Total Synthesis of (-)-Lasonolide A

Barry M. Trost, Craig E. Stivala, Daniel R. Fandrick, Kami L. Hull, Audris Huang, Caroline Poock, Rainer Kalkofen

Research output: Contribution to journalArticlepeer-review

Abstract

The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first-generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene-alkyne coupling. This type of coupling typically generates branched products; however, through a detailed investigation, we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom-economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a β-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantioselectivity.

Original languageEnglish (US)
Pages (from-to)11690-11701
Number of pages12
JournalJournal of the American Chemical Society
Volume138
Issue number36
DOIs
StatePublished - Sep 14 2016

ASJC Scopus subject areas

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

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