A short, stereocontrolled, and practical synthesis of alpha-methylomuralide, a potent inhibitor of proteasome function.

An efficient and practical synthesis of alpha-methylomuralide (3), a selective inhibitor of proteasomes, has been developed as outlined in Scheme 1. Among the advantages of this route of synthesis over previously described approaches are (1) ease of scale-up and (2) high yields (28% overall yield of alpha-methylomuralide from 6) and stereocontrol (including high enantiocontrol). The synthesis is well suited to the production of 3 in the quantities needed for material-intensive in vivo investigations.