Chemistry and Synthetic Study of Laetacystin, the First Non-Protein Neurotrophic Factor

Abstract

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 hydroxymethylation of oxazoline and an asymmetric allylboration of the aldehyde which introduce the hydroxyl and methyl substituants at C(6) and C(7). This new asymmetric approach furnished four stereoisomers of 3-hydroxyleucine as required starting material in high overall yield and enantiomeric purity. Furthermore, the construction of several active analogs and the structure-activity relationships of lactacystin are also described.