Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality

J Am Chem Soc. 2003 Sep 24;125(38):11482-3. doi: 10.1021/ja0365781.

Abstract

Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benzodiazepine perturbs this equilibrium and preferentially stabilizes one ring conformer. We report that N-i-Pr 1,4-benzodiazepine-2-ones derived from (S)-Ala and (S)-Phe can be deprotonated and alkylated in 86-99% ee, despite the fact that the original chiral center is destroyed in the deprotonation step. We attribute this highly enantioselective alkylation to the chiral memory of the benzodiazepine ring. This protocol provides easy access to the previously unexplored "quaternary" 1,4-benzodiazepine-2-ones.

Publication types

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

MeSH terms

  • Benzodiazepinones / chemical synthesis*
  • Benzodiazepinones / chemistry
  • Molecular Conformation
  • Stereoisomerism
  • Thermodynamics

Substances

  • Benzodiazepinones