Stereoselective Synthesis of Biologically Relevant Heterocycles via Brønsted Acid Catalysis

通过布伦斯台德酸催化立体选择性合成生物相关杂环

• 批准号: 10202815
• 负责人: Kimberly Sue Petersen
• 金额: $ 39.6万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202815
• 关键词: 3-Dimensional; Achievement; Acids; Amino Acids; Biochemistry; Biological; Carbon; Catalysis; Chemistry; Communities; Complex; Cyclization; Data; Development; Esters; Evaluation; FDA approved; Funding; Geometry; Goals; Handedness; Indoles; Institution; Investigation; Laboratory Research; Lactams; Lactones; Lead; Mentors; Methodology; Methods; Natural Products; Nature; Nitriles; Nitrogen; North Carolina; Pattern; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphoric Acids; Preparation; Process; Publications; Reaction; Research; Research Personnel; Science; Shapes; Structure; Students; System; Underrepresented Populations; Underrepresented Students; United States National Institutes of Health; Universities; Work; base; beta-Lactams; career; enantiomer; experience; innovation; insight; novel; novel strategies; rapid technique; small molecule; symposium; undergraduate research experience; undergraduate student

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.

项目摘要 该提案的目标是为不同的非对称制备产生创新策略， 杂环基序，包括含有手性中心的含N化合物。实现这一目标， 预计将有利于药物化学运动，因为>59%的FDA批准的药物包括氮- 含有环系统和>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。为了在拟议的 过程中，布朗斯台德酸将用于催化立体选择性环化反应，重点是 使用市售手性磷酸。我们假设手性磷酸 与起始羟基和氨基酯和腈络合以引发环化反应， 优先产生一种产物对映体而不是另一种。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现有技术水平的重大进步。 初步结果支持我们的方法的有效性，我们将提供洞察的潜在用途， 生成的产品。我们将制备的环结构是进一步操纵成其他结构的理想候选者。 生物相关结构或多样化和评估本身。值得注意的是， 将主要由M. S.和本科生研究人员。