Total Synthesis of Amphidinol 3: A General Strategy for Synthesizing Amphidinol Analogs and Structure-Activity Relationship Study

Amphidinol 3 (AM3) is a potent antifungal produced by the dinoflagellate Amphidinium klebsii. It was difficult to determine the absolute configuration of AM3 by using scarce natural product due to the presence of numerous stereogenic centers on the acyclic carbon chain. Since the absolute configuration was partially determined based on the insufficient evidences, originally proposed structure has been revised three times. Although recent progress on structure determination by computational analysis is remarkable, total synthesis is still the most reliable way to confirm structures. The first total synthesis of AM3 was achieved via expeditious assembly of three components in five steps, confirming the revised structure of AM3 after more than twenty years since its first discovery. The established synthetic route would be a general strategy for synthesizing am-phidinol congeners. An artificial and simplified analog of AM3 which elicited antifungal activity comparable to that of AM3 was designed and synthesi...