Enantioselective Aldol Reaction of alpha-Ketoester and Cyclopentaone Catalyzed by L-Proline

A concise and enantioselective synthesis of (S)-ethyl 2-cyclopentyl-2-hydroxy-2-arylacetate, a key intermediate for the muscarinic receptor, is reported. The tertiary stereogenic center was constructed with good stereoselectivity through the L-proline-catalyzed direct asymmetric aldol reaction of ethyl arylglyoxylate and cyclopentanone. The carbonyl of the condensation product was reduced using a modified Clemmensen reaction which provided an easier workup and was more environmentally acceptable. The enantioselectivity of the aldol reactions was between 58.3%-93.2%, which means that the stereoselective is efficient in controlling configuration of reaction product.