Auxiliary controlled enantioselective synthesis of 3-aryl-prolines

The synthesis of optically active cis 3-aryl proline derivatives was achieved in a five-step sequence involving an enantioselective aza-Claisen rearrangement as the key step. Initially, suitable cinnamyl amines were generated via a Pd(0) catalyzed amination of the corresponding N-allyl mesylates using optically active proline derivatives as chiral auxiliaries. The zwitterionic aza-Claisen rearrangement with azidoacetyl fluoride gave the corresponding α-azido-γ,δ-unsaturated amides with a complete simple and a moderate to high induced diastereoselectivity. The so formed unsaturated azides were subjected to a reductive cyclization developed by Evans and Sabol to generate the 2,3-cis-3-arylproline amides with high yields. The absolute configuration of one representative compound was proven by X-ray analysis. The removal of the auxiliary was difficult but succeeded at the stage of the unsaturated amide by treatment with acid without decrease of the diastereoselectivity. The so obtained 3-arylprolines are useful key fragments in biologically interesting (cyclo-) peptides and peptidomimetics.