Synthetic Strategies for Cyclobutane Derivatives Without Employing [2 + 2] Cycloaddition and Their Application in Organic Synthesis

The cyclobutane ring stands as a remarkable structural motif, renowned for its presence in natural products and its unique reactivity in organic synthesis. Its inherent ring strain drives selective C─C bond cleavage and ring expansion, making it a compelling target for synthetic chemists. While [2 + 2] cycloaddition remains a classic method for cyclobutane construction, this approach is often unsuitable for intricately embedded cyclobutane moieties in complex natural products. To overcome these limitations, innovative synthetic strategies have been developed, bypassing direct cycloaddition to achieve precise and efficient cyclobutane assembly. This review highlights these methodologies and their transformative applications, expanding the synthetic repertoire for cyclobutane derivatives in organic chemistry.