HMG-CoA Reductase Inhibitors Aldolase-Catalyzed Synthesis of Chiral Lactol

36 HMG-CoA REDUCTASE INHIBITORS ALDOLASE-CATALYZED SYNTHESIS OF CHIRAL LACTOL 

The chiral lactol 126 is a key intermediate required for the synthesis of various HMG-CoA reductase inhibitors such as atorvastatin and rosuvastatin. 

HMG-CoA reductase inhibitors aldolase-catalyzed synthesis of chiral lactol. 

The chemical method for the synthesis of P2 moiety suffers from at least 50% yield loss in the resolution process [164]. Biocatalytic desymmetrization of substituted pyrrolidines to give the desired enantiomer is an attractive approach to access proline analogs. 

Turner s group demonstrated that a variety of 3,4-substituted mcso-pyrrolidines can be enantioselectively oxidized by the monoamine oxidase (MAO) mutant. The -p3UToline products were converted to amino acids through the corresponding nitriles. In another application, the chiral A -pyrrolines were directly used to prepare prolyl peptides in an Ugj reaction. This reaction has been applied to an efficient synthesis of Telaprevir. The directed evolution of MAO from Aspergillus niger provided variant with a broadened substrate specificity and high enanhoselectivity for several a-methyl amines. In further enzyme evolution, an improved variant was identified for secondary amines [165,166]. 

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