Computational Prediction of Enantioselectivity in Metal-Catalyzed Reactions

化学系的化学催化项目资助了圣母大学的Olaf Wiest和Paul Helquist小组的“金属催化反应中对映体选择性的计算预测”项目。该项目开发、验证并应用计算方法来预测立体选择性（分子中原子在空间中的一种排列优先形成而不是其他可能性）和区域选择性（在分子的特定位置优先形成新键而不是其他可能的位置）。正确预测过渡金属催化反应选择性的能力在制药和精细化工工业中具有广泛的影响。为了生产更安全、更有效、成本更低的药物，需要高度选择性的反应。该项目为研究生和本科生提供多学科训练，强调计算和实验方法之间的密切联系及其在实际问题中的应用。预测方法包括五个步骤：(i)利用电子结构方法计算目标反应的相关过渡结构，（ii）利用量子引导分子力学（Q2MM）对基态和过渡态力场（TSFF）进行参数化和验证，（iii）利用TSFF在过渡态进行全蒙特卡罗构象采样，计算相关非对映体过渡结构的自由能差，（iv）使用力场快速预测虚拟配体库的对映选择性，以及(v)选择和实验评估用于验证的顶级候选配体。这些方法用于合成有机化学中的各种重要反应，包括：(i) Mukaiyama醛缩，（ii） Heck芳基化，（iii）有机硼化合物在不饱和羰基上的1,4加成，以及（iv）亚胺还原。TSFFs和Q2MM代码可通过Github向科学界提供。

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.