Total Synthesis and Biological Evaluation of (−)-Apicularen A and Its Analogues

The total synthesis of (−)-apicularen A (1),
a highly cytostatic 12-membered macrolide, and its analogues is described.
The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesize C10–C11 functional
analogues of 1. The key steps of the total synthesis
include assembling of iodoalkene 12 and aldehyde 13 by Nozaki–Hiyama–Kishi (NHK) coupling, stereospecific
construction of 2,6-trans-disubstituted dihydropyran
by Pd­(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi
macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in the side chain
is installed by an efficient Cu­(I)-mediated coupling to complete the
synthesis. Analogues of C11-epi-, C11-deoxy-C10-α-hydroxy-,
and C10–C11 dehydrated apicularen A 3–5 were also prepared. Cytostatic activities of (−)-apicularen
A and the three analogues for three different cancer cell lines are
described.