Total synthesis and biological evaluation of (+)-neopeltolide and its analogues

Haruhiko Fuwa, Asami Saito, Shinya Naito, Keiichi Konoki, Mari Yotsu-Yamashita, Makoto Sasaki

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

The stereocontrolled total synthesis of the originally proposed (1) and correct (2) structures of (+)-neopeltolide, a novel marine macrolide natural product with highly potent antiproliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed SuzukiMiyaura coupling/ring-closing metathesis strategy. Alkylborate 44, which was generated in situ from iodide 34, was coupled with enol phosphate 8 by a Suzuki-Miyaura coupling. Ring-closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34. Our convergent strategy enabled us to construct the 14-membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure-activity relationships of 2, led to the discovery of a structurally simple yet potent cytotoxic analogue, 9-demethylneopeltolide (54).

Original languageEnglish
Pages (from-to)12807-12818
Number of pages12
JournalChemistry - A European Journal
Volume15
Issue number46
DOIs
Publication statusPublished - 2009 Nov 23

Keywords

  • Macrocycles
  • Natural products
  • Ring-closing metathesis
  • Suzuki-Miyaura coupling
  • Total synthesis

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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