In Prof. Zhang Xinglong’s recent Nature paper with Associate Professor Ming Joo Koh from the National University of Singapore (NUS), they introduce a visible-light photocatalytic “atom-swapping” strategy that converts readily available oxetanes into valuable saturated four-membered pharmacophores (for example, azetidines, thietanes and cyclobutanes) via a ring-opening/ring-reconstruction sequence.
The Zhang’s Group at CUHK led the DFT mechanistic studies that explain why this transformation is unusually chemoselective, activating the endocyclic oxetane oxygen preferentially even in the presence of other potentially reactive functionalities. From a mechanistic standpoint, the calculations support a conceptually simple sequence: light-driven catalysis generates a highly activated electrophilic intermediate that directs the oxetane into a controlled ring-opening pathway, producing a reactive “pre-organised” intermediate (effectively a dihalide-like platform) that can then be closed back into a four-membered ring after the desired atom/unit is installed. In other words, rather than a complicated network of competing pathways, the chemistry proceeds through a guided open–rebuild process that “edits” the ring by replacing the oxetane oxygen-derived connectivity with a new heteroatom or carbon fragment trapping partner.
These computational insights not only validate the proposed mechanism, but also help establish general design principles for extending single-atom editing to other saturated heterocycles, thereby supporting the broader goal of streamlined late-stage diversification in medicinal chemistry.
Details: Photocatalytic oxygen-atom transmutation of oxetanes