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

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.

Figure 1

a) Previous work: (i) Diversity‐oriented synthesis of CNS targeting azetidines, (ii) ABB‐Li in the synthesis of acyl‐azetidines. b) This work: Four‐component synthesis of functionalized azetidines.

Figure 2

In situ IR spectroscopy studies. Assignments made based on steady state IR measurements and relative absorbance changes, see Supporting Information. Absorbances normalized to values between 0 and 1.

Scheme 1

Scope of the [1,2]‐Brook rearrangement/strain‐release‐driven anion relay reaction. Reactions performed on 0.322 mmol of acyl silane E¹. Isolated yields given. ^a Using the corresponding triethyl acylsilane. ^b Reactions warmed to rt for 16 h.

Scheme 2

[1,2]‐Brook rearrangement/strain‐release‐driven anion relay reaction. a) Scope of silyl enol ether functionalization. b) Application to the synthesis of PF‐04418948. Reactions performed with 0.20 mmol of crude 4 a, see Supporting Information for full conditions. Isolated yields from 4 a given. ^{a 1}H NMR yield. ^b One‐pot reaction from 7 a. ^c Reaction warmed to rt for 16 h. ^d Basic aqueous workup. ^e Acidic aqueous workup. ^f With TBAF and Cs₂CO₃. ^g With BF₃⋅OEt₂. ^h With TsN=IPh or CAN.