Development of a general, sequential, ring-closing metathesis/ intramolecular cross-coupling reaction for the synthesis of polyunsaturated macrolactones

Scott E. Denmark, Joseck M. Muhuhi

Research output: Contribution to journalArticle

Abstract

A general strategy for the construction of macrocyclic lactones containing conjugated Z,Z-1,3-diene subunits is described. The centerpiece of the strategy is a sequential ring-closing metathesis (RCM) that forms an unsaturated siloxane ring, followed by an intramolecular cross-coupling reaction with a pendant alkenyl iodide. A highly modular assembly of the various precursors allowed the preparation of unsaturated macrolactones containing 11-, 12-, 13-, and 14-membered rings. Although the RCM process proceeded uneventfully, the intramolecular cross-coupling required extensive optimization of palladium source, solvent, fluoride source, and particularly fluoride hydration level. Under the optimal conditions (including syringe pump high dilution), the macrolactones were produced in 53-78% yield as single stereoisomers. A benzo-fused 12-membered-ring macrolactone containing an E,Z-1,3-diene unit was also prepared by the same general strategy. The E-2-styryl iodide was prepared by a novel Heck reaction of an aryl nonaflate with vinyltrimethylsilane followed by iododesilylation with ICl.

Original languageEnglish (US)
Pages (from-to)11768-11778
Number of pages11
JournalJournal of the American Chemical Society
Volume132
Issue number33
DOIs
StatePublished - Aug 25 2010

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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