Chapter 5 Alkaloids of the Calabar Bean

- Chapter 5 ALKALOIDS OF THE CALABAR BEAN SEIICHI TAKANO A N D KUNIO OGASAWARA Phurmuceuticul Instilute Tohoku Universitv Aohayumu, Sendui 980. Japan

I . Introduction .......

.................. ................................................................. HI. Synthesis of the Alkaloids .................................................................. ........... A. Brief Outline of Syntheses Established prior to 1970 B. Syntheses after 1971 ..................................................................... IV. Pharmacology.. ................................................................... .......................................... References 11. Structures of the

225 225 226 226 226 247 249

I. Introduction

The alkaloids of the Calabar bean (Physostigmu uenenosum) were reviewed in Volumes 2 ( I ) , 8 (2), 10 ( 3 ) ,and 13 (4) of this treatise, covering the period up to 1970. In the intervening years no new alkaloids have been discovered. However, considerable advances have been made in both the synthesis and pharmacology of the alkaloids. A number of syntheses including entirely new approaches and an enantiocontrolled route as well as the first total synthesis of racemic geneserine have been accomplished. In addition, the remarkable enantiospecificity in pharmacological activities such as antiacetylcholinesterase and analgesic activities has been recognized. This chapter outlines investigations reported during the period from 1971 to the end of 1988, focusing mostly on synthesis.

11. Structures of the Alkaloids

Isolation of seven alkaloids from the Calabar bean is reported to date (Fig. I). Of these, the structures of (-)-calabatine (6) (C17H~5N~03) 225

THE ALKALOIDS. VOL 76 Copyright 0 1989 hy Academic !‘re\\. Inc All right\ of reproduction in any form renerved

226

SEIICHI T A K A N O A N D K U N l O OGASAWARA

(-)-physostigmine (1)

MeycoQ&J HO

(-)-norphysostigrnine (2)

M HeO N I H Me

C

o

,

e

N 0'

(-)-eseramine (3)

(-)-calabatine (6);C17H,503N, Me (-)-calabacine ( 7 ) ;C17H,503N,

Me

(-)-physovenine (4)

(-)-geneserine (5)

FIG. I . Alkaloids isolated from the Calabar bean.

and (-)-calabacine (7) (C17H25NZ03) have not been determined since their isolation was reported in 1963 ( 5 ) . 111. Synthesis of the Alkaloids

A. BRIEFOUTLINE OF SYNTHESES ESTABLISHED PRIOR TO 1970 Of the five alkaloids with known structures, physostigmine (l),eseramine (3), and physovenine (4) have been synthesized (1-4). Since the conversion of physostigmine (l),a principal alkaloid, to physovenine (4) (6) and geneserine ( 5 ) (7,8) has also been established, synthesis of the former implies acquisition of the latter two alkaloids in a formal sense. Up to 1970, the synthesis of geneserine ( 5 ) was not reported because its structure had been considered to be the N-oxide of physostigmine (1)until 1969 (9-11) since its first isolation in 1915 (12). The four approaches to the synthesis of physostigmine (1) may be classified into four types based on the key step employed: (i) the Fischer indolization route, (ii) the indole alkylation route, (iii) the oxindole alkylation route [including synthesis of physovenine (411, and (iv) the oxidative indolization route (1-4) (Scheme 1).

B.

S Y N T H E S E S A F T E R 1971

There have been more than 10 syntheses of physostigmine (1) and related alkaloids reported since 1971. They include entirely new ap-

227

5. ALKALOIDS OF THE CALAEAR BEAN

(i) Fischer indolization route

L+

1

EtMgBr Me1

rNHNH2

R

O

e

N

9

p

h

(ii) lndole alkylation route

-

t

(iii) Oxindole alkylation route

I

Hlo

1

h

EtONa CICHzCN

,

Me Me

Me

physostigmine (1)

13

(iv) Oxidative indolization route

\

aq. K3Fe(CN)6 I H I

14

Me Me 15

SCHEME I . Outline of syntheses established prior to 1970.

proaches to construct the alkaloid framework, the first enantiocontrolled and the first total synthesis of synthesis of natural (-)-physostigmine (l), racemic geneserine ( 5 ) . It should be pointed out that the same intermediate 27 of geneserine (9,which could be obtained by (v) the isochromanone route or by (vi) the radical cyclization route, may be used not only for geneserine (5) but also for physostigmine (1)and physovenine (4) (Scheme 2). Improved syntheses based on classical routes such as the Fischer indolization route and the oxindole alkylation route have also been reported. The former could provide substantial amounts of the racemic alkaloids, while the latter made possible the practical production of both the natural and the unnatural enantiomers of the alkaloids with the development of a highly efficient method for resolving the racemic intermediate. The latter may be particularly interesting from the pharma-

228

SEIICHI TAKANO A N D KUNIO OGASAWARA

(iii) Enantiocontrolled route

Y

lhv Me

H2

M e o w22c N 1) LDA 2) hydrolysis 3) alkylation

I

C02Et 20

17

18

Me physostigrnine (1)

I

I

Me Me 25

k

27

4

I

F-

I

Me 29

t

BuaSnH

26 (v) lsochrornanone route

I

I

Me Me TfO24 (iv) 1,3-Dipolar addition route

I

Me 28 (vi) Radical cyclization route

SCHEME 2. Outline of syntheses established after 1971.

5. ALKALOIDS OF THE CALABAR BEAN

229

cological point of view, since the enantiospecificity of biological activities has been recognized in recent pharmacological investigations of physostigmine (1) and related alkaloids. The syntheses established after 1971 are outlined chronologically in the order in which they were developed.

I . Synthesis of Physostigrnine a. Synthesis of Racemic Physostigrnine via the Photochemical Route. The photochemical valence isomerization of 1,2-dihydronaphthaIenes to l,la,2,6b-tetrahydrocycloprop[b]indenes (e.g., 30 + 31) is well established (13). Ikeda and co-workers applied this photochemical rearrangement to 1,2-dihydroquinoline derivatives and observed that the same type of reaction took place in these heterocycles to give rise to cycloprop[blindoles in moderate yields (e.g., 32 + 33) (14). This finding was immediately exploited in a synthesis of racemic physostigmine (1)by the same authors (15). Unfortunately, the key reaction did not proceed in good yield with the appropriate substrate for construction of the natural product; nevertheless, an entirely new approach to the alkaloid was established.

30

C02Et

32

31

CO,Et 33

Photolysis of 1,2-dihydroquinoline 19, obtained in 47% yield from 6-methoxy-4-methylquinoline 34 by the Reissert reaction (16), in ethanol in a Pyrex tube afforded the endo-cyanocycloprop[b]indole 20 in 10% yield as a single product. On alkaline hydrolysis 20 furnished the furo[2,3-b]indole 38 in 69% yield. Formation of 38 was assumed to occur by sequential hydrolysis to the anion 35, ring opening to the indolenine 36, hydrolysis of the cyano group, and recyclization as shown in Scheme 3 . After N-methylation of 38 with methyl iodide in a sealed tube, the resulting 39 was heated with methylamine to give the lactam 40 which was reduced with LiAIH4 to give racemic esermethole (41) in 25% overall yield from 38. Conversion to 41 to racemic physostigmine (1) in two steps had already been established (1,2).

230

SEllCHI TAKANO AND KUNIO OGASAWARA

Me

hv,

KCN, 47%

I

34

CN

EtOH, Pyrex tube 2"C.g h

CO,Et

I

CO,Et

19 10% KOH

M

aq. EtOH 120-130 "C

35

20

e

o

e

C

N

Meocfb 36

Me1

YHo H

37

Me 39

38

25%

69%

acetone 60 "C sealed tube 4.5 h

Me Me 40

100%

(f)-eserrnethole (41) 100%

SCHEME 3. Synthesis of racemic physostigmine. The lkeda approach

b. Synthesis of Racemic Physostigmine via the Acyliminium Route. In 1978, Wijnberg and Speckamp (17) disclosed a new approach to racemic physostigmine (1)employing acyliminium cyclization (18)as the key step, a route which they developed by themselves. The synthesis devised by these authors did not start from an indole derivative but from the succinimide 47 corresponding to the A-C framework of the alkaloid. In order to avoid the difficulties encountered in the preparation of the nitrated imide 48 starting from the nitrated precursor, the introduction of the nitro group was performed at a later stage. Thus, 3-ethoxybenzaldehyde (42) was first converted to the imide 47 in 60% yield via a sequence

-[

j

23 1

5. ALKALOIDS OF THE CALAEAR BEAN

E t O D C H O
E t O m N C 0 2 E t

KCN

+

TiCI,

\

42

co

cone. HCI

MeOH,

43

92%

E W , y L L O z H

30 min

11

44

n AcCl

45

IL4h

E0 t&0 ;2Et

CH3NHz b

46 (76% from 43) 1) Mel, K,C03 2) NaBH,

fum HN03

D

conc HCI. Me

Me 48: Rl=N02, R2=H

47

O’C, 4h

49: Rl=H, R2=NO2

-

50: X=Y=O 51 : X=H, OH, Y=O 52: X=O, Y=H, OH

16

LiAIH,

-EtoQ&AoI OHC 53

Me AcO-

J

Me CHO 54 74%

““6 \

I H I

known-

physostigmine (1)

Me Me

(k)-eserethole (55)

SCHEME 4. Synthesis of racemic physostigmine. The Speckamp approach

232

SEIICHI TAKANO AND KUNIO OGASAWARA

of five steps (19). Nitration of 47 with fuming nitric acid in acetic acid gave the desired nitro-imide 48 in 40% yield accompanied by the regioisomer 49 in 25% yield. Alkyiation of 48 with methyl iodide in the presence of potassium carbonate occurred regioselectively at the benzylic carbon to afford the single product 50 in 85% yield. Reduction of 50 with sodium borohydride in the presence of hydrochloric acid (NaBH4/Ht), the conditions established by Speckamp and co-workers (18,20), occurred at the more crowded site in a 3 : 1 selection to give a mixture of the regioisomers from which the desired carbinol-lactam 51 could be obtained in 60% yield after separation of the regioisomer 52 by recrystallization. After catalytic hydrogenation of 51, the resulting amine 16 was treated with acetic formic anhydride at 0°C to give the tricyclic N8-formyl compound 54 in 74% yield in one step via concomitant formation of the acyliminium intermediate 53 and cyclization. On reduction with LiAIH4 54 furnished racemic eserethole 55 in 74% yield which had previously been converted to racemic physostigmine (1) (1,2) (Scheme 4). c. Synthesis of Racemic Physostigmine via the Fischer Indolization Route. As apparent from the first synthesis of physostigmine (1) by Robinson and co-workers in the early 1930s (21), the Fischer indolization approach is one of the most straightforward routes to construct the alkaloid framework. In 1975, Rosenmund and Sotiriou reported the synthesis of ethyl 3-formylbutyrate (61) and its transformation to the physostigmine framework by the Fischer indolization reaction (22). In 1979, Rosenmund and Sadri disclosed a synthesis of racemic physostigmine (1) starting from the same aldehyde 61 and employing a slight modification of the established procedure (23). The synthesis seemed to be very practical since the conversion could be carried out neatly from the aldehyde (61) in good overall yield. Ethyl 3-formylbutyrate (61) was prepared in 15% overall yield from ethyl crotonate (56) by sequential hydrobromination, cyanation, reductive amination with N,N'-diphenylethylenediamine(59) in the presence of Raney nickel catalyst, and acid-catalyzed hydrolysis as shown in Scheme 5. The phenylhydrazone 63 obtained from 61 with the phenylhydrazine 62 was stirred in ethanolic hydrogen chloride at 40°C for 90 min, followed by alkaline hydrolysis of the initially produced indolenium ester 64 to yield the tricyclic lactone 66 in one step in 72% yield via the hydroxyindolinecarboxylate 65 after acid work-up. Condensation of 66 with methylamine followed by reduction of the resulting lactam 67 with LiAIH4 afforded racemic eserethole (55) in 82% yield (Scheme 5). Although yield of the starting aldehyde 61 requires improvement, this synthesis seems to be quite practical since it could be carried out neatly in 59% overall yield

. moEt .yF;02E 233

5 . ALKALOIDS OF THE CALABAR BEAN

\/&yoEf HBr-AcOH 0

0-5 "C, 3 h

KCN

0

Br

56

CN 0

96%EtOH 75 o c

57 98%

58 42-45%

P h N H b N H P h 59

20% HCI

AcOH, MeOH Raney nickel

U

H2

EtoYl \

62

N-NH2 Me

61

35%overall

. Eton N-N-

A C 0 2 E t

HC'

63

EtOH -40 "C, 90 min then 40% KOH acid work up

I

Me

. ; ~\ c No 2OH- ]

-

Me

Eton%~ --. 65

known

\

Me 66

b

I

I

Me 64

0

OHC

60

N N I H I Me Me 67

(+)-physostigmine (1)

O

72% from 6 1

SCHEME 5. Synthesis of racemic physostigmine. The Rosenmund approach.

in three steps to give eserethole (55). Conversion of 55 to physostigmine (1) had already been established (1,2). d. Synthesis of Natural (-)-Physostigmine via the Enantiocontrolled Route. Alkaloids used in medicine such as (-)-physostigmine (1)occur in nature in one specific enantiomeric form, and generally only the specific enantiomer shows biological effects. Enantiocontrol is, therefore, a critical factor in the synthesis of biologically active natural compounds.

234

SEIICHI TAKANO A N D KUNIO OGASAWARA

The first enantiocontrolled synthesis of the natural ( - ) enantiomer of physostigmine (1)was achieved by Takano and co-workers in 1982 (24)by employing the chirality transfer method they established (25). Starting from (-)-(S)-0-benzylglycidol (21) (26). accessible efficiently in large amounts from D-mannitol (271, the synthesis involved stereoselective methylation of the chiral lactone (69) in the key step where the original chirality of the starting material was efficiently transferred to the chiral quaternary center of the alkaloid with the requisite stereochemistry. The synthesis, however, is unsatisfactory due to nonregioselectivity in the nitration step at a later stage. Condensation of 21 with the phenylacetonitrile (22) followed by alkaline hydrolysis afforded the y-lactone 69 in 63% overall yield as an 1 : 1 epimeric mixture. Methylation of the lithium enolate 70 generated in situ from 69 furnished a 8 : 1 mixture of the lactones 23 and 71 which were readily separated by a single column chromatography step to give 23 in 80% yield together with an 11% yield of the unwanted epimer 71. The observed overwhelming formation of the former lactone (23) indicated that the alkylation occurred mainly on the side remote from the benzyloxymethyl group of the enolate intermediate 70. After removal of the unwanted group of 23, the chiral lactone 72 obtained was transformed to the lactam 73 in 78% overall yield. On nitration with copper(I1) nitrate in acetic anhydride (28) 73 yielded a mixture of three regioisomers 74, 75, and 76 from which the requisite amine 77 could be isolated in a pure state in 38% overall yield by chromatographic separation from the unnecessary regioisomers after catalytic hydrogenation. Treatment of 77 with LiAIH4 afforded the tricyclic aminal 79 with the alkaloid framework directly in 60% yield via concomitant reductive cyclization. Reductive methylation of 79 with 30% formalin and sodium cyanoborohydride gave (-)-esermethole (41) which was further converted to (-)-eseroline (15), the penultimate intermediate of (-)-physostigmine (1) (29), on exposure to boron tribromide in rnethylene chloride (Scheme 6). Since an efficient synthesis of (+)-(R)-0-benzylglycidol (21) (30)has also been established, the pharmacologically interesting unnatural (+)-physostigmine (1) may also be obtained by the same methodology. e. Synthesis of Racemic Physostigmine via the Intramolecular 1,3Dipolar Addition Route. An ingenious synthesis of racemic physostigmine (1) by a fundamentally new methodology making use of an intramolecular 1.3-dipolar cycloaddition was devised in 1983 by Smith and Livinghouse (31). These authors retrosynthetically dissembled the alkaloid into an unprecedented olefin-formamidine l ,3-dipolar species like 25 (Scheme 7). Assemblage of the alkaloid framework based on their

o x O B n

-.

LDA

.

Meo&OBn

M e o W C N

21

235

5 . ALKALOIDS OF THE CALABAR BEAN

KOH-EtOH M e 0 acid work up

\

68

22

69 OBn 63% overall

THF, -78 "C-rt

LDA

Me1 THF -78 "C-rt

I

OBn

23

71

1) H,/Pd-C, HClOd (cat) 2) KOH-MeOH, then NalO, then NaBH,. acid work up

180 "C sealed tube

72

Me

76

19%

75

73

5-10 "C

Me

0,

Me 72%

74

Me

I

I

t

Me 378 0

77

38%

SCHEME 6. Synthesis of (-)-physostigmine. The Takano approach

OBn

236

SEIICHI TAKANO A N D K U N I O OGASAWARA

25

1 SCHEME

7

retrosynthetic analysis was realized by employing organosilicon chemistry which allowed concurrent generation of the expected formamidine 1,3-dipolar intermediate and internal cycloaddition toward the nonactivated double bond in a single operation. The aminoolefin (82) obtained from the acetanilide 80 in a three-step sequence of reactions was converted to the formamide 83 in 88% yield by sequential formylation and methylation. Treatment of 83 with methyl trifluoromethanesulfonate followed by trimethylsilylmethylamine gave the formamidine 84 in 77% yield. Methylation of 84 with methyl trifluoromethanesulfonate, followed by exposure of the resulting salt (24) to tetra-n-butylammonium fluoride brought about a facile generation of the 1,3-dipolar species 25 and concurrent intramolecular cyclization to furnish racemic eserethole (55) in 70% yield (Scheme 8). This method may be widely applicable to the synthesis of numerous natural products which contain the pyrrolidine ring. f. Synthesis of Racemic Physostigmine via the Isochromanone Route. Fukumoto and co-workers (32) discovered an interesting tandem electrocyclic [3,3]-sigmatropic rearrangement giving rise to high yields of the 4,4-disubstituted isochroman-3-ones when the allyl esters of certain benzocyclobutenecarboxylic acids were heated under reflux in o-dichlorobenzene. As shown in Scheme 9, reaction of the benzocyclobutene 26 proceeded with concurrent generation of the o-quinodimethane intermediate 86, electrocyclic cyclization to the keteneacetal 87, and [3,3]-sigmatropic rearrangement to furnish the isochromanone 26 in a single operation. Utilizing the isochromanone 26, the same authors obtained intermediate 95 (8)common to the synthesis of the Calabar bean alkaloids physostigmine (1)as well as physovenine (4) and geneserine (5). Thus, 4-allyl-6-methoxy-4-methylisochroman-3-one (26) obtained in 100% yield from the thermolysis of allyl 1,2-dihydro-5-methoxy-lmethylbenzocyclobutene-1-carboxylate(86) in o-dichlorobenzene, was first reduced to the diol88 with LiAIH4 (Scheme 10). After having trapped one of two hydroxy groups of 88 selectively as the bromoether 89 on treatment with N-bromosuccinimide in tetrahydrofuran, the remaining benzylic alcohol group was first oxidized with Jones reagent to give the

237

5 . ALKALOIDS OF THE CALABAR BEAN

Y-COCH,

80

H ..

1) BnOCHO

Me

Me

24

-.

“‘a&)

known

25

(&)-physostigmine(1)

\

I H I Me Me W-eserethole f551

SCHEME8. Synthesis of racemic physostigmine. The Livinghouse approach.

85

L

86

[3,3]-sigmatropic reaction

87

M

e

O

V

26

SCHEME9. Tandem sigmatropic formation of the isochromanone (26) from the benzocyclobutene (85).

238

SEIICHI T A K A N O A N D K U N I O OGASAWARA

26

;;;"M 0 ;e 0 -

\

___)

M

e

O

\

OH 88

q

y(oJ,

OH 89

+ Br

Me

H 94

Y O

90 : X=H 91: X=OH 92: X=N3

ii

93

95

Mead \

HVo' R

?

Me

97: R=C02Me 77: R=H

known

96

\

-

(f)-physostigmine (1)

I H I Me Me (t)-esermethole (41)

SCHEME 10. Synthesis of racemic physostigmine. The Fukumoto approach.

aldehyde 90 which then was further oxidized with sodium chlorite in the presence of sulfamic acid (33) to produce the carboxylic acid 91 in 81% overall yield from 88. The Curtius-type reaction using diphenylphosphoryl azide (34) 91 furnished the carbamate 93 in quantitative yield in one step. When the Curtius process was carried out under standard conditions (35)via the corresponding acyl azide intermediate 92, the yield of 93 was decreased to 48%. Compound 93 was then converted to the key oxindole 95 in satisfactory overall yield by sequential reductive cleavage of the bromoether bond with zinc-copper and oxidation of the resulting alcohol 94 with pyridinium dichromate. Oxidative cleavage of the double bond of 95 with sodium periodate and osmium tetroxide followed by reductive amination of the resulting aldehyde with methylamine hydrochloride and sodium cyanoborohydride

5 . ALKALOIDS OF THE CALABAR BEAN

239

afforded the lactam carbamate 97 via concommitant intramolecular nucleophilic cleavage of the imide bond of 96 by the secondary amino group in the molecule (36). Selective cleavage of the carbamate bond using a complex of dimethyl sulfide and aluminum chloride (37) gave the known amino lactam 77, in 40% overall yield from 95, whose conversion to physostigmine (1) had already been accomplished (24). Although this synthesis required rather lengthy steps from the starting isochromanone 26, the reported overall yield of the final product was not low. As mentioned in Sections II,B,2,b and III,B,3,a, it should be mentioned that the intermediate lactam 95 was utilized by the same authors as the key intermediate in the synthesis of two other Calabar bean alkaloids, physovenine (4) and geneserine (5). g. Synthesis of Racemic Physostigmine via the Improved Oxindole Alkylation Route. Total synthesis of physostigmine (1) by Julian and Pikl in 1935 (38) was accomplished from the cyano-oxindole 13 by catalytic reduction to the amine 99, its three-step conversion to 100, followed by reductive cyclization to eserethole (55) using sodium in ethanol. This reductive cyclization required large amounts of sodium and ethanol which made the original method very impractical. However, Yu and Brossi (39) established an improved version of the Julian synthesis using the methoxy analog (98) of Julian's starting material 13. Thus, the carbamate 102, obtained quantitatively from amine 101, was refluxed with LiAlH4 in tetrahydrofuran to afford racemic esermethole (41) in 82% yield in one step by concurrent reduction of the carbamate group and reductive cyclization. Similarly, they also achieved direct conversion of the cyanide 98, the precursor of the amine 101, to N'-noresermethole (103) in 80% yield. Racemic esermethole (41) could also be obtained in 80% yield from 103 by carbamoylation followed by reduction of the resulting 104 with LiAlH4 (Scheme 1 I ) . Synthesis of N'-noresermethole (103) also implies a formal synthesis of eseramine (3), since the conversion of 103 to 3 had previously been established (40).

h. Synthesis of Natural (-)- and Unnatural (+)-Physostigmine via the Improved Oxindole Alkylation Route. Prior to the above-mentioned efficient synthesis of racemic esermethole (41) and N'-noresermethole (103), Schonenberger and Brossi (41) developed an efficient method for resolution of racemic N'-noresermethole (103) obtained by the original Julian method (38). Reaction of racemic N'-noresermethole (103) with (-)-(S)-( I -phenylethyl)isocyanate afforded the less polar (+)-urea 106 and the more polar (-)-urea 105 in 37 and 40% yield, respectively, after chromatographic separation of the product obtained as a mixture of diastereomers. The ureas 105 and 106 decomposed cleanly in refluxing

240

SEIICHI T A K A N O A N D KUNIO O G A S A W A R A

I

Me 13: R=Et 98: R=Me

Me

99 : Rl=Et, R,=H 1 0 0 : R,=Et, R,=Me 101 : R,=Me, R,=H 1 0 2 : R,=Me, R,=CO,Et

I

I Me

R,

(f)-esermethole (41): R,=R,=Me (f)-eserethole (55): R,=Et, R,=Me (k1-N I-noresermethole (103 ): Rl=Me, R,=H

104: R,=Me. R,=CO,Et

SCHEME 1 1 . Synthesis of racernic physostigmine. The Brossi approach.

I M sodium pentyloxide in n-pentyl alcohol within 1 hr, affording as the basic materials (+)-N'-noresermethole (103) and (-)-N'-noresermethole (103), respectively, which were isolated as the oxalate salts. Since an improved method which could efficiently produce racemic N'-noresermethole (103) had been established by the same authors' group Me 1) (3-PhCHNCO (104) M e I.

MeoO+~ \

YHY Me H (?)-lo3

2) separation

0

0 J Me ,

\

Me

H

Meoom Me

and Me* CONHCHPh

(-)-lo5

\

y ye.

NH Me CONHCHPh (+)-lo6

MeooqJ *

(+)-lo5 nC5H11 0 N a nC5H1 10H,reflux

YHN Me H

(+)-lo3

Me Me (+)-esermethole (41): R=Me (+)-eseroline(15): R=H (+)-physostigmine (1): R=MeNHCO

SCHEME 12. Synthesis of (+)-physostigmine. The Brossi approach.

24 I

5. ALKALOIDS OF THE CALABAR BEAN

(see Section III,B, 1 ,g) both enantiomers of physostigmine (1) became readily available in large amounts applying the resolution method described here. Thus, the fumarate salt of (+)-N'-noresermethole (103), obtained from the less polar urea 106, was treated with formaldehyde and triethylamine followed by sodium borohydride to afford (+)-esermethole (41) in 62% yield by reductive methylation. The unnatural (+) enantiomer of physostigmine (1) could be obtained in 73% overall yield from 41 by de-0-methylation with boron tribromide followed by carbamoylation of the resulting (+)-eseroline (15) with methyl isocyanate (42) (Scheme 12). The same authors' group also disclosed a practical synthesis of natural (-)-physostigmine (1) starting from the fumarate of ( -)-N'noresermethole (103) obtained from the more polar urea 105 by employing a slightly different procedure which could also produce pharmacologically interesting N'-substituted-N'-norphysostigmines and another Calabar bean alkaloid, (-)-eseramine (3) (43). Thus, the fumarate of ( - ) - N ' noresermethole (103) was first treated with benzyl bromide in the presence of sodium hydrogen carbonate to give (-)-N'-benzyl- 1noresermethole (107) which was then converted to Nl-benzylnorphysostigmine (1) in 48% overall yield by sequential de-0-methylation to 108 and its carbamoylation to 109. Hydrogenolytic debenzylation of 109 using palladium hydroxide on carbon afforded (-)-N'-norphysostigmine (110), in 72% yield, which furnished natural (-)-physostigmine (1)in 63% yield on reductive methylation with formalin and sodium borohydride. Natural (-)-eseramine (3) was obtained in 98% yield on carbamoylation of 110 with methyl isocyanate (Scheme 13). Because derivatives of both natural

(-)-lo6

nC5H1, ONa nC5Hl 10H, reflux

-UqJI H I Me H

(-)-lo3

107: R=Me 108: R=H 109: R=MeNHCO

110: R=H

(-)-physostigmine (1): R=Me (-)-eseramine (3): R=MeNHCO

SCHEME 13. Synthesis of (-)-physostigmine. The Brossi approach.

242

SEIICHI TAKANO AND KUNIO OGASAWARA

and unnatural antipodes of physostigmine (1) as well as eseroline (3) are expected to exhibit interesting physiological activities, this synthesis may be particularly useful for pharmacological investigations. 2. Synthesis of Physovenine Since physostigmine (1) is known to be transformed to physovenine (4) ( 6 ) , the aforementioned syntheses of physostigmine (1) imply formal routes to 4. However, two direct syntheses of racemic physovenine (4) have been established since 1970. a. Synthesis of Racemic Physovenine via the Indole Alkylation Route. Although alkylation of the oxindole 29 with ethylene oxide in the presence of sodium ethoxide produced the primary alcohol 111 which was convertible to physovenine (4) via 113 (44), it has been reported that reaction of the Grignard derivatives of the corresponding indole derivative 112 failed to yield the product with physovenine framework 114 on treatment with alkylating agent (45) (Scheme 14). However, Onaka (46)

MeomMe -Meoe 0

L l

\

N Me 29

O

NaOEt in EtOH

\

y

o

Me 111

NdEtOH

I

H 112

MeMgl R, 113: R,=R,=Me

Me (+)-physovenine (4)

114: R,=Bn, R,=H SCHEME

14

first succeeded in obtaining the intermediate 117 of physovenine (4), though in low yield, by alkylating the Grignard derivative generated from 5-methoxy-3-methylindole(115) with ethylene oxide. Thus, treatment of 115 with methylmagnesium iodide followed by an excess amount of ethylene oxide in ether at room temperature afforded directly the tricyclic aminoacetal 117 in 13% yield after chromatographic purification. Treat-

5. ALKALOIDS OF THE CALABAR BEAN

243

ment of 117 with methyl iodide in the presence of sodium hydride gave the known compound 113, in 36% yield, which had previously been converted to racemic physovenine (4) (44) (Scheme 15).

MeowMe MeMgl

then

H

Et,O,

7

rt. 4 h

115

known

.

116

(+)-physovenine (4)

k 117: R=H (13%) 1 1 3 : R=Me (36%)

SCHEME15. Synthesis of racemic physovenine. The Onaka approach.

b. Synthesis of Racemic Physovenine by the Isochromanone Route. Fukumoto and co-workers synthesized racemic physovenine (4) using the same intermediate 95 used in the synthesis of physostigmine (1) (8a).Ozonolysis of 95, obtained from the isochromanone 26,followed by reduction of the ozonide mixture with sodium borohydride gave the diol 118 as a diastereomeric mixture with concomitant reduction of the imide carbonyl group in the molecule. On treatment with p-toluenesulfonic acid in methylene chloride the mixture furnished the tricyclic carbamate 119 in 86% overall yield from 95. Reduction of 119 with LiAIH4 did not yield the desired N-methyl derivative 113 but the secondary amine 117. The latter could be transformed to amine 113 in excellent overall yield on reductive methylation with formalin and sodium cyanoborohydride. Cleavage of the methyl ether group of 113 with boron tribromide followed by treating the resulting phenol 120 with methyl isocyanate afforded racemic physovenine (4) in 83% yield (Scheme 16). 3 . Synthesis of Geneserine

a. Synthesis of Racemic Geneserine via the Isochromanone Route. Since the first isolation of geneserine (5) by Polonovski in 1915 (12), it was not until 1969 that its structure was determined unambiguously as a tetrahydro- 1,2-oxazine by Hootele based on physicochemical examination which ruled out the originally proposed structure 121, the N-oxide of physostigmine (1) (9,10). However, Brossi and co-workers

244

SEIICHI TAKANO AND KUNIO OGASAWARA

95

118

113: R,=R2=Me 1 1 9 : R,=Me. R,=CO,Me 117: R,=Me, R,=H 1 2 0 : R,=H, R,=Me (*)- physovenine (4): R,=MeNHCO, R,=Me

SCHEME 16. Synthesis of racemic physovenine. The Fukurnoto approach.

later found that the N-oxide 121 really did exist as the salt 121a with the stereochemistry shown (X = CI) when geneserine (5) was treated with acid. They also observed that the salt reverted to geneserine (5) on exposure to base, indicating the intervention of an indolenium intermediate 122 under both acidic and basic conditions. Similarly, genesoline (5; MeNHCO = H) formed the N-oxide structure (121; MeNHCO = H) on exposure to acid (11) (Scheme 17). Although it was possible to transform physostigmine (1) to geneserine (5) by simple oxidation (7,8,11), the first total synthesis of racemic geneserine (5) was accomplished in 1986 by Fukumoto and co-workers using the same oxindole intermediate 95 used for the synthesis of

Me 5

121

122

121a

SCHEME 17

245

5. ALKALOIDS OF THE CALABAR BEAN

physostigmine (1) and physovenine (4) (47). Since selective manipulation of the methyl groups was found to be very difficult in later stages of the synthesis, 95 was first exposed to the complex generated from dimethyl sulfide and aluminum bromide (37) to afford the phenol-lactam 123a by spontaneous de-0-methylation and decarbomethoxylation. Double alkylation of 123a with methyl iodide in the presence of sodium hydride followed by de-0-methylation of the resulting dimethyl-lactam 123b with boron tribromide gave the N-methylphenol 123c which was treated with methyl isocyanate to furnish the carbamate 124 in satisfactory overall yield. Cleavage of the vinyl bond of 124 followed by reductive hydroxylamination of resulting aldehyde 125 afforded the hydroxylamine 126 in good overall yield. Finally, partial reduction of 126 with diisobutylaluminum hydride furnished directly racemic geneserine (5) via spontaneous cyclization of the carbinol amine intermediate 127, although the conversion ratio was not high (-35%). The yield of the final step was 75% based on consumption of the starting material (Scheme 18).

1) Me,SAIBr3 2) NaH,Mel

MeNCO

3) BBr3 C0,Me

R2

95

M

e

N

H

123a : R1=R2=H 123b : Rl=R2=Me 123C : Rl=H, R,=Me

C

O

I

e

1) Na10,-0s04

M e b $ C ) e / ; O H

2) MeNHOH,NaBH3CN

Me

'

N

O

I

Me

1 2 4 : X=CH2 1 2 5 : X=O

L

'

126

127

J

(f)-geneserine (5)

SCHEME 18. Synthesis of racemic geneserine. The Fukumoto approach

246

SEIICHI TAKANO AND KUNIO OGASAWARA

b. Synthesis of Racemic Geneserine via the Radical Cyclization Route. Synthetically, the isochromanone route seemed to be far from practical since it took too many steps to reach the key intermediate l23b from the starting material via the chromanone intermediate 26 even though interesting chemistry was involved. Recently, a much shorter and more concise route to the key intermediate 123b was devised by Jones and co-workers (48) that exploits intramolecular radical cyclization as the key step. The unsaturated amide 28 obtained from the nitrobenzene 128 in three steps was cyclized to give the known oxindole 29 (44) in 63% yield via the radical intermediates 129 and 130 on treatment with 1 equiv of tri-n-butyltin hydride in refluxing toluene (49). Treatment of 29 with ally1 bromide in the presence of lithium hexamethyldisilazide afforded the key intermediate 122 of the Fukumoto synthesis in 88% yield (Scheme 19).

28

129

MeomM ' y o Me 29

130

Fukumoto synthesis -

\

y o Me

+ (+)-geneserine (5)

122

SCHEME 19. Synthesis of racernic geneserine. The Jones approach

This method, however, is still not practical from a synthetic point of view, because a much more efficient synthesis of 29 and an equivalent oxindole 12 of the Jones synthesis had already been established in 1935 by Julian and Pikl starting from p-ethoxyacetanilide (131) and employing the intramolecular Friedel-Crafts reaction in the synthesis of physostigmine (1) (38,44)(Scheme 20).

247

5 . ALKALOIDS OF THE CALABAR BEAN

EtO

1 ) Na. Me,SO,.

,

'Q,,,

A 2.

xylene

2) KOH, aq. EtOH

*

EtO0BrLMe

\

3) CH3CHBrCOBr

N

H

Me

131

132

O

alkylation "

O ' mN IM O e

I Me

Me 133

80%from 1 3 1

12: R=Et 29: R=Me

SCHEME 20. Synthesis of the 3-methyloxindoles. The Julian approach.

IV. Pharmacology The well-known pharmacological effects of (-)-physostigmine (1) are based on inhibition of acetylcholinesterase (50). (-)-Physostigmine (1)is used clinically in the treatment of glaucoma (51) and myasthenia gravis (52) and for protection against organophosphate poisoning (53).It has also been reported that oral and intravenous administration of (-)-physostigmine (1) significantly improved memory in patients with Alzheimer's disease (54). However, opposite results have also been reported (55). Brossi and co-workers (43)examined the anticholinesterase activity of (-)-N1-norphysostigmine (110), (-)-eseramine (3), and other N'substituted analogs of (-)-physostigmine (1) which were prepared readily by their synthetic method (39,4143).Among these (-)-NI-norphysostigmine (110) was found to be as potent as (-)-physostigmine (1). In uitro inhibition of acetyl- (AChE) and butyryl- (BChE) cholinesterases was also examined using carbamate analogs of (-)-physostigmine (l),and the carbamates 134,135, and 136 were all more than three times more potent against human plasma BChE than (-)-physostigmine (1) (56). Enantiomeric comparison of the physiological activities of natural (-) and unnatural (+) enantiomers of physostigmine (1) together with related compounds has also been investigated by Brossi and co-workers (57). It was found that unnatural (+)-1 inhibits acetylcholinesterase from electric eel considerably less than natural (--)-1, but the unnatural antipode exhibits lower toxicity (57) and blocks the open channel of the nicotinic

248

SEIICHI T A K A N O A N D K U N I O OGASAWARA

134 : R=n-octyl 135 : R=n-butyl 136 : R=benzyl

"3"

Me Me

139a

138

137 : X=H 140 : X=Br

Me' 'd 139b

acetylcholine receptor (42). Furthermore, the unnatural antipode was found to prevent organophosphate-induced subjunctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamoylation (58). (-)-Eseroline (W), a major metabolite of (-)-physostigmine (l),was found to be an analgesic with a potency similar to that of natural morphine (59). This finding prompted an extensive pharmacological comparison of both enantiomers of eseroline (15) and derivatives which became readily available through the development of an efficient synthesis of (-1 and (+) enantiomers of N'-noreseroline (15) ( 3 9 , 4 1 4 3 ) . Brossi and co-workers (60)found that both enantiomers of eseroline (15) bind to opiate receptors of rat brain membranes with equal affinity and show opiate agonist properties as inhibitors of adenylate cyclase in uiuo. They confirmed, however, that only (-)-eseroline (15) shows potent narcotic activity enantiospecifically similar to that of morphine, but neither (+)-eseroline (15) nor natural forms of both N'-noreseroline (137) and the open dihydroseco analog 138 show analgesic effects (60,61). Eseroline (15) in solution is extremely sensitive to autooxidation, forming red dyes, with rubreserine (139) as the major constituent (62). In relation to pharmacological investigations, Brossi and co-workers unambiguously determined its structure by X-ray diffraction analysis as a resonance hybrid of the mesomers 139a and 139b (60). (- )-7-Bromoeseroline (140), prepared from (-)-physostigmine (1) by sequential bromination with N-bromosuccinimide and alkaline hydrolysis, was reported to be a potent, centrally acting analgesic, with excellent oral activity and stability, and superior to morphine in its antinoceptive effects in rodents with significantly reduced side effects (63).

5. ALKALOIDS OF THE CALABAR BEAN

249

Acknowledgments We thank Drs. Masahiro Yonaga and Kozo Shishido for helpful suggestions and Miss Reiko Ono for preparation of the manuscript. We are also grateful to Dr. Arnold Brossi who gave us valuable reference articles and kind suggestions.

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