A NEW MAGNESIUM-CATALYZED DOUBLY DIASTEREOSELECTIVE ANTI-ALDOL REACTION LEADS TO A HIGHLY EFFICIENT PROCESS FOR THE TOTAL SYNTHESIS OF LACTACYSTIN IN QUANTITY

A new process is described for metal-catalyzed doubly diastereoselecti ve Mukaiyama aldol coupling of a chiral tertiary alpha-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol prod uct. The metal requirement is strict, since of several salts tested on ly MgI2 functions as an effective catalyst. The MgI2-catalyzed aldol g reatly facilitates the total synthesis of lactacystin (1) and the corr esponding beta-lactone (2), microbial products which are potent and se lective inhibitors of proteasome function, cell cycle progression, and gene regulation. The method also allows the synthesis of analogues of 1 in which the 7 beta-methyl group of lactacystin is replaced by high er alkyl or aralkyl groups. Detailed experimental procedures are prese nted for the optimized synthesis of lactacystin on the scale required to meet the current needs of many hundreds of biological laboratories.