Proline Ester Enolate Claisen Rearrangement and Formal Total Synthesis of (-)-Cephalotaxine

A concise formal total synthesis of (-)-cephalotaxine was achieved via an ester enolate Claisen rearrangement (EECR). A series of EECRs of proline allyl esters were examined to obtain the desired relative stereochemistry of an azaspiranic tetracyclic backbone. An unexpected reversal or low diastereoselectivity of ( Z)-cinnamyl ester was observed. The diastereoselectivity was controlled by substitution patterns of a styrene region. This result represents a useful guide in aiding the prediction of stereochemical outcome of EECR of α-amino allylic esters.