Abstract
Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts1,2,3. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods4,5,6. Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns7,8,9,10. Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp2)–C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses.
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Acknowledgements
We thank J. Balsells, R. Lambert, B. Boyle and C. Gould for helpful discussion and for assistance in the preparation of this manuscript. A.L. also thanks C. Seath, H. Sakai, O. Garry and J. Xie for assistance in manuscript preparation. A.L. and C.J.O. thank the Ted Taylor family for a graduate fellowship. Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS) under grant no. R35 GM134897-04, the Princeton Catalysis Initiative, Janssen R&D and gifts from Merck, Bristol Myers Squibb, Genentech, GenMab and Pfizer. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS.
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D.W.C.M. conceived the work. A.L. and C.J.O. developed the couple-close protocol and experimental strategy. C.B.K. and M.C.B. helped design experiments and provided guidance. All authors discussed the results and contributed to editing the manuscript and preparing the Supplementary Information.
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D.W.C.M. declares a competing financial interest with respect to the Integrated Photoreactor. The remaining authors declare no competing interests.
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Extended data figures and tables
Extended Data Fig. 1 Proposed mechanistic scheme for the couple-close annulation reaction.
Metallaphotoredox cross-coupling (stage 1) is followed in the same reaction vessel by a photoredox-catalysed Minisci reaction (stage 2) to generate challenging semisaturated heterocyclic products. See Supplementary Information for a full description of the proposed mechanism.
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Long, A., Oswood, C.J., Kelly, C.B. et al. Couple-close construction of polycyclic rings from diradicals. Nature 628, 326–332 (2024). https://doi.org/10.1038/s41586-024-07181-x
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DOI: https://doi.org/10.1038/s41586-024-07181-x
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