EXPERIMENTS AND SPECULATIONS ON THE ROLE OF OXIDATIVE CYCLIZATION CHEMISTRY IN NATURAL PRODUCT BIOSYNTHESIS

Syntheses of [2-H-2,3-C-13]- and [2-H-2,3'-H-2(2)]proclavaminic acid, (22) and (29) respectively, are described. These labeled substrates were incubated with clavaminate synthase, a key enzyme acting in the biosynthesis of the lactamase inhibitor clavulanic acid, in the presence of ferrous ion, alpha-ketoglutaric acid and molecular oxygen. The apparent oxidative cyclization/desaturation chemistry evident in the conversion of proclavaminic acid (8) to clavaminic acid (9) takes place without loss or exchange of label at C-2 and C-3' in the substrate. These observations point to notable similarities to sulfur insertion reactions in natural product biosynthesis and lead to the proposition of a generalized mechanism for oxidative cyclization invoking substrate heteroatom participation. By extension of this mechanistic hypothesis, a new biogenetic speculation is advanced to account for polyether formation, for example, in monensin (52) and brevetoxin A (55).