Computational Prediction of Enantioselectivity in Metal-Catalyzed Reactions

金属催化反应中对映选择性的计算预测

• 批准号: 1565669
• 负责人: Olaf Wiest
• 金额: $ 50.68万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1565669&HistoricalAwards=false
• 关键词: Computational; Prediction; Enantioselectivity; Metal; Catalyzed

The Chemical Catalysis program in the Division of Chemistry is funding the project "Computational Prediction of Enantioselectivity in Metal-Catalyzed Reactions" in the groups of Olaf Wiest and Paul Helquist at the University of Notre Dame. The project develops, validates, and applies computational methods for the prediction of stereoselectivity (preferential formation of one arrangement of atoms in space over other possibilities in a molecule) and regioselectivity (preferential formation of new bonds at specific positions of a molecule over other possible positions). The ability to correctly predict reaction selectivity in transition metal catalysis has a broad impact in the pharmaceutical and fine chemicals industry. Highly selective reactions are needed to produce safer, more effective, and lower cost drugs. The project provides multi-disciplinary training for graduate and undergraduate students that emphasizes the close connection between computational and experimental approaches and their application to practical problems. The prediction method involves five steps: (i) calculation of the pertinent transition structures for the targeted reactions using electronic structure methods, (ii) parameterization and validation of ground- and transition state force fields (TSFF) using quantum-guided molecular mechanics (Q2MM), (iii) calculation of the free energy difference of the relevant diastereomeric transition structures using full Monte Carlo conformational sampling at the transition state with the TSFF, (iv) use of the force fields for rapid prediction of enantioselectivities for virtual ligand libraries, and (v) selection and experimental evaluation of top ligand candidates for validation. The methods are used for a variety of reactions of importance in synthetic organic chemistry, including: (i) Mukaiyama aldol condensations, (ii) Heck arylations, (iii) 1,4-addition of organoboron compounds to unsaturated carbonyls, and (iv) imine reductions. The TSFFs and the Q2MM code is available to the scientific community via Github.

化学划分的化学催化计划正在为“金属催化反应中对映射性的计算预测”在巴黎圣母院的Olaf Wiest和Paul Helquist组中提供资金。该项目开发，验证和应用计算方法来预测立体选择性（优先形成一个在太空中与分子中其他可能性相对于其他可能性的形成）和区域选择性（优先形成在分子比其他可能位置的特定位置的新键形成）。在过渡金属催化中正确预测反应选择性的能力对药品和细化学工业产生了广泛的影响。需要高度选择性的反应来产生更安全，更有效和较低的成本药物。该项目为研究生和本科生提供了多学科培训，这些培训强调了计算方法和实验方法之间的紧密联系及其在实际问题上的应用。预测方法涉及五个步骤：（i）使用电子结构方法计算针对目标反应的相关过渡结构，（ii）使用量子和过渡状态态力场（TSFF）的参数化和验证，使用量子定量分子力学（q2mm）（q2mm），（iii）使用相关的概念差异的量子差异构成完整概念构造的构型构造的完整概念差异，该结构是相关的概念差异，该概念差异是相关的概念差异。使用TSFF，（iv）使用力场来快速预测虚拟配体库的对映选择性，以及（v）选择和实验评估顶级配体候选物进行验证。这些方法用于合成有机化学中的各种重要性，包括：（i）Mukaiyama aldol冷凝，（ii）芳基化，（iii）有机果化合物对未饱和羰基的有机甲基化合物的1,4-条件。 TSFF和Q2MM代码可通过GitHub提供给科学界。