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Insights into Stereoselectivity Switch in Michael Addition-Initiated Tandem Mannich Cyclizations and Their Extension from Enamines to Vinyl Ethers

  • Liu-Peng Zhao
    Liu-Peng Zhao
    The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, University of Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, China
  • Sheng-Ye Zhang
    Sheng-Ye Zhang
    The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, University of Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, China
  • Hua-Kui Liu
    Hua-Kui Liu
    The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, University of Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, China
    More by Hua-Kui Liu
  • Yu-Jing Cheng
    Yu-Jing Cheng
    The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, University of Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, China
  • Zhi-Pan Liu*
    Zhi-Pan Liu
    The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, University of Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, China
    *Email: zpliu@fudan .edu.cn
    More by Zhi-Pan Liu
  • Lijia Wang*
    Lijia Wang
    The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, University of Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, China
    Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
    *Email: [email protected]
    More by Lijia Wang
  • , and 
  • Yong Tang*
    Yong Tang
    The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, University of Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, China
    *Email: [email protected]
    More by Yong Tang
Cite this: J. Am. Chem. Soc. 2023, 145, 28, 15553–15564
Publication Date (Web):July 4, 2023
https://doi.org/10.1021/jacs.3c04989
Copyright © 2023 American Chemical Society

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    Abstract

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    Both cis- and trans- tetracyclic spiroindolines are the core of many important biologically active indole alkaloids, but the divergent synthesis of these important motifs is largely hampered by the limited stereoselectivity control. A facile stereoinversion protocol is reported here in Michael addition-initiated tandem Mannich cyclizations for constructing tetracyclic spiroindolines, providing an easy access to two diastereoisomeric cores of monoterpene indole alkaloids with high selectivity. The mechanistic studies including in situ NMR experiments, control experiments, and DFT calculations reveal that the reaction undergoes a unique retro-Mannich/re-Mannich rearrangement including a C–C bond cleavage that is very rare for a saturated six-membered carbocycle. Insights into the stereoinversion process have been uncovered, and the major effects were determined to be the electronic properties of N-protecting groups of the indole with the aid of Lewis acid catalysts. By understanding these insights, the stereoselectivity switching strategy is also smoothly applied from enamine substrates to vinyl ether substrates, which are enriched greatly for the divergent synthesis and stereocontrol of monoterpene indole alkaloids. The current reaction also proves to be very practical and was successfully applied to the gram-scale total synthesis of strychnine and deethylibophyllidine in short routes.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c04989.

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    Accession Codes

    CCDC 2026716 (cis-3a), 1039508 (trans-3a), 2026714 (cis-3c), 2026715 (trans-3c), 2026718 (cis-3x), 2026719 (cis-3x′), 2207854 (cis-8a), 2207853 (trans-8a), 2207852 (trans-8o) and 2207851 (11a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

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    Cited By

    This article is cited by 1 publications.

    1. Alexandra K. Bodnar, Suzanne M. Szewczyk, Yang Sun, Yifeng Chen, Anson X. Huang, Timothy R. Newhouse. Comprehensive Mechanistic Analysis of Palladium- and Nickel-Catalyzed α,β-Dehydrogenation of Carbonyls via Organozinc Intermediates. The Journal of Organic Chemistry 2024, 89 (5) , 3123-3132. https://doi.org/10.1021/acs.joc.3c02572