Biosynthesis

BY J. STAUNTON

The main emphasis of research on alkaloid biosynthesis has shown a significant move away from recently fashionable problems. The terpenoid indole family of alkaloids no longer dominates the scene and the benzylisoquinoline and ergot alkaloids have also lost their prominent position.

It seems unlikely that any new area will achieve in the future the dominant role enjoyed in the recent past by the indole alkaloid family, and the major advances this year have been spread over several unrelated fields. For example the middle and late stages in the biosynthesis of the Ipecac and Cinchona alkaloids have been largely elucidated although important gaps remain to be filled. The interesting work of several groups on the role of lysine in alkaloid biosynthesis continues apace and much further work will be necessary before one can be sure of understanding the overall picture in this complex field. A major breakthrough on the peyote cactus alkaloids has solved a longstanding puzzle in isoquinoline biosynthesis and should stimulate fresh interest in the early stages of isoquinoline formation in other systems.

As the body of knowledge accumulates, it becomes increasingly unlikely that many pathways remain to be discovered. Thus, it is hardly surprising that many of the compounds under investigation this year have been found to arise by modification of already established pathways. However, there is promising evidence that the mesembrine alkaloids are biosynthesized by an unexpected, novel route and the past year has produced its full quota of surprises and puzzling results from both new and established pathways.

Terpenoid Indole Alkaloids. — A surprising development has taken place since the comprehensive review was published in last year's Report. The result came not from the biosynthetic study but from further investigation of the configuration at C(3) of vincoside (3). The stereochemistry at this position was uncertain because past research gave conflicting results. However, it has now been convincingly established that in vincoside the hydrogen at C(3) has the β-orientation.

This result is unexpected from the point of view of the biosynthetic chemist because the configuration at C(3) of vincoside is now opposite to that at the corresponding carbon of the next established intermediate, geissoschizine (4). It is not yet clear how this centre becomes epimerized in the biosynthesis but the following experimental facts have to be accounted for: (a) isovincoside [the C(3) epimer of vincoside] is not biologically active, and (b) the hydrogen at C(5) of loganin (1) [C(5) of loganin corresponds to C(3) of vincoside] is completely retained in the biosynthesis of the three main classes of indole alkaloid, represented in Scheme 1 by vindoline (6) [Aspidosperrna], catharanthine (7) [Iboga], and ajmalicine (8) [Corynanthe].

The retention of the hydrogen from C(5) of loganin implies that the epimerization takes place without cleavage of a carbon–hydrogen bond and thus provides a valuable clue to the mechanism of this intriguing process. In view of the importance of this result, it is essential to show that the hydrogen has not undergone an unexpected migration prior to the epimerization step. The predicted destination of the hydrogen from C(5) of loganin in the absence of a migration is marked by an asterisk in the structures in Scheme 1. The earlier experiment was repeated by administering [5-3H,O-methyl-3H]loganin to Vinca rosea plants. The three alkaloids (6), (7), and (8) were each found to retain both tritium labels without change in isotopic ratio and it was proved by degradation that, for each alkaloid, the activity incorporated into the skeleton resided specifically at the expected position. Thus, it is very probable that the epimerization process involves cleavage of a carbon–carbon or carbon–nitrogen bond. A similar process seems to operate in the biosynthesis of the Ipecac alkaloids and the problem will be discussed further in that section.

Eburnamine–Vincamine Alkaloids. — So far most of the effort on indole alkaloid biosynthesis has been concentrated on the Corynanthe, Aspidosperma, and Iboga systems. It is welcome, therefore, to see the preliminary results of an investigation of the biosynthesis of vincamine (10). Comparable incorporations were observed for [ar-3H]tryptophan, [ar-3H]stemmadenine (5), and [ar-3H]tabersonine (9). These results support the proposal that vincamine is a transformation product of the Aspidosperma system, and it will be interesting to see if further work supports the detailed mechanism proposed for the transformation.

Cinchona Alkaloids. — The biosynthetic route (Scheme 2) to the Cinchona alkaloids quinine (22), cinchonidine (21), and cinchoninine (23) is of exceptional complexity. Earlier work established that quinine is derived by combination of an indolic unit derived from tryptophan with a monoterpenoid unit derived from geraniol, via loganin. The close relationship to indole alkaloid biosynthesis implied by these results has been confirmed by the demonstration that vincoside succeeds loganin in the biosynthesis. In feeding experiments with C. ledgeriana shoots [ar-3H]vincoside was incorporated into each of the Cinchona bases (21), (22), and (23). By analogy with indole alkaloid biosynthesis it is likely that secologanin (2) is an intermediate between loganin and vincoside.

The proposal that the next stages of the pathway would involve intermediates of the Corynanthe type has received experimental support. Corynanthealdehyde (12) was not incorporated but the closely related corynantheal (13) did serve as an efficient precursor for all three Cinchona bases. Thus, the close parallel between the early stages of quinine biosynthesis and the corresponding stages (Scheme 1) of indole alkaloid biosynthesis is established.

From corynantheal onwards the pathways diverge completely. The generation of the skeleton of the Cinchona bases requires not...