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

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.