Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States.
J Org Chem. 2013 Mar 15;78(6):2213-47. doi: 10.1021/jo3026077. Epub 2013 Feb 13.
The total syntheses of amphidinolide B1 and the proposed structure of amphidinolide B2 have been accomplished. Key aspects of this work include the development of a practical, non-transition-metal-mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy, and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent antitumor activities with IC50 values ranging from 3.3 to 94.5 nM against human solid and blood tumor cells. Of the different stereoisomers, the proposed structure of amphidinolide B2 is over 12-fold more potent than the C8,9-epimer and C18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity.
已经完成了 amphidinolide B1 的全合成以及 amphidinolide B2 的假定结构的研究。这项工作的关键方面包括开发一种实用的、非过渡金属介导的方法来构建 C13-C15 二烯，确定用于非对映选择性甲基酮Aldol 反应的 α-螯合和偶极最小化模型，发现一种自发的 Horner-Wadsworth-Emmons 大环化策略，以及开发一种新颖的后期方法来构建烯丙基环氧化物部分。最初提出的 amphidinolide B2 的结构及其非对映异构体具有很强的抗肿瘤活性，对人实体瘤和血液肿瘤细胞的 IC50 值范围为 3.3 至 94.5 nM。在不同的立体异构体中，amphidinolide B2 的假定结构在人 DU145 前列腺癌细胞中的活性比 C8,9-差向异构体和 C18-差向异构体强 12 倍以上。这些数据表明，环氧化物的立体化学是抗癌活性的一个重要因素。
