Library Synthesis of Cyclobutanol Derivatives by Hyperbaric [2+2] Cycloaddition Reactions

Abstract

Cyclobutanes are attracting a growing interest in medicinal chemistry because of their unique structure and potentially advantageous pharmacological properties. Specifically, 1,3‐disubstituted cyclobutanes have been explored as conformationally restricted propyl isosteres in drug development. In this study, a concise two‐diversification‐point library of 3‐amino‐3‐[(arenesulfonyl)methyl]cyclobutanols was synthesized through a hyperbaric [2+2] cycloaddition reaction between sulfonyl allenes and benzyl vinyl ether as the key step. Three different sulfonyl allenes were used for synthesizing the core structures that were further derivatized by the addition of up to seven amines. The amino groups were incorporated in moderate to excellent diastereoselectivity through conjugate addition to the four‐membered‐ring scaffolds. Overall, this synthesis process demonstrates the potential for further chemical expansion and fragment growth in drug development.