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Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes

Author

Listed:
  • Marie L. J. Wong

    (Chemistry Research Laboratory)

  • Alistair J. Sterling

    (Chemistry Research Laboratory)

  • James J. Mousseau

    (Pfizer Medicine Design)

  • Fernanda Duarte

    (Chemistry Research Laboratory)

  • Edward A. Anderson

    (Chemistry Research Laboratory)

Abstract

Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.

Suggested Citation

  • Marie L. J. Wong & Alistair J. Sterling & James J. Mousseau & Fernanda Duarte & Edward A. Anderson, 2021. "Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21936-4
    DOI: 10.1038/s41467-021-21936-4
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    Cited by:

    1. Yonghong Liu & Zhixian Wu & Jing-Ran Shan & Huaipu Yan & Er-Jun Hao & Lei Shi, 2024. "Titanium catalyzed [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes for efficient synthesis of stilbene bioisosteres," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

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