The total synthesis of the antitumor macrolide, rhizoxin

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Abstract

The first total synthesis of the antitumor macrolide rhizoxin in a highly stereocontrolled manner has been achieved. The efficient construction of optically pure key building fragments designed based on rational retrosynthetic analysis was accomplished in a concise manner. Synthesis of the Right-Wing started from the chiral half-ester generated by asymmetric hydrolysis of the corresponding meso-diester using pig liver esterase. The remaining chiral centers of the fragment were constructed by cyclic hydroboration. Synthesis of the Left-Wing was accomplished starting from methyl (S) -3-hydroxy-2-methylpropionate which in turn had been prepared again by enzyme mediated transformation. Coupling of Right-Wing and Left-Wing was carried out by Julia condensation, and the macrocyclic lactone was constructed by intramolecular Horner-Emmons reaction. Finally, the stereoselective epoxidation was achieved cleanly after formation of unsaturated 16-membered macrocyclic lactone. Chromophore-side-chain moiety was constructed at final stage by reaction of the phosphineoxide in 80% yield with high selectivity (E/Z= >20/1). The present methodology will be useful for the synthesis of the homologues or man-made rhizoxins.

Original languageEnglish
Pages (from-to)122-137
Number of pages16
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Volume53
Issue number2
DOIs
Publication statusPublished - 1995 Jan 1

Keywords

  • Antitumor macrolide
  • Asymmetric hydrolysis
  • Chiral half ester
  • Cyclic hydroboration
  • First total synthesis
  • Intramolecular Horner Emmons reaction
  • Julia condensation
  • Meso-diester
  • Pig liver esterase
  • Stereoselective epoxidation

ASJC Scopus subject areas

  • Organic Chemistry

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