Enantioselective Total Synthesis of Amphidinolide F

摘要

Over 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated from the dinoflagellate Amphidinium sp. From this family, amphidi-nolides C (1-2) and F(3) are among the most complex and densely functionalized members (Scheme 1). These natural products 1-3 contain eleven stereogenic centers embedded within a 25-membered macrolactone including two trans-disposed tetrahydrofuran ring systems, a 1,4-diketone motif, and a highly substituted diene moiety at C9-C11. In addition to the sizable structural challenges present in 1-3, these macrolides have shown significant cytotoxic activity. Consequently, compounds 1-3 have attracted considerable synthetic attention from numerous laboratories including our own.Despite these sizable endeavors, neither amphidinolide C nor amphidinolide F have been successfully synthesized in the more than 20 years since their isolation. It should be noted that the stereochemical assignment of compound 3 is based on analogy to compound 1 and isolation from the same organism. Herein, we disclose the first total synthesis of amphidinolide F (3), and thus confirm both the absolute and relative stereochemistry of the natural product.