Department of Chemistry, Faculty and Graduate School of Science , Kyushu University , 744 Motooka , Nishi-ku , Fukuoka 819-0395 , Japan.
J Am Chem Soc. 2020 Feb 19;142(7):3472-3478. doi: 10.1021/jacs.9b11789. Epub 2020 Feb 6.
Amphidinol 3 (AM3) is a potent antifungal produced by the dinoflagellate . It was difficult to determine the absolute configuration of AM3 by using the scarce natural product due to the presence of numerous stereogenic centers on the acyclic carbon chain. Since the absolute configuration was partially determined on the basis of insufficient evidence, the 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 20 years since its first discovery. The established synthetic route would be a general strategy for synthesizing amphidinol congeners. An artificial and simplified analogue of AM3, which elicited antifungal activity comparable to that of AM3, was designed and synthesized. This is the first example of a biologically active artificial analogue possessing a shorter polyol moiety, providing insight on the antifungal mode-of-action.
Amphidinol 3 (AM3) 是一种由甲藻产生的强效抗真菌化合物。由于在非环碳链上存在许多手性中心，因此使用稀缺的天然产物难以确定 AM3 的绝对构型。由于最初的结构是基于不充分的证据部分确定的，因此该结构已被修订了三次。尽管最近在计算分析方面的结构确定方面取得了显著进展，但全合成仍然是确认结构最可靠的方法。 AM3 的首次全合成是通过在五步中快速组装三个组件来实现的，这确认了自首次发现以来经过 20 多年的 AM3 的修订结构。所建立的合成路线将是合成 amphidinol 同系物的一般策略。设计并合成了 AM3 的人工简化类似物，该类似物具有与 AM3 相当的抗真菌活性。这是首例具有较短多元醇部分的具有生物活性的人工类似物的实例，为抗真菌作用模式提供了见解。
