Small molecules with conformationally rigid, three-dimensional geometry are highly desirable in drug development, toward which a direct, simple-to-complexity synthetic logic is still of considerable challenges. Here, we report intermolecular aza-[2 + 2] photocycloaddition (the aza-Paternò–Büchi reaction) of indole that facilely assembles planar building blocks into ladder-shape azetidine-fused indoline pentacycles with contiguous quaternary carbons, divergent head-to-head/head-to-tail regioselectivity, and absolute exo stereoselectivity. These products exhibit marked three-dimensionality, many of which possess 3D score values distributed in the highest 0.5% region with reference to structures from DrugBank database. Mechanistic studies elucidated the origin of the observed regio- and stereoselectivities, which arise from distortion-controlled C-N coupling scenarios. This study expands the synthetic repertoire of energy transfer catalysis for accessing structurally intriguing architectures with high molecular complexity and underexplored topological chemical space.

具有构象刚性、三维几何形状的小分子在药物开发中非常受欢迎，而直接的、从简单到复杂的合成逻辑仍然面临着相当大的挑战。在这里，我们报道了吲哚的分子间氮杂-[2 + 2]光环加成（氮杂-Paternò-Büchi反应），该反应可以轻松地将平面结构单元组装成具有连续季碳、头对头发散的梯形氮杂环丁烷稠合二氢吲哚五环化合物/头尾区域选择性和绝对外切立体选择性。这些产品表现出明显的三维性，参考 DrugBank 数据库的结构，其中许多产品具有分布在最高 0.5% 区域的 3D 分数值。机理研究阐明了所观察到的区域选择性和立体选择性的起源，这些选择性和立体选择性是由畸变控制的 CN 耦合场景产生的。这项研究扩展了能量转移催化的合成库，以获取具有高分子复杂性和尚未充分探索的拓扑化学空间的结构有趣的结构。