Accessing ladder-shape azetidine-fused indoline pentacycles through intermolecular regiodivergent aza-Paternò–Büchi reactions

Accessing ladder-shape azetidine-fused indoline pentacycles through intermolecular regiodivergent aza-Paternò–Büchi reactions

16 February 2024 | Jianjian Huang, Tai-Ping Zhou, Ningning Sun, Huaibin Yu, Xixiang Yu, Rong-Zhen Liao, Weijun Yao, Zhifeng Dai, Guojiao Wu & Fangrui Zhong
A new intermolecular aza-Paternò–Büchi reaction has been developed for the synthesis of azetidine-fused indoline pentacycles with ladder-shaped 3D structures. This reaction enables the efficient formation of molecules with diverse regioselectivity and absolute exo stereoselectivity, which are highly valuable in drug development. The reaction involves the [2+2] photocycloaddition of indole with imines, leading to the formation of complex polycyclic structures with contiguous quaternary carbons. The reaction is highly selective, producing either head-to-head (H–H) or head-to-tail (H–T) isomers with exclusive exo stereoselectivity. Computational studies revealed that the reaction mechanism involves a unique C–N bond formation preceding C–C bond formation, which is different from previously reported aza-Paternò–Büchi reactions. The reaction is applicable to various aromatic compounds, including benzofurans, benzothiophenes, and indenes, and exhibits excellent regioselectivity and diastereospecificity. The resulting molecules exhibit high 3D scores, indicating their potential for drug discovery. This study expands the synthetic capabilities of energy transfer catalysis for accessing complex, structurally diverse molecules with high molecular complexity and underexplored topological chemical space.A new intermolecular aza-Paternò–Büchi reaction has been developed for the synthesis of azetidine-fused indoline pentacycles with ladder-shaped 3D structures. This reaction enables the efficient formation of molecules with diverse regioselectivity and absolute exo stereoselectivity, which are highly valuable in drug development. The reaction involves the [2+2] photocycloaddition of indole with imines, leading to the formation of complex polycyclic structures with contiguous quaternary carbons. The reaction is highly selective, producing either head-to-head (H–H) or head-to-tail (H–T) isomers with exclusive exo stereoselectivity. Computational studies revealed that the reaction mechanism involves a unique C–N bond formation preceding C–C bond formation, which is different from previously reported aza-Paternò–Büchi reactions. The reaction is applicable to various aromatic compounds, including benzofurans, benzothiophenes, and indenes, and exhibits excellent regioselectivity and diastereospecificity. The resulting molecules exhibit high 3D scores, indicating their potential for drug discovery. This study expands the synthetic capabilities of energy transfer catalysis for accessing complex, structurally diverse molecules with high molecular complexity and underexplored topological chemical space.
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