What factors affect the regioselectivity of oxidation by cytochrome P450? A DFT study of allylic hydroxylation and double bond epoxidation in a model reaction

Sam P. De Visser, François Ogliaro, Pankaz K. Sharma, Sason Shaik

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    Abstract

    Epoxidation (C=C) vis-à-vis allylic hydroxylation (C-H) reactions of propene with a model compound 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 protein pocket were mimicked by adding two external NH - S hydrogen bonds to the thiolate ligand and by introducing a nonpolar medium (with a dielectric constant, ε = 5.7) that can exert a polarization effect on the reacting species. A two-state reactivity (TSR) with high-spin (HS) and low-spin (LS) states were located for 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 were characterized as nonsynchronous but effectively concerted pathways. The computed KIE for C-H hydroxylation with and without tunneling corrections are large (>7), and they support the assignment of the corresponding transition states as hydrogen-abstraction species (Groves, J. T.; Han, Y.-Z. In Cytochrome P450: 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 kcal mol-1. Inclusion of zero-point energy reduces this difference but still predicts C=C/C-H > 1. Environmental effects were found to have major impact on the C=C/C-H ratio as well as on the stereoselectivity of the processes. Thus, two NH - S hydrogen bonds away from the reaction center reverse the regioselectivity and prefer hydroxylation, namely, C=C/C-H
    Original languageEnglish
    Pages (from-to)11809-11826
    Number of pages17
    JournalJournal of the American Chemical Society
    Volume124
    Issue number39
    DOIs
    Publication statusPublished - 2 Oct 2002

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