Theoretical and Experimental Investigation of Chiral Separation by Crystallization

手性，某些分子以具有相同物理性质的两个镜像（对映体）存在的能力，是生命的基本成分。在进化过程中，生物体选择只使用其中一个镜像来构建它们的手性分子;例如，所有生物体的氨基酸都具有相同的手性构型。这就解释了为什么引入生物体的药物的药理学或毒理学性质可以根据所使用的对映异构体而非常不同。不幸的是，这并不总是得到赞赏。沙利度胺悲剧中的出生缺陷仍然是这一事实的悲哀提醒。难怪监管部门现在制定了严格的指导方针，以防止这种情况再次发生，其他行业也变得越来越谨慎。例如，对映体纯的杀虫剂比外消旋杀虫剂（对映体的混合物）更受欢迎，因为它们更有效，对环境的影响更小。我们对手性分子生物活性的更好理解导致了对映体纯化合物市场的空前增长。然而，尽管在合成化学方面取得了进展，但我们仍然远远没有达到自然界的完美，自然界通过使用酶产生手性产物，酶的作用被高度优化以区分对映体。通常，化学合成的最终产物是外消旋混合物，其需要通过合适的分离方法（例如结晶）拆分成其手性组分。不幸的是，从外消旋熔体或溶液中结晶很少导致自发拆分（纯手性晶体的机械混合物）。当这不发生时，可以通过利用两种对映体与对映体纯的拆分剂不同地相互作用，形成具有不同物理性质的一对盐或分子复合物（非对映体）的事实来实现分离。通过明智地选择拆分剂，两种非对映异构体的溶解度将显著不同，并且通过结晶出溶解度较低的一种，它们的分离将是可能的。尽管该方法被广泛使用，但拆分剂和工艺条件的选择仍然基于试错实验。我们的研究旨在利用计算化学的进步和计算资源的增加来解决预测如何通过结晶分离对映体的挑战。我们现在有高度精确的方法来模拟原子水平上的分子相互作用。这将使我们能够从第一性原理出发预测非对映异构体的晶体结构、热力学稳定性和性质，进一步提高这些算法的准确性和可靠性。这些发展将导致理解和预测的自发决议，当这不发生时，决议效率为一个给定的外消旋混合物和拆分剂。然后，我们将能够通过改变其分子结构来设计拆分剂，以实现最佳分离，并随后优化工艺条件（例如温度）。不幸的是，开发和验证预测模型所需的全部实验数据，从晶体结构到分辨率效率，仅适用于少数系统。我们将利用化学，化学工程和分子建模的多学科能力，生成所需的实验数据以及计算建模。该研究既及时又具有重要的工业意义，因为其结果将有助于减少消耗资源的试错实验，并满足专业化学产品开发的紧迫时间表。这一项目的成功将降低生产成本，增加药品、食品和农用化学品的供应。

Chirality, the ability of some molecules to exist as two mirror images (enantiomers) with identical physical properties, is a basic ingredient of life. In the course of evolution, organisms opted to use just one of the mirror images for chiral molecules they are built from; for example amino acids of all living organisms have the same chiral configuration. This explains why the pharmacological or toxicological properties of drugs introduced to an organism can be very different depending on the enantiomer used. Unfortunately, this has not always been appreciated. Birth defects in the thalidomide tragedy still serve as a sad reminder of this fact. It is no wonder that regulatory authorities have now set strict guidelines to prevent this from happening again and other industries are becoming increasingly cautious. For example, enantiomerically pure insecticides are preferred over racemic ones (mixture of enantiomers) because they are more effective and have a smaller environmental impact.Our better understanding of the biological activity of chiral molecules has resulted in an unprecedented growth of the market for enantiomerically pure compounds. However, despite progress in synthetic chemistry, we are still far from the perfection of nature which produces chiral products by using enzymes whose action is highly optimised to discriminate between enantiomers. Frequently, the end product of a chemical synthesis is a racemic mixture which needs to be resolved into its chiral components via a suitable separation method, such as crystallisation. Unfortunately, crystallisation from a racemic melt or solution rarely leads to spontaneous resolution (mechanical mixture of homochiral crystals). When this does not occur, separation can be achieved by exploiting the fact that the two enantiomers interact differently with enantiomerically pure resolving agents, forming a pair of salts or molecular complexes (diastereomers) with different physical properties. By judiciously choosing the resolving agent, the solubility of the two diastereomers will be substantially different and their separation will be possible by crystallising out the less soluble one. Despite the widespread use of this method, the choice of the resolving agent and process conditions is still based on trial-and-error experimentation. Our research aims to exploit the progress of computational chemistry and increased availability of computing resources to address the challenge of predicting how to separate enantiomers by crystallisation. We now have highly accurate methods to model the interactions of molecules at the atomic level. This will allow us to predict the crystal structure, thermodynamic stability and properties of the diastereomers from first principles, and further advance the accuracy and reliability of these algorithms. These developments will lead to the understanding and prediction of spontaneous resolution and, when this does not occur, the resolution efficiency for a given racemic mixture and resolving agent. We will then be able to design resolving agents by altering their molecular structure to achieve the best possible separation and subsequently optimise the process conditions (e.g. temperature). Unfortunately, the full range of experimental data needed to develop and validate the predictive models, from crystal structures through to resolution efficiencies, are only available for a few systems. We will use multidisciplinary capabilities in chemistry, chemical engineering and molecular modelling to generate the required experimental data alongside computational modelling. The research is both timely and of significant industrial importance, as outcomes will help reduce resource-consuming trial-and-error experimentation, and meet the aggressive timescales for the development of specialised chemical products. Success in this project will result in reduced production costs and greater availability of drugs, food products and agrochemicals.