Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir

J Am Chem Soc. 2017 Aug 9;139(31):10637-10640. doi: 10.1021/jacs.7b05806. Epub 2017 Jul 25.

Abstract

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.

MeSH terms

  • Acetates / chemical synthesis*
  • Acetates / chemistry
  • Acetates / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Catalysis
  • Cyclization
  • Hydrogen Bonding
  • Molecular Structure
  • Quantum Theory*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology

Substances

  • Acetates
  • Antiviral Agents
  • Quinazolines
  • letermovir