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Molecular editing of aza-arene C–H bonds by distance, geometry and chirality

Author

Listed:
  • Zhoulong Fan

    (The Scripps Research Institute)

  • Xiangyang Chen

    (University of California)

  • Keita Tanaka

    (The Scripps Research Institute)

  • Han Seul Park

    (The Scripps Research Institute)

  • Nelson Y. S. Lam

    (The Scripps Research Institute)

  • Jonathan J. Wong

    (University of California)

  • K. N. Houk

    (University of California)

  • Jin-Quan Yu

    (The Scripps Research Institute)

Abstract

Direct molecular editing of heteroarene carbon–hydrogen (C–H) bonds through consecutive selective C–H functionalization has the potential to grant rapid access into diverse chemical spaces, which is a valuable but often challenging venture to achieve in medicinal chemistry1. In contrast to electronically biased heterocyclic C–H bonds2–9, remote benzocyclic C–H bonds on bicyclic aza-arenes are especially difficult to differentiate because of the lack of intrinsic steric/electronic biases10–12. Here we report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally similar (C3 versus C7) positions on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C–H olefination, alkynylation and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative and late-stage C–H editing of quinoline-containing pharmacophores can be performed in a modular fashion in different orders to suit bespoke synthetic applications. This Article, in combination with previously reported complementary methods, now fully establishes a unified late-stage ‘molecular editing’ strategy to directly modify bicyclic aza-arenes at any given site in different orders.

Suggested Citation

  • Zhoulong Fan & Xiangyang Chen & Keita Tanaka & Han Seul Park & Nelson Y. S. Lam & Jonathan J. Wong & K. N. Houk & Jin-Quan Yu, 2022. "Molecular editing of aza-arene C–H bonds by distance, geometry and chirality," Nature, Nature, vol. 610(7930), pages 87-93, October.
  • Handle: RePEc:nat:nature:v:610:y:2022:i:7930:d:10.1038_s41586-022-05175-1
    DOI: 10.1038/s41586-022-05175-1
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    Cited by:

    1. Zhejun Jiang & Hao Huang & Chenxu Lu & Lianrong Zhou & Shengzhe Pan & Junjie Qiang & Menghang Shi & Zhengjun Ye & Peifen Lu & Hongcheng Ni & Wenbin Zhang & Jian Wu, 2024. "Ultrafast photoinduced C-H bond formation from two small inorganic molecules," Nature Communications, Nature, vol. 15(1), pages 1-8, December.
    2. Lucas Guillemard & Lutz Ackermann & Magnus J. Johansson, 2024. "Late-stage meta-C–H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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