Integrating organic chemistry and computational chemistry for efficient molecular discovery

几个有机化学导向的研究项目需要长期的、反复的、低效的和低成本的发现和开发过程。二十多年前，核磁共振光谱学和其他技术被整合到有机化学家的工具箱中，以显着改善这一过程。相比之下，加拿大只有少数有机化学小组真正整合了计算化学，以更深入地了解他们的有机分子或合成方法，而一些常规实验可以由实验人员直接进行，并获得重大利益。***我们的研究项目侧重于有机合成、计算化学和药物化学的整合，以提高合成催化、生物催化和药物发现的成功率。为此，我们开发并应用了计算友好且准确的预测工具，例如用于不对称催化剂设计的VIRTUAL CHEMIST软件包和用于药物设计的FORECASTER软件包。继续这一趋势，我们将进一步为有机化学家开发工具，并证明它们在有机化学实验室中的整合不仅是可能的，而且是有价值的。******研究计划和目标***我建议加强新型不对称催化剂的计算机辅助设计、合成和评价。我们已经开发了合成策略来制备类似脯氨酸的单环和双环支架，现在将作为基于VIRTUAL chemist的虚拟筛选和有机催化剂设计的起点。通过这一过程，将合成一系列催化剂并进行实验评价。* * * 2。ACE准确地预测了不对称反应和更具体的有机催化反应的立体选择性。提出了进一步的主要发展，包括发展金属力场来研究金属催化和验证。挑战之一是金属可以采用的各种配位几何形状（例如，铜可以是方形平面、四面体或介于两者之间）。以前，ACE是在文献数据上进行验证的，在整个研究计划中，验证现在将是实验性的。* * * 3。在过去的几年里，我们提出了新的概念，即指导/保护基团（DPGs）和瞬时DPGs (TDPGs)，使葡萄糖衍生物的区域选择性功能化无需保护基团。不稳定的共价键和非键相互作用调节分子中其他官能团的反应性，从而实现区域选择性转化。我们将通过计算机辅助设计和合成新型TDPGs，将TDPGs的概念扩展到核苷酸和多元醇，实验验证TDPGs与分子极性基团之间预测的额外非键相互作用，并将其应用于包括碳水化合物在内的多元醇的区域选择性操作

Background***Several organic chemistry-oriented research programs require long, iterative, inefficient and cost-ineffective discovery and development processes. Over 2 decades ago, NMR spectroscopy and other techniques were integrated into the organic chemist's toolbox to significantly improve this process. In contrast, only a handful of organic chemistry groups in Canada truly integrate computational chemistry to get more insights into their organic molecules or synthetic methodologies while some routine experiments could be carried out directly by experimentalists with major benefits.***Our research programs focuses on the integration of synthetic organic, computational and medicinal chemistry in order to increase the success rates in synthetic catalysis, biocatalysis and drug discovery. To do so, we develop and apply computational user-friendly and accurate predictive tools such as our software packages VIRTUAL CHEMIST for asymmetric catalyst design and FORECASTER for drug design. Continuing this trend, we will further develop tools for organic chemists and demonstrate that their integration in the organic chemistry lab is not only possible but also valuable.******Research program and objectives***1. I propose to enhance the computer-aided design, synthesis and evaluation of novel asymmetric catalysts. We have developed synthetic strategies to prepare proline-like mono- and bicyclic scaffolds, which will now be used as a starting point for VIRTUAL CHEMIST-based virtual screening and design of organocatalysts. Through this process, a selection of catalysts will be synthesized and experimentally evaluated. ***2. ACE accurately predicts the stereoselectivity of asymmetric reactions and more specifically organocatalysed reactions. Further major developments including the development of a force field for metals to study metal catalysis and validations are proposed. Among the challenges are the various coordination geometries that a metal can adopt (e.g., copper can be square planar, tetrahedral or in between). Previously, ACE was validated on literature data, throughout this research program the validations will now be experimental. ***3. In the past years, we have developed novel concepts of directing/protecting groups (DPGs) and transient DPGs (TDPGs) which enable the regioselective functionalization of glucose derivatives with no need for protecting groups. Labile covalent bonds and non-bonded interactions modulate the reactivity of other functional groups of the molecule enabling regioselective transformations. We will expand the concept of TDPGs to nucleotides and polyols through computer-aided design and synthesis of novel TDPGs, their experimental validation of the predicted additional non-bonded interactions between the TDPGs and the polar groups of the molecule and their application to regioselective manipulation of polyol including carbohydrates.**