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

项目摘要 药物生产是由新的化学转化的发展驱动的，因为它们可以允许 药物分子的快速合成通过简单的断开进行的反应， 在手性催化剂存在下的重要立体化学信息是特别有价值的。过多的 已经开发了BINOL衍生的磷酸催化的反应以形成碳-碳键， 然而，确定最佳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 对产品的催化剂知之甚少，在催化剂设计方面做出明智的决定。 开发新的反应是困难的。一种特殊的磷酸类， 部分由于其增加的复杂性，目前研究的手性磷酸是双轴手性磷酸（DAP）。这些催化剂， 含有第二个手性轴，已被证明有效地催化分子内烯丙基取代 反应，但优化的反应条件是 难以转化为其他杂环系统。该项目的主要目标是开发一个综合的 实验和计算模型，解释了DAP催化剂上的取代如何影响观察到的 合成对映体富集的杂环的烯丙基取代反应的选择性。为了解决这个 目的：1）研究手性DAP催化烯丙基化反应的机理 取代反应，和2）探测DAP催化剂在广泛的反应类别中的灵活性。民主行动党 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 和计算的分子片段来探测非共价相互作用的存在。该模型将 用于预测更具选择性的催化剂，其将通过包含以下物质来扩大目标反应范围： 以前无法接触的基板。一个可以预测新型手性DAP催化剂的综合模型 然后将进行改造。这种元分析方法将结合许多研究， 先前报道的BINOL衍生磷酸的转化，以有效地参数化 DAP支架，以实现更好的催化剂预测。总之，这些研究确定了催化剂如何 柔性和由此产生的非共价相互作用影响反应过渡态的稳定性， 高对映选择性产物，特别是用于手性杂环形成的那些。优化 这些方法的发展将最终允许合成获得广泛的药剂。

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.