Catalytic Asymmetric Synthesis of 3,4-Disubstituted Cyclohexadiene Carbaldehydes: Formal Total Synthesis of Cyclobakuchiols A and C

The first catalytic approach for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes through an inverse-electron demand Diels-Alder reaction is described. A variety of arylacetaldehydes and alpha,beta,gamma,delta-unsaturated aldehydes are tested under the mild reaction conditions catalyzed by L-proline to obtain the trans diastereomeric products with good yields and high enantioselectivities. The scope of this methodology is further extended to the asymmetric synthesis 3,4-disubstituted cyclohexane carbaldehydes and their derivatives. The practicality of this method is demonstrated by the gram-scale synthesis. This methodology is successfully applied for the formal total synthesis of cyclobakuchiol A, an antipyretic and anti-inflammatory agent, and cyclobakuchiol C.