Synthesis of derivatives of (2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoic acid, a constituent of the didemnins

Abstract

The syntheses of the two protected derivatives 7 and 16 of (2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoic acid, a constituent of the didemnin family of antineoplastic macrocyclic depsipeptides are described. The preparation of 7 was carried out by modification of a previously reported synthetic route whereas the use of derivative 16 represents a novel approach to the management of this sub-unit. Removal of the carboxy protecting groups from 7 or 16, followed by amide bond formation with derivatives of (S)-leucine, and oxidation in the cases of compounds deriving from 16, generates the diastereoisomeric intermediates 11, 22 and 23. In each of these either of the protecting groups can be removed in the presence of the other, allowing them to be elaborated further at either terminus. Previous work indicates that diastereoisomeric mixtures of such intermediates can, in principle, be used to obtain optically pure didemnins.