Highly enantioselective hydrogenation of ethyl 5,5-dimethoxy-3-oxopentanoate and its application for the synthesis of a statin precursor

摘要

The highly enantioselective hydrogenation of ethyl 5,5-dimethoxy-3-oxopentanoate (3) to ethyl 3-hydroxy-5,5-dimethoxypentanoate (4) - a key intermediate in the synthesis of pharmacologically important statin drugs - has been investigated. The stereo chemistry of the catalytic hydrogenation of the P-keto ester in the presence of a number of homogeneous chiral Rh-I and Ru-II complexes with phosphane ligands has been studied. The highest enantioselectivity for the homogeneous hydrogenation of 3 (up to 98.7 % ee) was achieved through an optimized version of Genet's procedure with a Ru[(R)-BINAP]Cl-2 pre-catalyst (substrate/catalyst ratio up to 20000:1, 50 bar H-2, 50 C, in MeOH). The transformation of alcohol R-(4) into ylide R-(6) as an important precursor of the chiral side chain of rosuvastatin is also illustrated