Syntheses and Biological Evaluation of (+)-Lactacystin and Analogs

• Published in: European journal of organic chemistry Vol. 2000; no. 14; pp. 2513 - 2528
• Main Authors: Masse, Craig E., Morgan, Adam J., Adams, Julian, Panek, James S.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag GmbH 01.07.2000; WILEY‐VCH Verlag GmbH
• Subjects: Aminohydroxylation; Asymmetric synthesis; Lactacystin; Proteasome inhibitor; Structure−activity relationship / Natural products
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/1099-0690(200007)2000:14<2513::AID-EJOC2513>3.0.CO;2-D

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 molecule 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 β‐lactone 2 are also presented, which provide insight into the structure activity relationship relative to the molecule’s inhibition of the 20S proteasome. Additionally, an analog of 2 is discussed regarding its clinical evaluation for the treatment of cerebral ischemia and stroke.