基质氧化是否决定了循环烯和烯由细胞染色体p450氧化的区域选择性?
Shimrit Cohen1, Sebastian Kozuch, Carina Hazan
1Department of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Journal of the American Chemical Society
|August 24, 2006
概括
计算研究表明,单独的反应障碍不能预测P450cam催化中的选择性. 一个运动模型准确地预测了烯和环烯的环氧化选择性,为P450异酶行为提供了洞察力.
科学领域:
- 计算化学的计算化学
- 生物化学 生物化学
- 化学动力学 化学动力学
背景情况:
- 细胞染色体P450酶 (P450s) 对于代谢各种化合物至关重要.
- 了解氧化反应中的P450选择性对于药物开发和毒理学至关重要.
- P450cam是研究氧化机制的深入研究的模型酶.
研究的目的:
- 通过P450cam化合物I.调查基C-H氧化与C=C环氧化在环烯和中的选择性.
- 评估P450催化选择性的反应障碍与动力模型的预测能力.
- 为了解和预测P450异酶选择性的建立一个一般基础.
主要方法:
- 密度函数理论 (DFT) 的计算.
- 量子力学/分子力学 (QM/MM) 的计算.
- 在平稳状态条件下,应用先前开发的催化循环的动态表达.
主要成果:
- 直接氧化过程的相对障碍是观察到的选择性的不良预测因素.
- 一个动力模型准确地预测了的独家C=C环氧化.
- 动力模型预测,在环烯中,环氧化对氧化有较小的偏好,与实验观测一致.
结论:
- 在P450cam催化中的选择性更好地由催化循环的动力模型解释,而不是单个反应障碍.
- 开发的动态表达提供了一个一般框架,用于预测各种P450异酶的选择性.
- 这项工作促进了对P450酶机制和基质选择性的理解.
相关概念视频
02:35Regioselectivity of Electrophilic Additions-Peroxide Effect
In the presence of organic peroxides, the addition of hydrogen bromide to an alkene yields the isomer that is not predicted by Markovnikov’s rule. For example, the addition of hydrogen bromide to 2-methylpropene in the presence of peroxides gives 1-bromo-2-methylpropane. This addition reaction proceeds via a free radical mechanism, which reverses the regioselectivity. The free radical reaction mechanism involves three stages: initiation, propagation, and termination.
02:36Regioselectivity and Stereochemistry of Hydroboration
A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
01:26Thermal and Photochemical Electrocyclic Reactions: Overview
Electrocyclic reactions are reversible reactions. They involve an intramolecular cyclization or ring-opening of a conjugated polyene. Shown below are two examples of electrocyclic reactions. In the first reaction, the formation of the cyclic product is favored. In contrast, in the second reaction, ring-opening is favored due to the high ring strain associated with cyclobutene formation.
00:59Reactions at the Benzylic Position: Oxidation and Reduction
The benzylic position describes the position of a carbon atom attached directly to a benzene ring. Benzene by itself does not undergo oxidation. In contrast, the benzylic carbon is quite reactive in the presence of strong oxidizing agents such as KMnO4 or H2CrO4. Therefore, alkylbenzenes are readily oxidized to benzoic acid, irrespective of the type of alkyl groups.
01:17Thermal Electrocyclic Reactions: Stereochemistry
The stereochemistry of electrocyclic reactions is strongly influenced by the orbital symmetry of the polyene HOMO. Under thermal conditions, the reaction proceeds via the ground-state HOMO.
Selection Rules: Thermal Activation
Conjugated systems containing an even number of π-electron pairs undergo a conrotatory ring closure. For example, thermal electrocyclization of (2E,4E)-2,4-hexadiene, a conjugated diene containing two π-electron pairs, gives trans-3,4-dimethylcyclobutene.
Selection Rules: Thermal Activation
Conjugated systems containing an even number of π-electron pairs undergo a conrotatory ring closure. For example, thermal electrocyclization of (2E,4E)-2,4-hexadiene, a conjugated diene containing two π-electron pairs, gives trans-3,4-dimethylcyclobutene.
01:26Photochemical Electrocyclic Reactions: Stereochemistry
The absorption of UV–visible light by conjugated systems causes the promotion of an electron from the ground state to the excited state. Consequently, photochemical electrocyclic reactions proceed via the excited-state HOMO rather than the ground-state HOMO. Since the ground- and excited-state HOMOs have different symmetries, the stereochemical outcome of electrocyclic reactions depends on the mode of activation; i.e., thermal or photochemical.
Selection Rules: Photochemical Activation
Selection Rules: Photochemical Activation