Stereoselective Synthesis of Biologically Relevant Heterocycles via Brønsted Acid Catalysis

项目总结 这项提议的目标是为不对称准备不同的 杂环基序，包括含有手性中心的含氮化合物。实现这一目标的关键是 预计将有利于药物化学活动，因为&gt；59%的FDA批准的药物包括一种氮- 含有环系和&gt；56%的FDA批准的药物含有立体中心，绝对 其构型通常对分子的活性至关重要。在计划中引发不对称 过程中，将使用布朗斯特酸催化立体选择性环化反应，重点是 商业上可用的手性磷酸的使用。我们假设手性磷酸将 与起始羟基、氨基酯和腈形成的络合物，引发环化反应， 优先生成一个产物对映体而不是另一个。我们的方法可以快速构建复杂的分子 在温和的条件下，我们的研究将导致比目前最先进的技术有显著的进步。 初步结果支持我们方法的有效性，我们将提供对 生成的产品。我们将准备的环形结构是进一步操作其他 生物相关的结构或多样化和评价本身。值得注意的是，这些调查 将主要由硕士和本科生研究人员推进。

PROJECT SUMMARY The goal of this proposal is to generate innovative strategies for the asymmetric preparation of different heterocyclic motifs, including N-containing compounds, that contain a chiral center. Realization of this goal is expected to benefit medicinal chemistry campaigns because >59% of FDA approved drugs include a nitrogen- containing ring system and >56% of FDA approved drugs contain a stereogenic center, the absolute configuration of which is often critical to the activity of the molecule. To induce asymmetry in the proposed processes, a Brønsted acid will be used to catalyze a stereoselective cyclization reaction, with a focus on the use of commercially available chiral phosphoric acids. We hypothesize that the chiral phosphoric acid will complex with the starting hydroxy and amino esters and nitriles to initiate a cyclization reaction that preferentially generates one product enantiomer over the other. Our methods rapidly build complex molecules under mild conditions, and our research will result in a significant advance over current state of the art. Preliminary results support the validity of our approach and we will offer insight into the potential uses of the generated products. The ring structures we will prepare are ideal candidates for further manipulation into other biologically relevant structures or for diversification and evaluation themselves. Notably, these investigations will be advanced primarily by M.S. and undergraduate student researchers.