Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide-2a

Keita Sakamoto, Akihiro Hakamata, Arihiro Iwasaki, Kiyotake Suenaga, Masashi Tsuda, Haruhiko Fuwa

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki–Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2–5 as candidates for the correct structure. Accordingly, total syntheses of 2–5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2–5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

Original languageEnglish
Pages (from-to)8528-8542
Number of pages15
JournalChemistry - A European Journal
Volume25
Issue number36
DOIs
Publication statusPublished - 2019 Jun 26

Keywords

  • configuration determination
  • cytotoxicity
  • macrocycles
  • natural products
  • total synthesis

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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