Amphidinolide B: Total Synthesis, Structural Investigation, and Biological Evaluation

作者：Lu Liang; Zhang Wei; Nam Sangkil; Horne David A; Jove Richard; Carter Rich G^*

来源：Journal of Organic Chemistry, 2013, 78(6): 2213-2247.

DOI：10.1021/jo3026077

The total syntheses of amphidinolide B-1 and the proposed structure of amphidinolide B-2 have been accomplished. Key aspects of this work include the development of a practical, non-transitionmetal-mediated method for the construction of the C-13-C-15 diene, the identification of alpha-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 B-2 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 B-2 is over 12-fold more potent than the C-8,C-9-epimer and C-18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity.

• 出版日期2013-3-15