Toward a computational tool predicting the stereochemical outcome of asymmetric reactions: Development and application of a rapid and accurate program based on organic principles
Toward a computational tool predicting the stereochemical outcome of asymmetric reactions: Development and application of a rapid and accurate program based on organic principles
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DOI：
10.1002/anie.200704774
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Moitessier, Nicolas
中科院分区：
文献类型：
--
作者：
Corbeil, Christopher R.;Thielges, Sabine;Moitessier, Nicolas
目前实践的不对称催化剂发现通常依赖于昂贵的，有时是偶然的逐步优化和/或文库筛选。[1]我们相信，这种模式即将发生变化，因为计算预测方法已经达到了一定的准确性水平，消除了现在手动完成的许多步骤。我们在此报告的早期版本的一个新的程序，ACE（不对称催化剂评价），其基本概念，并评估其适用性和准确性区分有效的不对称催化剂或手性助剂从劣质的。虽然许多努力已被导向计算机辅助药物设计工具的发展，有很少的调查到不对称催化剂设计的计算工具。近年来，量子力学（QM）和量子力学/分子力学（QM/MM）[2]的研究取得了很大进展，并对不对称反应的立体选择性进行了精确的预测。[3-6]然而，QM方法需要数月的计算来筛选潜在催化剂库，以寻找新的催化剂。为了解决这个问题，开发了其他方法，包括反向对接[7，8]和定量结构选择性关系[9-11]，更具体地说，使用量子力学相互作用场。[12作为QM技术的另一种替代方案，已经使用了应用于基态结构的分子力学。[14]先进的MM为基础的过渡态（TS）技术，准确地预测TS结构和它们的相对势能，也有报道。[15]虽然这些方法（例如，Q2 MM（QM引导的MM），[16]使用TSFF（过渡态力场），[17] SEAM（两个势能函数的接缝），[18，19] EVB（经验价键），[20，21]和MCMM（多配置MM）[22]）在定位和调查TS方面显示出巨大的潜力，只有极少数研究报道试图预测反应的立体化学结果，[7，8，14，23-28]而在设计新的不对称催化剂方面的应用更少。[13事实上，力场的一个主要缺点是缺乏金属络合物的精确参数，这是模拟金属催化反应所必需的，需要专门开发。ACE是一个基于分子力学的独立程序，从简单的有机化学原理发展而来。例如，Hammond-Leffler假设指出TS与能量最接近的物质（反应物或产物）最相似。根据这一原理，ACE从反应物和产物的线性组合构建TS，包括描述TS在势能面上的位置的因子λ [Eq. (1),
Asymmetric catalyst discovery as currently practiced often relies on expensive, and sometimes serendipitous, stepwise optimization and/or library screening.[1] We believe that this paradigm is poised to change, as computational predictive methods have reached a level of accuracy that obviates many steps now done manually. We report herein the early version of a new program, ACE (asymmetric catalyst evaluation), its underlying concepts, and the assessment of its applicability and accuracy in distinguishing efficient asymmetric catalysts or chiral auxiliaries from inferior ones. Although much effort has been directed toward the development of computer-aided drug design tools, there has been little investigation into computational tools for asymmetric catalyst design. Nowadays, the fields of quantum mechanics (QM) and quantum mechanics/molecular mechanics (QM/MM)[2] are highly developed and have yielded accurate predictions of asymmetric reaction stereoselectivities.[3–6] However, QM methods would require months of computation to screen a library of potential catalysts in the search for new ones. To address this issue, other methods were developed, which include reverse docking [7, 8] and quantitative structure–selectivity relationships [9–11] and more specifically the use of quantum mechanics interaction fields.[12, 13] As another alternative to QM techniques, molecular mechanics applied to ground-state structures have been used.[14] Advanced MM-based transition-state (TS) techniques, which accurately predict TS structures and their relative potential energies, have also been reported.[15] Although these methods (eg, Q2MM (QM-guided MM),[16] using TSFF (transition-state force fields),[17] SEAM (seam of two potential-energy functions),[18, 19] EVB(empirical valence bond),[20, 21] and MCMM (multiconfiguration MM)[22]) have shown great potential in locating and investigating TSs, only a very few studies were reported that attempted to predict the stereochemical outcome of reactions,[7, 8, 14, 23–28] with even fewer applications to the design of new asymmetric catalysts.[13, 29, 30] In fact, one major shortcoming of force fields is the lack of accurate parameters for metal complexes, which are necessary to model metal-catalyzed reactions and need to be specifically developed.[31]ACE is a molecular-mechanics-based independent program that has been developed from simple organic chemistry principles. For example, the Hammond–Leffler postulate states that the TS is most similar to the species (reactants or products) which it is closest to in energy. Following this principle, ACE constructs TSs from a linear combination of reactants and products, including a factor λ describing the position of the TS on the potential-energy surface [Eq.(1),