The efficient design of (C)sp 3 -rich molecular scaffolds with defined exit vectors is central to expanding drug-like chemical space. Here, we report a boron-enabled strategy for the synthesis of polysubstituted housanes from nonsymmetrical dienes. A geminal diboron system ensures site-, regio-, and diastereoselectivity in an energy transfer-catalyzed [2 + 2] cycloaddition of nonsymmetrical dienes while also facilitating the mild generation of a cyclobutyl anion that triggers a stereospecific intramolecular annulation via conjugate addition, delivering complex housanes, with three defined exit vectors, in just two steps. Systematic derivatization across all substituents demonstrates the breadth of chemical diversification, while mechanistic and density functional theory (DFT) computational studies reveal the stereoelectronic origins of diastereoselectivity and the counterintuitive electrophile-driven reactivity of the housane framework. This work establishes housanes as stable, derivatizable, and structurally rigid fragments that provide multidirectional exit vectors, offering a powerful platform for the exploration of three-dimensional (3D) chemical space in medicinal chemistry.
