Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments

Research output: Contribution to journalArticle

  • Authors:
  • Paul R. Mears
  • Steven Hoekman
  • Claire E. Rye
  • Fiona P. Bailey
  • Dominic P. Byrne
  • And 2 others
  • External authors:
  • Patrick A. Eyers
  • Eric J. Thomas

Abstract

Bryostatins with modified C17–C27 fragments have not been widely studied. The synthesis of 20,20-difluorinated analogues was therefore investigated. Such substitution would inhibit dehydration involving the C19-hydroxyl group and stabilise the ring-closed hemiacetal tautomers. Following preliminary studies, allyldifluorination was used to prepare difluorinated alkenols. Oxidation followed by stereoselective Wittig reactions of the resulting α,α-difluorinated ketones gave (E)-α,β-unsaturated esters that were taken through to complete syntheses of 2-hydroxytetrahydropyrans corresponding to C17–C27 fragments of 20,20-difluorinated bryostatin. These compounds showed modest binding to protein kinase Cα isozyme. Attempts were also undertaken to synthesise macrocyclic 20,20-difluorinated analogues. During preliminary studies, allyldifluorination was carried out using a 2-alkyl-3-bromo-1,1-difluoropropene.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1487-1505
JournalOrganic & biomolecular chemistry
Volume17
Issue number6
Early online date16 Jan 2019
DOIs
Publication statusPublished - 2019