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Copper-mediated synthesis of drug-like bicyclopentanes

Nature volume 580, pages 220–226 (2020)Cite this article

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Abstract

Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. These structures are often generated from [1.1.1]propellane via opening of the internal C–C bond through the addition of either radicals or metal-based nucleophiles3,4,5,6,7,8,9,10,11,12,13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.

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Fig. 1: Direct three-component coupling of [1.1.1]propellane.
Fig. 2: Plausible mechanism and catalyst evaluation for three-component coupling.
Fig. 3: Radical precursor scope for three-component coupling.
Fig. 4: Nucleophile scope of three-component coupling.
Fig. 5: Rapid functionalization of drugs and natural products and preparation of pharmaceutical analogues.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

Research reported in this publication was supported by the NIH National Institute of General Medical Sciences (1R35GM134897-01) and gifts from Merck, Bristol-Myers Squibb, Eli Lilly and Janssen Research and Development LLC. We acknowledge Y. Liang for discussions.

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Author notes

  1. These authors contributed equally: Xiaheng Zhang, Russell T. Smith

Authors and Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, NJ, USA

    Xiaheng Zhang, Russell T. Smith, Chip Le & David W. C. MacMillan

  2. Janssen Research and Development, San Diego, CA, USA

    Stefan J. McCarver, Brock T. Shireman & Nicholas I. Carruthers

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Contributions

X.Z., R.T.S., C.L. and S.J.M. performed and analysed the experiments. X.Z., R.T.S., C.L. and D.W.C.M. designed the experiments. S.J.M., B.T.S. and N.I.C. provided intellectual contributions. R.T.S., X.Z. and D.W.C.M. prepared the manuscript.

Corresponding author

Correspondence to David W. C. MacMillan.

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Supplementary information

Supplementary Information

The file contains Figures S1-S18, encompassing optimization data, control experiments, additional examples, relevant cyclic voltammetry and UV-Vis data, experimental procedures, and characterization data.

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Zhang, X., Smith, R.T., Le, C. et al. Copper-mediated synthesis of drug-like bicyclopentanes. Nature 580, 220–226 (2020). https://doi.org/10.1038/s41586-020-2060-z

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