Chemoenzymatic Synthesis of δ-Keto β-Hydroxy Esters as Useful Intermediates for Preparing Statins

Enantiopure (R)‐3‐hydroxy‐5‐oxohexanoic acid esters have proven to be useful intermediates in the synthesis of the side chain of statins, in view of the recently described preparation of rosuvastatin and other statins through aldol reactions. Herein, an improved synthesis of these intermediates, by combining chemical and enzymatic reactions, is described. In particular, the selective reduction of a δ‐ketal β‐keto ester was identified as a key step to obtain derivatives with satisfactory optical purities for use in the synthesis of statins. An improved synthesis of an enantiopure (R)‐3‐hydroxy‐5‐oxohexanoic acid ester is described. The selective reduction of a δ‐ketal β‐keto hexanoate methyl ester with ketoreductase enzymes (e.g., KRED‐130) successfully provides an intermediate for the synthesis of statins in high yields with excellent optical purities; TBDMS = tert‐butyldimethylsilyl.