Chapter 9 Synthesis of the Aspidosperma Alkaloids

-CHAPTER b

SYNTHESIS OF THE ASPZDOSPERMA ALKALOIDS J. EDWINSAXTON School of Chemistry The University of Leeds Leeds LS2 9JT, U K I. Introduction ................................................................................... 11. The Aspidospermine Group ...................... 111. Vindorosine and Vindoline

V. The Vindolinine Group .............................................. VI. The Meloscine Group .. ........................

343

366

VIII. The Kopsine Gr References ......

I. Introduction

For the purpose of this chapter the Aspidosperma alkaloids will include all those based on the aspidospermidine (1)and vincadifformine (2) ring systems, together with those such as meloscine (3), which are derived by obvious rearrangement of one or other of these systems. The last summary of synthesis in this area was published in 1979 (I). During the last 16 years these alkaloids have continued to exert a fascination on, and offer a challenge to, organic chemists engaged in the art of synthesis, and several notable and ingenious synthetic routes have been developed, either by the application of modern sophisticated synthetic methods, or by brilliant attempts to mimic the presumed biosynthesis of these alkaloids in the laboratory. Several of the most talented contemporary exponents of the art of organic synthesis have made outstanding contributions in this area, and such is the volume of work published in the period under discussion that it will be possible only to discuss in brief outline what has been achieved. All of the major alkaloids have now yielded to synthesis, including those of the meloscine and kopsine groups, which, in terms of their ring systems, would appear to offer the greatest challenge. THE ALKALOIDS. VOL SO 00YY-YSYX/YX $2500

343

Copyright 0 I Y Y 8 by Academic Press All rights of reproduction in any form reserved.

344

SAXTON

(+)-Aspidosperrnidine (1)

(-)-Vincadifformine (2)

Meloscine (3)

11. The Aspidospermine Group

In the years 1963-1980 synthesis in this group was dominated essentially by Stork’s classical, elegant synthesis of aspidospermine itself (2), and by its numerous variants, and by the work of Ban and his co-workers. Since then, other new, radical approaches have been developed by Magnus, Overman, and their collaborators, among others. The synthesis by Magnus and his co-workers (3) proceeds via a transient indole-2,3-quinodimethane(4) which spontaneously undergoes a thermal electrocyclic ring closure to give the tetracycle ( 5 ) containing the desired cis ring junction. A Pummerer reaction on (5) gave the trifluoroacetate (6),which was converted into ( 5 ) aspidospermidine [( +.)-1]by cyclization, reduction, and deprotection stages (Scheme 1). Conceptually, the most original approach to the Aspidosperma alkaloids is the tandem aza-Cope rearrangement-Mannich cyclization route developed by Overman et al. ( 4 ) . Originally introduced in a synthesis of 11-methoxytabersonine (q.v.) its versatility allows it to be modified to afford syntheses of several other alkaloids in this group, including N,acetylaspidoalbidine (7) (Scheme 2). In this synthesis the tricyclic urethane (8) was first constructed by coupling of the hydropyrindinone derivative (9) with the dianion derived from the trimethylsilylcyanhydrin (10) (5). A

9. SYNTHESIS

OF THE ASPIDOSPERMA ALKALOIDS

i Ts

345

a-N

Me

Ts

phsiANA Ts

I

t

Ts

iii,iv

I

vi. vii

(?)-Aspidospermidine((?)-l]

SCHEME 1. Reagents: (i) PhSCH2CH2NH2;(ii) PhCI, 140°C; (iii) m-CPBA, NaHC03, CH2C12,0°C; (iv) TFAA, CH2C12.0°C; (v) PhCI, 130°C; (vi) Raney Ni, EtOH; (vii) LiAIH4.

Wittig reaction on (S), followed by hydrolysis of the urethane and amide functions and reaction with formaldehyde, gave an oxazoline (ll),which on acid treatment underwent an aza-Cope rearrangement, followed by an internal Mannich reaction and further cyclization, to give the indolenine (12). Obvious stages then gave (+)-deoxylimapodine (13), which had

346

SAXTON

already been converted into (t)-Na-acetylaspidoalbidine(7) by oxidation with mercury(I1) acetate (6). (N.B. The structures 7 and 13 represent the enantiomers of the natural alkaloids.) The earlier synthesis of Na-acetylaspidoalbidine,by Ban and coworkers, relied on the pivotal tetracyclic lactam (14), prepared by a novel photoisomerization of the lactam (15), followed by the conventional addition of ring D. Alkylation of (14) gave the intermediate (16), which on reduction and deprotection gave (2)-quebrachamine [(+)-17]; alternatively, partial reduction of 16, deprotection, further reduction, and acetylation afforded a new synthesis of (5)-N-acetylaspidospermidine(18)(7). When the lactam (14) was subjected to a Claisen condensation with dimethyl oxalate, a twocarbon unit was attached to C-20; conventional manipulation of the product then afforded ( +)-deoxylimapodine (13) and ( 5)-Na-acetylaspidoalbidine (7). In yet another application, oxidation of (14) with oxygen and LDA at low temperature resulted in the introduction of a hydroxyl group to C-20, which thereby allowed the synthesis of (+)-deoxyaspidodispermine (19) to be completed (Scheme 3) (6). Pearson and Rees have contributed an ingenious synthesis of limaspermine (20) by taking advantage of the fact that iron carbonyl complexes of alkoxycyclohexadienes behave as stable equivalents of cyclohexenone ycations. The initial synthesis (8)required some 30 stages, but in a subsequent modification (9) limaspermine was prepared in seven stages fewer from phydroxyphenylacetic acid. This abbreviated route consists essentially of a new approach to the Stork-type tricyclic ketone 21, and the synthesis was completed by Stork’s method, followed by demethylation of the ether functions. Meyers and Berney (20) have reported an asymmetric synthesis of the tricyclic ketone 22, which thus constitutes a formal synthesis of (+)aspidospermine, the enantiomer formerly regarded as unnatural, but now known to occur in Aspidosperma pyrifolium Mart. (22). Other work reported in recent years includes syntheses of (-)-aspidospermidine (ent-1) (22),(5)-aspidospermidine [(+)-l] (23),(+)-aspidospermidine (1) (14), Na-benzylaspidospermidine( 2 9 , (t)-eburcine (23) and (+)-16-epieburcine (26).

III. Vindorosine and Vindoline Owing to its obvious importance as one of the components of the oncolytic alkaloid vinblastine, vindoline (and its 11-demethoxy analogue, vindorosine), have naturally attracted considerable attention. Buchi’s celebrated

i-iii

c-1-BUCOHN

I

IV

- vi

AC

ti

SCHEME2. Reagents: (i) BuLi, THF, -70°C. then add 9; (ii) 3~ HCI, MeOH, pH 6.5; (iii) LiOH, MeOH, H 2 0 ; (iv) Ph3P=CH2,23"C; (v) KOH, EtOH, H20,210°C (vi) (CH20),, Na2S04,23°C; (vii) CSA, Na2S04, PhH, 80°C; (viii) LiAIH4; (ix) Na, NH3; (x) HC02NH4, Pd-C; (xi) Ac20.

348

SAXTON

I

Quebracharnine (17)

ii-vi

(14)

xvi, x vii, ix,

t

xiii, xiv

1

xviii, ix, x

x, ix, xii (f)-Deoxylimapcdine (13)

I

(f)-N-Aoetylaspidoalbidine(7)

Et

ix, xii

AC

(1 8 )

Ac Deoxyaspidodisperrnine(19)

SCHEME3. Reagents: (i) MeOH, hv, (ii) PhCOC1, NEt3; (iii) dihydropyran, CSA; (iv) LDA, CICH2CH2CH21;(v) MeCH2CH2NH2,CH2C12,r.t.; (vi) NaH, KI, 18-crown-6; (vii) LDA, THF, HMPA; (viii) EtI, -60°C; (ix) LiAlH4, THF; (x) 10% HCI, THF; (xi) LiAIH4; (xii) Ac20, py; (xiii) LiAIH4 (excess), dioxane, heat: (xiv) Ht, H2O; (xv) LDA, (C02Me)2;(xvi) NH2NH2,KOH, HO(CH2)20(CH2)20H.100-200°C; (xvii) CH2N2;(xviii) 0 2 , LDA, -78°C.

synthesis (27) has been reexamined by several groups of workers, and five new syntheses of the tetracyclic intermediate 24 (28J9) or its 11-methoxy derivative (20,21) have been reported, together with a notable synthesis of Buchi's pentacyclic ketone 25a (22).

9. SYNTHESIS

OF THE ASPIDOSPERMA ALKALOIDS

349

COU

g-)&$@ Limaspermine (20)

(21)

.

Et

H'

Me02

(22)

Me

H

16 C02Me

Eburcine (23)

0

The new synthesis of vindorosine and vindoline by Langlois and his collaborators (23) also consists of an independent synthesis of the ketones 25a, b, but some variations in the later stages of a Buchi-type synthesis were also introduced. Following an exploratory investigation in which the vindorosine intermediate 25b was prepared, the synthesis of 25a was achieved from 7-methoxy-N,-methyl-3,4-dihydro-/3-carboline in an overall yield of 26% (Scheme 4). The rearrangement reactions of 26a to 27a and of 26b to 27b proceeded in the remarkably high yields of 70% and 73%, respectively. In the final stages of the vindorosine-vindoline synthesis, Langlois and co-workers used a different reagent for the introduction of the oxygen functionality to C-16. Whereas Biichi had oxidized the ketoesters 28a, b by means of hydrogen peroxide in the presence of strong base,

iii

I

-

I xiii,xiv

xv, iii

( f l $H

R

\+

M N e 3

0-

0

4

tt

Et

(37)

(26a) R = OW, u-H at C-3 (26b) R = H. U-H at C-3 (32) R = OMe, 0-H at C-3

(34a)R = O M e (34b) R = H

Me

H

Me0 c 2

1

0

Et

(35) (27a) R = OMe (27b) R = H

I

xix

v, vi

‘Et

(2%) R = O W (25b) R = H

-

‘Et Me0 (28a) R = O M e (28b) R = H

2

0

(36)

?-

Vindorosine (30)R = H Vindoline (31) R = OMe

SCHEME4. Reagents: (i) MeSOCH2Li,THF, DMSO; (ii) TsOH, THF, H20; (iii) NaBH3CN, MeOH; (iv) Raney nickel, MeCOMe; (v) (Me0)2C0,NaH; (vi) methylketene ethyl trimethylsilyl acetal, Bu,NF (vii) m-CPBA; (viii) Zn, AcOH, H20; (ix) LiAlH4, THF, -78°C; (x) Ac20, py; (xi) PhPOCI2, heat; (xii) NaHC03, H20; (xiii) KH, MeI, D M F (xiv) KH, Ac20, DMF; (xv) LDA, THF, -78” to 0°C; (xvi) NaOMe, MeOH; (xvii) r-BuOCI, CH2C12,O”C,then DBU; (xviii) NaBH3CN. TFA, MeOH; (xix) CH20, NaBH3CN, AcOH, MeCN.

9.

SYNTHESIS OF THE ASPIDOSPERMA ALKALOIDS

351

Langlois and co-workers oxidized the trimethylsilyl ethers 29 with rn -chloroperbenzoic acid, but they then had to interpose a reduction stage to remove the &-oxide function simultaneously introduced. Reduction and acetylation stages then gave vindorosine (30) and vindoline (31). The stereoselective synthesis of (-)-vindoline by Feldman and Rapoport (24) involved, in the early stages, the enantioselective preparation of the tetracyclic P-ketosulfoxide 32 from L-aspartic acid, via the tetrahydropyridine derivative 33. However, rearrangement of 32 to the pentacyclic intermediate 27a was accompanied by racemization, presumably via the reverse Mannich intermediate 34a. The product 27a was therefore the same as Langlois’ ketone, prepared from the racemic 3a-H epimer 26a. In order to avoid racemization, an alternative route was devised, in which the ketoester 35 was used as the substrate for rearrangement, by treatment of its 7chloroindolenine derivative with base. In this way, the r6les of C-2 and the future C-16 were reversed, i.e., C-2 became electrophilic and C-16 nucleophilic in the 7-chloroindolenine derivative, and the tendency of 35 and its relatives to racemize via a reverse Mannich reaction was suppressed. The product 36 of the rearrangement was then converted into the ketoester 28a, the late intermediate in the synthesis of vindoline by Langlois and coworkers (Scheme 4). It was subsequently shown (25) that the P-ketosulfoxide 26b itself, prepared from optically pure precursors, is racemic. The racemization must therefore occur during its preparation, and not during the rearrangement reaction to the ketone 27. In contrast, esters of type 37 are configurationally stable. Various workers have investigated the possibility of preparing vindorosine and vindoline by partial synthesis from more accessible alkaloids in this group. The first of these was Kutney’s conversion of ( 2 ) vincaminoridine (38), via 11-methoxy-N-methylvincadifformine, into vindoline, by a rather lengthy sequence of functional group transpositions (26).

Vincaminoridine (38)

Owing to the relative abundance of tabersonine (39), methods have also been explored for its conversion into both vindorosine (30)and vindoline

352

SAXTON

(31). The method of Danieli er af. (27a) involved oxidation of 39 by means of benzeneseleninic anhydride, which gave the C-17 hydroxy derivative (ma), presumably via hydration, during workup, of the N,, C-17 didehydro derivative initially obtained, the stereochemistry of attack being determined by the adjacent ethyl group. Oxidation of the product 40a at C-16, also at the &face, by rn-chloroperbenzoic acid was accompanied by oxidation of Nb, with the formation of 41; reductive methylation, removal of the N oxide function, and acetylation then gave vindorosine (30) (Scheme 5). The conversion of tabersonine into vindoline, prompted by the relative inaccessibility of 11-methoxytabersonine (42), required the initial introduction of a methoxyl group into position 11. Since this could not be achieved on tabersonine itself, it was first converted by reduction with sodium cyanoborohydride into 2,16-dihydrotabersonine, and thence into its N,-acetyl derivative (27b). Preparation of the 11-methoxy derivative then became an exercise in aromatic chemistry. Fortuitously, the dehydrogenation of the 2J6-dihydro-ll-methoxytabersonineso obtained simultaneously introduced the desired C-17 hydroxyl group, to give the intermediate (40b), and the synthesis of vindoline was then completed as before. The brilliant enantioselective synthesis of vindorosine and vindoline by Kuehne and his collaborators (28), the first to be recorded, is an extension of their synthesis of tabersonine (39) and 11-methoxytabersonine (42) (q.v.). The methods employed for the conversion of these alkaloids into vindorosine and vindoline resembled in principle those used by Danieli er al. However, since the starting materials for these syntheses are available in R, S, and racemic forms, both enantiomers and the racemic forms of these alkaloids are accessible by total synthesis. The most recent synthesis (29) of the vindoline ring system involves a radical new approach in which rings C and E are formed by an ingenious tandem cyclization-cycloaddition of a transient carbenoid intermediate 43, generated from the diazo-imide 44 by treatment with rhodium acetate (Scheme 6). This carbenoid presumably cyclizes to a dipole 45 which subsequently cycloadds across the indole 8-bond to give the hexacyclic product 46. Removal of the amide carbonyl group via the thioamide, followed by hydrogenolysis of the C-21 to oxygen bond in acid solution, then gave desacetoxy-17-oxo-14,15-dihydrovindorosine (47), whose structure and stereochemistry were unequivocally established by X-ray crystal structure analysis. The potential of this new route for the total synthesis of vindorosine and vindoline is obvious; indeed, the 11-methoxy derivative of 47 has already (1978) been converted into vindoline by Kutney and co-workers. Although it does not strictly belong in this section, mention may be made at this point of the first total synthesis (30) of (5)-obscurinervidine (48),

9. SYNTHESIS

353

OF THE ASPIDOSPERMA ALKALOIDS

(-)-Tabersonine (39) R = H 1I -Methow-tabersonine(42) R = OMe

(40a) R = H (40b) R=OMe

0-

Catharosine R = H

(41) R = H

Iv Vindorosine (30)R = H Vindoline (31) R=OMe

SCHEME 5 . Reagents: (i) PhSeOOSeOPh; (ii) m-CPBA; (iii)CH20, NaBH3CN, pH 4.2; (iv) Raney nickel; (v) AczO, NaOAc, r.t.

354

SAXTON

C02Me I

vi-viii

SCHEME 6. Reage?ts: (i) (Im),CO; (ii) H02CCH2C02Me,i-PrMgCI; (iii) N-methylindole )~ PhH, 50°C; (vi) 3-acetyl chloride, 4 A mol. sieves: (iv) MsN3, NEt3; (v) R ~ , ( O A C (cat.), Lawesson’s reagent, heat; (vii) Raney nickel; (viii) H2, Pt02, MeOH, HCI.

since it shares some features with the vindorosine syntheses, notably the application of the Takano cyclization for the generation of rings A-D, and the attachment of ring E by Biichi’s method.

9. SYNTHESIS OF THE

355

ASPIDOSPERMA ALKALOIDS

1

Obscurinervidine (48) 57a

R

R

H

H

-

2

57b

Me

H

57c

H

OW

-

Vincadifforrnine (2)

DBUWt

Minovine

Ervinceine

IV. The Vincadifformine Group

.

Synthetic work in this area has in recent years been dominated by the versatile biomimetic synthesis developed by Kuehne and his collaborators, together with outstanding original contributions from Overman and Magnus. Kuehne’s original concept involved the construction of a spirocyclic quaternary ammonium salt 49 which, it was anticipated, would fragment to yield a secodine derivative 50 on treatment with base; this would, in turn, spontaneously cyclize to give ( 2)-vincadifformine (2). This approach was brilliantly and elegantly exploited and high yields of the anilinoacrylate alkaloids were obtained. In the first synthesis (31) of (2)-vincadifformine the quaternary ammonium salt 49 was obtained from the indoloazepine ester 51, which was itself prepared by two independent methods, via the p-carboline derivative 52 or the y-carboline derivative 53; evidently, both must proceed via the common intermediate 54 (Scheme 7). Extension to the synthesis of 11-methoxy-vincadifformine(ervinceine) required the intermediate 55, which was readily obtained by synthesis from N-benzyl4-piperidone via the y-carboline derivative 56 (32). Subsequently, a much improved synthesis was developed (32),in which the secodine precursors were spirocyclic tetrahydro-P-carbolinium salts, e.g., 57a-c, rather than indoloazepine esters; these can readily be prepared from tetrahydro-p-carboline derivatives, themselves obtained by reaction of the appropriate tryptamine with pyruvic ester. By this means

(53)R = H

li

(56) R = O

CI

M

1

ii NCH2Ph

R

(55)R = OMe

1

iii, iv

R

@ -4Q ’

N

H

\

co2m

Vincadifformine (2) R = H Ervinceine

R

’ N

H

(50)

Et

co2w

R = OMe

SCHEME7. Reagents: (i) r-BuOCI, PhH, NEt3: (ii) TICH(C02Me),, PhH; (iii) H2, Pd-C, AcOH; (iv) Br(CH2),CHEtCH0, TsOH, MeOH, Nz. 40°C; (v) NEt3, MeOH, 60°C.

9. SYNTHESIS OF THE

ASPIDOSPERMA ALKALOIDS

357

(t)-vincadifformine (4)-2,(?)-minovine (N,-methylvincadifformine),and (+-)-ervinceine (11-methoxy-vincadifformine) were synthesized in relatively high yield, in essentially two stages from tryptamine. Indoloazepine esters, e.g., 58, can also condense with aldehydes at NI, and the &position of the indole ring to give bridged tertiary bases, and in a further demonstration of the versatility of this synthesis, Kuehne and his collaborators have used this reaction in a synthesis of 3-0x0-vincadifformine (59)(33), which was obtained in 85% yield from the bridged epimeric azepines 60,presumably via the oxosecodine derivative 61 (Scheme 8). These syntheses emphasize the fugitive nature of the secodines, and underline the difficulties inherent in their isolation; however, since the primary purpose in preparing them is as precursors of the anilinoacrylate alkaloids, their spontaneous cyclization is, if anything, an advantage. Nevertheless, Raucher and co-workers have synthesized secodine (62)itself (34) and, during a synthesis of minovincine (63),Kuehne and Earley prepared 20,21-didehydro-19-oxosecodine(64),which proved to be the first example of a stable, isolable secodine derivative (35). Kuehne and his collaborators have adapted this approach to the synthesis of tabersonine (39),and three syntheses have been recorded (28,36a-c). Chronologically, the first of these (36a) involved the condensation of the

3-0x0-vincadifforrnine(59)

(61)

SCHEME 8. Reagent: (i) OHCCHEtCH2CH2CO2Me.PhMe, Nz. 4

A mol. sieves, heat.

358

SAXTON

Secodine (62)

co Me 2

Minovincine (63)

indoloazepine ester 58 with the lactol chloride 65 as an initial stage, and the second (36b) the condensation of 58 with the epoxyaldehyde 66. The latter was dramatically improved when the aldehyde 66 became available in its enantiomeric forms, but the synthesis was not regioselective, owing to ambiguity in the stage which involved the opening of the epoxide function, and a further improvement was achieved (28) when the lactol chloride 65 was prepared in optically active (at the asterisked carbon atom), as well as racemic, forms. A notable feature of these syntheses was the diastereoselectivity observed, the stereochemistry being controlled by that at the future C-14. The initial pentacyclic product isolated was 14-hydroxyvincadifformine, which on dehydration gave tabersonine (39)(Scheme 9). Since the lactol chloride (65)was available in R, S, and racemic forms, the synthesis of both enantiomeric forms, and the racemate, of tabersonine was achieved (28). Similarly, by use of the methoxylated indoloazepine ester 67the synthesis of both enantiomers, and the racemate, of ll-methoxytabersonine (42) was completed. Kuehne's third synthesis of tabersonine (39)proceeded via the critical secodine intermediate 68,which was constructed from the indoloazepine ester 58 and the sensitive 0-chlorodivinyl ketone 69. Thermal cyclization of 15-oxosecodine (68)then gave 15-0x0-vincadifformine(70), which could not be reduced and dehydrated to tabersonine (39)since the related alcohol is a neopentyl alcohol with an equatorial hydroxyl group, which is prone to rearrangement. Instead, 15-0x0-vincadifformine was brominated and reduced to a 14,15-bromohydrin, which gave tabersonine (39)on elimina-

9. SYNTHESIS

14-Hydroxyvincadinormine R = H

14-Hydroxyewinceine R = OMe

OF THE ASPIDOSPERMA ALKALOIDS

359

Tabemnine (39) R = H 11-Methoxy-tabemnine (42) R = OMe

SCHEME 9. Reagents: (i) boric acid, MeOH, heat, 24 h; (ii) PPh3, MeCN, CC4, 70°C.

tion of hypobromous acid by means of McMurry’s reagent (Scheme 10) (36c). More recently, Kuehne et al. have completed two syntheses of minovincine (35,37) by a similar biomimetic approach; and two other syntheses of vincadifformine consist essentially of alternative routes to the secodine intermediate 50 (38,39). Simple modifications of these routes have afforded syntheses of 3-0x0-vincadifformine (40),its ethyl ester analog (42) and its N,-methyl derivative, 3-oxominovine (40). Independent syntheses of vincadifformine, tabersonine, and their 3-OX0 derivatives (42,43) have also been recorded, together with a synthesis of 18,19-didehydrotabersonine (44).

360

SAXTON

..

- Et

cw

v-viii

Et H Tabersonine (39)

-

SCHEME 10. Reagents: (i) CH2=CHMgBr, THF, Ar; (ii) (COC1)2,CH2CI2,DMSO, -60°C. Ar; (iii) MeOH; (iv) PhMe, Ar, heat. 10 h; (v) i-PrzNH, n-BuLi, THF, hexane; (vi) (CH2. C H Z N H ~THF, ) ~ , -78°C. then Br2. C H A X (vii) NaBH4, MeOH;, (viii) LiAIH4, TiC13, THF. Ar, heat, 2 hr.

Yet another adaptation of Kuehne's biomimetic synthesis has resulted in the preparation of (2)-cylindrocarine (71) ( 4 3 , a member of the aspidospermine group.

Cylindrocarine (71)

9. SYNTHESIS

OF THE ASPIDOSPERMA ALKALOIDS

361

11-Methoxy-tabersonine (42), important as an intermediate in vindoline synthesis, has been synthesized by three groups of workers; of these syntheses, that owing to Kuehne et al. (28) has been summarized above. In the first synthesis, Overman et al. (46) introduced their ingenious tandem aza-Cope-Mannich cyclization route for the preparation of the tabersonine ring system. This involved the construction of the intermediate 72, as shown in Scheme 11; this was then reacted with paraformaldehyde to give an oxazolidine 73, which rearranged thermally without added acid, and subsequently cyclized, to give 1l-methoxy-l,2,14,15-tetradehydroaspidospermidine (74) stereospecifically and in high yield. Evidently, traces of formic acid in the reaction mixture were sufficient to catalyze the formation of 75 from the oxazolidine 73; this then suffered an aza-Cope rearrangement to give an intermediate 76 which was ideally set up for an internal Mannich reaction. Cyclization of the product afforded the imine 74, which, on methoxycarbonylation, gave 11-methoxy-tabersonine (42). Magnus and co-workers’ first contribution in this area was a synthesis (the first) of 3-0x0-tabersonine (77) (47).This was followed by an investigation (48) in which it was established that their synthetic approach was consistent with the presence of a methoxyl group at position 11. An additional refinement in the eventual synthesis (49) was the incorporation, at the outset, of an asymmetric unit which thereby ensured that the synthesis was stereoselective. The intermediate 78 was prepared, as outlined in Scheme 12, and the asymmetric unit was then discarded by a reverse DielsAlder fragmentation, to give the pentacyclic enone 79. Since the phenylthio group could not be removed without affecting the 14,15-double bond, the latter was deliberately saturated during the desulfurization stage; it was then reintroduced, and the ester group attached to C-16 was incorporated by Vilsmeier formylation, oxidation, and esterification, and the synthesis of (-)-11-methoxy-tabersonine (42) was completed by removal of the urethane ester group (49). Finally, in this group, Overman et al. (50)have used the N-acetylaspidoalbidine intermediate (12) in a synthesis of deoxoapodine (80).

V. The Vindolinine Group Synthetic work in this small group is entirely due to Levy and his collaborators, who have reported two partial syntheses of tuboxenine (81) (SZ), and one of vindolinine (82) and 16-epi-vindolinine (83) (52). The vindolinine synthesis involved the cyclization, by sonochemical means, of

q

cok

COMe

i-iv Et

V

*

Q

1

SPh

SOPh

vi

x, xi

xii. xiii

OM

*

(72)

(76)

(74)

(75)

1l-Methoxy-labersonine(42)

SCHEME 11. Reagents: (i) PhSCHCICH2CH2CI,ZnBr2, CH2CI2,25°C; (ii) NaI, MeCOEt, Ar, heat; (iii) NH3, CHCI3, r.t., 2 days: (iv) CIC02Me, PhNEt2, PhMe; (v) m-CPBA, CHCI,; (vi) o-C6H4CIZr CaC03, 165°C;(vii) BuLi, THF, -78°C; (viii) HCI, HzO, Et20,0°C; (ix) LiOH, MeOH, r.t.; (x) Ph3PMeBr, BuLi, T H F (xi) 40% KOH, MeOH, heat, 8 h; (xii) (CH20)n, PhMe, Na2S04; (xiii) heat, 6 h; (xiv) LDA, CIC02Me, THF, -78°C.

* a

Me0

/ N

bMe 2

&Me 2

0

h2Me

(78)

S

* Et

&Me

I

2

...

Xlll -xvI

(-)-11-Methoxy-tabemnine (42)

SCHEME12. Reagents: (i) EtAIC12; (ii) resolution; (iii) BuMe2SiC1, imidazole, DMF; (iv) Zn, CH2Br2,Tic&, THF; (v) KF, H20, THF (vi) (COC1)2, PhMe, lO"C, then DBMP, PhMe, heat; (vii) m-CPBA, NaHC03, CH2C12, H20; (viii) TFAA, DBMP (ix) 210°C; (x) Raney nickel (W-2), EtOAc; (xi) ( p-PhOC&PS2)2, THF, 0°C; (xii)p-MeC&SOCl, i-Pr2NEt,PhMe, 110°C; (xiii) MeI; (xiv) NaBH.,, MeOH (xv) POCl3, DMF (xvi) 2~ NaOH, (xvii) NaC102, H20, H2NS03H,MeCOMe, CH2=CMeOAc; (xviii) CH2N2;(xix) 1M NaOMe, MeOH, r.t.

364

SAXTON

19-iodo-tabersonine (84), prepared from vindolinine, which gave a mixture of vindolinine (82) and 16-epi-vindolinine (83), together with their 19epimers (Scheme 13). The yields and proportions of the four epimers de-

* Et H

COMe 2

3-0x0-tabersonine (77)

H

CoMe 2

Tuboxenine (81)

Deoxoapodine (80)

Me H

CoMe 2

19-lodotabersonine (84)

\ e M & \

H

\

H

Vindolinine (82)

/

N H

tJ9

16-Epivindolinine (83)

SCHEME13. Reagents: (i) ultrasound (500 W, 20 KHz), THF, Na, Ar, 0°C; (ii) ultrasound (60 W, 45 KHz), THF. Na, Ar, 0°C.

9. SYNTHESIS OF

365

THE ASPIDOSPERMA ALKALOIDS

pended on the conditions used; at lower ultrasonic intensities vindolinine (82) and 16-epi-vindolinine (83) were obtained in a 1 : 2 ratio, but at higher intensities all four 16J9-epimers were formed.

c Q ~ ; NHCOBu o c H 2 p h -

2

-

2

vi-x

H

o

H

Meloscine (3) p-H at C-16 Epimeloscine (85) a-H at C-16

SCHEME 14. Reagents: (i) KOH, EtOH, HzO, 130°C; (ii) (CHzO),, CSA, PhH, heat; (iii) (Me2CH),C6H2SO2N,, n-Bu4NBr. 18-crown-6, PhH, H 2 0 , KOH; (iv) MeOH, Et20, hv. (v) KOH, EtOH, H20, 150°C; (vi) Na, NH,; (vii) TsCI. py. CHCI,; (viii) o-02NC6H4SeCN, NaBH,, EtOH; (ix) rn-CPBA, CH2C12, -70°C; (x) Me2S. NEt,, r.t.

366

SAXTON

VI. The Meloscine Group Overman et d ’ s synthesis (50,53) of meloscine (3)and epimeloscine (85) shared common starting materials with their synthesis of N-acetylaspidoalbidine (7).The oxazolidone 86,on hydrolysis with alkali, gave the precursor of the methylene-iminium ion 87 which, when heated with acid, underwent tandem aza-Cope rearrangement and internal Mannich cyclization to give the tricyclic ketone 88 (Scheme 14). Photochemical rearrangement of the derived a-diazoketone resulted in ring contraction, to give the amide-ester 89, and the synthesis was completed by hydrolysis and lactam formation, separation of epimers, and introduction of the terminal double bond.

VII. The Aspidofractinine Group Ban’s second synthesis of aspidofractinine (90) (54) is a variant of his original synthesis ( 5 9 , which was described in Vol. 17 (I), and essentially consists of improvements in the later stages. Levy and co-workers’ remarkably brief synthesis (56a) makes use of the previously prepared oxindole ketoester 91, which was cyclized directly to 3,19-dioxo-aspidofractinine(92)by polyphosphoric acid. Sequential reduction of the carbonyl groups then gave aspidofractinine (90) (Scheme 15), and reduction by means of lithium aluminum hydride gave 19-hydroxyaspidofractinine (56b). Gramain and his collaborators have more recently completed two syntheses of 19-oxo-aspidofractinine, and therefore, in a formal sense, (+)aspidofractinine; in both syntheses the final stage involved oxidative cyclization of 19-0x0-aspidospermidine (57). Inevitably, the incorporation of functional groups into the aspidofractinine ring system, as in (-)-kopsinine (93),pleiocarpine, and kopsijasmine requires a more elaborate synthetic approach. The synthesis of the first of these, 93,together with (-)-kopsinilam (94),was achieved by Magnus and Brown in an investigation ultimately aimed at the synthesis of the dimeric alkaloid, pleiomutine (58).The tetracyclic base (99,prepared by the indole was quinodimethane route from N,-protected 2-methylindole-3-aldehyde, acylated by means of (+)-R-p-tolylsulfinylacetic acid; the desired diastereoisomer was then separated and elaborated to the diene 96, the absolute configuration of which was deduced by application of the Weiss homoannular diene rule, a conclusion that was subsequently confirmed by X-ray crystal structure analysis of the sulfoxide 97. A Pummerer rearrangement

9. SYNTHESIS OF

THE ASPIDOSPERMA ALKALOIDS

367

Aspidofractinine (90) SCHEME 15. Reagents: (i) PPA, heat; (ii) TsOH, PhMe, heat, 15 hr; (iii) Me30BF4;(iv) NaH, DMF; (v) TsOH, PhMe, heat; (vi) HSCH2CH2SH, BF3, AcOH; (vii) Raney nickel, EtOH; (viii) LiAIH4.

on 97 gave N,-protected 5,22,-dioxo-kopsane (98), the 0-dicarbonyl system in which was cleaved, the carboxyl group thus released was esterified, and the N,-protecting group was removed, to give (-)-kopsinilam (94). Reduction of the lactam carbonyl group then gave (-)-kopsinine (93) (Scheme 16). In another notable communication from Kuehne and co-workers, the synthesis of (5)-kopsinine (93) and several related alkaloids was reported (59). In this synthesis, the pentacyclic intermediate 99 was built up by the familiar biomimetic route; alkylation, followed by oxidative elimination, then gave the diene N-oxides 100a-c, which reacted with

368

SAXTON

,”

-0,

’N

’CI

..

R

0

i, ii

R

R =p-M”OSH4S9

1

iii, iv

Ar =p-MeC H

(95)

6 4

n

-

ArS---

- CI

ArS

---

v, vi

R R

vii - ix

X

R

I

xi -xiii

(98)

n

xiv, xv

H

H CqMe

(-)-Kopsinilam (94)

(-)-Kopsinine (93)

SCHEME 16. Reagents: (i) (+)-R-p-tolylsulfinylacetic acid, C6HIIN=C=N-CH2CH2NMe (CH2CH2)206 T s ; (ii) separation of diastereoisomers; (iii) TFAA, CH2CI2;(iv) PhCI, 130°C; (v) CH2=CHCH2Br, KN(S~MC,)~; (vi) 100°C; (vii) HN=NH; (viii) m-CPBA: (ix) 240°C (x) TFAA: (xi) KOH, MeOH, (xii) Li, NH3, -78°C; (xiii) MeOH, HCI: (xiv) Lawesson’s reagent: (xv) Raney nickel.

9. SYNTHESIS

OF THE ASPIDOSPERMA ALKALOIDS

369

phenyl vinyl sulfone to give the hexacyclic sulfones 10la-c, with concomitant reduction of the N-oxide function. Hydrogenation-hydrogenolysis of lOla with Raney nickel then gave (+)-pleiocarpinine (102), and similar treatment of lOlb or lOlc gave (2)-kopsinine (93). Oxidation of (?)pleiocarpinine completed the synthesis of (2)-aspidofractine (103), and N,-methoxycarbonylation of ( 2)-kopsinine gave (+)-pleiocarpine (104). Finally, thermal cyclization of ( 5)-pleiocarpinine and (5)-kopsinine afforded ( 2)-N,-methylkopsanone (105) and (+)-kopsanone (106), respectively (Scheme 17). Independent syntheses of the diene ester 107 and its N-methyl derivative (60,61) constitute additional syntheses of these alkaloids, while Wenkert’s syntheses of N,-methoxycarbonyl-17-oxo-aspidofractinine(62) and ( 2 ) aspidofractinine (23c) also proceed via a ring C diene. The synthetic contributions of Magnus and his collaborators were taken a stage further with a characteristically ingenious synthesis of ( 5 ) kopsijasmine (108) (63). The diene intermediate 109, prepared earlier (64) during the synthesis of kopsan-22-one, was converted by alkylation, internal Diels-Alder cycloaddition, reduction, and oxidation stages, into the sulfoxide 110 which, in spite of the fact that elimination of phenylsulfinic acid would have given an anti-Bredt lactam, gave the acetate 111 when heated in the presence of silver acetate and acetic acid. Standard stages then led to (5)-kopsijasmine (log), the major point of interest in these last few stages being the use of sodium and anthracene to remove the arylsulfonyl group (the use of sodium and naphthalene also resulted in the reduction of the 16,17-double bond) (Scheme 18).

VIII. The Kopsine Group Synthetic work in this subgroup is, so far, entirely due to Magnus and coworkers. The first investigation (64,65),which resulted in the synthesis of kopsan22-one (106), involved the preparation of the intermediate 109, on to which the additional rings were attached as in the preparation of 110, except that in this case the alkylation stage was performed with ally1 bromide. Diels-Alder cycloaddition then gave the heptacyclic intermediate 112, which has the kopsane ring system rather than the alternative fruticosane skeleton. Elimination-readdition of phenylsulfininc acid from the related sulfoxide gave the isomeric sulfoxide 113, and a second Pummerer rearrangement then gave the dioxo compound 114. Standard stages then led to kopsan-22-one (106) and kopsan-5,22-dione (115) (Scheme 19).

SCHEME 17. Reagents: (i) PhSeNEt,, N2, 20°C (ii) boric acid, CHzCIz, Nz, heat; (iii) 2 X m-CPBA, (iv) NaH, MeI, DMF; (v) NaH,PhCH2Br, DMF (vi) PPh3; (vii) PhS02CH=CH2, 100"C,12 h; (viii) Raney nickel, H20, EtOH, heat; (ix)MeOH, sealed tube, 200°C; (x) PhNEt3 Mn04; (xi) C1CO2Me,NazC03, CH2C12,N2, r.t.

vi

I

XN.

xv

$5

M"sc

K o p s i j j i n e (lOe)

SCHEME 18. Reagents: (i) KH; (ii) CH2=CC1CH21; (iii) PhMe, heat; (iv) TsNHNH2, NaOAc, THF,EtOH, H20; (v) rn-CPBA, NaHC03; (vi) AgOAc, AcOH, 205°C; (vii) LiOH, H20,THF (viii) Jones' reagent; (ix) MeOH, NaOH, (x) DBN, DME, heat; (xi) Na, anthracene, DME, -30°C; (xii) CIC02Me, K2C03, Et3NBuCI; (xiii) CH2N2, THF, Et2O; ( x ~ v )BH3.THF (xv) 6 M HCI, heat.

0

-- a Ar

Ar

0

c--

\

/ Ar

Ar

'a

(109)

x-xii

Ar

Ar

& H

(113)

I

v. xiii

XN

H

Kopsan-522dione (115)

Kopsan-Zane (106) Ar = p-MeOCgtO

thrwshout

SCHEME 19. Reagents: (i) H2N(CH&CH=CHCI, 4 A mol. sieves; (ii) C13CCH20COCl, i-Pr2NEt,PhC1,120"C; (iii) Zn, AcOH, THF, H2O; (iv) PhSCH2COCl. m-CPBA; (v) TFAA, CH2CI2; (vi) 130"C, PhCI; (vii) KN(SiMe&, THF (viii) CH2=CHCH2Br; (ix) 100°C; (x) TsNHNH2, NaOAc, EtOH; (xi) m-CPBA; (xii) 230°C; (xiii) TFAA, PhCl, 130°C; (xiv) Li, NH3, THF (XV)Moffatt oxidation; (xvi) LiAIH4.

9. SYNTHESIS OF THE

O

a

373

ASPIDOSPERMA ALKALOIDS

I-Ill

O

&NAr

@

3

(114) Ar = 0 SC H OMe-p 2 6 4

NC02Me

iv, v

ONco2&

@Nco2k

ix, vii

t y

N c o p

Kopsine (116)

SCHEME 20. Reagents: (i) NaOH, MeOH. THF, then HCI. H 2 0 ;(ii) Na, CloHx,DME, then CIC02Me. H20, K2C03, PhCHZNEt3CI; (iii) Me2CHCH2O2CCI.NEt3, NaBH4, T H F (iv) oNCSeC6H4N02,PBu3, T H F (v) H202; (vi) Os04. NMO, f-BuOH, THF, H 2 0 ; (vii) (COC1)2. DMSO, NEt3, CH2C12; (viii) LDA, THF, -78°C; (ix) BH3. THF, then 5 M HCI.

374

SAXTON

Finally, Magnus et al. (66) have used the intermediate 114 in a synthesis of kopsine (116)itself. Base-catalyzed fission of the /3-dicarbonyl system in 114,followed by a sequence of standard stages, led to the 16,22-methylene compound 117,which was hydroxylated, then oxidized (Swern) to the ahydroxyaldehyde 118. The kopsine skeleton was reformed by basecatalyzed formation of the 6,22-bond, and kopsine (116)was obtained by removal of the lactam carbonyl group, and a final Swern oxidation (Scheme 20). This synthesis also constitutes a formal synthesis of isokopsine (119),

6H

lsokopsine (119)

Frutiiosine (120) 16&OH F r u t i m i n e (121) 16a-OH

fruticosine (UO), and fruticosamine (Ul), all of which have been previously prepared from kopsine (67).

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9. SYNTHESIS 10. 11. 12. 13.

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

28. 29. 30.

31. 32. 33. 34. 35. 36.

OF THE ASPIDOSPERMA ALKALOIDS

375

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376

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