Total Synthesis of (+)-Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)-gracilamine (1) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza-Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91%ee) by an organocatalytic enantioselective aza-Friedel-Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)-gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.