The Vincadifformine Group

The anilinoacrylate alkaloids have been the subject of intensive study during the past two decades, and numerous syntheses of vincadifformine, tabersonine, and their relatives have been reported. This area has been dominated by the versatile biomimetic synthesis developed by Kuehne and 

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The early synthesis of ( )-vincadifformine and ( )-minovine, by Kutney et al, was discussed in Volume 17 (I) and details of this work have since been published (326). Details of the synthesis of tabersonine by Takano et 

Kuehne s prodigious output on the synthesis of the anilinoacrylate alkaloids began with a sjmthesis of vincadifformine (76) and its 11-methoxy derivative, ervinceine (87) (328,329). The basic strategy involved the construction of a spirocyclic ammonium salt 552 from either the tetrahydro-iS-carboline derivative 553 (328) or the isomeric y-carboline derivative 554 (329), presumably via the common intermediates 555 and 556. When treated with base, ring C in the spirocyclic ammonium salt 552 was opened by 

a modified version of the synthesis was reported, in which the important secodine precursor is a tetrahydro-jS-carboline derivative, such as 557-559, rather than an indoloazepine ester, as in 560. This led to a simpler synthesis, the tetrahydro-/3-carboline derivatives required for the preparation of 557-559 being obtained directly from the appropriate trypt-amine derivative and pyruvic acid ester. By this route, ( )-vincadifformine (76), ( )-minovine (A g-methylvincadifformine) and ( ) ervinceine (87) were synthesized in comparatively high yield, and in essentially two stages from the starting tryptamine (330). 

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Kuehne s remarkable synthesis of the vincadifformine group of alkaloids has been extended,107 and an alternative mechanism for the crucial complex stage in the synthesis has been proposed. 

The alkaloids of the vincadifformine group are extremely difficult to quaternize at N, . In fact, attempts to form the b-methiodide from 2,16-dihydrotabersonine 323 result in the formation of the Ng-methyl derivative, and the A a-trifluoroacetyl derivative of 323 fails to react with methyl iodide in methanol. Interestingly, when 2,16-dihydrotabersonine is acylated with... 

The Kuehne biomimetic synthesis of alkaloids of the vincadifformine group (vide infra) proceeds via a transient secodine derivative, which is not usually isolated. However, in one of two syntheses of minovincine (265)... 

The iboga alkaloids behave differently from the vincadifformine group on photochemical oxidation iboxyphylline is rapidly oxidised at C-16 to give a hydroxy-indolenine, but only in the presence of oxygen and in the absence of cyanide. 

The vincadifformine-tabersonine group of alkaloids provide a rich field for the study of oxidative rearrangements. New work reported recently101" includes a study of the oxidation of 3-oxovincadifformine (189) with m-chloroper oxy benzoic acid (Scheme 27). The products were 3-oxovincamine (190), 3-oxo-16-ep/-vincamine (191), and a dilactam (192), which is simply the result of oxidative fission of the 2,16 bond. Under carefully controlled conditions, the hydroxy-indolenine (193) was isolated, and it was subsequently shown to be an intermediate (as expected) in the formation of (190)—(192). Photochemical oxidative rearrangement gave similar results. 

The same group of workers have also investigated the dye-sensitized photo-oxygenation of vincadifformine. After reduction of the reaction mixture with sodium thiosulfate, the related 16-hydroxyindolenine derivative 285 was obtained, which (without isolation) was rearranged in acetic acid to vincamine in 46% yield. Tabersonine behaved similarly (277). These results are broadly in agreement with those obtained by L6vy and his collaborators in an independent study of the photochemical oxidative rearrangement of vincadifformine (218). 

In view of the importance of vindoline (44) as a constituent of the oncolytic bisindole alkaloid vinblastine, methods for the synthesis of both vindorosine (43) and vindoline from members of the quebrachamine and vincadifformine groups have been extensively investigated. The first results... 

Reduction with formic acid50 provides a way of cleaving the C(21)—C(7) bond (Scheme 15) in (— )-vincadifformine (40b) and (— )-tabersonine (40c) previously it was necessary to remove the ester group and reduce the resulting indolenine (for example as above). Formic acid is unique in providing of itself both a proton, to produce a concentration of indoleninium cation (43), which in... 

The stereochemistry of eburine was established by correlation with (—)-vincadifformine (2) (40). Reduction of (—)-vincadifformine (2) with zinc in acetic acid gave the 2,16-dihydro derivative 74, identical with eburine except for optical rotation. Epimerization of eburine with sodium methoxide gave 16-epieburine, which could be oxidized with lead tetraacetate to (+)-vincadifformine (75). This reaction could not be carrie d out on eburine itself consequently, eburine has the structure 76 in which the carbomethoxyl group is /3 (40). 

The second new alkaloid was readily identified as (+)-(20R)-pseudo-vincadifformine (219) [a]D+430°. This alkaloid, showing a molecular ion at m/e 388, exhibited a typical base peak at m/e 124, a characteristic ion at m/e 214 (ion A), but no m/e 309 (ion D). The PMR spectrum showed a triplet at 0.95 ppm for the methyl of the ethyl group, and no olefinic proton was observed. The compound was identical with (-)-(20S)-pseudovin-cadifformine prepared from (+)-catharanthine (201) except for optical rotation. 

Vinca minor, cultivated in Georgia, USSR, has been shown to contain ( )-vincadifformine and vincine, both already known to occur in this species, together with apovincamine and 11-methoxyvincadifformine.92 Voaphylline, voaphylline hydroxyindolenine, and 11-hydroxytabersonine have been isolated from the leaves of Tabernanthe pubescens,43/ and 5,22-dioxokopsane (177) from the root bark of Alstonia venenata R. Br. 93 this is the first report of an alkaloid of the heptacyclic kopsine group in this species. 

The influence of aromatic substituents (chlorine, bromine, or nitro-groups) on the ease of oxidative rearrangement of derivatives of vincadifformine into derivatives of... 

It should be noted that in the group C bases, just as for the ebum-amine-vincamine group, compounds turn up with different stereochemistries thus, in V. minor there is also found the levo form of racemic vincadifformine first isolated from V. difformis (Table III). Since rac-vincadifformine has recently been reported (86) from V. minor, it is just possible that it might be an artifact produced from the true natural product, the levo form, during its isolation. 

Aspidospermine-Aspidofractine-Eburnamine Group. The leaves of Pandaca minutiftora contain (+)-vincadifformine, which also occurs in the leaves of Amsonia tabernaemontana, together with ten other alkaloids [tabersonine, (+)-l,2-dehydroaspidospermidine, (—)-quebrachamine, lochnericine, ( ) and (—)-vincadine, (-)and ( )-epivincadine, (+)-14,15-dehydrovincadine, and (+)-14,15-dehydroepivincadine] the roots contain the first four alkaloids and ebumamonine. 

Goniomitine (135), an alkaloid of a new structural type from the root bark of Gonioma malagasy E. May, is apparently the result of a much more far-reaching transformation of a vincadifformine precursor (146). Its structure was deduced on the basis of an analysis of its NMR spectra, including a comparison of its C chemical shift data with those of tryptophol and guettardine (136). It is included in this group on the basis of its presumed derivation from vincadifformine (77) by a series of plausible, unexceptional... 

The next target for synthesis by Kuehne s group was tabersonine (78), and three syntheses were recorded (134,323,332-334). Following the synthesis of racemic tabersonine (332) from the indoloazepine ester 560 and the lactol chloride 563, the procedure was refined by use of the chiral epoxyaldehyde 564 (333,334), which eventually afforded enantioselective syntheses of both (-)-vincadifformine (76) and (-)-tabersonine (78). Subsequently (323),... 

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