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

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.

 

Comments：

The passage describes a successful method for the modular synthesis of substituted azetidines using a multicomponent [1,2]-Brook rearrangement/strain-release-driven anion relay sequence. This method leverages the strain-release ring-opening of azabicyclo[1.1.0]butane to drive the equilibrium of the Brook rearrangement, allowing for rapid reaction. Three electrophilic coupling partners can be added sequentially to azabicyclo[1.1.0]butyl-lithium to access a diverse compound library. The effectiveness of this methodology is demonstrated through a 4-step synthesis of the EP2 receptor antagonist PF-04418948. Despite the favorable properties that azetidine rings can provide to drug compounds, methods for the diversity-oriented synthesis of azetidine-based structures are limited, making this methodology a valuable contribution to the field. The in situ infra-red spectroscopy confirms the rapidity of the reaction.

Related Products

Cat.No.	Product Name	Information
S7211	PF-04418948	PF-04418948 is a potent and selective prostaglandin EP₂ receptor antagonist with IC50 of 16 nM. Phase 1.

Related Targets

Prostaglandin Receptor