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

Author:
Palimkar, Sanjay S., Uenishi, Jun’ichi, Ii, Hiromi
Source:
Journal of organic chemistry 2012 v.77 no.1 pp. 388-399
ISSN:
1520-6904
Subject:
aldehydes, chemical reactions, copper, macrolides, moieties, neoplasms, organic chemistry
Abstract:
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 synthesizeC10–C11 functional analogues of 1. The key steps of the total synthesis include assembling of iodoalkene 12 and aldehyde 13by 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.
Agid:
5498657