基板の酸化が,サイトクロームp450によるサイクロヘキセンとプロペンの酸化の地域選択性を決定するのか?
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
まとめ
計算による研究は,反応障壁だけではP450cam触媒の選択性を予測できないことを明らかにしています. 運動モデルはプロペンとサイクロヘクセンのエポキシデーション選択性を正確に予測し,P450イソ酵素の行動に関する洞察を提供します.
科学分野:
- コンピューティング・ケミストリー
- バイオケミストリー バイオケミストリー
- 化学動力学 化学動力学
背景:
- サイトクロームP450酵素 (P450s) は,様々な化合物の代謝に不可欠です.
- 酸化反応におけるP450の選択性を理解することは,薬物開発と毒理学にとって不可欠です.
- P450camは,酸化機構を調査するためのよく研究されたモデル酵素です.
研究 の 目的:
- P450cam コンパウンドIによるサイクロヘキセンとプロペンのC=CエポキシデーションとC=Cエポキシデーションの対照性におけるアリルC-H水酸化の選択性を調査する.
- P450の触媒選択性に関する運動モデルと反応障壁の予測力を評価する.
- P450イゾ酵素の選択性を理解し,予測するための一般的な基礎を確立する.
主な方法:
- 密度関数理論 (DFT) の計算.密度関数理論 (DFT) の計算.密度関数理論 (DFT) の計算.密度関数理論 (DFT) の計算.密度関数理論 (DFT) の計算.密度関数理論 (DFT) の計算.密度関数理論 (DFT) の計算.
- 量子力学/分子力学 (QM/MM) による計算.
- 安定状態の条件下における触媒サイクルに対して,以前に開発された運動表現の適用.
主要な成果:
- 直接的な酸化プロセスの相対的な障壁は,観察された選択性の悪い予測者である.
- 運動モデルはプロペンのC=Cエポキシデーションを正確に予測します.
- 運動モデルは,サイクロヘクセンのヒドロキシル化よりもエポキシデーションをわずかに好むことを予測し,実験観察と一致しています.
結論:
- P450cam触媒の選択性は,個々の反応障壁によって説明されるよりも,触媒サイクルの運動モデルによって説明される.
- 開発された運動表現は,様々なP450同酵素の選択性を予測するための一般的な枠組みを提供します.
- この研究は,P450酵素のメカニズムと基板選択性の理解を進めています.
関連する概念動画
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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