Catalytic Intermolecular\nAsymmetric [2π + 2σ]\nCycloadditions of Bicyclo[1.1.0]butanes: Practical Synthesis of Enantioenriched\nHighly Substituted Bicyclo[2.1.1]hexanes

The high percentage of sp<sup>3</sup>-hybridized carbons\nand the\npresence of chiral carbon centers could contribute to increased molecular\ncomplexity, enhancing the likelihood of clinical success of drug candidates.\nThree-dimensional (3D) bridged motifs have recently garnered significant\ninterest in medicinal chemistry. Bicyclo[2.1.1]hexanes (BCHs) are\nemerging 3D benzene bioisosteres, but the synthesis of chiral, highly\nsubstituted BCHs has been underexplored. Herein, we disclose the Lewis\nacid-catalyzed asymmetric intermolecular [2π + 2σ] cycloaddition\nof bicyclo[1.1.0]butanes with coumarins, 2-pyrone, or chromenes to\naccess diverse enantioenriched 1,2,3,4-tetrasubstituted BCHs bearing\nvicinal tertiary-quaternary stereocenters. The key to success is the\nintroduction of chiral bisoxazoline ligands to effectively suppress\nthe side reactions, inhibit significant racemic background reactions,\nand fine-tune the reactivity and regio-, enantio-, and diastereoselectivities\nof the reactions. The resulting BCHs hold significant potential as\nbenzene bioisosteres in the synthesis of chiral BCHex-Sonidegib and\nBCHex-BMS-202, mimicking the anticancer drug Sonidegib and the PD-1/PD-L1\ninhibitor BMS-202, respectively. The outcome highlights the positive\nimpact of bioisosteric replacement on physicochemical properties,\nwhile maintaining comparable antitumor activity to their aryl-containing\ncounterparts.