title: Total synthesis and biological evaluation of (+)-gambieric acid A and its analogues.
abstract: 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.
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishigai
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Fuwa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hashizume
authors.forename: Ryo
authors.initials: R
authors.lastname: Fukazawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Cho
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002922:Ciguatoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004987:Ethers / Q000737:chemistry; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D004987:Ethers; D002922:Ciguatoxins; C080898:gambieric acid A