Total synthesis of gambieric acid A, a potent antifungal polycyclic ether metabolite, has been accomplished for the first time, which firmly established the complete stereostructure of this natural product.
In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B-ring exocyclic enol ether 32 was prepared through a Suzuki-Miyaura coupling of the B-ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A-ring by using diastereoselective bromoetherification as the key transformation. Suzuki-Miyaura coupling of 32 with acetate-derived enol phosphate 49, followed by ring-closing metathesis of the derived diene, produced the D-ring. Subsequent closure of the C-ring through a mixed thioacetalization completed the synthesis of the A/BCD-ring fragment 8. The A/BCD- and F'GHIJ-ring fragments (i.e., 8 and 9) were assembled through Suzuki-Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven-membered F'-ring. After the oxidative cleavage of the F'-ring, the E-ring was formed as a cyclic mixed thioacetal (i.e., 70) and then stereoselectively allylated by using glycosylation chemistry. Ring-closing metathesis of the diene 3 thus obtained closed the F-ring and completed the polycyclic ether skeleton. Finally, the J-ring side chain was introduced by using a Julia-Kocienski olefination in the presence of CeCl3 to complete the total synthesis of gambieric acid A (1), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.
The first total synthesis of (+)‐gambieric acid A, a potent antifungal marine polycyclic ether, has been accomplished by H. Fuwa, M. Sasaki et al. in their Full Paper on in a convergent manner by relying on Suzuki–Miyaura reaction for the assembly of the A/BCD‐ and F′GHIJ‐ring fragments and a ring‐closing metathesis for formation of the nonacyclic backbone. The total synthesis unambiguously establishes the structure of this extraordinary complex molecule, thus demonstrating the important role of organic synthesis in the structural elucidation of natural products.
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