A Novel and Efficient Synthesis of a Highly Active Analogue of <i>clasto</i>-Lactacystin β-Lactone

Abstract

Herein, we describe a new convergent synthesis of a more potent analogue of clasto-lactacystin β-lactone (2), PS-519 compound 4, which is currently in preclinical development for the treatment of ischemia−reperfusion injury in stroke and myocardial infarction. The synthetic strategy relies on building two intermediates (an oxazoline and an aldehyde) which are joined through a doubly diastereoselective aldol reaction, setting up the requisite unichiral centers in the final product (4). The facial selectivity and ultimate stereocontrol are achieved by employing a trivalent aluminum Lewis acid, Me2AlCl, in a chelation-induced reaction which yields a single aldol adduct. The efficiency of the synthetic approach has allowed for the preparation of multigram quantities of clinical grade material, which will support Phase I studies.