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

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.