Enantioselective radical C-H amination for the synthesis of β-amino alcohols

Nat Chem. 2020 Aug;12(8):697-704. doi: 10.1038/s41557-020-0482-8. Epub 2020 Jun 22.

Abstract

Asymmetric, radical C-H functionalizations are rare but powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regioselective C-H amination of alcohols to access medicinally valuable chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol was transiently converted to an imidate radical that underwent intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C-H amination enabled broad access to chiral β-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl and propargyl C-H bonds. Mechanistic experiments revealed that triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity, enabling the synthesis of several important classes of chiral β-amines by enantioselective, radical C-H amination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amination
  • Amino Alcohols / chemistry*
  • Carbon / chemistry*
  • Catalysis
  • Copper / chemistry
  • Hydrogen / chemistry*
  • Stereoisomerism

Substances

  • Amino Alcohols
  • Carbon
  • Copper
  • Hydrogen