The enantioselective introduction of electrophiles a to carbonyl groups is a central topic in asymmetric synthesis. Although asymmetric a-alkylations have been well developed, high enantioselectivity in a-arylation of ketones has only been achieved in a very limited number of cases. These involve arylation of trisubstituted enolates using binap-Pd complexes which gives non-epimerizable, tetrasubstituted ketones. [1,2] However, this strategy cannot be used in the desymmetrization/arylation of cyclic ketones, since even if the enolate was generated enantioselectively, the ketone product would racemize the starting enolate (through proton transfer) at the high temperatures required for arylation.
An alternative strategy involves a-arylation of b-ketoesters with aryl lead reagents (Scheme 1). [3] This strategy can be rendered asymmetric through 1) desymmetrization/bketoester formation, [4] 2) arylation, [3] and 3) decarboxylation and subsequent equilibration.
However, a direct asymmetric arylation of cyclohexanones would clearly be superior. If this could be achieved, we envisaged that this strategy could be applied to a short asymmetric synthesis of the alkaloid (À)-epibatidine (1) (Scheme 2). Herein, we describe our success in achieving these goals.