Total Synthesis and Biological Evaluation of (+)-Gambieric Acid A and Its Analogues

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 SuzukiMiyaura 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. SuzukiMiyaura 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 FGHIJ-ring fragments (i.e., 8 and 9) were assembled through SuzukiMiyaura 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 JuliaKocienski 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.