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Single-atom logic for heterocycle editing

Nature Synthesis volume 1, pages 352–364 (2022)Cite this article

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Abstract

Medicinal chemistry continues to be impacted by new synthetic methods. Particularly sought after, especially at the drug discovery stage, is the ability to enact the desired chemical transformations in a concise and chemospecific fashion. To this end, the field of organic synthesis has become captivated by the idea of ‘molecular editing’—to rapidly build onto, change or prune molecules one atom at a time using transformations that are mild and selective enough to be employed at the late stages of a synthetic sequence. In this Review, the definition and categorization of a particularly promising subclass of molecular editing reactions, termed ‘single-atom skeletal editing’, are proposed. Although skeletal editing applies to both cyclic and acyclic compounds, this Review focuses on heterocycles, both for their centrality in medicinal chemistry and for the definitional clarity afforded by a focus on ring systems. A classification system is presented by highlighting methods (both historically important examples and recent advances) that achieve such transformations, with the goal to spark interest and inspire further development in this growing field.

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Fig. 1: Definition and classification of single-atom molecular editing.
Fig. 2: Ring contractions that leverage classical carbonyl chemistry.
Fig. 3: Select developments in single-atom ring contractions of heterocycles.
Fig. 4: Single-atom deletions that leverage carbonyl chemistry.
Fig. 5: Select developments in single-atom deletions from nitrogenous heterocycles.
Fig. 6: Ring expansions that leverage carbonyl chemistry.
Fig. 7: Select advances in single-atom ring expansions.
Fig. 8: Single-atom insertions that leverage carbonyl chemistry.
Fig. 9: Recent advances in single-atom insertions into heterocycles.
Fig. 10: Dream reactions in single-atom skeletal editing and promising precedents.

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Acknowledgements

R.S. is grateful to the National Institutes of Medical Science (R35 GM13045) and Merck Research Laboratories for funding portions of the work described herein. M.D.L. thanks the Packard Foundation and National Institutes of Health (R35 GM142768) for funding. S.F.K. is grateful for a National Science Foundation Fellowship.

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  1. These authors contributed equally: Jisoo Woo, Sojung F. Kim.

Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, CA, USA

    Justin Jurczyk, Sojung F. Kim & Richmond Sarpong

  2. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Jisoo Woo, Balu D. Dherange & Mark D. Levin

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All the authors contributed to the inception, organization and writing of this manuscript, which was overseen by R.S. and M.D.L. All the figures were finalized by J.J. from initial drafts created by all the co-workers. J.J. led the writing of the section Contractions, S.F.K. wrote the section Deletions, J.W. led the writing of the section Expansions and B.D.D. wrote the Insertions section.

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Correspondence to Richmond Sarpong or Mark D. Levin.

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Jurczyk, J., Woo, J., Kim, S.F. et al. Single-atom logic for heterocycle editing. Nat. Synth 1, 352–364 (2022). https://doi.org/10.1038/s44160-022-00052-1

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