Mechanistic studies of the biomimetic epoxy ester-orthoester and orthoester-cyclic ether rearrangements.

The relative rates of acid-catalyzed rearrangements of epoxy esters to [3.2.1]bicyclic orthoesters, the subsequent rearrangements of these ortho esters to substituted tetrahydrofurans, and the rates of orthoester hydrolysis at pH 4.75 were measured in NMR kinetics experiments. The ease of formation and stabilities of these orthoesters compared favorably with the OBO-type [2.2.2]bicyclic orthoesters typically used as protecting groups of carboxylic acids. Studies with 13C NMR-detected 18O-labeling show that epoxy ester rearrangement takes place preferentially via 6-exo cyclization, although the 7-endo process competes when the distal center of the epoxide is disubstituted. The ortho ester-cyclic ether rearrangement was shown by 18O-labeling to occur exclusively via intermediacy of a five-membered dioxonium ion. The structures of the hydrolysis products also indicate the intermediacy of a dioxolanium ion during hydrolysis. The implications for a hypothetical biosynthesis of marine polyether toxins are discussed.

Synthesis of 2-methyl-D-erythritol via epoxy ester-orthoester rearrangement.

The biomimetic epoxy ester[bond]orthoester rearrangement has been applied to a new synthesis of 2-methyl-D-erythritol, a branched five-carbon sugar of importance to the deoxyxylulose pathway of isoprenoid biosynthesis. The intermediate orthoacetate is one of the few [2.2.1]-orthoesters to have been reported. Labeling studies with O-18 indicated that this reaction proceeds exclusively via a 5-exo cyclization. NMR analysis of chiral esters indicated an ee of 87% for the starting epoxide and an ee of 86% for the product. This route represents a rapid and convenient method for the synthesis of 2-methyl-D-erythritol and is expected to be useful for generating isotopically labeled intermediates for biochemical studies.