The high percentage of sp3-hybridized carbons and the presence of chiral carbon centers could contribute to increased molecular complexity, enhancing the likelihood of clinical success of drug candidates. Three-dimensional (3D) bridged motifs have recently garnered significant interest in medicinal chemistry. Bicyclo[2.1.1]hexanes (BCHs) are emerging 3D benzene bioisosteres, but the synthesis of chiral, highly substituted BCHs has been underexplored. Herein, we disclose the Lewis acid-catalyzed asymmetric intermolecular [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes with coumarins, 2-pyrone, or chromenes to access diverse enantioenriched 1,2,3,4-tetrasubstituted BCHs bearing vicinal tertiary-quaternary stereocenters. The key to success is the introduction of chiral bisoxazoline ligands to effectively suppress the side reactions, inhibit significant racemic background reactions, and fine-tune the reactivity and regio-, enantio-, and diastereoselectivities of the reactions. The resulting BCHs hold significant potential as benzene bioisosteres in the synthesis of chiral BCHex-Sonidegib and BCHex-BMS-202, mimicking the anticancer drug Sonidegib and the PD-1/PD-L1 inhibitor BMS-202, respectively. The outcome highlights the positive impact of bioisosteric replacement on physicochemical properties, while maintaining comparable antitumor activity to their aryl-containing counterparts.