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

项目摘要 制药生产是由新的化学转化的发展推动的，因为它们可以 药物分子的巧妙合成。通过简单的断开进行的反应，以及设置 在手性催化剂存在的情况下，重要的立体化学信息特别有价值。过多的 二元醇衍生的磷酸催化形成碳-碳键的反应已经开发出来，并 然而，在这些情况下使用，确定最好的手性催化剂可能是具有挑战性的，因为最佳选择是 通常依赖于底物。由于导致手性信息从 对产品的催化剂了解很少，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，几乎没有收到机械原理 研究双轴向手性磷酸(DAP)，部分原因是其复杂性增加。这些催化剂， 它们含有第二手性轴，已被证明有效地催化分子内烯丙基取代。 合成富含对映体杂环的反应，但优化的反应条件为 很难转化为其他杂环体系。这个项目的主要目标是开发一种综合的 解释DAP催化剂上的取代如何影响观察值的实验和计算模型 富含对映体杂环合成中烯丙基取代反应的选择性。要解决这个问题 目的：1)研究手性DAP催化烯丙基的反应机理 取代反应，以及2)探索DAP催化剂在广泛的反应类别中的灵活性。《人民党》 催化剂将通过分析相关实验数据中的线性自由能关系来进行参数化 并计算了探测非共价相互作用存在的分子片段。然后这个模型将会 被用来预测一种更具选择性的催化剂，该催化剂将通过包含 以前无法接触到的底物。一种预测新型手性DAP催化剂的综合模型 然后将开发转换。这种元分析方法将结合对许多 以前报道的BINOL衍生磷酸的转化，以便有效地参数化 DAP支架实现了更好的催化剂预测。总而言之，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 具有高度对映体选择性的产品，特别是那些用于手性杂环形成的产品。优化和优化 这些方法的发展最终将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.