Abstract:Straightforward synthetic approach for direct constructing functionalized γ-lactams is highly valuable given their ubiquity in bioactive molecules yet challenging due to instability of the products and difficulties in controlling diastereoselectivity. We herein report the design and synthesis of a naphthylbased pyrene-containing covalent organic framework and utilize it as heterogeneous photocatalyst in visible-light catalytic cascade reactions between tryptamine-derived isocyanides and phosphine oxides. A broad range of 3-(2aminophenyl)-γ-lactams are isolated in good yields undermild conditions and 3-(2-isocyanobenzyl)-indoles are also tolerated, giving (2-aminophenyl)-tetrahydroquinolines in moderate yield. Experimental studies and theoretical calculations reveal that a proton-coupled electron transfer process occurs between the excited covalent organic framework and phosphine oxide, which subsequently triggers a series of cascade reactions involving cyclization, semipinacol rearrangement, and dehydrogenation/hydration processes. Notably, the in situ generated spiroindolenine is identified to be the key intermediate. Illustrated by the efficient synthesis of 3-(2-aminophenyl)-γ-lactams,thisworksetsaprecedentfor the development of heterogeneous photocatalytic strategies for constructing complex bioactive molecules.

Authors:Xiangfeng Lin,Jianguo Li, Jiaxian Zheng,Xiaowei Cai1,Liwei Wang,Rongjian Sa, Chuanling Si, Dong Jiang, Jie Wang, Yusuke Yamauchi & Zhanhui Yuan

Nature Communications,2025,16,10818

link:https://doi.org/10.1038/s41467-025-66469-2