title: Total synthesis and structure revision of didemnaketal B.
abstract: Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV-1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7-C21 spiroacetal domain by means of a strategy exploiting Suzuki-Miyaura coupling, 2) an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1-C7 acyclic domain, and 3) a Nozaki-Hiyama-Kishi reaction for the construction of the C21-C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner's stereochemical assignment led us to postulate that the absolute configuration of the C10-C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester (PGME) method to the C7-C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan), Fax: (+81) 22-217-6214. hfuwa@m.tohoku.ac.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Fuwa
authors.forename: Takashi
authors.initials: T
authors.lastname: Muto
authors.forename: Kumiko
authors.initials: K
authors.lastname: Sekine
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013729:Terpenes / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001688:Biological Products; D017320:HIV Protease Inhibitors; D013141:Spiro Compounds; D013729:Terpenes; C554891:didemnaketal B; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: natural products; spiroacetals; stereochemical assignment; structure elucidation; total synthesis