Formal synthesis of (+)-lactacystin based on a novel radical cyclisation of an α-ethynyl substituted serine

A diastereoselective 5-exo-dig radical cyclisation of the bromoamide 7 produced from the enantiopure alpha-ethynyl Substituted amino alcohol 5 led to the pyrrolidinone 8 (2:1 alpha:beta epimers) in 70% yield. Oxidative cleavage of the alkene bond in 8, followed by a stereoselective alpha-methylsulfanylation of the resulting 4-keto derivative 9, next led to the methylsulfanyl derivative 10. Finally. the pyrrolidinone derivative 10 was converted into the key intermediate 12 used previously in an enantioselective synthesis of (+)-lactacystin. (C) 2003 Elsevier Ltd. All rights reserved.