4.8 Article

The mechanism behind enhanced reactivity of unsaturated phosphorus(v) electrophiles towards thiols

Journal

CHEMICAL SCIENCE
Volume 12, Issue 23, Pages 8141-8148

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d1sc01730f

Keywords

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Funding

  1. Institute for Basic Science in Korea [IBS-R010-A1]
  2. Leibniz-Forschungsinstitut fur Molekulare Pharmakologie (FMP)
  3. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy [EXC 2008 - 390540038]
  4. Deutsche Forschungsgemeinschaft [SPP1623, GRK2473, SFB765]
  5. Einstein Foundation Berlin
  6. Boehringer Ingelheim Fonds
  7. Fonds der Chemischen Industrie
  8. Leibniz Society [SAW-2018-FMP-4-P5label, T18/2017]
  9. Studienstiftung des Deutschen Volkes

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This study investigated the reactivity of P(v) electrophiles towards thiols, revealing the influence of vinyl and ethynyl substituents on overall reactivity, and the key role of hyperconjugation in stabilizing intermediates. The study also provided a detailed mechanistic picture for designing P(v)-based electrophiles with fine-tuned reactivity profiles.
Vinyl- and ethynyl phosphorus(v) electrophiles are a versatile class of thiol-reactive reagents suitable for cysteine-selective peptide and protein modifications, especially for the generation of antibody conjugates. Herein we investigated the reactivity of various P(v) reagents towards thiol addition. Complementing previous studies, we observed that the heteroatoms X (X = S, O, NH) as well as the vinyl- vs. ethynyl-substituent bound to phosphorus greatly influence the overall reactivity. These experimentally observed trends, as well as the high Z-selectivity for thiol additions to ethynyl derivatives, were further elucidated using DFT calculations. Hyperconjugation was a key means of stabilizing the intermediate generated upon the thiol addition, thus determining both the reactivity and stereoselectivity of unsaturated P(v) electrophiles. Specifically, the energetically low-lying sigma antibonding orbital of the P-S bond more readily stabilizes the electron density from the lone pair (LP) of the generated carbanion, rendering the phosphonothiolates more reactive compared to the derivatives bearing oxygen and nitrogen. Our studies provide a detailed mechanistic picture for designing P(v)-based electrophiles with fine-tuned reactivity profiles.

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