A New Magnesium-Catalyzed Doubly Diastereoselective <i>anti</i>-Aldol Reaction Leads to a Highly Efficient Process for the Total Synthesis of Lactacystin in Quantity

Abstract

A new process is described for metal-catalyzed doubly diastereoselective Mukaiyama aldol coupling of a chiral tertiary α-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol product. The metal requirement is strict, since of several salts tested only MgI2 functions as an effective catalyst. The MgI2-catalyzed aldol greatly facilitates the total synthesis of lactacystin (1) and the corresponding β-lactone (2), microbial products which are potent and selective inhibitors of proteasome function, cell cycle progression, and gene regulation. The method also allows the synthesis of analogues of 1 in which the 7β-methyl group of lactacystin is replaced by higher alkyl or aralkyl groups. Detailed experimental procedures are presented for the optimized synthesis of lactacystin on the scale required to meet the current needs of many hundreds of biological laboratories.