Chapter 6 Syntheses of Bisbenzylisoqueinoleine Alkaloids

-CHAPTER

6---

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS MAURICESHAMMA The Pennsylvania State University University Park, Pennsylvania AND

VASSILST. GEORGIEV U S V Pharmaceutical Corporation Tuekahoe, New York

I. Introduction. .... .............................................. 11. Dauricine-Type A1 oids ........................................... 111. Magnolamine-Type Alkaloids. ....................................... IV. Berbamine-Oxyacanthine-TypeAlkaloids. . . ...................... V. Thalicberine-Type Alkaloids . . . . . . . . . . . . . . ...................... VI. Trilobine-Isotrilobine-Type Alkaloids . . . . . . ...................... VII. Menisarine-Type Alkaloids .......................................... VIII. Tiliacorine-Type Alkaloids ....................... ................ I X . Liensinine-Type Alkaloids ....................... ................ X. Curine-Chondocurine-TypeAlkaloids. ................................ XI. Miscellaneous Syntheses ............................................ XII. Syntheses Using Phenolic Oxidative Coupling ......................... X I I I . Synthesis Using Electrolytic Oxidation. ....................... .. XIV. Use of Pentafluorophenyl Copper ................................. References ........................................................

319 320 336 341 348 354 357 359 361 363 381 383 387 387 389

I. Introduction Well over a hundred bisbenzylisoquinoline alkaloids are presently known. The two benzylisoquinoline units may be bonded together by one, two, or three diaryl ether linkages. When only one diaryl linkage is present, this bond is involved in tail-to-tail or head-to-tail coupling and never in head-to-head coupling. When linked by two or three diaryl ether linkages, the two benzylisoquinoline units can be bonded either head-to-head or head-to-tail. The resultant diversity in the structures of the bisbenzylisoquinoline alkaloids, coupled with their known or

320

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

potential pharmacological activity, has stimulated substantial interest in their synthesis. This chapter will deal with the preparation of bisbenzylisoquinolines in the order of their structural complexity. Although several interesting and reliable syntheses of bisbenzylisoquinolines have been worked out, e.g., those of ( )-cepharanthine, ( +)-isotetrandrine and related bases, ( + )-0-methylthalicberine, ( k )N-methyldihydromenisarine, ( k )-0-methyltiliacorine, and ( k )-cycleanine, no reliable synthesis of the pharmacologically important ( )-tubocurarine as yet exists. Furthermore, the complexity of the synthetic problem is such that the successful syntheses referred t o above are invariably long and must involve the judicious use of several functional protective groups. Biogenetic-type syntheses using phenolic oxidative coupling of monomeric benzylisoquinolines have unfortunately proven of limited value due sometimes to low yields, but more importantly because it is head-to-head coupling that occurs most readily in vitro, a mode of coupling not encountered in nature. A novel approach to bisbenzylisoquinoline synthesis concerns the electrolytic oxidation of the salts of monomeric phenolic benzylisoquinolines, but so far only one such example has been reported. The most promising new route to the bisbenzylisoquinolines involves the use ofpentafluorophenyl copper in the formation of the diary1 linkage and this method will be discussed toward the end of this chapter.

+

11. Dauricine-Type Alkaloids The first attempt a t the synthesis of a dauricine degradation product was carried out a number of years ago when dauricine methyl methine (2) was prepared and was found to be identical with material derived from naturally occurring ( - )-dauricine (3),Scheme 1 ( 1 ) . The sequence in Scheme 1 represents one of the early pioneering efforts in the bisbenzylisoquinoline series. The use of the Erlenmeyer azlactone synthesis in the preparation of the dicarboxylic acid 1 should be noted. Several syntheses of enantiomeric and diastereomeric mixtures of dauricines ( 5 ) are available. The first synthesis was accomplished through the Ullmann -+ Arndt-Eistert +Bischler-Napieralski sequence (Scheme 2). It was not possible to separate the components of the final mixture (2-5). The second synthesis is a variation of the one described above (4-6). Condensation of the diacid chloride of 6 with homoveratrylamine gave the required diamide 4.

6 0

X

Q -t

\

6

X

Q

8 0,

/ \

0

0

$ 5,

\

3

322 MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

K

U

w

N

8 8

m

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

323

6

In the third instance, Ullmann condensation of the racemic bromotetrahydrobenzylisoquinoline 7 with racemic armepavine (8) yielded, following hydrolysis, a mixture of dauricines (4-6).

7

8

R = benzyl or scetyl

The first synthesis of a clean optically active derivative of dauricine involves the preparation of ( - )-O-methyldauricine (ll),identical with material derived from the natural product (7). Controlled bromination of ( - )-armepavine yielded ( - )-3'-bromoarmepavine (9). O-Methylation then furnished 10, which was condensed under Ullmann conditions with ( - )-armepavine to supply 11, Scheme 3. Several other syntheses of O-methyldauricine are also available. The first of these follows the now well established route involving initial synthesis of the diacid chloride of 1 and its further condensation with homoveratrylamine. The ultimate product was again a product with mixed stereochemical landscape-an enantiomeric-diastereomerk mixture (8). A more arresting approach t o O-methyldauricine was carried out primarily t o prove the usefulness of Reissert intermediates (9). ( _+ )-Armepavine was first prepared in high yield through a Reissert sequence as indicated in Scheme 4. The other required moiety, ( f )-lo, was generated by either of the two routes described in Scheme 5. A related approach t o O-methyldauricine involves a rare instance of bis-Reissert reaction. The dialdehyde 13 was first prepared and then condensed with 2 moles of 12 to yield the dibenzoate 14. The corresponding diol (15) was hydrogenolyzed with hydrogen bromide and zinc in acetic acid to the bisbenzylisoquinoline 16. N-Methylation and reduction then furnished a mixture of O-methyldauricines (9). The

324

c

E

-2

5

-

D X 0,

0

fjp

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

m

6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

2

I y=0

325

326

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

CH30

3-Rromoanis-

CH,O CH30Q N , c , P h CN 12

II

0

phenyi lithium, aldehyde, - 40°C

1. KOH,

ethanol, water 2. z n . nnr

3 cH3 CH30$ Br

0--CPh

I/

0

CH30

CH30 CH30 Br

2. 1. CHJ NaBH,

CH30 \

CH3O Br

CH3O

CH3

\ ( k 1-10

or

% NaH,

CH30 Br@

NaBH4

CH30 CH,O

0

1. Zn, HBr 2. CH.1 3. NaBH+

Br

(+)-lo

CH30

SCHEME 5

yields were unusually high throughout this sequence and represent a distinct improvement over the previous syntheses. Yet another synthesis of an 0-methyldauricine mixture utilizing Reissert intermediates proceeded via the condensation of 2 moles of the anion of 12 with the diphenyl ether 17. Basic hydrolysis then yielded the bisbenzylisoquinoline 16 ( 9 ) .The use of Reissert compounds in the synthesis of bisbenzylisoquinolines has been recently further extended

(94.

6.

oHc>o

SYNTHESES OF BISBENZYLISOQUINOLINE

ALKALOIDS

327

OCH,

13

R * o < R

OCH,

\ 14 15 16

R=Ph-COO R=OH R = H

17

A synthesis of ( - )-0-methyldauricine (11) was achieved as a result of preparative work in the berbamunine series. Ullmann condensation of (-)-18 with (-)-armepavine yielded the dimer 19 which upon acid hydrolysis, and diazomethane 0-methylation supplied ( - )-0-methyldauricine (11) (10).

Br

328

\ X

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

W

6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

329

330

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

Sodium in liquid ammonia reduction of the synthetic dimer 20, a diastereomeric racemate prepared as indicated, afforded diamines 21 and 22. Compound 21 corresponds t o a mixture of dauricines, while 22 is a mixture of deoxydauricines, Scheme 6 (11).An alternate synthesis of 22 is also available through Ullmann condensation of ( k )-23 with (k)-24 (12). The latest and most efficient synthesis of ( f )-0-

OH 24

23

methyldauricine follows the classical lines outlined in Scheme 7 above. The final product was a mixture of diastereomers from which ( & )-0-methyldauricine could be separated (13). The diary1 ether 25, obtained through an Ullmann sequence, was condensed with two moles of 3-methoxy-4-benzyloxyphenethylamine. The product was the diamide 26, which was converted stepwise into a mixture of 0-methyl-0,O-dibenzylmagnolamine(27), Scheme 8 ( 1 4 ) . The dimeric immonium hydrochloride 28 had previously been obtained by a similar sequence (15).

C10 H

OCHaPh

PhCHaO

H C10

28

A first attempt t o synthesize magnoline followed the course outlined in Scheme 9 but aborted when dimer 29 failed to debenzylate (16). A modified route was then adopted which eventually provided a mixture of magnolines (30), Scheme 10 (16).

0 c1’‘GCHS

> ‘ 4

OCH,

OCH,

/p C

H

\

a

-

C \C’

-

H

25

26

SCHEME 8

27

1. pciJ 3. H,, Pt 3. HCOH, HCOOH

332

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

H

o

o

G

c

H

2

D

o

'

a

C

H

&

O

O

H

I. 9061. 2. Ethyl chloroformate

No

3-Methoxy-4benzyloxy. phenethylamine

\

OH

O\\ ,C-CH, c1

\C1

OCH,

CH,O

pN\ Fo 1. POCI. 3. 2. CH.1 NaRH,

H

SCHEME 9

4. E O H , ethanol

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

0

CHz--6, C1

//

333

0

c1

3-Methoxy-4-hydroxyphenethylamine

f

m1r3cH30p OCOOC,H,

1. Ethyl chloroformate 2. 3. CHDI POCla

H

/

t

b

\

o

H

&

OCOOCzH5

\

H3C’

30

SCHEME10

31

31

33

SCHEME 11

5. 4. NaOH, NaBH, ethanol

+

334

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

The alternate pathway to a bisbenzylisoquinoline,namely, condensation of two tetrahydrobenzylisoquinoline units by means of an Ullmann reaction, was also tried and provided a mixture of magnolines (30) (17). The same sequence was then applied using optically active intermediates. Thus, ( + )-31was condensed with ( -)-32.( - )-Magnoline(33) was generated following hydrolysis of the benzyloxy protective groups, Scheme 11 (18). It should be noted here that (-)-magnoline (33)is enantiomeric with ( + )-berbamunine. I n related work, ( 5 )-34 was condensed with ( _+ )-35to give rise to a mixture of daurinolines 36, Scheme I 2 (19).Daurinoline itself has the ( - ,- ) or (R, R ) configuration.

34

35

36

SCHEME 12

The alkaloid ( - )-cuspidaline is represented by expression 37,and a synthesis of ( f )-cuspidaline was carried out through a bis-BischlerNapieralski reaction. Following reduction, h7-methylation, and catalytic debenzylation, it was possible to separate the diastereomeric mixture of ( 5 )-cuspidaline by fractional crystallization, Scheme 13 (20). ( & )-4’-O-Methylberbamunine (38) has also been obtained by essentially the same route (20).An alternate but closely related preparation of a mixture of cuspidalines is also available using the intermediate 39 (21).

6. SYNTHESES

335

OF BISBENZYLISOQUINOLINE ALKALOIDS

COOH

I

CHaCOOH

3-Methox y-4-benzyloxy-

phcnethylamine. decalin, A

P

1

H3C

/

Fractional crystallization

_____j

SCHEM E

13

336

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

39

111. Magnolamine-Type Alkaloids The structure of magnolamine (42) was first confirmed by the synenantiothesis of the optically active tetra-0-methylmagnolamine (4l), meric with naturally derived ( + )-tetra-0-methylmagnolamine (43). Ullmann condensation of ( - )-6’-bromolaudanosine (40) with ( - )armepavine gave a small yield of 41 whose physical properties compared favorably with those of 43 (22). Likewise, a diastereomeric tetra-0methylmagnolamine was obtained by the Ullmann condensation of ( - )-6’-bromolaudanosine with ( + )-armepavine (23). A synthesis of a stereoisomeric mixture of magnolamines has been reported, but it was not possible to separate the components of this mixture (24, 25). This synthesis, which relies upon early formation of the diphenyl ether linkage, is outlined in Scheme 14.Noteworthy in this synthetic sequence are the hydrolysis of the methylenedioxy group, the further protection of the o-diphenol as the dibenzyl ether, and the bisBischler-Napieralski cyclization leading to the required skeleton of magnolamine. I n point of fact, a bis-Bischler-Napieralski cyclization had been carried out earlier in the magnolamine series when the diacid 44,obtained by either of the two routes indicated in Scheme 15, had been converted to the analog 45 of magnolamine (26). A mixture of enantiomeric and diastereomeric magnolamines has

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

0CH3 40

OCH, 41

and

OH 42

337

CH300C

COOCH,

PhCH2CI, NaOH, CHBOH

I

OH c H

3

o

o

c a ~C

O

O

C

H

3 2. 1. Basic SOCl,,hydrolysis pyridine 3. CAaN2

t

OCH,Ph OCH,Ph 3-Methoxy-4-benzyloxyphenethylamine, silver benzoate, N(C2Hda ( Arndt-Eistert)

OCH,Ph

H

OCHaPh

H3C

CH3

OH Mixture of enantiomeric and diastereomeric m a g n o l a m i n e s SCHEME 14

1. POC13 2. C H ~ I 3. NaRH, 4. Conc. HCI, ethanol

OCH,

c

’

-

c

H

z

~

o

~

~

KCN, acetone ethanol,

~

&

~

OCH, OCH, CHa-CN

-

poa~ Hydrolysis

OCH, HOOCCH,

\ OCH, I OCH,

\

44

or alternatively,

Br

-

OCH,

44 C H 3 0 0 C - H ~ C ~ o ~ C H 2 C O O C Hydrolysis H 3

\ then, 44

S0Cl2

OCH,

OCH, Diacid chloride

1. 3-Methoxy-4-benzyloxyphenethylamine 2. PC15, CHCI. (Bischler-Napieralski) 9

OCH, 45

SCHEME 16

340

M A U R I C E SHAMMA A N D VASSIL ST. GEORGIEV

also been prepared through Ullmann condensation of two tetrahydrobenzylisoquinoline units. This sequence, which uses both benzyloxy and ethoxycarbonyloxy protective groups, is shown in Scheme 16 ( 2 7 ) .The simple analog 46 of magnolamine has also been prepared through the Ullmann condensation of two tetrahydrobenzylisoquinoline units and was obtained as an isomeric mixture (28). 3H30 PhCH,O’

PhCH,O 1. POCI., toluene

C,H,OOCO

2. CH31 3. NaRH,

w

t

HO

then,

CH30

yl

PhCH,O

OCHzPh

CH3

+ HO

OCH,Ph

1. Ullmann 2. Hydrolysis

Mixture of enantiomeric and diastereomeric magnolamiries SCHEME 16

P

\

o 46

\

d

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

341

IV. Berbamine-Oxyacanthe-Type Alkaloids Initial efforts in this series provided preparations of such intermediates as 47 to 50 (29-34). The first synthesis of ( + )-tetrandrine (54) was achieved in low yield by Ullmann condensation of ( + )-N-methyl(51) coclaurine (53)with ( - )-3’,8-dibromo-N,O,O-trimethylcoclaurine

48

HOOC

COOH

49

50

obtained by bromination of 53 followed by 0-methylation. 0 , O Dimethylbebeerine (55) should have been a by-product of this condensation but was not actually isolated and characterized, Scheme 17

(35).

+

An interesting total synthesis of optically active natural ( )isotetrandrine (65) ( - )-phaeanthine (66),and ( + )-tetrandrine (54) has been achieved (36, 37). The first required intermediate, ( - )-0-benzyl-8bromolaudanidine (56), was prepared through exploitation of a Willgerodt reaction as shown in Scheme 18.

342

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

I

rtl. K I .

K~(:o~.

pyridinr. A

SCHEME 17

Another intermediate was N-tert-butoxycarbonyl-4-hydroxy-3methoxyphenethylamine (57) and the preparation of this urethan is given in Scheme 19. The tert-butoxycarbonyl group is removable by acid but is resistant to hydrogenolysis and base hydrolysis under relatively mild conditions. Ullmann condensation of 56 with 57 furnished the diary1 ether 58 in good yield. Catalytic debenzylation was followed by

55

6.

SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS

S

CHa

ll

I c=o

CF,--CN

A0

9, morpholine, A

OCHIPh OCH3

343

NaOH

OCH,Ph OCH, 1. POCl3 2. NaBR, 3. Resolution via

I-(+ )-tartaric acid salts 4. HCOH. NaBH,

OCH,Ph OCH,

/

H3C H-

a:-; Br

56

SCHEME 18

another Ullmann condensa-ion with the -bird required intermediate, namely, methyl p-bromophenylacetate, to supply the bisdiaryl ether 59, again in good yield, Scheme 20. When the bisdiaryl ether 60 was heated, the amide 61 was produced, which generated the key imine 62 upon Bischler-Napieralski cyclization. tcrt-Rutyl aaidoformate, N(CzH,)3, cthyl acetate

PhCH,O c H 3\0 p N H z

Hz.

PhCH,O 0- tert-butyl

HO 0-&t-butyl 57

/

56

+ 57

1. Hz, Pd/C, PdClz (debenzylation) 2. Methyl p-bromophenylacetate, CuO, K2C03, pyridine, A

CUO. KzCOa, pyridine, A

+

58 1. OH@, then H 3 0 @

(hydrolysis)

2. p-Nitrophenol, DCC

/N

fo

O--t&-butyl

/

59

SCHEME 20

(ester formation) 3. CF,COOH (removal Of tcrt-butoxyrarbon yl)

6.

60

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

-

345

POCI3, CHC13

DMF, pyridine, A

A

61

The reduction of imine 62 was studied under a variety of experimental conditions. With sodium borohydride in methanol, a 3 : 2 ratio of bisbenzylisoquinolines 63 and 64 was obtained, which were N-methylated t o ( + )-isotetrandrine (65) and ( - )-phaeanthine (66), respectively. But when zinc in sulfuric acid was utilized on the racemate of 62, only 64, as the racemate, could be isolated. No stereospecificity in the reduction of 62 was observed with Adains catalyst containing a trace of concentrated hydrochloric acid. AT-Methylationof racemic 64 gave a racemic compound composed of ( - )-phaeanthine (66) and its enantiomer (+)-tetrandrine (54), Scheme 21 (37).Since ( )-66has been isolated from a natural source and resolved into its optical antipodes (37a), the present synthesis amounts also t o a total synthesis of ( + )-tetrandrine. The first successful syntbssis of ( i )-cepharanthine (73), belonging to the oxyacanthine series, w5Fachieved through the Bischler-Napieralski cyclization of the key bislGtam 72. One precursor of this important intermediate was the substituted aminourethan 69, which was prepared from species 67 and 68 as shown in Schemes 22 and 23 ( 3 8 , 3 9 ) . The lower half of cepharanthine was prepared as in Scheme 24, taking advantage of the fact that a benzyloxy group can be hydrogenolyzed while a tert-butyl ester is immune. Condensation of 69 w i t h 9 0 furnished the urethan 71, which was converted to the bislactam 32. Bischler-Napieralski cyclization gave a bisimine, which could be rexuced to a bis secondary amine either with

346

x 0

s + i!

x 0

X

0

.%&

0

X

V

V

0

,

O

\

z ‘x

-

0

W

W

In W

;& -

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

u, X

6.

SYNTHESES OF BISBENZYLISOQUINOLINE

I

Br

347

ALKALOIDS

Br

67

SCHEME 22

Adams catalyst or with sodium borohydride. Since the ratios of the two diastereomers obtained from each of these reductions were different, the available mixtures of secondary amines were combined, Nmethylated, and then separated by chromatography. One of the products isolated proved t o be ( & )-cepharanthine (73),Scheme 25 (38'39). It was found possible t o convert the unusual bisbenzylisoquinoline alkaloid stepinonine (74) to N,O-dimethyltetrahydrostepinonine(75), which in turn could be selectively oxidized with Jones' reagent to the

C

H

3

0

rNo1

1. Ethyl chloroformate, pyridine

Ph-CH,

2. Zn/Hn, HCI

-0-

H0

C

\

CI

C,H,OCO

HO

It

0 CH30 HO 0

OCHpPh

OCHIPh 68

then,

67

+ 68

1. CuO, K1C03. pyridine, A

2. Dil. HCI (formyl hydrolysis)

OCH,Ph 69

SCHEME 23

348

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

COOH

COO-tert-Bu ter2-Butyl alcohol, POC13, pyridine

OCHSPh COO- tert-Bu

H a , PdtC

~

bOCH2€?h

A

~OOCH. p-Toluen esulfonic acid (removal of CU,A ( ~ l ~ r n a n n )

tcrl-Bu group)

+

70

SCHEXE24

ketone 76. R e d u c h n of this ketone first with zinc in acetic acid and then with sodium borohydride yielded a mixture of O-methylrepandine (77) and O-methyloxyacanthine (78) (39a). A mixture of enantiomeric and diastereomeric berbamines (82) and oxyacanthines (83) was obtained through the following sequence. Schotten-Baumann reaction of the diamine 47 with the diacid chloride 79 gave amides 80 and 81, which could be separated. Bischler-Napieralski cyclization using phosphorus oxychloride produced the corresponding 3,4-dihydroisoquinolines. N-Alkylation with methyliodide, borohydride reduction, and subsequent acid hydrolysis generated isomeric mixtures of berbamine 82 and oxyacanthine 83, respectively (39b).

V. Thalicberine-Type Alkaloids ( + )-Thalicberine (84) and ( +)-O-methylthalicberine (85) are representative of a group of bisbenzylisoquinoline alkaloids found in Thalictrum species (Ranunculaceae), and a synthesis of ( + )-O-methylthalicberine has been reported (40, 41). Ullmann condensation of ( + )-O-benzyl-8-bromolaudanidine (86) with the phenolic tert-butylurethan 87 afforded the diary1 ether 88, which was then hydrogenolyzed t o the phenol 89, Scheme 26.

CH,O'

1. POClD

HN

2. H., Pt or NaRHI

3. HCOH.NaBH,

4. Chromatography

\ H3C

H

78

79.

SCHEME 25

6. SYNTHESES OF BISEENZYLISOQUINOLINE ALKALOIDS

351

352

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

84 85

R = H R = CH,

CuO, K,CO.,

+

0-tert-Bu

OCHaPh 86

87

0- tert-Bu

OCH,Ph 88

0 -tert-Bu

OH 89

SCHEME 26

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS Y)

m

LI

a

1

m

\

353

354

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

Phenol 89 was condensed in a second Ullmann condensation with methyl-p-bromophenylacetate to yield the ether 90, which was converted to the amide 91 by the p-nitrophenyl ester method. BischlerNapieralski cyclization then gave the imine 92. Reduction of this imine with sodium borohydride gave only a single compound, namely, the desired amine 93. N-Methylation furnished the final product, ( + )-O-methylthalicberine (85)) identical with the natural material, Scheme 27.

VI. Trilobine-Isotrilobine-Type Alkaloids The alkaloids ( + )-trilobine (94) and ( + )-isotrilobine (95) possess a diphenylenedioxy bridge connecting the two top aromatic rings. It has been possible to interrelate chemically bases of the berbamineoxyacanthine group, which contain two diary1 ether linkages, to those belonging to the trilobine-isotrilobine series, and these interrelationships will be discussed briefly here. When naturally occurring ( )-isotetrandrine (65) was heated with hydrobromic acid a t lOO"C, the demethyl derivative 96 was obtained. This derivative cyclized to the trilobine-type compound 97 upon more drastic treatment with hydrobromic acid, and diazomethane O-methylation yielded the methyl ether 98, Scheme 28 (42).

+

94 95

R = H R = CH,

I n a similar vein, ( + )-tetrandrine (54)) which is diastereoisomeric with ( + )-isotetrandrine (65), was converted to the diphenylenedioxy derivative 99 (43). The starting alkaloids in the two examples above belong to the berbamine series, but diphenylenedioxy formation can also be brought about in the oxyacanthine series. Thus, oxyecanthine (100) itself was converted into the derivative 101 (44) while N-methyldihydroepistephanine (102)led to the levorotatory antipode 103 of natural

6.

H3C

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

CH3

H

355

HBr, 100°C,3 hours

65

H3C a > ?/N 'H &

/

HBr. 130-135°C, 3 hours

/ \

0 \

OH 96

97

98

SCHEME 28

54

R = H R = CH3

~

356 MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

6.

SYNTHESES OF BISBENZYLISOQUINOLINE

357

ALKALOIDS

104 1. HBr, HOAc, 100°C 2. HBr, 140-145°C

3. CHaNa

t

(+-1-95

SCHEME 29

( + )-isotrilobine (45).Finally, taking advantage of the known fact that in dilute acid ( + )-oxyacanthine (100) undergoes isomerization to ( - )-repandine (104),it was found possible to convert ( + )-oxyacanthine into natural ( + )-isotrilobine, Scheme 29 (46). Inubushi and co-workers have recently adapted their synthesis of ( + )-isotetrandrine and ( - )-phaeanthine to preparations of ( + )obaberine and ( -t)-trilobine (46a).

VII. Menisarine-Type Alkaloids The alkaloid ( + )-menisarine possesses the structure 105, which incorporates a diphenylenedioxy bridge, and an interesting synthesis of ( )-N-methyldihydromenisarine (107) has been achieved. The first stage of the synthesis concerned the preparation of the diamine 106, which was carried out via a double Ullmann, as shown in Scheme 30 (47, 48). The lower half (1) of the molecule was prepared using a Willgerodt reaction as per Scheme 31.

105

358

MAURICE SRAMMA AND VASSIL ST. OEORGIEV

cu, pyridine. A

Br

t

OCH,

OH

OH

OCH,

OCH,

106

SCHEME 30

Condensation of the diacid chloride of 1 with the diamide 106 a t high dilution, followed by Bischler-Napieralski ring closure, reduction, and Eschweiler-Clarke N-methylation furnished the desired racemic product 107, Scheme 32 (47, as), which was spectrally identical with the product derived from the reduction and N-methylation of natural ( + )-menisarine (105).

don

1. CH&OCI, AICI., 2. Dlmethyl GS. sulfate

0

II

'

~

0

0

c

~

c

HWillgerodt 3

6. 108

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

+ Diacid chloride of 1

359

+

2. NaBH,

107

SCHEME 32

VIII. Tiliacorine-Type Alkaloids ( + )-Tiliacorine and its diastereomer ( + )-tiliacorinine have been assigned structure 108 on the basis of extensive degradative studies ( 4 t h ) .These two alkaloids are unusual in having a biphenyl system in lieu of the usual diary1 linkage. A total synthesis of ( k )-O-methyltiliacorine (109) has been described in detail (49). Unsymmetrical Ullmann condensation of the bromophenols 110 and 111 yielded a mixture of three products from which the desired diester 112 was isolated by chromatography. Homologation and conversion to the diamine 113 was followed by condensation with the diacid chloride 114. The resulting bisamide 115 was converted to a mixture of ( f )-0methyltiliacorine and O-methyltiliacorinine by well established transformations. Careful chromatography of this mixture yielded ( f )-0methyltiliacorine, spectroscopically and chromatographically identical with material derived from the alkaloid. The diastereoisomeric ( f )-0methyltiliacorinine was obtained only in trace amounts, Scheme 33 (49).

360

MAIJRICE SHAMMA A N D VASSIL ST. GEORGIEV

C H 3 O O C ~ O C H a ~

'

1. K salts formation

B r D 2. 3. c Cu-bran=, Chromatography 0 diphenyl 0 ether, c A H 3

t

\

HO

OH

Br 110

C

111

H

3

0

0

C

vD C O O C H ,

1. LiAlH, 2. 3. S0Clz KCN 4. H.,

o\ 112

113

then,

113

+

COCl

__f

114

115

NYR)

6.

SYNTHESES OF BISBENZYLISOQUINOLINE

ALKALOIDS

361

1. CHJ 2. NaBH, 3. POC1. 4. H2, Pt

5. HCOH, HCOOH

t

108 R = H 109 R = CH,

SCHEME 33

IX. Liensinine-Type Alkaloids The alkaloid ( + )-liensinine (118) incorporates head-to-tail coupling through a diary1 ether linkage. A total synthesis of this alkaloid was achieved on the heels of the initial isolation and characterization reports. Ullmann condensation of ( - )-116 with ( - )-117 followed by hydrolysis gave the optically active alkaloid (50, 51). A synthesis of a diastereomeric mixture of liensinines, by a somewhat similar pathway, is also available ( 5 2 ) . The related alkaloid ( - )-isoliensinine (122)yields ( - )-O,O-dimethylisoliensinine (121)on treatment with diazomethane. Derivative 121 was synthesized by Ullmann condensation of ( - )-119 with ( - )-120 (53). Finally, optically active ( - )-isoliensinine (122) was obtained by the sequence in Eq. 1 ( 5 4 ) .Worthy of attention are the new conditions for the Ullmann condensation ( 5 2 , 5 4 )involving the use of copper powder, potassium carbonate, a small amount of potassium iodide, and dry pyridine heated to 155-160'c in a current of nitrogen. These conditions give better yields (about 15y0)than the usual Ullmann condensation. The newer base ( - )-neferine (123), related t o liensinine and isolienshine, was synthesized by a similar approach (Eq. 2 ) (55).

CH,O

HO

PhCH,O

Y~cH,\ /

\

+

I IBr I / I Y \ C H 3

PhCH,O

\

116

1. Ullmann 2. H,OB

cH30m

117

‘CH,

Hac,5:>:3 O

\ b

F

O

O

I

OCH,

119

120

H

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

CH,O

363

PhCH,O

LY

CH30

CuO, K.COa. pyridine, A

\CH,

HO CH30 0R

!

\

C

CH,

H

,

1 OCH,

OCH, 123

X. Curine-Chondocurine-Type Alkaloids

It was conclusively demonstrated in 1970 that the hitherto accepted structure for the alkaloid ( + )-tubocurarine,which had been represented as 124, was in error and that the correct structure is 125 (56, 57). This finding was of particular interest not only because of the importance of ( )-tubocurarine as a neuromuscular blocking agent, but also because of the fact that supposed total syntheses of the racemic di-0-methyl ether of tubocurarine iodide as well as of racemic tubocurarine iodide

+

364

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

c

H

3

0

m

X0 ,H

$4 \

I

0

124

m

125

had been claimed previously. A description of the synthetic work on tubocurarine follows. This description is complicated not only because of the above mentioned change in structural assignment, but also by the failure of the workers involved in the synthetic work in clearly differentiating between enantiomers, racemates, and diastereomers while comparing samples (58-62). As a preliminary attempt at the synthesis of the dimethyl ether of tubocurarine, the simple dimer 126 was constructed as described in Scheme 34. The product 126 was obtained as a mixture of two diastereomers from which the predominant racemate (mp 96-99°C) could be isolated (58). Essentially the same approach was utilized in the preparation of the so-called “di-0-methyl ether of tubocurarine iodide ’) (127), Scheme 35 (58, 59). The UV spectrum of one salt so obtained was apparently close t o or identical with the spectrum of an authentic sample of the di-0methyl ether of ( + )-tubocurarine iodide, and this finding was taken as proof of structure.* It must be pointed out, however, that most tetrahydrobenzylisoquinolines, as well as bisbenzylisoquinolines such as tubocurarine or its dimethyl ether, exhibit a maximum absorption near 280 nm, so that UV spectroscopy is not a reliable basis for comparison. Another criterion used was a mixture melting point between the

* There seems to be some confusion in the assignments of melting points of the final products. I n reference ( 5 8 ) , two supposed diastereomeric tubocurarine iodides were obtained (mp 131-135°C and 223-228°C). But in reference ( 5 9 ) , only one melting point was quoted [mp 257-268°C (ethanol)]. This latter material apparently gave no melting point depression with a sample of the natural salt (mp 262-264”C), even though no formal resolution was carried out on the synthetic material.

6.

365

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

CH,O

CH,O C

PhCH,O

___,

3' H

HO

,

'

O

P N,

"

CH3 C H 3 0

r

~

3

'

+

(636 ..jCx; 5'6

CH,O

CH,O

CH30\/ G

N

\

C

H

,

1.

Homoveratrylaminr

,

N\CH3

0

2. PO('I3

\

CH,

I

/

OCH,

CH,

OCH3

COOCH, OCH,

SCHEME 34

I . H,, Pt 2. HC'OH, HCOOH

cH30)3? Jy ' FOOH

+

HO

NHa

PhCH,O

PhCH,O

Ly

Cu, KOH, pyridine, 16O-18O0C

2. 209. HCI, A, 2 hours

z

OCH,Ph

OCH, OCH,

1. Zn, dil. HOAc, A, 1.5 hours 2. CHJ.CH30H

I "H 3 c \ : f 0 C H 3 H,C/ OCH,

OCH, SCHEME 35

127

368 MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

m

e

a 0, m

0

6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

U

4

m c

9

369

w

t

6.

SYNTHESES OF BISBENZYLISOQUINOLINE

ALKALOIDS

371

naturally derived dextrarotatory di-0-methyl ether of tubocurarine iodide and the synthetic isomer, in which apparently no depression was observed. Such a comparison is, of course, invalid since (a) a racemate usually has a different melting point from that of a pure enantiomer, (b) melting points of bisbenzylisoquinoline salts are often unreliable and difficult t o reproduce, and (c) the structure assigned to ( + )-tubocurarine and its di-0-methyl ether was in error in the first place. A synthesis of the unsubstituted tubocurarine analog 129 is also known, Scheme 36 (63). The product proved t o be a mixture of two racemates, mp 225227°C and 121-124°C. As an extension of the synthetic work on the so-called “di-0-methyl ether of tubocurarine,” a preparation of the di-0-methyl ether of racemic chondodendrine (130) was carried out, Scheme 37 (64). A slightly different approach t o the so-called “di-0-methyl ether of tubocurarine” has also been recorded, Scheme 38 (60). The starting material was the diimine 131, which was known from previous work. Each of the two diastereomeric racemates of 132 gave two bismethiodides upon treatment with methyl iodide, a result that is somewhat difficult to rationalize; and one of these four isomeric salts, namely, that melting 257.5-259”c, was claimed to be identical with the dextrorotatory di-0-methyl ether iodide of natural ( + )-tubocurarine iodide. The criteria for comparison were simply closeness of UV spectra and melting points. A claim of a synthesis of a material assumed t o be identical with natural ( + )-tubocurarine iodide was put forward, even though an actual

1. Cu, K,COa,

CH,

2. Zn, HOAc

% Bismethiodide salts

131

133 SCHEME 38

372

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

CH30 K@ ‘0

, Cu, A

+

OCHaPh CH,O

Ac.0, pyridine

0

----.-+

A

OCHaPh

CHa

OCHaPh

I COOCH, CHa &:H

OCH, 133

C H d , NaOH, CH30H, A

3”’

OCH,

HNdo HN ’ OCH,Ph

Br

OCH,Ph

CH,

OCH,

184

OCH,

135

6.

SYNTHESES OF BISBENZYLISOQUINOLINE

ALKALOIDS

373

then,

IQ

134

H H,C' 3

c

,

IQ

l

H~ OCH,

136

SCHEME 39

separation of optical isomers had not been carried out. This synthesis is further obscured by the fact that two phenols corresponding t o structure 133were asserted t o exist, as well as two of the acetates 134 and two of the diamides 135.The final salt 136 was obtained as two compounds, one melting 257-260.5"C and the other 210-212°C. The former salt was claimed to be identical with (+)-tubocurarine iodide on the basis of UV spectral comparisons and identity of melting points ( !), Scheme 39 (61),even though no separation of enantiomers was performed. 1. A c p O 2. P0Cl3, C H C L A 3. H30@ 4. Cu, K.C03, pyridine, 150-1 80°C 5. Zn , AOAc

$H2

t

OCH,Ph HN&OH

HN&oH

/ OCH,

137

SCHEME 40

OCH,

374

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

Finally, a synthesis of racemic so-called N , N ’-demethylchondodendrine ” (137)) erroneously assumed by the authors t o be identical with chondrofoline, has also been advanced and is described in Scheme 40 (62).Two products were obtained a t the conclusion of the sequence, and one of them was assumed to correspond t o chondrofoline on the basis of UV spectral comparisons and a negative Millon test. It was later shown by other workers that the correct structure for chondrofoline is 138 (65)) so that the claim of a synthesis of chondrofoline is unfounded (62). ((

H

3

c

,

: 0~

3

OCH, 138

I n other attempts a t the synthesis of tubocurarine-type bases, Ullmann condensation of the dibromotetrahydrobenzylisoquinoline 139 with the N-methylcoclaurine salt 140 was investigated but did not lead t o characterizable product (66).Studies of the efficient Ullmann condensation of phenols with aromatic halides substituted a t the ortho position(s)with nitro group(s)have been carried out and have culminated in the preparation of the imide 141 (67-69). 0,O-Dimethylcurine (143) was presumably obtained in the course of the previously described syntheses. But a more reliable preparation of this compound involves the Ullmann condensation between the levorotatory dibromotetrahydrobenzylisoquinoline 139 and the levorotatory diphenolic tetrahydrobenzylisoquinoline 142 (70). When the catalyst for the condensation consisted of cuprous chloride in the presence of potassium carbonate and pyridine and the conditions were heating a t 155-165’C for 24 hours, a small yield of optically active 0,O-dimethylcurine (143) together with a larger amount of 144 was obtained. When, however, the two starting tetrahydrobenzylisoquinolines were racemic rather than levorotatory and the catalyst was cupric oxide in pyridine

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

375

141

heated a t 160-170°C for 50 hours, the products consisted of a small yield of a mixture of 0,O-dimethylcurines together with a mixture of tetrandrines and isotetrandrines (54), as well as a mixture of 144. Ullmann condensation of 2 moles of the racemic phenolic tetrahydrobenzylisoquinoline 145 followed by N-methylation yielded the hayatine analog 146 (2'1). Turning now to the structurally simpler alkaloid ( - )-cycleanbe (147), a promising route to its preparation appeared to be Ullmann condensation of 2 moles of 8-bromoarmepavine, since the alkaloid is symmetrical.

376

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

1. Cu, aq. NaOH, A 2. C H J

c1

OCH,

145

'o

OCH3 146

One such attempt using ( k )-8-bromoarmepavine (148) and the superior cupric oxide-potassium carbonate-pyridine catalyst gave some of the dimer 149 but none of the expected mixture of cycleanines (72). A fully authenticated first total synthesis of ( k )-cycleanine (147) involved as a first hurdle the synthesis of the amino acid 151 as well as that of its corresponding methyl ester 155 (73, 7 4 ) . The aldehyde 150 was condensed with nitromethane to give a yellow nitrostyrene. Catalytic hydrogenation over Adams catalyst in acetic acid then gave the required amino acid 151, Scheme 41. Furthermore, the methyl ester 155 of the acid 151 was synthesized by the following alternate route. 3,4-Dimethoxy-5-bromophenethylamine, prepared by the reduction of the nitrostyrene 152 under Clemmensen CH,O CH30

:\CH3

+I$

::::q cH30 Br

6 44 CH,

CH,O

CH3

OH

H 3 c \ : M 0 C H 3

CH, OCH,

147

OCH, 148

I49

cH30vcH0 4 *(I 6.

SYNTHESES OF BISBENZYLISOQUINOLINE

CH30

1. CH3NOa

ALKALOIDS

377

"CH30 " " T N H ,

2. Ha, Pt, HOAc

CH,COOH

CH,COOH

150

151

SCHEME 41

conditions, was converted to the N-carbobenzoxy derivative 153. Ullmann condensation between 153 and methyl p-hydroxyphenylacetate afforded the product 154, and catalytic removal of the blocking group gave rise to the desired methyl ester 155, Scheme 42. The amino acid 151 was next protected as its N-carbobenzoxy derivative 156. Condensation between 155 and 156 furnished the amide 1. Zn/Hg, HCl c

H

3

0

T

v

"

0

2

2. Ph-CHP-O-C

' 40

c1

CH30 Br 152

CH,O

cH30qT

H o ~ c H 2 - - C O O C H I . CuO, K.CO3, pyridine

Br

t

OCH,Ph

153

CH30

CH&OOCH, 154

SCHEME 42

CH2COOCHS 155

378

=.I;

I

“s

0, M

I

0

G

MAURICE SHAMMA AND VASSIL ST. OEORGIEV

6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS m

+

379

380

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

157, which was converted t o the carboxylic acid 158. Esterification of 158 with p-nitrophenol and DCC was followed by treatment with hydro-

gen bromide to remove the carbobenzoxy group. The resulting amine hydrobromide 159 readily suffered cyclization t o the bisamide 160, and Fischler-Napieralski cyclization followed by reduction led to a mixture of tetrahydroisoquinolines. N-Methylation finally furnished a mixture

cH30v cH30 44 66

CH,O

Po

\

CH30

HN&z s”^

N\CH3

OCH,Ph

3 H c

o & .

.

OCH,Ph

.

.

H .C \ N ) OCH,

163

164

OCHaPh

I

I

H,CLN&

CH, OCH, 165

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

381

of products which generated ( t )-cycleanhe (147)after chromatography. Two other products obtained from the chromatographic separation were the dimers 161 and 162, Scheme 43. A later study in the cycleanine series demonstrated that BischlerNapieralski cyclization of the amide 163 proceeds in two directions to supply ultimately amines 164 and 165 (75). XI. Miscellaneous Syntheses The alkaloid aztequine was supposedly isolated from the leaves of yoloxochitl, Tabma mexicana Don. (Magnoliaceae) and was assigned structure 166 with no delineation of stereochemistry. This assignment is certainly in error, since in the same paper the unlikely claim was made that hydroiodic acid ruptured the diaryl ether linkage of the alkaloid without touching the methoxyl groups (?‘G).

I

I

OH

166

OH

Attempted syntheses of 166 either involve initial preparation of the diaryl ether corresponding to the two bottom rings, followed by further elaboration to construct the two tetrahydroisoquinoline units, or include an Ullmann condensation to bond together the two tetrahydrobenzylisoquinoline units (77-79). The bisbenzylisoquinolines 167, 168, and 169, which have no analogs in nature, have been synthesized through Ullmann condensation between 170 and 171 in the case of 167; 172 and 173 in the case of 168; and 174 and 175 in the case of 169 ( 8 0 , S l ) .

167

382

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

168

169

170 R, = OH, R, = H 171 R1 = Br, R, = H 172 R, = H, Ra = OH 173 R, = H, R, = Br 174 R1 = H, RP = OH 175 R, = Br, R, = H

The dimer 176 has also been prepared in the course of a study of structural requirements for tumor-inhibitory activity among bisbenzylisoquinolines (13).

Lastly, an important related synthesis that should be a t least mentioned here in passing is that of the alkaloid ( + )-thalicarpine (177), which is an aporphine-benzylisoquinoline rather than a bisbenzylisoquinoline (82-84).

6.

383

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

XU. Syntheses Using Phenolic Oxidative Coupling Historically, significant attempts a t the phenolic oxidative coupling of tetrahydrobenzylisoquinoline free bases were reported as early as 1932, but they generated only dibenzopyrrocolines (85, 86). The first phenolic oxidative coupling leading to a bisbenzylisoquinoline was not reported until 1962, when it was shown that ferricyanide oxidation of the quaternary salt ( +_ )-magnocurarine iodide (178) at pH 10 yielded the dimer 180 in 1Sy0yield (87, 88).

-0‘

RO

178 R = H

179

R = CH3

XQ

0 # RO

OR

R = H 181 R = CH, 180

x@

384 MAURICE SHAMMA AND VASSIL ST. GEORGIEV

6.

SYNTHESES OF BISBENZYLISOQUINOLINE

ALKALOIDS

385

Similarly, ( f )-4’-O-methylmagnocurarine iodide (179) furnished the corresponding dimer 181, while ( )-armepavine methiodide, which has a methoxy group a t C-7 and a hydroxy a t C-4‘, could not be dimerized (87-89). I n a variation on this theme, and using the free base instead of the quaternary salt, it was demonstrated that ferricyanide oxidation of ( f )-4’-O-methyl-N-methylcoclaurine (182) in a two-phase system of chloroform-0.1 N sodium carbonate (pH 11.4) a t or below room temperature resulted in formation of the racemic diastereomers 183 and 184 in about 15% yield and separable by chromatography, Scheme 44 (901. It will be recalled that in an initial attempt it had been found that ( k )-armepavine methiodide did not dimerize a t room temperature. Reexamination of this oxidation under more severe conditions, namely, 0.1 N sodium carbonate solution and potassium ferricyanide on a steam bath or 1 N sodium hydroxide and silver nitrate a t room temperature, produced the carbon-carbon dimer 185 in about 15y0 yield (91,92).

185

In an atte.mpt to prepare the aporphine base ( f )-N-methylcaaverine (186) by phenolic oxidative coupling, the ferric chloride oxidation of racemic tetrahydrobenzylisoquinoline 187 was investigated. The products were the dienone 188 in 2.4y0 yield and the dimeric benzylisoquinoline 189 in 1.1% yield, Scheme 45 (93). A few studies have also been concerned with the enzymatic oxidation of tetrahydrobenzylisoquinolines. Oxidation of ( 5 )-N-norarmepavine (190) a t pH 6.5 with crude horseradish peroxidase and hydrogen peroxide yielded a complex mixture that included small yields of the isoquinolines 191, 192, and 193, Scheme 46 (94). Other investigations have dealt with the enzymatic oxidation of phenethyltetrahydroisoquinolines (95, 96).

c HO H 3 0 p N \ C H 3

CH3

aq. FeCl,, 30:40'C

+ H3C'

J&K l.

N

HO 188

187

186

SCHEME 45

CH3

'

\ 189

OH

6.

HO

SYNTHESES OF BISBENZYLISOQUINOLINE

J 9 190

ALKALOIDS

387

cH30pJ CH,O

191

HO OH

OH 192

198

SCHEME 46

XIII. Synthesis Using Electrolytic Oxidation The first preparation of a naturally occurring bisbenzylisoquinoline alkaloid, namely, dauricine, using an oxidative method occurred when the sodium salt of ( )-N-carbethoxy-N-norarmepavine (194) was subjected to electrolysis using tetramethylammonium perchlorate as the electrolyte, a graphite anode, and a platinum cathode (97). A mixture of the dimers 195 and 196 was obtained and separated. The dimer 196 then furnished a racemic and diastereomeric mixture of dauricines 3 following 0-benzylyation, reduction, and catalytic debenzylation. Such an electrolytic oxidative dimerization was unsuccessful when the nitrogen function was not protected, Scheme 47.

XIV. Use of Pentafluorophenyl Copper The most promising avenue to the bisbenzylisoquinolines presently appears to be via an improved Ullmann diary1 ether synthesis utilizing pentafluorophenyl copper in dry pyridine. Thus condensation of

388

mz -

MAURICE SHAMMA AND VASSIL ST. GEORGIEV

CaH5OOC /N

Electrolysis in wet

acetonitrile

b

O

e Nee

194

C2H,00C/N

CH,O

OCH,

195

+

196

then,

H3C’

1. 2. PhCH.CI, ImiAIH4 base

196

3. H., PdIC

NP

O

C

HOCH3 3

t

SCEEME 47

cH3 CH3O

6.

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

389

( + ) - 6'-bromolaudanosine (197)with ( + )-armepavine and pentafluoro-

phenyl copper in dry pyridine gave an impressive 53y0yield of the dimer 198, the S,S isomer of tetra-0-methylmagnolamine (98). Analogous condensations have also led to the preparation of aporphine-benzylisoquinoline dimers (98).

I

OCH, 198

REFERENCES

H. Kondo, Z. Narita, and S. Ueyo, Ber. 68, 519 (1935). T. Kametani and K. Fukumoto, Pet. Lett. 2771 (1964). T. Kametani and K. Fukumoto, J. Chem. SOC.6141 (1964). K. Fujitani, Y. Aoyagi, and Y. Masaki, Yakuqaku Zasshi 84, 1234 (1964). K . Fujitani, Y. Aoyagi, and Y. Masaki, Yakuqaku Zasshi 86, 654 (1966). T. Kametani, S. Takano, R. Yanase, C. Kibayashi, H. Ida, S. Kano, and K. Sakurai, Chem. Pharm. Bull. 14, 73 (1966). 7. M. Tomita, K. It6, and H. Yamaguchi, Chem. P h a m . Bull. 3, 449 (1955). 8. I. N. Gorbacheva, G. V. Bushbek, L. P. Varnakova, L. M. Shulov, and N. A. Preobrazhenskii, Zh. Obxh. Khim. 27, 2297 (1957). 9. F. D. Popp, H. W. Gibson, and A. C. Noble, J . Orq. Chem. 31, 2296 (1966). 9a. D. C. Smith and F. D. Popp, J . Heterocycl. Chem. 13, 573 (1976). 10. T. Kametani, K. Sakurai, and H. Iida, Yakugaku Zasshi 88, 1163 (1968). 11. K. Fujitani and Y. Masaki, Yakugaku Zasshi 86, 660 (1966). 1. 2. 3. 4. 5. 6.

390

MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

12. M. Tomita and J. Niimi, Yakugaku Zasshi 79, 1019 (1959). 13. S. M. Kupchan and H. W. Altland, J. Med. Chem. 16, 913 (1973). 14. I. N. Gorbacheva, L. P. Varnakova, E. M. Kleiner, I. I. Chernova, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 28, 167 (1957). 15. I. N. Gorbacheva, E. N. Tzvetkov, L. P. Varnakova, A. I. Gavrilova, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 25, 1423 (1955). 16. T. Kametani, R. Yanase, S. Kano, and K. Sakurai, J. Heterocycl. Chem. 3,239 (1966). 17. T. Kametani, H. Iida, and K. Sakurai, Chem. Pharm. Bull. 16, 1623 (1968). 18. T. Kametani, H. Iida, and K. Sakurai, J. Chem. SOC.C 500 (1969). 19. T. Kametani, S. Takano, T. Kobari, H. Iida, and M. Shinbo, Chem. Pharm. Bull. 16, 1625 (1968). 20. M. Tomita, K. Fujitani, Y. Masaki, and Y. Okamoto, Chem. Pharm. Bull. 16, 70 (1968). 21. T. Kametani and F. Satoh, Chem. Pharm. Bull. 16, 773 (1968). 22. M. Tomita and K. It6, Yakugaku Zasshi 78, 103 (1958). 23. M. Tomita and K. It6, Yakugaku Zasshi 78, 605 (1958). 24. T. Kametani and H. Yagi, Tet. Lett. 953 (1965). 25. T. Kametani and H. Yagi, Chem. Pharm. Bull. 14, 78 (1966). 26. I. N. Gorbacheva, M. I. Lerner, G. G. Zapesochnaya, L. P. Varnakova, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 27, 3353 (1957). 27. T. Kametani, H. Yagi, and S. Kaneda, Chem. Pharm. Bull. 14, 974 (1966). 28. J. Niimi, Yakugaku Zmshi 80, 123 (1960). 29. H. Kondo, H. Kataoka, and Y. Baka, Annu. Rep. I T S U U Lab. 5 , 59 (1954); C A 49, 14781e (1955). 30. H. Kondo, H. Kataoka, and K. Kigasawa, Annu. Rep. I T S U U Lab. 6, 46 (1955); C A 50, 10113a (1956). 31. W. M. Whaley, L. Starker, and M. Meadow, J. Org. Chem. 19, 833 (1954). 32. W. M. Whaley, L. N. Starker, and W. L. Dean, J. Org. Chem. 19, 1018 (1954). 33. W. M. Whaley, W. L. Dean, and L. N. Starker, J. Org. Chem. 19, 1020 (1954). 34. W. M. Whaley, M. Meadow, and W. L. Dean, J. Org. Chem. 19, 1022 (1954). 35. M. Tomita, K. Fujitani, and T. Kishimoto, Yakugcku Zasshi 82, 1148 (1962). 36. M. Tomita, Y. Inubushi, and Y. Masaki, Japanese Pat. 7121396; CA 76, 59845b (1972). 37. Y. Inubushi, Y. Masaki, S. Matsumoto, and F. Takami, J. Chem. SOC.C 1547 (1969). 37a. S. M. Kupchan, N. Yokoyama, and B. S. Thyagarajan, J. Pharm.Sci. 50,164 (1961). 38. M. Tomita, K. Fujitani, and Y. Aoyagi, Tet. Lett. 1201 (1967). 39. M. Tomita, K. Fujitani, Y. Aoyagi, andY. Kajita,Chem. Pharm. Bull. 16,217 (1968). 39s. T. Ibuka, T. Konoshima, and Y. Inubushi, Chem. Pharm. Bull. 23, 133 (1975). 39b. T. Kametani, H. Iida, S. Kano, S. Tanaka, K. Fukumoto, S. Shibuya, and H. Yagi, J. Heterocycl. Chem. 4, 85 (1967). 40. E. Fujita and A. Sumi, Chem. Pharm. Bull. 18, 2591 (1970). 41. E. Fujita, A. Sumi, and Y. Yoshimura, Chem. Pharm. Bull. 20, 368 (1972). 42. M. Tomita, Y. Inubushi, and M. Kozuka, Chem. Pharm. Bull. 1, 360 (1953). 43. Y. Inubushi, Chem. Pharm. Bull. 2, 1 (1954). 44. Y. Inubushi and M. Kozuka, Chem. Pharm. Bull. 2 , 215 (1954). 45. M. Tomita and H. Furukawa, Yakugaku Zasshi 83, 676 (1963). 46. M. Tomita and H. Furukawa, Yakugaku Zmshi 84, 1027 (1964). 468. Y. Inubushi, Y. Ito, Y. Masaki, and T. Ibuka, Tet. Lett. 2857 (1976). 47. M. Tomita, S. Ueda, and A. Teraoke, Tet. Lett. 635 (1962). 48. M. Tomita, S . Ueda, and A. Teraoka, Yakugaku Zmshi 83, 87 (1963).

6.

SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS

391

48a. M. Shamma, J. E. Foy, T. R. Govindachari, and N. Viswanathan, J . Org. Chem. 41, 1293 (1976). 49. B. Anjaneyulu, T. R. Govindachari, and N. Viswanathan, Tetrahedron 27,439 (1971). 50. Y.-Y. Hsieh, P.-C. Pan, W.-C. Chen, and Y.-S. Kao, Sci. Sin. 12, 2018 (1964); C A 62, 9184b (1965). 51. Y.-Y. Hsieh, P.-C. Pan, W.-C. Chen, and Y . 3 . Kao, Yao Hsueh Hweh Pao 13, 166 (1966); C A 65, 8979d (1966). 52. T. Kametani, S. Takano, K. Masuko, and F. Sasaki, Chem. Pharm. Bull. 14,67 (1966). 53. M. Tomita, H. Furukawa, T. H. Yang, and T. J. Lin, Tet. Lett. 2637 (1964). 54. T. Kametani, S. Takano, H. Iida, and M. Shinbo, J. Chem. SOC.C 298 (1969). 55. H. Furukawa, Yakugaku Zasshi 85, 335 (1965). 56. A. J. Everett, L. A. Lowe, and S. Wilkinson, Chem. Commun. 1020 (1970). 57. H. M. Sobell, T. D. Sakore, S. S. Tavale, F. G. Canepa, P. Pauling, and T. J. Petcher, Proc. Natl. Acad. Sci. U.S.A. 69, 2212 (1972). 58. L. V. Volkova, 0. N. Tolkachev, and N. A. Preobrazhenskii, Dokl. Akad. NaukSSSR 102, 521 (1955); C A 50, 4990i (1956). 59. 0. N. Tolkachev, V. G. Voronin, and N. A. Preobrazhenskii, Zh. Obshch. Khim. 29, 1192 (1958). 60. V. G. Voronin, 0. N. Tolkachev, and N. A. Preobrazhenskii, Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 5, 449 (1962); C A 59, 2877e (1963); and V. Voronk, 0. Tolkachev, A. Prokhorov, V. Chernova, and N. Preobrazhenskii, Khim. Geterotsikl. Soedin. 4, 606 (1969); CA 31, 79277p (1970). 61. V. G. Voronin, 0. N. Tolkachev, and N. A. Preobrazhenskii, Dokl. Akad. Nauk SSSR 122, 77 (1958); C A 53, 1345f (1959). 62. 0. N. Tolkachev, L. P. Kvashnina, and N. A. Preobrazhenskii, Zh. Obshch. Khim. 36, 1764 (1966). 63. E. N. Tzvetkov, I. N. Gorbacheva, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 27, 3370 (1957). 64. V. I. Shvets, L. V. Volkova, and 0. N. Tolkachev, Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 5, 445 (1962); C A 59, 2876h (1963). 65. J. Baldas, I. R. C. Biek, Q. N. Porter, and M. J. Vernengo, Chem. Commun. 132 (1971). 66. H. Hellmann and W. Elser, Ann. 639, 77 (1961). 67. M. F. Grundon and H. J. H. Perry, J. Chem. SOC.3531 (1954). 68. J. R. Crowder, M. F. Grundon, and J. R. Lewis, J. Chem. SOC.2142 (1958). 69. M. F. Grundon, J. Chem. Soc. 3010 (1959). 70. T. Kametani, H. Iida, and K. Sakurai, J. Chem. SOC.C 1024 (1971). 71. K. P. Agarwal, S. Rakhit, S. Bhattarcharji, and M. M. Dhar, J.Sci. Ind. Res., Sect. B 19, 479 (1960); C A 55, 16585a (1961). 72. M. Tomita, Y. Aoyagi, Y. Sakatani, and K. Fujitani, Chem. Pharm. Bull. 15, 1996 (1967). 73. M. Tomita, K. Fujitani, and Y. Aoyagi, Tet. Lett. 4243 (1966). 74. M. Tomita, K. Fujitani, and Y. Aoyagi, Chem. Pharm. Bull. 16, 62 (1968). 75. M. Tomita, Y. Aoyagi, Y. Sakatani, and K. Fujitani, Chem. Pharm. Bull. 16, 56 (1968). 76. E. S. Pallares and E. M. Garza, Arch. Biochem. 16, 275 (1948). 77. T. Kametani, K. Fukumoto, and M. Ro, Yakugaku Zusshi 84, 532 (1964). 78. T. Kametani, M. Ro, and Y. Iwabuchi, Yakugaku Zasshi 85, 355 (1965). 79. T. Kametani, H. Iida, M. Shinbo, and T. Endo, Chem. Pharm. Bull. 16, 949 (1968). 80. J. Niimi, Yakugaku Zusshi 80, 451 (1960).

392

M A U R I C E SHAMMA A N D VASSIL ST. GEORGIEV

81. J. Niimi, Yakugaku Zasshi 80, 791 (1960). 82. S. M. Kupchan and A. J. Liepa, Chem. Commun. 599 (1971). 83. S. M. Kupchan, A. J. Liepa, V. Kameswaran, and K. Sempuku, J . Am. Chem. SOC. 95, 2995 (1973). 84. For other syntheses of aporphine-benzylisoquinolinealkaloids, see M. Tomita, H. Furukawa, S.-T. Lu, and S. M. Kupchan, Tet. Lett. 4309 (1965); Chem. Pharm. Bull. 15, 959 (1967); R. W. Doskotch, J. D. Phillipson, A. B. Ray, and J. L. Beal, Chem. Commum. 1083 (1969); J . Org. Chem. 36, 2409 (1971). 85. C. Schopf and K. Thierfelder, Ann. 497, 22 (1932). 86. R. Robinson and S. Sugasawa, J. Chem. SOC.789 (1932). 87. B. Franck, G. Blaschke, and G . Schlingloff, Tet. Lett. 439 (1962). 88. B. Franck and G. Blaschke, Ann. 668, 145 (1963). 89. B. Franck, G. Blaschke, and G. Schlingloff, Angew. Chem., Int. Ed. Engl. 3, 192 (1964). 90. M. Tomita, Y . Masaki, K . Fujitani, and Y. Sakatani, Chem. Pharm. BuZZ. 16, 688 (1968). 91. A. M. Choudhury, I. G. C. Coutts, A. K. Durbin, K. Schofield, and D. J. Humphreys, J. Chem. SOC.C 2070 (1969). 92. See also M. Tomita, Y. Masaki, and K. Fujitani, Chem. Pharm. BuZZ. 16, 257 (1968); M. Tomita, I(.Fujitani, Y. Masaku, and K.-H. Lee, ibid. 251. 93. T. Kametani and I. Noguchi, J . Chem. SOC.C 502 (1969). 94. Y. Inubushi, Y. Aoyagi, and M. Matsuo, Yet. Lett. 2363 (1969). 95. T. Kametani, S. Takano, and T. Kobari, J . Chem. SOC.C 9 (1969). 96. T. Kametani, H. Nemoto, T. Kobari, and S. Takano, J . HeterocycZ. Chem. 7, 181 (1970). 97. J. M. Bobbitt and R. C. Hallcher, Chem. Commun. 543 (1971). 98. M. P. Cava and A. Afzali, J. Org. Chem. 40, 1553 (1975).