~, the presence of two methoxyl groups detected by functional group analysis. Preliminary chemical studies elucidated many features of the structure, leaving only the exact nature of the aliphatic portion of the molecule unknown. I n particular, hydrogenation gave dihydrocylindrocarpine (LXXVII) whose UV-spectrum was now superimposable on that of aspidospermine (11),showing that the molecule contained the N-acyl- 17-methoxydihydroindole nucleus. Alkaline hydrolysis of both cylindrocarpine (LXXV) and dihydrocylindrocarpine (LXXVII) cleaved only the ester grouping and gave the corresponding acids, cylindrocarpic and dihydrocylindrocarpic acid, as their hydrochlorides (LXXVIII and LXXIX, respectively). The latter was reesterified with diazomethane regenerating dihydrocylindrocarpine (LXXVII), proving that cylindrocarpine contains a carbomethoxyl group, and accounting for the second methoxyl group. I n order t o elucidate the nature of the AT,,-acylgrouping, both cylindrocarpine (LXXV) and its dihydro dcrivative (LXXVII) were hydrolyzcd with hydrochloric acid to cleave the amide as well as the ester grouping. I n both cases, cylindrocarpinic acid dihydrochloride (LXXX) was obtained, and from the nonbasic fraction were isolated,
14. Aspidosperma
AND RELATED ALKALOIDS
41 1
respectively, cinnamic and dihydrocinnamic acids. The unusual UVspectrum of cylindrocarpine is therefore simply a superimposition of the N-acyldihydroindole and cinnamoyl chromophores. The UV-spectra of cylindrocarpinic acid (LXXX, free amino acid) and deacetylaspidospermine (VI) in neutral and acidic media are practically identical, showing the characteristic reduction of wavelength and intensity on protonation of N, (Table Ill).This is in accordance with the presence of identical chromophores in both compounds. The preceding experiments cast no light on the nature of the aliphatic carbon skeleton, but examination of the NMR-spectrum showed that this was similar t o that of aspidospermine (11).In particular, the characteristic absorption due to the C-2 proton was found at 4.4S and those due to the CHz-N-CHz protons at 3.31-2.90 6, while in the absence of an N-acetyl peak the singlet due t o the isolated C-19 hydrogen atom is plainly visible. No side chain terminal methyl group absorption was observed and, assuming an aspidospermine skeleton, the carbomethoxy group could be provisionally placed in that position ((3-21). I n the aromatic portion of the spectrum, not only were the expected eight aromatic protons detected, but also two doublets with J = 16 cjsec due to the trans-cinnamic vinyl protons. It remained t o convert cylindrocarpine (LXXV) t o a known aspidospermine derivative. This was achieved by elimination of the carbomethoxy and cinnamoyl groups in the following manner. Cylindrocarpine (LXXV) was reduced with lithium aluminum hydride to a mixture of the y-phenylpropyl compound (LXXXI.) and dihydrocylindrocarpol (LXXXII). The latter, separated by chromatography, was oxidized with chromic acid in acetic acid t o the corresponding aldehyde, dihydrocylindrocarpal (LXXXIII),which by Wolff-Kishner reduction gave the known deacetylaspidospermine (VI).Cylindrocarpine can therefore be given the structure LXXV. Cylindrocarpidine, C23H30N204, the minor alkaloid of A . cylindrocarpon, was suspected from its NMR-spectrum (Table IV) t o be the N,-acetyl analog of cylindrocarpine (LXXV) since the absorption pattern was almost identical, except in that no peaks were seen corresponding to the cinnamoyl group, these being replaced by a threeproton singlet at 2.22 6 due t o an N-acetyl group. Confirmation was obtained by acid hydrolysis which gave cylindrocarpinic acid dihydrochloride (LXXX) and acetic acid (44),and the structure of cylindrocarpidine is therefore represented by the expression LXXVI (10, 29). The LXXX obtained had rotation identical with that from cylindrocarpine (LXXV) and consequently these two alkaloids have the same absolute configuration. That this is the same as that of aspidospermine
412 B . GILBERT
14. Aspidospermu AND RELATED ALKALOIDS
T
413
4 14
B. GILBERT
(11)was shown by the similarity in sign and shape of the ORD-curves of cylindrocarpidine and aspidospermine ( 10). Although the structures of these two alkaloids were proved without recourse to mass spectral measurements, spectra have subsequently been determined for the derivatives N-decinnamoylcylindrocarpol (LXXXIV), its O,N,-diacetyl derivative (LXXXV), and N-decinnamoyl-N-ethylcylindrocarpol (LXXXVI). All three show the expected pattern with peaks corresponding to a, b, and c fragments and their homologs as observed for other aspidospermine-type alkaloids (Section 11,D). It should be noted, however, that due to the extra oxygen atom in LXXXIV and LXXXVI and the acetoxy group in LXXXV the c peak appears a t m/e 140 in the first two cases and a t m/e 182 in the last instead of a t m/e 124 as in aspidospermine (52).
N. LIMASPERMINE AND RELATED ALKALOIDS Limaspermine, C~zH30N203,occurs in A . lirnae and was separated from the accompanying aspidolimine (LIII) and aspidocarpine (XLIV) by silica gel chromatography ( 33; see Section 11,J).I t s red-violet ceric sulfate reaction after heating was typical of an N-acylindoline and this was confirmed by the UV-spectrum (Table 111)which resembled that of demethylaspidospermine (XXXVII, 2 5 ) , showing the same bathochromic shift in alkaline solution (40a) which is attributable to the presence of a phenolic hydroxyl group. The presence of an amide group was confirmed by IR-absorption a t 1631 em-1, the low frequency of this peak indicating chelation with a hydroxyl group, which itself absorbed as a broad band, and it was therefore reasonable t o place the phenolic OH a t position 17. The nature of the amide group was elucidated by acid hydrolysis which gave propionic acid, and the third oxygen atom was accounted for by acetylation which gave 0,O-diacetyllimaspermine (LXXXVIII), which absorbs a t 1764 em-1 (phenolic acetate) and 1734 em-1 (alkyl acetate), thus indicating the presence of an alcoholic as well as a phenolic hydroxyl in limaspermine (LXXXVII). The foregoing information suggested a 17-hydroxy-N-propionylindoline structure, and this was fully confirmed by the NMR-spectrum (Table I V ) which showed the presence of three aromatic protons and a hydrogen-bonded phenolic hydroxyl group (singlet at 10.58 6). More important, the portion of the spectrum due to aliphatic protons was very similar to that of aspidolimine (LIII), except that no peaks were found that corresponded to a methoxyl group or a terminal methyl of an ethyl side chain. Other characteristic features of the aspidospermine (11)
14. Aspidosperma
415
AND RELATED ALKALOIDS
skeleton (29) such as the C-2 quartet a t 4.12 6 and the CH2--Nb-CH2 multiplet at about 3.0 6 were present, while the quartet and triplet due respectively to the methylene and methyl groups of N-propionyl were in the same positions as for aspidolimine (LIII). The absence of the side chain C-methyl and the presence of a triplet at 3.25 6 clear of other absorption, which is shifted downfield to 4.0 6 (overlapping the C-2 proton quartet) in the spectrum of the diacetate (LXXXVIII), show that the alcoholic hydroxyl group is primary and suggest that it is in
.
LXXXVII
LXXXVIII LXXXIX
I
xc
XCI
U
b
HH Me0 Me0
C
Ac H H
H
.
EtCO
Ac
Ac EtCO
Ac
H H H
c
position 2 1 of an aspidospermine-type molecule. The structure LXXXVII thus deduced for limaspermine is fully confirmed by its mass spectrum (Table V). Peaks are found corresponding t o the usual a, b, and c fragments, that due to c being, as is normal, the strongest peak of the spectrum. Its position (m/e 140) indicates that it contains the alcoholic oxygen atom which therefore must be in position 21. The a , or M-28, peak (m/e 342) is relatively weak, but is accompanied by a much stronger peak at m/e 324 due to loss of water, and by other smaller peaks a t m/e 267 (further loss of the propionyl group) and m/e 311 (a- CH2OH). Peaks due to loss of water and of CHzOH are also found accompanying c a t m/e 122 and 109, respectively, while a peak at m/e 110 is attributed
416
B. GILBERT
to loss of CH20 by a cyclic mechanism (c to c') (33, 54). Among the minor bases of A . limae there have also been isolated three other C-21 alcohols, the 16-methoxy derivative of limaspermine (XCI, 33), 1'imapodine (N-depropionyl-N-acetyllimaspermine,LXXXIX), and its 16-methoxy derivative, XC (120). The fact that other 17-hydroxy-N-acylindolinesof the ( - )-aspidospermine series have positive rotations of the order of 100" indicates that limaspermine ([ E]D + 108" in chloroform) and XCI ([ .IU + 118" in chloroform) also belong to this configurational group (54a). This has been confirmed by interrelation with haplocine (CCI-D) and ( - )-palosine (XXXIX, Section IV, D, 113c),and with cylindrocarpine (LXXV, 120).
0. TABERSONINE Tabersonine (XCII), a n amorphous base which occurs in the seeds of Amsonia tabernaemontana (65, Volume VII, p. 134), in some Xtemmadenia species (66,66a),and in Tabernaemontana alba (sea),is a member of a distinct group of aspidospermine-type alkaloids which bear an extra carbon atom in the form of a carbomethoxyl group linked t o position 3. The other members of this group are described briefly in Section 11, P and in detail in Chapter 12. The UV-spectrum (64, Table 111) and high negative rotation ([ED] - 310" in methanol) of tabersonine hydrochloride (64, 65) indicated at once that the alkaloid contained the same chromophore as akuammicine (CCXXV) and echitamidine (CCXLII, Chapter 8 ) , and this chromophore was subsequently shown (Volume VII, p. 127) to be Ph-NH-C=C-C02R. The NH (2.95 p ) and a$-unsaturated carboxylic ester bands (6.02 p and 6.2 p ) were also seen in the IR-spectrum. The NH group was not acetylated under usual conditions and the ester group was musually resistant t o hydrolysis (64). Examination of the mass spectrum (Table V, 7) showed that the correct molecuJar formula was C21H24N202, excluding a C20 akuammicine-like skeletm, and peaks a t m/e 92, 107, and 135 were similar to those encountered in vindolinine (CVI, 3) which has an aspidosperminelike skeleton with 6,7-doublebond. The presence of such a nonconjugated double bond had already been shown by catalytic hydrogenation t o 6,7-dihydrotabersonine (XCIII, an optically active form of vincadifformine which has identical IR-, NMR-, and mass spectra) in which the UV-spectrum remained similar to that of the parent alkaloid (64, 7 ) . Moreover, the NMR-spectrum of tabersonine (XCII) showed a peak due to two vinyl protons which disappeared in the dihydro derivative
14. Aspidosperma
417
AND EELATED ALKALOIDS
IX-A
T
4s HCI 110”
T
xcv KBHI OH-
418
B. GILBERT
(XCIII), so that the double bond is disubstituted. The NMR-spectrum also showed the presence of four aromatic protons (consistent with a strong IR-band a t 13.5 p ) , and an NH and a C-ethyl group. The presence of a very strong mje 124 peak (fragment c ) in the mass spectrum of 6,7dihydrotabersonine (XCIII) indicated that the C-ethyl group probably formed part of an ethylpiperidine ring in an aspidospermine-type framework (7). The aspidospermine-type skeleton was then confirmed in two ways. First, tabersonine (XCII) was converted to ( + )-quebrachamine (I)by two independent routes. One involved reduction of the 6,7-double bond followed by strong acid hydrolysis, which removes the carbomethoxyl group, completely shifting the double bond t o the 1,2-position, a reaction known for the other vinylogous amides, akuamniicine (CCXXV, 70) and fluorocurarine (67). The resulting indolenine (IX-A) is the optically active form of decarboniethoxyvincadifformine (superimposable IRand mass spectra, see Chapter 12) and is possibly the antipode of 1,2dehydroaspidospermidine (IX). The former (IX-A) was converted by alkaline borohydride t o ( + )-quebrachamine, an example of the retrograde Mannich reaction and reduction already known in the akuammicine series (19, Section 11, A, and Chapter 7). The same series of reactions, carried out in a different order, gave successively decarbomethoxytabersonine (XCIV), 6,7-dehydro-(+ )-quebrachamine (XCV), and ( + )-quebrachamine (I). These conversions establish the stereochemistry of C-5 in (-)-tabersonine (XCII) as opposite t o that of ( - )-aspidospermine (11). A second proof of the skeleton of tabersonine as represented by XCII was obtained by examination of the mass spectra of the four reduction products XCVI, XCVII, XCVIII, and XCIX. I n all these compounds, the 2,3-double bond has been reduced, thus permitting the normal aspidospermine-type fragmentation in the mass spectrometer. The reduction of this double bond without affecting the isolated 6,7-double bond may be effected either with zinc and acid (cf. 68) which gives 2,3-dihydrotabersonine (XCVI), or with lithium aluminum hydride which gives chiefly 2,3-dihydrotabersonol (XCVII) (64) and its deoxy derivative [XCVIII, 7, contrast the reduction of akuammicine which gives the 3-methylene derivative (68, 69), a difference which, together with NMR-spectral changes, may be due to conformational or even stereochemical differences from aspidospermine]. Compounds XCVI and XCVII now showed typical indoline UV-spectra (64, 7, Table 111)and the N,O-diacetate (C) of 2,3-dihydrotabersonoI showed a typical AT,acylindoline spectrum (64). The mass spectra showed the expected peaks a t m/e 252 (a‘) and 122 (c’, accompanied by m/e 121 ; compare
14. Aspidosperma
AND RELATED ALKALOIDS
419
vindolinine, Ref. 3) in which the reduction of two mass units as compared with the spectrum of aspidospermidine (m/e 254 and 124,Ref. 28) results from the presence of the 6,7-double bond. I n all three cases the C-3 substituent had been expelled together with C-3 and (3-4. Catalytic reduction of 2,3-dihydrotabersonol (XCVII) gave the fully reduced tetrahydrotabersonol (XCIX, an optically active form of dihydrovincadifforminol) which showed mass spectral peaks a t m/e 254 and 124 corresponding to the expected fragments a and c. It remained only to locate the nonconjugated double bond. This must be in the D ring, for it appears in fragment c’ (above) and, as it is not
COzMe C V I ; R = COzMe CVI-A; R = H, 6,7-dihydro
CIII; R = Me CIV; R = CHO CXIII; deacetyl-CIII
attacked by potassium borohydride (XCIV to XCV) or by zinc and sulfuric acid (XCII to XCVI), it cannot be adjacent to nitrogen ; positions 6,7are thus the only ones left for a disubstituted double bond.
P. Vinca ALKALOIDS OF
THE
ASPIDOSPERMINE GROUP
A number of alkaloids with the aspidospermine skeleton occur in the genus Vinca and are dealt with in detail in Chapter 12.They include the very important base vindoline (CIII) which not only occurs as the free base in Vinca rosea ( = Lochnera rosea = Catharanthus roseus) but also as part of the dimeric alkaloids vinblastine (vincaleucoblastine) and leurosine, whereas the N,-formyl analog, CIV, forins part of the dimeric alkaloid leurocristine ( 5 , 72a). These dimeric alkaloids have been used successfully for the treatment of certain forms of cancer in man (5). Vindolinine (CVI) has also been isolated from V . rosea and its dihydrodecarbomethoxp derivative, tuboxenin (CVI-A), which is the parent member of the series, occurs in a Pleiocarpn species (53). ( f )-Vineadifformine (XCIII, 6, 74)has already been mentioned as the racemic form of ( - )-6,7-dihydrotabersonine(Section 11, 0). It has been found in V . difformis and in Rhazya stricta (51b)where the ( + ) form also occurs.
420
B. GILBERT
The ( k ) and ( - ) forms have been found in V . minor, where it is accompanied by four other alkaloids of similar skeleton, minovine (CVIII, 74a), minovincinine (CVII), minovincine (CIX), and 16-methoxyminovincine (CX) ( 3 2 , 7 3 , 74a, 76). The mass spectra of some of these alkaloids and of their derivatives CI, CII, and CXIV-CXVI have been included in Table V where useful for purposes of comparison ( 7 5 ) .
Ri Rz XCIII H H CVII H O H C V I I I Me H
Ri Rz CI H COzMe CII CH3 H CXIV H CHzOH CXV H CH3 C X V I OMe CHzOH
CIX; R = H CX; R = O M e
R3 H H OH OH OH
111. The Aspidofractinine Group
A. INTRODUCTION This group of mainly hexacyclic alkaloids is derived from the aspidospermine skeleton by closure of C-21 with C-2, the original ethyl side chain thus forming a new six-membered ring. Aspidofractinine has been chosen as the parent member as it bears no substituent in the aliphatic portion of the molecule. The oldest known member, kopsine, isolated in the last century, differs from the others in being heptacyclic, C-3 being linked to (2-11 by a one-carbon bridge. The extraordinary cage structure of this group of alkaloids with quaternary centers a t C-2, C-5, and C-12
14. Aspidosperma
42 I
AND RELATED ALKALOIDS
is not susceptible to ordinary chemical degradative methods, and the present evidence for the skeleton therefore rests mainly on physical evidence. The group is a t present limited to four genera of the family Apocynaceae, namely, Aspidosperma, Hunteria, Kopsia, and Pleiocarpa.
B. INTERCORRELATIONSAND SKELETAL STRUCTURE I n the case of the aspidospermine group (Section 11),the nature of the carbon skeleton was elucidated for aspidospermine only, the structures of the ‘other members of the group following by correlation with this alkaloid, either directly or mass spectrometrically. Although mass spectrometry alone suggested the structure CXVII for the skeleton of some Aspidosperma alkaloids, the final proof of CXVII rests on both
CXVII
CXIX
cxx
4 stages
CXXXVI
CXXXIX
physical and chemical evidence obtained in simultaneous work in a number of laboratories on diverse alkaloids. This evidence is brought together in the sequel. The validity of such evidence for alkaloids other than the one under study depends on intercorrelation and this has been largely achieved. Pyrifoline (CXIX) has been related t o refractidine (CXX) by the mass spectral comparison of the alkaloids and a series of derivatives, and to aspidofiline (CXXXVI) by mutual conversion to a common intermediate (CXXXIX). Aspidofractine (CXLIII-A), which has been mass spectrally related to refractine (CL-A),is readily converted
422
B. GILBERT
H6
COzMe CL-A
CLXXXIV
CLXX
i
3 stages
&zMe CXLIII-A
R
COzMe CXLII-A LiAlHd
COzMe CXLVI-A
CXLII-D +
CH~OH CXLII-F
~ H ~ O H CXLVI-F
.
I
4 stages
COzMe CXLV-A
14. Aspidosperma
AND RELATED ALKALOIDS
42 3
to its deformyl derivative kopsinine (CXLII-A) and the corresponding alcohol, kopsinyl alcohol (CXLII-F).These two compounds have in turn been related chemically to kopsinilam (CXLII-D), pleiocarpine (CXLV-A), and kopsine (CLXX). Pleiocarpine (CXLV-A) has further been interrelated with pleiocarpinine (CXLVI-A) and pleiocarpinilam (CXLVI-D) through the common intermediate N-methylkopsinyl alcohol (CXLVI-F). It remains to convert a member of the kopsinine group to a member of the aspidofiline group unsubstituted on C-3. 1. Number of Rings
The hexacyclic nature of the alkaloids, except kopsine, follows from accumulated analytical data, together with precise molecular weight determination by mass spectrometry, which indicate that apart from the dihydroindole moiety there are four other rings or double bonds. The absence of vinyl protons in the NMR-spectra of the bases and the fact that vigorous hydrogenation reduced only the benzene ring showed that only a hindered tetrasubstituted double bond could be present. Such a grouping was excluded by later evidence which demonstrated the presence of three quaternary centers ; therefore, the aliphatic part of the alkaloids contains four rings and the molecules are hexacyclic. Similar methods showed that kopsine is heptacyclic. 2 . General Evidence f r o m Mass Spectrometry
The mass spectra of many alkaloids and their derivatives in this group have been measured and the principal peaks are recorded in Table V (80, 81,82,95, 102). It is readily seen that a common skeleton is probable for all except kopsine and relatives, since the main differences observed are due only to peripheral substituents (RI-R~in structure CXVIII). A general similarity of the spectra to those of aspidospermine (11) and its derivatives is seen in the universal presence of an M-28 peak and usually of a peak a t m/e 124 which is modified only in the two alkaloids pyrifoline (CXIX) and refractidine (CXX) which bear a D-ring substituent, but which is otherwise invariable no matter what modifications are made in the indolic part of the molecule or to the C-3 carbomethoxyl group. The principal difference from the aspidospermine-type cleavage is seen in the fact that the main piperidine-containing peak is usually not c but a peak 15 mass units smaller, that is, normally a t m/e 109. Coupled with the NMR-spectral evidence that these alkaloids contain no G-ethyl side chain and no C-2 proton (absence of characteristic absorption a t 0.65-0.70 6 and 4.0-4.5 a), it is reasonable to postulate an aspidospermine skeleton in which the side chain is tied into a sixth ring terminating a t C-2, and t o propose the breakdown illustrated in the formulas, in which the cleavages
42 4
B. GILBERT
involved are favored ones (Section 11, D). Evidence has been obtained for the correctness of the structures allocated t o the various fragments h-p in a manner similar to that already described in Section 11, D. Metastable peaks have been observed corresponding, for example, to the decompositions, h t o i (at mje 41.5 for CXXXV and m/e 45.2 for CXLII-0) and M+ to c (at m/e 52.5 for CXLII-0). Fragment h always arises by loss of the unsubstituted bridge, C-21, C-20, in the cases where C-3 carries a substituent, and therefore it always appears at M-28. That h contains C-3 is shown by its molecular weight, which accompanies variations in the R3 group, and deuteration on (2-3. Fragment i contains carbon atoms 10,6 and 7 , for when these are substituted the position o f i in the mass spectrum moves appropriately. Thus, in CXVII and CXXXIX, i appears at mje 109, but in 3',3', 10,iO-tetradeuterio-N-trideuteriomethylkopsinyl alcohol (CXLVIII-G from LiAlD4 reduction of pleiocarpine lactam A) i is shifted to in/e 111 and that this shift is due to the C-10 deuterium atoms is shown by the invariability of i when R1, Rz, and R3 are modified in other molecules. When position 6 is substituted by OH, OMe, or =0, corresponding shifts are observed in the mass of i (series N,-rnethyl-(i-deformyl-6-demethylrefractidine,CXXXI; deformylrefractidine, CXXII; and deformyl-6-dehydro-6-demethylrefractidine, CXXXV; see Table 77) and deuteration of C-7 results in a shift of two units in the position of i (see pair, deacetyl-6-dehydro-6demethylpyrifoline, CXXXIII, and its 1,7,7-trideuterio derivative, CXXXIV in Table V). Evidence for the position of these substituents will be described in the sequel. These same carbon atoms are also found in fragment c which accompanies i in all the above changes. That the ethyl chain of c contains C-20 and C-21 and not C-4 and C-3 follows from its constant value, no matter what modifications are made to the substituent on C-3. The extra hydrogen atom that fragment c carries on C-21 does, however, come from C-3 as is shown by its increase by one mass unit when the C-3 hydrogen atom is replaced by deuterium (pair, N,-methyldeforniylnorrefractinol, CLI-Q and N,-dideuteriomethyldeformyl-3-deuterionorrefractinol, CLII-Q, obtained by the LiAlH4 and LiAID4 reduction, respectively, of the corresponding ketone). The transfer of hydrogen to C-21 by the mechanism pictured in the formula is only possible when the C-3 proton is and close t o C-21, as is the case in the naturally occurring alkaloids of the kopsinine-refractine type and their derivatives produced without epimerization. In the 3-is0 series of epimerized alkaloids and their derivatives, this proton is c( and its distance from C-21 precludes its transfer, in accordance with which is the absence of fragment c from their spectra. (Small c peaks sometimes observed have been attributed to contamination with nonepirnerized material, and to
14. Aspidosperma AND
425
RELATED ALKALOIDS
m
Ri CXVII CXXII CXXXI CXXXIII CXXXIV
cxxxv
CXXXVI CXXXIX
Rz R3
RI
R4
H H H H H OMe H Me H O H OMe H H =O OMe D H =0, i, Dz H H H = O OH Ac H H OMe H H H
H H
CXLII-F CXLII-G CXLII-0 CXLV-D CXLVI-D CXLVIII-G CLI-Q CLII-Q
M P
~
H H
H H
H
H OMe OMe
Rz H H H COzMe CH3 CDJ CDzH
R3
CHzOH CDzOH Me COzhlc CO&Ie CDiOH H,OH D,OH =CHz
=O
R4 H H H H , 10, =O H, 10, =O H, 10,Dz H H H H
426
B. GILBERT
check this, epimerization was conducted with NaOD in deuteriomethaiiol SO that the epimerized C-3 hydrogen would be replaced by deuterium, leaving the unepimerized C-3hydrogen unchanged. I n accord with expectation, no trace of deuterium transfer was observed.) The proximity which is necessary for this transfer is also illustrated by the lower relative intensity of the c peak in C-3 unsubstituted alkaloids such as aspidofiline (CXXXVI), refractidine (CXX), and pyrifoline (CXIX) where there is no sterically hindered bulky C-3 substituent to push C - 3 over toward the 21-20 bridge. Transfer of a hydrogen atom t o fragment i is also often observed, in molecules substituted on C-3, to produce a peakj a t m/e 110. I n cases where the C-3 substituent atom, C-3' or 0, carries an a-hydrogen atom, this is the proton transferred, as is shown by replacement by deuterium when j moves to m/e 111 (pair, kopsinyl alcohol, CXLII-F, and 3',3'-dideuteriokopsinyl alcohol, CXLII-G, by reduction of kopsinine with LiAlD4; see Table V). When the C-3 substituent does not carry an a-hydrogen atom, the mje 110 peak is due to the presence of natural isotopes in i , while in molecules having a double bond a t '2-3, for example, M and P, the main fragmentation paths are blocked and the m/e 110 peak cannot be ascribed a structure. A further peak a t m/e 81 which sometimes accompanies i results from its further decomposition (reversed Diels-Alder), as is established by a metastable peak a t m/e 60.5 (102). I n many spectra of alkaloids of this group, the indolic peaks are small as compared with the aspidospermine-type molecules. I n some cases they starid out, however, and peaks corresponding to fragments m and n occur in the spectra of O-methyldeacetylaspidofiline (CXXXIX)and deformylrefractidine (CXXII), while the lactams, pleiocarpinilam (CXLVI-D) and pleiocarpine lactam A (CXLV-D),exhibit intense peaks due to the fragments 1 and p (102). On the basis of the foregoing information, it has been possible to determine the complete structures of alkaloids in this group by use of reactions designed only to modify superficial substituents (80, 81, 82, 95). Other possible skeletal structures which might be compatible with the observed spectra are excluded by chemical evidence described subsequently. 3. N , I s Located in a Pive-Membered Ring ( E ) This is shown by the IR-absorption of the three lactams, pleiocarpine lactam A (CXLV-D), pleiocarpinilam (CXLVI-D), and kopsinilam (CXLII-D; Section 111, H), which is compatible only with their being y-lactams [compare, for example, 8- and 10-oxoaspidospermine (XX, XI), Section 11, C].
14. Aspidosperma
AND RELATED ALKALOIDS
427
4. NbI s Also Located in a Six-Membered Ring ( D ) Similar lactams, for example, refractalam (8-0x0-CXXII,Section Ill,
D), pleiocarpine lactam B (CXLV-E) and the related kopsinine lactam (CXLII-E,Section Ill, G)show IR-absorption due to an amide carbonyl group in a six-membered ring. Also, zinc dust distillation of pleiocarpine (CXLV-A, 95) and kopsinine (CXLII-A, 101) gives 3,5-diethylpyridine, an indication of structural similarity to aspidospermine which also gives this product derived from the piperidine ring D containing Nb. The ketones deacetyl-6-dehydrodemethylpyrifoline (CXXXIII) and deformyl-6-dehydrodemethylrefractidine(CXXXV, Section 111, D) are located in a six-membered ring as shown by their IR-absorption. Conclusive evidence has been obtained that the carbonyl groups in these two compounds are located in the same ring as Nb. 5. C-3 Lies in a Six-Membered Ring
The carbon atom, C-3, which in the kopsinine subgroup bears a carbomethoxyl substituent, has been shown by the mass spectral evidence summarized above not to be in the six-membered ring which contains Nb. That it lies in a strained six-membered ring is indicated by degradation of the carbomethoxyl groups of refractine (CL-A) and aspidofractine (CXLIII-A) to C-3 ketones (CXLIX-P and CXLII-P), whose IRabsorption occurs a t unusually low wavelengths ( 5 . 7 G 5 . 7 8 p) (Section 111,G). 6. Ring E Contains a Chain of T w o Methylene Qrouys Terminating in a
Quaternary Center, C-12, and the Tertiary Nb The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the P-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (11),it is reasonable t o expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which (2-11 is substituted by the C-3’ bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-11 shows as a singlet (2.82 6) in the NMR-spectrum and C-12 is therefore quaternary.
7. Ring D Contains a Chain of Three Carbon Atoms between Nband (7-5
Evidence was presented under subsection 4 above tha.t ring D is six-membered and contains the ketonic carbonyl group of deacetyl6-dehydrodemethylpyrifoline (CXXXIII). When this ketone was exhaustively deuterated, only two deuterium atoms were introduced, which is consistent with the carbonyl’s lying between a quaternary
428
B. GILBERT
center, C-5, and a methylene group, C-7. Moreover, when the ketone was reduced under Clemmensen conditions, an olefin (CXLI) was obtained that contained a 6,7-double bond whose resistance to reduction by zinc and acid shows that this compound is not an enamine and there must be another carbon atom (C-8) between the double bond and Nb (Section 111,D, E). The preparation of the two lactams CXLII-E and CXLV-E shows that C-8 is a methylene group (Section 111,Q). 8. Ring F Contains a Pair of Carbon Atoms, C-3 and C-4, between Two Quaternary Centers, C-2 and C-5 As already mentioned, the NMR-spectra of the aspidofractinine-type alkaloids show that they do not have any hydrogen atom on C-2. The adjacent atom in ring F, C-3, bears a carbomethoxyl group in, for example, kopsinine (CXLII-A), the position of this group being established by the formation of a six-membered cyclic urethane (CLIV) involving N, from the derived alcohol, kopsinyl alcohol (CXLII-I?) (Section 111,G). The related N-methylkopsinyl alcohol (CXLVI-F) was converted by way of alkaline or thermal decomposition of its mesylata (CXLVI-I), to the olefins, N-methylkopsinylene (CXLVI-M) and N-methylisokopsinylene (CXLVI-N). N-Methylkopsinylene has an exocyclic methylene group whose vinyl protons show a 12-line ABXz pattern in the NMR-spectrum demonstrating the presence of two protons on C-4. I n isokopsinylene, the double bond has moved into the ring and the remaining C-4 proton, now absorbing in the vinyl region, clear of other absorption, shows weak coupling (J = 1.5 cjsec) only with the allylic C-3' methyl group. C-4 is therefme attached to a quaternary center (Section 111,G). 9. Positions 2 and 5 Are Linked by a n Unsubstituted Ethylene Chain
Only two carbon atoms have not been accounted for in the aliphatic portion of the molecule and these are clearly those expelled as ethylene in the formation of the ion h (M-28)in the mass spectrometer. In order to satisfy the conditions that C-2 and C-5 must be quaternary and that the C-3 ketone, e.g., CXLIX-P, is six-membered, these two carbon atoms must link positions 2 and 5 as in aspidospermine. 10. The Relation between C-3 and Ring El and the Stereochemistry of the Alkaloids The evidence already presented encompasses all the aliphatic carbon atoms of the alkaloids, the dihydroindole structure of rings A and B resting on UV-, NMR-, and mass spectral data as well as on the production of indole derivatives during the zinc dust distillation and alkali
14. Aspidosperma AND RELATED ALKALOIDS
429
fusion of pleiocarpine and kopsine (95, 103). The skeleton CXVII represents the only manner of linking the groupings described that is compatible with all the data mentioned. The demonstration of a C-3 to C-11 bridge through only one carbon atom in kopsine (CLXX) proves that the bonds 2-3 and 12-11 are disposed cis with respect to rings B and C in this alkaloid. From models, it is evident that ring E must be cis fused to ring C and the relative stereochemistry of C-19 is thus also established. If it is assumed that no inversion at C-12 and C-19 takes place during the pyrolysis of kopsinyl iodide (CXLII-J) to kopsane (CLXXXIV) which has been directly related to kopsine (Section 111, J),then the relative stereochemistry of all the ester alkaloids is established. The relative stereochemistry of the nonester alkaloids follows from the cis E/C fusion mentioned above. The correlation of the two groups with one another and with aspidospermine (11)has yet to be achieved.
C. ASPIDOFRACTININE From the residues remaining after the removal of the major alkaloids, refractidine, refractine, and aspidofractine (Sections 111, D, G) from Aspidosperma refractum, VPC and thin-layer chromatography enabled the separation and purification of a noncrystalline minor base, aspidofractinine, ClgH24N2. The IR-spectrum showed an NH band a t 3.10 p and the mass spectrum proved to be identical with that of O-methyldeacetylaspidofiline (CXXXIX, Section 111,E) with the sole exception that those peaks which correspond to indole-containing fragments were found at mass numbers 30 units lower. Aspidofractinine is thus the unsubstituted parent (CXVII) of the hexacyclic group which forms the subject of this section (102).
CXVII
D. PYRIFOLINE, REFRACTIDINE, AND REFRACTALAM Pyrifoline (CXIX)and refractidine (CXX) are abundant constituents, respectively, of the closely similar species, Aspidosperrna pyrifoliurn (49) and A. refracturn (81). Pyrifoline, shown by analysis and mass spectrometry to be C23H30N203, contains two methoxyl groups, while refractidine, CzlHzsN202, contains only one. The UV-spectrum of pyrifoline
430
B. GILBERT
is coincident with that of aspidospermine, and taken together with the fact that there is absorption due to three aromatic protons in the NMRspectrum, this shows that a 17-methoxy-N-acyldihydroindolechromophore is present. Refractidine showed UV-absorption characteristic of an N-acyldihydroindole unsubstituted in the aromatic ring (Table 111), confirmed by the appearance of absorption due to four aromatic protons in the NMR-spectrum. The NMR-spectra (Table IV) and acid hydrolysis of the two alkaloids to their deacyl derivatives, CXXI and CXXII,
CXIX CXXI CXX CXXII CXXIII CXSlV
Ri Olle
OXe
H
H
H H
4c
H CHO H Me CD2H
CSXV CXXVI CXXVII CXXX CXXXI CXXXII
Rz
OMe H OMe H H H H Ac H Me H CDzH
R3
H
D H
H
CXXXIII CXXXIV CXXXV
RI R2 Me0 H OMe D
H
H
H
H
Ri
AC
CXXVIII; R = OMe CXXIX; R = H
respectively, showed that pyrifoline has an N,-acetyl and refractidine an N,-formyl group. The difference in molecular formula of the two alkaloids is thus explained by the 17- and N,-substituents. Functional group analysis and NMR-spectra show the absence of a C-ethyl side chain and a (2-2 hydrogen atom (absence of absorption a t 0.65-0.70 6 and 4.0-4.5 a), excluding the two alkaloids from the aspidospermine group, and the lack of evidence for a double bond indicates a hexacyclic structure (81). The mass spectra of the two bases and all their corresponding derivatives are identical except for appropriate shifts in the masses of the molecular ion and fragments h, m,and n,due t o the different substitution
14. Aspidosperma
AND RELATED ALKALOIDS
43 1
pattern in the indolic part of the molecule (Table V). Pyrifoline and refractidine therefore have the same aliphatic structure ( 2 l ) , and the evidence that this structure is based on the skeleton CXVII has already been presented (Section 111, B). It remained to locate the aliphatic methoxyl group present in both alkaloids. This group is selectively demethylated by boiling concentrated hydrochloric acid to give, respectively, the alcohols CXXV and CXXVII in which the c and i peaks are found 14 mass units lower than in the parent alkaloids (loss of CHZ). The secondary nature and equatorial configuration of the alcohol group was shown by acetylation to give CXXVIII and CXXIX, respectively, in whose NMR-spectra a clear one-proton quartet was observed a t 4.63 6 and 4.73 6, respectively (J = 5, 10.5 cjsec) due to the CH(0Ac) group flanked by two nonequivalent protons. Confirmation of the presence of only two vicinal protons was obtained by Oppenauer oxidation of the alcohol (CXXV) with cyclohexanone and aluminum phenoxide to the six-membered ketone (CXXXIII, IR, 5.89 p), which was equilibrated with excess sodium deuteroxide in deuteriomethanol to give the trisdeuterio derivative, CXXXIV, (accompanied by material not deuterated on Na). The carbonyl group thus has only two cr-hydrogen atoms and the mass spectra of the ketone and its deuterated derivative (Table V) showed that both the carbonyl group and the adjacent hydrogen, or, respectively, deuterium, atoms were retained in the c and i fragments. On the basis of skeleton CXVII and the evidence presented in Section 111, B, 2 for the structure of these fragments, only position 6 for the carbonyl group is compatible with these observations. Among other derivatives of the two alkaloids prepared in order to confirm the correctness of the interpretation placed upon the mass spectra, were the corresponding ketone in the refractidine series (CXXXV, I R , 5.9 p ) , the 6-deuterio derivative of deacetyl-6-demethylpyrifoline(CXXVI), and the compounds CXXIII, CXXIV, CXXXI, and CXXXII. I n all cases the mass spectral peaks were found a t the predicted m/e values (Table V). The methoxyl group of pyrifoline (CXIX) and refractidine (CXX) is therefore located securely in position 6. Of some interest is the ease of hydrolysis of the aliphatic methoxyl groups of these alkaloids which, in common with the sharp drop in pKi (33% dimethylformamide) which is observed on passing from the alcohol, CXXV (7.25), to the ketone, CXXXIII (5.90), would seem t o point to an interaction with Nb. Examination of models does not show proximity between these two positions, however. A similar change in basicity is seen in the pairs, ajmalidine (ketone, pKi 6.3) and sandwicine (alcohol, pKi 8.5) (98, 99), and kopsine (ketone, pKi 4.28) and dihydrokopsine A (alcohol, pKi 6.1) (109, 100). The two ketones, like CXXXIII,
432
B. GILBERT
are P-keto-amines in which the keto group is held rigidly away from the basic nitrogen atom. I n addition, the six-membered lactam 8-0x0-CXXII has been encountered in A . refracturn (37).
E. ASPIDOFILINE Aspidofiline (CXXXVI), one of the simplest members of the group, was the first alkaloid t o be isolated from A . pyrifoliurn (79). It was readily separated from the accompanying pyrifoline by virtue of its alkali solubility. The phenolic hydroxyl group so indicated is confirmed by the bathochromic shift of the UV-spectrum observed on addition of alkali. The spectrum is characteristic of a 17-hydroxy-N-acyldihydroindoleand the IR-spectrum shows a hydrogen-bonded amide carbonyl band a t
CXXXVI CXXXVII CXXXVIII CXXXIX CXL
Ri
Rz
H
Ac Ac Ac
Ac Me Me
H
CXLI
cxxxIII
H Et
6.14 p. Further confirmation is obtained from the NMR-spectrum which shows a singlet a t 10.13 6 due to the bonded 17-hydroxyl (compare demethoxyaspidospermine and aspidocarpine), while a three-proton singlet at 2.30 6 shows the N,-acyl group to be acetyl. Analysis and the mass spectrometrically determined molecular weight established the empirical formula as C21H~sN202.The oxygen atoms are already accounted for, so it remained to elucidate the nature of the hexacyclic carbon-nitrogen skeleton. Aspidofiline yields an 0-acetate (N,-tertiary) and is methylated with diazomethane in 24 days to 0-methylaspidofiline (CXXXVIII). The resistance to methylation of similarly hydrogenbonded phenolic hydroxyl groups has been encountered already with aspidocarpine and demethylaspidospermine (Section 11,G, I)and in those
14. Aspidosperma
AND RELATED ALKALOIDS
433
cases methylation was effected with dimethyl sulfate. This method was also used with aspidofiline, but as in this group N,-methylation is rapid, the O,N,-dimethyl quaternary sulfate resulted, from which CXXXVIII was regenerated by pyrolysis of the corresponding methohydroxide in high vacuum. Acid hydrolysis of the methyl ether yielded 0-methyldeacetylaspidofiline (CXXXIX). Mass spectral examination of aspidofiline and its three derivatives, CXXXVII, CXXXVIII, and CXXXIX, showed in each case an M-28 peak (h) and peaks a t m/e 124 and 109 (c and i ) . This similarity to other alkaloids of the group, considered together with the absence of NMR-absorption due to a C-ethyl side chain or a C-2 hydrogen atom, led t o the proposal of structure CXXXVI (see Section 111,R , 2). Proof that the proposed structure was correct was obtained by correlation with pyrifoline (CXIX).The ketone, CXXXIII (Section 111, D), was subjected to the Clemmensen reduction which unexpectedly gave the olefin, CXLI (i peak a t m/e 107) and th’is was hydrogenated t o 0-methyldeacetylaspidofiline (CXXXIX) (80).
F. SOMEALKALOIDS OF Aspidosperma populifoliurn Ten alkaloids have been isolated from A . populifolium, of which the greater part belong t o the aspidofractinine group (48). They include ( + )-0-methyldeacetylaspidofiline [CXXXIX, optical enantiomer of that derived from aspidofiline (Section 111,E)], its 16-methoxy analog, CXLI-A, and their respective N,-formyl derivatives, CXLI-B and CXLI-C. The structures of all four compounds could be established by comparison of their IR-, UV-, NMR-, and especially mass spectra with
?,I
‘*’ I
CXXXIX H CXLI-A Me0
H H
those of known aspidofiline derivatives and in the case of CXXXIX, by chromatographic comparison with its enantiomer. The UV-spectra of the dimet,hoxy compounds CXLI-A and CXLI-C, were closely similar to those of deacetylpyrifolidine (XLVII) and pyrifolidine (XLVI), respectively, while the presence of two ortho-hydrogens on the benzene
434
B. GILBERT
ring was established by NMR-spectroscopy (6.28 and 6.86 6 , doublets, J = 9 cjsec). On this basis, the methoxyl groups of these bases could be located in positions 16 and 17 (48).
G. KOPSININE, ASPIDOFRACTINE, PLEIOCARPINE, AND REFRACTINE PLEIOCARPININE, The five alkaloids mentioned in the title differ only in the substituent on N, or, in the case of refractine, by the presence of a methoxyl group a t C-17. It is convenient, therefore, t o consider their chemistry together. The natural sources of the alkaloids are recorded in Table I, and interconversions that have related them were described in Section 111,B. The bases are all levorotatory. Analyses of the bases and their salts and particularly mass spectral molecular weight determination established the empirical formulas, and examination of the UV-spectra and comparison with model compounds showed that all were dihydroindoles, kopsinine (CXLII-A)having a free N,-H, and aspidofractine (CXLIII-A),refractine (CL-A), and pleiocarpine (CXLV-A)being acylated. I n addition to the UV-, the IR- (N,-CHO, 6.0 p ; N,-COZMe, 5.87 p ) and NMR-data (N,-CHO, 9.5 6 ; N,-COZMe, 3.8 S), together with acid hydrolysis and reacylation (with formic-acetic anhydride or formic acid for aspidofractine and refractine and with methyl chlorocarbonate for pleiocarpine) established the nature of the acyl groups. The more strongly basic nature of pleiocarpinine (CXLVI-A) and its red ceric sulfate reaction, together with the absence of an NH band in the IR-spectrum suggested an N-alkyldihydroindole, and that the N, substituent was methyl was shown by the fact that pleiocarpine and pleiocarpinine give a common reduction product, N,-methylkopsinyl alcohol (CXLVI-F),with lithium aluminum hydride (87, 49, 91, 92).
The NMR-spectra (Table I V ) showed that pleiocarpine and aspidofractine were unsubstituted in the benzene ring (note the characteristic downfield doublet with fine structure due to the C-17 aromatic proton which lies close to the N,-acyl group), while refractine had a C-17 methoxyl (position from UV- and NMR-aromatic patterns which resemble those of aspidospermine). The remaining two oxygen atoms SO far unaccounted for in each of the alkaloids were located in a carbomethoxyl group (IR-, 5.7P5.80 p ; NMR-, ca. 3.7 6,methyl singlet) (82, 91, 92).
The principal evidence for the aliphatic structure of the alkaloids was presented in Section 111, B, where it was shown that they have the car-
14. Aspidosperrna
AND RELATED ALKALOIDS
435
bon-nitrogen skeleton represented in the formulas A-Q in the accompanying illustration. Some transformations of a peripheral nature are described below. 1. Rings D and E
Direct oxidation of pleiocarpine (CXLV-A) with permanganate gave a mixture of two Nb-lactams,the five-membered lactam A (CXLV-D, v, 1712 or 1683 cm-1) and the six-membered lactam B (CXLV-E, v, 1672 cm-1) whose UV-spectra were unaltered and which could be reduced back to a mixture of kopsinyl alcohol (CXLII-F) and its N-methyl derivative (CXLVI-F),thus demonstrating that no skeletal change had taken place. The formation of these neutral lactams has been cited (Section 111, B, 3, 4) as evidence that N, lies a t the junction of a fiveand a six-membered ring (rings E and D, respectively) (95). 2 . The Carbornethoxyl Group I s Linked to a Carbon Atom Which Also Bears a Xingle Hydrogen Atom
Mild alkaline hydrolysis of refractine and aspidofractine gave the free acids (CXLIX-B and CXLII-B, respectively) which on reformylation and reesterification did not give back the parent alkaloids (37; see, however, 89), but isomeric esters which were named isorefractine and isoaspidofractine (CL-C and CXLIII-C, respectively). Treatment of the deformyl derivatives CXLIX-A and CXLII-A with sodium methoxide in methanol effected the same isomerization directly to give the deformyl isoesters, CXLIX-C and CXLII-C, respectively. The carbomethoxyl group is thus attached in a sterically unfavorable configuration t o a carbon atom which also bears a hydrogen atom; the presence of this hydrogen atom may be confirmed by its replacement by deuterium to give CXLIX-S when the same epimerization is performed with sodium deuteroxide in deuteriomethanol (see Section 111, B, 2 and Table V). That only epimerization was involved was established by carrying deformylrefractine (CXLIX-A) and deformylisorefractine (CXLIX-C) through the series of transformations COzMe CHzOH (For T) --+ CHzOTs ( H or W) +=CH2 (M). The olefinic final product no longer has a hydrogen atom on C-3 and, in accordance with expectation, the same olefin (CXLIX-M), was obtained in both series. Further confirmation of the C-3 hydrogen is seen in the NMR-spectra of the hydrocarbons (0)in which the -C02Me of the original alkaloids has been reduced to CH3 [reduction of the tosylate (CXLIX-W) via desulfurization of the thiophenyl ether (CXLIX-Y) (82), Raney nickel in ethanol on the iodide (CXLII-J), or Wolff-Kishner reduction of the
-
436 B. GILBERT
14. Aspidosperma AND RELATED ALKALOIDS
PI
437
438
B. GILBERT
aldehyde (CLV, 95)]. I n all cases a new methyl doublet a t 1.1-1.3 6 (J = 6 c/sec) shows coupling with a single C-3 proton. 3. The Carbomethoxyl Group I s Located on C-3 Kopsinyl alcohol [CXLII-F, LiAIH4 reduction of kopsinine (deformylaspidofractine CXLII-A),or pleiocarpine (CXLV-A)which also gives the N-methyl derivative] forms two ring compounds which link the alcoholic group to N, through a one-carbon bridge. One is the carbinolamine ether, CLIII, formed by the action of formaldehyde, the other a cyclic urethane (CLIV) prepared with benzyl chlorocarbonate and alkali. The latter shows IR-carbonyl absorption (5.88 p) characteristic of a six-membered cyclic urethane (95; cf. 82, 89,91, 92) (note that CLIV can only maintain planarity of the amide group if formed from isokopsinyl alcohol), and the original CHzOH group, and hence the carboniethoxyl of the parent alkaloids is situated /3 to N,. Furthermore, the C-3 substituent, whether -C02Me or any derived group, is always found in the fragment h (M-28) in numerous mass spectra and therefore cannot be located on C-20 or C-21 which are expelled in the formation of this fragment. Fragment h decomposes to fragment i which has been shown (Section 111,B, 2) to incorporate the D ring, C-10 and C-4. The carbomethoxyl group is thus limited to C-3 and C-11, with the foregoing evidence excluding the latter position. The transformation of the carbomethoxyl group to the exocyclic olefin (M) has already been described. Further transformation of the N,-deformyl olefins (CXLII-M and CXLIX-M) via their N,-formyl derivatives and by ozonization to the N,-formyl norketones (CXLIII-P and CL-P, respectively) led to the deformyl norketones (CXLII-P and CXLIX-P). The IR-absorption of these (ca. 5.77 p) showed that the carbonyl group and hence the original carbomethoxyl group probably lay in a strained six-membered ring. 4.
The Stereochemistry of the Alkaloids
(See also Section 111,B, 10.) Only structure A for the five alkaloids is compatible with the foregoing facts. Moreover, as will be seen subsequently (Section 111,J),kopsinyl iodide (CXLII-J)may be transformed into kopFane (CLXXXIV)in which the C-3’ carbon atom forms a bridge between C-3 and C-11. This requires the C-3, C-4 bridge to be cis to ring E ; the stereochemistry of the remaining centers follows automatically. That the carbomethoxyl group has the a configuration is shown not only by this bridge formation but also by its instability with respect to the is0 series in which the group must possess the less hindered /3 orientation.
14. Aspidosperma
AND RELATED ALKALOIDS
439
H. KOPSINILAM AND PLEIOCARPINILAM The amides kopsinilam (CXLII-D) and pleiocarpinilam (CXLVI-D) occur together with the more strongly basic pleiocarpine, pleiocarpinine, and kopsinine (Table I). Their weak basicity derives from the dihydroindole nitrogen which, as is shown by the UV-spectra and ceric color reaction (N-CH3, red; NH, orange), is not acylated. The IR-spectra (v, COzMe, 1736-1740 cm-1; v , CO-Nb, 1684-1696 cm-1) suggest the presence of an ester function as well as a five-membered lactam. The nonreactivity of pleiocarpinilam toward methyl iodide confirmed that this involved Nb (note that steric hindrance prevents quaternization of Na). Lithium aluminum hydride reduction of pleiocarpinilam (CXLVI-D) and kopsinilam (CXLII-D) gave, respectively, N-methylkopsinyl alcohol (CXLVI-F) and kopsinyl alcohol (CXLII-F) and thus there was every likelihood that these alkaloids were the E-ring lactams derived from pleiocarpinine and kopsinine, respectively. The correctness of this view was shown by synthesis. Pleiocarpinilam was obtained by the direct permanganate oxidation of pleiocarpinine (CXLVI-A) in acetone, while kopsinilam could be prepared, in a similar manner, from N-acetylkopsinine (CXLIV-A) followed by acid hydrolysis of the acetyl group, or from pleiocarpine lactam A (CXLV-D) by hydrolysis and simultaneous decarboxylation of the N-carbomethoxyl followed by reesterification of the C-3 carboxylic acid. It was established that these two amides are not formed by the action of air and light on pleiocarpinine and kopsinine and that the amides are therefore not artifacts. No trace of pleiocarpine lactam A or any sixmembered lactam was encountered (96).
I. KOPSIFLORINE, KOPSILONGINE, AND KOPSAMINE The three alkaloids named in the title occur together with kopsinine in Kopsia longi$ora (86, 57, 90), and kopsamine was shown (88) to be identical with the “kopsine” isolated in 1920 from K . $avida (85, perhaps a wrong identification of K . pruniformis Reichb. f. et Zoll. ex Bakh. f.). The name kopsamine was retained, as “kopsine” now refers to another alkaloid. Analysis of the bases and their salts established the empirical formulas while the IR-spectrum indicated the presence of ester (v, 1740 cm-1) and amide (v, 1688 cm-1) groups in all three alkaloids. Mild alkaline hydrolysis of kopsamine, C24H28N207 (CLVIII),and of kopsiflorine, C23H~8N205(CLVI), resulted in cleavage of afi ester
440
B . GILBERT
group to give kopsaminic (CLX) and kopsiflorinic (CLIX) acids, respectively. These acids could be remethylated t o the parent bases, but on treatment with dilute acid, they decarboxylated to give kopseine (CLXIII) and kopsifloreine (CLXI), in which compounds a new weakly basic secondary amine had been generated, as was shown by formation of the nitroso derivatives, CLXVI and CLXIV. Kopseine and kopsifloreine retained the original ester group which could be hydrolyzed under more vigorous conditions to give, respectively, kopsamic (CLXIX) and kopsifloric (CLXVII)acids. A similar acid (CLXVIII) could also be obtained by vigorous hydrolysis of kopsilongine, C Z ~ H ~ ~ (CLVII), NZO~ and reesterification with diazomethane gave kopsilongeine (CLXII), a product corresponding in every way t o kopseine and kopsifloreine and
/
Ri H CLVI H CLVII C L V I I I 0-CHz-0 H CLXI H CLXII C L X I I I 0-CHz-0 CLXIV H CLXV H C L X V I 0-CHz-0
Rz H OMe
/
CO zMe
CbzMe R3 COzMe COzMe COzMe
H H OMe H H H NO OMe NO NO
Ri CLIX CLX
~
H 0-CHz-0
COzQ
Rz H
CLXVII CLXVIII CLXIX
Ri
Rz
H H 0-CHz-0
H OMe
forming a nitroso derivative, CLXV. These results indicated the presence of the groupings N-COZMe and C-C02Me in the three alkaloids; examination of the parent bases and their decarbomethoxy derivatives showed that they were dihydroindoles. The spectra and functional group analysis indicated that kopsilongine contained a 17-methoxy and kopsamine a 16,1i’-methylenedioxy grouping whereas kopsiflorine was unsubstituted in the benzene ring. The strong similarity in the chemical behavior of the three bases suggested that otherwise they were of identical structure, and this has subsequently been shown to be true (89, 97).
14. Aspiclosperma
AND RELATED ALKALOIDS
44 1
J. KOPSINEAND RELATED ALKALOIDS Although kopsine (CLXX) was probably isolated in the last century
(83, 84), the true nature of its unusual cage-like structure has only become known recently (101). Preliminary investigations (103, 104, 105)
showed that it was a dihydroindole containing a carbomethoxyl group. In later work (100, log), the correct molecular formula, C~zH24N204,was established and by comparison of the UV-spectrum with model compounds and mild alkaline hydrolysis accompanied by decarboxylation to a dihydroindole (CLXXI) unsubstituted on N, (UV-, benzenoid in acid), it was shown that the carbomethoxyl group was attached to that nitrogen atom. From the IR-spectrum, a five-membered ketone (v, 1757 cm-1) and a hydroxyl group hydrogen-bonded to the N-carbomethoxyl (v, OH, 3268 cm-1; COZMe, 1679 cm-1) were recognized. The presence of the hydroxyl was confirmed by the NMR-spectrum which showed a singlet a t 7.2 6 that could be eliminated by previous treatment of the base with deuterium oxide (100, 101, 109). Furthermore, the hydroxyl and ketone groups were probably vicinal since kopsine reacted with periodate (107, 110). Both kopsine (CLXX) and decarbomethoxykopsine (CLXXI) resist acetylation, indicating that the hydroxyl group was probably tertiary and that N , was sterically hindered. The ketone could be reduced to two epimeric alcohols; dihydrokopsine-A (CLXXII)resulted with sodium borohydride reduction (100, 109))whereas catalytic hydrogenation gave dihydrokopsine-B (CLXXIV, 100, 104). Both formed only a monoacetate. Kopsine shows no vinyl absorption in the NMR-spectrum and could not be further reduced (except by catalytic hydrogenation of the benzene ring). The molecule therefore contains seven rings, since subsequent evidence excludes a tetrasubstituted double bond. Evidence was then accumulated to establish the relation of the ketonic carbonyl to Nb. This was first obtained by examination of two lactams. One, “lactam A” (CLXXV),was the final oxidation product of either of the epimeric alcohols dihydrokopsine-A or -B, in which the secondary hydroxyl had been reoxidized and a new carbonyl group had been introduced adjacent to Nb, as could be recognized both from its neutrality and from the IR-spectrum (v, 1675 cm-1) of its N,-decarbomethoxy derivative (CLXXVI). The same lactam A resulted from the direct oxidation of kopsine itself. The other, “lactam B ” (CLXXVII), was an intermediate oxidation product of dihydrokopsine-B in which the secondary hydroxyl had not suffered alteration. Comparison of the IR-absorption of both lactams with that of kopsinilam (CXLII-D) and
442
B. GILBERT 0
0
t-
CLXXV; R = COzMe CLXXVI: R = H
CLXXVII
CLXXII; R = COZMe CLXXIII; R = H
/
i
C,O, pyridine
t-
CLXXIV
CLXXXVI
CLXX; R = COzMe CLXXI; H = H
CLXXVIII; RI = CHs, RI = H CLXXIX; R I = H. Rz = D
CLXXXIV; R = H CLXXXV; R = Ac
CLXXX
I
J
/
CXL1I.J
CLXXXVII; R = COeMe CLXXXVII-A; R = H
RI CLXXXI
COzMe
CLXXXII-A COpMe CLXXXII-B COrEt
CLXXXIII
CLXXXVII-B; R = COzMe CLXXXVII-C: R = H
Rt =O
&H
14. Aspidosperrna
AND RELATED ALKALOIDS
443
pleiocarpinilam (CXLVI-D) indicated that they were five-membered, and further comparison with 10,ll-dioxoaspidospermine(XIII, Section 11,C, Ref. 24) showed that “lactam A” could not be an a-keto lactam. However, in the NMR-spectrum of this compound (CLXXV) a singlet could be distinguished at 2.82 6 which became a slightly resolved doublet (2.63 6, J = 1 c/sec) in the hydroxy lactam B (CLXXVII). This could be attributed to the groupings CO-CH(CR2)-CONb in lactam A and CH(OH)-CH(CR2)-CONb in lactam B where R is not hydrogen and it was also possible t o say that the two hydrogen atoms in the latter were oriented at an angle of nearly 90” to one another, thus establishing the configuration of the C-3’ hydroxyl (101, see also 111). The same relation between the ketonic carbonyl group of kopsine and Nb was demonstrated by study of the Hofmann degradation of the methiodide. This yielded an a,/?-unsaturated ketone CLXXX whose double bond lay in a terminal methylene group (IR-, v, =CH2, 945, 920, 1629; Y , CO, 1748 cm-1; NMR-, two vinyl singlets at 5.07 and 6.3 6). Three reduction products (CLXXXI, CLXXXII-A, and CLXXXII-B) of this methine were prepared. In each case a new methyl doublet at 0.48-0.58 6, coupled (J = 7-7.5 clsec) to a single a-proton, could be recognized. This proton (on C-11) appeared in the spectrum of CLXXXI as a quartet at 3.7 6 with the same coupling constant (101). Reaction of the diol, CLXXXII-A, with periodate confirmed that it was an a-glycol. The foregoing experiments establish that kopsine contains two fivemembered rings apart from the dihydroindole moiety. One of these rings contains an a-hydroxy ketone in which the hydroxyl is tertiary. The other contains R&-CH-CH2-Nb, in which none of the groups R is hydrogen and the ketonic carbonyl is attached to the carbon atom to Nb.These two rings can only be accommodated in the partial structure CLXXXIII. To this may be added the fact that the hydroxyl group is close t o -N, and also that Nb is probably also involved in a six-membered ring since 3,Ei-diethylpyridineresults from the zinc dust distillation of kopsine (105). This and the occurrence of kopsine (CLXX) and pleiocarpine (CXLV-A)in plants of the same genus led to the belief that the two alkaloids might be structurally related. In fact, a direct correlation was achieved. Kopsinyl iodide (CXLII-J,Section 111,G), obtained from pleiocarpine (CXLV-A), was pyrolyzed to give in 60% yield a heptacyclic hydrocarbon kopsane (CLXXXIV) which forms an N,-acetate (CLXXXV) and a five-membered lactam (CLXXXVI) (NMR-spectrum similar to that of CLXXVII). The new ring which has been formed in kopsane does not therefore involve N, or C-10 and it is not a cyclopropane (NMR-spectrum clear from 0-0.9 6). Examination of models shows that, barring rearrangement, the new ring must involve closure of
444
B. GILBERT
C-3' with C-11. Prolonged treatment of kopsine with hydriodic acid and red phosphorus gave a small yield of the same hydrocarbon, kopsane (CLXXXIV), Taken in combination with the previously described evidence, this establishes the structure CLXX for kopsine. The mass spectrum of kopsine (Table V) is quite different from those of other alkaloids of this group which do not possess the extra ring, in t,hat the base peak, derived directly from the molecular ion (metastable peak at 209), occurs at m/e 282. That this involves the loss of the CO-C(0H) grouping and three more carbon atoms, but not of the N,substituent was shown by the spectra of the three derivatives CLXXI, CLXXVIII, and CLXXIX in which the base peak followed changes at N, but was not affected by alterations on C-3'. The results did not permit a unique structural interpretation (106, 107). Two other alkaloids, fruticosine and fruticosamine (Section 111, K , 109, 113), isomeric with kopsine, possess similar mass spectra. Kopsine (CLXX) undergoes reversible acyloin rearrangement by heating in tetralin t o give an isomer, isokopsine (CLXXXVII, 111).Similarly, bythe action of dilute alkali on kopsine or decarbomethoxykopsine (CLXXI),an equilibrium mixture of the latter with decarbomethoxyisokopsine (CLXXXVII-A) is obtained. I n isokopsine (CLXXXVII), hydrogen bonding is no longer observed between the tertiary hydroxyl group (v, 3509 cm-1, no downfield proton in the NMR-spectrum) and the N,-carbomethoxyl (v, 1706 cm-1). To confirm its structure, decarbomethoxyisokopsine (CLXXXVII-A) was directly related, via its sodium borohydride reduction product decarbomethoxydihydroisokopsine (CLXXXVII-C), to isokopsine, from which the same compound could be obtained by successive borohydride reduction to dihydroisokopsine (CLXXXVII-B) followed by hydrolysis of the N,-carbomethoxyl group (111). Both decarbomethoxykopsine (CLXXI) and its is0 derivative (CLXXXVII-A) occur in the leaves of K . fruticosa ( 113).
K. Kopsia ALKALOIDS OF UNKNOWN STRUCTURE Five alkaloids of unknown structure that may well belong to the aspidofractinine-kopsine group have been reported. Three, kopsaporine, kopsingine, and kopsingarine, have been isolated from K . singapurensis (108, 89, 56). The other two, fruticosine and fruticosamine, occur with kopsine in K. fruticosa (109, 100, 113). Both are isomers of kopsine and similarly contain an N-carbomethoxydihydroindole nucleus unsubstituted in the benzene ring, a five-membered ketone, and a hydroxyl group. Fruticosamine is converted into fruticosine by mild alkali or stronger acid treatment. Fruticosamine resists acetylation and does not
14. Aspidosperma
AND RELATED ALKALOIDS
445
form a methiodide, whereas fruticosine forms both acetate and methiodide. Although the similarity of the mass spectra of these alkaloids and kopsine suggests a similar skeleton, there are some notable differences, among which are the secondary nature of the hydroxyl group in fruticosine and the resistance of the five-membered ketone to reduction (109). IV. The Aspidoalbine Group A. ASPIDOALBINE AND ITS N-ACETYLANALOG The study of Aspidosperma album (see Volume VII, p. 129) in two laboratories resulted in the isolation of aspidoalbine and its N-acetyl analog [(CLXXXVIII+ CLXXXIX, 52) which have been separated (42,48)]as well as aspidocarpine and its demethyl derivative (Section 11, I, Refs. 42, 48). The UV-spectrum of aspidoalbine is similar to that of aspidocarpine (XLIV), showing the same bathochromic shift in alkali, and together with the IR-absorption a t 3.1-3.5 p (hydrogen-bonded hydroxyl) and 6.17p (amide carbonyl), suggesting that the alkaloid was also a 17-hydroxy-N-acyldihydroindole. Elementary analysis and mass spectrometry established the empirical formula as C24H32N205, although the latter showed the presence of a lower homolog, the nature of the mixture being resolved by acid hydrolysis which gave, after esterification and vapor phase chromatography of the volatile acid fraction, methyl propionate (mainly) and methyl acetate. The alkaloid mixture thus consisted principally of a 17-hydroxy-N-propionyldihydroindoletogether with a smaller proportion of the N-acetyl analog. Two methoxyl groups accounted for two of the remaining three oxygen atoms, and the NMR-spectrum (Table IV) showed that these were in the aromatic ring, since only a single aromatic proton singlet at 6.826 was observed. It was assumed that this proton occupied the rarely oxygenated 14 position. The fifth oxygen atom was not in a carbonyl group nor could it be acylated and it was therefore assumed to be ethereal. Methylation of the mixed alkaloid (CLXXXVIII + CLXXXIX) with dimethyl sulfate in acetone (note nonformation of an N,-metho salt, which is indicative of a steric hindrance around N, similar to that observed in the aspidospermine group) gave impure 0-methylaspidoalbine (CXC+ CXCI) from which the deacyl derivative, CXCII, was obtained by acid hydrolysis. Pure 0-methylaspidoalbine (CXC) and its lower homolog, CXCI, were prepared by acylation of CXCII, and in their NMR-spectra could be recognized the C-2 proton quartet, characteristic of the aspidospermine series, The mass spectra of aspidoalbine and its 0-methylated derivatives
5)
C X C I X ; R = Ac C X C I X - A ; R = COEt
CXCVIII
Series B
Serics A
JXXXIV LXXXV LXXXVI
H2C\;/\
_Ri _R2 H
Ac Et
CXCIII CXCIV CXCV CXCVI CXCVII
H
Ac
H
~~
Ri H H
Ac Et CD2CD3
RZ R J H H Ac H H
H D H H H
C'
I,,I \CHzORz C
Me0
R1 (H)
R
Series A , Rz = H Series B. Re = OMe
446
a'
14. Aspidosperrna
AND RELATED ALKALOIDS
447
CXC, CXCI, and CXCII show the M-28 and weak indole peaks expected for an aspidospermine-like molecule. However, a strong M-44 peak (loss of CHzCHzO) also appears, and the base peak is found a t m/e 138 instead of a t m/e 124. Thus, aspidoalbine probably has an aspidospermine-type skeleton modified in the ring D area which contains the ethereal oxygen atom. Reduction of 0-methyldeacylaspidoalbine (CXCII) with lithium aluminum hydride gave an alcohol (CXCIII), and this showed the most intense peak a t m/e 140 which was shifted further to m/e 141 when the reduction was effected with lithium aluminum deuteride. The susceptibility to reduction under these conditions is characteristic of a carbinolamine ether, and since the indole peaks, 6 and homolog, remain unchanged during the foregoing transformations, this ether must terminate adjacent to Nb (52). The exact nature of the ether ring was demonstrated as follows. Oxidation of the 0-methyl-N,-acetyl derivative of aspidoalbine (CXCI) with chromium trioxide-pyridine yielded a five-membered lactam (CXCVIII) and a five-membered lactone (CXCIX, 52). The composition of the lactone shows that two hydrogen atoms in CXCI have been replaced by oxygen, and at the same time it was observed that a two-proton quartet which appears at 4.02 6 in the 100-mc NMR-spectrum of 0-methyldeacylaspidoalbine (CXCII) had disappeared. This quartet could therefore be ascribed to a methylene group (C-21 in formula CC) adjacent to the ethereal oxygen atom. It was shown by spin-decoupling to be coupled to two nonequivalent protons, respectively 2.05 and 2.72 ppm upfield (on C-20 in formula CC). When the coupling between these was also eliminated by double decoupling, then each in turn could be made to absorb as a singlet, thus demonstrating that the next adjacent carbon atom ((3-5in formula CC) bore no hydrogen atom (114). Confirmation that no hydrogen atom was attached to the carbon atom (C-19 in formula CC) on the other side of the ethereal oxygen atom was obtained by examination of the 100-mc spectra of 0-methyldeacylaspidoalbinol (CXCIII) and its deuterio derivative (CXCIV). The only difference between the spectra rests in the absence from the second of a sharp signal a t 2.17 6 [the position in which the C-19 proton absorbs in aspidospermine and pyrifolidine (Table IV)], showing that a lone proton is generated by the LiAlH4 reduction of the carbinolamine ether which therefore terminated at a quaternary center. The ether ring may thus be represented by partial formula CC (52). Both the aforementioned NMR-singlet exhibited by CXCIII and the existence of the five-membered lactam (CXCVIII) support the earliercited mass spectral evidence that aspidoalbine has an aspidosperminetype skeleton. Further confirmation of this was obtained by comparison
448
B . GILBERT
of the mass spectra of the three aspidoalbinol derivatives CXCIII, its
N,O-diacetate, CXCV, and its N-ethyl derivative, CXCVI, with those of three corresponding decinnamoylcylindrocarpol derivatives, LXXXIV, LXXXV, and LXXXVI, whose preparation was described in Section 11, M. All three pairs showed the expected identity of the piperidine-containing peaks (c and satellites) while the indole-containing peaks ( b and satellites) were shifted in the aspidoalbinol derivatives by 60 mass units due to the two extra methoxyl groups present. The M-28 species (fragment a in Section 11, D) which decomposes to give fragment c as is shown by the recognition of metastable peaks, was particularly weak in the spectra of the aspidoalbinol derivatives and this was attributed t o a probably opposite configuration at C-19 with respect to the cylindrocarpol derivatives. Subsequent work (1 13i)has shown, however, that the principal ring-opened reduction product of an aspidoalbine derivative has C-19, p-H (as in cylindrocarpol), the (2-19, a-epimer being a minor product. The accommodation of the ether ring as represented by CC in the aspidospermine skeleton can only be made in the manner represented by formula CLXXXVIII for aspidoalbine, and the mass spectral fragments observed may be rationalized as a', b, and Models permit the construction of two stereoisomers of this structure, one with the ether ring on the same side of the molecule as is the ethyl group of aspidospermine. The co-occurrence of aspidoalbine with alkaloids of the aspidosperminetype made it probable that this was the true configuration ( 5 2 ) ,and this has now been established by interrelation with obscurinervidine (CCI-R), neblinine (CCI-S),and aspidocarpine (XLIV, 113i). GI.
B. ASPIDOLIMIDINE I n addition to seven alkaloids of the aspidospermine group (Section 11, F, I, J, and N) isolated from Aspidosperma limae, this plant also yielded
a base aspidolimidine, whose NMR- and mass spectra were not consistent with membership of that group. The UV-spectrum of aspidolimidine is very similar to those of aspidocarpine (XLIV) and aspidolimine (LIII), which accompany it in the plant. Indeed, the same aromatic substitution pattern is shown by NMR-spectra in which a hydrogen-bonded 17hydroxyl group may be recognized a t 10.78 6, an aromatic methoxyl group singlet at 3.88 6, and two ortho hydrogen atoms a t 6.73 6 and 7.09 6 (J = 8 clsec). An N,-acetyl group is also present (2.32 6). The difference from the aspidocarpine-type spectrum lies in the absence of C-ethyl absorption and the presence of absorption due to three protons
14. Aspidosperma AND
449
RELATED ALKALOIDS
instead of only one in the 4.0 6 region. A similar feature in the spectrum of aspidoalbine (CLXXXVIII) could be attributed to the absorption of the C-2 and the two C-21 protons. I n fact, a comparison of the mass spectra of aspidolimidine and aspidoalbine showed that the aliphatic portions of the two molecules were identical, each showing the base
CCI CCI-L CCI-K CCI-0
Ri Rz OMe OH H H H H OMe O H
Ri
R3 Ac H Ac COEt
CCI-B CCI-C CCI-D CCI-E CCI-F CCI-G
Me
H H Ac H Me
Rz Ac Ac COEt COEt H COEt
Ri CCI-A H CCI-M H CCI-N M e 0
Rz
R3
Me
CHO EtCO EtCO
H H
I Et CCI-I;
R
= OTs
R = SPh XXXIX; R = H CCI-J;
LXXXIV CCI-H LXXXVII
Ri
Rz
Me Me
COEt
H
H
COEt
peak (c) at m/e 138.The molecular ion appeared a t m/e 384 ( C Z Z H ~ ~ N Z O ~ ) , 30 mass units lower than in the case of aspidoalbine, and a similar shift was observed in the M-28 (a’),M-44 (loss of C-2O,C-21,0 bridge), and b peaks due to the absence in aspidolimidine of the C-15 methoxyl group. The alkaloid may therefore be assigned the structure CCI (40).
C. DICHOTAMINE AND 1-ACETYLASPIDOALBIDINE The alkaloid dichotamine, C Z I H ~ ~ Noccurs ~ O ~ in , Vallesia dichotoma together with vallesine, aspidospermine, reserpine, and akuammidine. The UV-spectrum was indicative of a 17-methoxy-Na-formyldihydroindole structure, and the IR-spectrum showed two carbonyl bands, one
450
B . GILBERT
due to the expected N-formyl function, the other to a five-membered lactone (5.67 p ) (41). Subsequently, the molecular formula was confirmed mass spectrometrically, while lithium aluminum hydride reduction of the deformyl compound gave decinnamoylcylindrocarpol (LXXXIV) and its 19-epimer in equal amounts, establishing the structure (CCI-A) for dichotamine (113e). Also found in V . dichotoma were haplocidine (CCI-C), whose structure and stereochemistry were proved independently by methylation with dimethyl sulfate to the highly crystalline 0-methyl derivative (CCI-B), removal of the N,-acetyl group by acid hydrolysis, and lithium aluminum hydride reduction to decinnamoylcylindrocarpol (LXXXIV) and its 19-epimer ; and the unsubstituted compound CCI-K, named 1-acetylaspidoalbidine (with the parent of the aspidoalbine series, CCI-L, being designated as aspidoalbidine to simplify nomenclature). The structure of CCI-K was determined by its analogous reactions and mass spectrometric fragmentation patterns of derivatives with those of haplocidine and its 0-methyl derivative (CCI-C and CCI-B) (113e).
D. HAPLOCINE AND HAPLOCIDINE Preliminary investigation of the plant Haplophyton cimicidum indicated the presence of an alkaloid haplophytine, possibly closely related to the Aspidosperma alkaloids (113a). A reinvestigation of the plant has resulted in the isolation of eburnamine (CCCXL), isoeburnamine (CCCXLI),0-methyleburnamine (CCCXL-A)(see Section VIII, E), and several alkaloids belonging to the aspidoalbine group (113b). Among these the structures of haplocine (CCI-D) and haplocidine (CCI-C) have been elucidated. The UV-absorption (A,, 219, 258, 291-292 mp) of the alkaloids was consistent with their being 17-hydroxy-Na-acyldihydroindoles. This was confirmed by the appearance of a hydrogen-bonded amide carbonyl peak a t 6.13 p in the IR-spectrum which shifted to 6.00 p in the spectrum of the 0-acetate, CCI-E. The phenolic nature of the hydroxyl group followed from the additional carbonyl absorption of the 0-acetate, CCI-E, at 5.69 p. Deacylation of both alkaloids gave the same product, depropionylhaplocine (CCI-F), and reacylation experiments showed that haplocidine (CCI-C) was its N-acetyl and haplocine (CCI-D), its N-propionyl derivative (113b). That the third oxygen atom of haplocine was present in a carbinolamine ether ring was shown by methylation to 0-methylhaplocine (CCI-G),followed by catalytic reduction which opened this ring stereospecifically to give a single product, CCI-H, which contained a new
14. Aspidosperma
AND RELATED ALKALOIDS
45 1
primary alcoholic group. The structure and stereochemistry of CCI-H were established by reduction of the -CHzOH group to -CH3 by way of the tosylate, CCI-I, and the crystalline thiophenyl ether, CCI-J, to palosine (XXXIX) identical with an authentic sample prepared from aspidospermine (11)(11310, 113c). Furthermore, catalytic reduction of haplocine led directly to the known alkaloid limaspermine (LXXXVII). The similarity of the observed behavior of haplocine with that of aspidoalbine led to the structure CCI-D for the alkaloid, and hence to CCI-C for haplocidine.
E. CIMICINE AND CIMICIDINE I n addition to the alkaloids haplocine and haplocidine described in Section IV, D, the plant Haplophyton cimicidum contains two hexacyclic alkaloids, cimicine, CzzHz6N204, (CCI-M) and cimicidine, Cz3HzsNz05, (CCI-N)which contain a y-lactone ring (IR,5.65 and 5.71 split carbonyl in nujol) (113j, k, 1, m). The NMR-spectra of these two alkaloids resembled one another, the principal difference resting in the presence of an aromatic methoxyl peak (3.876) in the spectrum of CCI-N absent from CCI-M. Furthermore, the NMR-spectrum of cimicine was similar to that of haplocine (CCI-D), leaving no doubt that it was a 17-hydroxy-Napropionyldihydroindole. The empirical formula suggested that cimicine (CCI-M)might be simply 21-oxohaplocine, and this was proved by direct oxidation of haplocine to cimicine in low yield using chromium trioxide in pyridine (compare the similar oxidation of 0-methylaspidoalbine, Section IV, A). The supposition that cimicidine is 16-methoxycimicine (CCI-N) is in accord with its NMR-(2 ortho aromatic H, 6.73, 7.026, J = 8 clsec) and IR-spectra. Both bases suffer cleavage of the carbinolamine lactone ring on catalytic hydrogenation to yield zwitterionic amino acids (compare reduction of haplocine, Section IV, D) (113j).
F. OTHERALKALOIDS OF
THE
ASPIDOALBINE GROUP
Recent studies have led t o the isolation of other alkaloids of this group. notably the parent member, CCI-L, which occurs in Aspidosperma fendleri Woodson, and has been named fendleridine. The principal base from this plant, fendlerine, is the Na-propionyl analog (CCI-0) of aspidolimidine (Section IV, B) with which it has been interconverted (113f).
A lactone, CXCIX-A, related to dichotamine, cimicine, and cimicidine
452
B. GILBERT
(Sections IV, C, D) but bearing three aromatic methoxyl groups, has been isolated from an Aspidosperma sp. Its structure follows from its interconversion with the known lactone CXCIX derived from aspidoalbine (Section IV, A) (113g).
G. OBSCURINERVINE AND RELATED ALKALOIDS I n addition t o aspidocarpine (XLIV) and aspidolimine (LIII), Aspidosperma obscurinervium Azambuja also contains three lactonic alkaloids : obscurinervine, mp 204"-205' (dec.), [a]L7 - 54" ; dihydroobscurinervine, mp 184°-1850 (dec.), [a]? - 61" ; and obscurinervidine, mp 206"-207" (dec.), [a]: -39". Recent studies have shown these to possess the structures CCI-P, CCI-Q, and CCI-R, respectively (113i). A dihydroindolic structure for these bases was suggested by their superimposable UV-spectra (A, 218, 253-255, 308-312 mp; E 50,000, 6,000, 3,000) while the presence of a y-lactone was indicated by strong IRabsorption a t 1755 cm-1. The first two exhibit strong M-Et and M-Me, and the last only M-Me peaks (loss of R2) in the mass spectrum, but the stability of the polycyclic skeleton results in only low intensity indolic peaks of which the most notable occurs a t mje 244 for all three molecules. The alkyl group Rz (ethyl or methyl),the lone aromatic proton, and two aromatic methoxyl groups may be recognized in the NMR-spectra of the bases, while with obscurinervine (CCI-P) and obscurinervidine (CCI-R) the two vinylic protons in positions 6 and 7 may be distinguished. Mild hydrogenation of obscurinervine gives the dihydro derivative (CCI-Q) which accompanies it in the plant. The alkaloid neblinine (CCI-S), mp 257"-258", from A . neblinae, is a demethoxy derivative of obscurinervidine (113i).3
CCI-P OMe CCI-Q OMe CCI-R OMe CCI-S H
Et Et Me Me
6,7-dihydro
3 Dihydroobscurinervidine also occurs in A . obscurinervium and the 22-ethyl homolog of neblinine (CCI-S, R1 = H, Rz = E t ) has been isolated from A . neblinae. Synthesis of a reduction product of neblinine from aspidocarpine established the relative stereochemistry a t four centers, that at the other two following from NMR data ( 1 13i).
14. Aspidosperma
AND RELATED ALKALOIDS
453
V. The Condylocarpine Group A. INTRODUCTION This small group, which at the time of writing comprises nine alkaloids occurring in the genera Aspidosperma, Diplorrhyncus, Pleiocarpa, and Stemmadenia of the family Apocynaceae, is important as its members represent close biogenetic relatives of the ulein group alkaloids (115). The common biogenetic origin of stemmadenine (CCXIII)and echitamine (Chapter 8) is also clear. B. ASPIDOSPERMATINE, ASPIDOSPERMATIDINE, AND RELATED ALKALOIDS
Aspidosperma quebrachoblanco is a source of several aspidosperminetype alkaloids which have been discussed in Section 11, C and E. By use of alumina and vapor phase chromatography, six alkaloids were isolated whose mass spectra showed them to be related to one another but not to belong to the aspidospermine group. Five were characterized by a base peak a t m/e 136 (compare m/e 124 for the aspidospermine group) and contained a hydrogenatable double bond while the sixth had the base peak at m/e 138 and did not contain this double bond. The alkaloids were named by their molecular weights [later names (118) in parentheses] : 266-B (aspidospermatidine), 280-B (N,-methylaspidospermatidine), 296-B (deacetylaspidospermatine), 308-B (N,-acetylaspidospermatidine), 338-B (aspidospermatine), and 340-B (dihydroaspidospermatine), the last being the saturated member of the group. The UV-spectra of aspidospermatidine and aspidospermatine showed that they were, respectively, a dihydroindole unsubstituted in the aromatic ring and on N, and an N-acyldihydroindole bearing a methoxyl group ortho t o N, as in aspidospermine (11). The difference in molecular weight between the two corresponded to (Me0 + CH&O-2H) so that it was reasonable to assume that the N-acyl group in aspidospermatine was acetyl. In accordance with expectation, the indole peaks, b and homolog, differed by 30 mass units due to the methoxyl group alone (28, 51a). The isolation of 3-ethylpiperidine by the zinc dust distillation of aspidospermatidine and deacetylaspidospermatine made it probable that the m/e 136 peak derived from a piperidine ring incorporated in the aliphatic part of the molecule. An ideal model compound, dihydrodecarbomethoxyakuammicine (CCII, mol. wt. 266) was known (19). Its
454 B. GILBERT
R
---f
14. Aspidosperma
i
f
AND RELATED ALKALOIDS
455
456
B. GILBERT
mass spectrum was very similar to that of aspidospermatidine (266-B) but not quite identical. The strong m/e 136 peak was present and indicated that a molecule of this skeleton fragmented according to the scheme indicated in the formulas to give fragments b and r . It will be noted that there is no ethylene bridge to be lost in this molecule and this is in accord with the absence of an M-28 peak from the spectra. It was clear that the structure of aspidospermatidine represented some slight modification of the structure CCII and a clue was obtained from the mass spectra of the dihydro derivatives of both compounds (CCIII and CCV). I n both cases the base peak was now shifted to m/e 138 while the indole peaks remained unchanged. A new peak appeared in the spectrum of CCIII at m/e 199, which was absent from that of dihydroaspidospermatidine. An examination of the postulated initial breakdown product, q, of CCIII indicated that it would further decompose not only by cleavage a t x (to give r, m/e 138), but also at y which is both allylic and /3 to nitrogen (see Section 11, D and Refs. 20, 21) to give s, and indeed s has the required molecular weight of 199. The production of s involves loss of the three skeletal carbon atoms, 16, 15, and 20 as well as the ethyl side chain. If the side chain had not been at C-20, then the loss observed would have been 28 mass units less and the s ion would be found at m/e 227. Such a peak is in fact found in the spectrum of dihydroaspidospermatidine, and the ethyl group is therefore at 14, the only position which is consistent with the production of 3-ethylpyridine by dehydrogenation (28, 21, 51a). Structure CCIV is thus established for aspidospermatidine, some slight doubt remaining over the position of the double bond, although the absence of terminal methylene absorption in the IR-spectrum excludes the alternative C-CH-CHz formulation for the side chain. Since the only differences observed in the spectra of the accompanying alkaloids were in the indole peaks, it was possible to formulate them as CCVI-CCX. Confirmatory interconversions, CCVIII to CCIV, CCIX to CCVII, and CCIX to CCX, were made. Base 338-B (CCIX) was recognized by its mp, rotation, and composition as the aspidospermatine that Hesse isolated from the same plant in 1882 (59). The fragmentation pattern proposed for alkaloids of this skeleton has been confirmed by the observation that spermostrychnine (CCXI) and its deacetyl derivative (CCXII) (21), as well as numerous other derivatives of the same basic skeleton substituted in positions 14, 16, and 20 (see following sections and Ref. 115a), fragment in the same way. I n many cases the structures of these compounds have been proved independent of mass spectrometry. An exception to the normal breakdown pattern is seen in strychanone (CCXLIV)in which the 16-carbonyl group
14. Aspidospermu
AND RELATED ALKALOIDS
457
blocks the usual path (36, 128, Section 11,D, L). Breakdown patterns for various unsaturated derivatives of the aspidospermatidine skeleton have been worked out by examination of a series of compounds derived from akuammicine and other alkaloids (115a). An alternative and more probable cleavage of aspidospermatidine itself is illustrated by the production of q' and r ' . A minor alkaloid of Aspidosperma compactinervium has been identified as CCXII-A. Its methyl ether (CCXII-B) differs from aspidospermatine only in the location of the aromatic methoxyl group. As in the case of the foregoing alkaloids the structural determination was based on mass spectrometry of the alkaloid and its derivatives CCXII-B and CCXII-C. The latter, in which the ethylidene side chain has been reduced, shows the s peak at mje 299 (227 + Me0 + Ac - 2H),thus locating this grouping in position 14. The position of the aromatic hydroxyl group is based on theUV-spectrum of CCXII-A [A 218,252,260 (sh), 294, and 300 mp] (48).
A C
CCXII-A; R = H C C X I I - B ; R = Me CCXII-C; R = Me, 14,19-dihydro
C. CONDYLOCARPINEAND STEMMADENINE Stemmadenine (CCXIII) was first isolated from Stemmadenia donnellsmithii (8), where it occurs with (+)-quebrachamine (I) and some iboga-type bases. Subsequently, it has also been found in Diplorrhyncus condylocurpon ssp. mossumbicensis, where it occurs together with condylocarpine (CCXV), normacusine-B (Section VIII, B), two yohimbines, norfluorocurarine, and mossambine (Section VI, B and C, Ref. 116). Analysis and mass spectral molecular weight determination established the empirical formula, C21H26N203, for stemmadenine (8, 116, 117). Its UV-spectrum was characteristic of an indole (cf. ref. 5 5 ) , while the IRspectrum indicated the presence of a normal ester grouping (1718 cm-1) and the absence of any substituent in the indole aromatic ring (116). These findings were fully borne out by NMR-spectroscopy which showed the presence of an indole NK (9.3 6), four aromatic protons, and a carbomethoxyl methyl singlet (3.79 6). A single vinyl proton quartet (5.4 6)
1
CCXIII
CCXVI
/
CCXVIl
1 . KbfnOa, HCl, 5'
2. Heat
CHz
CCXIV
t
CCXVIII
m/e 123
I
ccxv
ccxx
1
I
CCXIX
I
CCXXI CCXXIII-A 14,lY saturated l4p-H CCXXIII-B 14,19 saturated 14a-H
Q
I
S
LiAlHa
P
4
I
I
CH2
A
I
+ CCIV
CCXXII CCXXIII
14,19 saturated
COzMe
ccxxIv
Ri
CCXXIV-A Me0 CCXXN-B Me0 CCXXIV-C Me0
Rz H H
T
2,16-dihydro
AO 2,16-dihydr0
tl
460
B. GILBERT
and a methyl doublet ( 1.7 6) were indicative of the grouping C=CH-CH3. This double bond could be hydrogenated (117). The mass spectrum of stemmadenine exhibited, besides the molecular ion, peaks a t M-30 (loss of CH20) and M-18 (loss of HzO). The latter suggested the presence of a hydroxyl group and the former, considered together with an NMR-spectroscopic signal a t 4.38 6 (CH2 of CHzOH) and the fact that formaldehyde can be isolated during the conversion of stemmadenine into condylocarpine (see below), further indicated that this hydroxyl group must be primary. Palladium dehydrogenation of stemmadenine gave 3-ethylpyridine and a compound, C25HzzNz02, showing carbonyl absorption a t 5.88 p and an extended indole chromophore in the UV spectrum. The structure of this compound, which is symmetrical, was solved entirely by NMRspectroscopy. I n the spectrum eight aromatic protons could be recognized, six normally placed and two further downfield which must be close to one of the two carbonyl groups. Four other protons made up an AzX2 pattern, of which two protons appear a t 4.43 6 (between CO and the indole double bond) and the other two a t 2.78 6 so that the grouping Ar-CH(C0)-CHZ-CH(CO)-Ar was present. Finally, the remaining hydrogen atoms could be located in two ethyl groups which absorbed as a quartet and a triplet. These features can only be assembled in the structure, CCXVI, which may be seen to be formed from two units of structure, CCXVII, with the loss of one carbon atom. The part structure, CCXVII, and 3-ethylpyridine together contain all the carbon atoms of stemmadenine, and the two fragments could be linked to give the part structure CCXVIII for the alkaloid [linkage of C-16 in CCXVII to N, is excluded as condylocarpine (CCXV, see below) is not an enamine] in which it remains to complete one more ring between (3-16 and some point on the piperidine ring. Such a part structure is fully in accord with the appearance of the strongest peak in the mass spectrum of stemmadenine a t m/e 123, a peak which can be rationalized as the piperidine fragment t (117). Proof of the point of attachment of C-16 came from the conversion of stemmadenine into condylocarpine by direct oxidation of the hydrochloride with aqueous permanganate followed by heating, which gave formaldehyde as a by-product (117). The condylocarpine obtained had the same physical properties, including high positive rotation, as the natural material ( 116). Condylocarpine has the characteristic a-methyleneindoline carboxylic ester chromophore found also, for example, in akuammicine (CCXXV) and tabersonine (XCII, Section 11, 0), and which gives rise to the high rotation and t o IR-spectroscopic bands a t 6.0 p (conjugated C02Me) and 6.25 p (conjugated double bond), and
14, Aspidosperma
AND RELATED ALKALOIDS
46 1
NMR-absorption at 8.72 6 (N,-H) and 3.78 6 (COzCH3). NMR-spectroscopy also showed that the ethylidene group of stemmadenine was still present. The absorption in the 4.0 6 region (which may be assigned to protons allylic to one double bond and next to nitrogen, or to protons allylic to two double bonds) showed two single proton absorptions. Position 3 (partial structure CCXIX) is therefore substituted and can only be linked to C-7, while C-16 may be linked to positions 15 or 21 (117).
Clemmensen reduction of condylocarpine (CCXV) gave the tetrahydro derivative (CCXX) [note the strange reduction of an isolated double bond for which a mechanism has been proposed (1IS)] in whose mass spectrum could be seen the now familiar breakdown pattern to give fragments r and s characteristic of the dihydroaspidospermatidine skeleton (Section V, B) but in which r now bears the C-16 carbomethoxyl group. In particular, the position of s a t m/e 227 [as in dihydroaspidospermatidine (CCV) and not as in tetrahydrodecarbomethoxyakuammicine (CCIII)] fixes the position of the ethyl group as (3-14 and not C-20. The structure of condylocarpine is thus CCXV and of stemmadenine, CCXIII, with the oxidative interconversion passing through the intermediate CCXIV. Further confirmation of structure CCXV was sought by decarbomethoxylation of condylocarpine in strong hydrochloric acid (compare tabersonine, Section 11, 0, and akuammicine, Ref. 19) to the indolenine CCXXI followed by reduction t o the indoline CCXXII. This compound was expected to be identical to aspidospermatidine (CCIV) but it was not. The identity of the mass spectra of CCXXII and CCIV, however, show that the former does in fact have the structure shown and this was confirmed by the identity of the mass spectra of the dihydro derivatives of the two compounds, CCXXIII and CCV. The difference must exist in the stereochemistry a t C-19 (or less probably C-2) (118). In this connection, it is interesting t o note that condylocarpine has a positive rotation in contrast to the negative rotations normally observed in a-methyleneindoline alkaloids. This a t first indicated an “unnatural ” configuration for both this alkaloid and stemmadenine, which itself occurs together with “ unnatural ” ( + )-quebrachamine. The full absolute stereochemistry of condylocarpine was finally established by correlation with akuammicine (CCXXV) by way of its dihydro-derivative, tubotaiwine (CCXXIV, Section V, D ; Ref. 118a). The configurations of both condylocarpine and stemmadenine a t position 15 are in fact “natural,” t h e positive rotation of the former being attributed t o its inversion at C-7 with respect t o the akuammicine group alkaloids.
462
B. GILBERT
D. TUBOTAIWINE From the leaves of Pleioearpa tubicina, in addition to bases described in Sections 111,G, and VI, C, there has been isolated an alkaloid, tubotaiwine, of structure CCXXIV (119). The same substance also occurs in the root bark of Aspidosperrna lirnae (120). Tubotaiwine is dihydrocondylocarpine and like the parent base is decarboxylated by hydrochloric acid. The product, condyfoline (CCXXIII-A, [aID+ 348"), undergoes heat-catalyzed transformation to a mixture of its 20-epimer (CCXXIII-B, [a]=+ 31aa) and tubifoline (CCXXXIX, [a]=- 361", Section 1'1, C), the latter of known absolute configuration. The transformation proceeds by way of an intermediate analogous to CCXIV in which the 3-7 bond has opened. The stereochemistry at position 15is unaffected and, as it controls the configurations a t positions 3 and 7, the absolute configurations of condyfoline (CCXXIII-A) and hence of tubotaiwine (CCXXIV) and condylocarpine (CCXV) at these centers follow (118a).
E.
1~-METHOXY-14,19-DIHYDROCONDYLOCARPINE
Although the alkaloids of Aspidosperma populifolium are preponderantly ofthe aspidofractinine type, one of them (CCXXlV-A)was clearly excluded from this class by its IR- (ACHC1- 5.98 and 6.25 p, MeOzC--C=C) and UV- (Table 111)spectra. The latter was somewhat similar to that of condylocarpine (CCXV),the differences being accountable to an aromatic methoxyl group whose presence was indicated by the NMR-spectrum (OCH3, 3.74 6, coincident with the COzMe peak; 3 aromatic protons only). A further difference from condylocarpine and akuammicine lay in the presence of an ethyl (0.70 6, triplet) rather than ethylidene side chain. Membership to the condylocarpine rather than to the akuammicine group was established by mass spectral examination of the dihydro derivative (CCXXIV-B).The spectrum paralleled that of condylocarpine except in that the s peak appeared a t rnle 257 (227 + 30 due to the aromatic methoxyl), while the indolic peaks were also shifted upward by 30 mass units. The UV-spectra of CCXXIV-B and its N-acetyl derivative, CCXXIV-C, corresponded t o those of la, 1,2,3,4,4a-hexahydro-7methoxycarbazole and its N-acetyl derivative, respectively (120a), thus placing the methoxyl group in the 1 1 position (condylocarpine numbering). The alkaloid CCXXIV-A may thus be formulated as 11-methoxy14,19-dihydrocondylocarpine(48).
14. Aspidosperma
AND RELATED ALKALOIDS
463
VI. Alkaloids Related to Akuammicine A. INTRODUCTION Alkaloids with the skeleton of akuammicine (CCXXV) are widely distributed in the family Apocynaceae and in the genus Strychnos of the family Loganiaceae. Comparatively few members of this group have been isolated so far, however, from plants of the genera under discussion. Together with the preceding isomeric group, they differ from the aspidospermine-type alkaloids in possessing a C19 skeleton if we include the C-16 carboxyl, in contrast to tabersonine (XCII),for example, which has a C20 skeleton including the carboxyl carbon atom.
B. MOSSAMBINE Mossambine occurs with a number of other alkaloids (Section V, C) in Diplorrhyncus mossambicensis (121, 122, 116). Its high negative rotation (-498' in chloroform), UV- (A 230, 300 and 330 mp), and IR-spectra (conjugated COZMe, v, 1653 cm-1; conjugated double bond, v, 1603 cm-1) marked it as a member of the a-methyleneindoline carboxylic ester group of alkaloids. Elementary analysis and mass spectral molecular weight determination established the empirical formula, C20H22N302. A modified Kuhn-Roth determination (44)showed the presence of one C-methyl group, whereas after catalytic hydrogenation, the same determination showed C-ethyl. The hydrogenation product, 19,20-dihydromossambine (CCXXVIII), had the same UV-absorption as mossambine itself and so the alkaloid must contain a grouping, C=CHCH3, unconjugated with the main chromophore. Although mossambine was too insoluble for NMR-determination, examination of the spectra of its 2,16-dihydro and decarbomethoxy derivatives (see below) showed the vinyl proton quartet (5.53-5.55 6) and coupled allylic methyl doublet (1.66 6, J = 6 cjsec) typical of such an ethylidene group. Acetylation of mossambine gave a mono-0-acetate (CCXXVII, v, 1740, 1355 cm-1) whose NMR-spectrum exhibited a new single proton triplet at 4.8 6 due to the group C-CH(0Ac)-C in which there are also two hydrogen atoms vicinal to the acetate group. There are three known types of alkaloid which contain the cr-methyleneindoline carboxylic ester chromophore, those which are typified by tabersonine (XCII), akuammicine (CCXXV), and condylocarpine (CCXV), respectively. The first is excluded since it has a C20 skeleton as against the C19 skeleton of mossambine. The molecular formula of
464
B. GILBERT
C C XXV; R = H C C XXVI; R = O H CCXXVII: R = OAC
U
C C X X X V I I I ; R = H ; 1Sg - H CCXXIX; R = OH
CCXXXV; R = H CCXXX; R = O H
P R' = COzMe or Me
CCX X V III; R = OH CCX X X V II; R = H
CCXXXIII; R = O H
CCXXXI
CCXXXVI; R = H C C XXXIV; J-t = OH
9
CCXXXII
r R' = COzMe or Me
For compounds with R = H, t h e following stereochemistry h a s been established: At C-5, (2-6, 8, C-3, a ;or-H at (3-3, (2-15, (2-20.
14. Aspidosperrna
AND RELATED ALKALOIDS
465
mossambine, however, was in accord with its being a hydroxy derivative of either of the other two compounds, both of which also possess an ethylidene group. Various other chemical similarities confirmed this supposition. For example, the conjugated double bond of mossambine could be selectively reduced with zinc and acid to give 2,16-dihydromossambine (CCXXIX), a dihydroindole (UV- and low rotation) unsubstituted in the aromatic ring (NMR-), while further catalytic reduction resulted in the uptake of two hydrogen atoms and the saturation of the ethylidene side chain. Vigorous acid hydrolysis of mossambine resulted in simultaneous decarboxylation with the production of an indolenine (CCXXXI, A, 220, 262 mp) which with alkaline borohydride underwent the reverse Mannich reaction and reduction to give an indole (CCXXXII, A, 227, 283, 289 mp). This series of reactions, typical of alkaloids of the types mentioned above (19, 123, 69), show that Nh is linked to the 8-indole position through one carbon atom, the sequence being pictured : 0
n c.
H+ N,=C--CCN,
__f
€IN,-C=C
C=Nt
+ HN*--C=C
CH-N,
Furthermore, lithium aluminum hydride reduction of mossambine (CCXXVI) followed the same course as with akuammicine (68), yielding a dihydroindole (A, 245, 301 mp) with an exocyclic methylene group (CCXXXIII,v, 1640 cm-1) in which the only remaining oxygen atom was that of the original hydroxyl group. Catalytic reduction of CCXXXIII gave the C-16 methyl derivative (CCXXXIV) (121, 122). The foregoing information does not distinguish between the akuammicine and condylocarpine skeletons. This distinction may be readily made as has been seen in the case of aspidospermatidine (Section V, B) by examination of the mass spectrum of a fully reduced derivative (115a). I n fact, comparison of the spectra of tetrahydromossambine (CCXXX) and tetrahydroakuammicine (CCXXXV) revealed a very similar pattern for both (Table V), the only important difference being that the r and s peaks were 16 units higher in the case of the mossambine derivative, showing that the alcoholic oxygen atom was present in both. If the ethyl side chain of tetrahydromossambine were in the 14 position as in tetrahydrocondylocarpine (CCXX), then the s fragment would contain it. The fact that, as in tetrahydroakuammicine, it does not, limits the ethyl group to position 20, the only carbon atom absent from s which could accommodate an ethylidene group in the original mossambine. The same conclusion may be reached from the spectra of the pair CCXXXIV and CCXXXVI. These results are also supported by the spectra of derivatives which retain the 2,16- and/or 19,20 double-bond (115a).
466
B . GILBERT
The secondary hydroxyl group present in mossambine can only be placed on C-5, (2-21, or C-14, since these are the only suitable atoms in common between the fragments r and s. Positions 5 and 21 are excluded because the hydroxyl is not eliminated during borohydride, zinc and acid, or lithium aluminum hydride reduction. Position 14 for this group is in full,accord with the NMR-absorption (above) and with other mass spectral data (absence in the spectra of CCXXX and CCXXXV of OH in the homolog of indolic fragment b which contains C-5, and in the spectra of CCXXIX and CCXXXVIII in fragment u which contains C-21). Mossambine thus has structure CCXXVI (122), the stereochemistry remaining a t present undefined. The fact that mossambine is, like akuammicine, levorotatory suggests, however, that the configuration at positions 7, 3, and 15 is the same as in the latter which has been related directly to the Wieland-Gumlich aldehyde (68, 77, 123, 124). It is of interest that Nb-metho salts of mossambine sometimes exhibit a carbonyl band in the IR-spectrum (1698 cm-I), pointing to a possible Hofmann cleavage (122, 121).
C. NORFLUOROCURARINE, DIHYDROAKUAMMICINE, TUBIFOLINE, AND TUBIFOLIDINE Among the seven alkaloids that were isolated from Diplorrhyncus mossumbicensis was a base C19HzoN20 with unusually high rotation ( - 12qO"in chloroform). Its carbonyl activity and UV-spectrum (A, 242, 299, 360 mp) were reminiscent of fluorocurarine (Chapter 15, Refs. 133-137) and comparison of the methochloride of the new base with fluorocurarine demonstrated complete identity. The alkaloid is therefore norfluorocurarine (CCXL, 116, 132). Three related alkaloids have been found in the leaves of Pleiocurpa tubicina. One is the known compound 19,20-dihydroakuammicine (CCXXXVII, 70, 69, 137a), while the other two, tubifoline and tubifolidine, are respectively its decarbomethoxy derivative, the indolenine, CCXXXIX, and the corresponding dihpdroindole, CCIII (119). A compound strychene of structure CCXXXIX has been prepared from dihydrodeoxyisostrychnine (67, 125).
D. COMPACTINERVINE The bark of Aspidosperma cornpnctinervium contains an alkaloid, compactinervine, whose high negative rotation, UV- (A 237, 297, 331) and IR-spectra (conjugated COZMe, 6.04 p ; conjugated double bond,
14. Aspidosperma
AND RELATED ALKALOIDS
467
6.30 p) showed that, like mossambine, it belongs to the akuammicine class. Although solvation precluded precise analyses, a molecular ion corresponding t o the empirical formula CzoH24N204 could be obtained when the alkaloid was introduced directly into the ion source of the mass spectrometer. Thus there are two oxygen atoms to account for, besides those present in the carbomethoxyl function; and both of these were shown to be alcoholic by smooth acetylation to a diacetate (CCXLI-A). The vicinal nature of the two hydroxyls was further shown by reaction with periodate which gave acetaldehyde (125a). Several characteristic reactions of akuammicine-type alkaloids are exhibited by compactinervine (CCXLI). For example, the conjugated double bond is reduced by zinc and acid to give dihydrocompactinervine (CCXLI-B), whose mass spectrum corresponds to that of tetrahydroakuammicine (CCXXXV), the s peak a t m/e 199 indicating a C-20 side chain (see Section V, B). Furthermore, treatment with strong acid results in decarboxylation to the indolenine CCXLI-C which undergoes the reverse Mannich condensation and reduction with alkaline borohydride to an indole (CCXLI-D). Lithium aluminum hydride reduces the m$-unsaturated ester grouping of compactinervine to an exocyclic methylene derivative (CCXLI-E) analogous to the corresponding reduction product of akuammicine (cf. Section VI, B). The mass spectra of both this product (CCXLI-E) and its trideuterio analog (CCXLI-F, obtained with LiAlD4) resembled those of the corresponding two akuammicine derivatives ( 125a). From these facts it was certain that compactinervine (CCXLI)had the dihydroakuammicine skeleton and it remained to place the two hydroxyl groups. On biogenetic grounds, positions 19 and 20 are attractive, since these are oxygenated in the related alkaloids echitamidine (CCXLII, 126) and lochneridine (CCXLIII, 127). That these positions are the true ones is shown by two observations. First, the r peak in the mass spectrum of dihydrocompactinervine (CCXLI-B) appears at m/e 228, 32 units higher than in the analogous tetrahydroakuammicine (CCXXXV), while the s peak is identical in the two spectra. The two oxygen atoms responsible for this shift are thus limited t o positions 15, 18, 19, 20, and 21, the only ones present in r but absent from s (see Section VI, B). Second, compactinervine (CCXLI) shows a methyl doublet at 1.15 in the NMR-spectrum analogous t o that of echitamidine (CCXLII) and due to the grouping CH(0H)CHs(125a). An attempt to synthesize compactinervine (CCXLI) by osmium tetroxide hydroxylation of akuammicine (CCXXV) failed since the product, CCXLI-H, differed stereochemically. However, both diols, CCXLI-H and compactinervine, gave the same 19-ketone CCXLI-G on oxidation with
468
B . GILBERT
the Jones reagent, and the only stereochemical difference was therefore at C-19 (125a). The complete absolute stereochemistry of compactinervine follows from this observation, for the vic-glycol, CCXLI-H, derived from akuammicine of known absolute configuration, must have both hydroxyl groups E . The 20-hydroxyl of compactinervine is therefore a , and the 19-hydroxyl/3. The equatorial tertiary hydroxyl in position 20 is note-
C‘CSLI; Ii = H C C X L I - A ; R = Ac
CCS1,I-c
CCXL-D
14. Aspidosperrna
AND RELATED ALKALOIDS
469
worthy in that it acetylates readily, but resists dehydration, in contrast to the 20 p-axial hydroxyl of lochneridine (CCXLIII) which dehydrates on attempted acetylation (125a, 127).
VII. The Uleine Group A. INTRODUCTION Alkaloids of this group have been discovered in the genera Aspidosperma, Tabernaernontana, Excavatia, and Ochrosia ; in the first they are well distributed, uleine itself being the major alkaloid of at least eight species. Uleine represents a link between the other more highly aromatic members of the group and the condylocarpine-type bases from which it differs in the lack of the 5,6 tryptamine bridge. Wenkert has suggested a biosynthetic route for the formation of this alkaloid (115).
B. ULEINEAND RELATED ALKALOIDS Uleine (CCXLV) was first isolated from Aspidosperrna ulei (138, Volume VII, p. 129) and has since been found in a number of other species (see Table I and Refs. 140, 141, 49, 48). It has the composition C18H22N2, and contains a double bond which is readily hydrogenated to give dihydrouleine (CCXLVI), a compound with the indole chromophore. The UV-spectrum of uleine (Table 111)showed that the double bond was conjugated with the indole nucleus; the similarity of the absorption to that of diacetylallocinchonamine (CCXLVII) suggested that one end of the double bond was linked (0 the a-indolic position. The NMR-spectrum showed that the double bond lay in an exocyclic methylene group (two vinyl singlets a t 5.27 and 4.98 6, absent in the spectrum of dihydrouleine) and established the presence of four aromatic protons and an indole NH grouping (Table IV). These results were in accord with the IR-absorption (v, 3440, N H ; 1635 and 877, =CH2; 740 em-1, 0-disubstituted benzene). An N-methyl (NMR-)and a C-ethyl group (modified Kuhn-Roth, Ref. 44, and NMR-) were also found to be present (138, 142). Uleine methiodide underwent a facile Hofmann degradation t o give an optically inactive compound (CCXLVIII), which retained the two nitrogen atoms and had carbazole UV-absorption. A further Hofinann degradation eliminated N1,and gave a product (CCXLIX) with somewhat extended carbazole absorption, which underwent ready catalytic reduction with saturation of one double bond to give a substituted
470
B. GILBERT
carbazole (CCL) which could also be obtained directly from uleine or dihydrouleine by selenium dehydrogenation (138). The second Hofmann product (CCXLIX) was recognized as a vinylcarbazole by oxidative cleavage of the double bond with osmium tetroxide and then periodate,
cCSL\-l
CCSLVlIl
I CCXLVII
\
CCXLlS
CCL
CCLIV
2,3-saturated
I CCLV 1. LIIS04 2. estcrification
CCLl
('CLII
CCLVI; R = H CCLVII; R = Ale
which gave a yellow aldehyde (CCLI) (v, CO, 1675 cm-1; NMR, CHO, 10.72 6). Comparison of the UV-spectrum of this aldehyde with those of 1-, 2 , 3-, and 4-formylcarbazole (143) left no doubt that it was a 2formylcarbazole. Furthermore, the NMR spectrum of CCLI showed the
14. Aspidosperma
AND RELATED ALKALOI1)S
47 1
presence of five aromatic protons, an aromatic methyl (2.75 S), and an aromatic ethyl group (quartet at 3.15 6, triplet a t 1.35 a), these two substituents occupying two of the remaining three positions ‘in the carbazole C ring. The location of the methyl group is clearly position 1 since it derives from the original exocyclic methylene group, and that of the ethyl substituent follows from the NMR spectrum of uleine itself which exhibits a one proton doublet a t 4.07 6 (J = 2 c/sec) which must be both “allylic ” and next to nitrogen (compare condylocarpine, Section v , C) and have only one neighboring proton, a requirement compatible only with strucure CCXLV for uleine and hence structure CCLI for the aldehyde (142). The structure of CCLI was confirmed by decarbonylation to l-methyl3-ethylcarbazole (CCLII) which was synthesized as follows. Ethyl 2-oxalylbutyrate and the Mannich base, ethyl-p-dimethylaminoethyl ketone condensed t o the cyclohexenone, CCLIII, which was reduced with zinc to CCLIV. The Fischer indole synthesis was then applied to this ketone and led via the phenylhydrazone, CCLV, to the tetrahydrocarbazole carboxylic acid, CCLVI, whose methyl ester, CCLVII, was dehydrogenated over palladium charcoal to 1-methyl-3-ethylcarbazole (CCLII) identical with the degradation product. The chemistry of uleine (CCXLV) parallels that of gramine, and the methiodide (CCLVII-D) suffers facile nucleophilic attack a t the benzylic 4-position with cleavage of the C-4-N bond. Thus with methoxide
m/e209 R = H m/e223 R = Me
m/e 180
m/e222 R = E t m/e 207 R = CH2’
m/e208 m/e 194
m/e 237
Principal mass spectral fragments from uleine (CCXLV)
R = Me R =H
CCLVII-D
CCLVII-A
CCXLV; R CCXLVI; R CCLVII-P; R CCLVII-B; R CCLVII-C; R CCLVII-Q; R
= Me = Me, 1,l‘-dihydro = Me, 1,l’-dideuterio
=H = AC = Et
c R =H R = Me
td
J
t
m/e 209 m/e 223
Ri
CCXLVIII; R = Me CCLVII-J; R = AC CCLVII-K; R = H
CCLVII-E CCLVII-L CCLVII-F CCLVII-M CCLVII-G CCLVII-N CCLVII-H CCLVII-I CCLVII-0
H
Ri
Rz
OM0 OM0
Me
CN
CN H H-
Me,1,l’-dihydro
Me Me, 1,l’-dihydro Me Me, 1,l’-dihydro
( -;>
Ac
OMe OMe
Ac Ac, 1,l’-dihydro
L/
14. Aspidosperma AND
RELATED ALKALOIDS
473
ion, cyanide ion, and lithium aluminum hydride the tetrahydrocarbazoles, CCLVII-E, CCLVII-F, and CCLVII-G, respectively, are obtained. The 4-methoxy-compound, CCLVII-E, readily loses methanol to give the same carbazole (CCXLVIII) as is obtained by Hofmann degradation of uleine. A similar nucleophilic attack a t position 4 results in the formation of the pyridinium salt, CCLVII-H, in which the pyridinium group can be readily displaced by methoxyl (warm methanol), the resulting 4-methoxytetrahydrocarbazole, CCLVII-I, being readily converted via CCLVII-J and -K to the above carbazole, CCXLVIII (143a). Lithium aluminum hydride reduction of uleine (CCXLV) gives dihydrouleine (CCXLVI), for which reaction a possible mechanism has been proposed ( 143a). Dihydrouleine methiodide behaves toward nucleophilic reagents similarly to uleine methiodide and the corresponding series of tetrahydrocarbazoles, CCLVII-L, CCLVII-MI, and CCLVII-N, have been prepared. The reaction of dihydrouleine with acetic anhydride and pyridine followed by methoxide also parallels that of uleine with the formation of CCLVII-0 (143a). Prom an examination of the mass spectra of uleine, dihydro- and dideuteriouleine (CCLVII-P, LiAlD4 on uleine), and the N-acetyl (CCLVII-C) and N-ethyl analogs (CCLVII-Q, LiAlH4 on CCLVII-C) of uleine much information has been accumulated on the probable breakdown path of these alkaloids in the mass spectrometer (see formulas). An important intermediate species is undoubtedly the carbazole, CCLVII-K, whose mass spectrum is practically identical with that of the isomeric uleine (143a).
CCLVIL-U
Among compounds related to uleine that have been isolated from A . dasycarpon are N-noruleine (CCLVII-B),dasycarpidone (CCLVII-A), the corresponding alcohol, dasycarpidol, N-nordasycarpidone, and 1 , l ’ dihydro- 1’-hydroxyuleine. Dasycarpidone may be obtained from uleine by ozonolysis, or from dasycarpidol by oxidation with chromium trioxide in pyridine. 1,1’-Dihydro-1’-hydroxyuleine has been synthesized from uleine by hydroboration (143b). Apparicine, an alkaloid of novel skeleton present in A . dasycarpon and several other species, has been shown t o have the structure CCLVII-U (37).
474
B. OILBEBT
C. OLIVACINE,DIHYDROOLIVACINE, AND GUATAMBUINE The yellow optically inactive alkaloid olivacine (CCLVIII) was first isolated from Aspidosperma olivaceum ( 140)and has subsequently been encountered in many Aspidosperma species (Table I,Refs. 141, 145,147, 48) as well as in Tubernuemontana psychotrifolia H.B.K. (148). Its empirical formula, C17H14N2, and complex UV-spectrum indicated a highly aromatic structure ; the alteration of UV-absorption in acid showed that the basic nitrogen atom was involved in the chromophore (140,149).Olivacine methiodide gave a red anhydronium base (CCLIX) with alkali (145).Meanwhile, another base, guatambuine (U-alkaloid-C, CCLX), C18H20N2, which had first been found in A. ulei (139)and which is present in several species often side by side with olivacine (Table I), was shown to be the N-methyltetrahydro derivative of olivacine both by dehydrogenation of the optically active base and by reduction of olivacine methiodide catalytically or with borohydride to racemic guatambuine (141,149).Guatambuine, remarkable in that both enantiomers have been encountered in the same species (147),is a much stronger base than olivacine (Table V I ) and has carbazole UV-absorption, the identity of the acid and neutral spectra showing that the reduced ring was that containing N1,which was now no longer linked to the chromophore. Analogy with ellipticine (Section VII, D) and comparison of the pKi and UV-spectroscopic data of a number of pyridocarbazoles then (151,152) demonstrated that olivacine was a lOH-pyrido-4,3-b-carbazole and led to the proposal of structure CCLVIII for this alkaloid and hence CCLX for guatambuine (149,153). The correctness of these proposals was readily shown by Hofmann degradation of guatambuine to CCLXI and thence to the same series, CCXLVIII, CCXLIX, and CCL, which had resulted from the degradation of uleine (Section VII, B). Alternative proof of the structure of olivacine was obtained by two syntheses. I n the first of these (150) the starting material, 2-amino-6cyanotoluene, represented ring C, and after transformation to the corresponding phenylhydrazine (CCLXII), rings A and B were built on by a Fischer (Borsche) indole synthesis to give the 2-cyano-1-methyl5,6,7,8-tetrahydrocarbazole(CCLXIII). Difficulty with the dehydrogenation of this compound led to its conversion to the corresponding ester (CCLXV) which smoothly dehydrogenated to the carbazole ester, CCLXVI, in which the carbomethoxyl group provides the starting point for building up ring D. The best method of homologation of the ester was found to be the Arndt-Eistert synthesis via the acid chloride, CCLXVIII, and diazoketone, CCLXIX, to the amide, CCLXX. This amide was then (CCLXXII) by transformed to 2-(~-aminoethyl)-~-methylcarbazole
CCLVIIl
CCLXXIV
I <
CCL XXIII IIofmann II
CHzCHzNHCOCH3
T
2.
CCLXI CCLXX
I .1
CCLXIX
C CX LI X CCLXVIII CCL
I
II
CHzCHzC. CHI
C C LX X X l I
CHzCHzCOCH3
C C LX X X I
CHzCONHz
1.
CCXLVIII
NOH CCLXXXlll
T
H2, I’d-C
CH=CHCOCH3
4
MepC10, KOH
CCLXXX
CHO
C C LX X I X
CH3
COCHNz
t
I
COCl
T
SOCh, DMF
I
CCLXVIl
COzH
CCLXVI
COZEt
Me I C CLX I I
CCLXIII; R = CN CCLXIV; R = COzH CCLXV: R = COpEt
/I
t-
Ed,
CsHs
T
CCLXXV; R = Hz CCLXXVI; R = =CHOH CCLXXVII: R = =CHOPri
475
y
C C LX X V I I I
476
B. GILBERT
dehydration and hydrogenation of the intermediate cyanide, and thence into dihydroolivacine (CCLXXIV) by a Zischler-Napieralski ring closure of the N-acetyl derivative (CCLXXIII). Dehydrogenation of CCLXXIV gave olivacine (150).The second synthesis ( 154)began with the known l-keto-1,2,3,4-tetrahydrocarbazole (CCLXXV) in which rings A, B, and C are ready-formed. The initial atom of ring D was best introduced as a hydroxymethylene group a t position 2 by base-catalyzed condensation with ethyl formate. The hydroxymethylene group of CCLXXVI was then protected as its isopropyl ether (CCLXXVII) while a methyl group was introduced a t position 1 by reaction of the ketonic carbonyl with methyl lithium; loss of water and the protecting group gave the dihydrocarbazole aldehyde, CCLXXVIII. The aldehyde could be very readily dehydrogenated (with disproportionation and simultaneous production of CCLXXIX)to the carbazole aldehyde, CCLXXX. The building up of ring D was now achieved by a route quite different from that of the previous synthesis. Condensation of the aldehyde, CCLXXX, with acetone gave the a,P-unsaturated ketone, CCLXXXI, which was catalytically reduced and transformed to the oxime, CCLXXXIII. This oxime was subjected to a simultaneous Beckmann rearrangement and Bischler-Napieralski condensation to give dihydroolivacine which was dehydrogenated as before to olivacine itself (154). These two syntheses also constitute syntheses of racemic guatambuine. This alkaloid (CCLX) was also obtained by catalytic reduction of the methiodide of dihydroolivacine (CCLXXIV) (150). I n addition, the preparation of N-demethylguatambuine was described (150),as well as alternative routes to the aldehyde (CCLXXX) and corresponding acid (CCLXVII) (154).Dihydroolivacine occurs naturally in A . ulei and may be separated from the accompanying dihydroellipticine (Section VII, D) by thin layer chromatography (155,,139,149,150).Compounds with this chromophore may be recognized by the appearance of a new intense absorption peak in their acid UV-spectra a t approximately 377 nip as well as strong absorption in the IR-spectrum between 6 and 7 p (139, 149,150, 158). Recent investigation of Aspidosperma nigricans has resulted in the isolation of olivacine N-oxide (CCLXXXIII-A).This somewhat unstable compound may be reduced to olivacine (CCLVIII) by brief treatment with zinc and mineral acid. The N-oxide (CCLXXXIII-A) may be prepared from olivacine by perbenzoic oxidation. It is also the initial product of the action of hydrogen peroxide in warm acetic acid on olivacine, a reaction which yields as one of its final products the red isomeric amide, 2-oxo-2,3 dihydroolivacine (CCLXXXIII-B). The N oxide may be distinguished from the latter not only by its UV-spectrum
14. Aspidosperma
477
AND RELATED ALKALOIDS
(A,, 236,252,300,311,330,and 345 m p ; E, 16350, 14280,51490,65420, 5420, 5300) which differs little from that of olivacine, but also by the mass spectrum in which the base peak a t M-16 (m/e 246) corresponds to loss of one oxygen atom from the molecular ion to give a positively charged olivacine molecule-ion (48). Me A - A , H \ N H
Me I
Me
CCLXXXIII-A
CCLXXXIII-B
D. ELLIPTICINE, DIHYDROELLIPTIC~NE, AND N-METHYLTETRAHYDROELLIPTICINE Ellipticine (CCLXXXIV) was first isolated from Ochrosia elliptica and 0. sandwicensis A.DC. (156) and subsequently from Aspidosperrna subincanurn (see note 3, Table I) (157, 158) as well as from other plants (Table I, Ref. 161). I t s UV-spectrum is complex and very similar to that
of olivacine (CCLVIII), and reduction of its methiodide with borohydrid2 gave A'-methyltetrahydroellipticine (CCLXXXV) ( 156) which had been previously isolated from A . ulei (U-alkaloid-B, 139) and also from A . subincanurn. Natural N-methyltetrahydroellipticinewas optically inactive and exhibited a carbazole UV-spectrum which, like that of the optically active guatambuine (CCLX), was unaffected by acid, thus showing that the basic nitrogen atom lay in a reduced ring and was insulated from tkie carbazole chromophore (139). The structure of ellipticine and hence of its tetrahydro derivative was established by a remarkable three-step synthesis from indole. Condensation with 3-acetylpyridine in the presence of zinc chloride gave the bisind olylpyridylethane (CCLXXXVI) in which i t remains only to form the C ring. Reductive acetylation of the pyridine ring with zinc and acetic anhydride yielded the N,C-diacetyldihydropyridine derivative (CCLXXXVII, A, CO, 5.80, 6.05 p ) in which the remaining two carbon atoms of ring C have been introduced. Pyrolysis of CCLXXXVII gave ellipticine (CCLXXXIV) in 2% yield (157). The result was confirmed by a second synthesis. The dimethylated C ring was built onto indole by condensation of hexane-2,5-dione with the reactive indolic 2,3 positions. Formylation of the resulting 1,4-dimethylcarbazole (CCLXXXVIII)with N-methylformanilide proceeded preferentially in the 3-position to give the aldehyde CCLXXXIX whose
47 8 B. GILBERT
0
\
J-Jx
G x
V v
1
Zn,AcaO
T
Ha, N :
Me I
CCLXXXVI
Me I
CCLXXXVIII
ccxc
T
Me
CCLXXXIX
T structure was established by Wolff-Kishner reduction to 1,3,4-trimethylcarbazole. Condensation of CCLXXXIX with 2,2-diethoxyethylamine gave the Schiff’s base (CCXC) and, although this compound resisted attempts a t cyclization, its dihydro derivative (CCXCI)was successfully cyclized and dehydrogenated to ellipticine (CCLXXXIV) (159, 160). An independent synthesis of ellipticine follows, in its initial stages, the first olivacine synthesis reported in Section VTI, C. Instead of the monomethylcyanophenylhydrazine (CCLXII), a corresponding dimethyl compound, 3-cyano-2,5-dimethylphenylhydrazine (CCXCI-A), was employed as starting material. As far as the ester, methyl 1,kdimethylcarbazole-2-carboxylate (CCXCI-B), the two syntheses are parailel. Ring D was then built up, however, by the series of reactions, COzMe
CHzOH
+CHO
___f
-CH=CH-NOz
--+
CHzCHzNHz
The final ring closure again paralleled the olivacine synthesis passing through the intermediate N-formyl rather than the N-acetyl, amine, to give 1,2-dihydroellipticine (CCXCIII) from which ellipticine was obtained by palladium dehydrogenation (16Oa). When the tertiary bases had been removed from the extract of Peruvian A . subincanum, the quaternary bases were extracted with butanol and crystallized as their nitrates. Two salts were separated by preparative paper chromatography, and one of these was recognized as ellipticine methonitrate. The second had a UV-spectrum similar to that of the 1,%dihydropyridocarbazole [e.g., 1,2-dihydroolivacine (CCLXXIV), Section VII, C] chromophore in acid solution. Furthermore, reduction with sodium borohydride gave N-methyltetrahydroellipticine (CCLXXXV). The second quaternary alkaloid was thus N-methyl-l,2-dihydroellipticine (CCXCII) in the form of its nitrate; this was confirmed by oxidation of the tetrahydro compound (CCLXXXV) with mercuric acetate and acidification with nitric acid to give the same salt. The corresponding tertiary base (CCXCIII) was also isolated and its structure confirmed both by conversion into the quaternary methochloride (CCXCII chloride) and by synthesis from ellipticine by reduction to the air-sensitive tetrahydroellipticine (CCXCIV) which gave 1,2-dihydroeIlipticine by dehydrogenation with 0,lO-phenanthraquinone (158). Dihydroellipticine (CCXCIII) was first encountered admixed with dihydroolivacine in A . uZei (U-alkaloid-D, 139, 155). Among other alkaloids of Ochrosia species there has been isolated a methoxyellipticine (156, 161).
Me
Me
CCXCI-A
Me
I
1. KOH/glycol
2. CHeNz
1. EtOCHO, 120'
i
2. POCIS, xylene
ccxcIII
CCXCI-B
482
33. GILBERT
VIII. Tetrahydro f3-Carboline and Related Alkaloids A. YOHIMBINE AND TETRAHYDROALSTONINE DERIVATIVES A number of these alkaloids, which are widely encountered in the family Rubiaceae and in the genus RauwolJa of the family Apocynaceae, have also been found in the genera under discussion. The occurrence of yohimbine (CCXCV),,L?-yohimbine(CCXCVI), and reserpine (CCXCVII) is recorded in Table I . I n addition, an 1l-methoxyyohimbine (CCXCVIII) has been isolated from Aspidosperma oblongum and its structure determined by mass and UV-spectrometry (see below, and Ref. 162). An alkaloid, poweridine, formulated as 17-0-acetyl-1l-methoxyyohimbine (CCXCIX), occurs in Ochrosia poweri and was shown to belong t o the yohimbine class by dehydrogenation to 7-hydroxyyobyrine (CCC)whose formation, together with the UV-spectrum of poweridine, establishes the position of the original methoxyl group. The preparation of a ,L?-lactone (CCCII, v, CO, 1803 cm-1) by dehydration of the 11-methoxyyohimbic acid (CCCI) from poweridine indicated that the hydroxyl and carbomethoxyl groups of this acid were vicinal and cis. The remainder of the stereochemistry remains a t present unknown (161). Among the yohimbine-like alkaloids with a heterocyclic ring E the most widespread is isoreserpiline (CCCV) whose methochloride has also been &countered. The occurrence of this alkaloid and of aricine (CCCIII), reserpinine (CCCIV),reserpiline (CCCLVI), and ajmalicine (CCCXVII), is recorded in Table I. A 5,6-dimethoxyindole related to isoreserpiline is elliptamine which occurs in four Ochrosia species as well as in Excavatia coccinea (161). A representative of the group in which ring E is open is dihydrocorynantheol (CCCVI), which occurs in two Aspidosperma species (163, 48). The methochloride of this compound has been isolated from Hunteria eburnea ( 164). 10-Methoxydihydrocorynantheol(CCCVIA) and a 19,20-dehydro derivative (CCCVI-B) have also been encountered in Aspidosperma discolor (113d) and other Aspidosperma species (48). Alkaloids which could be identical with CCCVI, CCCVI-A, and CCCVI-B as well as a dehydro derivative of CCCVI and a series of four similar bases bearing a 16-carbomethoxyl group have been found in A . oblongum (164a). The identification of alkaloids of this type has been greatly facilitated by the introduction of mass spectrometry (165,162,163).By examination of a large number of derivatives, the breakdown pattern has been established, the principal peaks being represented by the fragments v and w which are formed by a cyclic transfer of electrons in ring D
OR3
Ri Rz R3 R4 Stereochemistry CCXCV H Me H H Y CCXCVI H Me H H P-y CCXCVII OMe Me Me OTMB 3-epi-a-Y CCXCVIII OMe Me H H unknown CCXCIX OMe Me Ac H unknown CCCI OMe H H H unknown Stereochemistry (substituent or angular H ) : Y = 3a,15a,l6a,17a,20P. /3-Y = 3~t,15a,16~(,17P,20/3. 3-epi-a-Y = 3/3,15a,16/3,17a,1813,ZO~t.
ai Q
0
ccc
CCCII
.U
bH20H
Ri CCCVI; R = H CCCVI-A; R = OMe* CCCVI-B; R = OMe, 19,20-dehydro*
* Stereochemistry unknown.
Rz
CCCIlI OMe H CCCIV H OMe CCCV OMe OMe
$
z1
484
B. GILBERT
(CCXCV,p. 486). These fragments are accompanied bv x and y (reverse Diels-Alder cleavage of ring C, formula CCCXVI) and all these four peaks occur in all yohimbine-type alkaloids whether ring E is homocyclic, heterocyclic, or open (165, 163). I n addition, there is always present in the mass spectra of this group a strong M-1 peak which is largely formed by the loss of the C-3 hydrogen atom. I n the heterocyclic ring E alkaloids, there is an additional indolic peak which has been assigned structure z (165).The described combination of peaks is not found in indole alkaloids based on the sarpagine, ibogamine, or eburnamine skeletons which each furnish a distinctive pattern (166, 167, 168, 169, 170, 51). The structures assigned to the fragments observed are based on the following evidence (165, 171). 1. The M - 1 Peak:
Fifty per cent of the M-1 peak is found a t M-2 in the spectra of 3-deuterioyohimbine (CCCVII, prepared by NaBD4 reduction of 3,4-dehydroyohimbine perchlorate) and of 3,5,6-trideuterioajmalicine (CCCIX, prepared by NaBD4 reduction of serpentine hydrochloride), so that onehslf of the hydrogen lost in the formation of this peak comes from C-3 or, in the case of ajmalicine, from C-3 and C-6. 2. Peaks v, w,x, and y Incorporate the Indolic Portion of the Molecule These four peaks remain invariable a t m/e 170, 169, 184, and 156 respectively when alterations are made in ring E as in the series, CCXCV, CCCX, CCCXI, CCCXII, and CCCXIII, and they do- not therefore contain atoms from this ring. The addition of substituents at positions 1, 3, 10, and 11 results in a corresponding increment in the mass of these fragments as is seen in the spectra of CCCXIV, CCCXV, and CCCVII (Table V). The importance of these peaks is explained by the ready cleavage of the allylically activated 3,14 bond.
3. The Structure of Peaks v and w Peak v, already shown to contain the indole residue, contains in addition carbon atoms 3,5, and 6, for in the spectrum of 3,5,6-trideuterioajmalicine (CCCIX) all three deuterium atoms are retained in this fragment. I n the spectrum of 3,14-dideuterioajmalicine (CCCVIII),prepared from serpentine by the successive action of NaBH4, HC1, and NaBD4, however, only one deuterium atom is retained in v which therefore does not contain C-14. Fragment w is derived from v by loss of one hydrogen from either C-5 or C-6 and this is shown by the fact that in the spectrum of 3,5,6-trideuterioajmalicine (CCCIX) w is split into two peaks, one in which one, and one in which two deuterium atoms have been retained.
14. Aspidosperma
AND RELATED ALKALOIDS
485
As the C-3 atom is always retained, the partial loss must occur from C-5 or C-6, which would seem t o indicate that there is no preference for the loss of deuterium over hydrogen in this case (compare 19-deuterio-17methoxyquebrachamine, Section 11, B). 4. The Xtructure of Fragment x I n the spectrum of 3,5,6-trideuterioajmalicine(CCCIX), all three deuterium atoms are retained, but in that of 3,14-dideuterioajmalicine (CCCVIII) only one deuterium atom appears in x. This fragment must therefore contain C-21 since it cannot contain C-14. 5. The Structure of Fragment y C-3 is present in this fragment (2 above) and from the spectrum of 3,14-dideuterioajmalicine (CCCVIII) it is seen that C-14 is also incorporated. Fragment y only retains two of the deuterium atoms of 3,5,6trideuterioajmalicine and therefore cannot contain (3-5. F'ragment y represents the strongest indolic peak in the spectra of the hetero ring E alkaloids because in these the 14,15 bond in the intermediate aa is doubly allylieally activated. The spectra may be used to distinguish the two most common stereochemical forms, those of ajmalicine (CCCXVII) and tetrahydroalstonine (CCCXVIII), since in the former the peak x is more intense than w or w, while in the latter and in yohimbine it is weaker. Examples are seen in the spectra of CCCIII-CCCV and CCCXVII-CCCXIX (Table V. Refs. 165, 37). B.
NORMACUSINE-B,
POLYNEURIDINE, AND AKUAMMIDINE
Notmacusine-B was first obtained by the thermal decomposition of its quaternary methochloride, macusine-B, which was isolated from Strychnos toxifera." It was found to be identical with 10-deoxysarpagine (CCCXX) and its N,-methyldihydro derivative was identical with deoxyisoajmalol-B (CCCXXIII) (172, 173), thus establishing its structure and absolute stereochemistry (177, see Chapter 22). Subsequently, normacusine-B has been found in Diplorrhyncus mossambicensis (named tombozine, 116, 121, 122) and in Aspidosperma polyneuron (165). Another alkaloid of A. polyneuron, polyneuridine, C21H24N203, differs from normacusine-B by C02CH2. It contains a carbomethoxyl group as was shown by hydrolysis to the acid, CCCXXIV, which was
* Maciisine-R also occurs in A . polyneuron (173a).
I
Rz
Rz
Rz
2,
w
X
R4 Ri CCXCV H CCCX H CCCXI H CCCXII H CCCXIII H CCCXIV OMe CCCXV H
Rz Rs
R4
H COzMe OH H COzMe H H H =o H =O H H COzMe =O H H =O Me H H
Ri
Stereochemistry
Y a-Y allo-Y
Y
Y
H R3
Y
R1 Rz R3 R4 CCCVII H CCCVIII H CCCIX D
H H D
D D D
H D H
Ri CCCXVII H CCCXVIII H CCCXIX H CCCIV H CCCIII OMe cccv OMe
Rz H H OMe OMe H OMe
Stereochemistry A T A T T T
Stereochemistry (substituent OT angular H ) : Y = 3a. 15a, 16e, 17a, 208. a-Y = 3a, 15a, 168, (17a), 20a. d o - Y = 3a, 15a, (168, 17/3), 20a. A z a 3a, 15a, 19a, 208. T = 3a, 15a, 19a, 20a.
488
2
P;
0,
\
/
U
P Y
\
/
xEr
B . GILBERT
t
RI R2 R3 CCCXXIV H CHzOH CO2H CCCXXV H CH~OAC CO2Me CCCXXXVI Me CHzOH COsMe HOCH2,
CCCXX; R =H CCCXXVIII; R = Ac
CCCXXXII
,C02Me
R3,
COOMe
I CCCXXXVIII
I
cccxxxv11 CCCXXIII CCCXXIX CCCXXXIV CCUXXXV
bb
m/e 168
tu
m/e 169
cc
m/e249
I
Ri R2 Me H H H H Me OMe H
R3 H CHzOH H H
* 2O.m-Et;t 20,P-Et
dd rnle223
R4 CHzOH* C02Me Met Me
490
B. GILBERT
isolated as the hydrochloride and remethylated to the parent alkaloid. Polyneuridine also formed a mono-0-acetate (CCCXXV), demonstrating the presence of an alcoholic hydroxyl group. The possibility thus existed that polyneuridine was a carboinethoxy derivative of normacusine-B and this was supported by lithium aluminum hydride reduction to the diol, CCCXXVI, whose diacetate, CCCXXVII. was sufficiently soluble in deuteriochloroform for NMR-spectroscopic comparison with the monoacetate (CCCXXVIII) of normacusine-B. In fact a strong similarity was observed, the only major difference between the two spectra being the presence in that of CCCXXVII of absorption due to two acetate methyl groups (1.92 and 2.03 6) and to four protons corresponding to two CHzOAc groups while normacusine-B acetate showed absorption due to only one such group. The four aromatic protons, indole NH, and ethylidene group of normacusine-B were all also present in polyneuridine, the latter being confirmed by hydrogenation to dihydropolyneuridine (CCCXXIX). Meanwhile, comparison of the mass spectra of polyneuridine and normacusine-B had also revealed a strong similarity between the two alkaloids. Both exhibited M-31 peaks, and as this is only attributable to loss of the primary alcoholic function as CHzOH in normacusine-B, it was reasonable to assume the presence of such a grouping in polyneuridine. Moreover, both spectra contained intense peaks a t m/e 168 and 169 which remained invariable through a series of derivatives in which the carbomethoxyl group of polyneuridine and the alcoholic function and double bond of both alkaloids were modified. These P-carbolinic peaks compare with the v and w peaks of the yohimbine-type molecules which occur a t m/e 170 and 169, respectively, when the aromatic ring is unsubstituted. The lowering of one mass unit in each is attributable to the presence of the extra 5,16 bond which must be broken to produce the P-carboline fragments bb and w. These fragments are observed in sarpagine-type molecules (e.g., CCCXXXIV and CCCXXXV) substituted in the aromatic ring and on N, when the appropriate molecular weight shifts are observed (167), so that there is no doubt that they derive from the indolic part of the molecule (Table V). It was therefore assumed that polyneuridine (CCCXXI) possessed a sarpagine skeleton both the carbomethoxyl and primary alcoholic groupings being located on the C-16 atom, a supposition which was supported by the fact that the aldehyde (CCCXXIX-A) prepared by chromic acid oxidation of polyneuridine contained no a-hydrogen atom (failure to exchange with sodium deuteroxide in deuteromethanol), and by the recognition in the mass spectra of a fragment cc in which the two substituent)s and one skeletal carbon atom are missing (165, 165a, b).
14. Aspidosperrna
AND RELATED ALKALOIDS
491
Confirmation of the proposed structure was obtained by comparison with the isomeric alkaloid akuammidine (CCCXXII), which occurs in Picralima nitida (Volume VII, p. 122) and Rhazia stricta (named rhazine, 62), and whose structure has been established both chemically (174) and by X-ray diffraction (175). Both alkaloids undergo retroaldolization with loss of the primary alcohol group to an ester (CCCXXX or CCCXXXI) which, on lithium aluminum hydride reduction, furnishes normacusine-B (CCCXX) (174, 165). Also both alkaloids similarly reduced yield the same diol, akuammidinol (CCCXXVI).Thus, the structure CCCXXI for polyneuridine was established, including the absolute configuration of the skeleton (165). The orientation of the two C-16 substituents was established in two ways. First, the degradation of vincamedine (CCCXXXII) by chromic acid oxidation to the indolenine CCCXXXIII led, by way of the reverse Mannich condensation and reduction with alkaline borohydride (compare Sections 11, B, 0 and VI, B), to polyneuridine (CCCXXI) which cannot therefore have the alternative configuration (176). Second, the establishment of the C-16 orientation in akuammidine (175)required the structure CCCXXI for polyneuridine by difference. Polyneuridine is thus "normacusine-A," the tertiary base corresponding to the quaternary methochloride macusine-A which occurs in S . toxifera (173), and whose structure has been established by X-ray diffraction (178). Its N,-methyl derivative is the alkaloid voachalotine (CCCXXXVI) which occurs in Voacanga chalotiana (179, 176). The C-18 methyl group lies trans to the 20-21 bond (175, 178, see formulaCCCXXXVI1) as is also the case withechitamine,(CCCXXXVIII) and those alkaloids of the akuammicine type that have been related to the Wieland-Gumlich aldehyde (Chapter 7). It will be noted that polyneuridine is one member of a closely related group of alkaloids, which includes not only vincamedine and echitamine but also akuammine (CCCXXXVIII-A), #-akuammigine (CCCXXXVIII-B) (184a, b), picraline (179a, e), and quebrachidine (CCCXXXVIII-D, see following section). C.
QUEBRACHIDINE
A wide variety of alkaloids has been encountered in the bark of Aspidosperma puebrachoblanco (see Table I). An investigation of the leaf alkaloids yielded a new base, quebrachidine (CCCXXXVIII-D, 179b), whose UV- ( h 242, 290) and NMR-spectra were indicative of a dihydroindole unsubstituted in the benzene ring, while the IR-spectrum showed the presence also of the groupings NH, OH, and C02R. The NMRspectrum further indicated that the ester was a carbomethoxyl group
CCCXSXIX
Ri
CCCXXXVIII-A; R = OH CCCXXXVJII-B; R = H
\
Ri Rz CCCXXXVJII-E Ac Ac CCCXXXVIII-F CHO CHO CCCx xx I I Me Ac
8
-
;;:; IH N H' i ;
oTqz tj
W M
%
H
\
CCCXXXVTIJ-D
\
CCCXXI
14. Aspidosperma
T
X
Y
403
F-
d x 0
AND RELATED ALKALOIDS
/ II I1
X 4 SIX
Y Y U
+x
55 xx xx xx
88 vv
494
B. GILBERT
(3.6 6) and that there was an ethylidine group present (three protons at 1.5 6, doublet; one proton a t 5.1 6, quartet, J = 6.5 clsec). A second basic nitrogen atom was indicated by the pKi 6.7. Quebrachidine formed an N,O-diacetate (OAc, v, 1745 cm-1, 3-proton singlet, 1.72 6 ; N-Ac, V , 1658 cm-I, 3-proton singlet, 2.45 6) whose UV-spectrum (A 250) showed that the dihydroindole nitrogen had been acetylated. A comparison of the NMR-spectra of the parent base and the diacetate showed that the former was a secondary alcohol since a single proton peak due to CHOH was shifted downfield by 2 ppm in the acetate. The nature of the skeletal structure of the alkaloid became clear from a comparison of the mass spectra of the base and particularly of its diacetate with that of vincamedine (CCCXXXII). Quebrachidine itself shows a molecular ion peak at m/e 352 establishing the molecular formula, C~lH24N203,while indolic peaks appear at m/e 130 and 143 confirmatory of the unsubstituted dihydroindole structure. Of special interest however is the parallel fragmentation of quebrachidine (CCCXXXVIII-D), quebrachidine diacetate (CCCXXXVIII-E), and vincamedine (CCCXXXII, Table V) which shows that all three have the same alicyclic skeleton. The fragmentation of this skeleton appears to involve as a principal process the rupture of the 2-3 and 5-6 bonds with the production of two fragments, either of which may bear the positive charge. Thus, for quebrachidine the indolic peak b at m/e 130 is accompanied by a peak, p p , at M-130. The diacetate also shows b at m/e 130 (N,-acetyl is lost as ketene) and p p a t M-(130+42). I n the case of vincamedine, the b peak is observed at m/e 144 due to the presence of an N,-methyl group, while p p appears at M-144. The peak p p thus represents that part of the molecule not present in fragment 6 , and in conformity with this is accompanied by satellites qq and w at mle values corresponding to the loss of acetyl (pp-42)and further loss of methanol (qq-32; or for quebrachidine, pp-32) (179b). Further confirmation of the structure (CCCXXXVIII-D) for quebrachidine was obtained by opening the five-membered ring by lead tetraacetate oxidation to an indolenine and reverse Mannich cleavage and reduction with borohydride. As in the case of vincamedine (Section VIII, B), the product was polyneuridine (CCCXXI). A similar oxidation of the product CCCXXXVIII-G (obtained from quebrachidine by successive formylation to CCCXXXVIII-F, and LiAlH4 reduction) gave by direct reverse Mannich cleavage the aldehyde CCCXXXVIII-I whose mass spectrum showed i t to have the same skeleton as deoxyajmalal-A (CCCXXXVIII-J). Morevoer, the diol CCCXXXVIII-G gave a monoacetate (CCCXXXVIII-H) identical with that obtained by reduction and acetylation of vincamedine (CCCXXXII, 179c).
14. Aspidosperma AND RELATED ALKALOIDS
495
Knowledge was still lacking of the stereochemistry at C-2 and C-17. A comparison of the mass spectra (cf. 179d) of ajmaline (CCCXXXVIII-K) and tetraphyllicine (CCCXXXVIII-L), which have @-H, with that of quebrachidine showed differences, although ajmaline shows peaks corresponding t o the expected b, b + 13, and p p fragments. A very close resemblance was observed between the spectra of quebrachidine and 2-epi-21-deoxyajmaline (CCCXXXVIII-M) and it may be assumed that the former has C-2, a-H (179b). The secondary hydroxyl group a t C-17 is cis to the carbomethoxyl function, as in ajmaline, since the diol, CCCXXXVIII-G, forms an isopropylidene derivative (CCCXXXVIII-N) impossible for the reverse configuration.
D. HARMAN-3-CARBOXYLIC ACID Among the water-soluble bases of Aspidosperma polyneuron there has been isolated an ester which after methanolysis yielded the known compound 3-carbomethoxyharman (CCCXXXIX) which was recognized by its NMR- and mass spectra (180, 181, Tables I V and V). The natural alkaloid is presumably a glycosidic ester of the corresponding acid.
E. EBURNAMINE AND RELATED ALKALOIDS The known alkaloids eburnamine (CCCXL),eburnamonine (CCCXLII), eburnamenine (CCCXLIII), and possibly isoeburnamine (CCCXLI) have been isolated from plants of the genera Pleiocarpa, Aspidosperma, and Rhaxia (Table I, Refs. 91, 53, 28, 51). These alkaloids were first discovered in Hunteria eburnea (Chapter 11)and their structures (183) and stereochemistry ( 183a) determined. Related alkaloids occur in the genus Vinca (184, 78, 170) and in both this genus and in Aspidosperma their identification in minute quantities has been made possible by mass spectrometry (51, 170) in which the breakdown path has been elucidated by isotopic replacement ( 5 1). The main fragments produced from eburnamenine (CCCXLIII) probably have the structures shown in the formulas ee, ff, and g g ; the fact that it is ring E that survives in these fragments is shown conclusively by the spectra of 14-deuterioeburnamenine (CCCXLIV), dihydroeburnamenine (CCCXLV), and 14-deuteriodihydroeburnamenine (CCCXLVI) in which each of the peaks suffers progressive increments of one mass unit. Peak gg is weak in the spectrum of eburnamonine (CCCXLII) in which another peak, hh, appears, derived from ff by the loss of 28 units. When the carbonyl
CCCXL
CCCXLV
CCCXLVI
CCCXLI
ff M-29 14,15-saturated
\
CCCXLII
1
ee‘
M-70
ff’ M-29
LiAlDl
CCCXLVII
CCCXLN 496
hh
14. Aspidosperma
AND RELATED ALKALOIDS
497
oxygen was replaced (partially) by Ol8, this peak, in contrast t o all the others, underwent no alteration. The peak hh therefore involves the loss of CO f r o m 8 and may be allocated the structure shown (51).It will be seen that the postulated cleavages 1 and 2 are highly favored ones, for they not only involve the breakage of allylically activated bonds but in most cases by a suitable shift of electrons the E ring in the resultant fragments can become fully aromatic (170,51).The reverse Diels-Alder reaction pictured as occurring in ring C is characteristic of the mass spectral breakdown of molecules containing a singly unsaturated sixEburnamine (CCCXL)gives the same spectrum membered ring (21,185). as eburnamenine (CCCXLIII) but may be distinguished by lithium aluminum deuteride reduction to 14-deuteriodihydroeburnamenine (CCCXLVI)(51). 0-Methyleburnamine (CCCXL-A),found in Haplophyton cimicidum, was identified by loss of methanol to eburnamenine (CCCXLIII) and chromic acid oxidation to eburnamonine (CCCXLII, 113b).
F. TUBOFLAVINE A novel canthine-type alkaloid, tuboflavine (CCCXLVIII), has been isolated from the bark of Pleiocarpa tubicina (186).Its highly aromatic nature was recognized from the UV-spectrum (A 215, 264,289,323, 401) which, although unchanged in alkali, underwent a large bathochromic shift in acid or on formation of the methiodide. The empirical formula,
CCCXLVIII
CCCXLVIII-A
CCCXLVIII-B
C ~ ~ H ~ Z N Zwas O , confirmed mass spectrometrically. Tuboflavine is reduced by lithium aluminum hydride to a mixture of two compounds, both of which have the UV-absorption of indolic-N-methylharman, indicating substitution of N,. By the successive action of dilute alkali and methanolic hydrochloric acid, tuboflavine was cleaved to l-carbomethoxy-/3-carboline (CCCXLVIII-A), a result which would exclude a true canthine-type structure based on the skeleton (CCCXLVIII-B).
498
B. GILBERT
The NMR-spectrum of tuboflavine exhibited absorption characteristic of an aromatic ethyl group (CH3, 1.32 6, triplet; CH2, 2.8 6, quartet, J = 7.5 cjsec) and seven aromatic protons, and was fully consistent with structure CCCXLVIII for the alkaloid (186).
G. FLAVOCARPINE Earlier work (186a, 186b, 186c) had shown the presence of physiologically active alkaloids in the plants Pleiocurpu tubicina and P. mutica and the chemistry of some of the tertiary bases from these plants has been described in Sections 111,G, H ; V, D ; VI, C ; and in the preceding section. After complete removal of the chloroform-soluble bases of P. mutica, it was found (186d)that the alkaline aqueous extract still gave a strong Mayer reaction and by way of butanol extraction, precipitation of the picrates, recovery of the free amino acid by ion exchange followed by countercurrent distribution, it was possible t o isolate the yellow zwitterionic alkaloid, flavocarpine (CCCXLVIII-C). The complex UVspectrum of the alkaloid was very similar to that of flavopereirine (CCCXLVIII-D, 186d, 186f, 186g) from which the principal difference lay in the presence in the former of an ionized carboxyl group (v, 1595 cm-1). The NMR-spectrum (trifluoroacetic acid solution) showed that an aromjttic ethyl group (1.55 6, triplet; 3.42 6, quartet) was also present in flavocarpine (186d). Methylation of flavocarpine (CCCXLVIII-C) with methanol and hydrochloric acid gave the methyl ester chloride (CCCXLVIII-E) which, with sodium carbonate, yielded the red anhydronium base, CCCXLVIIIF. The methyl ester chloride suffered reduction of the C ring with sodium borohydride, to give an indole (CCCXLVIII-G, cf. 186h), and this provided a safe distinction from a pyridocarbazole-type structure (cf. 152) for the ester which would have suffered reduction in ring D t o leave a carbazole chromophore in the product (149, 158). Mass spectral molecular weight determination established the presence of one residual double bond in CCCXLVIII-G, not conjugated with the indole chromophore (UV-spectrum), but conjugated with the carbomethoxyl group (IR, v, 1705 cm-1). The absence of vinyl proton absorption in the NMRspectrum showed that it was tetrasubstituted and this evidence, combined with biogenetical probability and the appearance of a v peak at m/e 170 in the mass spectrum (see Section VIII, A), suggests structure CCCXLVIII-G for the reduction product. Full confirmation of the skeleton and position of the ethyl substituent was obtained by direct
14. Aspidosperma
499
AND RELATED ALKALOIDS
decarboxylation of flavocarpine (CCCXLVIII-C) to flavopereirine (CCCXLVIII-D) (186d). Synthesis of flavocarpine was achieved by use of a modification of the method worked out by Ban and Seo (186i), in which a 2-chloropyridine is condensed with 3-( 2-bromoethyl)-indole to form th'e required ring system directly. Thus, to provide the eventual carboxyl group of flavocarpine, a cyano group was introduced into 3-ethylpyridine. This was
it CCCXLVIII-C; R CCCXLVIII-D; R CCCXLVIII-E; R CCCXLVIII-P; R CCCXLVIII-Q; R
= COz-
H (salt) = COzMe = CONHz = COzH
I
MeOzC CCCXLV1TI-G
v
in/e 170
=
OQ
I
OMe I
I
R
RI
CCCXLVIII-H; R = H CCCXLVIII-K; R = CN
CCCXLVIII-I
Ri Rz CCCXLVIII-J C N H CCCXLVIII-L CN c1 CCCXLVIII-M CONHz C1
CCCXLVIII-D; R = H (anhydronium) CCCXLVIII-F; R = COzMe
CCCXLVIII-0
CCCXLVIII-N
effected by preparation of the N-oxide, CCCXLVIII-H, methylation to the iodide, CCCXLVIII-I, and direct cyanation (cf. 186j) followed by fractionation of the products (distinction of correct isomer, CCCXLVIIIJ, by NMR-spectroscopy and conversion to 3,4-diethylpyridine). The required chlorine atom was introduced by treatment of the N-oxide, CCCXLVIII-K, with phosphorus oxychloride in hot chloroform, the
500
XXXR
. . . . .. .. .. ..
B. GILBERT
G L
N
$3
+
zh
14. Aspidosperma
(3 N
AND RELATED ALKALOIDS
V
5 v v
H H
55
v vv v vv
501
502
B. GILBERT
required isomer, CCCXLVIII-L, again being distinguished by NMRabsorption. For the condensation with the bromoethylindole, CCCXLVIII-N, the solid amide, CCCXLVIII-M, was preferred to the liquid cyanide, and the product, CCCXLVIII-0, was readily dehydrogenated with tetrachloroquinone t o the amide of flavocarpine (CCCXLVIII-P). Hydrolysis with aqueous hydrochloric acid furnished flavocarpine itself as the hydrochloride (CCCXLVIII-Q) from which the free base identical with natural flavocarpine (CCCXLVIII-C) was obtained by passage through an ion-exchange resin (186d).
H. CARAPANAUBINE The alkaloid carapanaubine, C23H28N206, which occurs in Aspido-
sperma carapanauba, was remarkable in that although it had a non-
indolic UV-spectrum its NMR-spectrum was very similar to that of isoreserpiline (CCCV, Table IV), the only significant difference being the position of the N, proton which was farther downfield (8.73 6) with carapanaubine than with isoreserpiline (7.95 6). The presence of an extra carbonyl band in the IR-spectrum and of an extra oxygen atom in the molecule coupled with the UV- and NMR-data led to the supposition that carapanaubine was an oxindole in which rings A, D, and E were identical with the corresponding rings in isoreserpiline (271). I n order to settle this question, a number of oxindoles (CCCXLIX-CCCLIII), prepared by the tertiary butyl hypochlorite (187, 188) or lead tetraacetate (189) oxidation and rearrangement of the corresponding indoles (CCCXVII, CCCL-A, CCCIX, CCCVIII, CCCIII), were examined mass spectrally. It was thus possible to establish the breakdown pattern represented by the formulas ii-nn in which the structures of the various fragments were elucidated by deuteration in the positions 3, 5 , 6, and 14 (CCCL-CCCLII) and by the presence of a methoxyl group in the aromatic ring (CCCLIII). I n the spectrum of carapanaubine the principal peaks were found in positions identical with those exhibited by mitraphylline (CCCXLIX) and aricine oxindole (CCCLIII), with the sole exception that those fragments which incorporated the benzene ring were shifted to higher mle values corresponding to the presence of two methoxyl groups in that ring. Carapanaubine thus has the structure CCCLIV and i t remained only to settle the stereochemistry. I n the NMR-spectrum of carapanaubine the coupling between the C-19 proton (octet a t 4.56 6) and the C-18 methyl protons (doublet a t 1.4 6, J = 6 c/sec) was eliminated by spin decoupling and the C-19 proton absorption then appeared as a doublet with J = 5.7 c/sec due to
14. Aspidosperma
AND RELATED ALKALOIDS
503
coupling with the lone C-20proton. Carapanaubine cannot therefore have the C-19 CC, DIE-trans configuration of mitraphylline (CCCXLIX) nor the C-19 /I, DIE-cis configuration of formosanine (CCCLV) since these alkaloids have been shown to have smaller 19,ZO-HHcoupling conshants (190).There was every possibility, therefore, that carapanaubine had the C-19 a , DIE-cis stereochemistry as in reserpiline (CCCLVI) and isoreserpiline (CCCV) (191, 192). This was fully confirmed by synthesis from reserpiline (CCCLVI)using the lead tetraacetate oxidation method applicable t o indolic alkaloids with cis D/E ring junction (189). The intermediate 7-acetoxy-7H-reserpiline (CCCLVII) was rearranged in methanol containing a little acetic acid and, as under these conditions oxindoles equilibrate to a mixture of the “A” (CONH, a ) and “ B ” (CONH, /3) stereoisomers, two products were obtained, one of them being carapanaubine (CCCLIV).It has been shown that the oxindoles resulting from this type of rearrangement have the 3-aH configuration irrespective of the starting material; the two oxindoles obtained were therefore isoreserpiline oxindoles A and B. The B configuration was allocated to carapanaubine, as it moved more slowly on paper chromatography-a property characteristic of the more strongly basic B isomers (189, 187).
I. ISORESERPILINE-+-INDOXYL The isolation of isoreserpiline-+-indoxy1 (CCCLVII-A) from Aspidosperma discolor has been reported (113d). The structure of this yellow alkaloid, which has also been encountered in Rauwolfia species, was established by synthesis from isoreserpiline (CCCV) (192a, 192g). The synthesis of +-indoxyls from indoles differs from that of oxindoles, described in the preceding section, only in the final treatment of the intermediate 7-acyloxy-7H-indolenine [in this case 7-m-bromobenzoyloxy-7H-isoreserpiline (CCCLVII-B)] with methanolic alkali instead of weak acid (192a).
J. OCHROPAMINE AND OCHROPINE The alkaloids ochropamine (CCCLVII-C)and ochropine (CCCLVII-D) from Ochrosia poweri are the only representatives of the growing 2acylindole class so far encountered in the genera under study (192d). The nature of the chromophore (A 243 and 315 mp, E 18,900, 17,700) present in CCCLVII-C was determined both by alkaline degradation to 2-acetyl-1,3-dimethylindole and by comparison with the known 1-keto1,2,3,4-tetrahydrocarbazole.The presence of carbomethoxyl (5.78 p,
504
13. GILBERT
2.58 8) and N-methyl groups suggested a relation t o vobasine (CCCLVIIE) whose structure and stereochemistry are known (192e, 192f). Com-
parison of the NMR spectra of vobasine, ochropamine, and ochropine left no doubt as t o the skeletal and relative stereochemical identity of the three alkaloids, and showed that ochropamine (CCCLVII-C)differed from vobasine only in possessing an N,-methyl group (NMR, 4.056), while ochropine (CCCLVII-D) contained in addition an aromatic methoxyl group. This was located by UV-comparison with model compounds (192d). MeOIC \
RI CCCLVII-C CCCLVII-D CCCLVII-E
Rz
H Me OMe Me H H
R,
Rz
IX. Alkaloids of Unknown Structure A. ALKALOIDSOF Pleiocarpa SPECIES Three alkaloids whose structure is unknown at the time of writing have been isolated from Pleiocarpa mutica (91). One of them, pleiocarpamine, C2oH22N202, is a pentacyclic indole in which N, is substituted. Nb is tertiary and the two oxygen atoms have been located in a carbomethoxyl group. The alkaloid bears an ethylidene side chain (91, 53). The other two, pleiomutine and pleiomutinine, are double alkaloids. Pleiomutine shows UV-absorption similar to that of leurosine and vinblastine and contains, therefore, an indole and a dihydroindole chromophore. The UV-spectrum of pleiomutinine, on the other hand, extends to longer wavelengths showing distinct similarity t o the spectra of vobtusine and callichiline (193). I n the species P. tubicina the occurrence of the two lactams pleiocarpinilam and kopsinilam has been described (Section 111, H). I n addition, a third lactam was isolated from this plant which exhibited IR-absorption bands a t 1763 and 1687 cm-1 (96).
B. ALKALOIDSOF Ochrosia SPECIES A number of species of the genus Ochrosia have been investigated, and among the alkaloids already discussed are ellipticine and methoxyellipticine from 0. elliptica (Section VII, D). Other alkaloids from this species include elliptinine for which structure CCCLVIII has been
14. Aspidosperma
AND RELATED ALKALOIDS
505
proposed (156). 0. sandwicensis yielded an unnamed base with UVabsorption a t 238 and 290 mp (156). An unnamed alkaloid from 0. oppositifoZia, C ~ ~ H ~ ~ Nhas Z Othe , same composition as methoxyellipticine. The UV-absorption (A 242, 275, 290, 335 mp; loge 4.35, 4.59,
CCCLVIII
4.66, 3.71) is also very similar (194). Australian and New Guinea species, notably 0. poweri, contain a number of alkaloids (161), including elliptamine, C24H3oNz05, powerine, C21H26N204, and poweramine, C23H30Nz04 (161). Elliptamine, the most widespread, is unstable in the form of the free base. It forms an orange-red picrate. Powerine and poweramine may be 5- and 6-methoxy indoles, respectively (161).
C. ALKALOIDS OF Aspidosperma, Rhazya, AND Stemmadenia I n addition to olivacine and guatambuine (Section VII, C), an unnamed alkaloid, mp 186"-188", resembling uleine in its color reactions, has been isolated from Aspidosperma australe (147)s. A glycosidic alkaloid, quebrachacidine, C26Hz8N2011, has been found in A. quebrachoblanco (195), and its aglycone has been prepared. Several alkaloids have been reported in A . oblongum and A . album (196), notably kromantine, mp 176", [aID+ 159" (in chloroform), from the latter species (196a). Among the many alkaloids of Rhazya stricta (seeTable I),the structure of the alkaloid rhazinine remains to be determined (197). This indolic base, C19H24N20, contains a primary alcoholic group but, unlike akuammidine (CCCXXII)which accompanies it in the plant, it contains no G-methyl (197). Other alkaloids of the same plant include rhazidine, CzoHzsN203, HzO, mp 278-279", [.ID - 21" (in ethanol) (199, 200, 62). Two unnamed alkaloids, mp 233"-235" (dec.) and 135"-139", respectively, were isolated from Stemmadenia donnell-smithii, but no further information is available on these a t the time of writing (8). REFERENCES 1. R.B. Woodward, Nature 162, 155 (1948). 2. Sir Robert Robinson, 'I The Structural Relationsof NaturalProducts." OxfordUniv. Press, London and New York, 1955.
3. C. Djerassi, S. E. Flores, H. Budzikiewicz, J. M. Wilson, L. J. Durham, J. Le Men, M. M. Janot, M. Plat, M. Gorman, and N. Neuss, Proc. NatE. Acad. Sci. U.S. 48, 113 (1962).
3
This alkaloid has been identified as apparioine [CCLVII-U p. 473 (37)].
506
B . GILBERT
4. M. Gorman, N. Neuss, and K. Biemann, J . Am. Ch,em. SOC.84, 1058 (1962). 5. G. H. Svoboda, I. S. Johnson, M. Gorman, and N. Neuss,J. Phrcrm. Sci. 51,707 (1962). 6. C. Djerassi, H. Budzikiewicz, J. M. Wilson, J. Gosset, and M. M. Janot, Tetrahedron Letters p. 235 (1962). 7. M. Plat, J. Le Men, M. M. Janot, J . M. Wilson, H. Budzikiewicz, L. J. Durham, Y . Nagakawa, and C. Djerassi, Tetralbedron Letters p. 271 (1962). 8. F. Walls, 0 . Collera, and A. Sandoval, Tetrahedron 2, 173 (1958). 9. C. Djerassi, R.Gilbert, J. N. Shoolery, L .F. Johnson, and K. Biemann, Ezperientia 17, 162 (1961). 10. C. Djerassi, A. A. P. G. Archer, T. George, B. Gilbert, and L. D. Antonaccio, Tetrahedron 16, 212 (1961). 10a. J . Mokrj., I. KompiB, L. Dubravkovb, and P. SepEoviE, Tetrahedron Letters p. 1185 (1962). lob. J. Mokry and I. KompiB, Chem. Zvesti 17,852 (1963). 11. J. F. D. Mills and S. C. Nyburg, J . Chem. SOC.p. 1458 (1960). 12. G. F. Smith and J . T. Wrobel, J . Chem. SOC.p. 1463 (1960). 13. H. Kny and B. Witkop, J . Org. Chem. 25, 635 (1960). 14. E. Wenkert, Experientia 15, 165 (1959) (see footnote 53). 15. B. U‘itkop,J. Am. Chem. SOC.79, 3193 (1957). 16. B. Witkop, J. Am. Chem. SOC.70, 3712 (1948). 17. L. A. Cohen, J. W. Ualy, H. Kny, and B. Witkop,J. Am. Chem. SOC.82,2184 (1960). 18. K. Biemann and G. Spiteller, Tetrahedron Letters p. 299 (1961). 18a. K. Biemann and G. Spiteller, J . Am. Chem. SOC.84, 4578 (1962). 19. G. F. Smith and J. T. Wrobe1,J. Chem. SOC.p. 792 (1960). 20. J. H. Benyon, “Mass Spectrometry and its Applications t o Organic Chemistry.” Elsevier, Amsterdam, 1960. 2 1. K. Biemann, “Mass Spectrometry, Organic Chemical Applications.” McGraw-Hill, New York, 1962. 22. J. F. D. Mills and S. C. Nyburg, Tetrahedron Letters No. 11, 1 (1959). 23. &. Schmutz and H. Lehner, Helv. Chim. Acta 42, 874 (1959). 24. H. Conroy, P. R. Brook, and Y . Amiel, Tetrahedron Letters No. 11, 4 (1959). 25. B. Witkop and J. B. Patrick, J . Am. Chem. SOC.76, 5603 (1954). 26. H. Conroy, P. R. Brook, M. K. Rout, and N. Silverman,J. Am. Chem. SOC.SO, 5178 (1958). 27. A. J . Everett, H. T. Openshaw, and G. F. Smith, J . Chem. SOC. p. 1120 (1957). 27a. G. Stork and J. E. Dolfini, J . Am. Chem. SOC.85, 2872 (1963). 27b. G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz, and R. Terrell, J . Am. Chem. SOC.85, 207 (1963). 28. K. Biemann, M. Friedmann-Spiteller, and G. Spiteller, Tetrahedron Letters p. 485 (1961). 28a. H. Budzikiewicz, C. Djerassi, and D. H. Williams, “Structure Elucidation of Natural Products by Mass Spectrometry,” Vol. I : Alkaloids. Holden-Day, Sen Francisco, 1964. 28b. P. Bommer, W. McMurray, and K. Biemann, J . Am. Chem. SOC.86, 1439 (1964). 29. C. Djerassi, A. A. P. G. Archer, T. George, B. Gilbert, J. N. Shoolery, and L. F. Johnson, Ezperientia 16, 532 (1960). 30. S. McLean, K. Palmer, and L. Marion, Can. J . Chem. 38, 1547 (1960). 31. M. Pinar and H. Schmid, Helv. Chim. Acta 45, 1283 (1962). 32. M. Plat, J. Le Men, M. M. Janot, H. Budzikiewicz, J. M. Wilson, L. J. Durham, and C. Djerassi, Bull. SOC.Chim. France p. 2237 (1962).
14. Aspidosperma AND RELATED ALKALOIDS
507
33. M. Pinar, W’.von Philipsborn, W. Vetter, and H. Schmid, HeZw. C’him.Acta 45,2260 (1962). 34. 0. 0. Orazi, R. A. Corral, J. S. E. Holker, and C. Djerassi, J . Org. Chem. 21, 979 (1956); Anales Asoc. Quim. Arg. 44, 177 (1956). 35. C. Djerassi, H. W. Brewer, H. Budzikiewicz, 0. 0. Orazi, and R. A. Corral, Experientia 18, 113 (1962). 36. C. Djerassi, H. W. Brewer, H. Budzikiewicz, 0. 0. Orazi, and R. A. Corral, J . Am. C‘hem. Soc. 84, 3480 (1962). 37. C. Cjerassi, J. M. Ferreira, S. E. Flores, T. George, B. Gilbert, H. J. Monteiro, H. Budzikiewicz, J. M. Wilson, L. J. Durham, R. J. Owellen, and E. Bianchi, Unpublished work (1963). 38. A. J. Ewins, J. Chem. SOC.105, 2738 (1914). 38a. A. C. Paladini, E. A. Ruveda, R. A. Corral, and 0. 0. Orazi, Anales Asoc. Quim. Arg. 50, 352 (1962). 38b. P. Relyveld, Pharm. Weekbhd 98, 175 (1963). 39. E. Schlittler and M. Rottenberg, Hell. Chim. Acta 31, 446 (1948). 40. J. Aguayo Brissolese, C. Djerassi, and B. Gilbert, Chem. Ind. (London)p. 1949 (1962). 40a. J. M. Ferreira, B. Gilbert, R. J. Owellen, and C. Djerassi, Experientia 19, 585 (1963). 41. J. S. E. Holker, M. Cais, F. A. Hochstein, and C. Djerassi, J. Org. Chem. 24, 314 (1959). 41a. V. Deulofeu, J . De Langhe, R. Labriola, and V. Carcamo, J . Chem. SOC.p. 1051 (1940). 42. C. Ferrari, S. McLean, L. Marion, and K. Palmer, Can. J . Chem. 41, 1531 (1963). 43. W. I. Taylor, N. Raab, H. Lehner, and J. Schmutz, Helw. Chim. Acta 42,2750 (1959). 44. C. F. Garbers, H. Schmid, and P. Karrer, Helw. Chim. Acta 37, 1336 (1954). 45. S. McLean, Can. J . Chem. 38, 2278 (1960). 46. L. Jurd, Arch. Biochem. Biophys. 63, 376 (1956). 47. V. Deulofeu, Personal communication (1962). 48. B. Gilbert, A. P. Duarte, Y. Nakagawe, J. A. Joule, S. E. Flores, J. A. Brissolese, J. Campello, E. P. Carrazzoni, R. J. Owellen, E. C. Blossey, hnd C. Djerassi. TObe published (1964). 49. B. Gilbert, L. D. Antonaccio, A. A. P. G. Archer, and C. Djerassi, Experientia 16, 61 (1960). 50. K. Bowden, I. M. Heilbron, E. R. H. Jones, and B. C. L. Weedon,J. Chem. SOC.p. 39 (1946). 51. H. K. Schnoes, A. L. Burlingame, and K. Biemann, TetrahedronLettem p. 993 (1962). 51a. K. Biemann, M. Spiteller-Friedmann, and G. Spiteller, J. Am. Chem. SOC.85, 631 (1963). 51b. G. F. Smith and M. A. Wahid, J . Chem. SOC.p. 4002 (1963). 52. C. Djerassi, L. D. Antonaccio, H. Budzikiewicz, J. M. Wilson, and B. Gilbert, Tetrahedron Letters p. 1001 (1962). 53. H. Schmid, Unpublished work (1963). 54. F. W. McLafferty, Anal. Chem. 31, 2072 (1959). 54a. S. McLean, Can.J. Chem. 42, 191 (1964). 55. N. Neuss, “Physical Data of Indole and Dihydroindole Alkaloids,” 4th rev. ed., Vol. I. Eli Lilly and Co., Indianapolis, Indiana, 1960. 56. N. Neuss, “Physical Data of Indole and Dihydroindole Alkaloids,” 4th rev. ed., Vol. 11. Lilly, Indianapolis, Indiana, 1962. 57. R. E. Woodson, Ann. Missouri Botan. Garden 38, 119 (1951).
508
B. GILBERT
J. Schmutz, Pham. Acta Helv. 36, 103 (1961). 0. Hesse, Ann. Ghem. 211, 249 (1882). E. Schlittler and E. GBllert, Helv. Chim. Acta 34, 920 (1951). E. GQllertand B. Witkop, Helv. Chim. Acta 35, 114 (1952). A. Chatterjee, C. R. Ghosal, N. Adityachaudhury, and S. Ghosal, Chem. Ind. (London)p. 1034 (1961). 63. L. D. Antonaccio, Rev. Quim.I d . ( R i o de Janeiro) 26, 149 (1957). 64. M. M. Janot, J. Le Men, and C. Fan, Compt. Rend. Acad. Sci. 248, 3005 (1959). 65. M. M. Janot, H. Pourrat, and J. Le Men, Bull. Soc. Chim. France p. 707 (1954). 66. A. Sandoval, Unpublished work (1958) cited in reference 7. 66a. 0. Collera, F. Walls, A. Sandoval, F. Garcia, J . Herran, and M. C. Perezamador, Bol. Inst. Quim. Univ. Nac. Auton. Mexico 14, 3 (1962). 67. K. Bernauer, W. Arnold, C. Weissmann, H. Schmid, and P. Karrer, Helv. Chim. Acta 43, 717 (1960). 68. M. M. Janot, J. LeMen, A. LeHir, J. Levy, andF. Puisieux, Compt. Rend. Acad. Sci, 250, 4383 (1960). 69. J. Levy, J. Le Men, and M. M. Janot, Bull. SOC.Chim. France p. 979 (1960). 70. K. Aghoramurthy and Sir Robert Robinson, Tetrahedron 1, 172 (1957). 71. M. M. Janot, J. Le Men, and C. Fan, Bull. Soc. Chim. France p. 891 (1959). 72. M. Gorman, N. Neuss, G. H. Svoboda, A. J. Barnes, and N. J. Cone, J . Am. Pharm. Assoc. Sci. Ed. 48, 256 (1959). 72a. N. Neuss, M. Gorman, W. Hargrove, N. J. Cone, K. Biemann, G. Buchi, and R. E. Manning, J . Am. Chem. Soc. 86, 1440 (1964). 73. J. Mokrj., I. KompiB, L. Dubravkova, and P. SevEoviE, I U P A C Congr. Nut. Prod., Prague, 1962; Experientia 19, 311 (1963). 74. J . Gosset, J. Le Men, and M. M. Janot, Ann. Pharm. Franp. 20,448 (1962). 74a. J. Mokrj., L. D6bravkov&, and P. SepEoviE, Experientia 18, 564 (1962). 75. M. M. Janot, in “The Chemistry of Natural Products,” Vol. 2, p. 635. Butterworths, London (1963). 76. M. Plat, E. Fellion, J. Le Men, and M. M. Janot, Ann. Pharm. Franp. 20, 899 (1962). 77. P. N. Edwards and G. F. Smith. Proc. Chem. Soc. p. 215 (1960).78. J. Mokry, 1. KompiB, and P. SefEoviE, Tetrahedron Letters p. 433 (1962). 79. L. D. Antonaccio, J . Org. Chem. 25, 1262 (1962). 80. C. Djerassi, R. J . Owellen, J. M. Ferreira, and L. D. Antonaccio, Experientia 18, 397 (1962). 81. B. Gilbert, J . M. Ferreira, R. J. Owellen, C. E. Swanholm, H. Budzikiewicz, L. J. Durham, and C. Djerassi, Tetrahedron Letters p. 59 (1962). 82. C. Djerassi, T. George, N. Finch, H. F. Lodish, H. Budzikiewicz, and B. Gilbert, J . Am. Chem. Soc. 84, 1499 (1962). 83. M. Greshoff, Ber. 23, 3537 (1890). 84. W. P. H. van den Driessen Mareeuw, Ned. Tijdschr. Pharm. Chem. Toxicol. 8, 199 (1896). 85. K. Gorter, Jaarb. Dept. Landb. Ned.-Ind. p. 240 (1920). 86. L. J. Webb, Australia, Commonwealth Sci. Ind. Res. Organization Bull. No. 268 (1952). 87. W. D. Crow and M. Michael, AustralianJ. Chem. 8, 129 (1955). 88. N. G. Bisset, W. D. Crow, and Y. M. Greet, AustralianJ. Chem. 11, 388 (1958). 89. W. D. Crow and M. Michael, Australian J . Chem. 15, 130 (1962). 90. W. D. Crow, Compt. Rend. Congr. Assoc. Sci.Pays Ocean Indien, 3“,Tananarive, 1957, Sect. G p. 39 (Pub. 1958); Chem. Abstr. 53, 17432e (1959).
58. 59. 60. 61. 62.
14. Aspidospermu 91. 92. 93. 94. 95.
AND RELATED ALKALOIDS
509
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143b. M. Ohashi, J. A. Joule, B. Gilbert, and C. Djerassi, Ezperientia I n press (1964). 144. M. A. Ondetti and V. Deulofeu, Tetrahedron Letters No. 1, 18 (1960). 145. G. B. Marini-Bettolo, Ann. Chim. (Rome)49, 869 (1959). 146. P. Carvalho-Ferreira, G. B. Marini-Bettolo, and J. Schmutz, Ezperientia 15, 179 (1959) 147. M. A. Ondetti and V. Deulofeu, Tetrahedron 15, 160 (1961). 148. M. Gorman, N. Neuss, N. Cone, and J. A. Deyrup,J. Am. Chem.SOC. 82,1142 (1960). 149. G. B. Marini-Bettolo and J. Schmutz, HeZv. Chim. Acta 42, 2146 (1959). 150. J. Schmutz and H. Wittwer, Helv. Chim. Acta 43, 793 (1960). 151. R. F. H. Manske and M. Kulka, Can. J. Res. 27B, 291 (1949). 152. R. F. H. Manske and M. Kulka, J. Am. Chem. SOC.72, 4997 (1950). 153. R. B. Woodward and G. A. Iacobucci, cited in reference 144. 154. E. Wenkert and K. G. Dave, J. Am. Chem. SOC.84, 94 (1962). 155. H. Lehner and J . Schmutz, Helv. Chim. Acta 44, 444 (1961). 156. S. Goodwin, A. F. Smith, and E. C. Homing, J . Am. Chem. SOC.81, 1903 (1959). 157. R. B. Woodward, G. A. Iacobucci, and F. A. Hochstein, J . Am. Chem. SOC.81, 4435 (1959). 158. G. Buchi, D. W. Mayo, and F. A. Hochstein, Tetrahedroia 15, 167 (1961). 159. P. A. Cranwell and J . E. Saxton, Chem. I n d . (London)p. 45 (1962). 160. P. A. Cranwell and J. E. Saxton, J. Chem. Soc. p. 3482 (1962). 16Oa. T. R. Govindachari, S. Rajappa, and V. Sudarsanam, IndianJ. Chem. 1,247 (1963). 161. F. A. Doy and B. P. Moore, Australian J . Chem. 15, 548 (1962). 162. G. M. Spiteller and M. Spiteller-Friedmann, Monatsh. Chem. 93, 795 (1962). 163. B. Gilbert, L. D. Antonaccio, and C. Djerassi, J . Org. Chem. 27, 4702 (1962). 164. J. D. M. Asher, J. M. Robertson, G. A. Sim, M. F. Bartlett, R. Sklar, and W. I. Taylor, Proc. Chem. SOC.p. 72 (1962). 164a. G. Spiteller and M. Friedmann-Spiteller, Monatsh. Chem. 94, 779 (1963). 165. L. D. Antonaccio, N. A. Pereira, B. Gilbert, H. Vorbrueggen, H. Budzikiewicz, J . M. Wilson, L. J. Durham, and C. Djerassi, J. Am. Chem. SOC.84, 2161 (1962). 165a. M. Ohashi, H . Budzikiewicz, J. M. Wilson, C . Djerassi, J. Levy, J. Gosset, J. LeMen, and M. M. Janot, Tetrahedron 19, 2241 (1963). 165b. E. Clayton, R . I. Reed, and J . M. Wilson, Tetrahedron 18, 1449 (1962). 166. K. Biemann, Tetrahedron Letters No. 15, 9 (1960). 167. K. Biemann,J. Am. Chem. SOC.83, 4801 (1961). 168. K. Biemann and M. Friedmann-Spiteller, Tetrahedron Letter8 p. 68 (1961). 169. K. Biemann and M. Friedmann-Spiteller,J . Am. Chem. SOC.83, 4805 (1961). 170. M. Plat, D. D. Manh, J. Le Men, M. M. Janot, H. Budzikiewicz, J. M. Wilson, L. J. Durham, and C. Djerassi, Bull. SOC.Chim. France p. 1082 (1962). 171. B. Gilbert, J . Aguayo Brissolese, N. Finch, W. I. Taylor, H. Budzikiewicz, J. M. Wilson, and C. Djerassi,J. Am. Chem.SOC.85, 1523 (1963). 172. A. R. Battersby and D. A. Yeowell, Proc. Chem. SOC.p. 17 (1961). 173. A. R. Battersby, It. Binks, H. F. Hodson, end D. A. Yeowell,J. Chem. SOC. p. 1848 (1960). 173a. F. Fish, M. Qaisuddin, and J. B. Stenlake, Chem. Ind. (London)p. 319 (1964). 174. J. Levy, J. LeMen, andM. M. Janot, Compt. Rend. Acad. Sci. 253, 131 (1961). 175. S. Silvers and A. Tulinsky, Tetrahedron Letters p. 339 (1962). 176. M. M. Janot, J. Le Men, J. Gosset, and J. Levy, Bull. SOC.Chim. France p. 1079 (1962). 177. M. F. Bartlett,, R. Sklar, W. I. Taylor, E. Schlittler, R. L. S. Amai, P. Beak, N. V. Bringi, and E. Wenkert, J. Am. Chem. SOC.84, 622 (1962).
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178. A. T. McPhail, J. M. Robertson, G. A. Sim, A. R. Battersby, H. P. Hodson, and D. A. Yeowell, Proc. Chem. SOC.p. 223 (1961). 179. N. Defay, M. Kaisin, J. Pecher, and R. H. Martin, Bull. SOC.Chim. Belges 70, 475 (1961). 179a. L. Olivier, J. Levy, J. Le Men, andM. M. Janot, Ann. Pharm. Franp. 20,361 (1962). 179b. M. Gorman, A. L. Burlingame, and K. Biemann, Tetrahedron Letters p. 39 (1963). 179c. M. M. Janot, J. Le Men, and C. Fan, Compt. Rend. Acad. Sci. 247, 2375 (1958). 179d. G. Spiteller and M. Spiteller-Friedmann, Tetrahedron Letters p. 147 (1963). 179e. A. Z. Britten, G. F. Smith, and G. Spiteller, Chem. Ind. ( L o n d o n )p. 1492 (1963). 180. L. D. Antonaccio and H. Budzikiewicz, Monatsh. Chem. 93,962 (1962). 181. H. R. Snyder, C . H. Hansch, L. Katz, S. M. Parmerter, and E. C. Spaeth, J. Am. Chem. SOC.70, 219 (1948). 182. P. J. Scheur and J. T. H. Metzger, J . Org. Chem. 26, 3069 (1961). 183. M. F. Bartlett and W. I. Taylor, J . Am. Chem. SOC.82, 5941 (1960). 183a. E. Wenkert et al., Unpublished results (1963). 184. J . Trojanek, 0. Strouf, J. Holubek, and 2. cekan, Tetrahedron Letters p. 702 (1961). 184a. G. F. Smith and J . A. Joule, J . Chem. SOC.p. 312 (1962). 184b. J. Levy, J . Le Men, and M. M. Janot, Bull. SOC.Chim. France p. 1658 (1961). 185, K. Biemann, Angew. Chem. 74, 102 (1962); Angew. Chem. Intern. Ed. Engl. 1, 98 (1962). 186. C. Kump, J. Seibl, and H. Schmid, Helv. Chim. Acta 46,498 (1963). 186a. M. Raymond-Hamet, Compt. Rend. Acad. Sci. 244, 2991 (1957). 186b. A. K. Kiang and B. Douglas, Malayan Phurm. J . 6,138 (1957). 1860. D. P. N. Tsao, J. A. Rosecrans, J. J. de Feo, and H. W. Youngken, Econ. Botany 15 99 (1961). 186d. G. Biichi, R. E. Manning, and F. A. Hochstein,J. Am. Chern. SOC.84, 3393 (1962) 1860. 0. Bejar, R.'Goutarel, M. M. Janot, and A. Le Hir, Cmpt. Rend. Acad. Sci. 244, 2066 (1957). 186f. N. A. Hughes and H. Rapoport, J . Am. Chem. SOC.SO, 1604 (1958). 186g. K. B. Prasad and G. A. Swan, J . Chem. SOC.p. 2024 (1958). 186h. B. Witkop, J . A m . Chem. SOC.75, 3361 (1953). 186i. Y. Ban and M. Seo, Tetrahedron 16, 5 (1961); Chem. Ind. (London) p. 235 (1960). 186j. T. Okamoto and H. Tani, Chem. Pharm. Bull. (Tokyo)7, 925 (1959). 187. N. Finch and W. I. Taylor, J . Am. Chem. SOC.84, 1318, 3871 (1962). 188. J. Shave1 and H. Zinnes, J . Am. Chem. SOC.84, 1320 (1962). 189. N. Finch, C. W. Gemenden, I. H. Hsu, and W. I. Taylor, J . Am. Chem. SOC.85, 1520 (1963). 190. E. Wenkert, B. Wickberg, and C. Leicht, Tetrahedron Letters p. 822 (1961). 191. E. Wenkert, B. Wickberg, and C. Leicht,J. Am. Chem. SOC.83,505 (1961). 192. M. Shamma and J. B. Moss, J . Am. Chem. SOC.83, 5038 (1961). 192a. N. Finch, W. I. Taylor, and P. R. Ulshafer, Ezperientia 19, 296 (1963). 192b. R. F. Raffauf and M. B. Flagler, Econ. Botany 14, 37 (1960). 192c. F. A. Hochstein, K. Murai, and W. H. Boegemann, J . Am. Chem. SOC.77, 3551 (1955). 192d. B. Douglas, J. L. Kirkpatrick, B. P. Moore, and J. A. Weisbach, Australkn J . Chem. 17,246 (1964). 1920. U. Renner, D. A. Prins, A. L. Burlingame, and K. Biemann, Helv. Chim. Acta 46, 2186 (1963). 192f. M. P . Cava, S. K. Talapatra, J . A. Weisbach, B. Douglas, and G. 0. Dudek, Tetrahedron Letters p. 53 (1963).
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AND RELATED ALKALOIDS
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192g. N. Finch, I. H. Hsu, W. I. Taylor, H. Budzikiewicz, and C. Djerassi, J. Am. C'hern. SOC.8 6 , 2620 (1964). 193. R. Goutarel, A. Rassat, M. Plat, and J. Poisson, Bull. Soc. Chim. France p. 893 (1959). 194. A. Bums, M. Osowiecki, and 0. Schindler, Compt. Rend. Acad. Sci. 247, 1390 (1958). 195. P. Tunman and J. Rachor, Naturwissenschaften 47, 471 (1960). 196. K. H. Palmer, Thesis, Nottingham Univ., Nottingham (1954);cited in reference 58. 196a. P. Relyveld, Pharm. Weekblad 98, 47 (1963). 197. G. Ganguli, N. Adityachaudhury, V. P. Arya, and A. Chatterjee, Chem. Ind. (London) p. 1623 (1962). 198. C. Vamvacas, W. von Philipsborn, E. Schlittler, H. Schmid, and P. Karrer, Helw. Chim. Acta 40, 1793 (1957). 199. N. Aditya Chaudhury, G . Ganguli, A. Chatterjee, and G. Spiteller, Indian J . Chem. 1, 363 (1963). 200. N. Aditya Chaudhury, C. R . Ghosal, and G. Ganguli, Indian J . Chem. 1, 95 (1963).
1. Introduction ......................................................
I1. The Aspidospermine Group ......................................... A. Introduction ................................................... B. Quebrachamine ................................................ C. Aspidospermine ................................................ D. NMR- and Mass Spectra of the Aspidospermine-Type Alkaloids . . . . . E. Some Minor Alkaloids of Aspidasperma quebrachoblancoand Rhazya strictu F. Demethoxyvallesine, Demethoxyaspidospermine, and Demethoxypalosine ....................................................... G. Demethylaspidospermine ........................................ H . Vallesine and Palosine ........................................... I. Aspidocarpine and Demethylaspidocarpine ......................... J. Aspidolimine ................................................... K . Pyrifolidme and Deacetylpyrifolidme .............................. L . Spegazzinine and Spegazzinidine .................................. M. Cylindrocaxpine and Cylindrocarpidine ............................ N . Limaspermine and Related Alkaloids .............................. 0. Tabersonine ................................................... P. Vinca Alkaloids of the Aspidospermine Group ......................
336 337 337 337 361 367 395 398 399 400 400 403 404 405 410 414 416 419
I11. The Aspidofractinine Group ......................................... A. Introduction ................................................... B . Intercorrelations and Skeletal Structure ........................... C. Aspidofractinine ................................................ D. Pyrifoline. Refractidine. and Refractalam .......................... E. Aspidofiline .................................................... F. Some Alkaloids of Aspidosperm populifolitm ...................... G. Kopsinine. Aspidofractine. Pleiocarpine. Pleiocarpinine. and Refractine H. Kopsinilam and Pleiocarpinilam .................................. I. Kopsiflorine. Kopsilongine. and Kopsamine ........................ J. Kopsine and Related Alkaloids ................................... K . K o p s k Alkaloids of Unknown Structure ...........................
420 420 421 429 429 432 433 434 439 439 441 444
IV. The Aspidoalbine Group ............................................ A. Aspidoalbine and Its N-Acetyl Analog ............................. B Aspidolimidine ................................................. 336
445 445 448
.
B . GILBERT
336 C. D. E. F. G.
Dichotamine and 1-Acetylaspidoalbidine . . . . . . . . . . . . . . . . . . . . . . . . . . . Haplocine and Haplocidine . . . . .... Cimicine and Cimicidine . . ................... Other Alkaloids of the Asp bine Group ......................... Obscurinervine and Related Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449 450 451 451 452
453 V . The Condylocarpine Group .......................................... A. Iiitroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453 B . Aspidospermatine, Aspidospermatidine, and Related Alkaloids . . . . . . . . 453 C. Condylocarpine and Stemmadenine . . . . . . . . . . . . 457 I). Tubotaiwine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 E. 11.Methoxy.14,19.dihydroeondylocarpin e . . . . . . . . . . . . . . . . 462
VI . Alkaloids Related t o Akuammicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . il. Introduction . . . . . . . ......................................... B. Mossambine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Norfluorocurarine D . Compactinervine .
463 463 463 466 466
................. V I I . The Uleine Group . . . A. Introduction . . . . ................. B. Uleine and Relate C . Olivacine, Dihydroolivacine, and Guatambuine . . . . . . . . . . . . . . . . . . . . . D . Ellipticine, Dihydroellipticine, and N-Methyltetrahydroellipticine. . . . .
469 469 469 474 477
V I I I . Tetrahydro /3-Carbolineand Related Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . A . Yohimbine and Tetrahydroalstonine Derivatives . . . . . . . . . . B. Normacusine.B, Polyneuridine, and Akuammidine . . . . . . . . . . . . . . . . . . C. Quebrachidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Harman-3-carboxylicAcid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Eburnamine and Related Alkaloids ............................... F. TuboAavine ............................... . . . . . . . . . . . . . . . . . . . . . G. Flavocarpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Carapanaubine ...................... ........... ...... I. Isoreserpiline.+.indoxyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J . Ochropamine and Ochropine ......................................
482 482 485 491 495 495 497 498 502 503 503
1X . Alkaloids of Unknown Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Alkaloids of Pleiocarpa Species ................ B. Alkaloids of Ochrosia Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Alkaloids of Aspidosperma, Rhnzya, and Sternmadeniu . . . . . . . . . . . . . . .
504 504 504 505
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
..........
505
.
I Introduction
The great advance in our knowledge of the chemistry of this group during the past few years is indicated by the fact that a t the time of completion of the previous review (Volume VII. Chapter 10)no structure was known. whereas a t the time of the present writing. the structures of more than 100 alkaloids from these genera have been elucidated . A list
14. Aspidosperma AND RELATED ALKALOIDS
337
of the alkaloids at present known with their plant sources and physical properties is given in Table I. These bases may conveniently be divided into eight groups, each of these groups ranging over two or more of the seven genera under discussion.
11. The Aspidospermine Group
A. INTRODUCTION This group of alkaloids, whose basic carbon skeleton wtts not readily explained by the earlier biosynthetic hypotheses (1, a), appears to be relatively restricted in nature, occurring principally in the genera Aspidosperma, Kopsia, Pleiocarpa, and Stemmadenia of the family Apocynaceae. Similar alkaloids, for example, vindolinine (CVI, 3), vindoline (CIII, 4,5 ) , and vincadifformine (XCIII, 6), occur in Vinca or Catharanthus species and tabersonine (XCII, 7) is found in the genus Amsonia as well as in Stemmadenia (Section 11, 0 and P). The parent alkaloid of the group, quebrachamine (I),is also one of the most widely distributed. Although as an indole it is distinct from all the other members of the group, which are dihydroindoles, its obvious relation to the others justifies its inclusion here.
B. QUEBRACHAMINE The earlier literature on quebrachamine has been dealt with in previous volumes, and its occurrence in some new sources is recorded in Table I. Most important from the biogenetic point of view is the existence in nature of both optical enantiomers. The common levorotatory form corresponds in absolute configuration t o aspidospermine (11,vide infra), while the dextrorotatory form found in Stemmadenia donnell-smithii (8) is related to (+)-pyrifolidine (XLVI, 9, 10) and to (-)-tabersonine (XCII, 7). The Vinca minor alkaloids vincadine (11-A) and vincaminoreine (11-B)are the 3-carbomethoxy- and 3-carbomethoxy-Na-methyl derivatives, respectively, of ( + )-quebrachamine (10a). The same plant (lob). also contains ( k )-indolic-N-methylquebrachamine The determination of the structure of quebrachamine (I)followed on that of aspidospermine (11),and was indeed suggested at the time that this latter structure was published (11, 12, 13, 14). In work prior to this, Witkop and his co-workers were able to show that the two alkaloids were related, since both gave on zinc dust distillation a mixture from which
TABLE I
w w ca
PHYSICAL CONSTANTSAND PLANT SOURCES PART1. Quebrachamine and its derivatives
Compound'
Formula
mP ("C)
Quebrachamine, 1, a 38, 59; b 23, 63; c 34; d 5 2 ; e 51, 62; f Volume VII, 60, 61; E 38b
ClgHzeNz
146-147
Dextrorotatory, g 8 Racemic Salts (see Volume 11)
147-149 114-1 16
[uID2
-108 (c) -91 (e) - 110 (a) - 100 (d) +111 (c)
Reference 23, 34 55 8 6, 8
PART 2. Aspidospermidine and its derivatives Formula
Aspidospermidine(282A), XXXI, C ~ ~ H Z a ~ 28,51a; N Z , e,51 1,2-Dehydroaspidospermidine,IX, C ~ ~ H Z ~ e 51b NZ, Demethoxyvallesine, XXXII, CzoHz~Nz0,h 37 Demethoxyaspidospermine, XXXIII, C21HZsN20, h 40a; i 48; mm 48 Demethoxypalosine, XXXIV, Cz~H30Nz0,j 40; h 408 A',-methylaspidospermidine, XXXV, CzoHzsNz, a 28, 51a Aapidosine, XXXVI, C1gHzeNzO
w
0
16
17
Ne.
H
H
H
H H
H H
CHO
H H H
H H OH
mP (" C)
[elD
120-121 amorph.
+ 243(e)
+17(e)
Ac
amorph.
- 15 (c)
EtCO Me H
115-120
- 17 (c)
265.5-257.5
- 16 (e)
Reference
28, 51b 28, 51a, b 37 40a 40 28 38, 25, 26
Demethylaspidospermine, XXXVII, C21H2sN202, h 40e; i 48 Deacetylaspidospermine, VI, CzoHzsNzO, a 28, 51a; b 38a
H
OH
Ac
amorph.
H
OMe
H
109-111
11-Hydroxy-10-0xoaspidospermine(A),XII,
CzzHzsNz04. CsHs 11-Acetoxy-10-oxoaspidospermine(A), XV, C24H30Nz05 11-Hydroxy-10-oxoaspidosperrnine(B), XVI, CzzHzgN204 10,11-Dioxoaspidospermine, XIII, CzzHzsNz04. CeHa oxime, C22H27N304. CaHs 11-Chloro-10-oxoaspidospermine, XIV, CzzH27ClNz03 Vallesine, XXXVIII, Cz1H2sN202, k 41 ; 1 39 Aspidospermine, 11, CzzH30Nz02, a 38; b 23; m Volume 11; k 41,41a; 139 10-Oxoaspidospermine, XI, CzzHzsNz03. CeH6 8-Oxoaspidospermine, XX, CzzHzsNzOa Apoaspidospermine, LI, C15HzzNz02 Palosine, XXXIX, C23H32N202, b 23 N,-Isobutyryldeacetylaspidospermine, XL, Cz4H34Nz02 N,-Benzoyldeacetylaspidospermine, Cz7H32N202 N,-Carbethoxydeacetylaspidospermine,C23H3zN203 N,-Methyldeacetylaspidospermine,XLI, CzlH3oNzO N-Ethyldeacetylaspidospermine, XVII, CzzH32NzO N,-Benzyldeacetylaspidospermine,C27H34N20 0,N-Diacetylaspidosine, C23H3oN203 Demethylaspidocarpine, L, C21HzsNz03, d 42 Aspidocarpine, XLIV, C22H3oN203, n 30; j 31, 40; ii 48; p 113 i; d 42 Aspidolimine, LIII, C23H32N203, j 31, 40; q 47; p 113 i Deacetylpyrifolidine, XLVII, C21H30N202, r 37 Pyrifolidine, XLVI, C23H32N203, Dextrorotatory, r 10
H
H
OMe OMe
CHO Ac
40a, 25
228-230
25, 26, 28, 38, 38a 24
211 247 249 261 294-296 154-1 56 208-209
24 24 24 24 24 41, 39 23, 26, 38
115 174-176 224-225
H H H H H H H H OH OMe
OMe OMe OMe OMe OMe OMe OMe OAc OH OH
EtCO iPrC0 PhCO CO2Et CH3 Et PhCHz Ac Ac Ac
149-152 162-164 187-190 125.5-128 amorph. 111-112 119.5-120.5 158-1 58.5 156-158 168.5-169.5
OMe OMe
OH OMe
EtCO
OMe
OMe
Ac
150-1 51 153-154 148-150.5 152-154 147.5-150
H
+ 119 (c) +3
(0)
-92 (c) -93 (c) -99 ( 0 )
- 132 (c) - 128 (c) - 86 (0)
+ 125 (c) + 140 (c) + 133 (c) - 5 (c) + 7 (0) - 94 ( 0 ) 90 (c)
+
24 24 30 30 23,43 43 25,39 25 25, 28, 51s 25 25 25 30,42 30, 31 31 30 9 30,28 10
TABLE I-Continued Formula
Compound
W
[elD
N,
16
17
N,-Ethyldeacetylpyrifolidine, LVII, Cz3H3sNz02
OMe
OMe
Et
0-Acetylaspidocarpine, XLV, Cz4H32N204 0-Acetylaspidolimine, LIV, C25H34Nz04 Picrate, B .C~H3N307 0-Propionylaspidolimine,L v , C26H36N204 Picrate, B. CsH3N307 0,O-Diacetyldemethylaspidocarpine, XLIX, C25H32N205
OMe OMe
OAc OAc
Ac EtCO
OMe
EtCOO
EtCO
OAc
OAc
Ac
-
-~
Reference
amorph. amorph.
-21
(c)
165-167
-8
(c)
semi-cryst.
+ 20 ( c )
193-195.5 179-181 144-145
+ 10 (c)
254-257 104.5-106
+ 63 ( c ) + 176 (c)
36 36 30,31 31 31 31 31 30
PART3. Aspidospermine-type alkaloids oxygenated a t C-3and their derivatives Formula
Compound
Deacetylspegazzinine, LXII, C I ~ H Z ~ N Z O ~ Spegazzinine, LXIV, C21H28N203, c 34 0-Methyldeacetylspegazzinine, LXIII, CaoHzsNzOz 0-Methylspegazzinine, LXV, CzzH30NzOa 0-Methyl-0-acetylspegazzinine, LXVI, C24H32N204 0-Methyl-0-benzoylspegazzinine, LXVII, CzgH34N204 0,O-Diacetylspegazzinine,LXVIII, Cz5H32N205 Spegazzinidine, LXIX, C Z ~ H Z ~ N cZ 35, O ~36 , 0,O-Dimethylspegazzinidine, LXX, C23H32N204 0,O-Dimethyl-0-tosylspegazzinidine, LXXIV, C30H38Nz06S O,O-Dimethyl-3-dehydrospegazzinidine, LXXI, C23H3oN204
16
17
H
OH OH
H H H H H H OH OMe OM0 OMe
N,
3
H
OH OH OH OH OAc PhCOO OAc OH OH OTs
OMe
Ac H Ac Ac Ac Ac Ac Ac Ac
OMe
Ac
OMe
OMe
OMe OMe OAc OH OMe
=O
amorph. amorph. amorph.
192-194
amorph.
237-238 167-169 158-160 185-187 or
155-160
- 64 ( c )
- 136
-23 ( c )
+ 97 + 123 ( c ) + 186
- 156 (c) +42 (c) - 53
34 34 34 34 34 34 34 35,36 35,36 36 35,36
b P
0
PART 4. Aspidospermine-type aIkaloids oxygenated at C-21 and their derivatives Compound
Formula mp ("C)
[c(ID
Reference
- 122 (c)
10 29, 10 10 10
COzH
11,s-118.5 168-169 146-147 236-238 and 245-248 265 (dec.)
DHC
CO2H
203-217
DHC Ac EtCO
H H
OMe OH OH OMe OMe OMe
H DHC Et
CHO CHaOH CH2OH CHzOH CHaOH CHzOH
H
OMe
CnHii
CHzOH
48-49
29, 10
H H
OMe OAc
Ac EtCO
CHzOAc CHzOAc
OMe
OH
Ac
CHzOH
148-150 amorph. 122-123 220
+ 131 (c)
52 33 33 120
OMe
OH
EtCO
CHzOH
174- 175
+118(c)
33,120
H
CHeOH
175-1 77
~
16
17
Cylindrocarpidine, LXXVI, C Z ~ H ~ O Ns 49, ~ O10 ~, Cylindrocarpine, LXXV, C30H34Nz04, s 49, 10 Dihydrocylindrocarpine, LXXVII, C30H36N~04 Cylindrocarpinic acid dihydrochloride, LXXX, CzoHz8ClzNz03. E t O H
H H H H
Cylindrocarpic acid hydrochloride, LXXVIII, CzsH33CINzO4 Dihydrocylindrocarpic acid hydrochloride, LXXIX, CzsH35ClNz04 Dihydrocylindrocarpal, L X X X I I I , CzgH34Nz03 Limapodine, L X X X I X , Cz~HzsNnOs,j 120 Limaspermine, LXXXVII, CzzH30N203, j 33 Decinnamoylcylindrocarpol, LXXXIV, CzoHz8NzOz Dihydrocylindrocarpol, LXXXII, CznH36Nz03 N,-Ethyldecinnamoylcylindroca.rpo1,LXXXVI, CzzH3zNzOz N,-y-phenylpropyldecinnamoylcylindrocarpol, LXXXI, CznH3sNzOz 21-Acetoxyaspidospermine, LXXXV, C z 4 H 3 ~ N ~ 0 4 0,O-Diacetyllimaspermine, LXXXVIII, Cz~H3.gN205 Picrate, B. C~H3N307 21-Hydroxyaspidocarpine( 16-methoxylimapodine), XC, C ~ ~ H ~ O Nj 120 ZO~, 21-Hydroxyaspidolimine( 16-methoxylimaspermine), XCI, C Z ~ H ~ Z N jZ120 O~,
N,
21
OMe OMe OMe OMe
Ac Cin DHC H
COzMe COzMe
H
OMe
Cin
H
OMe
H H H H
-
COzMe
COzH
amorph. 177-178 175-175.5 145-147 amorph. amorph.
- 181 (c) - 126 (c) - 3 (w)
10 10
+ 110 (c) f 108 (c)
+2 -98 (c)
10 120 33 52 10 52
.
N-Deacyl-0-methylaspidoalbinol, CXCIII, C2&€82N2O6
52
TABLE I-Continued PART 5. Aspidospermine-type alkaloids bearing a carbon substituent at C-3 and their derivatives -
~~~
~~
~~~~
Compound Tabersonine, XCII, C Z I H Z ~ N Z Ot Z65; , g 66a; u 66a; v 66a; w 66a Hydrochloride, B .HCI Vincadifformine, ( = 6,7-dihydrotabersonine),XCIII, CziHzsNz0z Minovine (N,-methylvincadifformine), CVIII, CZZHZENZOZ Minovincinine, CVII, CziHzaNz03 Minovincine, CIX, CzlHzsNz03 16-Methoxyminovincine, CX, C2zHzeNz04 2,3-DihydrotabersonoI, XCVII, CzoHzsNzO N,,O-diacetate, C, Cz4H30Nz03
Formula mP
2,3
6,7
3
20
(" C)
A
A
COzMe
H
amorph.
A
COzMe
H
A
COzMe
H
A A A
COzMe COzMe COzMe CHzOH CHzOAc
OH =O =O
A A
H H
196 (dec.) 124-125 amorph. 79-81 amorph. amorph. amorph. 186 196
[.ID
Reference 7, 64, 65
- 310 ( m )
rac. - 540 (e) 0 (e) -418 (e) - 504 (e) -414 (0) 82 ( e )
+
64, 65 6, 74 7, 32 74a 32, 76 32 32 32 7, 64 64
a,
8 W
M
3
PART6. Miscellaneous alkaloids with t h e aspidospermine skeleton a n d their derivatives
-
Vindoline Deacetylvindoline Dih ydrovindoline
__
Compound
16-Methoxy-N,-methyl-4-oxoaspidospermidine Vindolinine CVI dihydrochloride, B .2HC1 Other derivatives (see Ref. 3)
Formula CIII CXIII CXI CV CVI
CzsH3zNzOs Cz3Hm~Nz05 CzsHdzOs CZIHZENZOZ CziHz4NzOz
mP
Reference
(" C)
154-1 55 156-157 121-1 24 and 164-166 130-1 32 250-252 210-212 214-2 18
+42 (c) i-52 ( c )
+ 12 (c) - 72 (w) - 8 (w)
- 18 (w)
72 72 4 4 3, 72, 71 71 72 3
PART 7. Aspidofractinine-type alkaloids unsubstituted in position 3 Formula Compound
Aspidofractinine, CXVII, C I ~ H ~ x~ 102 N, Aspidofiline, CXXXVI, CzlHz6NzO~,r79 0-Methyldeacetylaspidofiline, CXXXIX, CzoHzaNzO, y 48
N-Formyl-0-methyldeacetylaspidofiline, CXLI-B, CzlHz6NzOz, Y 48 0-Methylaspidofiline, CXXXVIII, CzzHzaNzOz 0-Acetylaspidofiline, CXXXVII, Cz3HzsNz03 16,17-Dimethoxyaspidofractinine,CXLI-A, CzlHzaNzOz, y 48 N-Formyl-16,17-dimethoxyaspidofractinine, CXLI-C, CzzHzaNz03, Y 48 Deformylrefractidine, CXXII, CeoHzaNzO Dihydrochloride, B .2HC1 Methiodide, B.MeI Z, Refractidine, CXX, C Z ~ H Z ~ N ZxO81 N-Methyldeformylrefractidine, CXXIII, CziHzaNzO 6-Demethyldeformylrefractidine, CXXVII, C19H~4N20 N-Aretyl-6-demethyldeformylrefractidine, CXXX, C z l H ~ 6 N z 0 ~ N,-Methyl-6-demethyldeformylrefractidine, CXXXI, CzoHz6NzO N,O-~iacetyl-6-demethyldeformylrefractidine, CXXIX,
Cz3HzsNz03 6-Dehydrodemethyldeformylrefractidine,CXXXV, C19HZzN20 Deacetylpyrifoline, CXXI, CzlHzsNzOz Perchlorate, B .HC104
Pyrifoline, CXIX, C Z ~ H ~ ~ Nr Z 81,O49 ~, 6-Demethyldeacetylpyrifoline, CXXV, CzoHz6NzOz 6-Acetyldemethylpyrifoline, CXXVIII, C Z ~ H ~ ~ N ~ O ~ 6-Dehydrodemethylpyrifoline, CXXXIII, CzoH24NzOz
N,
6
(" C)
H OH
Ac
H
H H H
amorph. 190-1 9 1 129-131
OMe
H
OMe
CHO
H
amorph.
OMe OAc 16,17 (0Me)z 16,17(0Me)z H
Ac Ac
H
H
H
amorph. 179-181 140- 142
CHO
H
amorph.
H
OMe
H
CHO Me
OMe OMe
H H H
Ac
amorph. 189-193 258.5-259.5 158-160 104-106 163-164 2 18-2 19 160-161 193-194
H H
H
H
Me
OH OH OH
Ac
OAc
H
H H
OMe
OMe OMe OMe OMe
Ac
OMe
Ac
OAc
OMe
H
H
=O
OH
=O
[.ID
mP
17
132-136 amorph. 2 70-2 7 5 (dec.) 142-144 202-203 197-199 158-160
- 174 (c) -8 (c)
or
+ 3 (c)
+ 53 (c)
- 141 (c)
Reference
102 80, 79 80 48
80 80 48 48
- 53 (c) -31 (e)
- 140 (c) - 86 (c)
-24 (c) 4-39 (c) - 44 (c) +44 (c)
+ 10 (c)
- 14 (c)
+ 102 (c) - 20 (c) + 170 (c)
+ 24 (c)
81 37 37 81 37 81 81 81,102 81 81,37 81 37 49, 81 81 81 81
TABLE I-Continued ~
~~
W rp
PART 8. Aspidofractinine-type alkaloids substituted in position 3
rp
Compound
[aID
Reference
- 62 t o - 77 (c)
91, 82,87
~
Kopsinine, CXLII-A, CzlHz6NzOz, z 87, && 91; b b 96; o 48
H
H
COzM0
105
Aspidofractine, CXLIII-A, CzzHzeNz03, x 82 N-Acetylkopsinine, CXLIV-A, Cz3HzsNz03 Pleiocarpine, CXLV-A, Cz3HzsNz04, &a 91; b b 93, 96; cc 94 Pleiocarpinine, CXLVI-A, CzzHzsNzOz, tm 91; b b 96; cc 94
H
CHO Ac COzMe Me
COzMe COzMe COzMe COzMe
197 184-1 85 141-142 135-136
H CHO
COzMe COzMe
amorph. 157.5-159 and 191-192 amorph. 109-110 155-156 190-1 9 1 144-145 210-211
Doformylrefractine, CXLIX-A, CzzHzsNz03 Refractine, CL-A, Cz3HzsNz04, x 49; y 48 Deformylieoaspidofractine, CXLII-C, Cz1Hz6NzOz Isoaspidofractine, CXLIII-C, CzzHz6Nz03 Deformylisorofractine, CXLIX-C, CzzHzsNz03 Isorefractine, CL-C, Cz3HzsNz04 KopsiAorine, CLVI, Cz3HzsNz05, z 87 Kopsilongine, CLVII, Cz4H3oNz06, z 87
H
H H OM0
OM0 H
H
OMe OMe
H
OMe
H CHO
CO~MO COzMe H COzM0 CHO COzMe COzMe OH,COzMe COzMe OH,COzMe
- 142 (c)
-116 ( m ) - 56 (c) -23 (c)
82, 91 96 91, 92 91 94 82 49, 82
+7 (c) + 3 (c) 34 (0) 76 (c) -67 (c) -18 (c)
37 82 82 82 87 87, 89
-48 (c)
87, 88, 85 89
- 145 (c) - 124 (c)
+
+
16.17
Kopsamine, CLVIII, Cz4HzsNz07, z 87 Kopsaminic acid, CLX, Cz3HzeNz07.+HzO
OzCHz
OzCHz
COzMe COzH
OH, C O ~ M O OH,COzMe
205-206 131
OH,COzMe OH,COzMe OH,COzMe
148-149 148-149 119-120
17
KopsiAoreine CLXI, CziHz6Nz03 Nitroso-, CLXIV, CziHz5N304 Kopsilongeine, CLXII, CzzHzsNz04
H
H OMe
H NO
H
89 89 89
W
W M
E
16,17
H NO
OH, COzMe OH, COzMe
145-146 185-186
89 89
H H
H H
COzH COzH
OM0
H
COzH
209-21 1 280-281 273-274
89 37 37
H
H H
OH, COzH OH, COzH
242-250 198 199
H
OH, COzH
220-221
H
H
COzMe
254-254.5
H H
COzMe
COzMe
190 249-250
H H H H
H
COzMe COzMe
205-207 201-202 131-132 162
OzCHz OzCHz 17
Kopsinic acid, CXLII-B, CzoHz4NzOz Deformylisoaspidofractic acid, CXLII-B, CzoHz4NzOz Dihydrochloride, B. 2HC1 Deformylisorefractic acid, CXLIX-B, C Z I H Z ~ N Z O ~ Dihydrochloride, B .2HC1 Kopsifloric acid, CLXVII, CzoH34Nz03. HzO Kopsilongic acid, CLXVIII, CziHz6N~O4.3HzO
OMe
+20(m)
37 89 89
16,17
O~. Kopsamic acid, C L X I X , C Z I H Z ~ N Z 3HzO
OzCHz
89
17
Kopsinilam ( l o - o s o ) , CXLII-D, CziHz4NzO3, aa 96; bb 96; cc 96 Pleiocarpine lactam A( 10-oxo),CXLV-D, Cz3Hz+$"05 Pleiocarpinilam (lo-oxo), CXLVI-D, CzzHzsNzO3, aa 96; bb 96; cc 96 Kopsinine-8-lactait1, CXLII-E, CziHz4NzO3 Pleiocarpine lactam B (8-oxo),CXLV-E, Cz3HzfiNzOj N-Methylkopsinal, CLV, C Z ~ H Z ~ N ~ O Kopsinyl alcohol, CXLII-F, CzoHzfiNzO N-Methylkopsinyl alcohol, CXLVI-F, CZiHzsNzO 0-AcetaLe, CXLV1-K, Cz3HmNzOz Deformylrefractinol, C X L I X - F , CziHzsNzOz Deformylisorefractinol, CXLIX-T, CzlHzsNzOz .MeOH 0-Acetate, C~3H3oNzO3 Kopsinyl tosylate, C X L I I - H , C Z ~ H ~ ~ N Z O ~ S Deformylrefractinol tosylate, C X L I X - H , C Z E H ~ ~ N Z O ~ S Deformylisorefractinol tosylate, CXLIX-W, CzsH34Nz04S Kopsinyl iodide, C X L I I - J , CzoHzsINz
H
H OMe OMe OMe
H
OMe OMe
H
CH3
COzMe Me
H
Me Me
H H H
H H
H H
COZMe
CHO CHzOH CHzOH CHzOAc CHzOH CHzOH CHzOAc
CHzOTs CHzOTs CHzOTs CHzI
136-137 124-125 153-154 101-103 amorph. amorph. 147-148 amorph. I62 (dec.)
- 13 ( c )
96
-53 (c)
95 96
- 82 (c)
-47 (c) -3 (c) + 6 (c) -57 (c) - 50 ( c ) - 17 (c)
96 95 95 82, 89, 91, 92 91, 92 91 82 37 37 82 82 37 95
+Z
U
*e
M
ti b
c
'F1 c3 @ 01
TABLE I-Continued
Compound
N,O-Methylenekopsinyl ether, CLIII, CzlHzeNzO Kopsinyl N,-carboxylate, CLIV, CzlH24NzOz Kopsinylene, CXLII-M, CzoHz4Nz Picrate, B. CeH3N307 N-Methylkopsinylene, CXLVI-M, CzlHzeNz Deformylrefract-3-ene, CXLIX-M, CzlHzeNzO N-Methylisokopsinylene, CXLVI-N, CzlHzeNz Kopsinane, CXLII-0, CzoHzeNz N-Methylkopsinane, CXLVI-0, CzlHzsNz Deformylrefractane, CXLIX-0, CzlHzsNzO Noraspidofractone, CXLIII-P, CzoHzzNzOz Deformylnorrefractone, CXLIX-P, CzoHz4NzOz Norrefractone, CL-P, C Z ~ H ~ ~ N Z O ~
w
Formula
mP
~
17
N,
H H H
CHzOCHz CO-Q-CHz H =CHz
H
Me
H H H OMe H OMe
H Me H Me H CHO H
=CHz =CHz =C(CH3) CH3 CH3 CH3 =O =O
OMe
CHO
=O
OM0
[aID
Reference
(" C)
3
101-103 200-201 amorph. 183-187 68-70 amorph. 124-126 118 112-1 14 amorph. 140-142 202-209 (dec.) 184-189
-85 (c)
- 102 (c)
- 10 (0) - 240 (c)
95 95 82, 37 95 95 82 95 95 95 82 37 82
-51 (c)
37,102
[alD
Reference
PART 9. Kopsine and derivatives Formula
Compound
mP
N,
3
3'
(" C)
Kopsine, CLXX, C2zHz4Nz04, dd 100, 103, 109
COzMe
OH
=O
218
Dihydrokopsine-A (NaBH4), CLXXII, CzzHzeNz04
COzMe
OH
OH
256-257 (dec.)
+ 16 (e)4 - 18 (c)
104, 55 109, 112 100, 109, 112
W
8 W
M
E
0-Acetate, CzlHzsNzOs
COzMe
OH
OAc
COzMe
OH
OH
COzMe
OH
OAc
Kopsine Lactam A (10-OXO), CLXXV, CzzHzzNz05
COzMe
OH
=O
CLXXVII, CzzHz4NzOs Dihydrokopsine Lactam R ( 10-OXO),
COzMe
OH
OH
170-1 7 1 (dec.) 223-225 (dec.) 214-215 (dec.) 234-235 (dec.) 222-224
Decarbomethoxykopsine, CLXXI, C~OHZZNZOZ, dd 113
H
OH
=O
240-242
Ethyl carbonate, Cz3HzeN204 Dihydrodecarbomethoxykopsine (NaBH4),CLXXIII, CzoHz4NzOz Dihydrodecarbomethoxykopsine (Hz/Pt),CzoHz4NzOz
H H
OCOzEt OH
=O OH
H
OH
OH
=O
217 266-268 and 276 178-180 and 190-1 9 1 190-192 160.5-162.5 238-240 248-250 and 260-261 278-280
H H H
252-254 244 (dec.) 163-1 64.5 162-163 155 154-155 174-1 75
Dihydrokopsine-B (Hz/Pt),CLXXIV, CzzHzsNzO4 0-Acetate, Cz4HzsNz05
Isokopsine, CLXXXVII, CzzHz4Nz04 Dihydroisokopsine, CLXXXVII-B, CzzHz6Nz04 Decarbomethoxyisokopsine, CLXXXVII-A, CzoHzzNzOz, dd 113 Dihydrodecarbomethoxyisokopsine,CLXXXVII-C, CzoHz4NzOz Decarboinethoxykopsine lactam (10-oxo), CLXXVI, CzaHzoNz03 Kopsine methine, CLXXX, Cz3HzsNz04 Dihydro, Cz3HzsNz04 Tetrahydro, Cz3H30N204 Carbethoxytetrrthydro, C Z ~ H ~ Z N Z O ~ Kopsane, CLXXXIV, CzoH24Nz N-Acetyl, CLXXXV, C2zHzsNzO 10-Lactam, CLXXXVI, CzoHz2NzO
H
H Ac H
OH
H H H
100,112 100,101 100,112
+30 (e)
100, 101, 109,112 100, 101, 112 100, 109, 104 100 100,109 111
-82(~)
111 111 111 111 100,101 101,112 101,112 101,112 101,112 101,112 101 101
TABLE I-Continued W
rp
m
PART10. Compounds related t o aspidoalbine Formula
Compound 15, 16, 17 Fendleridine, CCI-L, C ~ ~ H ~ ~ G N 113f ZO, 1-Acetylaspidoalbidine, CCI-K, CzlHzsNzOz, 1~1130 Deacylhaplocine, CCI-F, ClgH24N202 Haplocidine, CCI-C, C21H26N203, F 113b, k 1138 Haplocine, CCI-D, CzzHzsN203, F 113b 0-Methylhaplocidine, CCI-B, CzzHzsNz03 0-Methylhaplocine, CCI-G, CzaH30Nz03 0-Acetylhaplocine, CCI-E, C24H3oN204 Dichotamine, CCI-A, C21Hz4Nz04, k 41, 113e Aspidolimidine, CCI, j 40, d 113h Fendlerine, CCI-0, G 113f N,-Acetyldepropionylaspidoalbine,CLXXXIX, CzaH30Nz05, d 42, 52; H 48 Aspidoalbine, CLXXXVIII, Cz4H32N205, d 42, 52 ; H 48 0-Methyldepropionylaspidoalbine, CXCII, CzzHaoN204 N,-Acetyl-0-methyldepropionylaspidoalbine, CXCI, C24H3zNz05 10-0x0, C24H30NzOs 0-Methylaspidoalbine, CXC, C25H34Nz05 CXCI-21-lactone, C24H3oNzOe CXC-21-lactone, Cz5H3zNzO6, CXCIX-A, ee 113g
mP
N,
21
H
H
17-OH 17-OH 17-OH 17-OMe 17-OMe 17-OAc 17-OMe 16-OMe,17-OH 16-OMe,17-OH 15, 16-(OMe)z,17-OH
Ac EtCO Ac EtCO EtCO CHO Ac EtCO Ac
15, 16-(OMe)2, 17-OH
EtCO
15, 16, 17-(OMe)3
15, 16, 17-(OMe)3 15, 16, 17-(OMe)3 15, 16, 17-(OMe)3
185-1 86 173-174 250 (dec.) 183-184 186-187 237-239 240-241 194-195 263-265 196- 199 185-186 175-179 or 194-1 95 174-177
Ac
H
148-149
Ac
177-178
EtCO Ac EtCO
CH2
co
CO
[O L ] ~
Reference
(" C)
2 14-2 18 128-131 225-226 180-182
+ 239 (c) + 174 (c)
113f 1130 113b 113b 113b 113e 113c 113b 113e 40, 113h 113f 42, 48
+ 164 (c)
42
+ 46
(0)
- 116 (c)
-36 (m)
52 52
+22 (m) + 9 (c) - 114 (m)
52 42, 52 52 113g
ej W M
2
PART11. Compounds with t h e aspidospermatidine or strychane skeleton
Compound
Formula
16
[.In
Reference
20
mP ("C)
=CHMe
H
184-1 86
28. 51a
=CHMe
€1
149-152
118
=CHMe
H
amorph.
28. 51a
=CHMe
H
amorph.
28, 51a
=CHMe
H
amorph.
28. 51a
=CHMe
H
157-159
Et
H
amorph.
Et
H
amorph.
+213 (c)
48
=CHMe
H
167-168
+900 (c) 870 (e) +584 (c)
116, 117, 75 120, 118a
~
N,
14 ~~
Aspidospermatidine, CCIV, ClsHzzNz, H H a 28, 51a 1,2-DihydrodecarbomethoxycondyloH H carpine, CCXXII, C18HzzNz N-Acetylaspidospermatidine, CCVIII, Ac H C Z O H Z ~ N ZaO28, , 51a H N-Methylaspidospermatidine, CCVI, Me C ~ ~ H Z ~a N28,Z 51a , Deacetylaspidospermatine, CCVII, H(12-OMe) H C ~ ~ H Z ~ NaZ28, O ,51a H Aspidospermatine, CCIX, CzlHz,jNzOz, Ac( 12-OMe) a 28, 51a Dihydroaspidospermatine, CCX, Ac( 12-OMe) H C21HZsNzOz, a 28, 51a 1l-Methoxy-14,19-dihydrocondylocarpine, H( 11-OMe) A , COzMe CCXXIV-A, CziHz1jNzO3, y 48 H Condylocarpine, CCXV, CzoHzzNzOz, ff 116 A, COzMe Tubotaiwine, CCXXIV, CzoHz4NzOz, bb 119; j 120 Picrate Tetrahydrocondylocarpine, CCXX, CzoHz~jNzOz Decarbomethoxyakuammicine, ClsHzoNz 19,2O-Dihydrodecarbomethoxyakuammicine, C C X X X I X , ClsHzzNz, bb 119 Tubifoline picrate5
H
A,COzMe
a-Et
H
amorph.
H
COzMe
Et
H
171-1 72 145-147
A A
H H
H H
=CHMe a-Et
80-84 amorph. 194-196
-73 (e)
28, 59, 51a 28, 51a
+
119,120 118 -361 (ea)
19 67, 118a 119
TABLE I-Continued
Compound
Formula
Na
16
14
20
[aID
Reference
- 298 (c)
122
mP (" C)
0 01
o
-
H
OH
=CHMe
190
H
H
=CHMe
187-189
19
H
H
8-Et
176-177
119, 19
A , COzMe
H
=CHMe
181-182.5
H
A , COzMe
H
P-Et
173-175
H
A , COzMe
OH
=CHMe
240
H H
A , COzMe A , COzMe
OAc OH
=CHMe Et
111
H
A , COzMe
H
CHOHMe
H
A , COzMe
H
135 (hydr.) -515 244 (anhydr.) 220 211-214 607 (dec.)
H
A , COzMe
H
19-Dehydr0, CCXLI-G, CzoHzzNz04
H
A , COzMe
H
19,20-Diacetate, CCXLI-A, Cz4HzeNzOa
H
A , COzMe
H
Decarbomethoxymossambine, CCXXXI, A CisHzoNzO 1,2-Dihydrodecarbornethoxyakuammicine, H CCIL CiBHzzNz Tetrahydrodecarbomethoxyakuammicine = H Tubifolidine, CCXXXIX-A, C I ~ H Z ~ N bbZ 119 , Akuammicine, CCXXV, CzoHzzNzOz H 19,20-Dihydroakuammicine,CCXXXVII, CzoHz4NzOz Mossambine, CCXXVI, CzoHzzNz03, ff 121, 116 0-Acetate, CCXXVII, CzzH24Nz04 19,20-Dihydromossambine,CCXXVIII, CzoHz4Nz03 Echitamidine, CCXLII, CzoHz4Nz03 0-Acetate, CzzHzaNzOa Lochneridine, CCXLIII, CzoH~4Nz03 Compactinervine, CCXLI, CzoHz4Nz04, gg 127
+
- 470 (c) - 498 (c)
-523 (c)
+
OH (Et C L M e M e:{
1(;:
-745 (0) - 727 (m) 720 (m) - 673 (m)
AcMe
19, 77, 69,131 125, 69, 19,1378 116, 122
Pj 0
p W
122 121 130, 126 126 129, 127, 75
110-120 235 (dec.)
- 640 (PI
125a
224-226 (dec.)
- 607 (c)
125a
208
- 623 (c)
125a
M
T:
Dihydro, CCXLI-B, CzoHzaNz04
H
COzMe
H
19-Epi, CCXLI-H, CzoHz4Nz04
H
A, COzMe
H
H
A, CHO
H
C:OHMe =CHMe
H
a-COzMe
H
=CHMe
Norfluorocurarine, CCXL, C19HzoNz0, ff 116 Methochloride, B HCl 2,16-Dihydroakuammicine,CCXXXVIII, CzoHz4NzOz Tetrilhydroakuammicine, CCXXXV, CzoHz6NzOz 2,16-Dihydromossambine, CCXXIX, CzoHz4Nz03 Tetrahydromossambine, CCXXX, CzoHzaNz03 2,16-Dihydrocompactinervine, CCXLI-B, CZOH26"204
.
H
H
m-COzMe
H
COzMe
OH
H
COzMe
OH
H
COzMe
H
CzOHMe
,5-Et =CHMe
cr
265-270 (dec.)
-44 (c)
12th
222-224 (dec.)
-680 (p)
125a
184-186 270 (dec.) 140
-1230(~)
- 18
135-137 197-198
+24(c)
Et
OHMe
116 133-1 37 68, 6% 137a, 75 137a 122 122
265-270 (dec.)
-44
(0)
48
Stemmadenine, CCXIII, Cz1Hz6Nz03, g 8 ; u 66a; v 66a Degradation product (KBH4) ex akuammicine, CigHzeNz Degradation product (KBH4) ex mossambine, CCXXXII, CisHzsNzO Degradation product (KBH4) ex compactinervine
01
m
[a]=
Reference
20
mP (" C)
+329(p)
116
N,
16
H
CHzOH, COzMe
=CHMe
H
189-191
H
H
=CHMe
H
H
OH
=CHMe
125-150 and 160-1 62 2 15-2 16
H
H
H
b
5 8 2
r-
Formula 14
+
b
PART12. Indoles related to stemmadenine Compound
~
/OH \CHOHMe
230-232
19 -62 (c)
M U
m
122 48
w m c
TABLE I-Continued
W
01 E3
PART 13. Compounds related t o uleine and the pyridocarhazole bases
Compound
Formula
[aID
Reference
+ 18 (c)
138, 147
~
Uleine, CCXLV, hh 138; ii 140; j j 49; kk 141, 147; 11 143h; i 48; mm 48; nn 48; o 48; K 37 Dihydrouleine, CCXLVI Olivacine, CCLVIII, ii 140; kk 141, 147; 00 158; pp 145; nn 48; i 48; qq 148; J 48 1,2-Dihydroolivacine, CCLXXIV, hh 139 1,2,3,4-Tetrahydroolivacine N-Acetyltetrahydroolivacine Guatambuine, CCLX, dextrorotatory, hh 139; kk 141, 147; pp 145, 146;'ll 143b; J 48 Levorotatory, kk 147 Racemic, kk 147 Methiodide Ellipticine, CCLXXXIV, rr 156; ss 156; tt 161; uu 161; vv 161; 00 157, 158 Methonitrate, 00 158 1,2,-Dihydroellipticine,CCXCIII, hh 139, 00 158 Methonitrate, 00 158 1,2,3,4-Tetrahydroellipticine, CCXCIV N-Acetyltetrahydroelipticine N-Methyltetrahydroellipticine,CCLXXXV, h h 139; 00 158; C 163; I1 143b
ClsHZzNz, methanolate C18Hz4N2 Ci7Hi4N2
76-118 118-120 (cap.) 75-1 15 318-324 (dec.) 307-318 290-295 238-244 249-252
(dec.) (dec.) (dec.) (dec. )
232-234 (dec.) 299-301 (dec.) 311-315 (dec.)
C18H2oNz
293-304 (dec.) 296-300 301-303 (dec.) 160-165 (dec.) 272.5-273 224.5-225
-llO(c)
+112(p)
- 106 (PI
138 140, 141, 147 150 150 150 139, 141, 147, 146 147 147, 150 144, 147 156 158 158 158 158 158 139, 158
W W
PART14. Indole and oxindole alkaloids related to /?-carboline and their derivatives
Compound
Formula
mP
(" C)
3-Carbomethoxyharman, CCCXXXIX, b 180 11-Methoxyyohimbine stereoisomer, ww 162 Deacetylpoweridine, CCXCVIII Isodeacetylpoweridine /?-Lactone, CCCII Poweridine, CCXCVII, x x 161 LiAlH4 diol Dihydrocorynantheol, CCCVI, y y 163; zz 48
252-253 148-149 222 (dec.) 197 (dec.) 277 (dec.) 226 (dec.) 215 (dec.) 181-183
Methochloride, cc 164 10-Methoxydihydrocorynantheol, CCCVI-A, h 113d; ee 48; ww 164a 19,20-Dehydro, CCCVI-B, h 113d; ee 37; ww 48 Ajmalicine, CCCXVII, v 66a
272-273 165-166
Aricine, CCCIII, y y 163
186-187 (dec.)
Reserpinine, CCCIV, zz 48 Reserpiline, CCCLVI, h 113d
243-244 (dec.) amorph.
Isoreserpiline, CCCV, k 41; h 171; 113d; rr 156; tt 161; uu 161 ; vv 161 Methochloride, rr 182 Isoreserpiline-4-indoxyl, CCCLVII-A, h 113d Isoreserpiline oxindole (see Carapanaubine below)
210-212 (dec.)
184-185 253-254 (dec.)
283-985 (dec.) 250-253 (dec.)
[.ID
Reference 180 162 161 161 161 161 161 198, 163
-5(a)
- 19 (c)
- 37 (P)
+ 6 3 (w-m)
- 16 (p)
198 113d, 48
-65 (p) 113d, 48 - 61 (c) 66a, 55, -48 (p) 192b -89 (c) 55, 192b, -66(p) 192~ -59 (0) -131 (c) 65, 192b - 69 (m) 113d, 192b - 14 (P) -82 (p) 55, 192b -134(m)
182 113d, 192a
w
TABLE I-Continued
01
ip
Compound
Formula
Norrnacusine-B, CCCXX, ff 116, 121; b 165
Reference 245 and 275
172, 165, 116, 121
Methochloride 0-Acetate, CCCXXVIII
248-249 223
Dihydro, ZOor-Et
189-190 or 159-160 192 and 219-220 279
173 165, 121, 116, 177 172, 165
Dihydro-0-acetate, 2Oa-Et Methiodide (macusine-B iodide), b 173a
172 173, 121, 116 174, 176 165 174, 175
Dehydroxymethylpolyneuridine, CCCXXX t-Butyl ester, CCCXXXI Akuammidine, CCCXXII, k 113e; D (Volume V I I )
231 246-247 2 34-2 36
Polyneuridine, CCCXXI, b 165
245-247.5
165, 178, 176 173, 165 173 165, 176 174, 165
Methiodide = macusine-A iodide Methochloride 0-Acetate Akuainmidinol, CCCXXVI
B.Me1
274 (dec.) 252 (dec.) 278 260-265
0,O-Diacetate 17-Dehydropolyneuridine(aldehyde), CCCXXIX-A
C24H28NZO4 CziHzzNz03
224-227 285-286
165 165
td
z r ?:
Polyneuridinic acid, CCCXXIV Hydrochloride Quebrachidine, CCCXXXVIII-D, a 179b 0,N-Diacetate, CCCXXXVIII-E N-Methylquebrachidinol, CCCXXXVIII-G Hydrochloride Monoacetate, CCCXXXVIII-H N-Methylquebrachidinal, CCCXXXVIII-I Eburnamenine, CCCXLIII, cc 183; aa 91; a 28, 51a, 51; e 51 Picrate Eburnamine, CCCXL, cc 183; aa 53, 91; e 51; F 113b Isoeburnamine, CCCXLI, F 113b 0-Methyleburnamine, CCCXL-A, F 113b Eburnamonine, CCCXLII, cc 183; e 51 Tuboflavine, CCCXLVIII, bb 186 Carapanaubine, CCCLIV, A 171
CzoHz3ClNz03 CziHz4NzOa CzsHzsNz05 CziHz6NzOz Cz3HzsNz03 CziHz4NzOz C1gHzzNz CigHdzO CigHz4NzO CzoHzaNzO CigHzzNzO CiaHizNzO Cz3HzsNzOs
255-265 276-278 amorph. 255-260 199-201 212-215 amorph. 196 181 217 181 183 207-208 221-223
+54 (c)
+183 (c)
- 93 (0) +111 (c)
+ 89 (0) -101
(0)
165 179b 179b 179b 179b, 179c 179b Chapter11 Chapter 11 Chapter11 113b Chapter 11 186 171
~
3 %
i! b-
w
U
z
5
-
Pleiocarpamine, a a 91 Pleiomutine, aa 91 Dipicrate Distyphnate Pleiomutinine, a& 91 Lactam 3 (P.tubicina)
b
Q
F
PART15. Alkaloids of unknown structure and their derivatives
Compound
w rp
Formula ___ CzoHzzNzOz C4z-43Hsz-tieN402 B. 2C6H3N307 B. 2C~H3N308 C40H46-48N402
mP (" C) 159 amorph. 230 230 220 287-290 (dec.)
U b-
[@ID
Reference
+123(c) -97 (c)
91.53 91 91 91 91 96 - u 1
k
s
0
u1
TABLE I-Continued
0
01 Q,
Compound
Formula
mP (" C)
[a]=
Reference
108, 89, 56 .108, 89, 56 108, 89 109, 113, cf. 100 109, 113
Kopsingine, B 108, 89, 56
270-274 (dec.)
+75 ( c )
Kopsaporine, B 108, 89, 56 Kopsingarine, B 108, 89 Fruticosine, dd 53, 100, 109
224 (dec.) 230 (dec.) 225-226
+48 (c)'
0-Acetylfruticosine Decarbomethoxyfruticosine Isodecarbomethoxyfruticosine 0-Acetyldecarbomethox yfruticosine Fruticosamine, dd 109, 113 Elliptinine, rr 156 Unnamed, 0. sandwicensis Hydriodide Unnamed, 0. oppositifolin Methoxyellipticine, rr 156; ss 156; tt 161; uu 161; vv 161 Elliptamine Picrate Powerine LiAIH4 product, picrate Poweramine, xx 161 Ochropine, xx 192d Unnamed, A. australe
115-118 or 132-134 292-293 290-294 211-212 177-181 231-233 215 (dec.) 282-284 270-272 (dec.) 170 188-189 (dec.) 212 (dec.) 241-242 146 186-1 88
- 19 (c)
+43 (c) - 255 -I-27 0
-216 (a)
- 229 (a)
109 109 109 109, 113 156 156 194 156, 55 161 161 161 161 161 55, l92d 147
td
B
W M
E
Quebrachacidine, a 195 Aglycone Rhazinine, e 62, 197 Tosylate ~~
Cz6Hz8Nz011 Ci9Hz4NzO ~
~~~
234-238 315-32 1 115-1 16 280 (dec.)
- 250 + 4 (e)
195 195 197 197
~
Plant sources: a, Aspidosperma quebrachoblanco Schlecht; b, A. polyneuron Mull.-Arg. ; c, A. chakensis Speg. ; d, A. album (Vahl) R. Benth. ; e, R h z y a stricta Decaisne; f, G o n i o m k a m s s i E. May; g, Stemmadenia donnell-srnithii (Rose) Woodson; h, Aspidosperrna discolor A.DC. ;i, A . eburneum Fr. All. ;j, A. limae Woodson; k, Vallesia dichotoma Ruiz et Pav. ; 1, V . glabra (Cav.) Link; m, Aspidosperma quirandy Hassler (57, 58); n, A . megalocarpon Mull.-Arg.; 0,A . multijlorunz A.DC.; p, A . obscurinervium Azambuja; q, A . triternatum Rojas Acosta; r, A . pyrifolium Mart. ; s, A . cylindrocarpon Mull.-Arg.; t, Amsonia tabernaemontana Walt.; u, Stemrnadenia tomentosa Greenman var. palmeri; v, S. pubescens Benth. (S. obovata K. Schum.); w, Tabernaemontana citrifolia L. ( T. alba Mill. or Nicholson); x, Aspidosperma refracturn Mart. ; y . A. populifolium A.DC. ; z, Kopsia longifiora Merrill; aa, Pleiocarpa mutica Benth. ; bb, P. tubicina Stapf; cc, Hunteria eburnea Pichon ;dd, Kopsia fruticosa A.DC. ;ee, Adspidosperma spp. ;ff, Diplorrhyncus condylocarpon (Mull.-Arg.) Pichon spp. nzossambicensis (Benth.) Duvign. ( D . mossambicensis Benth.); gg, Aspidosperma compactinerviurn Kuhlm. ; hh, A. ulei Mgf. ; ii, A. olivaceum Mull.-Arg,; jj, A. pyricollum Mull.-Arg. ; kk, A. australe Mull.-Arg. ;11, A. dasycarpon A.DC. ; mm, A. gomezianum A.DC. ; nn, A. subincanum Mart. (Brazil)-see 0 0 3 ; 00, A. subincanum Mart. (Peru)-see nn3; pp, A. longipetiolatum Kuhlm. ; qq, Tabernaemontana psychotrzfolia H.B.K. ; rr, Oehrosia elliptica Labill. ; ss, 0. sandwicensis A.DC. ; tt, 0. moorei F. Muell. ; uu, 0. glomerata Valeton; vv, 0. coccinea Mgf. (Ezcavatia coccinea Mig. T. and B.); ww, Aspidosperma oblongum A.DC. ; xx, Ochrosia poweri Bail. ; yy, Aspidosperma marcgravianum Woodson; zz, A. auriculatum Mgf. ; A, A. carapanauba Pichon; B, Kopsia singapurensis Ridley; C, A. parvifolium A.DC. ; D, Picralima nitida (Stapf) Th. and H. Durand ( P . klaineanu Pierre); E, A . sandwithianurn Mgf.; F, Haplophyton cimicidum A.DC.; G, A . fendleri Woodson; H, A . spruceanum Benth.; J, A . nigricans Handro; K , A . hilurianurn Mull.-Arg. 2 Rotation in: c, chloroform; a, acetone; d, dioxane; e, ethanol; m, methanol; w, water; ea, ethyl acetate. 3 Two specimens of Aspidosperma subincanum Mart. have been studied, one collected in Peru and the other in Brazil. The alkaloids isolated, although chemically related, were different with the exception of olivacine, which occurs in both. 4 Whether this difference is due to solvent or to the existence of two enantiomeric forms of kopsine is not clear. 5 Cornpare strychene picrate, mp 150-153" and 178-184" (67). 1
? b
' 2
%
8
2U
2G
kL
Ei
z1
358
B. GILBERT
3,ij-diethyl- and 3-ethyl-5-methylpyridinecould be isolated as the mixed picrate (15, 16, 12). Other dehydrogenation products which were not identified consisted of /3-alkylindoles, methylcarbazoles, and a substituted ci- or /3-carboline. Oxidation of quebrachamine under a variety of
11-A; R = H 11-B; R = Me
XCII
conditions gives products which are probably indolenines. For example, ozone and peracids give a hydroxy base, C19HzsNzO (probably 111, 13); catalytic oxidation gives C19HzGNzOZ (probably IV) which is readily converted to I11 (15). A tribromide, C19HZ3NzBr3, probably of similar
111;R = O H I V ; R = OOH V; R = C N
structure, is obtained by treatment of quebrachamine with N-bromosuccinimide (13). The hydroxy base (111)is reconverted to quebrachamine (I)by lithium aluminum hydride, whereas alkali converts it to a mixture of an oxindole and an indoxyl. Yet another indolenine, of probable structure V, was obtained by the action of cyanogen bromide on ( + )-quebrachamine (8). Hydrolysis with alcoholic alkali gave back ( + )-quebrachamine.
14. Aspidosperrna
359
AND RELATED ALKALOIDS
An examination of the NMR-spectrum of quebrachamine (I) (17) showed the absence of an a-hydrogen on the indole nucleus and confirmed the absence of an N-methyl group. The real confirmation that quebrachamine had structure I came with the use of mass spectrometry by Biemann and Spiteller (18, 18a). First, the zinc dust distillation was examined and its products, separated by vapor phase chromatography (VPC), were shown to be 3-ethylpyridine (75y0),3-methyl-5-ethylpyridine ( l a % ) , 3-ethyl-4-methylpyridine( 5 % ) , and 3,5-diethylpyridine (5%) together with 3-methylindole, 2-ethylindole, 2,3-dimethylindole, 2,3-diethylindole, and a methylethylindole. It will be seen that the major pyridine fragment does not require rearrangement for its formation and, together with 2,3-diethylindole, contains all the carbon atoms of structure I . I n order to provide a model with identical aliphatic structure, aspidospermine (11)was converted to 17-methoxyquebrachamine (VIII). Deacetylaspidospermine (VI) was oxidized with iodine and alkali to the indolenine VII, which although contaminated by unchanged VI was recognized by its UV-spectrum and its conversion by lithium aluminum deuteride to monodeuterio-VI. Compound VII was susceptible t o a reverse Mannich condensation (19, see arrows in VII but note that reaction may not proceed in two stages as indicated) and, on reduction with sodium borohydride, it gave 17-methoxyquebrachamine (VIII) which was separated from the accompanying unchanged deacetylaspidospermine (VI) by alumina chromatography. A comparison of the mass spectra of I and VIII left no doubt as to the complete identity of the aliphatic portions of the two molecules as can be seen from Table I1 in which the main peaks are given. The fragments expected from the breakdown of I (20, 21) are in fact TABLE I1 MASSSPECTRA OF QUEBRACHAMINE (I),17-METHOXYQUEBRACHAMINE(VIII), AND ~ ~ - D E U T E R 17-METHOXYQUEBR IOACHAMINE (19d-VIII) Molecular weight of fragment/charge = m/e Indoles Alkaloid Quebrachamine VIII 19d-VIII
M+ M-Me M-Et 282 312 313
267 297
253 283 284
Piperidines 157 187 187
143 173 173
138 138 139
125 125 126
110 110 111
96 96 97
360
B. GILBERT
observed. In the spectrum of V I I I those that contain the indole nucleus are shifted to molecular weights 30 units higher, corresponding to the addition of the 17-methoxyl group, whereas those containing the aliphatic piperidine portion appear a t identical m/e values. Confirmation that the m/e 124 peak in fact represents the piperidinic ring was obtained by preparation of 19-deuterio-17-methoxy-quebrachamine(19d-VIII) by using sodium borodeuteride, and in its spectrum this peak was partly
I JICO
H
I
Meo
\'I
ii TI1
i
19d-VIII; R = D
I
\ iiijc
1Ji
inje 110
injc 125
mie 96
i
inje 124; R = H mje 125; R = D
14.
d S p ~ d O S p ~ ? W % AND Cl RELATED ALKALOIDS
361
shifted to m/e 125 (two-thirds), part remaining a t m/e 124 (note preferential loss of C-19 H over C-19 D). Both the transitions m/e 138t o m/e 110 and m/e 125 to m/e 96 were confirmed by observed metastable peaks (see Section 11,D). 17-Methoxyquebrachamine (VIII) has the rotation, - 103" in dioxane, compared with - 111" found for quebrachamine (I)in the same solvent, and the optical rotatory dispersion (ORD) curves are very similar. It may therefore be deduced that ( - )-quebrachamine has the same absolute configuration a t position 5 as does aspidospermine. The closure of a bond between positions 12 and 19, presumably involved in the natural synthesis of aspidospermine-type alkaloids from quebrachamine, has been shown (18) to occur during the zinc dust distillation of the latter when a compound I X was isolated whose mass spectrum was exactly comparable with that of the indolenine VII, except for the 30-unit shift in the indole-containing fragments (Table V). Substance I X has subsequently been found in nature (Section 11,E). The total synthesis of ( f )-quebrachamine has been achieved by a modification of the route used for the synthesis of aspidospermine (Section 11,C; ref. 27a). Condensation of the intermediate X X X - J with phenyl hydrazine gave dl-IX which on borohydride reduction yielded ( f )-quebrachamine (I). C. ASPIDOSPERMINE The structure of aspidospermine (11) was practically solved by chemical degradative methods (see formula CCCCXXXIII, Volume VII, p. 131) but the final location of the ethyl side chain and the relative stereochemistry only became known after the single crystal X-ray study of its methiodide (22, 11) which was shown to have structure X.l Extensive degradative work, the results of which appeared side by side with those of the X-ray determination, had shown the nature of the structure around both nitrogen atoms and established the size of rings D and E (24, 12). Chromic acid oxidation of aspidospermine gave three lactams (XI, XII, and XIII, 24). The IR-carbonyl frequency (1680 cm-1) of the new amide group in lactam X I shows it to be in a five-membered ring, while the presence in the NMR-spectrum of a nonequivalence quartet a t 2.37 6 1 Stereochemical formulas show relative but not absolute configuration throughout Sections 11-IV.
362
B. GILBERT
(J = 16 cisec), attributable to the two protons at C-11, showed by the absence of further splitting that there is no hydrogen atom at position 12. This is supported by the fact that the single hydrogen atom at C-11 in the hydroxylactam XI1 shows only a singlet at 3.83 8 shifted to 5.10 8 in the acetate, XV, where it is well clear of other absorption. That no rearrangement had taken place during the formation of these two lactams was established by conversion of XI1 t o X I using phosphorus oxychloride to give XIV and then zinc dust followed by reduction of XI to the known N,-deacetyl-N,-ethylaspidospermine (XVII, 25). These results establish R3C. CHzCHzN in the five-membered ring E. Following this, other experiments elucidated the nature of ring D. Mild dehydrogenation of aspidospermine (11) with mercuric acetate gave 7,8-dehydroaspidospermine(XVIII),whose perchlorate (XIX)has the double bond in the expected 8,9 position showing C=N+ absorption at 1698 em-1. Sodium borohydride reduction of this salt to aspidospermine showed that no skeletal change had occurred, while silver oxide oxidation in aqueous dioxane gave the six-membered lactam (XX, vc0, 1625 em-1) in which the carbonyl group is in ring D. The characteristic 8-lactam absorption was clearer in the deacetyl derivative (XXI). IR-evidence and, particularly, coupling of 7,s-dehydroaspidospermine (XVIII) with phenyl diazonium chloride, which from its mechanism must take place at position 7 to give XXII, established the presence of a hydrogen atom in this position in XVIII and hence excluded structure CCCCXXXIII (Volume VII) for aspidospermine. The formation of 3,5diethyl- and 3-methyl-5-ethylpyridine during the dehydrogenation of aspidospermine under vigorous conditions (25) thus involves a rearrangement of the ethyl side chain. These results establish the series N-CHzCHZ in the six-membered ring D. The presence of a third adjacent methylene group was shown in another series of degradative steps. Aspidospermine N,-methiodide (X, 26, 2 7 ) which is reconverted t o aspidospermine under Hofmann degradation conditions, suffered the Emde degration (26, 24) to give the dihydromethine (XXIII) whose methiodide underwent Hofmann degradation to give the methine XXIV in which rings D and E have been opened and which has a terminal methylene group (IR-,910,995 em-1; NMR-, two one-proton quartets at 5.01 and 5.05 6 in the vinyl region). In addition, it has a vinyl hydrogen atom flanked by four vicinal protons (NMR-complexmultiplet at 4.24 6). As we know that position 12 is quaternary, this vinyl proton cannot be in position 11, and it must therefore be in position 7, the nitrogen having remained attached to carbon 10. From the aforementioned NMRabsorption, we may deduce that there is a methylene group in position 6.
XII; R = OH X I V ; R = C1 X V ; K = OAc X V I ; H. = O H (epimer of XII)
XX
I
i
0
J 363
PIIS*(’I
364
B. GILBERT
This result was confirmed by cleavage of the double bond in XXIV to give the aldehyde XXV, in which the aldehydic hydrogen atom shows a 1: 2 : 1 triplet a t 9.83 6 and therefore lies adjacent t o a methylene group in position 6. Furthermore, isomerization of the methine XXIV with hydrochloric acid moves the double bond to the 6,7 position (XXVI) as shown by the appearance of an allylic methyl group in the NMRspectrum (1.68 6, doublet, J = 2.6 cisec), and in this compound (XXVI) there are two vinyl protons (multiplet a t 5.47 6). The transformation of XXIV t o XXVI does not involve rearrangement because both compounds on reduction yield the same dihydro derivative, XXVII.
1
1. HCI-Hs0
z,3lcI
I
1. JleI 2. KOt-Uu
Me0
SSVIII
SSIS
XXIV
XSX
Ac XXVI
XXVII
No real evidence was adduced for the quaternary center a t position 5 in aspidospermine (11),but the formation of lactams and compounds containing C=N,, in which the nitrogen has necessarily the planar configuration excludes any bridging of the two rings D and E.
14. Aspidosperma
AND RELATED ALKALOIDS
365
Evidence for the six-membered ring C was lacking, and an attempt to clarify this portion of the molecule was made starting with the N,dimethiodide of deacetylaspidospermine (XXVIII, 12). Emde degradation gave X X I X in which the aryl-nitrogen bond has been cleaved. This underwent Hofmann elimination of N, on prolonged heating with methyl iodide to give a base containing only one nitrogen atom which could be XXX, which contains a hydrogenable double bond. Unfortunately, no quinoline derivative or other recognizable product could be isolated from the dehydrogenation of this compound, probably because of the two resistant quaternary centers in ring C. The synthesis of aspidospermine (11)has been achieved (27a).Starting with n-butyraldehyde in which the a-methylene group represents the eventual quaternary carbon atom a t position 5, acrylic ester was added by way of the enamine synthesis (27b) to give XXX-A. A second enamine synthesis using methyl vinyl ketone furnished the aldehyde XXX-B which by spontaneous condensation gave the isolable cyclohexenone, XXX-C, in which the final ring C is present and the propionic side chain provides the carbon atoms of ring D. A Mannich-type addition of ammonia to XXX-C led to the bicyclic amides XXX-D containing rings C and D. Reaction of XXX-D in the Fischer indole synthesis with o-methoxyphenylhydrazine led to the two isomeric indoles XXX-E and XXX-F, showing that enolization of XXX-D occurs away from, rather than toward, the ring junction. To induce enolization in the desired direction, it was necessary to build on ring E, which was achieved by lithium aluminum hydride reduction o f the amide carbonyl group of XXX-D (the ketonic carbonyl was protected as the ethylene ketal) to give the amine, XXX-G, which furnished the tricyclic amide, XXX-I in two steps. A slow acetic acid-catalyzed Fischer indole synthesis using this amide still gave only indolic material showing that enolization, even under these equilibrating conditions, proceeded away from the ring junction, due to the fact that enolization in the desired direction would have resulted in a strained five-membered ring containing three trigonal atoms. Reduction of the keto-amide, XXX-I to the keto-amine X x x - J removed two of these atoms, and the Fischer synthesis with this compound yielded an indolenine which was the dl-form of 1,2-dehydrodeacetylaspidosperniine (VII). The fact that this product, had the correct stereochemistry derives from the equilibration of the asymmetric centers a t positions 12 and 19 by the reversible conversion to dl-XXX-K (see Section 11, B) during the Fischer synthesis (note too that the intermediate phenylhydrazone could similarly equilibrate), VII being the most stable stereoisomer. Lithium aluminum hydride introduced hydrogen on the desired side of the molecule (see Section 11,B, Refs. 18,
366
B. GILBERT
xxx-I
XXX-H
XXX-J
\/+/U I H
I Me0
I Me0
dl-VII
Ac
dl-I1
14. Aspiclosperma
AND RELATED ALKALOIDS
367
18a) at position 2, and acetylation of the product furnished dl-aspidospermine whose IR- and mass spectra were identical with those of the natural alkaloid (27a).
D. NMR- AND MASS SPECTRA OF THE ASPIDOSPERMINE-TYPE ALKALOIDS Although NMR was only partly responsible for the structure determination of aspidospermine (11)and the mass spectrum of the alkaloid was only measured after its structure was known, these two physical methods have had immense application in subsequent investigations of related alkaloids. For this reason, the more important data have been collected in Tables I V and V. Considering first the NMR-spectra, the nature of the aromatic substitution pattern may often be deduced from the absorption between 7.3 and 6.6 6 [see pyrifolidine (XLVI), aspidocarpine (XLIV), and aspidoalbine (CLXXXVIII), for example], especially when the data are taken in conjunction with the UV-absorption spectrum (Table 111). Of the nonaromatic protons, the one found furthest downfield is the C-2 hydrogen atom, which appears as a quartet centered at 4.0-4.5 6 (29,45). The absence of this peak is indicative of substitution at this point and is an important means of recognizing alkaloids of the aspidofractinine group (Section 111) in which the sixth ring terminates at position 2 . Alkaloids which lack the C-2 proton but which bear a carbomethoxy group on C-3, e.g., refractine (CL-A),exhibit a quartet at about 3.8 8 due to the C-3 proton. The four protons next to nitrogen in positions 8 and 10 absorb in the region 3.3 to 2.9 6 and in all the alkaloids based on the aspidospermine skeleton form a characteristic pattern which is not obscured by other absorption (9, 29) and which is profoundly altered in the spectra of the related hexacyclic bases (Sections I11 and IV). The single proton on C-19, not having any neighbor, produces a singlet from 2.2-2.5 6 which is sometimes hidden by absorption due to the N-COCH3 where this group is present, though in these cases, its presence may be deduced from the integration curve. In addition to these absorptions, there are usually easily recognized three proton singlets due to aromatic methoxyl groups a t 3.75-3.90 8 and to the methyl group of an N-acetyl at 2.2 6. I n the case of N,-propionyl compounds a quartet may be observed at 2.3-2.8 6 due to the COCHz protons, though in a 60-mc spectrum, slight overlapping occurs with the N,-C( 19)H absorption in some cases. The methyl group of such a propionyl group exhibits a triplet centered a t approximately 1.25 8. The terminal methyl group of
TABLE 111
W
% --
UV-DATA Wavelength, mp
Chromophorel
Reference
log € 2 ~
Dihydroindoles (N,H) Unsubstituted, XCVI Unsubstituted, CXXII-Me1 16-Methoxy-, CXVI 17-Methoxy-, C X L I X - F
16,17-Dimethoxy-,X L V I I
n3
ac
n n
ac n aC
15,16,17-Trimethoxy-, CXCII 17-Hydroxy-,X X X V I N-Alkyldihydroindoles N,-Methyl, CXLVI-A 16-Methoxy-,C I I I 17-Methoxy-, X L I
16,17-Dimethoxy-,L V I I N -Acyldihydroindoles N-Formyl, C X X N-Acetyl, CXLIV-A N-Carbomethoxy-, CXLV-A 17-Methoxy, -11 16,17-Dimethoxy-,X L V I
alk n
n
n
n n ac n
n
n n
n n
245, 2984 226, 260(sh),5 268(sh) 225, 250(sh), 300 212, 245, 288 215, 268, 275 215, 293 230, 279 as neutral 212, 240(sh), 305 245, 292
3.86, 3.48 3.58 3.98, 3.65, 3.52 4.56, 3.88, 3.41 4.36, 3.22, 3.23 4.40, 3.50 3.97, 3.30
206, 254, 211, 251, 220, 266, 218, 272, 218, 263,
4.42, 3.97, 3.52 4.52, 3.85, 3.71 4.42, 3.87, 3.40 3.47, 2.86, 2.86 4.36, 3.80, 3.48
300 304 305 278 305
208,253, 278,288 210, 257, 286, 294 206.5, 246, 282.5, 289.5 220, 257, 280-290(sh) 223, 252,286
~-
7 37 32 37
9, 10
4.48, 3.85, 3.63 3.66, 3.24
4.36,4.16, 4.33,4.15, 4.49, 4.20, 4.56, 4.09 4.55, 3.99,
3.72, 3.67 3.77, 3.74 3.51, 3.48 3.37
91 55, 72 25 36
81 96 91 25 10
n
16,17-Dimethoxy-,L X X 15,16,17-Trimethoxy-, CXC 17-Hydroxy-, L X X X V I I 16,17-Dihydroxy-,L X I X 16-Methoxy-17-hydroxy-,LIII 15,lR-Dimethoxy-17-hydroxy-, CLXXXVIII Indolenines Decarbomethoxymossambine, CCXXXI 1,2-Dehydrodeacetylaspidosperinine, VII
a-Methyleneindolines Vincadifformine, X C I I I Condylocarpine, CCXV Norfluorocurarine, CCXL 16-Methoxyrninovincine, CX 11-Methoxy-14,19-dihydrocondylocarpine, CCXXIV - A
n alk n alk n alk n alk
222, 250, 290(sh) 218,258, 295 221, 261, 292 230, 258(sh), 311 225, 260, 295(sh) 216, 237, 304 228, 264 224, 307 227, 267 308
4.48, 3.85, 3.27 4.51, 4.15, 3.58 4.40, 3.92, 3.55 4.39, 3.80, 3.74 4.30, 3.89 4.29, 4.24, 3.44 4.43, 3.94 4.42, 3.73 4.16, 3.88 3.64
n n
220, 262 228, 236(sh), 255, 307
4.32, 3.84 4.22,4.14, 3.69, 3.65
121
n
225, 300, 328 228, 295, 328 242, 299, 360 230, 250, 325 255, 286, 327
3.97, 4.03, 4.19 4.04, 4.01, 4.17 3.98, 3.57, 4.25 4.05, 4.03, 4.14 4.17, 4.04, 4.05
6 116 116 32
n n
n n n n
36 52 33 36 31 52
18
48
w t+
b
9. 3 % 3 -3
z U
P d
Fr3 M
tl P
t-
x
Extended indole Uleine, CCXLV
n
209, 309
4.38, 4.30
138
Py.ridociirbazoles Olivacine, CCLVIIl6
n
224, 239, 269, 277, 288, 293, 315, 330, 345, 377 242, 307, 351, 412
4.32,4.22, 4.54,4.71, 4.89,4.8S, 3.61, 3.73, 3.52, 3.58 4.45,4.92, 3.78, 3.59
160
ac
t. 5 F:
u
TABLE 111-Continued
Chromophorel
Ellipticine methonitrate Anhydronium base from olivacine methiodide, CCLIX 1,2-Dihydroellipticine, CCXCIII 1,2-Dihydroolivacine, CCLXXlV Guatambuine, CCLX7 Oxindole Carapanaubine, CCCLIV $-Indoxy1 Isoreserpiline-~-indoxyl,CCCLVII-A
Wavelength, mp
4 0
Reference
log €2
n n
241, 249, 307, 356, 423 270, 336, 373,400, 510
4.38, 4.36, 4.86, 3.72, 3.68 3.58,4.69, 3.88, 3.78,3.60
158 149
n
236, 244, 271(sh), 281, 302, 313,382 235, 270(sh), 279, 301, 312, 378 239, 248,275, 330, 344 235, 283, 314, 377 241, 250(sh), 263, 300, 330, 344
4.45,4.30,4.46,4.64, 4.18,4.30,4.43
158
ac n ac n
4.42, 4.45, 4.63, 4.48,4.46,4.59, 4.43, 4.63, 4.33, 4.64, 4.51, 4.38,
4.15, 4.28, 4.36 3.94, 3.63 4.32 4.30, 3.60, 3.52
W
139, 150
B z
W M
n ac
215, 244, 278(sh), 300(sh) 222, 246(sh), 278, 300(sh)
4.57, 4.23,3.80, 3.66 4.56, 3.79, 3.61,4.15
171
n
226, 251, 282, 402
4.36, 4.46,4.07, 3.74
113d
1 Many examples of the chromophores recorded are found in other alkaloid groups, especially that of the curare alkaloids (see Chapter 15). An excellent collection of spectra is found in refs. 55 and 56. 2 Log E rather than E values have been given for uniformity, as most literature values are so recorded. 3 Abbreviations: n = neutral, ac = acid, alk = alkaline. 4 Kopsinine shows peaks a t 205, 246, and 295 mp. 5 sh = shoulder. 6 Ellipticine (CCLXXXIV) has a similar spectrum (156, 55). 7 N-Methyltetrahydroellipticine(CCLXXXV) has a similar spectrum (158, 55).
TABLE IV
NMR- DATA^ PART1. Simple derivatives of aspidospermidine Position of protons; 6 , ppm; no. of peaks; J, cjsec
-
Compound
Demethoxyaspidospermine, X X X I I I
Aromatic2
Na
19
8,lO
213
H
substitution
acyl
H
CHz
CH3
2.93-3.35
0.73
40a
2.3s
2.9-3.3
0.72
40
2.28s
2.9-3.3
0.72
40a
3 5U
2.9-3.3 2.8-3.3
0.67 0.69
29 30,45
$
2.23s
ca. 3.0
0.62
31
2.17s
2.9-3.3
0.67
9, 30
0.75
36
4.08q, J = 6,lO 4.08q, J = 6.5,lO
Demethylaspidospermine, XXXVII
6.9m
Aspidospermine, I1 Aspidocarpine, XLIV
7.0m 6.53t. J = 9
Aspidolimine, L I I I
6.65q, J = 8
4.07q, J = 6,lO 4.50q 3.95q, J = 5.5,lO 4.12q, J = 6.5, 10.5 4.50q, J = 6,lO 4.05d, J=8 4.5q 4.4% J = 6.5,lO 4.12q
Demethoxypalosine, XXXIV
Pyrifolidine, XLVI Spegazzinidine, LXIX
6.6%
J = 8.2 6.57q
Cylindrocarpidine, LXXVI Cylindrocarpine, LXXV
7.0m 7.17m
Limaspermine, LXXXVII
6.92m
w
16,17
8.13m( 17-H) 7.16m(3H) 8.13m(17-H) 7.07m(3H)
2.27s
10.83s 3.89s 3.80s 10.77s 3.88s 11.0s 3.77, 3.84 5.84m, 11.1s 3.88s 3.84s 10.88s
2.38q 1.24t J = 6.5 2.32s 2.20s 2.27s 2.57q 1.25t J=7 2.22s 2.48s 2.22s -5
2.57q J = 7.5
2.45s 2.48s
2.9-3.35 2.9-3.3 ca. 3.0
-4 -4
3.52t6, J=7
Reference
.”
2
b
6
& Y
Eti
U
bw b 5 F1
29 29 33
0
4
w
TABLE IV-Continued
PART2. Aspidospermidine derivatives bearing a carbomethoxyl group at C-3
Compound
Aromatic
6,7 vinyl
19 H
COzMe
~-
~
8 CHz
21 CH3
Reference
~~
Tabersonine, XCII Vincadifformine, XCIII Minovine, CVIII Mmovmcine, CIX Vindolinine,* CVI
7. O m 7.0m 6.95 6-7 lines 6 08d, 6 30% 6 91d, J = 2 5,s
Vindoline, CIII
5.75s
3.64s 3.75s
-
5.6-6.3 12 lines 5.23, 5.88, ,,J = 10
3.78s 3.68s 3.80~9
8.98 8.88 3.25 8.8 4.5 approx. 2.68
0.77
2.65
3.4
1.85 0.95d 5=7 0.487
7,66a 6,66a 32 32
3 4
~
PART3. Aspidofractinine and kopsine-type alkaloids and their derivatives
Compound ~
~~
Aromatic .
Aspidofiline, CXXXVI Refractidine, CXX Pyrifolme, CXIX Deacetylpyrifoline, CXXI 6-Acety1-6-demethylpyrifoline, CXXVIII
Pleiocarpine, CXLV-A Refractine, CL-A
6 or 3 substitution
N*
17
substitution
-
19 H ~~
7.0m 6.93m 6.75m 7.0m
7.72d( 17-H), 7.17m 6.9m
3.35s 3.33s 3.33s 2.02s, 4.63q, J = 5, 10.5 3.72s 3.68s
10.02s 3.81s 3.78s 3.80s
2.32s 8.37s 2.12s
-
11 H
_____________~
3.0m
2.12s
-3.0m -3.15m
9.47s
-
3.82s 3.85s
8,lO CH2
Reference -~
80,37 81 81,37 37 81,37
3.0m
91
3.0m
82, 37
Isorefractine, CL-C Deformylrefractine, CXLIX -A Deformylisorefractine, CXLIX-C N-Methyldeformylrefractinol, CLI-F
6.9m G.73m 6.8m 6.8m
N-Methylkopsinylene, CXLVI-M N-Methylkopsinane, CXLVI-0
A'-Methylisokopsinylene, CXLVI-N X-Methylenekopsinyl ether, CLIII
3.78s 3.75s 3.80s 3.95oct J = 2.5, 6.5,12 5.0 2 x 6 lines 1.3d J = 6.5 2.03d J = 1.5
Kopsine, CLXX
7.4m
7.2S'U
Fruticosamine11 Fruticosinell
7.251~1 7.70(17-H) 7.2m
5.52br10 3.1710 4.79q'Z
Kopsine-l0-lactam,11CLXXV
3.83s 3.80s 3.82s 3.77s
--
9.20s
N
2.90s
3.0m 2.9m 3.1 3.0m
37 37 37 37
95 95 95 4.48q
95
3.93s
100, 101, 109 109 109
J=7
3.90s 3.88s 3.75d J=1 3.5d J = -1 3.57s
Dihydrokopsine- 10-lartam, CLXXVlI Kopsane- 10-lactam,ll CLXXXVl
2.82s
101
2.63d J = -1
101 101
PART4. Aspidoalbine-type alkaloids and their derivatives Compound
Aromatic
l5,16,17 N, substltutlorl substitution
21 CHz
-~ ~
Aspidolimidine, CCI
Aspidoalbine, CLXXXVIII
6.73d 7.09d J=8 6.82s
0-Methyl-depropionylaspidoalbine, CXCII
6.89
3.88s 0.78s 3.86s 3.85s
2.32s
4.05m
-4.3m
8,10 CHz _ _ -2.85m
-
Reference 40
52
3. O m
4.02q _ _ _ _ ~
52 ~~
w 4 w
TABLE IV-Continued
W
4
ip
PART5. Alkaloids related to condylocarpine and mossambine and their derivatives ~~~
N,
Aromatic
Compound
16 substitution
3,15
H
19
18
Reference
~
3.78s
Condylocarpine, CCXV 2,16-Dihydromossambine, CCXXIX
6.8m
Decarbomethoxymossambine, CCXXXI Echitamidine, CCXLII
7.05m
8.68
3.89s
Lochneridine, CCXLIII Stemmadenine, CCXIII
7.35111
9.3
3.77s 3.79s 4.38
3.92m 4.12d J=2
5.32q
1.58d
117
5.55
1.66d J=6
122
5.33
122 126
1.16d J=6 0.77m 1.7d
5.4q
td
127 117
PART6. Indole and oxindole alkaloids and their derivatives ~~
~
Compound Uleine, CCXLV 3-Carbomethoxy-1-methyl-P-carboline, CCCXXXIX
Aromatic 7.34m 7.0-8.7m
N,
COzMe
8.38s 9.40s
3.95s
17 __ 5.27s 4.98s (vinyl)
18
19 -~
0.83m
Reference -
~
142
(Et) 180
Yohimbine, CCXCV 8-Yohimbine, CCXCVI Dihydrocorynantheol, CCCVI
7.25m 7.17m 7.2m
7.90s 7.87s 8.80s
0Acetyldihydrocorynantheol
7.15m
8.12s
Isoreserpiline, CCCV
6.77s, 6.90s 6.55s, 6.74s
7.95s
3.72s
8.73s
3.61s
Carapanaubine, CCCLIV 0,O-Diacetylakuammidinol, CCCXXVII
6.25m
8.43s
0-Acetylnormacusine-B, CCCXXVIII
6.25m
8.57s
3.77s 3.88s 4.05q (CH20Ac) 7.37s (vinyl) 7.44s (vinyl) 4.0m (CH20Ac) 3.93m (CH20Ac)
0.88 (Et) 0.87 (Et) 1.37d
(J = 6) 1.40d
(J = 6) 1.59d
(J = 6.5) 1.57d ( J =7)
37 37 63, 37 63, 37 4.44 oct 4.56 oct (J = 6, 5.7) 5.35q (J = 6.5) 5.38q ( J =7)
171
171 165 165
1 For model compounds, see refs. 45,17,101,66a. Abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, oct = octet, m = multiplet, br = broad. 2 CHCl3 proton appears at 7.28 6. 3 Position of principal peak. 4 C02CH3; cylindrocarpidine, 3.58 6 ; cylindrocarpine, 3.56 6. 5 Trans-cinnamoyl vinyl protons show two doublets at 6.75 and 7.72 6 (J = 16). 6 Shifted to 4.0 6 in the acetate. 7 The high field position of the aliphatic proton absorption in tabersonine and vindoline may be due to increased shielding by ring currents from the aromatic ring (7, 51b). 8 c-2proton absorbs a t 3.85 6, doublet, J = 4.5 c/sec in N-methylvindolinol acetate (3). 9 Aromatic OCHs coincident. 10 Eliminated after replacement of active hydrogen by deuterium. 11 Absorption in 4.0-4.5 6 region attributed in the kopsine lactams to a C-8 proton. 12 Due to CH-CH(OH), converted to a doublet by treatment with D2O.
TABLE V
W
4 Q,
MASS SPECTRAL DATA PART1. Alkaloids which fragment as aspidospermine
Compound
Mol. wt. of fragmentlcharge = m/el
Reference
-
Mf2
a2
282 312 313 342 324 338 296 326 354 412
254 284 285 314 296 310 268 298 326 384
b3
c4
130 160 1615 190 130 130 144 174 160
124 124 1246 124 124 124 124 124 124 182 182 124 124 124 124 124 124 1408 140 140 141 14P
Other peaks -
Aspidospermidine, X X X I Deacetylaspidospermine, VI 2-d Deacetylpyrifolidine, XLVII Demethoxyaspidospermine, X X X I I I Demethoxypalosine, X X X I V N-Methylaspidospermidine, X X X V N-Methyldeacetylaspidospermine, X L I Aspidospermine, I1 21-Acetoxyaspidospermine, LXXXV 0,N-Diacetyl-0-methyldeacylaspidoalbinol, CXCV Pyrifolidine, XLVI Aspidocarpine, XLIV Aspidolimine, L I I I Spegazzinine, LXIV Spegazzinidine, L X I X Demethylaspidospermine, XXXVII Limaspermine, L X X X V I I N-Decinnamoylcylindrocarpol, L X X X I V 0-Methyldeacylaspidoalbinol,CXCIII 19-d, CXCIV N-Et.hyldecinnamoylcylindrocarpo1, LXXXVI
-7
384 370 3842 356 372 340 370 328 388
356 342 3562 312 328
356
328
220 190 176 176
3428 300
146
-7
220 220
.-
28, 21 9, 21 21
339, 311, 1099
9 40a 40 28,21 28 28,21 52 52 28, 37 40 40 36 36 40a 33 52 52 52 52
m
2 EM
N-Ethyl-0-methyldeacylaspidoalbinol, CXCVI N-CD3CH3, CXCVII 2,3-Dihydrotabersonine, XCVI Dihydrovincadifformine, CI 2,3-Dihydrotabersonol, XCVII Dihydrovincadifforminol, XCIX ( = tetrahydrotabersonol) 20-Hydroxydihydrovincadifforminol, CXIV 2,3-Dihydrotabersonane, XCVIII Dihydrovincadifforminane, CII 20-Hydroxydihydrovincadiff orminane, CXV Vindoline, CIII Dihydrovindoline, CXI 16-Methoxy-N,-methyl-4-oxoaspidospermidine, CV 20-Hydroxy- 16-methoxy-2,3-dihydrovincadifforminol, CXVI
416
7
338 340 310 312
252 254 252 254
328 294 296 312 45610 45810 340 358
270 252 254 270 296 298 298 300
248 250
140 122 124
121
124 140
174 174 174 160
124 140 122 124 124 140
309, 282, 135 311, 28410.11 166"
52 52 7 6 7 6, 7 32 7 32 32 21 4,21 4, 21 32
"
PART2. Aspidospermine-type compounds with a 2,3-double bond
Compound
Tabersonine, XCII Vincadifformine (6,7-dihydrotabersonine),XCIII Minovincinine, CVII 0-Acetylminovincinine Minovine, CVIII Minovincine, CIX 16-Methoxyminovincine, CX
Mol. wt. of fragment/charge = m/e
M+ 336 338 3548 39610 352 35214 382
g12
228 214 244
c
124 1408 18210 124 138 138
Other peaks 135, 107, 9213
Reference
7
6, 7 32 32 32 32 32
w
4
4
W 41 06
TABLE V-Continued
PART3. Aspidospermine-type compounds with a l,2-double lbond (indolenines) Mol. wt. of fragmentlcharge = m/e Compound
1,2-Dehydroaspidospermidine,I X 1,2-Dehydroaspidospermine, VII
PART4. Aspidofractinine-type compounds
Reference
~-
M+
M-29
M-70
C
280 310
251 281
210 240
124
28 21
G)
E
b
~_
M
Mol. wt. of fragment/charge = m/e Compound
Reference M+
Aspidofractinine, CXVII 0-Methyldeacetylaspidofiline, CXXXIX 6,7-Dehydro-CXXXIX,CXLI N-Ethyldeacetylaspidofiline, CXL Aspidofiline, CXXXVI 0-Methylaspidofiline, CXXXVIII 0-Acetylaspidofiline, CXXXVII Deformylrefractidine, CXXII N-Methyldeformylrefractidine, CXXIII
280 310 308 324 3382 3522 3802 310 32419.20
h 252 282 280 296 3102 3242 3522 282 296
Indole 14415 17415 18816 18815 188 14415 15815
C
124 124 124 124 124 124 154 154
i 109 109 107 109 109 109 109 139 139
Other peaks
29517 130, 10918 10918
102 80 80 37 80 80 80 81 81,37
E
N-CD2H analog, CXXIV Deacetylpyrifoline, CXXI Refractidine, CXX Pyrifoline, CXIX Deformyldemethylrefractidine, CXXVII N -Acetyldeformyldemethylrefractidine,CXXX N-Methyldeformyldemethylrefractidine,CXXXI N-CDzH analog, CXXXII Deacetyl-6-demethylpyrifoline,CXXV 6-Deuterio analog, CXXVI N,O-Diacetyldeformyldemethylrefractidine, CXXIX 6-Acetyl-6-demethylpyrifoline, CXXVIII 6-Dehydrodeformyldemethylrefractidine,CXXXV 6-Dehydrodeacetyldemethylpyrifolhe,CXXXIII 1,7,7-Trideuterio analog, CXXXIV Kopsinine, CXLII-A Aspidofractine, CXLIII-A Pleiocarpine, CXLV-A Deformylrefraatine, CXLIX-A Refractine, CL-A Isorefractine, CL-C 3-Deuterio analog, CL-S Pleiocarpine lactam A, CXLV-D
326 340 33819 3822 2968 3388 3108 312 326 327 3802 410 294 324 327 338 36620 396 368 39620 396 397
298 312 31019 3542 2688 310 282 284 298 299 35229 10 382 266 296 299 310 338 368 340 368
Pleiocarpinilam, CXLVI-D Kopsinyl alcohol, CXLII-F N-Methylkopsinyl alcohol, CXLVI-F N-Trideuteriomethyl-3’,3’, 10,lO-tetradeuteriokopsinyl alcohol, CXLVIII-G Deformylrefractinol, CXLIX-F
3108 324
282 296
3408
312
16015 17415 14415 17415 14415 14415 15815 16015
17415 174 14415 174 14415 17415 17515 157
259 27212 215 22812
12424
81 81 81 81 81 81 81 81 81 81 81 81 81 81 81 82, 37 82, 37 95 82,37 82,37 102 102 102
12424
102
124 124 126
10922 109 111
82, 37 95 102
124
109
154 154 154 154 140 140 140 140 140 141 182 182 138 138 140 12422 124 124 124 124 absent23 absent23
139 139 139 139 125 125 125 125 125 126 16710 167 123 123 125 10922 109 109 109 109
109 10918 307,21 10918 130
130
154 154
37
TABLE V-Continued
W W
3
~
._
~
Mol. wt. of fragment/charge = m/e
Compound
~
M+
h
__
Indole
C
i
Other peaks
Reference
~-
0 -Acetyldeformylisorefractinol
38225
35425
109
3’,3’-Dideuterio analog, CXLIX-V
384
35625
109
Kopsinylene, CXLII-M
292
264
109
220,207,182, 168,129,12226
37,102
Aspidofract-3-ene, CXLIII-M
320
2922827
10922
213,164,130, 12226
37
Deformylrefract-3-ene, CXLIX-M
32228
109
250,16226
350
29428 3222.27
124
Refract-3-ene, CL-M
124
109
250, 243, 12226
37 37
Deformylnoraspidofractone, CXLII-P
294
266
124
10922
238,209,156, 130, 122,11526
37
Noraspidofractone, CXLIII-P
3222
2942
124
10922
238,209,156, 143,130,12226
37
Deformylnorrefractone, CXLIX-P
324
296
124
10922
268,239,201, 12226
37
Norrefractone, CL-P
352
3242927
124
281,268,12226
Deformylnorrefractol, CXLIX-Q
326
10922
96
37 37,102
1243
82 82
M
z *
H
62
z
M
PART5. Kopsine-like compounds Mol. wt. of fragment/charge = m/e
Compound
-
-
Mf
Reference
-~
Other peaks
M-28
__
-
-
Kopsine, CLXX
38027
Decarbomethoxykopslne, CLXXI ,V,-Methyldecarbomethoxydlhydrokopslne, CLXXVIII 3'-Deuter1odecarbomethoxyd1hydrokopsine, CLXXLX Fruticosamine Fruticosine
35227
28225
254(w)
322 338
224 238
210(W)
325
224
196(w)
380 380
35227 35227
282 282
107,106, 109 107 107 107 243 321,230
109 109
PART6. Aspidoalbine-type compounds
Mol. wt. of fragment/charge = m/e
Compound
~~~
M+
n'
M-44
b3
c'
310 326 340 356 400 414 400 358
294 310 324 3402 384 398 3842 342
130 146 160
138 138 138 138 138 138 138 138
Other peaks
Reference
~ _ _ _ _ _
1-Acetylaspidoalbidine, CCI-K Haplocidine, CCI-C 0-Methylhaplocidine, CCI-B Aspidolimidine, CCI Aspidoalbine, CLXXXVIII 0 -Methylaspidoalbine, CXC CXCI 0 .Methyl-N,-acetyldepropionylaspidoalbine, CXCII 0-Methyldepropionylaspidoalbine,
338 354 368 3842 428 442 42S2 386
176
220
160 149,310,311 110,160
110,160
113e 113e 113e 40 52 52 52 52
TABLE V-Continued
W 00 t.3
PART7. Aspidospermatidine- and strychane-like compounds Mol. wt. of fragmentlcharge = m/e Compound
Reference Mf
Dihydroaspidospermatidine, CCV Dihydroaspidospermatine, CCX Tetrahydrocondylocarpine,C C X X Aspidospermatidine, CCIV N-Acetylaspidospermatidine, CCVIII N-Methylaspidospermatidine, CCVI Deacetylaspidospermatine, CCVII Aspidospermatine, CCIX Tetrahydrodecarbomethoxyakuammicine,CCIII Tetrahydroakuammicine, C C X X X V Tetrahydromossambine, C C X X X 2,16-Dihydroechitamidine 16-Methyl-16-decarbomethoxytetrahydroakuammicine, C C X X X V I 16-Methyl-16-decarbomethoxytetrahydromossambine, C C X X X I V Spermostrychnine, C C X I Deacetylspermostrychnine, C C X I I 2,16-Dihydrodecarbomethoxyakuammicine, CCII 2,16-Dihydroakuammicine,C C X X X V I I I 2,16-Dihydromossambine, C C X X I X
r
8
227
268 340 326 266 308 280 296 338 268 326 342 342 282
138 138 196 136 136 136 136 136 138 196 212 212 152
298
168
215
368 326 266 324 340
166 166 136 194 210
271 229
227
199 199 215 199 199
b3
U
Other peaks
130 160 130 130 130 144 160 160 130 130 130 130
28,21 28,21 118 28,21 28,21 28,21 28,21 28,21 28,21 122 122 126 I22 122
160 160 130 130 130
139 139
25129 25129 26729
21 21 28, 21 122 122
td
8 W
2
PART 8. Yohimbine- and ajmalicine-like compounds Mol. wt. of frctgment/charge = m/e Compound
Reference Mf 3548,25,27
V
W
2
Y
Other peaks
170
169
184
156
165, 162
17.Deoxy-a-yohimbine, CCCX
170
169
184
156
165
Alloyohimbone, CCCXI
170
169
184
156
165
16-Ketoyohimbane, CCCXII
170
169
184
156
165
Yohimbinone, CCCXIII
170
169
184
156
165
Seredone, CCCXIV
230
229
244
216
165
200
199
214
186
162
N-Methylyohimbane, CCCXV
184
183
198
170
165
3-Deuterioyohimbine, CCCVII
171
170
185
157
165 165
Yohimbine (and stereoisomers)
11-Methoxyyohimbine, CCXCVIII
38427.25
Tetrahydroalstonine, CCCXVIII
35227
170
169
184
156
Ajmalicine, CCCXVII
35227
170
169
184
156
225
165
3,5,6-Trideuterioajmalicine, CCCIX
35530
173
172, 171
187
158
228
165
3,14-Dideuterioajmalicine,CCCVIII
35430
171
170
185
158, 157
171
Tetraphylline, CCCXIX
38227
200
199
214
186
165
Aricine, CCCIII
38227
200
199
214
186
Tetramethylenetetrahydr0-/3-~arboline
22627
170
169
184(w)
156
165 197
165
w
TABLE V-Continued
PART9. Sarpagine-like compounds Mol. wt. of fragment/charge = m/e
Compound
M+ Bisdeoxyajmalol-B, CCCXXXIV 0-Methyl-17-deoxydihydrosarpagine, CCCXXXV Dih ydronormacusine - B Normacusine-B, CCCXX 0-Acetylnormacusine-B, CCCXXVIII Polyneuridine, CCCXXI 0-Acetylpolyneuridine, CCCXXV Akuammidine, CCCXXII 0,O-Diacetylakuammidinol, CCCXXVII 17,17-Dideuterio-CCCXXVII
cc
29420,27,32 328 2968.27 29419,20,27 33620,25,27 3528,19.20,25,27 3941%2 0 , 2 5 , 2 7 . 3 3 35219.20.25.27 40810.25.27.33 41010,25,27,33
dd31
W
237 253 249 249 249 249 249 249(w) 249(w)
223
Other peaks __~ _ _ _ _ _
bb
167 167
1823 1983 16915 169 169 169 169 169 169 169
168 1683 1683 1683 1683 1683 1683 1683
Reference
259,267 275,207 275,261 275 275 282, 275, 208 282, 275, 208
165 165 37 165 165a 165, 165a 165, 37 165, 37
PART10. Eburnamine-like compounds
Mol. wt. of fragment/charge = m/e
Compound
E burnamenine, CCCXLII I (eburnamine, isoeburnamine) 14-Deuterioeburnamenine, CCCXLIV
ff
ee
99
278
249
208
193
279
250
209
194
Mf
hh
____Other peaks
206
Reference
51, 170 51
W
E
W M
Apovincamine( 14-carbomethoxyeburnamenine) 11-Methoxyapovincamine Dihydroeburnamenine, CCCXLV 14-Deuteriodihydroeburnamenine, CCXLVI Eburnamonine, CCCXLIl 14-018-Eburnamonine Vincamine( 14-carbomethoxyisoeburnamine) 11-Methoxyvincamine
336
307
266
251
264
170
366 28027 281
337 251 252
296 210 211
281 195 196
294
170 51 51
224 226 284 22434 314 25434
209(w)
265 267 3258(w) 26534 3558(w) 29534
29427 296 3548.20.25.27 29434 3848,20,25.27 32434
81, 170
237 237
20934
23734
23934
26334
267, 252
51 170
297, 282
170
PART11. Oxindoles __ Mol. wt. of fragmentlcharge = m/e
Compound
22
kk
11
Reference mm
nn
M
___ Yohimbine oxindole A Yohimbine oxindole B Mitraphylline, CCCXLIX 3-Deuteriomitraphylline, CCCL 3,5,6-Trideuteriomitraphylline, CCCLI
37089 25 37089 25 3688.19,25 36930 37 1 3 O
2258 2258 22320
3,14-Dideuteriomitraphylline, CCCLII Aricine oxindole, CCCLIII Carapanaubine, CCCLIV Rhyncophylline
37030 39883 1 9 42882 19 38419.20.32
22520 22320 22320 23919.20.32
22520
1303 1303 1303 1303 132, 131 1303 1603 1903 1303
14522 14522 14522 14522927
159 159 159 159 161
171 171
17522 20522 14522
159 189 219 159
171 171 171 171
C
37 171 171
~
b
Fr
2C m
__
W 00
u1
TABLE V-Continued
w
00 5 2
PART12. Quebrachidine-like compounds Mol. wt. of fragmentlcharge = m/e Compound
Reference M+
Quebrachidine, CCCXXXVIII-D 0,N-Diacetylquebrachidine, CCCXXXVIII-E Vincamedine, CCCXXXII
352 43625 408
b 13035 13035 14435
PP
QP
rr
122 264 264
222 222
190 190 190
179b 179b 179b
m
PART13. Miscellaneous compounds
B
_- __ Compound
3-Carbomethoxyharman, CCCXXXIX Tetrahydroharman
Mol. wt. of fragmentlcharge = m/e
M+
Other peaks
240 186
182 171
Reference
180 165
1 Only principal peaks are recorded. Blanks in the table do not signify that a peak is missing but rather that it is not recorded in the literature. 2 In compounds bearing a n acyl substituent, RCO, on N,, the molecular ion is accompanied by peaks at M-RCO and M-RCO +H. Similar peaks may often be detected accompanying a. An RCO peak may usually be found in the lower mass range. 3 Accompanied by a peak 14 units higher. 4 Accompanied by peaks 1 ( c f H), 14 (cfCH2, weak) and 28 (c+ 2CH2, strong) units higher, except in CV whero c+COCHz appeers a t m/e 166. 5 Homologs show identical shift.
W M
Homologs show no shift. Weak or negligible M-28 peaks due perhaps to inverted stereochemistry at ‘2-19. 8 Accompanied by peaks 17 or 18 units lower due to loss of OH or water. 9 Due to loss of CHzOH (31 units) from Mf, a,and c. 10 Accompanied by peaks 60 units lower due to loss of acetic acid. 11 These peaks are due to fragment c plus atoms C-4 and C-3 with their substituents (see footnote 4). 1 2 Represents the indole fragment b carrying also atoms C-3 and C-4 with the carbomethoxyl [C(C02Me)=CHz]. 13 These fragments come from the piperidine or D ring and are seen in the spectrum of vindolinine, which also exhibits the following principal peaks: Mf, M-CH3, M-OCH3, m/e 277, 249, 230, 229, 216, 170, 156, 134, 122, 121, 120(3). 14 Accompanied by M-43 (loss of COCH3, side chain). 15 Accompanied by peaks 1 unit lower and 12, 13, and 14 units higher. 16 Base peak. 1 7 M-85 = M-(2CH3CO)+H. 18 Loss of CHzO from i. 10 Accompanied by a peak 31 units lower (loss of CH30 or CH20H). 20 Accompanied by a peak 15 units lower (loss of CH3). 21 M-75 = M-(CH3CO+MeOH). 22 Accompanied by a peak 1 unit higher. 23 Presence of m/e 124 has been shown to be due to refractine. 24i+H. 25 Accompanied by a peak 59 units lower (loss of CH3COO or COz CH3). 26 Cleaves abnormally due to extra double bond or ketone group. 27 Accompanied by a peak 1 unit lower. 28 Accompanied by a peak 30 units lower. 29 This fragment is due to an ion in which (2-16 aRd its substituent (where present) have been expelled from the molecular ion (115a). 30 Accompanied by a peak 2 units lower. 31 Structure dd (Section VIII, B formulas) has been ascribed to this fragment. 32 Accompanied by a peak 29 units lower (loss of CzH5). 33 Accompanied by a peak 119 units lower, M - ~ C H ~ C O Z H H or M-(CH3C02H+ C02CHa). 34 These are eburnamonine or methoxyeburnamonine peaks resulting from the loss of H .C02Me from vincamine or 11-methoxyvincamine, respectively. 35 Accompanied by peak 13 units higher. 6
7
F b P
b
*U
P
.
+
w
00
l
388
B. GILBERT
TABLE VI pK DATA Alkaloid
PK',
Solvent
Reference ~~
Aspidospermine, I1 Deacetylaspidospermine, VI N,-Benzoyldeacet ylaspidospermine Aspidocarpine, XLIV Pyrifolidine, XLVI Deacetylpyrifolidine, XLVII Spegazzinidine, LXIX 0,O-Dimethylspegazzinidine, LXX 3-Dehydro-O,O-dimethylspegazzinidine, LXXI Cylindrocarpine, LXXV Vindoline, C I I I Dihydrovindoline, CXI 16-Methoxy-A~~-methyl-4-oxoaspidospermidine, CV Vindolinine, CVI Refractidine, CXX Deformylrefractidine, CXXII Deformyldemethylrefractidine, CXXVII Pyrifoline, CXIX Deacetyldemethylpyrifoline, CXXV 6-Dehydrodeacetyldemethylpyrifoline, CXXXIII Kopsinine, CXLII-A Aspidofractine, CXLIII-A Pleiocarpine, CXLV-A Pleiocarpinine, CXLVI-A Refractine, CL-A Deformylrefractinol, CXLIX-F Kopsiflorine, CLVI Kopsilongine, CLVII Kopsamine, CLVIII Kopsine, CLXX Dihydrokopsine-A, CLXXII Decarbomethoxykopsine, CLXXI Dihydrodecarbomethoxykopsine-A, CLXXIII Fruticosamine Fruticosine 0-Methyldepropionylaspidoalbine,CXCIl
50% aq. EtOH 50% aq. EtOH 50% aq. EtOH
7.30 7.36 6.98 6.55 6.85 7.8 2.9,6.4,10.7 2.76,6.45 3.0,5.48
66% 50% 33% 33% 33%
DMFl aq. EtOH DMF DMF DMF
25 25 25 30 10,49 30 36 36 36
5.9 5.5 5.9 5.35
66% 66% 66% 66%
DMF DMF DMF DMF
10,49 72 4 4
66% DMF
72 92 81, 37 37 37 49 81 81
3.3,7.1 6.26 6.25 7.15 2.9,7.5 6.40 7.25 5.90
80% MCS1
DMF DMF DMF DMF aq. DMF aq. DMF
33% 33% 33% 66%
70% MeOH ttq. DMF aq. MCS aq. MCS aq. DMF aq. DMF 70% MeOH 70% MeOH 70% MeOH 800/, MCS
7.50 6.85 6.19 6.94 6.64 3.2,8.0 6.38 6.80 6.58 4.28 6.1 5.4 6.1
80% MCS
4.04 4.62 8.5
807; MCS
33% DMF ~
DMF =dimethylformamide; MCS = methyl cellosolve.
87 37 91 91 49 37 87 87 87 109 100 100 100 109 109
52
14. Aspidosperma
389
AND RELATED ALKALOIDS
TABLE VI-Continued
pK DATA
-
Alkaloid
PK:
~-
Solvent ~
~-
Uleine, CCXLV Dihydrouleine, CCXLVI Olivacine, CCLVIII
8.23 8.87 6.05-6.13
800/, MCS 80% MCS 80% MCS
Ellipticine, CCLXXXIV 1,2-Dihydro?livacine, CCLXXIV 1,2-Dihydroellipticine, CCXCIII Cuatambuine, CCLX N-Methyltetrahydroellipticirle, CCLXXXV 11-Methoxyyohimbine, CCXCVIII Polyneuridine, CCCXXI Akusmmidine, CCCXXII
5.78 8.09 7.53 7.87 7.49
80% MCS 80% MCS 80% MCS 80% MCY 800,6 MCS
7.1 6.60 6.30
66% U M F
Reference ~ _ _ _ _ 138 138 140, 149, 150 140 150 155 139 139 161 165 62
the C-ethyl side chain is easily distinguished from this, since its absorption is centered at 0.65 6 and contains two principal peaks separated by 5 4 clsec. The absence of this absorption shows that the side chain is substituted on its terminal carbon atom and this may either indicate the presence of a C-21 oxygen function as in cylindrocarpine (LXXV, 10, 29) or limaspermine (LXXXVII, 31), or that the carbon atoms 20 and 21 are involved in a sixth ring as in the aspidofractinine (Section 111) and aspidoalbine (Section IV) groups. Other functions which may be recognized from the NMR-spectrum include a phenolic hydroxyl whose presence is also seen by the change in the UV-spectrum in an alkaline medium (Table 111). Phenolic hydroxyls usually occur in this series in position 17 where hydrogen bonding with the carbonyl group of the N,-acyl is possible, and in these cases the OH proton peak is found a t 10.7-11.2 8. When the hydroxyl group is not in position 17 it is not found so far downfield, for example, the 16-OH of spegazzinidine absorbs at 5.84 6. Another downfield singlet found in the spectra of some alkaloids derives from the proton of an N,-formyl group which appears around 9.5 6. The three-proton singlet due t o the methyl group of a carbomethoxy function appears slightly upfield with respect to the aromatic methoxyl absorptions, occurring at 3.55-3.7 6. Other, less general deductions which may be made from NMR-absorption will be dealt with under specific cases in later sections. The use of NMR-spectroscopy mainly to determine the nature of peripheral groups has as its ideal complement mass spectrometry which
390
B. GILBERT
gives direct information about skeletal structure. I n some cases complete elucidation. of a structure has been possible by determining the mass spectrum by use of less than 1 mg of material ; it has therefore become possible to investigate successfully the minor Aspidosperma bases which were present in quantities too small to permit even elementary analysis (28, 51, 51a). I n the mass spectrometer, the alkaloid molecule is split by electron impact and those fragments which are sufficiently stable and which carry a positive charge are collected in order of their molecular weights. Ions carrying a double positive charge appear a t mi2 where m is their molecular weight. The information which may be derived from the pattern of relative intensity plotted against m/e (e representing the charge on the ion) can be divided into three parts (28a). First, the highest molecular weight peak is usually that of the molecular ion2, that is, the whole molecule singly charged. This peak is referred to as Mi- and is accompanied by minor peaks one and two units higher corresponding t o molecular ions containing heavier isotopes of nitrogen, hydrogen, carbon, and other elements (20, 21). From the molecular weight thus precisely determined, the molecular formula is derived, leaving no doubt as t o the correct number of hydrogen atoms. Although this was already possible by integration of the NMR-spectrum, the amount of material required for the mass spectral method is minute in comparison. Second, it is possible to classify an unknown alkaloid into a structural class provided that other alkaloids with the same carbon skeleton are known. The cleavage of the molecule is independent of many superficial substituents. I n the aspidospermine group, these have been found to include a hydroxyl or methoxyl substituent on the aromatic ring (18, lo), an oxygen function on the ethyl side chain, whether a t C-20 (32) or a t C-21 (33, 5 2 ) , a carbomethoxy or other one-carbon group or a hydroxyl group a t C-3 (6, 7 , 35,36), and a carbonyl group a t C-4 ( 3 6 ,4 ) . [Note that a 3-ketone fragments differently (361.1 Thus the characteristic pattern of aspidospermine (11)may be recognized in all related alkaloids and derivatives containing the same skeleton, the only difference being that those peaks which correspond t o fragments containing an extra substituent are shifted to higher molecular weight by a number of units equal to the molecular weight of the substituent, while alkaloids that do not contain the aromatic methoxyl group of aspidospermine exhibit a pattern due to the aromatic fragments a t correspondingly lower molecular weight. 2
For an exception see ref. 28b where peaks higher than the molecular ion were observed.
14. Aspidosperma
391
AND RELATED ALKALOIDS
Third, and most important, direct structural information may be obtained. It is often possible, especially when the method is used in conjunction with NMR and with deuteration, to determine the exact position of substituents and also to establish the nature of new skeletons without in many cases having to make any extensive degradations. The importance of this will be seen particularly in the sections on aspidofractinine-, aspidoalbine-, and condylocarpine-type alkaloids (Sections 111, IV, and V), whose structures do not lend themselves to easy degradation by classical methods, owing to the presence of quaternary centers.
b m/e 160
c m/e
124
The breakdown of deacetylaspidospermine (VI) is represented by the formulas a-c (9, 28, 21). That of aspidospermine itself (11) is similar, except that the group R which is acetyl in the parent alkaloid is either acetyl or hydrogen in fragment a, both peaks appearing in the spectrum, while in b the indole nitrogen atom bears a hydrogen atom. The evidence for the structures assigned t o fragments a , b, and c is threefold. First, these fragments may be predicted from the known breakdown patterns of simpler molecules (20, 21). It is known, for example, that bonds /3 to
392
B. GILBERT
nitrogen such as C-19 to C-12 and C-2 t o C-3 in V I are readily broken since the carbonium ion or radical produced, at C-19 or C-2, respectively, in the case under consideration, can be stabilized by the donation of electrons from the lone pair on the nitrogen atom. A similar stabilization, by delocalization, favors the production of allylic, benzylic, or similar radicals and ions, rendering the allylic and benzylic bonds subject t o facile cleavage. Stable ions are favored, especially those in which there are conjugated double bonds or enhanced aromatic character. I n addition, there is a tendency t o cleave bonds at a highly substituted carbon atom. In many cases a number of bonds are broken simultaneously by a concerted movement of electrons within a ring, and in deacetylaspidospermine (VI) the movement indicated by the arrows in the formula represents one of the principal manners of cleavage observed. The fact that the calculated molecular weights of the fragments a, b, and c so predicted are in accordance with the principal observed peaks is adduced as evidence in favor of these structures. It will be noted that C-3 and C-4 are expelled as ethylene producing the a peak at M-28, and this M-28 a fragment together with the c fragment at mje 124 are the characteristics of the aspidospermine group alkaloids (Table V). [Strychanone (CCXLIV) also shows these two peaks, although it does not have the aspidospermine skeleton (36).]It should be emphasized that the breakdown illustrated by the formulas is not the only one to take place. There is a strong peak at c + 28 t o which a structure such as d may be assigned, the C-4 to C-5 bond having resisted cleavage. Weaker peaks appear at c + 14 (e) and b + 14 (f).
CCXLIV
\
CI
U
m/e 254
I
COzMe
J. c m/e 124
Second, evidence for the structures of the fragments responsible for the peaks observed has been obtained by the detection of metastable peaks (20). Such a peak proves that a certain fragment, say x of mass m,, was formed by decomposition of another fragment, y, of mass my, the
14. Aspidosperma
AND RELATED ALKALOIDS
393
position of the metastable peak, m*, being given by the approximate equation :
As an example may be cited the case of dihydrovincadifformine (CI) in which the decomposition of the molecular ion (m/e 340) to fragment a (m/e 254) with expulsion of the elements of acrylic ester is documented not only by the presence in the spectrum of those two peaks but also by the appearance of a metastable peak a t 191. The further breakdown of a to give c (m/e 124) was recognized by a metastable peak a t 61 (6). Similarly, in deacetylaspidospermine the loss of ethylene from the molecular ion (m/e 312 to m/e 284) is accompanied by a metastable peak a t m/e 259 (21). Third, as mentioned previously, peaks a, b, and c have been found to occur in the spectra of alkaloids and derivatives substituted in various positions. I n many cases the location of these substituents has been established by independent evidence, and the substituted molecule has been converted into the unsubstituted by chemical methods establishing the identity of the skeleton. The variation of molecular weight found for fragments such as a, b, and c in such a series can be used to decide with certainty some of the constituent atoms of those fragments. For example, fragment a contains all the atoms in the original molecule with the exception of C-3 and C-4 and any substituents that these atoms carried. This is shown by the fact that no increase in the mass of fragment a is observed in the mass spectra of molecules substituted in these positions. Thus, for example, 2,3-dihydrovincadifformine(CI) and dihydrovincadifforminol (XCIX) both show fragment a a t m/e 254 (6) in the same position in which it is found in the spectrum of aspidospermidine (XXXI), the parent alkaloid of the aspidospermine series. I n aspidospermidine this peak lies a t M-28 (loss of CHzCHz), whereas in CI i t corresponds to M-86 (loss of CHz=CHCOzCH3) and in XCIX to M-58 (loss of CHz=CHCHzOH). The position of the carboxylic ester group in vincadifformine (XCIII) and hence of the corresponding substituents in C I and XCIX is established by the UV-spectrum as C-3 (6), so that the lost atoms are necessarily C-3 and C-4. A similar result is encountered in the mass spectrum of spegazzinidine (LXIX) where the a peak is found a t m/e 328 or M-44 (loss of CHOHCHz) and independent evidence has established that the hydroxyl group which is lost is located on (2-3. Independent chemical proof has also been obtained for the aspidospermine-type skeletons of vincadifformine and spegazzinidine.
394
B. GILBERT
A t the same time, substituents in positions 17 and 16 [series aspidospermidine (XXXI), deacetylaspidospermine (VI), and deacetylpyrifolidine (XLVII) in Table V] ; position 1 [series aspidospermidine (XXXI), demethoxyaspidospermine (XXXIII), demethoxypalosine (XXXIV), and N-methylaspidospermidine (XXXV)]; position 20 [pair dihydrovincadifforminane (tetrahydrotabersonane, CII) and 20hydroxydihydrovincadifforminane(CXV)]; and position 2 1 [pair aspidospermine (11) and 2 1-acetoxyaspidospermine (LXXXV)] result in corresponding changes in the molecular weight of a, demonstrating that a incorporates these carbon atoms.
R3
Rz ~~~
XXXI VI XLVII XXXIII XXXIV XXXV
Ri
H H Me0
H H
H
1L
Rz K3 H H Me0 H Me0 H H Ac H EtCO H Me
Ji
HO
Ac
OH
CI; R = COzMe LXIX XCIX; R = CHzOH XCIII; R = COzMe 2,3-douhle bond
CH3
CII;
R =H CXV; R = O H
Me0
Ac
11; R = H LXXXV; R = OAc
The same type of evidence supports the structures assigned to fragments b and c. Variations in the aromatic substitution produce in all cases the corresponding variation in the molecular weight of b while c is not affected by these changes. The hydrogen atom on C-2 is retained in fragment b , for when it is replaced by deuterium (1S), the b peak, found at m/e 160 in deacetylaspidospermine (VI), is shifted to m/e 161 (21). On the other hand, alterations in ring D or in the ethyl side chain are reflected in the molecular weight of c which is altered appropriately. For example, limaspermine (LXXXVII), which has a primary alcoholic group at C-21, exhibits peaks at m/e 140 (strongest peak in the spectrum), 122, and 109 which may be interpreted as due t o c (16 mass units higher than in the aspidospermine spectrum due to the C-21 oxygen), c-HzO, and c-CH20H (33). In contrast, the highly substituted dihydrovindoline
14. Aspidosperma
AND RELATED ALKALOIDS
395
(CXI) has a normal c peak at m/e 124 because none of the substituents is located on ring D or the ethyl side chain (4). The molecular weight of fragment d , the structure assigned (21) to the c + 28 peak which occurs at mje 152 in VI, is shifted to m/e 166 in the spectrum of the ketone (CV); whereas in its 3,3-dideuterio derivative, a further shift to m/e 168 is observed. This is strong evidence that d retains atoms 3 and 4, since the shifts are those calculated for the substitution of CO for CH2 in
cv position 4 and of CD2 for CH2 in position 3. The position of the carbonyl at C-4 is independently based on NMR-evidence. Similarly, in dihydrovindoline (CXI) the d peak is shifted t o mje 284, the shift of 132 mass units corresponding to the substitution of hydrogen atoms on C-3 and C-4 by COzCHz(+ 58), OH( + 16), and OAc( + 58). Returning to the spectrum of the ketone (CV), fragment b and its homolog fragment f,at mje 174 and 188 respectively, do not change their positions when the ketone is deuterated (excluding structures which contain C-3, for these fragments).
E. SOMEMINORALKALOIDS OF Aspidosperma quebrachoblanco AND
Rhazya stricta
In a reinvestigation of the minor alkaloids of A . quebrachoblanco,whose presence had already been indicated by Kesse (59) in 1882 (Vol. 11), Biemann et al. (28, 51a) were able t o isolate by a combination of alumina and gas chromatography about twenty compounds. The identification or structure determination of fifteen of these by mass spectrometry was described. Six belonged t o the aspidospermine group and four of these were the known compounds, aspidospermine (11), deacetylaspidospermine (VI), N,-methyldeacetylaspidospermine (XLI),and ( - )-pyrifolidine (XLVI). The three last-named had not previously been encountered in nature, V I and XLI having been prepared from aspidospermine (11)and vallesine (XXXVIII) (38, 39, 25). (-)-Pyrifolidine is identical with 0-methylaspidocarpine (XLVI) which has been prepared
396
B . GILBERT
from aspidocarpine (XLIV) (30). 0-Methylaspidocarpine (XLVI) has been shown (9) t o be the enantiomer of the alkaloid (+)-pyrifolidine which occurs in A . pyrifolium.
XXXI XXXV VI XLI
rr
(-)-XLVI
Ri H
H H H H OMe
Rz H
H OMe OMe OMe OMe
R3 H Me H Me Ae Ac
The two previously unknown compounds in the series were designated “Alkaloid 2 8 2 8 ” [later (51) named aspidospermidine] and “Alkaloid 296A” (or N-methylaspidospermidine), the numbers referring to their mass spectrometrically determined molecular weights. The first has also been found in Rhazya stricta (51). The mass spectrum of aspidospermidine differed from that of aspidospermine only in the shift of the mie values of all those peaks containing the benzene nucleus and N,, corresponding to the absence of substituents in these positions. Thus the &I+ and fragment a peaks appear 7 2 units lower down on the mass scale, corresponding to the absence of methoxyl (30) and acetyl (42) (see Table V). I n a similar manner, the spectrum of N-methylaspidospermidine parallels exactly that of N,-methyldeacetylaspidospermine (XLI), showing only a lowering of the mie values for the same two ions by 30 mass units that corresponds t o the absence of the nuclear methoxyl group. The structures of aspidospermidine and N,-methylaspidospermidme were thus shown t o be XXXI and XXXV, respectively, and aspidospermidine may be recognized as the parent of the aspidospermine group. The indolenine corresponding t o aspidospermidine was also isolated (28,51a).It was denominated “Alkaloid 280A” [later named 1,2-dehydroaspidospermidine (51)] and has structure IX. This compound had previously been obtained by the zinc dust distillation of quebrachamine (18, Section 11, B) and was subsequently found in R. stricta (51). It is
14. Aspidosperma
AND RELATED ALKALOIDS
397
noteworthy that the 21-methyl group of I X absorbs a t unusually high field in the NMR-spectrum, due t o shielding by the benzene ring not observed in compounds lacking the 1,2-double bond (51b). A compound with apparently the same structure (IX)has also been obtained both in the racemic and the levorotatory form ([aJI, - 225" in ethanol) by the degradation respectively of racemic vincadifformine (XCIII, 6, see Chapter 12) and (-)-tabersonine (XCII, 7 , Section 11, 0). As the levorotatory form of I X is converted by alkaline borohydride to ( + )-quebrachamine (I),it is probably the optical antipode of the product isolated from 8.stricta. The latter gives ( - )-quebrachamine and the configurationally related ( + )-aspidospermidhe (XXXI)on borohydride reduction (51b).
XCIII XCII 6,7-double bond 2N HC1
I
105"
IX
1
I
Hz cat
XXXI
The structure (IX) of 1,2-dehydroaspidospermidinerests on comparison of its UV- (Table 111)and mass spectra (characteristic peaks a t mje 280, 251, and 210) with that of l,%dehydroaspidosperniine ( V I l , Section 11,B). Lithium aluminum hydride reduction also gave aspidospermidine (XXXI, 28, 18, 51a, b). Nine other minor alkaloids of A . quebrachoblanco are dealt with in Sections V and VIII.
398
B. GILBERT
F. DEMETHOXYVALLESINE, DEMETHOXYASPIDOSPERMINE, AND DEMETHOXYPALOSINE The three alkaloids named in the title (XXXII, XXXIII, and XXXIV) are respectively the N,-formyl, -acetyl, and -propionyl derivatives of aspidospermidine (Section 11, E). Demethoxypalosine (XXXIV) has been isolated from Aspidosperma limae (40) and A . discolor (40a) and was characterized as an N,-acyldihydroindole by its UV-spectrum (Table 111)and IR-absorption a t 5.89 p. A strong band in the IR-spectrum a t 13.1 p indicated an unsubstituted benzene ring. The foregoing information was confirmed and the substance was shown to belong to the aspidospermine group by NMR- and mass spectrometry. I n the NMR-spectrum (Table IV) the 17-proton absorption is found a t 8.13 6 well downfield from the three-proton multiplet due t o the other aromatic protons which is centered a t 7.07 6. This shift is due t o the proximity of the carbonyl group of the N,-propionyl group. In the aliphatic part of the spectrum, absorptions which are characteristic of the
(X)/" H
o=c,
COR
R
a M-28
b m/e 130
XXXII; R = H XXXIII; R = Me XXXIV; R = Et
c m/e 124
aspidospermine skeleton (see Section 11, D) were found a t 4.08 6 (C-2 proton), 3.3-2.9 6 (CH2-Nb-CH2), 2.60-2.17 6 (quartet) and 1.401.08 6 (triplet, propionyl CH2, and CH3, respectively), and 0.75-0.45 (triplet, CH3 of a C-ethyl group). The mass spectrum (Table V) shows the molecular ion peak a t 338, confirming the molecular formula, C22H30N20 ; the other principal peaks are those characteristic of alkaloids of the aspidospermine group, that is, M-28 (m/e 310, fragment a ) , m/e 130 (fragment b accompanied by a homolog a t m/e 144), and mje 124 (fragment c, base peak of much higher intensity than any other and
14. Aspidosperma AND RELATED ALKALOIDS
399
accompanied by homologs at m/e 138 and 152). A strong peak at m/e 57 is due to the propionyl group on N,. From A . discolor has also been isolated the N,-acetyl analog, demethoxyaspidospermine (XXXIII, 40a). The alkaloid, which was separated chromatographically from the accompanying demethylaspidospermine (XXXVII, Section 11,G), was not obtained crystalline but was identified as demethoxyaspidospermine (XXXIII) by examination of its NMR- and mass spectra. The former resembled in all respects that of demethoxypalosine (XXXIV) with the exception of a threeproton singlet at 2 . 2 2 6 due to the N,-acetyl group which replaced the propionyl absorptions observed in the spectrum of XXXIV. The mass spectrum (Table V ) shows the molecular ion and M-28 (fragment a ) peaks 14 mass units lower than in the spectrum of XXXIV, while the b and c fragments and their homologs do not suffer this shift. Demethoxyvallesine (XXXII)has also been detected in the same plant (37).
G. DEMETHYLASPIDOSPERMINE The simplest of the phenolic members of the aspidospermine group, demethylaspidospermine (XXXVII),has been found in A . discolor (40a). It was isolated as its crystalline perchlorate ( 2 5 ) from which the oily free
XXXVI XXXVII XLII
Ri Rz H H
H Ac
Ac Ac
VI
XXXVIII; R I1; R XXXIX; R XL: R
=H = Me = Et = n-Pr
base was obtained. From the NMR- and mass spectra (Tables I V and V), the compound was recognized as the known aspidospermine derivative (XXXVII) which had previously been obtained by demethylation of aspidospermine (11) with aluminum chloride in nitrobenzene ( 2 5 ) . Confirmation of its identity was obtained by methylation with dimethyl sulfate and potassium carbonate in dry acetone t o give aspidospermine (11).It is noteworthy that the phenolic hydroxyl group in position 17 is strongly hydrogen-bonded to the carboayl group of the N,-acetyl (OH
400
B . GILBERT
shows NMR-singlet a t 10.83 6) and XXXVII does not suffer ready air oxidation as do phenolic bases in this series which lack the ilr-acyl group, e.g., aspidosine (XXXVI). As a result of the hydrogen bonding, the foregoing relatively vigorous conditions are necessary for inethylation but in spite of this the strong steric hindrance of N, (1 1, 12, 27) enables the direct isolation of the tertiary base aspidospermine, with little or no methylation of Nb having occurred (40a).
H. VALLESINE AND PALOSINE Vallesine (XXXVIII) and palosine (XXXIX) are respectively the N,-formyl and N,-propionyl analogs of aspidospermine (11).Vallesine which occurs in Vallesia glabra and V . dichotoma (Volume I1 and Ref. 41) has been related to aspidospermine (39, 2 5 ) and has therefore structure XXXVIII. Palosine (XXXIX) has been isolated from Aspidosperma polyneuron (23), where it occurs in admixture with aspidospermine and a ketonic base (43) in addition to other alkaloids (Table I). The separation of palosine from the mixture was very difficult but was finally achieved by chromatography on paper using formamide containing 10% of pure formic acid and 8% of ammonium formate as a buffered stationary phase with benzene: chloroform (4: 1) saturated with formamide as the mobile phase. Acid hydrolysis of palosine gave deacetylaspidospermine (VI) and propionic acid (43),the latter being identified by paper chromatography (44). Propionylation of deacetylaspidospermine gave palosine to which, therefore, the structure XXXIX may be given. I . ASPIDOCARPINE AND DEMETHYLASPIDOCARPINE Aspidocarpine (XLIV) was isolated by direct crystallization from the light petroleum extract of Aspidosperma megalocarpon (30), and was characterized as the perchlorate, hydrochloride, hydrobromide, and hydriodide. Its empirical formula is CZ2H30N203 and it contains one methoxyl group. Aspidocarpine represents an important chemical link between aspidospermine (11)and its relatives with one oxygen substituent in the benzene nucleus, on the one hand, and the related alkaloids with two oxygen substituents on the other, since it has been related directly with aspidospermine. The UV-spectrum of aspidocarpine, which is somewhat similar to that of aspidospermine, exhibits a large bathochromic shift on passing from
14. Aspidosperma
AND RELATED ALKALOIDS
40 1
neutral to alkaline solution (Table III),indicative of the presence of a phenolic hydroxyl group in the molecule. A carbonyl peak in the IRspectrum at 1632 em-1 indicated an amide group, and acid hydrolysis followed by steam distillation gave acetic acid, showing that this amide was present as an N-acetyl group. The low frequency of the amide carbonyl absorption and the absence of a hydroxyl peak in the IRspectrum, coupled with the olive-green ferric reaction of aspidocarpine and the fact that the phenolic hydroxyl group resists methylation with diazomethane, were indicative of strong hydrogen bonding between the O H and C=O groups. Evidence confirming these functional groups was obtained by acetylation to 0-acetylaspidocarpine (XLV) and methylation with dimethylsulfate in alkali (note that Nb resists methylation) to 0-methylaspidocarpine (XLVI) ([.Iu - 94" in chloroform, later shown t o be antipodal to ( + )-pyrifolidine, ["ID + 90" in chloroform; Refs. 9, 10) and in both XLV and XLVI the amide carbonyl absorption appeared a t higher frequencies (1666 and 1656 em-1, respectively) indicating that hydrogen bonding no longer occurred. 0-Methylaspidocarpine hydrolyzed with 10% hydrochloric acid gave 0-methyldeacetylaspidocarpine(XLVII) ( [aID- 4.9" antipodal to ( + )-deacetylpyrifolidine, [a]=+ 7" ; Refs. 9, lo), which could be reacetylated to XLVI. On these grounds, it was reasonable to propose the partial structure XLIII. The NMR-spectrum of aspidocarpine (XLIV) (30, 45) fully confirmed the foregoing, a hydrogen-bonded phenolic proton being found a t 10.83 6 and the N-acetyl methyl singlet a t 2.20 6. In addition, the methoxyl group exhibited a three-proton singlet at 3.73 6, and that it is an aromatic methoxyl is demonstrated by the presence of absorption due t o only two aromatic protons. These form a triplet with a large central peak a t 6.5 6, the small side peaks being separated by J = 9 cjsec which shows that these two protons are almost equivalent and are disposed ortho to one another. Most importantly, the aliphatic part of the spectrum closely resembles that of aspidospermine (II),showing the C-2 proton, CHz-N-CHz and C-ethyl absorptions (Table IV). The foregoing information really suffices t o place the methoxyl in position 16, but chemical evidence was also adduced to show that it was ortho to the phenolic hydroxyl. Demethylation of aspidocarpine (XLIV) with hydrobromic acid gave the unstable catechol XLVIII (ferric reaction, blood-red) which was acetylated to the triacetate (XLIX) in which the two 0-acetate absorptions in the IR-spectrum (1777 and 1767 em-1) showed them to be phenolic acetates. Alkaline hydrolysis of this triacetate gave demethylaspidocarpine (L), which was shown to be a catechol by the ferric reaction (blue-green passing t o deep-red in the
XLIII
Ri
__ LII Me LIII Me X L V I I Me XLVI Me XLV Me LIV Me LV Me
THB*
XLVIII
XLIV It2
It3
H H
H EtCO H
Me
Me
Ac Ac
EtCO
Ac Ac
EtCO EtCO
14. Aspidosperma
AND RELATED ALKALOIDS
403
presence of sodium carbonate), and by the strong bathochromic shift of the UV-spectrum in the presence of boric acid buffered with sodium acetate (30, 46). Aspidocarpine derivatives were found to couple with diazotized sulfanilic acid when either the C-17 OH or N, was unsubstituted but not when they were both substituted; this was used as evidence that positions 14 and 15, para t o these groupings, were unsubstituted. Finally, proof was obtained that the aliphatic portion of the aspidocarpine molecule was identical with the correspondingportion of aspidospermine by oxidation of the two compounds with chromic acid in dilute sulfuric acid. In both cases, the aromatic ring was destroyed and there was isolated the a-keto amide (LI), mp 224"-225", [ C L ]-~ 132" (chloroform). The identity of this oxidation product shows not only that aspidocarpine (XLIV) and aspidospermine (11) have an identical skeleton but also that they have the same absolute configuration at all four centers. Aspidocarpine has also been found in other Aspidosperma species (Table I) while demethylaspidocarpine (L) has been isolated from A . album (42).
J. ASPIDOLIMINE Aspidolimine (LIII) is one of the main constituents of the bark of A . limae, where it occurs together with a number pf other alkaloids (Sections11, F, I and IV, B ;Refs. 31,40). It is also foundin A. triternatum (47). The IR- and UV-spectra are practically identical with those of aspidocarpine (XLIV), although elementary analysis and the mass spectrum (molecular ion peak at m/e 384) show it to contain one CH2 group more than that alkaloid. Examination of the NMR-spectrum (31) shows that there is an N,-propionyl group present (N-COCHzCH3 quartet at 2.57 6, J = 7 c/sec; N-COCHZCH~ triplet at 1.25 6 , J = 7 cjsec) while the N,-acetyl three-proton singlet shown by aspidocarpine (Section 11,I) is absent. It was reasonable to suppose that aspidolimine (LIII) was the N,-propionyl analog of aspidocarpine, and this was readily shown t o be true both chemically (31) and by examination of the mass spectrum (40). Vigorous acid hydrolysis of the alkaloid gave depropionylaspidolimine (LII), which without isolation was acetylated to give 0-acetylaspidocarpine (XLV). Similar hydrolysis of aspidocarpine (XLIV) and propionylation of the product gave 0-propionylaspidolimine (LV). The mass spectrum of aspidolimine shows all of the characteristic peaks of the aspidospermine group alkaloids (Section 11, D, Table V). In addition to M+ and M-28, peaks are found at M-56 (loss
404
B. GILBERT
of the propionyl group and pick-up of one hydrogen) and at M-84 [M-(56+28)]. The strongest peak of the spectrum is found at m/e 124 (fragment c ) ,and the peaks due to fragment b and homologs are found at m/e values 16 mass units higher than in the spectrum of aspidospermine, corresponding to the extra oxygen atom in the aromatic ring.
K. PYRIFOLIDINE AND DEACETYLPYRIFOLIDINE ( - )-Pyrifolidine (XLVI) has already been mentioned as a constituent of A. quebrachoblanco (Section 11,E) and as the product of methylation of aspidocarpine (Section 11, I). Dextrorotatory pyrifolidine and its ( + )-deacetyl derivative (XLVII) occur in Aspidosperma pyrifolium (49,56).At the time of isolation, the levorotatory compound (XLVI)was not known. The UV-spectrum (Table 111) is somewhat different from those of known N-acyldihydroindoles. The NMR-spectrum, however, not only confirmed the presence of two methoxyl groups and an N-acetyl function already detected by functional group analysis, but showed that the compound belonged to the aspidospermine group (9, 10). The C-2 proton quartet at 4.50 6, CHzN-CHz multiplet at 3.31-2.90 6, and the side chain terminal methyl absorption at 0.67 6 were all placed exactly as found in the spectrum of aspidospermine. Elementary analysis and the integrated proton count showed that the empirical formula was C23H32N203, differing from aspidospermine by CH20, equivalent to the addition of the extra methoxyl group known t o be present. The presence of only two aromatic protons occupying adjacent positions on the benzene ring was shown by a two-proton quartet with J = 8.2 c/sec, and this shows that both methoxyl groups are aromatic and must be in one of the three orientations, LVIII, LIX, or LX. Biogenetically, LVIII and LIX with a methoxyl at C-17 were attractive. Of these, LVIII with the other methoxyl at C-14 was the less likely, as this group would be expected t o alter the NMR aliphatic “fingerprint” region which is in fact almost superimposable upon that of aspidospermine (11). Conclusive evidence that the aliphatic portion of the pyrifolidine molecule was in fact identical with that of aspidospermine (11)was obtained from the mass spectra of their deacetyl derivatives (XLVII and VI, Table V). These proved to be identical, save only in the shift of 30 units observed in the peaks attributable to fragments containing the aromatic nucleus, this shift being due to the extra aromatic methoxyl group. Finally, direct comparison of ( + )-pyrifolidine with ( - )-@methylaspidocarpine (XLVI) and of their respective deacetyl derivatives
14. Aspidosperma
AND RELATED ALKALOIDS
405
(XLVII) showed complete identity by IR-spectra and by chromatography, while the rotatory dispersion curves of ( + )-XLVI and ( - )XLVI were mirror images of one another, demonstrating that the two compounds were enantiomeric at all four centers. Pyrifolidine is thus one of a small group of indole alkaloids which exist in both enantiomeric
+ )-XLVII;R = H (+)-XLVI; R = AC (
VI; R = H 11; H. = AC
forms ; others are quebrachamine (I),vincadifformine (XCIII, 6, 74), akuammicine (CCXXV, 7 7 ) , guatambuine (CCLX, 147), and vincanorine (CCCXLII, 78). It is noteworthy that these alkaloids either contain only one asymmetric center or could have been formed from a precursor with only one center by a concerted reaction in which the configuration of the remaining centers might depend on that of the original. AND SPEGAZZINIDINE L. SPEGAZZININE
Evidence presented earlier (Volume VII, p. 132) led to the proposal of partial structure LXI (34) for spegazzinine and the suggestion was made that the molecule had the aspidospermine skeleton. This has subsequently been shown to be correct, but the evidence was obtained by a study of the related alkaloid spegazzinidine (LXIX). Both alkaloids occur in Aspidosperma chalensis, the proportion of each present having been found to vary with different specimens of the plant (35, 36). Spegazzinidine (LXIX) was shown by elementary analysis to be CzlHzsNz04, the number of hydrogens being confirmed by the mass spectral molecular weight determination. Its UV-spectrum resembles
406
B. GILBERT
that of spegazzinine (LXIV) and is of the aspidospermine type (Table 111).A bathochromic shift in alkaline solution similar to that shown by spegazzinine showed that it was also a phenolic base, and a carbonyl peak a t 6.13 p indicated the presence of the usual N-acyl function. The NMRspectrum of spegazzinidine (LXIX) confirmed the expected similarity to aspidospermine (11),exhibiting the characteristic CHz-N-CHz pattern, the N,-COCH3 methyl singlet, and the side chain terminal methyl absorption at 0.75 6. I n the aromatic region, a quartet due to two ortho protons, similar t o that of pyrifolidine (Section 11,K) was observed, while absorptions due t o two phenolic hydroxyl protons appeared, one a sharp singlet at 11.1 6 characteristic of a hydrogen-bonded hydroxyl in position 17, the other a broader band a t 5.84 6 due to a non-hydrogenbonded OH. Methylation of spegazzinidine (LXIX) with dimethyl sulfate (cf. aspidocarpine, Section II, I ; note that the alcoholic hydroxyl as well as N,, are unaffected) gave spegazzinidine dimethyl ether (LXX) whose NMR-spectrum now closely resembled that of pyrifolidine (XLVI). One striking difference existed between the NMR-spectra of spegazzinidine and its methyl ether on the one hand and aspidospermine and pyrifolidine on the other. This lay in the absorption due t o the C-2 proton which in the latter two alkaloids appears as a quartet, while with spegazzinidine and its methyl ether only a doublet is observed. This indicated that there was only one hydrogen atom a t C-3 and, as spegazzinidine dimethyl ether (LXX) still showed hydroxyl absorption in the IR-spectrum, it was reasonable to suppose that C-3 carried an alcoholic hydroxyl group. To confirm this, LXX was oxidized with chromium trioxide (50) to the ketone, 3-dehydrospegazzinidine (LXXI),in whose NMR-spectrum the doublet previously observed had disappeared and been replaced by a singlet a t 5.11 6. This observation is only consistent with a secondary alcoholic group having been present at C-3,and the further downfield shift of the C-2 proton peak in LXXI is caused by the adjacent carbonyl group (36). Independent evidence for the position of the carbonyl group in this ketone was obtained by exhaustive deuteration with sodium deuteroxide in DzO-CH~OD, when mass spectrometry showed that six deuterium atoms had entered the molecule (molecular ion raised from m/e 398 t o m/e 404). Three of these were in the acetyl group, since the m/e 4 3 peak (CH&O+) was shifted t o m/e 46 (CD&O+), and therefore three had entered a to the ketonic carbonyl (LXXII ; note that LXXIII is a by-product of the deuteration reaction). Only two positions in an aspidospermine skeleton have three a-hydrogen atoms-positions 3 and 20. The latter position is excluded by the NMRspectrum, and the carbonyl group is therefore at (2-3. Detailed study of the mass spectra of LXXI and its hexadeuterio derivative confirmed
14. Aspidosperma
AND RELATED ALKALOIDS
407
these findings (35, 36), although it should be noted that the 3-ketone does not, in contrast t o a 4-ketone (36, 4), fragment in the manner characteristic of aspidospermine (11) and its derivatives. Rather, it loses first the carbonyl group as CO, a behavior observed in other cyclic ketones (20, 21). The foregoing arguments have been based on the assumption that spegazzinidine has in fact the same skeleton as aspidospermine (11).That this is true was established in two ways. First, in the mass spectrum of spegazzinidine (LXIX) and of its dimethyl ether (LXX) the principal peaks are observed a t m/e values exactly coinciding with the calculated molecular weights of the fragments a, b, and c and their homologs that would be expected for a molecule with the aspidospermine skeleton but carrying two hydroxyl or, respectively methoxyl groups on the aromatic ring (Table V). It will be noted that the C-3 and C-4 atoms are not present in any of the aforementioned fragments. The nonappearance of the alcoholic oxygen, whose position has been proved, in these fragments has been cited (Section 11, D) as evidence that the C-3 and C-4 atoms are those initially lost in the breakdown of aspidospermine-type molecules under electron bombardment. This breakdown, which normally results in the loss of ethylene and the formation of the M-28 peak common to the spectra of most alkaloids of this group, results in the loss of vinyl alcohol, CHOH=CHz, or its equivalent, and the formation of an M-44 peak in the spectra of LXIX and LXX, which is raised t o M-45 when the alcoholic proton is replaced by deuterium. Second, direct chemical proof of the aspidospermine skeleton was obtained by conversion of spegazzinidine dimethyl ether (LXX) to its tosylate (LXXIV) which on reduction with lithium aluminum hydride gave ( - )-N,-deacetyl-N,-ethylpyrifolidine(LVII) identical, except for direction of rotation, with the product, ( + )-N,-deacetyl-N,-ethylpyrifolidine (LVII),obtained by a similar reduction of ( + )-pyrifolidine (XLVI). Since ( + )-pyrifolidine is antipodal to aspidospermine (Section 11, K), spegazzinidine has the same absolute configuration as aspidospermine (36). Finally, the coupling constant (J = 8 cjsec) observed €or the C-2 proton doublet in the NMR-spectrum of spegazzinidine shows that the C-2 and C-3 hydrogens are situated trans-diaxial with respect to one another. The C-3 hydroxyl group is therefore a-equatorial. A comparison of the NMR- and mass spectra of spegazzinine (LXIV) and it methyl ether (LXV) with those of spegazzinidine (LXIX) and its dimethyl ether (LXX)showed that the parent alkaloids differed only by the absence of the C-16 hydroxyl group in spegazzinine and of the C-16 methoxyl group in its methyl ether. In particular, the 5.84 6 signal due
!+
0 00
LXI
LXII LXIII LXIV LXV LXVI LXVII LXVIII
H H H Ac Me Ac Me Ac Me Ac Ac Ac
H Me
H
H H H Ac PhCO Ac
,/ RO LXIX
/
Ac a (M-44)
from LXIX; R = H fromLXX; R = Me
from LXIX; R = H from1,XX; R = Me
14. Aspidosperma AND RELATED ALKALOIDS
409
410
B. GILBERT
to the non-hydrogen-bonded phenolic grouping in LXIX is absent from the NMR-spectrum of spegazzinine, which shows absorption due to three aromatic protons, while in its mass spectrum the fragments a and b and relatives containing the aromatic ring appear a t m/e values 16 mass units lower (i.e., less one oxygen atom) than in the spectrum of spegazzinidine (LXIX). Similarly, a corresponding lowering of 30 mass units (CHzO) is observed when the spectra of spegazzinine methyl ether (LXV) and spegazzinidine dimethyl ether (LXX) are compared, all other peaks appearing at identical m/e values. I n accordance with previous experience (Section 11, D), therefore, spegazzinine may be allocated structure LXIV.
M. CYLINDROCARPINEA N D CYLINDROCARPIDINE Cylindrocarpine (LXXV) and cylindrocarpidine (LXXVI) occur in the trunk bark of Aspidosperma cylindrocarpon, and the former was first isolated by way of its crystalline perchlorate (49). The IR-spectrum of cylindrocarpine showed the presence of an ester (Aco, 5.79 p ) as well as an amide (A,,,, 6.06 p ) grouping, while the UV-spectrum showed the presence of a chromophore different from that of aspidospermine (11) and its relatives (Table 111).The integrated NMR-spectrum supported the empirical formula, C ~ O H ~ ~ Nand ZO confirmed ~, the presence of two methoxyl groups detected by functional group analysis. Preliminary chemical studies elucidated many features of the structure, leaving only the exact nature of the aliphatic portion of the molecule unknown. I n particular, hydrogenation gave dihydrocylindrocarpine (LXXVII) whose UV-spectrum was now superimposable on that of aspidospermine (11),showing that the molecule contained the N-acyl- 17-methoxydihydroindole nucleus. Alkaline hydrolysis of both cylindrocarpine (LXXV) and dihydrocylindrocarpine (LXXVII) cleaved only the ester grouping and gave the corresponding acids, cylindrocarpic and dihydrocylindrocarpic acid, as their hydrochlorides (LXXVIII and LXXIX, respectively). The latter was reesterified with diazomethane regenerating dihydrocylindrocarpine (LXXVII), proving that cylindrocarpine contains a carbomethoxyl group, and accounting for the second methoxyl group. I n order t o elucidate the nature of the AT,,-acylgrouping, both cylindrocarpine (LXXV) and its dihydro dcrivative (LXXVII) were hydrolyzcd with hydrochloric acid to cleave the amide as well as the ester grouping. I n both cases, cylindrocarpinic acid dihydrochloride (LXXX) was obtained, and from the nonbasic fraction were isolated,
14. Aspidosperma
AND RELATED ALKALOIDS
41 1
respectively, cinnamic and dihydrocinnamic acids. The unusual UVspectrum of cylindrocarpine is therefore simply a superimposition of the N-acyldihydroindole and cinnamoyl chromophores. The UV-spectra of cylindrocarpinic acid (LXXX, free amino acid) and deacetylaspidospermine (VI) in neutral and acidic media are practically identical, showing the characteristic reduction of wavelength and intensity on protonation of N, (Table Ill).This is in accordance with the presence of identical chromophores in both compounds. The preceding experiments cast no light on the nature of the aliphatic carbon skeleton, but examination of the NMR-spectrum showed that this was similar t o that of aspidospermine (11).In particular, the characteristic absorption due to the C-2 proton was found at 4.4S and those due to the CHz-N-CHz protons at 3.31-2.90 6, while in the absence of an N-acetyl peak the singlet due t o the isolated C-19 hydrogen atom is plainly visible. No side chain terminal methyl group absorption was observed and, assuming an aspidospermine skeleton, the carbomethoxy group could be provisionally placed in that position ((3-21). I n the aromatic portion of the spectrum, not only were the expected eight aromatic protons detected, but also two doublets with J = 16 cjsec due to the trans-cinnamic vinyl protons. It remained t o convert cylindrocarpine (LXXV) t o a known aspidospermine derivative. This was achieved by elimination of the carbomethoxy and cinnamoyl groups in the following manner. Cylindrocarpine (LXXV) was reduced with lithium aluminum hydride to a mixture of the y-phenylpropyl compound (LXXXI.) and dihydrocylindrocarpol (LXXXII). The latter, separated by chromatography, was oxidized with chromic acid in acetic acid t o the corresponding aldehyde, dihydrocylindrocarpal (LXXXIII),which by Wolff-Kishner reduction gave the known deacetylaspidospermine (VI).Cylindrocarpine can therefore be given the structure LXXV. Cylindrocarpidine, C23H30N204, the minor alkaloid of A . cylindrocarpon, was suspected from its NMR-spectrum (Table IV) t o be the N,-acetyl analog of cylindrocarpine (LXXV) since the absorption pattern was almost identical, except in that no peaks were seen corresponding to the cinnamoyl group, these being replaced by a threeproton singlet at 2.22 6 due t o an N-acetyl group. Confirmation was obtained by acid hydrolysis which gave cylindrocarpinic acid dihydrochloride (LXXX) and acetic acid (44),and the structure of cylindrocarpidine is therefore represented by the expression LXXVI (10, 29). The LXXX obtained had rotation identical with that from cylindrocarpine (LXXV) and consequently these two alkaloids have the same absolute configuration. That this is the same as that of aspidospermine
412 B . GILBERT
14. Aspidospermu AND RELATED ALKALOIDS
T
413
4 14
B. GILBERT
(11)was shown by the similarity in sign and shape of the ORD-curves of cylindrocarpidine and aspidospermine ( 10). Although the structures of these two alkaloids were proved without recourse to mass spectral measurements, spectra have subsequently been determined for the derivatives N-decinnamoylcylindrocarpol (LXXXIV), its O,N,-diacetyl derivative (LXXXV), and N-decinnamoyl-N-ethylcylindrocarpol (LXXXVI). All three show the expected pattern with peaks corresponding to a, b, and c fragments and their homologs as observed for other aspidospermine-type alkaloids (Section 11,D). It should be noted, however, that due to the extra oxygen atom in LXXXIV and LXXXVI and the acetoxy group in LXXXV the c peak appears a t m/e 140 in the first two cases and a t m/e 182 in the last instead of a t m/e 124 as in aspidospermine (52).
N. LIMASPERMINE AND RELATED ALKALOIDS Limaspermine, C~zH30N203,occurs in A . lirnae and was separated from the accompanying aspidolimine (LIII) and aspidocarpine (XLIV) by silica gel chromatography ( 33; see Section 11,J).I t s red-violet ceric sulfate reaction after heating was typical of an N-acylindoline and this was confirmed by the UV-spectrum (Table 111)which resembled that of demethylaspidospermine (XXXVII, 2 5 ) , showing the same bathochromic shift in alkaline solution (40a) which is attributable to the presence of a phenolic hydroxyl group. The presence of an amide group was confirmed by IR-absorption a t 1631 em-1, the low frequency of this peak indicating chelation with a hydroxyl group, which itself absorbed as a broad band, and it was therefore reasonable t o place the phenolic OH a t position 17. The nature of the amide group was elucidated by acid hydrolysis which gave propionic acid, and the third oxygen atom was accounted for by acetylation which gave 0,O-diacetyllimaspermine (LXXXVIII), which absorbs a t 1764 em-1 (phenolic acetate) and 1734 em-1 (alkyl acetate), thus indicating the presence of an alcoholic as well as a phenolic hydroxyl in limaspermine (LXXXVII). The foregoing information suggested a 17-hydroxy-N-propionylindoline structure, and this was fully confirmed by the NMR-spectrum (Table I V ) which showed the presence of three aromatic protons and a hydrogen-bonded phenolic hydroxyl group (singlet at 10.58 6). More important, the portion of the spectrum due to aliphatic protons was very similar to that of aspidolimine (LIII), except that no peaks were found that corresponded to a methoxyl group or a terminal methyl of an ethyl side chain. Other characteristic features of the aspidospermine (11)
14. Aspidosperma
415
AND RELATED ALKALOIDS
skeleton (29) such as the C-2 quartet a t 4.12 6 and the CH2--Nb-CH2 multiplet at about 3.0 6 were present, while the quartet and triplet due respectively to the methylene and methyl groups of N-propionyl were in the same positions as for aspidolimine (LIII). The absence of the side chain C-methyl and the presence of a triplet at 3.25 6 clear of other absorption, which is shifted downfield to 4.0 6 (overlapping the C-2 proton quartet) in the spectrum of the diacetate (LXXXVIII), show that the alcoholic hydroxyl group is primary and suggest that it is in
.
LXXXVII
LXXXVIII LXXXIX
I
xc
XCI
U
b
HH Me0 Me0
C
Ac H H
H
.
EtCO
Ac
Ac EtCO
Ac
H H H
c
position 2 1 of an aspidospermine-type molecule. The structure LXXXVII thus deduced for limaspermine is fully confirmed by its mass spectrum (Table V). Peaks are found corresponding t o the usual a, b, and c fragments, that due to c being, as is normal, the strongest peak of the spectrum. Its position (m/e 140) indicates that it contains the alcoholic oxygen atom which therefore must be in position 21. The a , or M-28, peak (m/e 342) is relatively weak, but is accompanied by a much stronger peak at m/e 324 due to loss of water, and by other smaller peaks a t m/e 267 (further loss of the propionyl group) and m/e 311 (a- CH2OH). Peaks due to loss of water and of CHzOH are also found accompanying c a t m/e 122 and 109, respectively, while a peak at m/e 110 is attributed
416
B. GILBERT
to loss of CH20 by a cyclic mechanism (c to c') (33, 54). Among the minor bases of A . limae there have also been isolated three other C-21 alcohols, the 16-methoxy derivative of limaspermine (XCI, 33), 1'imapodine (N-depropionyl-N-acetyllimaspermine,LXXXIX), and its 16-methoxy derivative, XC (120). The fact that other 17-hydroxy-N-acylindolinesof the ( - )-aspidospermine series have positive rotations of the order of 100" indicates that limaspermine ([ E]D + 108" in chloroform) and XCI ([ .IU + 118" in chloroform) also belong to this configurational group (54a). This has been confirmed by interrelation with haplocine (CCI-D) and ( - )-palosine (XXXIX, Section IV, D, 113c),and with cylindrocarpine (LXXV, 120).
0. TABERSONINE Tabersonine (XCII), a n amorphous base which occurs in the seeds of Amsonia tabernaemontana (65, Volume VII, p. 134), in some Xtemmadenia species (66,66a),and in Tabernaemontana alba (sea),is a member of a distinct group of aspidospermine-type alkaloids which bear an extra carbon atom in the form of a carbomethoxyl group linked t o position 3. The other members of this group are described briefly in Section 11, P and in detail in Chapter 12. The UV-spectrum (64, Table 111) and high negative rotation ([ED] - 310" in methanol) of tabersonine hydrochloride (64, 65) indicated at once that the alkaloid contained the same chromophore as akuammicine (CCXXV) and echitamidine (CCXLII, Chapter 8 ) , and this chromophore was subsequently shown (Volume VII, p. 127) to be Ph-NH-C=C-C02R. The NH (2.95 p ) and a$-unsaturated carboxylic ester bands (6.02 p and 6.2 p ) were also seen in the IR-spectrum. The NH group was not acetylated under usual conditions and the ester group was musually resistant t o hydrolysis (64). Examination of the mass spectrum (Table V, 7) showed that the correct molecuJar formula was C21H24N202, excluding a C20 akuammicine-like skeletm, and peaks a t m/e 92, 107, and 135 were similar to those encountered in vindolinine (CVI, 3) which has an aspidosperminelike skeleton with 6,7-doublebond. The presence of such a nonconjugated double bond had already been shown by catalytic hydrogenation t o 6,7-dihydrotabersonine (XCIII, an optically active form of vincadifformine which has identical IR-, NMR-, and mass spectra) in which the UV-spectrum remained similar to that of the parent alkaloid (64, 7 ) . Moreover, the NMR-spectrum of tabersonine (XCII) showed a peak due to two vinyl protons which disappeared in the dihydro derivative
14. Aspidosperma
417
AND EELATED ALKALOIDS
IX-A
T
4s HCI 110”
T
xcv KBHI OH-
418
B. GILBERT
(XCIII), so that the double bond is disubstituted. The NMR-spectrum also showed the presence of four aromatic protons (consistent with a strong IR-band a t 13.5 p ) , and an NH and a C-ethyl group. The presence of a very strong mje 124 peak (fragment c ) in the mass spectrum of 6,7dihydrotabersonine (XCIII) indicated that the C-ethyl group probably formed part of an ethylpiperidine ring in an aspidospermine-type framework (7). The aspidospermine-type skeleton was then confirmed in two ways. First, tabersonine (XCII) was converted to ( + )-quebrachamine (I)by two independent routes. One involved reduction of the 6,7-double bond followed by strong acid hydrolysis, which removes the carbomethoxyl group, completely shifting the double bond t o the 1,2-position, a reaction known for the other vinylogous amides, akuamniicine (CCXXV, 70) and fluorocurarine (67). The resulting indolenine (IX-A) is the optically active form of decarboniethoxyvincadifformine (superimposable IRand mass spectra, see Chapter 12) and is possibly the antipode of 1,2dehydroaspidospermidine (IX). The former (IX-A) was converted by alkaline borohydride t o ( + )-quebrachamine, an example of the retrograde Mannich reaction and reduction already known in the akuammicine series (19, Section 11, A, and Chapter 7). The same series of reactions, carried out in a different order, gave successively decarbomethoxytabersonine (XCIV), 6,7-dehydro-(+ )-quebrachamine (XCV), and ( + )-quebrachamine (I). These conversions establish the stereochemistry of C-5 in (-)-tabersonine (XCII) as opposite t o that of ( - )-aspidospermine (11). A second proof of the skeleton of tabersonine as represented by XCII was obtained by examination of the mass spectra of the four reduction products XCVI, XCVII, XCVIII, and XCIX. I n all these compounds, the 2,3-double bond has been reduced, thus permitting the normal aspidospermine-type fragmentation in the mass spectrometer. The reduction of this double bond without affecting the isolated 6,7-double bond may be effected either with zinc and acid (cf. 68) which gives 2,3-dihydrotabersonine (XCVI), or with lithium aluminum hydride which gives chiefly 2,3-dihydrotabersonol (XCVII) (64) and its deoxy derivative [XCVIII, 7, contrast the reduction of akuammicine which gives the 3-methylene derivative (68, 69), a difference which, together with NMR-spectral changes, may be due to conformational or even stereochemical differences from aspidospermine]. Compounds XCVI and XCVII now showed typical indoline UV-spectra (64, 7, Table 111)and the N,O-diacetate (C) of 2,3-dihydrotabersonoI showed a typical AT,acylindoline spectrum (64). The mass spectra showed the expected peaks a t m/e 252 (a‘) and 122 (c’, accompanied by m/e 121 ; compare
14. Aspidosperma
AND RELATED ALKALOIDS
419
vindolinine, Ref. 3) in which the reduction of two mass units as compared with the spectrum of aspidospermidine (m/e 254 and 124,Ref. 28) results from the presence of the 6,7-double bond. I n all three cases the C-3 substituent had been expelled together with C-3 and (3-4. Catalytic reduction of 2,3-dihydrotabersonol (XCVII) gave the fully reduced tetrahydrotabersonol (XCIX, an optically active form of dihydrovincadifforminol) which showed mass spectral peaks a t m/e 254 and 124 corresponding to the expected fragments a and c. It remained only to locate the nonconjugated double bond. This must be in the D ring, for it appears in fragment c’ (above) and, as it is not
COzMe C V I ; R = COzMe CVI-A; R = H, 6,7-dihydro
CIII; R = Me CIV; R = CHO CXIII; deacetyl-CIII
attacked by potassium borohydride (XCIV to XCV) or by zinc and sulfuric acid (XCII to XCVI), it cannot be adjacent to nitrogen ; positions 6,7are thus the only ones left for a disubstituted double bond.
P. Vinca ALKALOIDS OF
THE
ASPIDOSPERMINE GROUP
A number of alkaloids with the aspidospermine skeleton occur in the genus Vinca and are dealt with in detail in Chapter 12.They include the very important base vindoline (CIII) which not only occurs as the free base in Vinca rosea ( = Lochnera rosea = Catharanthus roseus) but also as part of the dimeric alkaloids vinblastine (vincaleucoblastine) and leurosine, whereas the N,-formyl analog, CIV, forins part of the dimeric alkaloid leurocristine ( 5 , 72a). These dimeric alkaloids have been used successfully for the treatment of certain forms of cancer in man (5). Vindolinine (CVI) has also been isolated from V . rosea and its dihydrodecarbomethoxp derivative, tuboxenin (CVI-A), which is the parent member of the series, occurs in a Pleiocarpn species (53). ( f )-Vineadifformine (XCIII, 6, 74)has already been mentioned as the racemic form of ( - )-6,7-dihydrotabersonine(Section 11, 0). It has been found in V . difformis and in Rhazya stricta (51b)where the ( + ) form also occurs.
420
B. GILBERT
The ( k ) and ( - ) forms have been found in V . minor, where it is accompanied by four other alkaloids of similar skeleton, minovine (CVIII, 74a), minovincinine (CVII), minovincine (CIX), and 16-methoxyminovincine (CX) ( 3 2 , 7 3 , 74a, 76). The mass spectra of some of these alkaloids and of their derivatives CI, CII, and CXIV-CXVI have been included in Table V where useful for purposes of comparison ( 7 5 ) .
Ri Rz XCIII H H CVII H O H C V I I I Me H
Ri Rz CI H COzMe CII CH3 H CXIV H CHzOH CXV H CH3 C X V I OMe CHzOH
CIX; R = H CX; R = O M e
R3 H H OH OH OH
111. The Aspidofractinine Group
A. INTRODUCTION This group of mainly hexacyclic alkaloids is derived from the aspidospermine skeleton by closure of C-21 with C-2, the original ethyl side chain thus forming a new six-membered ring. Aspidofractinine has been chosen as the parent member as it bears no substituent in the aliphatic portion of the molecule. The oldest known member, kopsine, isolated in the last century, differs from the others in being heptacyclic, C-3 being linked to (2-11 by a one-carbon bridge. The extraordinary cage structure of this group of alkaloids with quaternary centers a t C-2, C-5, and C-12
14. Aspidosperma
42 I
AND RELATED ALKALOIDS
is not susceptible to ordinary chemical degradative methods, and the present evidence for the skeleton therefore rests mainly on physical evidence. The group is a t present limited to four genera of the family Apocynaceae, namely, Aspidosperma, Hunteria, Kopsia, and Pleiocarpa.
B. INTERCORRELATIONSAND SKELETAL STRUCTURE I n the case of the aspidospermine group (Section 11),the nature of the carbon skeleton was elucidated for aspidospermine only, the structures of the ‘other members of the group following by correlation with this alkaloid, either directly or mass spectrometrically. Although mass spectrometry alone suggested the structure CXVII for the skeleton of some Aspidosperma alkaloids, the final proof of CXVII rests on both
CXVII
CXIX
cxx
4 stages
CXXXVI
CXXXIX
physical and chemical evidence obtained in simultaneous work in a number of laboratories on diverse alkaloids. This evidence is brought together in the sequel. The validity of such evidence for alkaloids other than the one under study depends on intercorrelation and this has been largely achieved. Pyrifoline (CXIX) has been related t o refractidine (CXX) by the mass spectral comparison of the alkaloids and a series of derivatives, and to aspidofiline (CXXXVI) by mutual conversion to a common intermediate (CXXXIX). Aspidofractine (CXLIII-A), which has been mass spectrally related to refractine (CL-A),is readily converted
422
B. GILBERT
H6
COzMe CL-A
CLXXXIV
CLXX
i
3 stages
&zMe CXLIII-A
R
COzMe CXLII-A LiAlHd
COzMe CXLVI-A
CXLII-D +
CH~OH CXLII-F
~ H ~ O H CXLVI-F
.
I
4 stages
COzMe CXLV-A
14. Aspidosperma
AND RELATED ALKALOIDS
42 3
to its deformyl derivative kopsinine (CXLII-A) and the corresponding alcohol, kopsinyl alcohol (CXLII-F).These two compounds have in turn been related chemically to kopsinilam (CXLII-D), pleiocarpine (CXLV-A), and kopsine (CLXX). Pleiocarpine (CXLV-A) has further been interrelated with pleiocarpinine (CXLVI-A) and pleiocarpinilam (CXLVI-D) through the common intermediate N-methylkopsinyl alcohol (CXLVI-F). It remains to convert a member of the kopsinine group to a member of the aspidofiline group unsubstituted on C-3. 1. Number of Rings
The hexacyclic nature of the alkaloids, except kopsine, follows from accumulated analytical data, together with precise molecular weight determination by mass spectrometry, which indicate that apart from the dihydroindole moiety there are four other rings or double bonds. The absence of vinyl protons in the NMR-spectra of the bases and the fact that vigorous hydrogenation reduced only the benzene ring showed that only a hindered tetrasubstituted double bond could be present. Such a grouping was excluded by later evidence which demonstrated the presence of three quaternary centers ; therefore, the aliphatic part of the alkaloids contains four rings and the molecules are hexacyclic. Similar methods showed that kopsine is heptacyclic. 2 . General Evidence f r o m Mass Spectrometry
The mass spectra of many alkaloids and their derivatives in this group have been measured and the principal peaks are recorded in Table V (80, 81,82,95, 102). It is readily seen that a common skeleton is probable for all except kopsine and relatives, since the main differences observed are due only to peripheral substituents (RI-R~in structure CXVIII). A general similarity of the spectra to those of aspidospermine (11) and its derivatives is seen in the universal presence of an M-28 peak and usually of a peak a t m/e 124 which is modified only in the two alkaloids pyrifoline (CXIX) and refractidine (CXX) which bear a D-ring substituent, but which is otherwise invariable no matter what modifications are made in the indolic part of the molecule or to the C-3 carbomethoxyl group. The principal difference from the aspidospermine-type cleavage is seen in the fact that the main piperidine-containing peak is usually not c but a peak 15 mass units smaller, that is, normally a t m/e 109. Coupled with the NMR-spectral evidence that these alkaloids contain no G-ethyl side chain and no C-2 proton (absence of characteristic absorption a t 0.65-0.70 6 and 4.0-4.5 a), it is reasonable to postulate an aspidospermine skeleton in which the side chain is tied into a sixth ring terminating a t C-2, and t o propose the breakdown illustrated in the formulas, in which the cleavages
42 4
B. GILBERT
involved are favored ones (Section 11, D). Evidence has been obtained for the correctness of the structures allocated t o the various fragments h-p in a manner similar to that already described in Section 11, D. Metastable peaks have been observed corresponding, for example, to the decompositions, h t o i (at mje 41.5 for CXXXV and m/e 45.2 for CXLII-0) and M+ to c (at m/e 52.5 for CXLII-0). Fragment h always arises by loss of the unsubstituted bridge, C-21, C-20, in the cases where C-3 carries a substituent, and therefore it always appears at M-28. That h contains C-3 is shown by its molecular weight, which accompanies variations in the R3 group, and deuteration on (2-3. Fragment i contains carbon atoms 10,6 and 7 , for when these are substituted the position o f i in the mass spectrum moves appropriately. Thus, in CXVII and CXXXIX, i appears at mje 109, but in 3',3', 10,iO-tetradeuterio-N-trideuteriomethylkopsinyl alcohol (CXLVIII-G from LiAlD4 reduction of pleiocarpine lactam A) i is shifted to in/e 111 and that this shift is due to the C-10 deuterium atoms is shown by the invariability of i when R1, Rz, and R3 are modified in other molecules. When position 6 is substituted by OH, OMe, or =0, corresponding shifts are observed in the mass of i (series N,-rnethyl-(i-deformyl-6-demethylrefractidine,CXXXI; deformylrefractidine, CXXII; and deformyl-6-dehydro-6-demethylrefractidine, CXXXV; see Table 77) and deuteration of C-7 results in a shift of two units in the position of i (see pair, deacetyl-6-dehydro-6demethylpyrifoline, CXXXIII, and its 1,7,7-trideuterio derivative, CXXXIV in Table V). Evidence for the position of these substituents will be described in the sequel. These same carbon atoms are also found in fragment c which accompanies i in all the above changes. That the ethyl chain of c contains C-20 and C-21 and not C-4 and C-3 follows from its constant value, no matter what modifications are made to the substituent on C-3. The extra hydrogen atom that fragment c carries on C-21 does, however, come from C-3 as is shown by its increase by one mass unit when the C-3 hydrogen atom is replaced by deuterium (pair, N,-methyldeforniylnorrefractinol, CLI-Q and N,-dideuteriomethyldeformyl-3-deuterionorrefractinol, CLII-Q, obtained by the LiAlH4 and LiAID4 reduction, respectively, of the corresponding ketone). The transfer of hydrogen to C-21 by the mechanism pictured in the formula is only possible when the C-3 proton is and close t o C-21, as is the case in the naturally occurring alkaloids of the kopsinine-refractine type and their derivatives produced without epimerization. In the 3-is0 series of epimerized alkaloids and their derivatives, this proton is c( and its distance from C-21 precludes its transfer, in accordance with which is the absence of fragment c from their spectra. (Small c peaks sometimes observed have been attributed to contamination with nonepirnerized material, and to
14. Aspidosperma AND
425
RELATED ALKALOIDS
m
Ri CXVII CXXII CXXXI CXXXIII CXXXIV
cxxxv
CXXXVI CXXXIX
Rz R3
RI
R4
H H H H H OMe H Me H O H OMe H H =O OMe D H =0, i, Dz H H H = O OH Ac H H OMe H H H
H H
CXLII-F CXLII-G CXLII-0 CXLV-D CXLVI-D CXLVIII-G CLI-Q CLII-Q
M P
~
H H
H H
H
H OMe OMe
Rz H H H COzMe CH3 CDJ CDzH
R3
CHzOH CDzOH Me COzhlc CO&Ie CDiOH H,OH D,OH =CHz
=O
R4 H H H H , 10, =O H, 10, =O H, 10,Dz H H H H
426
B. GILBERT
check this, epimerization was conducted with NaOD in deuteriomethaiiol SO that the epimerized C-3 hydrogen would be replaced by deuterium, leaving the unepimerized C-3hydrogen unchanged. I n accord with expectation, no trace of deuterium transfer was observed.) The proximity which is necessary for this transfer is also illustrated by the lower relative intensity of the c peak in C-3 unsubstituted alkaloids such as aspidofiline (CXXXVI), refractidine (CXX), and pyrifoline (CXIX) where there is no sterically hindered bulky C-3 substituent to push C - 3 over toward the 21-20 bridge. Transfer of a hydrogen atom t o fragment i is also often observed, in molecules substituted on C-3, to produce a peakj a t m/e 110. I n cases where the C-3 substituent atom, C-3' or 0, carries an a-hydrogen atom, this is the proton transferred, as is shown by replacement by deuterium when j moves to m/e 111 (pair, kopsinyl alcohol, CXLII-F, and 3',3'-dideuteriokopsinyl alcohol, CXLII-G, by reduction of kopsinine with LiAlD4; see Table V). When the C-3 substituent does not carry an a-hydrogen atom, the mje 110 peak is due to the presence of natural isotopes in i , while in molecules having a double bond a t '2-3, for example, M and P, the main fragmentation paths are blocked and the m/e 110 peak cannot be ascribed a structure. A further peak a t m/e 81 which sometimes accompanies i results from its further decomposition (reversed Diels-Alder), as is established by a metastable peak a t m/e 60.5 (102). I n many spectra of alkaloids of this group, the indolic peaks are small as compared with the aspidospermine-type molecules. I n some cases they starid out, however, and peaks corresponding to fragments m and n occur in the spectra of O-methyldeacetylaspidofiline (CXXXIX)and deformylrefractidine (CXXII), while the lactams, pleiocarpinilam (CXLVI-D) and pleiocarpine lactam A (CXLV-D),exhibit intense peaks due to the fragments 1 and p (102). On the basis of the foregoing information, it has been possible to determine the complete structures of alkaloids in this group by use of reactions designed only to modify superficial substituents (80, 81, 82, 95). Other possible skeletal structures which might be compatible with the observed spectra are excluded by chemical evidence described subsequently. 3. N , I s Located in a Pive-Membered Ring ( E ) This is shown by the IR-absorption of the three lactams, pleiocarpine lactam A (CXLV-D), pleiocarpinilam (CXLVI-D), and kopsinilam (CXLII-D; Section 111, H), which is compatible only with their being y-lactams [compare, for example, 8- and 10-oxoaspidospermine (XX, XI), Section 11, C].
14. Aspidosperma
AND RELATED ALKALOIDS
427
4. NbI s Also Located in a Six-Membered Ring ( D ) Similar lactams, for example, refractalam (8-0x0-CXXII,Section Ill,
D), pleiocarpine lactam B (CXLV-E) and the related kopsinine lactam (CXLII-E,Section Ill, G)show IR-absorption due to an amide carbonyl group in a six-membered ring. Also, zinc dust distillation of pleiocarpine (CXLV-A, 95) and kopsinine (CXLII-A, 101) gives 3,5-diethylpyridine, an indication of structural similarity to aspidospermine which also gives this product derived from the piperidine ring D containing Nb. The ketones deacetyl-6-dehydrodemethylpyrifoline (CXXXIII) and deformyl-6-dehydrodemethylrefractidine(CXXXV, Section 111, D) are located in a six-membered ring as shown by their IR-absorption. Conclusive evidence has been obtained that the carbonyl groups in these two compounds are located in the same ring as Nb. 5. C-3 Lies in a Six-Membered Ring
The carbon atom, C-3, which in the kopsinine subgroup bears a carbomethoxyl substituent, has been shown by the mass spectral evidence summarized above not to be in the six-membered ring which contains Nb. That it lies in a strained six-membered ring is indicated by degradation of the carbomethoxyl groups of refractine (CL-A) and aspidofractine (CXLIII-A) to C-3 ketones (CXLIX-P and CXLII-P), whose IRabsorption occurs a t unusually low wavelengths ( 5 . 7 G 5 . 7 8 p) (Section 111,G). 6. Ring E Contains a Chain of T w o Methylene Qrouys Terminating in a
Quaternary Center, C-12, and the Tertiary Nb The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the P-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (11),it is reasonable t o expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which (2-11 is substituted by the C-3’ bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-11 shows as a singlet (2.82 6) in the NMR-spectrum and C-12 is therefore quaternary.
7. Ring D Contains a Chain of Three Carbon Atoms between Nband (7-5
Evidence was presented under subsection 4 above tha.t ring D is six-membered and contains the ketonic carbonyl group of deacetyl6-dehydrodemethylpyrifoline (CXXXIII). When this ketone was exhaustively deuterated, only two deuterium atoms were introduced, which is consistent with the carbonyl’s lying between a quaternary
428
B. GILBERT
center, C-5, and a methylene group, C-7. Moreover, when the ketone was reduced under Clemmensen conditions, an olefin (CXLI) was obtained that contained a 6,7-double bond whose resistance to reduction by zinc and acid shows that this compound is not an enamine and there must be another carbon atom (C-8) between the double bond and Nb (Section 111,D, E). The preparation of the two lactams CXLII-E and CXLV-E shows that C-8 is a methylene group (Section 111,Q). 8. Ring F Contains a Pair of Carbon Atoms, C-3 and C-4, between Two Quaternary Centers, C-2 and C-5 As already mentioned, the NMR-spectra of the aspidofractinine-type alkaloids show that they do not have any hydrogen atom on C-2. The adjacent atom in ring F, C-3, bears a carbomethoxyl group in, for example, kopsinine (CXLII-A), the position of this group being established by the formation of a six-membered cyclic urethane (CLIV) involving N, from the derived alcohol, kopsinyl alcohol (CXLII-I?) (Section 111,G). The related N-methylkopsinyl alcohol (CXLVI-F) was converted by way of alkaline or thermal decomposition of its mesylata (CXLVI-I), to the olefins, N-methylkopsinylene (CXLVI-M) and N-methylisokopsinylene (CXLVI-N). N-Methylkopsinylene has an exocyclic methylene group whose vinyl protons show a 12-line ABXz pattern in the NMR-spectrum demonstrating the presence of two protons on C-4. I n isokopsinylene, the double bond has moved into the ring and the remaining C-4 proton, now absorbing in the vinyl region, clear of other absorption, shows weak coupling (J = 1.5 cjsec) only with the allylic C-3' methyl group. C-4 is therefme attached to a quaternary center (Section 111,G). 9. Positions 2 and 5 Are Linked by a n Unsubstituted Ethylene Chain
Only two carbon atoms have not been accounted for in the aliphatic portion of the molecule and these are clearly those expelled as ethylene in the formation of the ion h (M-28)in the mass spectrometer. In order to satisfy the conditions that C-2 and C-5 must be quaternary and that the C-3 ketone, e.g., CXLIX-P, is six-membered, these two carbon atoms must link positions 2 and 5 as in aspidospermine. 10. The Relation between C-3 and Ring El and the Stereochemistry of the Alkaloids The evidence already presented encompasses all the aliphatic carbon atoms of the alkaloids, the dihydroindole structure of rings A and B resting on UV-, NMR-, and mass spectral data as well as on the production of indole derivatives during the zinc dust distillation and alkali
14. Aspidosperma AND RELATED ALKALOIDS
429
fusion of pleiocarpine and kopsine (95, 103). The skeleton CXVII represents the only manner of linking the groupings described that is compatible with all the data mentioned. The demonstration of a C-3 to C-11 bridge through only one carbon atom in kopsine (CLXX) proves that the bonds 2-3 and 12-11 are disposed cis with respect to rings B and C in this alkaloid. From models, it is evident that ring E must be cis fused to ring C and the relative stereochemistry of C-19 is thus also established. If it is assumed that no inversion at C-12 and C-19 takes place during the pyrolysis of kopsinyl iodide (CXLII-J) to kopsane (CLXXXIV) which has been directly related to kopsine (Section 111, J),then the relative stereochemistry of all the ester alkaloids is established. The relative stereochemistry of the nonester alkaloids follows from the cis E/C fusion mentioned above. The correlation of the two groups with one another and with aspidospermine (11)has yet to be achieved.
C. ASPIDOFRACTININE From the residues remaining after the removal of the major alkaloids, refractidine, refractine, and aspidofractine (Sections 111, D, G) from Aspidosperma refractum, VPC and thin-layer chromatography enabled the separation and purification of a noncrystalline minor base, aspidofractinine, ClgH24N2. The IR-spectrum showed an NH band a t 3.10 p and the mass spectrum proved to be identical with that of O-methyldeacetylaspidofiline (CXXXIX, Section 111,E) with the sole exception that those peaks which correspond to indole-containing fragments were found at mass numbers 30 units lower. Aspidofractinine is thus the unsubstituted parent (CXVII) of the hexacyclic group which forms the subject of this section (102).
CXVII
D. PYRIFOLINE, REFRACTIDINE, AND REFRACTALAM Pyrifoline (CXIX)and refractidine (CXX) are abundant constituents, respectively, of the closely similar species, Aspidosperrna pyrifoliurn (49) and A. refracturn (81). Pyrifoline, shown by analysis and mass spectrometry to be C23H30N203, contains two methoxyl groups, while refractidine, CzlHzsN202, contains only one. The UV-spectrum of pyrifoline
430
B. GILBERT
is coincident with that of aspidospermine, and taken together with the fact that there is absorption due to three aromatic protons in the NMRspectrum, this shows that a 17-methoxy-N-acyldihydroindolechromophore is present. Refractidine showed UV-absorption characteristic of an N-acyldihydroindole unsubstituted in the aromatic ring (Table 111), confirmed by the appearance of absorption due to four aromatic protons in the NMR-spectrum. The NMR-spectra (Table IV) and acid hydrolysis of the two alkaloids to their deacyl derivatives, CXXI and CXXII,
CXIX CXXI CXX CXXII CXXIII CXSlV
Ri Olle
OXe
H
H
H H
4c
H CHO H Me CD2H
CSXV CXXVI CXXVII CXXX CXXXI CXXXII
Rz
OMe H OMe H H H H Ac H Me H CDzH
R3
H
D H
H
CXXXIII CXXXIV CXXXV
RI R2 Me0 H OMe D
H
H
H
H
Ri
AC
CXXVIII; R = OMe CXXIX; R = H
respectively, showed that pyrifoline has an N,-acetyl and refractidine an N,-formyl group. The difference in molecular formula of the two alkaloids is thus explained by the 17- and N,-substituents. Functional group analysis and NMR-spectra show the absence of a C-ethyl side chain and a (2-2 hydrogen atom (absence of absorption a t 0.65-0.70 6 and 4.0-4.5 a), excluding the two alkaloids from the aspidospermine group, and the lack of evidence for a double bond indicates a hexacyclic structure (81). The mass spectra of the two bases and all their corresponding derivatives are identical except for appropriate shifts in the masses of the molecular ion and fragments h, m,and n,due t o the different substitution
14. Aspidosperma
AND RELATED ALKALOIDS
43 1
pattern in the indolic part of the molecule (Table V). Pyrifoline and refractidine therefore have the same aliphatic structure ( 2 l ) , and the evidence that this structure is based on the skeleton CXVII has already been presented (Section 111, B). It remained to locate the aliphatic methoxyl group present in both alkaloids. This group is selectively demethylated by boiling concentrated hydrochloric acid to give, respectively, the alcohols CXXV and CXXVII in which the c and i peaks are found 14 mass units lower than in the parent alkaloids (loss of CHZ). The secondary nature and equatorial configuration of the alcohol group was shown by acetylation to give CXXVIII and CXXIX, respectively, in whose NMR-spectra a clear one-proton quartet was observed a t 4.63 6 and 4.73 6, respectively (J = 5, 10.5 cjsec) due to the CH(0Ac) group flanked by two nonequivalent protons. Confirmation of the presence of only two vicinal protons was obtained by Oppenauer oxidation of the alcohol (CXXV) with cyclohexanone and aluminum phenoxide to the six-membered ketone (CXXXIII, IR, 5.89 p), which was equilibrated with excess sodium deuteroxide in deuteriomethanol to give the trisdeuterio derivative, CXXXIV, (accompanied by material not deuterated on Na). The carbonyl group thus has only two cr-hydrogen atoms and the mass spectra of the ketone and its deuterated derivative (Table V) showed that both the carbonyl group and the adjacent hydrogen, or, respectively, deuterium, atoms were retained in the c and i fragments. On the basis of skeleton CXVII and the evidence presented in Section 111, B, 2 for the structure of these fragments, only position 6 for the carbonyl group is compatible with these observations. Among other derivatives of the two alkaloids prepared in order to confirm the correctness of the interpretation placed upon the mass spectra, were the corresponding ketone in the refractidine series (CXXXV, I R , 5.9 p ) , the 6-deuterio derivative of deacetyl-6-demethylpyrifoline(CXXVI), and the compounds CXXIII, CXXIV, CXXXI, and CXXXII. I n all cases the mass spectral peaks were found a t the predicted m/e values (Table V). The methoxyl group of pyrifoline (CXIX) and refractidine (CXX) is therefore located securely in position 6. Of some interest is the ease of hydrolysis of the aliphatic methoxyl groups of these alkaloids which, in common with the sharp drop in pKi (33% dimethylformamide) which is observed on passing from the alcohol, CXXV (7.25), to the ketone, CXXXIII (5.90), would seem t o point to an interaction with Nb. Examination of models does not show proximity between these two positions, however. A similar change in basicity is seen in the pairs, ajmalidine (ketone, pKi 6.3) and sandwicine (alcohol, pKi 8.5) (98, 99), and kopsine (ketone, pKi 4.28) and dihydrokopsine A (alcohol, pKi 6.1) (109, 100). The two ketones, like CXXXIII,
432
B. GILBERT
are P-keto-amines in which the keto group is held rigidly away from the basic nitrogen atom. I n addition, the six-membered lactam 8-0x0-CXXII has been encountered in A . refracturn (37).
E. ASPIDOFILINE Aspidofiline (CXXXVI), one of the simplest members of the group, was the first alkaloid t o be isolated from A . pyrifoliurn (79). It was readily separated from the accompanying pyrifoline by virtue of its alkali solubility. The phenolic hydroxyl group so indicated is confirmed by the bathochromic shift of the UV-spectrum observed on addition of alkali. The spectrum is characteristic of a 17-hydroxy-N-acyldihydroindoleand the IR-spectrum shows a hydrogen-bonded amide carbonyl band a t
CXXXVI CXXXVII CXXXVIII CXXXIX CXL
Ri
Rz
H
Ac Ac Ac
Ac Me Me
H
CXLI
cxxxIII
H Et
6.14 p. Further confirmation is obtained from the NMR-spectrum which shows a singlet a t 10.13 6 due to the bonded 17-hydroxyl (compare demethoxyaspidospermine and aspidocarpine), while a three-proton singlet at 2.30 6 shows the N,-acyl group to be acetyl. Analysis and the mass spectrometrically determined molecular weight established the empirical formula as C21H~sN202.The oxygen atoms are already accounted for, so it remained to elucidate the nature of the hexacyclic carbon-nitrogen skeleton. Aspidofiline yields an 0-acetate (N,-tertiary) and is methylated with diazomethane in 24 days to 0-methylaspidofiline (CXXXVIII). The resistance to methylation of similarly hydrogenbonded phenolic hydroxyl groups has been encountered already with aspidocarpine and demethylaspidospermine (Section 11,G, I)and in those
14. Aspidosperma
AND RELATED ALKALOIDS
433
cases methylation was effected with dimethyl sulfate. This method was also used with aspidofiline, but as in this group N,-methylation is rapid, the O,N,-dimethyl quaternary sulfate resulted, from which CXXXVIII was regenerated by pyrolysis of the corresponding methohydroxide in high vacuum. Acid hydrolysis of the methyl ether yielded 0-methyldeacetylaspidofiline (CXXXIX). Mass spectral examination of aspidofiline and its three derivatives, CXXXVII, CXXXVIII, and CXXXIX, showed in each case an M-28 peak (h) and peaks a t m/e 124 and 109 (c and i ) . This similarity to other alkaloids of the group, considered together with the absence of NMR-absorption due to a C-ethyl side chain or a C-2 hydrogen atom, led t o the proposal of structure CXXXVI (see Section 111,R , 2). Proof that the proposed structure was correct was obtained by correlation with pyrifoline (CXIX).The ketone, CXXXIII (Section 111, D), was subjected to the Clemmensen reduction which unexpectedly gave the olefin, CXLI (i peak a t m/e 107) and th’is was hydrogenated t o 0-methyldeacetylaspidofiline (CXXXIX) (80).
F. SOMEALKALOIDS OF Aspidosperma populifoliurn Ten alkaloids have been isolated from A . populifolium, of which the greater part belong t o the aspidofractinine group (48). They include ( + )-0-methyldeacetylaspidofiline [CXXXIX, optical enantiomer of that derived from aspidofiline (Section 111,E)], its 16-methoxy analog, CXLI-A, and their respective N,-formyl derivatives, CXLI-B and CXLI-C. The structures of all four compounds could be established by comparison of their IR-, UV-, NMR-, and especially mass spectra with
?,I
‘*’ I
CXXXIX H CXLI-A Me0
H H
those of known aspidofiline derivatives and in the case of CXXXIX, by chromatographic comparison with its enantiomer. The UV-spectra of the dimet,hoxy compounds CXLI-A and CXLI-C, were closely similar to those of deacetylpyrifolidine (XLVII) and pyrifolidine (XLVI), respectively, while the presence of two ortho-hydrogens on the benzene
434
B. GILBERT
ring was established by NMR-spectroscopy (6.28 and 6.86 6 , doublets, J = 9 cjsec). On this basis, the methoxyl groups of these bases could be located in positions 16 and 17 (48).
G. KOPSININE, ASPIDOFRACTINE, PLEIOCARPINE, AND REFRACTINE PLEIOCARPININE, The five alkaloids mentioned in the title differ only in the substituent on N, or, in the case of refractine, by the presence of a methoxyl group a t C-17. It is convenient, therefore, t o consider their chemistry together. The natural sources of the alkaloids are recorded in Table I, and interconversions that have related them were described in Section 111,B. The bases are all levorotatory. Analyses of the bases and their salts and particularly mass spectral molecular weight determination established the empirical formulas, and examination of the UV-spectra and comparison with model compounds showed that all were dihydroindoles, kopsinine (CXLII-A)having a free N,-H, and aspidofractine (CXLIII-A),refractine (CL-A), and pleiocarpine (CXLV-A)being acylated. I n addition to the UV-, the IR- (N,-CHO, 6.0 p ; N,-COZMe, 5.87 p ) and NMR-data (N,-CHO, 9.5 6 ; N,-COZMe, 3.8 S), together with acid hydrolysis and reacylation (with formic-acetic anhydride or formic acid for aspidofractine and refractine and with methyl chlorocarbonate for pleiocarpine) established the nature of the acyl groups. The more strongly basic nature of pleiocarpinine (CXLVI-A) and its red ceric sulfate reaction, together with the absence of an NH band in the IR-spectrum suggested an N-alkyldihydroindole, and that the N, substituent was methyl was shown by the fact that pleiocarpine and pleiocarpinine give a common reduction product, N,-methylkopsinyl alcohol (CXLVI-F),with lithium aluminum hydride (87, 49, 91, 92).
The NMR-spectra (Table I V ) showed that pleiocarpine and aspidofractine were unsubstituted in the benzene ring (note the characteristic downfield doublet with fine structure due to the C-17 aromatic proton which lies close to the N,-acyl group), while refractine had a C-17 methoxyl (position from UV- and NMR-aromatic patterns which resemble those of aspidospermine). The remaining two oxygen atoms SO far unaccounted for in each of the alkaloids were located in a carbomethoxyl group (IR-, 5.7P5.80 p ; NMR-, ca. 3.7 6,methyl singlet) (82, 91, 92).
The principal evidence for the aliphatic structure of the alkaloids was presented in Section 111, B, where it was shown that they have the car-
14. Aspidosperrna
AND RELATED ALKALOIDS
435
bon-nitrogen skeleton represented in the formulas A-Q in the accompanying illustration. Some transformations of a peripheral nature are described below. 1. Rings D and E
Direct oxidation of pleiocarpine (CXLV-A) with permanganate gave a mixture of two Nb-lactams,the five-membered lactam A (CXLV-D, v, 1712 or 1683 cm-1) and the six-membered lactam B (CXLV-E, v, 1672 cm-1) whose UV-spectra were unaltered and which could be reduced back to a mixture of kopsinyl alcohol (CXLII-F) and its N-methyl derivative (CXLVI-F),thus demonstrating that no skeletal change had taken place. The formation of these neutral lactams has been cited (Section 111, B, 3, 4) as evidence that N, lies a t the junction of a fiveand a six-membered ring (rings E and D, respectively) (95). 2 . The Carbornethoxyl Group I s Linked to a Carbon Atom Which Also Bears a Xingle Hydrogen Atom
Mild alkaline hydrolysis of refractine and aspidofractine gave the free acids (CXLIX-B and CXLII-B, respectively) which on reformylation and reesterification did not give back the parent alkaloids (37; see, however, 89), but isomeric esters which were named isorefractine and isoaspidofractine (CL-C and CXLIII-C, respectively). Treatment of the deformyl derivatives CXLIX-A and CXLII-A with sodium methoxide in methanol effected the same isomerization directly to give the deformyl isoesters, CXLIX-C and CXLII-C, respectively. The carbomethoxyl group is thus attached in a sterically unfavorable configuration t o a carbon atom which also bears a hydrogen atom; the presence of this hydrogen atom may be confirmed by its replacement by deuterium to give CXLIX-S when the same epimerization is performed with sodium deuteroxide in deuteriomethanol (see Section 111, B, 2 and Table V). That only epimerization was involved was established by carrying deformylrefractine (CXLIX-A) and deformylisorefractine (CXLIX-C) through the series of transformations COzMe CHzOH (For T) --+ CHzOTs ( H or W) +=CH2 (M). The olefinic final product no longer has a hydrogen atom on C-3 and, in accordance with expectation, the same olefin (CXLIX-M), was obtained in both series. Further confirmation of the C-3 hydrogen is seen in the NMR-spectra of the hydrocarbons (0)in which the -C02Me of the original alkaloids has been reduced to CH3 [reduction of the tosylate (CXLIX-W) via desulfurization of the thiophenyl ether (CXLIX-Y) (82), Raney nickel in ethanol on the iodide (CXLII-J), or Wolff-Kishner reduction of the
-
436 B. GILBERT
14. Aspidosperma AND RELATED ALKALOIDS
PI
437
438
B. GILBERT
aldehyde (CLV, 95)]. I n all cases a new methyl doublet a t 1.1-1.3 6 (J = 6 c/sec) shows coupling with a single C-3 proton. 3. The Carbomethoxyl Group I s Located on C-3 Kopsinyl alcohol [CXLII-F, LiAIH4 reduction of kopsinine (deformylaspidofractine CXLII-A),or pleiocarpine (CXLV-A)which also gives the N-methyl derivative] forms two ring compounds which link the alcoholic group to N, through a one-carbon bridge. One is the carbinolamine ether, CLIII, formed by the action of formaldehyde, the other a cyclic urethane (CLIV) prepared with benzyl chlorocarbonate and alkali. The latter shows IR-carbonyl absorption (5.88 p) characteristic of a six-membered cyclic urethane (95; cf. 82, 89,91, 92) (note that CLIV can only maintain planarity of the amide group if formed from isokopsinyl alcohol), and the original CHzOH group, and hence the carboniethoxyl of the parent alkaloids is situated /3 to N,. Furthermore, the C-3 substituent, whether -C02Me or any derived group, is always found in the fragment h (M-28) in numerous mass spectra and therefore cannot be located on C-20 or C-21 which are expelled in the formation of this fragment. Fragment h decomposes to fragment i which has been shown (Section 111,B, 2) to incorporate the D ring, C-10 and C-4. The carbomethoxyl group is thus limited to C-3 and C-11, with the foregoing evidence excluding the latter position. The transformation of the carbomethoxyl group to the exocyclic olefin (M) has already been described. Further transformation of the N,-deformyl olefins (CXLII-M and CXLIX-M) via their N,-formyl derivatives and by ozonization to the N,-formyl norketones (CXLIII-P and CL-P, respectively) led to the deformyl norketones (CXLII-P and CXLIX-P). The IR-absorption of these (ca. 5.77 p) showed that the carbonyl group and hence the original carbomethoxyl group probably lay in a strained six-membered ring. 4.
The Stereochemistry of the Alkaloids
(See also Section 111,B, 10.) Only structure A for the five alkaloids is compatible with the foregoing facts. Moreover, as will be seen subsequently (Section 111,J),kopsinyl iodide (CXLII-J)may be transformed into kopFane (CLXXXIV)in which the C-3’ carbon atom forms a bridge between C-3 and C-11. This requires the C-3, C-4 bridge to be cis to ring E ; the stereochemistry of the remaining centers follows automatically. That the carbomethoxyl group has the a configuration is shown not only by this bridge formation but also by its instability with respect to the is0 series in which the group must possess the less hindered /3 orientation.
14. Aspidosperma
AND RELATED ALKALOIDS
439
H. KOPSINILAM AND PLEIOCARPINILAM The amides kopsinilam (CXLII-D) and pleiocarpinilam (CXLVI-D) occur together with the more strongly basic pleiocarpine, pleiocarpinine, and kopsinine (Table I). Their weak basicity derives from the dihydroindole nitrogen which, as is shown by the UV-spectra and ceric color reaction (N-CH3, red; NH, orange), is not acylated. The IR-spectra (v, COzMe, 1736-1740 cm-1; v , CO-Nb, 1684-1696 cm-1) suggest the presence of an ester function as well as a five-membered lactam. The nonreactivity of pleiocarpinilam toward methyl iodide confirmed that this involved Nb (note that steric hindrance prevents quaternization of Na). Lithium aluminum hydride reduction of pleiocarpinilam (CXLVI-D) and kopsinilam (CXLII-D) gave, respectively, N-methylkopsinyl alcohol (CXLVI-F) and kopsinyl alcohol (CXLII-F) and thus there was every likelihood that these alkaloids were the E-ring lactams derived from pleiocarpinine and kopsinine, respectively. The correctness of this view was shown by synthesis. Pleiocarpinilam was obtained by the direct permanganate oxidation of pleiocarpinine (CXLVI-A) in acetone, while kopsinilam could be prepared, in a similar manner, from N-acetylkopsinine (CXLIV-A) followed by acid hydrolysis of the acetyl group, or from pleiocarpine lactam A (CXLV-D) by hydrolysis and simultaneous decarboxylation of the N-carbomethoxyl followed by reesterification of the C-3 carboxylic acid. It was established that these two amides are not formed by the action of air and light on pleiocarpinine and kopsinine and that the amides are therefore not artifacts. No trace of pleiocarpine lactam A or any sixmembered lactam was encountered (96).
I. KOPSIFLORINE, KOPSILONGINE, AND KOPSAMINE The three alkaloids named in the title occur together with kopsinine in Kopsia longi$ora (86, 57, 90), and kopsamine was shown (88) to be identical with the “kopsine” isolated in 1920 from K . $avida (85, perhaps a wrong identification of K . pruniformis Reichb. f. et Zoll. ex Bakh. f.). The name kopsamine was retained, as “kopsine” now refers to another alkaloid. Analysis of the bases and their salts established the empirical formulas while the IR-spectrum indicated the presence of ester (v, 1740 cm-1) and amide (v, 1688 cm-1) groups in all three alkaloids. Mild alkaline hydrolysis of kopsamine, C24H28N207 (CLVIII),and of kopsiflorine, C23H~8N205(CLVI), resulted in cleavage of afi ester
440
B . GILBERT
group to give kopsaminic (CLX) and kopsiflorinic (CLIX) acids, respectively. These acids could be remethylated t o the parent bases, but on treatment with dilute acid, they decarboxylated to give kopseine (CLXIII) and kopsifloreine (CLXI), in which compounds a new weakly basic secondary amine had been generated, as was shown by formation of the nitroso derivatives, CLXVI and CLXIV. Kopseine and kopsifloreine retained the original ester group which could be hydrolyzed under more vigorous conditions to give, respectively, kopsamic (CLXIX) and kopsifloric (CLXVII)acids. A similar acid (CLXVIII) could also be obtained by vigorous hydrolysis of kopsilongine, C Z ~ H ~ ~ (CLVII), NZO~ and reesterification with diazomethane gave kopsilongeine (CLXII), a product corresponding in every way t o kopseine and kopsifloreine and
/
Ri H CLVI H CLVII C L V I I I 0-CHz-0 H CLXI H CLXII C L X I I I 0-CHz-0 CLXIV H CLXV H C L X V I 0-CHz-0
Rz H OMe
/
CO zMe
CbzMe R3 COzMe COzMe COzMe
H H OMe H H H NO OMe NO NO
Ri CLIX CLX
~
H 0-CHz-0
COzQ
Rz H
CLXVII CLXVIII CLXIX
Ri
Rz
H H 0-CHz-0
H OMe
forming a nitroso derivative, CLXV. These results indicated the presence of the groupings N-COZMe and C-C02Me in the three alkaloids; examination of the parent bases and their decarbomethoxy derivatives showed that they were dihydroindoles. The spectra and functional group analysis indicated that kopsilongine contained a 17-methoxy and kopsamine a 16,1i’-methylenedioxy grouping whereas kopsiflorine was unsubstituted in the benzene ring. The strong similarity in the chemical behavior of the three bases suggested that otherwise they were of identical structure, and this has subsequently been shown to be true (89, 97).
14. Aspiclosperma
AND RELATED ALKALOIDS
44 1
J. KOPSINEAND RELATED ALKALOIDS Although kopsine (CLXX) was probably isolated in the last century
(83, 84), the true nature of its unusual cage-like structure has only become known recently (101). Preliminary investigations (103, 104, 105)
showed that it was a dihydroindole containing a carbomethoxyl group. In later work (100, log), the correct molecular formula, C~zH24N204,was established and by comparison of the UV-spectrum with model compounds and mild alkaline hydrolysis accompanied by decarboxylation to a dihydroindole (CLXXI) unsubstituted on N, (UV-, benzenoid in acid), it was shown that the carbomethoxyl group was attached to that nitrogen atom. From the IR-spectrum, a five-membered ketone (v, 1757 cm-1) and a hydroxyl group hydrogen-bonded to the N-carbomethoxyl (v, OH, 3268 cm-1; COZMe, 1679 cm-1) were recognized. The presence of the hydroxyl was confirmed by the NMR-spectrum which showed a singlet a t 7.2 6 that could be eliminated by previous treatment of the base with deuterium oxide (100, 101, 109). Furthermore, the hydroxyl and ketone groups were probably vicinal since kopsine reacted with periodate (107, 110). Both kopsine (CLXX) and decarbomethoxykopsine (CLXXI) resist acetylation, indicating that the hydroxyl group was probably tertiary and that N , was sterically hindered. The ketone could be reduced to two epimeric alcohols; dihydrokopsine-A (CLXXII)resulted with sodium borohydride reduction (100, 109))whereas catalytic hydrogenation gave dihydrokopsine-B (CLXXIV, 100, 104). Both formed only a monoacetate. Kopsine shows no vinyl absorption in the NMR-spectrum and could not be further reduced (except by catalytic hydrogenation of the benzene ring). The molecule therefore contains seven rings, since subsequent evidence excludes a tetrasubstituted double bond. Evidence was then accumulated to establish the relation of the ketonic carbonyl to Nb. This was first obtained by examination of two lactams. One, “lactam A” (CLXXV),was the final oxidation product of either of the epimeric alcohols dihydrokopsine-A or -B, in which the secondary hydroxyl had been reoxidized and a new carbonyl group had been introduced adjacent to Nb, as could be recognized both from its neutrality and from the IR-spectrum (v, 1675 cm-1) of its N,-decarbomethoxy derivative (CLXXVI). The same lactam A resulted from the direct oxidation of kopsine itself. The other, “lactam B ” (CLXXVII), was an intermediate oxidation product of dihydrokopsine-B in which the secondary hydroxyl had not suffered alteration. Comparison of the IR-absorption of both lactams with that of kopsinilam (CXLII-D) and
442
B. GILBERT 0
0
t-
CLXXV; R = COzMe CLXXVI: R = H
CLXXVII
CLXXII; R = COZMe CLXXIII; R = H
/
i
C,O, pyridine
t-
CLXXIV
CLXXXVI
CLXX; R = COzMe CLXXI; H = H
CLXXVIII; RI = CHs, RI = H CLXXIX; R I = H. Rz = D
CLXXXIV; R = H CLXXXV; R = Ac
CLXXX
I
J
/
CXL1I.J
CLXXXVII; R = COeMe CLXXXVII-A; R = H
RI CLXXXI
COzMe
CLXXXII-A COpMe CLXXXII-B COrEt
CLXXXIII
CLXXXVII-B; R = COzMe CLXXXVII-C: R = H
Rt =O
&H
14. Aspidosperrna
AND RELATED ALKALOIDS
443
pleiocarpinilam (CXLVI-D) indicated that they were five-membered, and further comparison with 10,ll-dioxoaspidospermine(XIII, Section 11,C, Ref. 24) showed that “lactam A” could not be an a-keto lactam. However, in the NMR-spectrum of this compound (CLXXV) a singlet could be distinguished at 2.82 6 which became a slightly resolved doublet (2.63 6, J = 1 c/sec) in the hydroxy lactam B (CLXXVII). This could be attributed to the groupings CO-CH(CR2)-CONb in lactam A and CH(OH)-CH(CR2)-CONb in lactam B where R is not hydrogen and it was also possible t o say that the two hydrogen atoms in the latter were oriented at an angle of nearly 90” to one another, thus establishing the configuration of the C-3’ hydroxyl (101, see also 111). The same relation between the ketonic carbonyl group of kopsine and Nb was demonstrated by study of the Hofmann degradation of the methiodide. This yielded an a,/?-unsaturated ketone CLXXX whose double bond lay in a terminal methylene group (IR-, v, =CH2, 945, 920, 1629; Y , CO, 1748 cm-1; NMR-, two vinyl singlets at 5.07 and 6.3 6). Three reduction products (CLXXXI, CLXXXII-A, and CLXXXII-B) of this methine were prepared. In each case a new methyl doublet at 0.48-0.58 6, coupled (J = 7-7.5 clsec) to a single a-proton, could be recognized. This proton (on C-11) appeared in the spectrum of CLXXXI as a quartet at 3.7 6 with the same coupling constant (101). Reaction of the diol, CLXXXII-A, with periodate confirmed that it was an a-glycol. The foregoing experiments establish that kopsine contains two fivemembered rings apart from the dihydroindole moiety. One of these rings contains an a-hydroxy ketone in which the hydroxyl is tertiary. The other contains R&-CH-CH2-Nb, in which none of the groups R is hydrogen and the ketonic carbonyl is attached to the carbon atom to Nb.These two rings can only be accommodated in the partial structure CLXXXIII. To this may be added the fact that the hydroxyl group is close t o -N, and also that Nb is probably also involved in a six-membered ring since 3,Ei-diethylpyridineresults from the zinc dust distillation of kopsine (105). This and the occurrence of kopsine (CLXX) and pleiocarpine (CXLV-A)in plants of the same genus led to the belief that the two alkaloids might be structurally related. In fact, a direct correlation was achieved. Kopsinyl iodide (CXLII-J,Section 111,G), obtained from pleiocarpine (CXLV-A), was pyrolyzed to give in 60% yield a heptacyclic hydrocarbon kopsane (CLXXXIV) which forms an N,-acetate (CLXXXV) and a five-membered lactam (CLXXXVI) (NMR-spectrum similar to that of CLXXVII). The new ring which has been formed in kopsane does not therefore involve N, or C-10 and it is not a cyclopropane (NMR-spectrum clear from 0-0.9 6). Examination of models shows that, barring rearrangement, the new ring must involve closure of
444
B. GILBERT
C-3' with C-11. Prolonged treatment of kopsine with hydriodic acid and red phosphorus gave a small yield of the same hydrocarbon, kopsane (CLXXXIV), Taken in combination with the previously described evidence, this establishes the structure CLXX for kopsine. The mass spectrum of kopsine (Table V) is quite different from those of other alkaloids of this group which do not possess the extra ring, in t,hat the base peak, derived directly from the molecular ion (metastable peak at 209), occurs at m/e 282. That this involves the loss of the CO-C(0H) grouping and three more carbon atoms, but not of the N,substituent was shown by the spectra of the three derivatives CLXXI, CLXXVIII, and CLXXIX in which the base peak followed changes at N, but was not affected by alterations on C-3'. The results did not permit a unique structural interpretation (106, 107). Two other alkaloids, fruticosine and fruticosamine (Section 111, K , 109, 113), isomeric with kopsine, possess similar mass spectra. Kopsine (CLXX) undergoes reversible acyloin rearrangement by heating in tetralin t o give an isomer, isokopsine (CLXXXVII, 111).Similarly, bythe action of dilute alkali on kopsine or decarbomethoxykopsine (CLXXI),an equilibrium mixture of the latter with decarbomethoxyisokopsine (CLXXXVII-A) is obtained. I n isokopsine (CLXXXVII), hydrogen bonding is no longer observed between the tertiary hydroxyl group (v, 3509 cm-1, no downfield proton in the NMR-spectrum) and the N,-carbomethoxyl (v, 1706 cm-1). To confirm its structure, decarbomethoxyisokopsine (CLXXXVII-A) was directly related, via its sodium borohydride reduction product decarbomethoxydihydroisokopsine (CLXXXVII-C), to isokopsine, from which the same compound could be obtained by successive borohydride reduction to dihydroisokopsine (CLXXXVII-B) followed by hydrolysis of the N,-carbomethoxyl group (111). Both decarbomethoxykopsine (CLXXI) and its is0 derivative (CLXXXVII-A) occur in the leaves of K . fruticosa ( 113).
K. Kopsia ALKALOIDS OF UNKNOWN STRUCTURE Five alkaloids of unknown structure that may well belong to the aspidofractinine-kopsine group have been reported. Three, kopsaporine, kopsingine, and kopsingarine, have been isolated from K . singapurensis (108, 89, 56). The other two, fruticosine and fruticosamine, occur with kopsine in K. fruticosa (109, 100, 113). Both are isomers of kopsine and similarly contain an N-carbomethoxydihydroindole nucleus unsubstituted in the benzene ring, a five-membered ketone, and a hydroxyl group. Fruticosamine is converted into fruticosine by mild alkali or stronger acid treatment. Fruticosamine resists acetylation and does not
14. Aspidosperma
AND RELATED ALKALOIDS
445
form a methiodide, whereas fruticosine forms both acetate and methiodide. Although the similarity of the mass spectra of these alkaloids and kopsine suggests a similar skeleton, there are some notable differences, among which are the secondary nature of the hydroxyl group in fruticosine and the resistance of the five-membered ketone to reduction (109). IV. The Aspidoalbine Group A. ASPIDOALBINE AND ITS N-ACETYLANALOG The study of Aspidosperma album (see Volume VII, p. 129) in two laboratories resulted in the isolation of aspidoalbine and its N-acetyl analog [(CLXXXVIII+ CLXXXIX, 52) which have been separated (42,48)]as well as aspidocarpine and its demethyl derivative (Section 11, I, Refs. 42, 48). The UV-spectrum of aspidoalbine is similar to that of aspidocarpine (XLIV), showing the same bathochromic shift in alkali, and together with the IR-absorption a t 3.1-3.5 p (hydrogen-bonded hydroxyl) and 6.17p (amide carbonyl), suggesting that the alkaloid was also a 17-hydroxy-N-acyldihydroindole. Elementary analysis and mass spectrometry established the empirical formula as C24H32N205, although the latter showed the presence of a lower homolog, the nature of the mixture being resolved by acid hydrolysis which gave, after esterification and vapor phase chromatography of the volatile acid fraction, methyl propionate (mainly) and methyl acetate. The alkaloid mixture thus consisted principally of a 17-hydroxy-N-propionyldihydroindoletogether with a smaller proportion of the N-acetyl analog. Two methoxyl groups accounted for two of the remaining three oxygen atoms, and the NMR-spectrum (Table IV) showed that these were in the aromatic ring, since only a single aromatic proton singlet at 6.826 was observed. It was assumed that this proton occupied the rarely oxygenated 14 position. The fifth oxygen atom was not in a carbonyl group nor could it be acylated and it was therefore assumed to be ethereal. Methylation of the mixed alkaloid (CLXXXVIII + CLXXXIX) with dimethyl sulfate in acetone (note nonformation of an N,-metho salt, which is indicative of a steric hindrance around N, similar to that observed in the aspidospermine group) gave impure 0-methylaspidoalbine (CXC+ CXCI) from which the deacyl derivative, CXCII, was obtained by acid hydrolysis. Pure 0-methylaspidoalbine (CXC) and its lower homolog, CXCI, were prepared by acylation of CXCII, and in their NMR-spectra could be recognized the C-2 proton quartet, characteristic of the aspidospermine series, The mass spectra of aspidoalbine and its 0-methylated derivatives
5)
C X C I X ; R = Ac C X C I X - A ; R = COEt
CXCVIII
Series B
Serics A
JXXXIV LXXXV LXXXVI
H2C\;/\
_Ri _R2 H
Ac Et
CXCIII CXCIV CXCV CXCVI CXCVII
H
Ac
H
~~
Ri H H
Ac Et CD2CD3
RZ R J H H Ac H H
H D H H H
C'
I,,I \CHzORz C
Me0
R1 (H)
R
Series A , Rz = H Series B. Re = OMe
446
a'
14. Aspidosperrna
AND RELATED ALKALOIDS
447
CXC, CXCI, and CXCII show the M-28 and weak indole peaks expected for an aspidospermine-like molecule. However, a strong M-44 peak (loss of CHzCHzO) also appears, and the base peak is found a t m/e 138 instead of a t m/e 124. Thus, aspidoalbine probably has an aspidospermine-type skeleton modified in the ring D area which contains the ethereal oxygen atom. Reduction of 0-methyldeacylaspidoalbine (CXCII) with lithium aluminum hydride gave an alcohol (CXCIII), and this showed the most intense peak a t m/e 140 which was shifted further to m/e 141 when the reduction was effected with lithium aluminum deuteride. The susceptibility to reduction under these conditions is characteristic of a carbinolamine ether, and since the indole peaks, 6 and homolog, remain unchanged during the foregoing transformations, this ether must terminate adjacent to Nb (52). The exact nature of the ether ring was demonstrated as follows. Oxidation of the 0-methyl-N,-acetyl derivative of aspidoalbine (CXCI) with chromium trioxide-pyridine yielded a five-membered lactam (CXCVIII) and a five-membered lactone (CXCIX, 52). The composition of the lactone shows that two hydrogen atoms in CXCI have been replaced by oxygen, and at the same time it was observed that a two-proton quartet which appears at 4.02 6 in the 100-mc NMR-spectrum of 0-methyldeacylaspidoalbine (CXCII) had disappeared. This quartet could therefore be ascribed to a methylene group (C-21 in formula CC) adjacent to the ethereal oxygen atom. It was shown by spin-decoupling to be coupled to two nonequivalent protons, respectively 2.05 and 2.72 ppm upfield (on C-20 in formula CC). When the coupling between these was also eliminated by double decoupling, then each in turn could be made to absorb as a singlet, thus demonstrating that the next adjacent carbon atom ((3-5in formula CC) bore no hydrogen atom (114). Confirmation that no hydrogen atom was attached to the carbon atom (C-19 in formula CC) on the other side of the ethereal oxygen atom was obtained by examination of the 100-mc spectra of 0-methyldeacylaspidoalbinol (CXCIII) and its deuterio derivative (CXCIV). The only difference between the spectra rests in the absence from the second of a sharp signal a t 2.17 6 [the position in which the C-19 proton absorbs in aspidospermine and pyrifolidine (Table IV)], showing that a lone proton is generated by the LiAlH4 reduction of the carbinolamine ether which therefore terminated at a quaternary center. The ether ring may thus be represented by partial formula CC (52). Both the aforementioned NMR-singlet exhibited by CXCIII and the existence of the five-membered lactam (CXCVIII) support the earliercited mass spectral evidence that aspidoalbine has an aspidosperminetype skeleton. Further confirmation of this was obtained by comparison
448
B . GILBERT
of the mass spectra of the three aspidoalbinol derivatives CXCIII, its
N,O-diacetate, CXCV, and its N-ethyl derivative, CXCVI, with those of three corresponding decinnamoylcylindrocarpol derivatives, LXXXIV, LXXXV, and LXXXVI, whose preparation was described in Section 11, M. All three pairs showed the expected identity of the piperidine-containing peaks (c and satellites) while the indole-containing peaks ( b and satellites) were shifted in the aspidoalbinol derivatives by 60 mass units due to the two extra methoxyl groups present. The M-28 species (fragment a in Section 11, D) which decomposes to give fragment c as is shown by the recognition of metastable peaks, was particularly weak in the spectra of the aspidoalbinol derivatives and this was attributed t o a probably opposite configuration at C-19 with respect to the cylindrocarpol derivatives. Subsequent work (1 13i)has shown, however, that the principal ring-opened reduction product of an aspidoalbine derivative has C-19, p-H (as in cylindrocarpol), the (2-19, a-epimer being a minor product. The accommodation of the ether ring as represented by CC in the aspidospermine skeleton can only be made in the manner represented by formula CLXXXVIII for aspidoalbine, and the mass spectral fragments observed may be rationalized as a', b, and Models permit the construction of two stereoisomers of this structure, one with the ether ring on the same side of the molecule as is the ethyl group of aspidospermine. The co-occurrence of aspidoalbine with alkaloids of the aspidosperminetype made it probable that this was the true configuration ( 5 2 ) ,and this has now been established by interrelation with obscurinervidine (CCI-R), neblinine (CCI-S),and aspidocarpine (XLIV, 113i). GI.
B. ASPIDOLIMIDINE I n addition to seven alkaloids of the aspidospermine group (Section 11, F, I, J, and N) isolated from Aspidosperma limae, this plant also yielded
a base aspidolimidine, whose NMR- and mass spectra were not consistent with membership of that group. The UV-spectrum of aspidolimidine is very similar to those of aspidocarpine (XLIV) and aspidolimine (LIII), which accompany it in the plant. Indeed, the same aromatic substitution pattern is shown by NMR-spectra in which a hydrogen-bonded 17hydroxyl group may be recognized a t 10.78 6, an aromatic methoxyl group singlet at 3.88 6, and two ortho hydrogen atoms a t 6.73 6 and 7.09 6 (J = 8 clsec). An N,-acetyl group is also present (2.32 6). The difference from the aspidocarpine-type spectrum lies in the absence of C-ethyl absorption and the presence of absorption due to three protons
14. Aspidosperma AND
449
RELATED ALKALOIDS
instead of only one in the 4.0 6 region. A similar feature in the spectrum of aspidoalbine (CLXXXVIII) could be attributed to the absorption of the C-2 and the two C-21 protons. I n fact, a comparison of the mass spectra of aspidolimidine and aspidoalbine showed that the aliphatic portions of the two molecules were identical, each showing the base
CCI CCI-L CCI-K CCI-0
Ri Rz OMe OH H H H H OMe O H
Ri
R3 Ac H Ac COEt
CCI-B CCI-C CCI-D CCI-E CCI-F CCI-G
Me
H H Ac H Me
Rz Ac Ac COEt COEt H COEt
Ri CCI-A H CCI-M H CCI-N M e 0
Rz
R3
Me
CHO EtCO EtCO
H H
I Et CCI-I;
R
= OTs
R = SPh XXXIX; R = H CCI-J;
LXXXIV CCI-H LXXXVII
Ri
Rz
Me Me
COEt
H
H
COEt
peak (c) at m/e 138.The molecular ion appeared a t m/e 384 ( C Z Z H ~ ~ N Z O ~ ) , 30 mass units lower than in the case of aspidoalbine, and a similar shift was observed in the M-28 (a’),M-44 (loss of C-2O,C-21,0 bridge), and b peaks due to the absence in aspidolimidine of the C-15 methoxyl group. The alkaloid may therefore be assigned the structure CCI (40).
C. DICHOTAMINE AND 1-ACETYLASPIDOALBIDINE The alkaloid dichotamine, C Z I H ~ ~ Noccurs ~ O ~ in , Vallesia dichotoma together with vallesine, aspidospermine, reserpine, and akuammidine. The UV-spectrum was indicative of a 17-methoxy-Na-formyldihydroindole structure, and the IR-spectrum showed two carbonyl bands, one
450
B . GILBERT
due to the expected N-formyl function, the other to a five-membered lactone (5.67 p ) (41). Subsequently, the molecular formula was confirmed mass spectrometrically, while lithium aluminum hydride reduction of the deformyl compound gave decinnamoylcylindrocarpol (LXXXIV) and its 19-epimer in equal amounts, establishing the structure (CCI-A) for dichotamine (113e). Also found in V . dichotoma were haplocidine (CCI-C), whose structure and stereochemistry were proved independently by methylation with dimethyl sulfate to the highly crystalline 0-methyl derivative (CCI-B), removal of the N,-acetyl group by acid hydrolysis, and lithium aluminum hydride reduction to decinnamoylcylindrocarpol (LXXXIV) and its 19-epimer ; and the unsubstituted compound CCI-K, named 1-acetylaspidoalbidine (with the parent of the aspidoalbine series, CCI-L, being designated as aspidoalbidine to simplify nomenclature). The structure of CCI-K was determined by its analogous reactions and mass spectrometric fragmentation patterns of derivatives with those of haplocidine and its 0-methyl derivative (CCI-C and CCI-B) (113e).
D. HAPLOCINE AND HAPLOCIDINE Preliminary investigation of the plant Haplophyton cimicidum indicated the presence of an alkaloid haplophytine, possibly closely related to the Aspidosperma alkaloids (113a). A reinvestigation of the plant has resulted in the isolation of eburnamine (CCCXL), isoeburnamine (CCCXLI),0-methyleburnamine (CCCXL-A)(see Section VIII, E), and several alkaloids belonging to the aspidoalbine group (113b). Among these the structures of haplocine (CCI-D) and haplocidine (CCI-C) have been elucidated. The UV-absorption (A,, 219, 258, 291-292 mp) of the alkaloids was consistent with their being 17-hydroxy-Na-acyldihydroindoles. This was confirmed by the appearance of a hydrogen-bonded amide carbonyl peak a t 6.13 p in the IR-spectrum which shifted to 6.00 p in the spectrum of the 0-acetate, CCI-E. The phenolic nature of the hydroxyl group followed from the additional carbonyl absorption of the 0-acetate, CCI-E, at 5.69 p. Deacylation of both alkaloids gave the same product, depropionylhaplocine (CCI-F), and reacylation experiments showed that haplocidine (CCI-C) was its N-acetyl and haplocine (CCI-D), its N-propionyl derivative (113b). That the third oxygen atom of haplocine was present in a carbinolamine ether ring was shown by methylation to 0-methylhaplocine (CCI-G),followed by catalytic reduction which opened this ring stereospecifically to give a single product, CCI-H, which contained a new
14. Aspidosperma
AND RELATED ALKALOIDS
45 1
primary alcoholic group. The structure and stereochemistry of CCI-H were established by reduction of the -CHzOH group to -CH3 by way of the tosylate, CCI-I, and the crystalline thiophenyl ether, CCI-J, to palosine (XXXIX) identical with an authentic sample prepared from aspidospermine (11)(11310, 113c). Furthermore, catalytic reduction of haplocine led directly to the known alkaloid limaspermine (LXXXVII). The similarity of the observed behavior of haplocine with that of aspidoalbine led to the structure CCI-D for the alkaloid, and hence to CCI-C for haplocidine.
E. CIMICINE AND CIMICIDINE I n addition to the alkaloids haplocine and haplocidine described in Section IV, D, the plant Haplophyton cimicidum contains two hexacyclic alkaloids, cimicine, CzzHz6N204, (CCI-M) and cimicidine, Cz3HzsNz05, (CCI-N)which contain a y-lactone ring (IR,5.65 and 5.71 split carbonyl in nujol) (113j, k, 1, m). The NMR-spectra of these two alkaloids resembled one another, the principal difference resting in the presence of an aromatic methoxyl peak (3.876) in the spectrum of CCI-N absent from CCI-M. Furthermore, the NMR-spectrum of cimicine was similar to that of haplocine (CCI-D), leaving no doubt that it was a 17-hydroxy-Napropionyldihydroindole. The empirical formula suggested that cimicine (CCI-M)might be simply 21-oxohaplocine, and this was proved by direct oxidation of haplocine to cimicine in low yield using chromium trioxide in pyridine (compare the similar oxidation of 0-methylaspidoalbine, Section IV, A). The supposition that cimicidine is 16-methoxycimicine (CCI-N) is in accord with its NMR-(2 ortho aromatic H, 6.73, 7.026, J = 8 clsec) and IR-spectra. Both bases suffer cleavage of the carbinolamine lactone ring on catalytic hydrogenation to yield zwitterionic amino acids (compare reduction of haplocine, Section IV, D) (113j).
F. OTHERALKALOIDS OF
THE
ASPIDOALBINE GROUP
Recent studies have led t o the isolation of other alkaloids of this group. notably the parent member, CCI-L, which occurs in Aspidosperma fendleri Woodson, and has been named fendleridine. The principal base from this plant, fendlerine, is the Na-propionyl analog (CCI-0) of aspidolimidine (Section IV, B) with which it has been interconverted (113f).
A lactone, CXCIX-A, related to dichotamine, cimicine, and cimicidine
452
B. GILBERT
(Sections IV, C, D) but bearing three aromatic methoxyl groups, has been isolated from an Aspidosperma sp. Its structure follows from its interconversion with the known lactone CXCIX derived from aspidoalbine (Section IV, A) (113g).
G. OBSCURINERVINE AND RELATED ALKALOIDS I n addition t o aspidocarpine (XLIV) and aspidolimine (LIII), Aspidosperma obscurinervium Azambuja also contains three lactonic alkaloids : obscurinervine, mp 204"-205' (dec.), [a]L7 - 54" ; dihydroobscurinervine, mp 184°-1850 (dec.), [a]? - 61" ; and obscurinervidine, mp 206"-207" (dec.), [a]: -39". Recent studies have shown these to possess the structures CCI-P, CCI-Q, and CCI-R, respectively (113i). A dihydroindolic structure for these bases was suggested by their superimposable UV-spectra (A, 218, 253-255, 308-312 mp; E 50,000, 6,000, 3,000) while the presence of a y-lactone was indicated by strong IRabsorption a t 1755 cm-1. The first two exhibit strong M-Et and M-Me, and the last only M-Me peaks (loss of R2) in the mass spectrum, but the stability of the polycyclic skeleton results in only low intensity indolic peaks of which the most notable occurs a t mje 244 for all three molecules. The alkyl group Rz (ethyl or methyl),the lone aromatic proton, and two aromatic methoxyl groups may be recognized in the NMR-spectra of the bases, while with obscurinervine (CCI-P) and obscurinervidine (CCI-R) the two vinylic protons in positions 6 and 7 may be distinguished. Mild hydrogenation of obscurinervine gives the dihydro derivative (CCI-Q) which accompanies it in the plant. The alkaloid neblinine (CCI-S), mp 257"-258", from A . neblinae, is a demethoxy derivative of obscurinervidine (113i).3
CCI-P OMe CCI-Q OMe CCI-R OMe CCI-S H
Et Et Me Me
6,7-dihydro
3 Dihydroobscurinervidine also occurs in A . obscurinervium and the 22-ethyl homolog of neblinine (CCI-S, R1 = H, Rz = E t ) has been isolated from A . neblinae. Synthesis of a reduction product of neblinine from aspidocarpine established the relative stereochemistry a t four centers, that at the other two following from NMR data ( 1 13i).
14. Aspidosperma
AND RELATED ALKALOIDS
453
V. The Condylocarpine Group A. INTRODUCTION This small group, which at the time of writing comprises nine alkaloids occurring in the genera Aspidosperma, Diplorrhyncus, Pleiocarpa, and Stemmadenia of the family Apocynaceae, is important as its members represent close biogenetic relatives of the ulein group alkaloids (115). The common biogenetic origin of stemmadenine (CCXIII)and echitamine (Chapter 8) is also clear. B. ASPIDOSPERMATINE, ASPIDOSPERMATIDINE, AND RELATED ALKALOIDS
Aspidosperma quebrachoblanco is a source of several aspidosperminetype alkaloids which have been discussed in Section 11, C and E. By use of alumina and vapor phase chromatography, six alkaloids were isolated whose mass spectra showed them to be related to one another but not to belong to the aspidospermine group. Five were characterized by a base peak a t m/e 136 (compare m/e 124 for the aspidospermine group) and contained a hydrogenatable double bond while the sixth had the base peak at m/e 138 and did not contain this double bond. The alkaloids were named by their molecular weights [later names (118) in parentheses] : 266-B (aspidospermatidine), 280-B (N,-methylaspidospermatidine), 296-B (deacetylaspidospermatine), 308-B (N,-acetylaspidospermatidine), 338-B (aspidospermatine), and 340-B (dihydroaspidospermatine), the last being the saturated member of the group. The UV-spectra of aspidospermatidine and aspidospermatine showed that they were, respectively, a dihydroindole unsubstituted in the aromatic ring and on N, and an N-acyldihydroindole bearing a methoxyl group ortho t o N, as in aspidospermine (11). The difference in molecular weight between the two corresponded to (Me0 + CH&O-2H) so that it was reasonable to assume that the N-acyl group in aspidospermatine was acetyl. In accordance with expectation, the indole peaks, b and homolog, differed by 30 mass units due to the methoxyl group alone (28, 51a). The isolation of 3-ethylpiperidine by the zinc dust distillation of aspidospermatidine and deacetylaspidospermatine made it probable that the m/e 136 peak derived from a piperidine ring incorporated in the aliphatic part of the molecule. An ideal model compound, dihydrodecarbomethoxyakuammicine (CCII, mol. wt. 266) was known (19). Its
454 B. GILBERT
R
---f
14. Aspidosperma
i
f
AND RELATED ALKALOIDS
455
456
B. GILBERT
mass spectrum was very similar to that of aspidospermatidine (266-B) but not quite identical. The strong m/e 136 peak was present and indicated that a molecule of this skeleton fragmented according to the scheme indicated in the formulas to give fragments b and r . It will be noted that there is no ethylene bridge to be lost in this molecule and this is in accord with the absence of an M-28 peak from the spectra. It was clear that the structure of aspidospermatidine represented some slight modification of the structure CCII and a clue was obtained from the mass spectra of the dihydro derivatives of both compounds (CCIII and CCV). I n both cases the base peak was now shifted to m/e 138 while the indole peaks remained unchanged. A new peak appeared in the spectrum of CCIII at m/e 199, which was absent from that of dihydroaspidospermatidine. An examination of the postulated initial breakdown product, q, of CCIII indicated that it would further decompose not only by cleavage a t x (to give r, m/e 138), but also at y which is both allylic and /3 to nitrogen (see Section 11, D and Refs. 20, 21) to give s, and indeed s has the required molecular weight of 199. The production of s involves loss of the three skeletal carbon atoms, 16, 15, and 20 as well as the ethyl side chain. If the side chain had not been at C-20, then the loss observed would have been 28 mass units less and the s ion would be found at m/e 227. Such a peak is in fact found in the spectrum of dihydroaspidospermatidine, and the ethyl group is therefore at 14, the only position which is consistent with the production of 3-ethylpyridine by dehydrogenation (28, 21, 51a). Structure CCIV is thus established for aspidospermatidine, some slight doubt remaining over the position of the double bond, although the absence of terminal methylene absorption in the IR-spectrum excludes the alternative C-CH-CHz formulation for the side chain. Since the only differences observed in the spectra of the accompanying alkaloids were in the indole peaks, it was possible to formulate them as CCVI-CCX. Confirmatory interconversions, CCVIII to CCIV, CCIX to CCVII, and CCIX to CCX, were made. Base 338-B (CCIX) was recognized by its mp, rotation, and composition as the aspidospermatine that Hesse isolated from the same plant in 1882 (59). The fragmentation pattern proposed for alkaloids of this skeleton has been confirmed by the observation that spermostrychnine (CCXI) and its deacetyl derivative (CCXII) (21), as well as numerous other derivatives of the same basic skeleton substituted in positions 14, 16, and 20 (see following sections and Ref. 115a), fragment in the same way. I n many cases the structures of these compounds have been proved independent of mass spectrometry. An exception to the normal breakdown pattern is seen in strychanone (CCXLIV)in which the 16-carbonyl group
14. Aspidospermu
AND RELATED ALKALOIDS
457
blocks the usual path (36, 128, Section 11,D, L). Breakdown patterns for various unsaturated derivatives of the aspidospermatidine skeleton have been worked out by examination of a series of compounds derived from akuammicine and other alkaloids (115a). An alternative and more probable cleavage of aspidospermatidine itself is illustrated by the production of q' and r ' . A minor alkaloid of Aspidosperma compactinervium has been identified as CCXII-A. Its methyl ether (CCXII-B) differs from aspidospermatine only in the location of the aromatic methoxyl group. As in the case of the foregoing alkaloids the structural determination was based on mass spectrometry of the alkaloid and its derivatives CCXII-B and CCXII-C. The latter, in which the ethylidene side chain has been reduced, shows the s peak at mje 299 (227 + Me0 + Ac - 2H),thus locating this grouping in position 14. The position of the aromatic hydroxyl group is based on theUV-spectrum of CCXII-A [A 218,252,260 (sh), 294, and 300 mp] (48).
A C
CCXII-A; R = H C C X I I - B ; R = Me CCXII-C; R = Me, 14,19-dihydro
C. CONDYLOCARPINEAND STEMMADENINE Stemmadenine (CCXIII) was first isolated from Stemmadenia donnellsmithii (8), where it occurs with (+)-quebrachamine (I) and some iboga-type bases. Subsequently, it has also been found in Diplorrhyncus condylocurpon ssp. mossumbicensis, where it occurs together with condylocarpine (CCXV), normacusine-B (Section VIII, B), two yohimbines, norfluorocurarine, and mossambine (Section VI, B and C, Ref. 116). Analysis and mass spectral molecular weight determination established the empirical formula, C21H26N203, for stemmadenine (8, 116, 117). Its UV-spectrum was characteristic of an indole (cf. ref. 5 5 ) , while the IRspectrum indicated the presence of a normal ester grouping (1718 cm-1) and the absence of any substituent in the indole aromatic ring (116). These findings were fully borne out by NMR-spectroscopy which showed the presence of an indole NK (9.3 6), four aromatic protons, and a carbomethoxyl methyl singlet (3.79 6). A single vinyl proton quartet (5.4 6)
1
CCXIII
CCXVI
/
CCXVIl
1 . KbfnOa, HCl, 5'
2. Heat
CHz
CCXIV
t
CCXVIII
m/e 123
I
ccxv
ccxx
1
I
CCXIX
I
CCXXI CCXXIII-A 14,lY saturated l4p-H CCXXIII-B 14,19 saturated 14a-H
Q
I
S
LiAlHa
P
4
I
I
CH2
A
I
+ CCIV
CCXXII CCXXIII
14,19 saturated
COzMe
ccxxIv
Ri
CCXXIV-A Me0 CCXXN-B Me0 CCXXIV-C Me0
Rz H H
T
2,16-dihydro
AO 2,16-dihydr0
tl
460
B. GILBERT
and a methyl doublet ( 1.7 6) were indicative of the grouping C=CH-CH3. This double bond could be hydrogenated (117). The mass spectrum of stemmadenine exhibited, besides the molecular ion, peaks a t M-30 (loss of CH20) and M-18 (loss of HzO). The latter suggested the presence of a hydroxyl group and the former, considered together with an NMR-spectroscopic signal a t 4.38 6 (CH2 of CHzOH) and the fact that formaldehyde can be isolated during the conversion of stemmadenine into condylocarpine (see below), further indicated that this hydroxyl group must be primary. Palladium dehydrogenation of stemmadenine gave 3-ethylpyridine and a compound, C25HzzNz02, showing carbonyl absorption a t 5.88 p and an extended indole chromophore in the UV spectrum. The structure of this compound, which is symmetrical, was solved entirely by NMRspectroscopy. I n the spectrum eight aromatic protons could be recognized, six normally placed and two further downfield which must be close to one of the two carbonyl groups. Four other protons made up an AzX2 pattern, of which two protons appear a t 4.43 6 (between CO and the indole double bond) and the other two a t 2.78 6 so that the grouping Ar-CH(C0)-CHZ-CH(CO)-Ar was present. Finally, the remaining hydrogen atoms could be located in two ethyl groups which absorbed as a quartet and a triplet. These features can only be assembled in the structure, CCXVI, which may be seen to be formed from two units of structure, CCXVII, with the loss of one carbon atom. The part structure, CCXVII, and 3-ethylpyridine together contain all the carbon atoms of stemmadenine, and the two fragments could be linked to give the part structure CCXVIII for the alkaloid [linkage of C-16 in CCXVII to N, is excluded as condylocarpine (CCXV, see below) is not an enamine] in which it remains to complete one more ring between (3-16 and some point on the piperidine ring. Such a part structure is fully in accord with the appearance of the strongest peak in the mass spectrum of stemmadenine a t m/e 123, a peak which can be rationalized as the piperidine fragment t (117). Proof of the point of attachment of C-16 came from the conversion of stemmadenine into condylocarpine by direct oxidation of the hydrochloride with aqueous permanganate followed by heating, which gave formaldehyde as a by-product (117). The condylocarpine obtained had the same physical properties, including high positive rotation, as the natural material ( 116). Condylocarpine has the characteristic a-methyleneindoline carboxylic ester chromophore found also, for example, in akuammicine (CCXXV) and tabersonine (XCII, Section 11, 0), and which gives rise to the high rotation and t o IR-spectroscopic bands a t 6.0 p (conjugated C02Me) and 6.25 p (conjugated double bond), and
14, Aspidosperma
AND RELATED ALKALOIDS
46 1
NMR-absorption at 8.72 6 (N,-H) and 3.78 6 (COzCH3). NMR-spectroscopy also showed that the ethylidene group of stemmadenine was still present. The absorption in the 4.0 6 region (which may be assigned to protons allylic to one double bond and next to nitrogen, or to protons allylic to two double bonds) showed two single proton absorptions. Position 3 (partial structure CCXIX) is therefore substituted and can only be linked to C-7, while C-16 may be linked to positions 15 or 21 (117).
Clemmensen reduction of condylocarpine (CCXV) gave the tetrahydro derivative (CCXX) [note the strange reduction of an isolated double bond for which a mechanism has been proposed (1IS)] in whose mass spectrum could be seen the now familiar breakdown pattern to give fragments r and s characteristic of the dihydroaspidospermatidine skeleton (Section V, B) but in which r now bears the C-16 carbomethoxyl group. In particular, the position of s a t m/e 227 [as in dihydroaspidospermatidine (CCV) and not as in tetrahydrodecarbomethoxyakuammicine (CCIII)] fixes the position of the ethyl group as (3-14 and not C-20. The structure of condylocarpine is thus CCXV and of stemmadenine, CCXIII, with the oxidative interconversion passing through the intermediate CCXIV. Further confirmation of structure CCXV was sought by decarbomethoxylation of condylocarpine in strong hydrochloric acid (compare tabersonine, Section 11, 0, and akuammicine, Ref. 19) to the indolenine CCXXI followed by reduction t o the indoline CCXXII. This compound was expected to be identical to aspidospermatidine (CCIV) but it was not. The identity of the mass spectra of CCXXII and CCIV, however, show that the former does in fact have the structure shown and this was confirmed by the identity of the mass spectra of the dihydro derivatives of the two compounds, CCXXIII and CCV. The difference must exist in the stereochemistry a t C-19 (or less probably C-2) (118). In this connection, it is interesting t o note that condylocarpine has a positive rotation in contrast to the negative rotations normally observed in a-methyleneindoline alkaloids. This a t first indicated an “unnatural ” configuration for both this alkaloid and stemmadenine, which itself occurs together with “ unnatural ” ( + )-quebrachamine. The full absolute stereochemistry of condylocarpine was finally established by correlation with akuammicine (CCXXV) by way of its dihydro-derivative, tubotaiwine (CCXXIV, Section V, D ; Ref. 118a). The configurations of both condylocarpine and stemmadenine a t position 15 are in fact “natural,” t h e positive rotation of the former being attributed t o its inversion at C-7 with respect t o the akuammicine group alkaloids.
462
B. GILBERT
D. TUBOTAIWINE From the leaves of Pleioearpa tubicina, in addition to bases described in Sections 111,G, and VI, C, there has been isolated an alkaloid, tubotaiwine, of structure CCXXIV (119). The same substance also occurs in the root bark of Aspidosperrna lirnae (120). Tubotaiwine is dihydrocondylocarpine and like the parent base is decarboxylated by hydrochloric acid. The product, condyfoline (CCXXIII-A, [aID+ 348"), undergoes heat-catalyzed transformation to a mixture of its 20-epimer (CCXXIII-B, [a]=+ 31aa) and tubifoline (CCXXXIX, [a]=- 361", Section 1'1, C), the latter of known absolute configuration. The transformation proceeds by way of an intermediate analogous to CCXIV in which the 3-7 bond has opened. The stereochemistry at position 15is unaffected and, as it controls the configurations a t positions 3 and 7, the absolute configurations of condyfoline (CCXXIII-A) and hence of tubotaiwine (CCXXIV) and condylocarpine (CCXV) at these centers follow (118a).
E.
1~-METHOXY-14,19-DIHYDROCONDYLOCARPINE
Although the alkaloids of Aspidosperma populifolium are preponderantly ofthe aspidofractinine type, one of them (CCXXlV-A)was clearly excluded from this class by its IR- (ACHC1- 5.98 and 6.25 p, MeOzC--C=C) and UV- (Table 111)spectra. The latter was somewhat similar to that of condylocarpine (CCXV),the differences being accountable to an aromatic methoxyl group whose presence was indicated by the NMR-spectrum (OCH3, 3.74 6, coincident with the COzMe peak; 3 aromatic protons only). A further difference from condylocarpine and akuammicine lay in the presence of an ethyl (0.70 6, triplet) rather than ethylidene side chain. Membership to the condylocarpine rather than to the akuammicine group was established by mass spectral examination of the dihydro derivative (CCXXIV-B).The spectrum paralleled that of condylocarpine except in that the s peak appeared a t rnle 257 (227 + 30 due to the aromatic methoxyl), while the indolic peaks were also shifted upward by 30 mass units. The UV-spectra of CCXXIV-B and its N-acetyl derivative, CCXXIV-C, corresponded t o those of la, 1,2,3,4,4a-hexahydro-7methoxycarbazole and its N-acetyl derivative, respectively (120a), thus placing the methoxyl group in the 1 1 position (condylocarpine numbering). The alkaloid CCXXIV-A may thus be formulated as 11-methoxy14,19-dihydrocondylocarpine(48).
14. Aspidosperma
AND RELATED ALKALOIDS
463
VI. Alkaloids Related to Akuammicine A. INTRODUCTION Alkaloids with the skeleton of akuammicine (CCXXV) are widely distributed in the family Apocynaceae and in the genus Strychnos of the family Loganiaceae. Comparatively few members of this group have been isolated so far, however, from plants of the genera under discussion. Together with the preceding isomeric group, they differ from the aspidospermine-type alkaloids in possessing a C19 skeleton if we include the C-16 carboxyl, in contrast to tabersonine (XCII),for example, which has a C20 skeleton including the carboxyl carbon atom.
B. MOSSAMBINE Mossambine occurs with a number of other alkaloids (Section V, C) in Diplorrhyncus mossambicensis (121, 122, 116). Its high negative rotation (-498' in chloroform), UV- (A 230, 300 and 330 mp), and IR-spectra (conjugated COZMe, v, 1653 cm-1; conjugated double bond, v, 1603 cm-1) marked it as a member of the a-methyleneindoline carboxylic ester group of alkaloids. Elementary analysis and mass spectral molecular weight determination established the empirical formula, C20H22N302. A modified Kuhn-Roth determination (44)showed the presence of one C-methyl group, whereas after catalytic hydrogenation, the same determination showed C-ethyl. The hydrogenation product, 19,20-dihydromossambine (CCXXVIII), had the same UV-absorption as mossambine itself and so the alkaloid must contain a grouping, C=CHCH3, unconjugated with the main chromophore. Although mossambine was too insoluble for NMR-determination, examination of the spectra of its 2,16-dihydro and decarbomethoxy derivatives (see below) showed the vinyl proton quartet (5.53-5.55 6) and coupled allylic methyl doublet (1.66 6, J = 6 cjsec) typical of such an ethylidene group. Acetylation of mossambine gave a mono-0-acetate (CCXXVII, v, 1740, 1355 cm-1) whose NMR-spectrum exhibited a new single proton triplet at 4.8 6 due to the group C-CH(0Ac)-C in which there are also two hydrogen atoms vicinal to the acetate group. There are three known types of alkaloid which contain the cr-methyleneindoline carboxylic ester chromophore, those which are typified by tabersonine (XCII), akuammicine (CCXXV), and condylocarpine (CCXV), respectively. The first is excluded since it has a C20 skeleton as against the C19 skeleton of mossambine. The molecular formula of
464
B. GILBERT
C C XXV; R = H C C XXVI; R = O H CCXXVII: R = OAC
U
C C X X X V I I I ; R = H ; 1Sg - H CCXXIX; R = OH
CCXXXV; R = H CCXXX; R = O H
P R' = COzMe or Me
CCX X V III; R = OH CCX X X V II; R = H
CCXXXIII; R = O H
CCXXXI
CCXXXVI; R = H C C XXXIV; J-t = OH
9
CCXXXII
r R' = COzMe or Me
For compounds with R = H, t h e following stereochemistry h a s been established: At C-5, (2-6, 8, C-3, a ;or-H at (3-3, (2-15, (2-20.
14. Aspidosperrna
AND RELATED ALKALOIDS
465
mossambine, however, was in accord with its being a hydroxy derivative of either of the other two compounds, both of which also possess an ethylidene group. Various other chemical similarities confirmed this supposition. For example, the conjugated double bond of mossambine could be selectively reduced with zinc and acid to give 2,16-dihydromossambine (CCXXIX), a dihydroindole (UV- and low rotation) unsubstituted in the aromatic ring (NMR-), while further catalytic reduction resulted in the uptake of two hydrogen atoms and the saturation of the ethylidene side chain. Vigorous acid hydrolysis of mossambine resulted in simultaneous decarboxylation with the production of an indolenine (CCXXXI, A, 220, 262 mp) which with alkaline borohydride underwent the reverse Mannich reaction and reduction to give an indole (CCXXXII, A, 227, 283, 289 mp). This series of reactions, typical of alkaloids of the types mentioned above (19, 123, 69), show that Nh is linked to the 8-indole position through one carbon atom, the sequence being pictured : 0
n c.
H+ N,=C--CCN,
__f
€IN,-C=C
C=Nt
+ HN*--C=C
CH-N,
Furthermore, lithium aluminum hydride reduction of mossambine (CCXXVI) followed the same course as with akuammicine (68), yielding a dihydroindole (A, 245, 301 mp) with an exocyclic methylene group (CCXXXIII,v, 1640 cm-1) in which the only remaining oxygen atom was that of the original hydroxyl group. Catalytic reduction of CCXXXIII gave the C-16 methyl derivative (CCXXXIV) (121, 122). The foregoing information does not distinguish between the akuammicine and condylocarpine skeletons. This distinction may be readily made as has been seen in the case of aspidospermatidine (Section V, B) by examination of the mass spectrum of a fully reduced derivative (115a). I n fact, comparison of the spectra of tetrahydromossambine (CCXXX) and tetrahydroakuammicine (CCXXXV) revealed a very similar pattern for both (Table V), the only important difference being that the r and s peaks were 16 units higher in the case of the mossambine derivative, showing that the alcoholic oxygen atom was present in both. If the ethyl side chain of tetrahydromossambine were in the 14 position as in tetrahydrocondylocarpine (CCXX), then the s fragment would contain it. The fact that, as in tetrahydroakuammicine, it does not, limits the ethyl group to position 20, the only carbon atom absent from s which could accommodate an ethylidene group in the original mossambine. The same conclusion may be reached from the spectra of the pair CCXXXIV and CCXXXVI. These results are also supported by the spectra of derivatives which retain the 2,16- and/or 19,20 double-bond (115a).
466
B . GILBERT
The secondary hydroxyl group present in mossambine can only be placed on C-5, (2-21, or C-14, since these are the only suitable atoms in common between the fragments r and s. Positions 5 and 21 are excluded because the hydroxyl is not eliminated during borohydride, zinc and acid, or lithium aluminum hydride reduction. Position 14 for this group is in full,accord with the NMR-absorption (above) and with other mass spectral data (absence in the spectra of CCXXX and CCXXXV of OH in the homolog of indolic fragment b which contains C-5, and in the spectra of CCXXIX and CCXXXVIII in fragment u which contains C-21). Mossambine thus has structure CCXXVI (122), the stereochemistry remaining a t present undefined. The fact that mossambine is, like akuammicine, levorotatory suggests, however, that the configuration at positions 7, 3, and 15 is the same as in the latter which has been related directly to the Wieland-Gumlich aldehyde (68, 77, 123, 124). It is of interest that Nb-metho salts of mossambine sometimes exhibit a carbonyl band in the IR-spectrum (1698 cm-I), pointing to a possible Hofmann cleavage (122, 121).
C. NORFLUOROCURARINE, DIHYDROAKUAMMICINE, TUBIFOLINE, AND TUBIFOLIDINE Among the seven alkaloids that were isolated from Diplorrhyncus mossumbicensis was a base C19HzoN20 with unusually high rotation ( - 12qO"in chloroform). Its carbonyl activity and UV-spectrum (A, 242, 299, 360 mp) were reminiscent of fluorocurarine (Chapter 15, Refs. 133-137) and comparison of the methochloride of the new base with fluorocurarine demonstrated complete identity. The alkaloid is therefore norfluorocurarine (CCXL, 116, 132). Three related alkaloids have been found in the leaves of Pleiocurpa tubicina. One is the known compound 19,20-dihydroakuammicine (CCXXXVII, 70, 69, 137a), while the other two, tubifoline and tubifolidine, are respectively its decarbomethoxy derivative, the indolenine, CCXXXIX, and the corresponding dihpdroindole, CCIII (119). A compound strychene of structure CCXXXIX has been prepared from dihydrodeoxyisostrychnine (67, 125).
D. COMPACTINERVINE The bark of Aspidosperma cornpnctinervium contains an alkaloid, compactinervine, whose high negative rotation, UV- (A 237, 297, 331) and IR-spectra (conjugated COZMe, 6.04 p ; conjugated double bond,
14. Aspidosperma
AND RELATED ALKALOIDS
467
6.30 p) showed that, like mossambine, it belongs to the akuammicine class. Although solvation precluded precise analyses, a molecular ion corresponding t o the empirical formula CzoH24N204 could be obtained when the alkaloid was introduced directly into the ion source of the mass spectrometer. Thus there are two oxygen atoms to account for, besides those present in the carbomethoxyl function; and both of these were shown to be alcoholic by smooth acetylation to a diacetate (CCXLI-A). The vicinal nature of the two hydroxyls was further shown by reaction with periodate which gave acetaldehyde (125a). Several characteristic reactions of akuammicine-type alkaloids are exhibited by compactinervine (CCXLI). For example, the conjugated double bond is reduced by zinc and acid to give dihydrocompactinervine (CCXLI-B), whose mass spectrum corresponds to that of tetrahydroakuammicine (CCXXXV), the s peak a t m/e 199 indicating a C-20 side chain (see Section V, B). Furthermore, treatment with strong acid results in decarboxylation to the indolenine CCXLI-C which undergoes the reverse Mannich condensation and reduction with alkaline borohydride to an indole (CCXLI-D). Lithium aluminum hydride reduces the m$-unsaturated ester grouping of compactinervine to an exocyclic methylene derivative (CCXLI-E) analogous to the corresponding reduction product of akuammicine (cf. Section VI, B). The mass spectra of both this product (CCXLI-E) and its trideuterio analog (CCXLI-F, obtained with LiAlD4) resembled those of the corresponding two akuammicine derivatives ( 125a). From these facts it was certain that compactinervine (CCXLI)had the dihydroakuammicine skeleton and it remained to place the two hydroxyl groups. On biogenetic grounds, positions 19 and 20 are attractive, since these are oxygenated in the related alkaloids echitamidine (CCXLII, 126) and lochneridine (CCXLIII, 127). That these positions are the true ones is shown by two observations. First, the r peak in the mass spectrum of dihydrocompactinervine (CCXLI-B) appears at m/e 228, 32 units higher than in the analogous tetrahydroakuammicine (CCXXXV), while the s peak is identical in the two spectra. The two oxygen atoms responsible for this shift are thus limited t o positions 15, 18, 19, 20, and 21, the only ones present in r but absent from s (see Section VI, B). Second, compactinervine (CCXLI) shows a methyl doublet at 1.15 in the NMR-spectrum analogous t o that of echitamidine (CCXLII) and due to the grouping CH(0H)CHs(125a). An attempt to synthesize compactinervine (CCXLI) by osmium tetroxide hydroxylation of akuammicine (CCXXV) failed since the product, CCXLI-H, differed stereochemically. However, both diols, CCXLI-H and compactinervine, gave the same 19-ketone CCXLI-G on oxidation with
468
B . GILBERT
the Jones reagent, and the only stereochemical difference was therefore at C-19 (125a). The complete absolute stereochemistry of compactinervine follows from this observation, for the vic-glycol, CCXLI-H, derived from akuammicine of known absolute configuration, must have both hydroxyl groups E . The 20-hydroxyl of compactinervine is therefore a , and the 19-hydroxyl/3. The equatorial tertiary hydroxyl in position 20 is note-
C‘CSLI; Ii = H C C X L I - A ; R = Ac
CCS1,I-c
CCXL-D
14. Aspidosperrna
AND RELATED ALKALOIDS
469
worthy in that it acetylates readily, but resists dehydration, in contrast to the 20 p-axial hydroxyl of lochneridine (CCXLIII) which dehydrates on attempted acetylation (125a, 127).
VII. The Uleine Group A. INTRODUCTION Alkaloids of this group have been discovered in the genera Aspidosperma, Tabernaernontana, Excavatia, and Ochrosia ; in the first they are well distributed, uleine itself being the major alkaloid of at least eight species. Uleine represents a link between the other more highly aromatic members of the group and the condylocarpine-type bases from which it differs in the lack of the 5,6 tryptamine bridge. Wenkert has suggested a biosynthetic route for the formation of this alkaloid (115).
B. ULEINEAND RELATED ALKALOIDS Uleine (CCXLV) was first isolated from Aspidosperrna ulei (138, Volume VII, p. 129) and has since been found in a number of other species (see Table I and Refs. 140, 141, 49, 48). It has the composition C18H22N2, and contains a double bond which is readily hydrogenated to give dihydrouleine (CCXLVI), a compound with the indole chromophore. The UV-spectrum of uleine (Table 111)showed that the double bond was conjugated with the indole nucleus; the similarity of the absorption to that of diacetylallocinchonamine (CCXLVII) suggested that one end of the double bond was linked (0 the a-indolic position. The NMR-spectrum showed that the double bond lay in an exocyclic methylene group (two vinyl singlets a t 5.27 and 4.98 6, absent in the spectrum of dihydrouleine) and established the presence of four aromatic protons and an indole NH grouping (Table IV). These results were in accord with the IR-absorption (v, 3440, N H ; 1635 and 877, =CH2; 740 em-1, 0-disubstituted benzene). An N-methyl (NMR-)and a C-ethyl group (modified Kuhn-Roth, Ref. 44, and NMR-) were also found to be present (138, 142). Uleine methiodide underwent a facile Hofmann degradation t o give an optically inactive compound (CCXLVIII), which retained the two nitrogen atoms and had carbazole UV-absorption. A further Hofinann degradation eliminated N1,and gave a product (CCXLIX) with somewhat extended carbazole absorption, which underwent ready catalytic reduction with saturation of one double bond to give a substituted
470
B. GILBERT
carbazole (CCL) which could also be obtained directly from uleine or dihydrouleine by selenium dehydrogenation (138). The second Hofmann product (CCXLIX) was recognized as a vinylcarbazole by oxidative cleavage of the double bond with osmium tetroxide and then periodate,
cCSL\-l
CCSLVlIl
I CCXLVII
\
CCXLlS
CCL
CCLIV
2,3-saturated
I CCLV 1. LIIS04 2. estcrification
CCLl
('CLII
CCLVI; R = H CCLVII; R = Ale
which gave a yellow aldehyde (CCLI) (v, CO, 1675 cm-1; NMR, CHO, 10.72 6). Comparison of the UV-spectrum of this aldehyde with those of 1-, 2 , 3-, and 4-formylcarbazole (143) left no doubt that it was a 2formylcarbazole. Furthermore, the NMR spectrum of CCLI showed the
14. Aspidosperma
AND RELATED ALKALOI1)S
47 1
presence of five aromatic protons, an aromatic methyl (2.75 S), and an aromatic ethyl group (quartet at 3.15 6, triplet a t 1.35 a), these two substituents occupying two of the remaining three positions ‘in the carbazole C ring. The location of the methyl group is clearly position 1 since it derives from the original exocyclic methylene group, and that of the ethyl substituent follows from the NMR spectrum of uleine itself which exhibits a one proton doublet a t 4.07 6 (J = 2 c/sec) which must be both “allylic ” and next to nitrogen (compare condylocarpine, Section v , C) and have only one neighboring proton, a requirement compatible only with strucure CCXLV for uleine and hence structure CCLI for the aldehyde (142). The structure of CCLI was confirmed by decarbonylation to l-methyl3-ethylcarbazole (CCLII) which was synthesized as follows. Ethyl 2-oxalylbutyrate and the Mannich base, ethyl-p-dimethylaminoethyl ketone condensed t o the cyclohexenone, CCLIII, which was reduced with zinc to CCLIV. The Fischer indole synthesis was then applied to this ketone and led via the phenylhydrazone, CCLV, to the tetrahydrocarbazole carboxylic acid, CCLVI, whose methyl ester, CCLVII, was dehydrogenated over palladium charcoal to 1-methyl-3-ethylcarbazole (CCLII) identical with the degradation product. The chemistry of uleine (CCXLV) parallels that of gramine, and the methiodide (CCLVII-D) suffers facile nucleophilic attack a t the benzylic 4-position with cleavage of the C-4-N bond. Thus with methoxide
m/e209 R = H m/e223 R = Me
m/e 180
m/e222 R = E t m/e 207 R = CH2’
m/e208 m/e 194
m/e 237
Principal mass spectral fragments from uleine (CCXLV)
R = Me R =H
CCLVII-D
CCLVII-A
CCXLV; R CCXLVI; R CCLVII-P; R CCLVII-B; R CCLVII-C; R CCLVII-Q; R
= Me = Me, 1,l‘-dihydro = Me, 1,l’-dideuterio
=H = AC = Et
c R =H R = Me
td
J
t
m/e 209 m/e 223
Ri
CCXLVIII; R = Me CCLVII-J; R = AC CCLVII-K; R = H
CCLVII-E CCLVII-L CCLVII-F CCLVII-M CCLVII-G CCLVII-N CCLVII-H CCLVII-I CCLVII-0
H
Ri
Rz
OM0 OM0
Me
CN
CN H H-
Me,1,l’-dihydro
Me Me, 1,l’-dihydro Me Me, 1,l’-dihydro
( -;>
Ac
OMe OMe
Ac Ac, 1,l’-dihydro
L/
14. Aspidosperma AND
RELATED ALKALOIDS
473
ion, cyanide ion, and lithium aluminum hydride the tetrahydrocarbazoles, CCLVII-E, CCLVII-F, and CCLVII-G, respectively, are obtained. The 4-methoxy-compound, CCLVII-E, readily loses methanol to give the same carbazole (CCXLVIII) as is obtained by Hofmann degradation of uleine. A similar nucleophilic attack a t position 4 results in the formation of the pyridinium salt, CCLVII-H, in which the pyridinium group can be readily displaced by methoxyl (warm methanol), the resulting 4-methoxytetrahydrocarbazole, CCLVII-I, being readily converted via CCLVII-J and -K to the above carbazole, CCXLVIII (143a). Lithium aluminum hydride reduction of uleine (CCXLV) gives dihydrouleine (CCXLVI), for which reaction a possible mechanism has been proposed ( 143a). Dihydrouleine methiodide behaves toward nucleophilic reagents similarly to uleine methiodide and the corresponding series of tetrahydrocarbazoles, CCLVII-L, CCLVII-MI, and CCLVII-N, have been prepared. The reaction of dihydrouleine with acetic anhydride and pyridine followed by methoxide also parallels that of uleine with the formation of CCLVII-0 (143a). Prom an examination of the mass spectra of uleine, dihydro- and dideuteriouleine (CCLVII-P, LiAlD4 on uleine), and the N-acetyl (CCLVII-C) and N-ethyl analogs (CCLVII-Q, LiAlH4 on CCLVII-C) of uleine much information has been accumulated on the probable breakdown path of these alkaloids in the mass spectrometer (see formulas). An important intermediate species is undoubtedly the carbazole, CCLVII-K, whose mass spectrum is practically identical with that of the isomeric uleine (143a).
CCLVIL-U
Among compounds related to uleine that have been isolated from A . dasycarpon are N-noruleine (CCLVII-B),dasycarpidone (CCLVII-A), the corresponding alcohol, dasycarpidol, N-nordasycarpidone, and 1 , l ’ dihydro- 1’-hydroxyuleine. Dasycarpidone may be obtained from uleine by ozonolysis, or from dasycarpidol by oxidation with chromium trioxide in pyridine. 1,1’-Dihydro-1’-hydroxyuleine has been synthesized from uleine by hydroboration (143b). Apparicine, an alkaloid of novel skeleton present in A . dasycarpon and several other species, has been shown t o have the structure CCLVII-U (37).
474
B. OILBEBT
C. OLIVACINE,DIHYDROOLIVACINE, AND GUATAMBUINE The yellow optically inactive alkaloid olivacine (CCLVIII) was first isolated from Aspidosperma olivaceum ( 140)and has subsequently been encountered in many Aspidosperma species (Table I,Refs. 141, 145,147, 48) as well as in Tubernuemontana psychotrifolia H.B.K. (148). Its empirical formula, C17H14N2, and complex UV-spectrum indicated a highly aromatic structure ; the alteration of UV-absorption in acid showed that the basic nitrogen atom was involved in the chromophore (140,149).Olivacine methiodide gave a red anhydronium base (CCLIX) with alkali (145).Meanwhile, another base, guatambuine (U-alkaloid-C, CCLX), C18H20N2, which had first been found in A. ulei (139)and which is present in several species often side by side with olivacine (Table I), was shown to be the N-methyltetrahydro derivative of olivacine both by dehydrogenation of the optically active base and by reduction of olivacine methiodide catalytically or with borohydride to racemic guatambuine (141,149).Guatambuine, remarkable in that both enantiomers have been encountered in the same species (147),is a much stronger base than olivacine (Table V I ) and has carbazole UV-absorption, the identity of the acid and neutral spectra showing that the reduced ring was that containing N1,which was now no longer linked to the chromophore. Analogy with ellipticine (Section VII, D) and comparison of the pKi and UV-spectroscopic data of a number of pyridocarbazoles then (151,152) demonstrated that olivacine was a lOH-pyrido-4,3-b-carbazole and led to the proposal of structure CCLVIII for this alkaloid and hence CCLX for guatambuine (149,153). The correctness of these proposals was readily shown by Hofmann degradation of guatambuine to CCLXI and thence to the same series, CCXLVIII, CCXLIX, and CCL, which had resulted from the degradation of uleine (Section VII, B). Alternative proof of the structure of olivacine was obtained by two syntheses. I n the first of these (150) the starting material, 2-amino-6cyanotoluene, represented ring C, and after transformation to the corresponding phenylhydrazine (CCLXII), rings A and B were built on by a Fischer (Borsche) indole synthesis to give the 2-cyano-1-methyl5,6,7,8-tetrahydrocarbazole(CCLXIII). Difficulty with the dehydrogenation of this compound led to its conversion to the corresponding ester (CCLXV) which smoothly dehydrogenated to the carbazole ester, CCLXVI, in which the carbomethoxyl group provides the starting point for building up ring D. The best method of homologation of the ester was found to be the Arndt-Eistert synthesis via the acid chloride, CCLXVIII, and diazoketone, CCLXIX, to the amide, CCLXX. This amide was then (CCLXXII) by transformed to 2-(~-aminoethyl)-~-methylcarbazole
CCLVIIl
CCLXXIV
I <
CCL XXIII IIofmann II
CHzCHzNHCOCH3
T
2.
CCLXI CCLXX
I .1
CCLXIX
C CX LI X CCLXVIII CCL
I
II
CHzCHzC. CHI
C C LX X X l I
CHzCHzCOCH3
C C LX X X I
CHzCONHz
1.
CCXLVIII
NOH CCLXXXlll
T
H2, I’d-C
CH=CHCOCH3
4
MepC10, KOH
CCLXXX
CHO
C C LX X I X
CH3
COCHNz
t
I
COCl
T
SOCh, DMF
I
CCLXVIl
COzH
CCLXVI
COZEt
Me I C CLX I I
CCLXIII; R = CN CCLXIV; R = COzH CCLXV: R = COpEt
/I
t-
Ed,
CsHs
T
CCLXXV; R = Hz CCLXXVI; R = =CHOH CCLXXVII: R = =CHOPri
475
y
C C LX X V I I I
476
B. GILBERT
dehydration and hydrogenation of the intermediate cyanide, and thence into dihydroolivacine (CCLXXIV) by a Zischler-Napieralski ring closure of the N-acetyl derivative (CCLXXIII). Dehydrogenation of CCLXXIV gave olivacine (150).The second synthesis ( 154)began with the known l-keto-1,2,3,4-tetrahydrocarbazole (CCLXXV) in which rings A, B, and C are ready-formed. The initial atom of ring D was best introduced as a hydroxymethylene group a t position 2 by base-catalyzed condensation with ethyl formate. The hydroxymethylene group of CCLXXVI was then protected as its isopropyl ether (CCLXXVII) while a methyl group was introduced a t position 1 by reaction of the ketonic carbonyl with methyl lithium; loss of water and the protecting group gave the dihydrocarbazole aldehyde, CCLXXVIII. The aldehyde could be very readily dehydrogenated (with disproportionation and simultaneous production of CCLXXIX)to the carbazole aldehyde, CCLXXX. The building up of ring D was now achieved by a route quite different from that of the previous synthesis. Condensation of the aldehyde, CCLXXX, with acetone gave the a,P-unsaturated ketone, CCLXXXI, which was catalytically reduced and transformed to the oxime, CCLXXXIII. This oxime was subjected to a simultaneous Beckmann rearrangement and Bischler-Napieralski condensation to give dihydroolivacine which was dehydrogenated as before to olivacine itself (154). These two syntheses also constitute syntheses of racemic guatambuine. This alkaloid (CCLX) was also obtained by catalytic reduction of the methiodide of dihydroolivacine (CCLXXIV) (150). I n addition, the preparation of N-demethylguatambuine was described (150),as well as alternative routes to the aldehyde (CCLXXX) and corresponding acid (CCLXVII) (154).Dihydroolivacine occurs naturally in A . ulei and may be separated from the accompanying dihydroellipticine (Section VII, D) by thin layer chromatography (155,,139,149,150).Compounds with this chromophore may be recognized by the appearance of a new intense absorption peak in their acid UV-spectra a t approximately 377 nip as well as strong absorption in the IR-spectrum between 6 and 7 p (139, 149,150, 158). Recent investigation of Aspidosperma nigricans has resulted in the isolation of olivacine N-oxide (CCLXXXIII-A).This somewhat unstable compound may be reduced to olivacine (CCLVIII) by brief treatment with zinc and mineral acid. The N-oxide (CCLXXXIII-A) may be prepared from olivacine by perbenzoic oxidation. It is also the initial product of the action of hydrogen peroxide in warm acetic acid on olivacine, a reaction which yields as one of its final products the red isomeric amide, 2-oxo-2,3 dihydroolivacine (CCLXXXIII-B). The N oxide may be distinguished from the latter not only by its UV-spectrum
14. Aspidosperma
477
AND RELATED ALKALOIDS
(A,, 236,252,300,311,330,and 345 m p ; E, 16350, 14280,51490,65420, 5420, 5300) which differs little from that of olivacine, but also by the mass spectrum in which the base peak a t M-16 (m/e 246) corresponds to loss of one oxygen atom from the molecular ion to give a positively charged olivacine molecule-ion (48). Me A - A , H \ N H
Me I
Me
CCLXXXIII-A
CCLXXXIII-B
D. ELLIPTICINE, DIHYDROELLIPTIC~NE, AND N-METHYLTETRAHYDROELLIPTICINE Ellipticine (CCLXXXIV) was first isolated from Ochrosia elliptica and 0. sandwicensis A.DC. (156) and subsequently from Aspidosperrna subincanurn (see note 3, Table I) (157, 158) as well as from other plants (Table I, Ref. 161). I t s UV-spectrum is complex and very similar to that
of olivacine (CCLVIII), and reduction of its methiodide with borohydrid2 gave A'-methyltetrahydroellipticine (CCLXXXV) ( 156) which had been previously isolated from A . ulei (U-alkaloid-B, 139) and also from A . subincanurn. Natural N-methyltetrahydroellipticinewas optically inactive and exhibited a carbazole UV-spectrum which, like that of the optically active guatambuine (CCLX), was unaffected by acid, thus showing that the basic nitrogen atom lay in a reduced ring and was insulated from tkie carbazole chromophore (139). The structure of ellipticine and hence of its tetrahydro derivative was established by a remarkable three-step synthesis from indole. Condensation with 3-acetylpyridine in the presence of zinc chloride gave the bisind olylpyridylethane (CCLXXXVI) in which i t remains only to form the C ring. Reductive acetylation of the pyridine ring with zinc and acetic anhydride yielded the N,C-diacetyldihydropyridine derivative (CCLXXXVII, A, CO, 5.80, 6.05 p ) in which the remaining two carbon atoms of ring C have been introduced. Pyrolysis of CCLXXXVII gave ellipticine (CCLXXXIV) in 2% yield (157). The result was confirmed by a second synthesis. The dimethylated C ring was built onto indole by condensation of hexane-2,5-dione with the reactive indolic 2,3 positions. Formylation of the resulting 1,4-dimethylcarbazole (CCLXXXVIII)with N-methylformanilide proceeded preferentially in the 3-position to give the aldehyde CCLXXXIX whose
47 8 B. GILBERT
0
\
J-Jx
G x
V v
1
Zn,AcaO
T
Ha, N :
Me I
CCLXXXVI
Me I
CCLXXXVIII
ccxc
T
Me
CCLXXXIX
T structure was established by Wolff-Kishner reduction to 1,3,4-trimethylcarbazole. Condensation of CCLXXXIX with 2,2-diethoxyethylamine gave the Schiff’s base (CCXC) and, although this compound resisted attempts a t cyclization, its dihydro derivative (CCXCI)was successfully cyclized and dehydrogenated to ellipticine (CCLXXXIV) (159, 160). An independent synthesis of ellipticine follows, in its initial stages, the first olivacine synthesis reported in Section VTI, C. Instead of the monomethylcyanophenylhydrazine (CCLXII), a corresponding dimethyl compound, 3-cyano-2,5-dimethylphenylhydrazine (CCXCI-A), was employed as starting material. As far as the ester, methyl 1,kdimethylcarbazole-2-carboxylate (CCXCI-B), the two syntheses are parailel. Ring D was then built up, however, by the series of reactions, COzMe
CHzOH
+CHO
___f
-CH=CH-NOz
--+
CHzCHzNHz
The final ring closure again paralleled the olivacine synthesis passing through the intermediate N-formyl rather than the N-acetyl, amine, to give 1,2-dihydroellipticine (CCXCIII) from which ellipticine was obtained by palladium dehydrogenation (16Oa). When the tertiary bases had been removed from the extract of Peruvian A . subincanum, the quaternary bases were extracted with butanol and crystallized as their nitrates. Two salts were separated by preparative paper chromatography, and one of these was recognized as ellipticine methonitrate. The second had a UV-spectrum similar to that of the 1,%dihydropyridocarbazole [e.g., 1,2-dihydroolivacine (CCLXXIV), Section VII, C] chromophore in acid solution. Furthermore, reduction with sodium borohydride gave N-methyltetrahydroellipticine (CCLXXXV). The second quaternary alkaloid was thus N-methyl-l,2-dihydroellipticine (CCXCII) in the form of its nitrate; this was confirmed by oxidation of the tetrahydro compound (CCLXXXV) with mercuric acetate and acidification with nitric acid to give the same salt. The corresponding tertiary base (CCXCIII) was also isolated and its structure confirmed both by conversion into the quaternary methochloride (CCXCII chloride) and by synthesis from ellipticine by reduction to the air-sensitive tetrahydroellipticine (CCXCIV) which gave 1,2-dihydroeIlipticine by dehydrogenation with 0,lO-phenanthraquinone (158). Dihydroellipticine (CCXCIII) was first encountered admixed with dihydroolivacine in A . uZei (U-alkaloid-D, 139, 155). Among other alkaloids of Ochrosia species there has been isolated a methoxyellipticine (156, 161).
Me
Me
CCXCI-A
Me
I
1. KOH/glycol
2. CHeNz
1. EtOCHO, 120'
i
2. POCIS, xylene
ccxcIII
CCXCI-B
482
33. GILBERT
VIII. Tetrahydro f3-Carboline and Related Alkaloids A. YOHIMBINE AND TETRAHYDROALSTONINE DERIVATIVES A number of these alkaloids, which are widely encountered in the family Rubiaceae and in the genus RauwolJa of the family Apocynaceae, have also been found in the genera under discussion. The occurrence of yohimbine (CCXCV),,L?-yohimbine(CCXCVI), and reserpine (CCXCVII) is recorded in Table I . I n addition, an 1l-methoxyyohimbine (CCXCVIII) has been isolated from Aspidosperma oblongum and its structure determined by mass and UV-spectrometry (see below, and Ref. 162). An alkaloid, poweridine, formulated as 17-0-acetyl-1l-methoxyyohimbine (CCXCIX), occurs in Ochrosia poweri and was shown to belong t o the yohimbine class by dehydrogenation to 7-hydroxyyobyrine (CCC)whose formation, together with the UV-spectrum of poweridine, establishes the position of the original methoxyl group. The preparation of a ,L?-lactone (CCCII, v, CO, 1803 cm-1) by dehydration of the 11-methoxyyohimbic acid (CCCI) from poweridine indicated that the hydroxyl and carbomethoxyl groups of this acid were vicinal and cis. The remainder of the stereochemistry remains a t present unknown (161). Among the yohimbine-like alkaloids with a heterocyclic ring E the most widespread is isoreserpiline (CCCV) whose methochloride has also been &countered. The occurrence of this alkaloid and of aricine (CCCIII), reserpinine (CCCIV),reserpiline (CCCLVI), and ajmalicine (CCCXVII), is recorded in Table I. A 5,6-dimethoxyindole related to isoreserpiline is elliptamine which occurs in four Ochrosia species as well as in Excavatia coccinea (161). A representative of the group in which ring E is open is dihydrocorynantheol (CCCVI), which occurs in two Aspidosperma species (163, 48). The methochloride of this compound has been isolated from Hunteria eburnea ( 164). 10-Methoxydihydrocorynantheol(CCCVIA) and a 19,20-dehydro derivative (CCCVI-B) have also been encountered in Aspidosperma discolor (113d) and other Aspidosperma species (48). Alkaloids which could be identical with CCCVI, CCCVI-A, and CCCVI-B as well as a dehydro derivative of CCCVI and a series of four similar bases bearing a 16-carbomethoxyl group have been found in A . oblongum (164a). The identification of alkaloids of this type has been greatly facilitated by the introduction of mass spectrometry (165,162,163).By examination of a large number of derivatives, the breakdown pattern has been established, the principal peaks being represented by the fragments v and w which are formed by a cyclic transfer of electrons in ring D
OR3
Ri Rz R3 R4 Stereochemistry CCXCV H Me H H Y CCXCVI H Me H H P-y CCXCVII OMe Me Me OTMB 3-epi-a-Y CCXCVIII OMe Me H H unknown CCXCIX OMe Me Ac H unknown CCCI OMe H H H unknown Stereochemistry (substituent or angular H ) : Y = 3a,15a,l6a,17a,20P. /3-Y = 3~t,15a,16~(,17P,20/3. 3-epi-a-Y = 3/3,15a,16/3,17a,1813,ZO~t.
ai Q
0
ccc
CCCII
.U
bH20H
Ri CCCVI; R = H CCCVI-A; R = OMe* CCCVI-B; R = OMe, 19,20-dehydro*
* Stereochemistry unknown.
Rz
CCCIlI OMe H CCCIV H OMe CCCV OMe OMe
$
z1
484
B. GILBERT
(CCXCV,p. 486). These fragments are accompanied bv x and y (reverse Diels-Alder cleavage of ring C, formula CCCXVI) and all these four peaks occur in all yohimbine-type alkaloids whether ring E is homocyclic, heterocyclic, or open (165, 163). I n addition, there is always present in the mass spectra of this group a strong M-1 peak which is largely formed by the loss of the C-3 hydrogen atom. I n the heterocyclic ring E alkaloids, there is an additional indolic peak which has been assigned structure z (165).The described combination of peaks is not found in indole alkaloids based on the sarpagine, ibogamine, or eburnamine skeletons which each furnish a distinctive pattern (166, 167, 168, 169, 170, 51). The structures assigned to the fragments observed are based on the following evidence (165, 171). 1. The M - 1 Peak:
Fifty per cent of the M-1 peak is found a t M-2 in the spectra of 3-deuterioyohimbine (CCCVII, prepared by NaBD4 reduction of 3,4-dehydroyohimbine perchlorate) and of 3,5,6-trideuterioajmalicine (CCCIX, prepared by NaBD4 reduction of serpentine hydrochloride), so that onehslf of the hydrogen lost in the formation of this peak comes from C-3 or, in the case of ajmalicine, from C-3 and C-6. 2. Peaks v, w,x, and y Incorporate the Indolic Portion of the Molecule These four peaks remain invariable a t m/e 170, 169, 184, and 156 respectively when alterations are made in ring E as in the series, CCXCV, CCCX, CCCXI, CCCXII, and CCCXIII, and they do- not therefore contain atoms from this ring. The addition of substituents at positions 1, 3, 10, and 11 results in a corresponding increment in the mass of these fragments as is seen in the spectra of CCCXIV, CCCXV, and CCCVII (Table V). The importance of these peaks is explained by the ready cleavage of the allylically activated 3,14 bond.
3. The Structure of Peaks v and w Peak v, already shown to contain the indole residue, contains in addition carbon atoms 3,5, and 6, for in the spectrum of 3,5,6-trideuterioajmalicine (CCCIX) all three deuterium atoms are retained in this fragment. I n the spectrum of 3,14-dideuterioajmalicine (CCCVIII),prepared from serpentine by the successive action of NaBH4, HC1, and NaBD4, however, only one deuterium atom is retained in v which therefore does not contain C-14. Fragment w is derived from v by loss of one hydrogen from either C-5 or C-6 and this is shown by the fact that in the spectrum of 3,5,6-trideuterioajmalicine (CCCIX) w is split into two peaks, one in which one, and one in which two deuterium atoms have been retained.
14. Aspidosperma
AND RELATED ALKALOIDS
485
As the C-3 atom is always retained, the partial loss must occur from C-5 or C-6, which would seem t o indicate that there is no preference for the loss of deuterium over hydrogen in this case (compare 19-deuterio-17methoxyquebrachamine, Section 11, B). 4. The Xtructure of Fragment x I n the spectrum of 3,5,6-trideuterioajmalicine(CCCIX), all three deuterium atoms are retained, but in that of 3,14-dideuterioajmalicine (CCCVIII) only one deuterium atom appears in x. This fragment must therefore contain C-21 since it cannot contain C-14. 5. The Structure of Fragment y C-3 is present in this fragment (2 above) and from the spectrum of 3,14-dideuterioajmalicine (CCCVIII) it is seen that C-14 is also incorporated. Fragment y only retains two of the deuterium atoms of 3,5,6trideuterioajmalicine and therefore cannot contain (3-5. F'ragment y represents the strongest indolic peak in the spectra of the hetero ring E alkaloids because in these the 14,15 bond in the intermediate aa is doubly allylieally activated. The spectra may be used to distinguish the two most common stereochemical forms, those of ajmalicine (CCCXVII) and tetrahydroalstonine (CCCXVIII), since in the former the peak x is more intense than w or w, while in the latter and in yohimbine it is weaker. Examples are seen in the spectra of CCCIII-CCCV and CCCXVII-CCCXIX (Table V. Refs. 165, 37). B.
NORMACUSINE-B,
POLYNEURIDINE, AND AKUAMMIDINE
Notmacusine-B was first obtained by the thermal decomposition of its quaternary methochloride, macusine-B, which was isolated from Strychnos toxifera." It was found to be identical with 10-deoxysarpagine (CCCXX) and its N,-methyldihydro derivative was identical with deoxyisoajmalol-B (CCCXXIII) (172, 173), thus establishing its structure and absolute stereochemistry (177, see Chapter 22). Subsequently, normacusine-B has been found in Diplorrhyncus mossambicensis (named tombozine, 116, 121, 122) and in Aspidosperma polyneuron (165). Another alkaloid of A. polyneuron, polyneuridine, C21H24N203, differs from normacusine-B by C02CH2. It contains a carbomethoxyl group as was shown by hydrolysis to the acid, CCCXXIV, which was
* Maciisine-R also occurs in A . polyneuron (173a).
I
Rz
Rz
Rz
2,
w
X
R4 Ri CCXCV H CCCX H CCCXI H CCCXII H CCCXIII H CCCXIV OMe CCCXV H
Rz Rs
R4
H COzMe OH H COzMe H H H =o H =O H H COzMe =O H H =O Me H H
Ri
Stereochemistry
Y a-Y allo-Y
Y
Y
H R3
Y
R1 Rz R3 R4 CCCVII H CCCVIII H CCCIX D
H H D
D D D
H D H
Ri CCCXVII H CCCXVIII H CCCXIX H CCCIV H CCCIII OMe cccv OMe
Rz H H OMe OMe H OMe
Stereochemistry A T A T T T
Stereochemistry (substituent OT angular H ) : Y = 3a. 15a, 16e, 17a, 208. a-Y = 3a, 15a, 168, (17a), 20a. d o - Y = 3a, 15a, (168, 17/3), 20a. A z a 3a, 15a, 19a, 208. T = 3a, 15a, 19a, 20a.
488
2
P;
0,
\
/
U
P Y
\
/
xEr
B . GILBERT
t
RI R2 R3 CCCXXIV H CHzOH CO2H CCCXXV H CH~OAC CO2Me CCCXXXVI Me CHzOH COsMe HOCH2,
CCCXX; R =H CCCXXVIII; R = Ac
CCCXXXII
,C02Me
R3,
COOMe
I CCCXXXVIII
I
cccxxxv11 CCCXXIII CCCXXIX CCCXXXIV CCUXXXV
bb
m/e 168
tu
m/e 169
cc
m/e249
I
Ri R2 Me H H H H Me OMe H
R3 H CHzOH H H
* 2O.m-Et;t 20,P-Et
dd rnle223
R4 CHzOH* C02Me Met Me
490
B. GILBERT
isolated as the hydrochloride and remethylated to the parent alkaloid. Polyneuridine also formed a mono-0-acetate (CCCXXV), demonstrating the presence of an alcoholic hydroxyl group. The possibility thus existed that polyneuridine was a carboinethoxy derivative of normacusine-B and this was supported by lithium aluminum hydride reduction to the diol, CCCXXVI, whose diacetate, CCCXXVII. was sufficiently soluble in deuteriochloroform for NMR-spectroscopic comparison with the monoacetate (CCCXXVIII) of normacusine-B. In fact a strong similarity was observed, the only major difference between the two spectra being the presence in that of CCCXXVII of absorption due to two acetate methyl groups (1.92 and 2.03 6) and to four protons corresponding to two CHzOAc groups while normacusine-B acetate showed absorption due to only one such group. The four aromatic protons, indole NH, and ethylidene group of normacusine-B were all also present in polyneuridine, the latter being confirmed by hydrogenation to dihydropolyneuridine (CCCXXIX). Meanwhile, comparison of the mass spectra of polyneuridine and normacusine-B had also revealed a strong similarity between the two alkaloids. Both exhibited M-31 peaks, and as this is only attributable to loss of the primary alcoholic function as CHzOH in normacusine-B, it was reasonable to assume the presence of such a grouping in polyneuridine. Moreover, both spectra contained intense peaks a t m/e 168 and 169 which remained invariable through a series of derivatives in which the carbomethoxyl group of polyneuridine and the alcoholic function and double bond of both alkaloids were modified. These P-carbolinic peaks compare with the v and w peaks of the yohimbine-type molecules which occur a t m/e 170 and 169, respectively, when the aromatic ring is unsubstituted. The lowering of one mass unit in each is attributable to the presence of the extra 5,16 bond which must be broken to produce the P-carboline fragments bb and w. These fragments are observed in sarpagine-type molecules (e.g., CCCXXXIV and CCCXXXV) substituted in the aromatic ring and on N, when the appropriate molecular weight shifts are observed (167), so that there is no doubt that they derive from the indolic part of the molecule (Table V). It was therefore assumed that polyneuridine (CCCXXI) possessed a sarpagine skeleton both the carbomethoxyl and primary alcoholic groupings being located on the C-16 atom, a supposition which was supported by the fact that the aldehyde (CCCXXIX-A) prepared by chromic acid oxidation of polyneuridine contained no a-hydrogen atom (failure to exchange with sodium deuteroxide in deuteromethanol), and by the recognition in the mass spectra of a fragment cc in which the two substituent)s and one skeletal carbon atom are missing (165, 165a, b).
14. Aspidosperrna
AND RELATED ALKALOIDS
491
Confirmation of the proposed structure was obtained by comparison with the isomeric alkaloid akuammidine (CCCXXII), which occurs in Picralima nitida (Volume VII, p. 122) and Rhazia stricta (named rhazine, 62), and whose structure has been established both chemically (174) and by X-ray diffraction (175). Both alkaloids undergo retroaldolization with loss of the primary alcohol group to an ester (CCCXXX or CCCXXXI) which, on lithium aluminum hydride reduction, furnishes normacusine-B (CCCXX) (174, 165). Also both alkaloids similarly reduced yield the same diol, akuammidinol (CCCXXVI).Thus, the structure CCCXXI for polyneuridine was established, including the absolute configuration of the skeleton (165). The orientation of the two C-16 substituents was established in two ways. First, the degradation of vincamedine (CCCXXXII) by chromic acid oxidation to the indolenine CCCXXXIII led, by way of the reverse Mannich condensation and reduction with alkaline borohydride (compare Sections 11, B, 0 and VI, B), to polyneuridine (CCCXXI) which cannot therefore have the alternative configuration (176). Second, the establishment of the C-16 orientation in akuammidine (175)required the structure CCCXXI for polyneuridine by difference. Polyneuridine is thus "normacusine-A," the tertiary base corresponding to the quaternary methochloride macusine-A which occurs in S . toxifera (173), and whose structure has been established by X-ray diffraction (178). Its N,-methyl derivative is the alkaloid voachalotine (CCCXXXVI) which occurs in Voacanga chalotiana (179, 176). The C-18 methyl group lies trans to the 20-21 bond (175, 178, see formulaCCCXXXVI1) as is also the case withechitamine,(CCCXXXVIII) and those alkaloids of the akuammicine type that have been related to the Wieland-Gumlich aldehyde (Chapter 7). It will be noted that polyneuridine is one member of a closely related group of alkaloids, which includes not only vincamedine and echitamine but also akuammine (CCCXXXVIII-A), #-akuammigine (CCCXXXVIII-B) (184a, b), picraline (179a, e), and quebrachidine (CCCXXXVIII-D, see following section). C.
QUEBRACHIDINE
A wide variety of alkaloids has been encountered in the bark of Aspidosperma puebrachoblanco (see Table I). An investigation of the leaf alkaloids yielded a new base, quebrachidine (CCCXXXVIII-D, 179b), whose UV- ( h 242, 290) and NMR-spectra were indicative of a dihydroindole unsubstituted in the benzene ring, while the IR-spectrum showed the presence also of the groupings NH, OH, and C02R. The NMRspectrum further indicated that the ester was a carbomethoxyl group
CCCXSXIX
Ri
CCCXXXVIII-A; R = OH CCCXXXVJII-B; R = H
\
Ri Rz CCCXXXVJII-E Ac Ac CCCXXXVIII-F CHO CHO CCCx xx I I Me Ac
8
-
;;:; IH N H' i ;
oTqz tj
W M
%
H
\
CCCXXXVTIJ-D
\
CCCXXI
14. Aspidosperma
T
X
Y
403
F-
d x 0
AND RELATED ALKALOIDS
/ II I1
X 4 SIX
Y Y U
+x
55 xx xx xx
88 vv
494
B. GILBERT
(3.6 6) and that there was an ethylidine group present (three protons at 1.5 6, doublet; one proton a t 5.1 6, quartet, J = 6.5 clsec). A second basic nitrogen atom was indicated by the pKi 6.7. Quebrachidine formed an N,O-diacetate (OAc, v, 1745 cm-1, 3-proton singlet, 1.72 6 ; N-Ac, V , 1658 cm-I, 3-proton singlet, 2.45 6) whose UV-spectrum (A 250) showed that the dihydroindole nitrogen had been acetylated. A comparison of the NMR-spectra of the parent base and the diacetate showed that the former was a secondary alcohol since a single proton peak due to CHOH was shifted downfield by 2 ppm in the acetate. The nature of the skeletal structure of the alkaloid became clear from a comparison of the mass spectra of the base and particularly of its diacetate with that of vincamedine (CCCXXXII). Quebrachidine itself shows a molecular ion peak at m/e 352 establishing the molecular formula, C~lH24N203,while indolic peaks appear at m/e 130 and 143 confirmatory of the unsubstituted dihydroindole structure. Of special interest however is the parallel fragmentation of quebrachidine (CCCXXXVIII-D), quebrachidine diacetate (CCCXXXVIII-E), and vincamedine (CCCXXXII, Table V) which shows that all three have the same alicyclic skeleton. The fragmentation of this skeleton appears to involve as a principal process the rupture of the 2-3 and 5-6 bonds with the production of two fragments, either of which may bear the positive charge. Thus, for quebrachidine the indolic peak b at m/e 130 is accompanied by a peak, p p , at M-130. The diacetate also shows b at m/e 130 (N,-acetyl is lost as ketene) and p p a t M-(130+42). I n the case of vincamedine, the b peak is observed at m/e 144 due to the presence of an N,-methyl group, while p p appears at M-144. The peak p p thus represents that part of the molecule not present in fragment 6 , and in conformity with this is accompanied by satellites qq and w at mle values corresponding to the loss of acetyl (pp-42)and further loss of methanol (qq-32; or for quebrachidine, pp-32) (179b). Further confirmation of the structure (CCCXXXVIII-D) for quebrachidine was obtained by opening the five-membered ring by lead tetraacetate oxidation to an indolenine and reverse Mannich cleavage and reduction with borohydride. As in the case of vincamedine (Section VIII, B), the product was polyneuridine (CCCXXI). A similar oxidation of the product CCCXXXVIII-G (obtained from quebrachidine by successive formylation to CCCXXXVIII-F, and LiAlH4 reduction) gave by direct reverse Mannich cleavage the aldehyde CCCXXXVIII-I whose mass spectrum showed i t to have the same skeleton as deoxyajmalal-A (CCCXXXVIII-J). Morevoer, the diol CCCXXXVIII-G gave a monoacetate (CCCXXXVIII-H) identical with that obtained by reduction and acetylation of vincamedine (CCCXXXII, 179c).
14. Aspidosperma AND RELATED ALKALOIDS
495
Knowledge was still lacking of the stereochemistry at C-2 and C-17. A comparison of the mass spectra (cf. 179d) of ajmaline (CCCXXXVIII-K) and tetraphyllicine (CCCXXXVIII-L), which have @-H, with that of quebrachidine showed differences, although ajmaline shows peaks corresponding t o the expected b, b + 13, and p p fragments. A very close resemblance was observed between the spectra of quebrachidine and 2-epi-21-deoxyajmaline (CCCXXXVIII-M) and it may be assumed that the former has C-2, a-H (179b). The secondary hydroxyl group a t C-17 is cis to the carbomethoxyl function, as in ajmaline, since the diol, CCCXXXVIII-G, forms an isopropylidene derivative (CCCXXXVIII-N) impossible for the reverse configuration.
D. HARMAN-3-CARBOXYLIC ACID Among the water-soluble bases of Aspidosperma polyneuron there has been isolated an ester which after methanolysis yielded the known compound 3-carbomethoxyharman (CCCXXXIX) which was recognized by its NMR- and mass spectra (180, 181, Tables I V and V). The natural alkaloid is presumably a glycosidic ester of the corresponding acid.
E. EBURNAMINE AND RELATED ALKALOIDS The known alkaloids eburnamine (CCCXL),eburnamonine (CCCXLII), eburnamenine (CCCXLIII), and possibly isoeburnamine (CCCXLI) have been isolated from plants of the genera Pleiocarpa, Aspidosperma, and Rhaxia (Table I, Refs. 91, 53, 28, 51). These alkaloids were first discovered in Hunteria eburnea (Chapter 11)and their structures (183) and stereochemistry ( 183a) determined. Related alkaloids occur in the genus Vinca (184, 78, 170) and in both this genus and in Aspidosperma their identification in minute quantities has been made possible by mass spectrometry (51, 170) in which the breakdown path has been elucidated by isotopic replacement ( 5 1). The main fragments produced from eburnamenine (CCCXLIII) probably have the structures shown in the formulas ee, ff, and g g ; the fact that it is ring E that survives in these fragments is shown conclusively by the spectra of 14-deuterioeburnamenine (CCCXLIV), dihydroeburnamenine (CCCXLV), and 14-deuteriodihydroeburnamenine (CCCXLVI) in which each of the peaks suffers progressive increments of one mass unit. Peak gg is weak in the spectrum of eburnamonine (CCCXLII) in which another peak, hh, appears, derived from ff by the loss of 28 units. When the carbonyl
CCCXL
CCCXLV
CCCXLVI
CCCXLI
ff M-29 14,15-saturated
\
CCCXLII
1
ee‘
M-70
ff’ M-29
LiAlDl
CCCXLVII
CCCXLN 496
hh
14. Aspidosperma
AND RELATED ALKALOIDS
497
oxygen was replaced (partially) by Ol8, this peak, in contrast t o all the others, underwent no alteration. The peak hh therefore involves the loss of CO f r o m 8 and may be allocated the structure shown (51).It will be seen that the postulated cleavages 1 and 2 are highly favored ones, for they not only involve the breakage of allylically activated bonds but in most cases by a suitable shift of electrons the E ring in the resultant fragments can become fully aromatic (170,51).The reverse Diels-Alder reaction pictured as occurring in ring C is characteristic of the mass spectral breakdown of molecules containing a singly unsaturated sixEburnamine (CCCXL)gives the same spectrum membered ring (21,185). as eburnamenine (CCCXLIII) but may be distinguished by lithium aluminum deuteride reduction to 14-deuteriodihydroeburnamenine (CCCXLVI)(51). 0-Methyleburnamine (CCCXL-A),found in Haplophyton cimicidum, was identified by loss of methanol to eburnamenine (CCCXLIII) and chromic acid oxidation to eburnamonine (CCCXLII, 113b).
F. TUBOFLAVINE A novel canthine-type alkaloid, tuboflavine (CCCXLVIII), has been isolated from the bark of Pleiocarpa tubicina (186).Its highly aromatic nature was recognized from the UV-spectrum (A 215, 264,289,323, 401) which, although unchanged in alkali, underwent a large bathochromic shift in acid or on formation of the methiodide. The empirical formula,
CCCXLVIII
CCCXLVIII-A
CCCXLVIII-B
C ~ ~ H ~ Z N Zwas O , confirmed mass spectrometrically. Tuboflavine is reduced by lithium aluminum hydride to a mixture of two compounds, both of which have the UV-absorption of indolic-N-methylharman, indicating substitution of N,. By the successive action of dilute alkali and methanolic hydrochloric acid, tuboflavine was cleaved to l-carbomethoxy-/3-carboline (CCCXLVIII-A), a result which would exclude a true canthine-type structure based on the skeleton (CCCXLVIII-B).
498
B. GILBERT
The NMR-spectrum of tuboflavine exhibited absorption characteristic of an aromatic ethyl group (CH3, 1.32 6, triplet; CH2, 2.8 6, quartet, J = 7.5 cjsec) and seven aromatic protons, and was fully consistent with structure CCCXLVIII for the alkaloid (186).
G. FLAVOCARPINE Earlier work (186a, 186b, 186c) had shown the presence of physiologically active alkaloids in the plants Pleiocurpu tubicina and P. mutica and the chemistry of some of the tertiary bases from these plants has been described in Sections 111,G, H ; V, D ; VI, C ; and in the preceding section. After complete removal of the chloroform-soluble bases of P. mutica, it was found (186d)that the alkaline aqueous extract still gave a strong Mayer reaction and by way of butanol extraction, precipitation of the picrates, recovery of the free amino acid by ion exchange followed by countercurrent distribution, it was possible t o isolate the yellow zwitterionic alkaloid, flavocarpine (CCCXLVIII-C). The complex UVspectrum of the alkaloid was very similar to that of flavopereirine (CCCXLVIII-D, 186d, 186f, 186g) from which the principal difference lay in the presence in the former of an ionized carboxyl group (v, 1595 cm-1). The NMR-spectrum (trifluoroacetic acid solution) showed that an aromjttic ethyl group (1.55 6, triplet; 3.42 6, quartet) was also present in flavocarpine (186d). Methylation of flavocarpine (CCCXLVIII-C) with methanol and hydrochloric acid gave the methyl ester chloride (CCCXLVIII-E) which, with sodium carbonate, yielded the red anhydronium base, CCCXLVIIIF. The methyl ester chloride suffered reduction of the C ring with sodium borohydride, to give an indole (CCCXLVIII-G, cf. 186h), and this provided a safe distinction from a pyridocarbazole-type structure (cf. 152) for the ester which would have suffered reduction in ring D t o leave a carbazole chromophore in the product (149, 158). Mass spectral molecular weight determination established the presence of one residual double bond in CCCXLVIII-G, not conjugated with the indole chromophore (UV-spectrum), but conjugated with the carbomethoxyl group (IR, v, 1705 cm-1). The absence of vinyl proton absorption in the NMRspectrum showed that it was tetrasubstituted and this evidence, combined with biogenetical probability and the appearance of a v peak at m/e 170 in the mass spectrum (see Section VIII, A), suggests structure CCCXLVIII-G for the reduction product. Full confirmation of the skeleton and position of the ethyl substituent was obtained by direct
14. Aspidosperma
499
AND RELATED ALKALOIDS
decarboxylation of flavocarpine (CCCXLVIII-C) to flavopereirine (CCCXLVIII-D) (186d). Synthesis of flavocarpine was achieved by use of a modification of the method worked out by Ban and Seo (186i), in which a 2-chloropyridine is condensed with 3-( 2-bromoethyl)-indole to form th'e required ring system directly. Thus, to provide the eventual carboxyl group of flavocarpine, a cyano group was introduced into 3-ethylpyridine. This was
it CCCXLVIII-C; R CCCXLVIII-D; R CCCXLVIII-E; R CCCXLVIII-P; R CCCXLVIII-Q; R
= COz-
H (salt) = COzMe = CONHz = COzH
I
MeOzC CCCXLV1TI-G
v
in/e 170
=
OQ
I
OMe I
I
R
RI
CCCXLVIII-H; R = H CCCXLVIII-K; R = CN
CCCXLVIII-I
Ri Rz CCCXLVIII-J C N H CCCXLVIII-L CN c1 CCCXLVIII-M CONHz C1
CCCXLVIII-D; R = H (anhydronium) CCCXLVIII-F; R = COzMe
CCCXLVIII-0
CCCXLVIII-N
effected by preparation of the N-oxide, CCCXLVIII-H, methylation to the iodide, CCCXLVIII-I, and direct cyanation (cf. 186j) followed by fractionation of the products (distinction of correct isomer, CCCXLVIIIJ, by NMR-spectroscopy and conversion to 3,4-diethylpyridine). The required chlorine atom was introduced by treatment of the N-oxide, CCCXLVIII-K, with phosphorus oxychloride in hot chloroform, the
500
XXXR
. . . . .. .. .. ..
B. GILBERT
G L
N
$3
+
zh
14. Aspidosperma
(3 N
AND RELATED ALKALOIDS
V
5 v v
H H
55
v vv v vv
501
502
B. GILBERT
required isomer, CCCXLVIII-L, again being distinguished by NMRabsorption. For the condensation with the bromoethylindole, CCCXLVIII-N, the solid amide, CCCXLVIII-M, was preferred to the liquid cyanide, and the product, CCCXLVIII-0, was readily dehydrogenated with tetrachloroquinone t o the amide of flavocarpine (CCCXLVIII-P). Hydrolysis with aqueous hydrochloric acid furnished flavocarpine itself as the hydrochloride (CCCXLVIII-Q) from which the free base identical with natural flavocarpine (CCCXLVIII-C) was obtained by passage through an ion-exchange resin (186d).
H. CARAPANAUBINE The alkaloid carapanaubine, C23H28N206, which occurs in Aspido-
sperma carapanauba, was remarkable in that although it had a non-
indolic UV-spectrum its NMR-spectrum was very similar to that of isoreserpiline (CCCV, Table IV), the only significant difference being the position of the N, proton which was farther downfield (8.73 6) with carapanaubine than with isoreserpiline (7.95 6). The presence of an extra carbonyl band in the IR-spectrum and of an extra oxygen atom in the molecule coupled with the UV- and NMR-data led to the supposition that carapanaubine was an oxindole in which rings A, D, and E were identical with the corresponding rings in isoreserpiline (271). I n order to settle this question, a number of oxindoles (CCCXLIX-CCCLIII), prepared by the tertiary butyl hypochlorite (187, 188) or lead tetraacetate (189) oxidation and rearrangement of the corresponding indoles (CCCXVII, CCCL-A, CCCIX, CCCVIII, CCCIII), were examined mass spectrally. It was thus possible to establish the breakdown pattern represented by the formulas ii-nn in which the structures of the various fragments were elucidated by deuteration in the positions 3, 5 , 6, and 14 (CCCL-CCCLII) and by the presence of a methoxyl group in the aromatic ring (CCCLIII). I n the spectrum of carapanaubine the principal peaks were found in positions identical with those exhibited by mitraphylline (CCCXLIX) and aricine oxindole (CCCLIII), with the sole exception that those fragments which incorporated the benzene ring were shifted to higher mle values corresponding to the presence of two methoxyl groups in that ring. Carapanaubine thus has the structure CCCLIV and i t remained only to settle the stereochemistry. I n the NMR-spectrum of carapanaubine the coupling between the C-19 proton (octet a t 4.56 6) and the C-18 methyl protons (doublet a t 1.4 6, J = 6 c/sec) was eliminated by spin decoupling and the C-19 proton absorption then appeared as a doublet with J = 5.7 c/sec due to
14. Aspidosperma
AND RELATED ALKALOIDS
503
coupling with the lone C-20proton. Carapanaubine cannot therefore have the C-19 CC, DIE-trans configuration of mitraphylline (CCCXLIX) nor the C-19 /I, DIE-cis configuration of formosanine (CCCLV) since these alkaloids have been shown to have smaller 19,ZO-HHcoupling conshants (190).There was every possibility, therefore, that carapanaubine had the C-19 a , DIE-cis stereochemistry as in reserpiline (CCCLVI) and isoreserpiline (CCCV) (191, 192). This was fully confirmed by synthesis from reserpiline (CCCLVI)using the lead tetraacetate oxidation method applicable t o indolic alkaloids with cis D/E ring junction (189). The intermediate 7-acetoxy-7H-reserpiline (CCCLVII) was rearranged in methanol containing a little acetic acid and, as under these conditions oxindoles equilibrate to a mixture of the “A” (CONH, a ) and “ B ” (CONH, /3) stereoisomers, two products were obtained, one of them being carapanaubine (CCCLIV).It has been shown that the oxindoles resulting from this type of rearrangement have the 3-aH configuration irrespective of the starting material; the two oxindoles obtained were therefore isoreserpiline oxindoles A and B. The B configuration was allocated to carapanaubine, as it moved more slowly on paper chromatography-a property characteristic of the more strongly basic B isomers (189, 187).
I. ISORESERPILINE-+-INDOXYL The isolation of isoreserpiline-+-indoxy1 (CCCLVII-A) from Aspidosperma discolor has been reported (113d). The structure of this yellow alkaloid, which has also been encountered in Rauwolfia species, was established by synthesis from isoreserpiline (CCCV) (192a, 192g). The synthesis of +-indoxyls from indoles differs from that of oxindoles, described in the preceding section, only in the final treatment of the intermediate 7-acyloxy-7H-indolenine [in this case 7-m-bromobenzoyloxy-7H-isoreserpiline (CCCLVII-B)] with methanolic alkali instead of weak acid (192a).
J. OCHROPAMINE AND OCHROPINE The alkaloids ochropamine (CCCLVII-C)and ochropine (CCCLVII-D) from Ochrosia poweri are the only representatives of the growing 2acylindole class so far encountered in the genera under study (192d). The nature of the chromophore (A 243 and 315 mp, E 18,900, 17,700) present in CCCLVII-C was determined both by alkaline degradation to 2-acetyl-1,3-dimethylindole and by comparison with the known 1-keto1,2,3,4-tetrahydrocarbazole.The presence of carbomethoxyl (5.78 p,
504
13. GILBERT
2.58 8) and N-methyl groups suggested a relation t o vobasine (CCCLVIIE) whose structure and stereochemistry are known (192e, 192f). Com-
parison of the NMR spectra of vobasine, ochropamine, and ochropine left no doubt as t o the skeletal and relative stereochemical identity of the three alkaloids, and showed that ochropamine (CCCLVII-C)differed from vobasine only in possessing an N,-methyl group (NMR, 4.056), while ochropine (CCCLVII-D) contained in addition an aromatic methoxyl group. This was located by UV-comparison with model compounds (192d). MeOIC \
RI CCCLVII-C CCCLVII-D CCCLVII-E
Rz
H Me OMe Me H H
R,
Rz
IX. Alkaloids of Unknown Structure A. ALKALOIDSOF Pleiocarpa SPECIES Three alkaloids whose structure is unknown at the time of writing have been isolated from Pleiocarpa mutica (91). One of them, pleiocarpamine, C2oH22N202, is a pentacyclic indole in which N, is substituted. Nb is tertiary and the two oxygen atoms have been located in a carbomethoxyl group. The alkaloid bears an ethylidene side chain (91, 53). The other two, pleiomutine and pleiomutinine, are double alkaloids. Pleiomutine shows UV-absorption similar to that of leurosine and vinblastine and contains, therefore, an indole and a dihydroindole chromophore. The UV-spectrum of pleiomutinine, on the other hand, extends to longer wavelengths showing distinct similarity t o the spectra of vobtusine and callichiline (193). I n the species P. tubicina the occurrence of the two lactams pleiocarpinilam and kopsinilam has been described (Section 111, H). I n addition, a third lactam was isolated from this plant which exhibited IR-absorption bands a t 1763 and 1687 cm-1 (96).
B. ALKALOIDSOF Ochrosia SPECIES A number of species of the genus Ochrosia have been investigated, and among the alkaloids already discussed are ellipticine and methoxyellipticine from 0. elliptica (Section VII, D). Other alkaloids from this species include elliptinine for which structure CCCLVIII has been
14. Aspidosperma
AND RELATED ALKALOIDS
505
proposed (156). 0. sandwicensis yielded an unnamed base with UVabsorption a t 238 and 290 mp (156). An unnamed alkaloid from 0. oppositifoZia, C ~ ~ H ~ ~ Nhas Z Othe , same composition as methoxyellipticine. The UV-absorption (A 242, 275, 290, 335 mp; loge 4.35, 4.59,
CCCLVIII
4.66, 3.71) is also very similar (194). Australian and New Guinea species, notably 0. poweri, contain a number of alkaloids (161), including elliptamine, C24H3oNz05, powerine, C21H26N204, and poweramine, C23H30Nz04 (161). Elliptamine, the most widespread, is unstable in the form of the free base. It forms an orange-red picrate. Powerine and poweramine may be 5- and 6-methoxy indoles, respectively (161).
C. ALKALOIDS OF Aspidosperma, Rhazya, AND Stemmadenia I n addition to olivacine and guatambuine (Section VII, C), an unnamed alkaloid, mp 186"-188", resembling uleine in its color reactions, has been isolated from Aspidosperma australe (147)s. A glycosidic alkaloid, quebrachacidine, C26Hz8N2011, has been found in A. quebrachoblanco (195), and its aglycone has been prepared. Several alkaloids have been reported in A . oblongum and A . album (196), notably kromantine, mp 176", [aID+ 159" (in chloroform), from the latter species (196a). Among the many alkaloids of Rhazya stricta (seeTable I),the structure of the alkaloid rhazinine remains to be determined (197). This indolic base, C19H24N20, contains a primary alcoholic group but, unlike akuammidine (CCCXXII)which accompanies it in the plant, it contains no G-methyl (197). Other alkaloids of the same plant include rhazidine, CzoHzsN203, HzO, mp 278-279", [.ID - 21" (in ethanol) (199, 200, 62). Two unnamed alkaloids, mp 233"-235" (dec.) and 135"-139", respectively, were isolated from Stemmadenia donnell-smithii, but no further information is available on these a t the time of writing (8). REFERENCES 1. R.B. Woodward, Nature 162, 155 (1948). 2. Sir Robert Robinson, 'I The Structural Relationsof NaturalProducts." OxfordUniv. Press, London and New York, 1955.
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3
This alkaloid has been identified as apparioine [CCLVII-U p. 473 (37)].
506
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