Vincadifformine synthesis

For convenience, the intermediate is depicted here as a spirocyclic ammonium salt, but it should be noted that such an intermediate has only been rigorously established in the vincadifformine synthesis using a-substituted <5-halogeno-aldehydes in other cases, an alternative mechanism may operate (see p. 223). 

Assembly of the indolazepine intermediate for synthesis of vincadifformine [92] encompasses a 1,2-rearrangement-retro Mannich-Mannich reaction sequence. Need-... 

In Kuehne s total synthesis of vincadifformine (89), the pentacyclic natural product was obtained when tetracyclic phenylselenide 88 was treated with 2.5 equivalents of n-Bu SnH and the radical initiator AIBN in refluxing benzene [52]. The stereochemistry of the phenylselenyl substituent in the tetracyclic precursor had no impact on the product yield. After the tertiary radical intermediate 90 was generated (Scheme 17), the 5-exo-trig cyclization was prohibited... 

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. 

In support of an ingenious scheme for the biosynthesis of vinca and iboga alkaloids proposed by Wenkert is an interesting synthesis accomplished by Kutney, Brown, and Piers by transannular cyclization of carbomethoxydihydrocleavamine (I), accomplished by oxidation with mercuric acetate in acetic acid at room temperature. Chromatography afforded as the main product the vinca alkaloid vincadifformine. 

The stereochemistry of vincatine (340) was finally established by a partial synthesis from (-)-vincadifformine (76), which conclusively proved that its absolute stereochemistry is 1R,2QS,21R (Scheme 15) (236). Initially assigned the enantiomeric configuration (7S,20f ,21S) (237,238), (-)-vincatine was synthesized from (-)-vincadifformine A b-oxide by a process that did not affect the stereochemistry at C-20, although the lability of the stereochemistry at C-7 and C-21 resulted in the formation of all four... 

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... 

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 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... 

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... 

Later, 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). 

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),... 

The synthesis by Das et al. (338) started from the previously prepared protected indoleacrylic ester derivative 579, which was activated by mesyla-tion and oxidation and condensed with an appropriate aminoacetal to give the indoloazepine derivative 580. Release of the aldehyde function, followed by cyclization to the quaternary anunonium ion, fragmentation to the secodine 418b, and spontaneous cyclization, then gave vincadifformine (76) in 50% overall yield from 579 (Scheme 72) (338). 

Szdntay s synthesis of 3-oxovincadifformine and 3-oxominovine (340-342) makes use of the same starting material 416 that was used in the earlier synthesis of vincadifformine. Here the carbon-carbon double bond... 

The most recent synthesis of vincadifformine, 3-oxovincadifformine, and tabersonine is described in yet another substantial contribution from... 

The synthesis of ( )-pseudovincadifformine (666) by Szantay and collaborators (270) accompanied the same workers synthesis of vincadifformine, discussed previously (Scheme 33). Thus, application of the Polonovski reaction to the N-oxide of tetrahydrosecodinol (417) gave the precursor 418b of vincadifformine, and also an isomeric secodine 696, which spontaneously cyclized to pseudovincadifformine (666) (Scheme 101). 

Following their recent synthesis of ( )-vincadifformine (Scheme 75) (343,344), Szantay and his collaborators have contributed another s3mthesis of pseudovincadifformine and its epimers (392). Condensation of the trypt-amine derivative 587 with the aldehydoester 698 gave, via an unstable secodine derivative, the epimeric tetracyclic esters 715, which, without separation, were subjected to debenzylation, with partial epimerization and cyclization. The product, a mixture of the two cis C/D-fused pentacyclic... 

Other workers have also used variations of the Kuehne biomimetic approach in the synthesis of ibophyllidine. Das and collaborators (338) prepared the secodine precursor 730 by an obvious modification of the route used in the synthesis of vincadifformine. Acid hydrolysis of 730, followed by quaternization, fragmentation, and cyclization, then gave the ibophyllidine ring system. Use of the racemic aminoacetal (/ 5-731) in the first essential stage in Scheme 109 was reported ultimately to give ibophyllidine (672) and 20-epi-ibophyllidine (673), whereas the simpler aminoacetal 732 gave desethyl-ibophyllidine (674). Subsequent repetition of this synthesis (394), using the chiral 5-aminoacetal (S-731) resulted in an enantioselective synthesis of (-f)-20-epi-ibophyllidine [(-(-)-673]. Similarly, the enantiomeric H-acetal (/ -731) was converted into (-)-20-epi-ibophyllidine [(-)-673]. Contrary to the earlier report, it now appears that no ibophyllidine is produced in these syntheses. 

In a study on biomimetic alkaloid synthesis the pentacyclic indole alkaloid vincadifformin (1) was synthesized in two steps starting from tryptamine hydrochloride (X) ... 

Another impressive contribution to synthesis in this area is the total synthesis of vincadifformine (211) and ervinceine (212) (=ll-methoxyvincadifformine) by... 

The use of 2-vinylindole species has played a large role in the total synthesis of the pentacyclic Aspidosperma alkaloids. In 1978, Kuehne reported an elegant synthesis of DL-vincadifformine (182) that featured as a key step the reaction of an indoloa-zepine 177 with the bromoaldehyde 178, thus leading to the in situ formation of 2-vinylindole species 181, which in turn underwent an intramolecular Diels-Alder reaction to provide 182 [71] (Scheme 42). Kuehne and others have used this same methodology, using the in situ generation of a 2-vinyl indole, followed by an intramolecular Diels-Alder reaction, to synthesize a number of Aspidosperma alkaloids and their analogs [72]. 

Kuehne ME, Roland DM et al (1978) Studies in biomimetic alkaloid syntheses. 2. Synthesis of vincadifformine from tetrahydro-b-carboline through a secodine intermediate. J Org... 

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