Four-Component Strain-Release-Driven Synthesis of Functionalized Azetidines

Angew Chem Int Ed Engl. 2022 Dec 23;61(52):e202214049. doi: 10.1002/anie.202214049. Epub 2022 Nov 27.

Abstract

Despite the favorable properties that azetidine rings can engender on drug-compounds, methods for the diversity-oriented synthesis of azetidine-based structures are significantly underdeveloped. Herein, we report the successful realization of a multicomponent [1,2]-Brook rearrangement/strain-release-driven anion relay sequence and its application to the modular synthesis of substituted azetidines. The rapidity of the reaction, as confirmed by in situ infra-red spectroscopy, leverages the strain-release ring-opening of azabicyclo[1.1.0]butane to drive the equilibrium of the Brook rearrangement. The three electrophilic coupling partners, added sequentially to azabicyclo[1.1.0]butyl-lithium, could be individually varied to access a diverse compound library. The utility of this methodology was demonstrated in a 4-step synthesis of the EP2 receptor antagonist PF-04418948.

Keywords: Azetidines; Bicyclic Compounds; Heterocycles; Multicomponent Reaction; Strained Molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anions / chemistry
  • Azetidines* / chemistry
  • Cyclization

Substances

  • Azetidines
  • Anions