Strain-Release Driven, Lewis Acid-Catalyzed, and Hexafluoroisopropanol-Mediated Reactions of Bicyclo[1.1.0]butanes

Conspectus Strain-release driven transformations of bicyclo[1.1.0]butanes (BCBs) have emerged as a powerful strategy for rapidly constructing functionalized cyclobutanes and complex bicyclic architectures through radical, nucleophilic, and electrophilic pathways. Owing to their unique reactivity and medicinal relevance, this Account highlights recent advances in exploiting BCBs for the synthesis of diverse bioisosteric bicyclic scaffolds and cyclobutanes. In 2023, we reported a Lewis acid-catalyzed, diastereoselective ring-opening of BCBs with β-naphthols, providing trisubstituted cyclobutane derivatives. Subsequently, thioindolinones were employed as nucleophilic partners in a diastereoselective formal ene reaction of mono-substituted BCBs, affording disubstituted cyclobutanes. Interestingly, replacing mono-substituted BCBs with disubstituted analogues resulted in a distinct reaction pathway, leading to the formation of trisubstituted cyclobutanethiols. Successively, we developed the Lewis acid-catalyzed annulation strategies involving BCBs for the construction of diverse bicyclic frameworks. The (3+2) annulation of BCBs with ynamides provided efficient access to bicyclo[2.1.1]hexene derivatives. Building on this, a (3+3) annulation with isatogens enabled the synthesis of bicyclo[3.1.1]heptane scaffolds. Furthermore, the use of para-quinone methides as coupling partners in a (4+3) annulation furnished bicyclo[4.1.1]octane derivatives, further showcasing the versatility of BCBs in strain-release annulation chemistry. We recently realized that BCBs can be activated in the presence of hexafluoroisopropanol (HFIP) via hydrogen bonding. In this context, the HFIP-mediated diastereoselective ring-opening of BCBs using peroxides furnished cyclobutane scaffolds. Additionally, a spiro-annulation of BCBs with α-halo hydroxamates, where HFIP enables simultaneous activation of BCBs and stabilization of the azaoxyallyl cation generated in situ from α-halo hydroxamates, affording functionalized spirocyclobutenes has been disclosed. Subsequently, the HFIP-mediated divergent reactivity of indolyl alcohols with BCBs where N-protected indolyl alcohols undergo (3+3) annulation and N-unprotected analogues favor (3+2) spiro-annulation has been uncovered. Mechanistic studies were conducted to elucidate the origin of this divergence. Further, we realized the strain-release driven hydroxy transfer to BCBs using diphenyl phosphine oxide for the diastereodivergent synthesis of cyclobutanol derivatives. Mechanistic studies have been carried out to understand the reaction mechanism and the origin of the diastereodivergent outcome. The strain-release driven transformations using BCBs are poised to continue flourishing, opening new avenues for reaction discovery and molecular construction. Future efforts are likely to focus on developing strategies to access tailor-made BCBs that can provide a direct route to three-dimensional drug-like molecules and extend enantioselective transformations for the synthesis of biologically important bicyclic motifs suitable for drug-design and clinical trials. Further, engaging BCBs in multicomponent reactions could result in multiple bond formations in one operation, thus generating molecular complexity, and is likely to attract modern synthetic chemists.