Mechanistic Investigations of Doubly Axially Chiral Phosphoric Acid Catalysts for the Synthesis of Enantioenriched Heterocycles

双轴手性磷酸催化剂合成对映体富集杂环的机理研究

• 批准号: 10217207
• 负责人: Julie L Hofstra
• 金额: $ 2.87万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217207
• 关键词: Academia; Address; Affect; Area; BINOL; Carbon; Catalysis; Chemical Structure; Chemicals; Computer Models; Data; Development; Disease; Experimental Models; Free Energy; Future; Geometry; Goals; Investigation; Investigative Reports; Knowledge; Libraries; Mentorship; Methods; Modeling; Molecular; Organic Chemistry; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Phosphoric Acids; Play; Preparation; Production; Reaction; Reporting; Research; Research Training; Role; Series; Students; System; Temperature; Training; Translating; career; catalyst; computerized tools; design; drug efficacy; drug synthesis; flexibility; improved; mathematical model; method development; novel; scaffold; small molecule

Project Summary Pharmaceutical production is driven by the development of novel chemical transformations as they can allow for the expedient synthesis of drug molecules. Reactions that proceed through simple disconnections and which set important stereochemical information in the presence of a chiral catalyst are particularly valuable. A plethora of BINOL-derived phosphoric acid catalyzed reactions to form carbon-carbon bonds have been developed and used in these contexts, however identifying the best chiral catalyst can be challenging as the optimal choice is often substrate dependent. Since the underlying mechanisms that result in the transfer of chiral information from the catalyst to the product are poorly understood, making informed decisions regarding catalyst design in the development of new reactions is difficult. One particular phosphoric acid class that has received little mechanistic study, partially due to its increased complexity, are doubly axially chiral phosphoric acids (DAP). These catalysts, which contain a second chiral axis, have been shown to effectively catalyze intramolecular allylic substitution reactions for the synthesis of enantioenriched heterocycles, however the optimized reaction conditions are difficult to translate to other heterocyclic systems. The primary objective of this project is to develop a combined experimental and computational model that explains how substitution on the DAP catalyst affects the observed selectivity of allylic substitution reactions for the synthesis of enantioenriched heterocycles. To address this objective, two specific aims are proposed: 1) investigate the mechanism of chiral DAP-catalyzed allylic substitution reactions, and 2) probe DAP catalyst flexibility across a broad set of reaction classes. The DAP catalysts will be parameterized by analyzing linear free energy relationships from correlated experimental data and computed molecular fragments that probe for the presence of non-covalent interactions. This model will then be used to predict a more selective catalyst that will expand the targeted reaction scope through the inclusion of previously inaccessible substrates. A comprehensive model that can predict chiral DAP catalysts for novel transformations will then be developed. This meta-analytical approach will incorporate the study of numerous transformations previously reported with BINOL-derived phosphoric acids in order to effectively parameterize the DAP scaffold to achieve better catalyst predictions. In summary, these studies determine how catalyst flexibility and the resulting non-covalent interactions affect the stability of reaction transition states affording highly enantioselective products, particularly those for chiral heterocycle formation. The optimization and development of these methods will ultimately allow synthetic access to a broad range of pharmaceutical agents.

项目摘要 药物生产是由新型化学转化的发展驱动的，因为它们可以允许 药物分子的权宜合成。通过简单断开连接进行的反应以及设置 在存在手性催化剂的情况下，重要的立体化学信息特别有价值。很多 已经开发了binol衍生的磷酸催化反应形成碳碳键的反应，并 在这些情况下使用，但是确定最佳的手性催化剂可能具有挑战性，因为最佳选择是 通常依赖于底物。由于导致手性信息从 该产品的催化剂的理解很少，在有关催化剂设计的明智决定 新反应的发展很困难。一个很少有机械的特定磷酸类 研究部分是由于其复杂性的增加，是双轴向手性磷酸（DAP）的双重轴向。这些催化剂， 含有第二个手性轴，已显示可有效催化分子内烯丙基替代 合成对映基杂环的反应，但是优化的反应条件是 很难转换为其他杂环系统。该项目的主要目的是开发一个合并的 实验和计算模型解释了DAP催化剂上的替代如何影响观察到的 烯丙基取代反应的选择性对映射杂环的合成。解决这个问题 目的，提出了两个具体目的：1）研究手性dap催化烯丙基的机理 替代反应和2）探针DAP催化剂在一系列广泛的反应类别中的灵活性。 DAP 催化剂将通过分析相关实验数据的线性自由能关系来参数化 和计算出的分子片段，以探测存在非共价相互作用的情况。然后，这个模型将 用于预测一种更具选择性的催化剂，该催化剂将通过包含 以前无法访问的底物。一个可以预测新颖的手性DAP催化剂的综合模型 然后将开发转换。这种荟萃分析方法将结合众多的研究 先前用binol衍生的磷酸报道的转化，以有效参数化 DAP支架以实现更好的催化剂预测。总而言之，这些研究决定了催化剂 灵活性和由此产生的非共价相互作用会影响反应过渡状态的稳定性 高度对映选择性产品，尤其是手性杂环形成的产品。优化和 这些方法的开发最终将允许合成访问广泛的药物。