Rational Tuning of the Reactivity of Three-Membered Heterocycle Ring Openings via SN2 Reactions
| Autor: | Carme Rovira, Jeroen Codee, Trevor Hamlin, Thomas Hansen, Alba Nin-Hill |
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| Přispěvatelé: | Organic Chemistry, AIMMS, Chemistry and Pharmaceutical Sciences, Theoretical Chemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Hansen, T, Nin-Hill, A, Codée, J D C, Hamlin, T A & Rovira, C 2022, ' Rational Tuning of the Reactivity of Three-Membered Heterocycle Ring Openings via S N 2 Reactions ', Chemistry-A European Journal, vol. 28, no. 60, e202201649 . https://doi.org/10.1002/chem.202201649 Chemistry-A European Journal, 28(60):e202201649. Wiley-VCH Verlag Chemistry: a European Journal, 28(60):e202201649 Chemistry European Journal |
| ISSN: | 0947-6539 |
| DOI: | 10.1002/chem.202201649 |
| Popis: | The development of small-molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the “electrophilic trap” that allows a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. Here we investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with a nitrogen (aziridine), phosphorus (phosphirane), oxygen (epoxide) or sulfur atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring opening of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C6H10Y with Y=NH, PH, O, S). It was revealed that the activation energy of the ring opening does not necessarily follow the trend that is expected from C−Y leaving-group bond strength, but steeply decreases from Y=NH, to PH, to O, to S. We illustrate that the HOMONu–LUMOSubstrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity. |
| Databáze: | OpenAIRE |
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