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

Jasper Tyler; Adam Noble; Varinder Kumar Aggarwal

doi:10.1002/anie.202214049

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

Jasper Tyler
, Adam Noble
, Varinder Kumar Aggarwal^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

45 Citations (Scopus)

155 Downloads (Pure)

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

Original language	English
Article number	e202214049
Journal	Angewandte Chemie - International Edition
Volume	61
Issue number	52
Early online date	27 Oct 2022
DOIs	https://doi.org/10.1002/anie.202214049
Publication status	Published - 14 Dec 2022

Bibliographical note

Funding Information:
J.T. thanks the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. We thank Christopher Cope for assistance performing ReactIR studies.

Publisher Copyright:
© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Research Groups and Themes

BCS and TECS CDTs
Organic & Biological

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Azabicyclo[1.1.0]butane in the strain-release-driven synthesis of functionalised azetidines
Tyler, J. L. (Author), Noble, A. (Supervisor) & Aggarwal, V. (Supervisor), 24 Jan 2023
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)

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@article{430cf25c32e547848949422fba038ed7,

title = "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",

author = "Jasper Tyler and Adam Noble and Aggarwal, \{Varinder Kumar\}",

note = "Funding Information: J.T. thanks the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. We thank Christopher Cope for assistance performing ReactIR studies. Publisher Copyright: {\textcopyright} 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",

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doi = "10.1002/anie.202214049",

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AU - Noble, Adam

AU - Aggarwal, Varinder Kumar

N1 - Funding Information: J.T. thanks the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. We thank Christopher Cope for assistance performing ReactIR studies. Publisher Copyright: © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

PY - 2022/12/14

Y1 - 2022/12/14

N2 - 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

AB - 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

U2 - 10.1002/anie.202214049

DO - 10.1002/anie.202214049

M3 - Article (Academic Journal)

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IS - 52

M1 - e202214049

ER -

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

Abstract

Bibliographical note

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Student theses

Azabicyclo[1.1.0]butane in the strain-release-driven synthesis of functionalised azetidines

Cite this