Toward a Total Synthesis of Okilactomycin. 1. A Direct, Enantiocontrolled Route to the Western Sector

Abstract

A synthesis of the western half of the macrocyclic ring framework of the antitumor antibiotic okilactomycin is described. The strategy employed rests on an efficient synthesis of meso-2,4-dimethylglutaric anhydride and ensuing resolution via reaction with (S)-(-)-α-methylbenzylamine, diborane reduction, and selective crystallization. Following acid-catalyzed cyclization to (2S,4R)-2,4-dimethyl-6-valerolactone, an acyclic stereocontrol strategy was adopted to achieve chain lengthening with appropriate incorporation of functionality. The sensitive aldehyde 2 was further homologated to β-keto ester 17 in a model reaction sequence performed to simulate its ultimate projected coupling to 3.