A formal synthesis of (+)-lactacystin from 4-hydroxyproline

A formal synthesis of (+)-lactacystin has been completed from trans-4-hydroxyproline, using a diastereoselective enolate acylation reaction as a key step. Diastereoselectivity was seen to vary as a function of the steric bulk of the C4-O-protecting group, and contrary to expectations, the best diastereoselectivities were obtained when the small methyl carbonate protecting group was used. The formal synthesis was then completed by intercepting Shibasaki’s route via methyl carbonate deprotection, dehydration, 3-pyrroline to 3-pyrrolinone oxidation, hydrogenation and N-CO2Me deprotection.