Syntheses and biological evaluation of (+)-lactacystin and analogs

Since its isolation in 1991, (+)-lactacystin (1) has attracted considerable attention among leading synthesis laboratories due to its highly selective and potent inhibition of the 20S proteasome. The syntheses of this molecul e described herein demonstrate several important strategies in the area of acyclic stereocontrol including the use of chiral metal enolate and chiral allylmetal-based bond construction methods. Several analogs of 1 and of the related beta-lactone 2 are also presented, which provide insight into the structure activity relationship relative to the molecule's inhibition of th e 20S proteasome. Additionally, an analog of 2 is discussed regarding its c linical evaluation for the treatment of cerebral ischemia and stroke.