A Classical Paradigm of Alkaloid Biogenesis Revisited: Acetonedicarboxylic Acid as a Biosynthetic Precursor of Lycopodine

摘要

As part of pur investigations of the mechanism of assembly of acetate-derived C_3 units that form part of the skeleton of a large number of alkaloids, we recently reported that the acetate-derived C_3 fragments, C-6,-7,-8 and C-14,-15,-16, of lycopodine (6) were derived in a manner that differs from either of the two modes of incorporation of [l,2-~(13)C_22]acetic acid for which precedent exists. These two previously established incorporation patterns are exemplified, on the one hand, by that found in the case of N-methylpelletierine, which was interpreted as arising by Mannich-type condensation of C-2 of acetoacetate with an iminium ion, and, on the other hand, by that observed in the cases of cocaine and the tropane alkaloids, which was interpreted in terms of a stepwise introduction of two acetate units. Each of these pathways generates a distinct and specific labeling pattern within the acetate-derived multicarbon unit of the alkaloids when label from sodium [l,2-~(13)C_2]acetate is incorporated. The incorporation pattern resulting from the entry of label from sodium [l,2-~(13)C_2]acetate into lycopodine was more complex than either of these and, in fact, represents a superposition of the two simpler patterns on one another. This result, together with the finding that [l,2,3,4-~(13)C_4]acetoacetic acid did not supply an intact C_3 unit but was incorporated only after cleavage to [l,2-~(13)C_2]acetic acid, led us to suggest that the acetate-derived C_3 fragments, C-6,-7,-8 and C-14,-15,-16, of lycopodine were introduced into the alkaloid via acetonedicar-boxylic acid (1), We now provide direct experimental evidence in support of this proposal.