Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation

Edna Mao, Cesar N. Prieto Kullmer, Holt A. Sakai, David W.C. MacMillan

Research output: Contribution to journalArticlepeer-review

Abstract

The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage. Herein, we report the realization of this approach through the conversion of aliphatic alcohols into the corresponding difluoromethylated analogues via the merger of benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)-CF2H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.

Original languageEnglish (US)
Pages (from-to)5067-5073
Number of pages7
JournalJournal of the American Chemical Society
Volume146
Issue number8
DOIs
StatePublished - Feb 28 2024

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

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