Total synthesis of (−)-microcarpalide, a novel microfilament disrupting metabolite

Abstract

The stereoselective total synthesis of (−)-microcarpalide, a recently discovered 10-membered lactone of fungal origin displaying a remarkable disrupting action on actin microfilaments, was accomplished by using ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. The diene ester required for the macrocyclization reaction was assembled via DCC-mediated esterification of two suitable partners, each bearing a terminal alkene group. The alcohol fragment was synthesized from n-bromohexane through a seven-step sequence entailing two consecutive stereoselective homologations of chiral boronic esters as strategic transformations for the sequential insertion of the two stereocentres with the final S absolute configuration, using (+)-pinanediol as the chiral director; final elaboration to the desired C₁₁ framework envisaged treatment with an allyl Grignard reagent and oxidative cleavage of the boronic scaffold. In contrast, the acidic fragment was prepared in ten steps from D-tartaric acid, whose C₄ backbone was elongated to the required C₇ skeleton by means of two distinct Swern–Wittig oxidation–homologation sequences.