High-Pressure-Mediated Fragment Library Synthesis of 1,2-Disubsituted Cyclobutane Derivatives

Mathilde A.C.H. Janssen, Rico Rappard, Tom Dekker, Mitchel Heiming, Marjolijn Beens, Dyon Pieters, Brian H.M. Kuijpers, Jorg C.J. Benningshof, Maikel Wijtmans, Iwan J.P. de Esch, Daniel Blanco-Ania, Floris P.J.T. Rutjes*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Cyclobutanes have attracted significant interest in medicinal chemistry because of their unique structure and potential advantages in pharmacological properties. Nevertheless, 1,2-disubstituted cyclobutanes remain underrepresented, both in the general chemical space and in fragment-based drug discovery libraries. In this study, a two-diversification-point library of cyclobutanesulfonamides was synthesized through a hyperbaric [2+2] cycloaddition reaction between ethenesulfonyl fluoride and tert-butyl vinyl ether as the key step. The sulfonyl fluoride was subsequently transformed into various sulfonamides, whereas the tert-butyl ether was converted into carbamates and triazoles to synthesize a fragment library. Overall, this synthesis contributes to addressing the underrepresentation of 1,2-disubstituted cyclobutane fragments, making a valuable addition to the field of fragment-based drug discovery.

Original languageEnglish
Article numbere202400797
Pages (from-to)1-7
Number of pages8
JournalEuropean Journal of Organic Chemistry
Volume27
Issue number45
Early online date29 Oct 2024
DOIs
Publication statusPublished - 2 Dec 2024

Bibliographical note

This article also appears in: Board Members Society Volumes: The Netherlands.


Publisher Copyright:
© 2024 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH.

Funding

We acknowledge funding from the Dutch Research Council (NWO) under Applied and Engineering Sciences Grant 18019 (Ready for growth: a new generation of highly versatile fragment libraries). We thank dr. Paul Tinnemans (Solid State Chemistry, Institute for Molecules and Materials, Radboud University) for elucidating the X-ray crystal structures. We acknowledge funding from the Dutch Research Council (NWO) under Applied and Engineering Sciences Grant 18019 (Ready for growth: a new generation of highly versatile fragment libraries). We thank dr. Paul Tinnemans (Solid State Chemistry, Institute for Molecules and Materials, Radboud University) for elucidating the X\u2010ray crystal structures.

FundersFunder number
Radboud Universitair Medisch Centrum
Nederlandse Organisatie voor Wetenschappelijk Onderzoek18019

    Keywords

    • Cyclobutanes
    • Ethenesulfonyl fluoride
    • Fragment library
    • High-pressure chemistry
    • Hyperbaric [2+2] cycloaddition

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