What Factors Affect the Regioselectivity of Oxidation by Cytochrome P450? A DFT Study of Allylic Hydroxylation and Double Bond Epoxidation in a Model Reaction
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- 作者：Sam P. de Visser ; Franç ; ois Ogliaro ; Pankaz K. Sharma ; and Sason Shaik
- 刊名：Journal of the American Chemical Society
- 出版年：2002
- 出版时间：October 2, 2002
- 年：2002
- 卷：124
- 期：39
- 页码：11809 - 11826
- 全文大小：370K
- 年卷期：v.124,no.39(October 2, 2002)
- ISSN：1520-5126
文摘
Epoxidation (C=C) vis-à-vis allylic hydroxylation (C-H) reactions of propene with a modelcompound I (Cpd I) of the enzyme cytochrome P450 were studied using B3LYP density functional theory.Potential energy profiles and kinetic isotope effects (KIE) were calculated. The interactions in the proteinpocket were mimicked by adding two external NH- - -S hydrogen bonds to the thiolate ligand and byintroducing a nonpolar medium (with a dielectric constant, 
= 5.7) that can exert a polarization effect onthe reacting species. A two-state reactivity (TSR) with high-spin (HS) and low-spin (LS) states were locatedfor both processes (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem.Soc. 2000, 122, 8977-8989. de Visser, S. P.; Ogilaro, F.; Harris, N.; Shaik, S. J. Am. Chem. Soc. 2001,123, 3037-3047). The HS processes were found to be stepwise, whereas the LS processes werecharacterized as nonsynchronous but effectively concerted pathways. The computed KIE for C-Hhydroxylation with and without tunneling corrections are large (>7), and they support the assignment ofthe corresponding transition states as hydrogen-abstraction species (Groves, J. T.; Han, Y.-Z. In CytochromeP450: Structures, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press:New York, 1995; Chapter 1; pp 3-48). In the gas phase, epoxidation is energetically favorable by 3.4 kcalmol-1. Inclusion of zero-point energy reduces this difference but still predicts C=C/C-H > 1. Environmentaleffects were found to have major impact on the C=C/C-H ratio as well as on the stereoselectivity of theprocesses. Thus, two NH- - -S hydrogen bonds away from the reaction center reverse the regioselectivityand prefer hydroxylation, namely, C=C/C-H <1. The polarity of the medium further accentuates the trendand leads to a change by 2 orders of magnitude in the regioselectivity, C=C/C-H 
1. Furthermore, sincethe environmental interactions prefer the LS over the HS reactions, both hydroxylation and epoxidationprocesses are rendered more stereoselective, again by 2 orders of magnitude. It follows, therefore, thatCpd I is a chameleon oxidant (Ogliaro, F.; Cohen, S.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000,122, 12892-12893; Ogliaro, F.; de Visser, S. P.; Cohen, S.; Kaneti, J.; Shaik, S. Chembiochem. 2001, 2,848-851; Ogliaro, F.; de Visser, S. P.; Groves, J. T.; Shaik, S. Angew. Chem., Int. Ed. 2001, 40, 2874-2878) that tunes its reactivity and selectivity patterns in response to the protein environment in which it isaccommodated. A valence bond (VB) model, akin to "redox mesomerism" (Bernadou, J.; Fabiano, A.-S.;Robert, A.; Meunier, B. J. Am. Chem. Soc. 1994, 116, 9375-9376), is constructed and enables thedescription of a chameleon transition state. It shows that the good donor ability of the thiolate ligand andthe acceptor ability of the iron porphyrin create mixed-valent situations that endow the transition state witha great sensitivity to external perturbations as in the protein pocket. The model is used to discuss thecomputed results and to relate them to experimental findings.
= 5.7) that can exert a polarization effect onthe reacting species. A two-state reactivity (TSR) with high-spin (HS) and low-spin (LS) states were locatedfor both processes (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem.Soc. 2000, 122, 8977-8989. de Visser, S. P.; Ogilaro, F.; Harris, N.; Shaik, S. J. Am. Chem. Soc. 2001,123, 3037-3047). The HS processes were found to be stepwise, whereas the LS processes werecharacterized as nonsynchronous but effectively concerted pathways. The computed KIE for C-Hhydroxylation with and without tunneling corrections are large (>7), and they support the assignment ofthe corresponding transition states as hydrogen-abstraction species (Groves, J. T.; Han, Y.-Z. In CytochromeP450: Structures, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press:New York, 1995; Chapter 1; pp 3-48). In the gas phase, epoxidation is energetically favorable by 3.4 kcalmol-1. Inclusion of zero-point energy reduces this difference but still predicts C=C/C-H > 1. Environmentaleffects were found to have major impact on the C=C/C-H ratio as well as on the stereoselectivity of theprocesses. Thus, two NH- - -S hydrogen bonds away from the reaction center reverse the regioselectivityand prefer hydroxylation, namely, C=C/C-H <1. The polarity of the medium further accentuates the trendand leads to a change by 2 orders of magnitude in the regioselectivity, C=C/C-H 1. Furthermore, sincethe environmental interactions prefer the LS over the HS reactions, both hydroxylation and epoxidationprocesses are rendered more stereoselective, again by 2 orders of magnitude. It follows, therefore, thatCpd I is a chameleon oxidant (Ogliaro, F.; Cohen, S.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000,122, 12892-12893; Ogliaro, F.; de Visser, S. P.; Cohen, S.; Kaneti, J.; Shaik, S. Chembiochem. 2001, 2,848-851; Ogliaro, F.; de Visser, S. P.; Groves, J. T.; Shaik, S. Angew. Chem., Int. Ed. 2001, 40, 2874-2878) that tunes its reactivity and selectivity patterns in response to the protein environment in which it isaccommodated. A valence bond (VB) model, akin to "redox mesomerism" (Bernadou, J.; Fabiano, A.-S.;Robert, A.; Meunier, B. J. Am. Chem. Soc. 1994, 116, 9375-9376), is constructed and enables thedescription of a chameleon transition state. It shows that the good donor ability of the thiolate ligand andthe acceptor ability of the iron porphyrin create mixed-valent situations that endow the transition state witha great sensitivity to external perturbations as in the protein pocket. The model is used to discuss thecomputed results and to relate them to experimental findings.