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Copper-mediated synthesis of drug-like bicyclopentanes

Author

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  • Xiaheng Zhang

    (Merck Center for Catalysis at Princeton University)

  • Russell T. Smith

    (Merck Center for Catalysis at Princeton University)

  • Chip Le

    (Merck Center for Catalysis at Princeton University)

  • Stefan J. McCarver

    (Janssen Research and Development)

  • Brock T. Shireman

    (Janssen Research and Development)

  • Nicholas I. Carruthers

    (Janssen Research and Development)

  • David W. C. MacMillan

    (Merck Center for Catalysis at Princeton University)

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 nucleophiles3–13. 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.

Suggested Citation

  • Xiaheng Zhang & Russell T. Smith & Chip Le & Stefan J. McCarver & Brock T. Shireman & Nicholas I. Carruthers & David W. C. MacMillan, 2020. "Copper-mediated synthesis of drug-like bicyclopentanes," Nature, Nature, vol. 580(7802), pages 220-226, April.
  • Handle: RePEc:nat:nature:v:580:y:2020:i:7802:d:10.1038_s41586-020-2060-z
    DOI: 10.1038/s41586-020-2060-z
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    Cited by:

    1. Changha Kim & Yuhyun Kim & Sungwoo Hong, 2024. "1,3-Difunctionalization of [1.1.1]propellane through iron-hydride catalyzed hydropyridylation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Mingshuo Chen & Yuang Cui & Xiaoping Chen & Rui Shang & Xiaheng Zhang, 2024. "C−F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Liang Ge & Chi Zhang & Chengkai Pan & Ding-Xing Wang & Dong-Ying Liu & Zhi-Qiang Li & Pingkang Shen & Lifang Tian & Chao Feng, 2022. "Photoredox-catalyzed C–C bond cleavage of cyclopropanes for the formation of C(sp3)–heteroatom bonds," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Heather A. Hintz & Christo S. Sevov, 2022. "Catalyst-controlled functionalization of carboxylic acids by electrooxidation of self-assembled carboxyl monolayers," Nature Communications, Nature, vol. 13(1), pages 1-7, December.

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