Intermediates Released from a Polyether-Producing Polyketide Synthase Provide Insight into the Mechanism of Oxidative Cyclization

摘要

Monensin A (1) from streptomyces cinnamonensis is an antibiotic ionophore widely used in veterinary medicine and also as a food additive in animal husbandry. It is one of the most important and best-studied members of a very large family of structurally related polyketide secondary metabolites, the polyethers. As with all natural polyethers, the molecule contains a multiplicity of asymmetric centers, but only one stereoisomer (out of 2~(17)) is produced by S. cinnamonensis. The molecular basis for this exquisite stereocontrol is not understood, and even the nature of the intermediates in polyether biosynthesis has until recently been a matter for conjecture. The results of early feeding studies using carbon-14-labeled precursors showed that monensin A is derived by a polyketide pathway from five acetate, one butyrate, and sever propionate units, and similar studies showed that oxygen atoms (O)1, (O)3, (O)4, (O)5, (O)6, and (O)10 arise from the carboxylate oxygen atoms of the corresponding carboxylic acid precursor units, while four other oxygen atoms, at C(13), C(17), C(21), and C(26), are derived from molecular oxygen (Scheme 1). On this basis, several plausible mechanisms have been suggested for the key oxidative steps. These hypotheses all involve the intermediacy of open-chain precursors, but the key difference concerns the stereochemistry of the double bonds (compare, for example, structures 2 and 3 in Scheme 2 a and b, respectively). However, the exact nature of the pathway has proved elusive because it has not been possible to detect any intermediates prior to oxidative ring formation.