CHEMISTRY AND SYNTHETIC STUDY OF LACTACYSTIN, THE FIRST NONPROTEIN NEUROTROPHIC FACTOR

A total synthesis of the microbial metabolite (+)-lactacystin (1), the first non-protein neurotrophic agent, has been achieved in 11 steps ( 14% overall yield) from 2(R), 3(S)-3-hydroxyleucine. The key steps in the elaboration of the lactam moiety include the stereoselective hydro xymethylation of oxazoline and an asymmetric allylboration of the alde hyde which introduce the hydroxyl and methyl substituents at C(6) and C(7). This new asymmetric approach furnished four stereoisomers of 3-h ydroxyleucine as required starting material in high overall yield and enantiomeric purity. Furthermore, the construction of several active a nalogs and the structure-activity relationships of lactacystin are als o described.