Biosynthesis of fungal metabolites: asperlactone and its relationship to other metabolites of Aspergillus melleus

Abstract

The biosynthesis of asperlactone (5) from [1,2-¹³C₂]-, [2-¹³C, 2-²H₃]- and [²H₃]-acetate has been investigated. The pattern of incorporation of intact acetate units was checked with [1,2-¹³C₂]acetate. The presence in the ¹³C n.m.r. spectrum of a two-bond coupling (J 7.5 Hz) between C-2 and C-8 was verified by sine bell resolution enhancement of the Free Induction Decay. Therefore these two carbons, originally Joined in a C₂ unit derived from acetate, become separated by a rearrangement, and so finish in a 1,3 relationship. The carbon skeleton is therefore built up in identical fashion to that of the co-metabolite aspyrone (1). The retention of two acetate-derived hydrogens from [2-¹³C, 2-²H₃]acetate at C-7 rules out the intermediacy of structures in which this carbon forms part of an aromatic ring. This experiment also confirms that C-10 can retain three deuterium atoms and so is a chain starter methyl group. The overall retention of acetate hydrogen was determined by a ²H n.m.r. study of [2-²H₃]acetate-enriched asperlactone. To account for these results a biosynthetic model involving partially reduced polyketone intermediates is suggested (Scheme 4). Mechanistically feasible decarboxylation and rearrangement steps are followed by stereospecific opening of an epoxide ring to generate aspyrone (1) or asperlactone (5). The possible derivation of the aromatic co-metabolites, mellein (2) and hydroxymellein (3), from the same intermediate (10), generated on the same polyketide synthase, is discussed.