Biosynthesis iboga alkaloids

In these cases the formal //-ammo acid relationship often is a result of late stage condensation or cyclization reactions (e.g. Mannich-type, Pictet-Spengler) within the biosynthesis Typical examples are cocaine and correlated tropane alkaloids, Catharanthus alkaloids or Iboga alkaloids like heyneanine. 

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. 

Since the last review on Picralima alkaloids was written (for Volume X) activity in this field has considerably abated and in consequence there is comparatively little new work to be reported. The main features of indole alkaloid biosynthesis have now been elucidated and the reader is referred to Battersby (1) for an authoritative summary of this fascinating topic. Preakuammicine (1) appears to be involved in the direct pathway to the Strychnos, Aspidosperma, and Iboga alkaloids, and although it has not been isolated from Picralima it is appropriate to include it here, and to note that its presence in very young seedlings of Vinca rosea has been established (2). Preakuammicine is almost certainly the precursor of akuammicine (2), a transformation which can also be achieved by treatment with base (2). 

Investigation into the final step involved in the biosynthesis of the aspidospermine and iboga alkaloids led to another general synthetic route to the aspidospermidine alkaloids (8). The conversion of dihydro-cleavamine (4a-H, VII) to 7j8-ethyl-5-desethylaspidospermidine (XX) and thence to its A-acetyl derivative (VIII) was mentioned in Section II,A. In parallel work carbomethoxydihydrocleavamine (4j3-H, LXVI) (for difference of configuration at C-4, see Gorman et al., 69a) was con-... 

Two alternative intramolecular Diels-Alder reactions of the putative alkaloid precursor dehy-drosecondine (70) have been postulated as a branch point in the biosynthesis of aspidosperma and iboga alkaloids <62JA98>. Reaction by path a, in which the acrylate moiety acts as the dienophile generates the iboga skeleton, (69) while path b, with the vinylindole acting as a diene, gives the aspidosperma structure (71) (Scheme 147). 

Dehydrosecodine (97) is believed to be a key intermediate in the biosynthesis of the Aspidosperma and Iboga alkaloids. The dihydro-derivative, secodine (102), has now been synthesized by a route involving a Claisen ortho ester rearrangement [(98) + (99) (100)] and in situ elimination of methanol [(100) - ... 

It is suggested in conclusion that (99) occupies a crucial position at the branchpoint in the biosynthesis of Corynanthe, Iboga, and Aspidosperma alkaloids.30... 

For (essentially) the first time recently, strains of C. roseus cultures have been obtained which will synthesize Strychnos, Iboga, and Aspidosperma alkaloids.34 This opens up the exciting possibility of studying the biosynthesis of those alkaloids lying beyond the Corynanthe type, such as (102), by using enzyme preparations from tissue cultures, which have proved so powerful for the early stages of biosynthesis (see above). 

The versatility of strictosidine as a central intermediate for the biosynthesis of a variety of alkaloids is based on the highly reactive dialdehyde produced by the action of strictosidine p-D-glucosidase. This reactive intermediate is converted by uncharacterized enzymes into the major corynanthe, iboga, and aspidosperma skeletons that are elaborated into die several hundred alkaloids found in Catharanthns roseus. Since the biosynthesis of strictosidine appears to occur within plant vacuoles, there has been much speculation, but little is known, about the factors that regulate the accumulation of strictosidine within the vacuole, or which trigger its mobilization for further elaboration. It is well known that glycosides of different natural product classes are located within plant vacuoles. 

Another all-carbon Diels-Alder reaction is proposed for the biosynthesis of the indole alkaloids tabersonine 1-6 and catharanthine 1-7 of the Aspidosperma and Iboga family [28-31]. The compounds are formed via strictosidine 1-3, the first nitrogen-containing precursor of the monoterpenoid indole alkaloids, and stemmadenine 1-4, which is cleaved to give the proposed intermediate dehy-drosecodine 1-5 with an acrylate and a 1,3-butadiene moiety (Scheme 1-1). 

The mode of biosynthesis of none of these alkaloids is known but, in the case of the iboga group, some guesses have been made (39, 63, 64), all of which start from the amino acids, tryptophan and dihydroxy-phenylalanine, and involve a fission of the latter s aromatic ring. A more sophisticated approach (65), starting from precursors of the aromatic amino acids, namely shikimic and prephenic acids, is apparently not in agreement with recent work on other indole alkaloids (66). The genesis of most indole alkaloids appears to stem from tryptophan and three... 

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).6 Comparable incorporations were observed for [ar-3H]tryptophan, [ar-3H]stemmadenine (5), and [ar-3H]taber-sonine (9). These results support the proposal7 that vincamine is a transformation... 

However, until now there is no case known, where the corresponding enzyme system, that is the Diels-Alder-ase, could be detected. Even in the biosynthesis of the iboga and aspi-dosperma alkaloids the final proof for a Diels-Alder reaction is still missing (Scheme 8)... 

Wenkert, E., Biosynthesis of indole alkaloids. The aspidosperma and iboga bases, J. Amer. Chem. Soc., 84, 98 (1962). 

Loganin is an iridoid glucoside which occupies a central position in the biosynthesis of Corynanthe, Aspidosperma, Iboga, Ipecacuanha, Cinchona, and structurally simpler monoterpene alkaloids. For a review of the extensive researches that led to confirmation of the key role of loganin in alkaloid biosynthesis, see A. R. Battersby, Biochem. Soc. Symp., 29, 157 (1970) A. R. Battersby, Chem. Soc. Spec. Period. Rep., 1, 31 (1971) A. I. Scott, Accts. Chem. Res., 3, 151 (1970). For a useful account of the chemistry of iridoid glucosides see, J. M. Bobbitt and K. -P. Segebarth in Cyclopentanoid terpene Derivatives, Eds., W. I. Taylor and A. R. Battersby, Marcel Dekker, New York, 1969, p 1. 

---