Desymmetrization of Cyclohexanones Using Chiral Lithium Amide

Significance

4-Substituted cyclohexanones were enantioselectively deprotonated using ­Simpkins’ (R,R)-base. Arylation of the desymmetrized enolate by coupling with diaryl iodonium salts afforded the desired α-monoarylated cyclohexanone in good yields and good to excellent ee. The thermodynamically more stable cis product is the dominant diastereomer. A reasonable range of functionalities was tolerated with these substrates. The methodology was successfully applied in a key step to synthesize a highly potent analgesic natural product (-)-epibatidine. The asymmetric total synthesis was accomplished in 31% yield over six steps from a commercially available starting material.