Total synthesis and structure revision of didemnaketalB

Haruhiko Fuwa, Takashi Muto, Kumiko Sekine, Makoto Sasaki

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

DidemnaketalB, 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 didemnaketalB questioned the stereochemical assignment made by Faulkner etal. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketalB, 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 didemnaketalB.

Original languageEnglish
Pages (from-to)1848-1860
Number of pages13
JournalChemistry - A European Journal
Volume20
Issue number7
DOIs
Publication statusPublished - 2014 Feb 10

Keywords

  • natural products
  • spiroacetals
  • stereochemical assignment
  • structure elucidation
  • total synthesis

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