Highly Enantioselective Synthesis of Both Enantiomers of γ-Substituted Butenolides by Bakers' Yeast Reduction and Lipase-Catalyzed Hydrolysis. Total Synthesis of (3AS,6aS)-Ethisolide, Whisky Lactone, and (−)-Avenaciolide

Reduction of 3-chloro-4-oxoalkanoates 5 with bakers' yeast gave (4 S )-3-chloro-4-hydroxyalkanoates, which were hydrolyzed and dehydrochlorinated to give (γ S )-alkylbutenolides with >96% ee. Reduction of 5 with NaBH 4 gave syn -3-chloro-4-hydroxyalkanoate 6 . Asymmetric hydrolysis of syn -4-chloro-3-hydroxyalkanoate (±)- 10 with lipase afforded (3 R,4 R )- 6 and (3 S,4 S )- 10 with high optical purities. Hydrolysis and dehydrochlorination of (3 R,4 R )- 6 gave (γ R )-alkylbutenolides with >85% ee. Total syntheses of (3a S,6a S )-ethisolide, whisky lactone, and (−)-avenaciolide from these butenolides are described.