The Pd-catalyzed intermolecular enantioselective aza-Heck reaction

Pd催化的分子间对映选择性氮杂-Heck反应

• 批准号: 10091477
• 负责人: Sean P Ross
• 金额: $ 2.29万
• 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: 2019-02-15 至 2021-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091477
• 关键词: Address; Alcohols; Alkenes; Amides; Amines; Amino Acids; Biological; Carbamates; Catalysis; Complex; Data; Development; Event; Foundations; Generations; Goals; Isotope Labeling; Libraries; Linear Regressions; Methodology; Methods; Natural Products; Nature; Oxidation-Reduction; Pathway interactions; Peptides; Pharmaceutical Preparations; Process; Quantitative Structure-Activity Relationship; Reaction; Regression Analysis; Research Project Grants; Series; Site; Structure; Techniques; Transition Elements; Walking; alpha synuclein; catalyst; computer studies; experimental study; novel; oxidation; pharmacophore; predictive modeling; rapid technique; success

Project Summary The ability to construct C–N bonds enantioselectively through a catalytic intermolecular process with simple robust methods remains a standing challenge in the field of transition metal catalysis. In particular, the development of the addition of amines and other nucleophiles to unactivated internal alkenes has proven to be especially challenging. Preliminary studies in the Sigman group have recently uncovered conditions to accomplish the first example of a Pd-catalyzed intermolecular enantioselective addition of amines to unactivated allylic alcohols through the use of the redox-relay Heck reaction strategy. A primary goal of this proposal is to understand the factors that govern this exciting new transformation so that it can be extended to a broader range of N–H nucleophiles and more challenging alkenes. To accomplish this, I will address a series of mechanistic questions to better understand the factors that are critical to the success of the reaction. Firstly, I will synthesize a systematic library of substrates and submit them to the reaction in order to develop quantitative structure activity relationships. With this data, predictive models will be determined through the use of correlation techniques that the Sigman group has recently developed. In addition, I will undertake mechanistic studies to determine whether the key aminopalladation event occurs through a syn- or anti- pathway, a factor that significantly effects the development and application of this methodology. On the basis of these experiments, I plan to extend this methodology to more highly substituted N–H nucleophiles (such as primary amides and carbamates) and a broader range of alkenes. The ability to convert achiral amines and alkenes to enantiopure chiral amines is a significant advancement that will allow the rapid generation of some of the most commonly encountered structural motifs found in natural products and chiral drugs.

项目摘要 通过催化分子间过程以对映体选择性构建C-N键的能力 在过渡金属催化领域，简单而稳健的方法仍然是一个长期的挑战。尤其是， 在未活化的内部烯烃中加成胺和其他亲核试剂的开发已被证明是 尤其具有挑战性。Sigman小组的初步研究最近发现了一些条件 完成了第一个Pd催化的胺的分子间对映选择性加成反应 未活化的烯丙醇通过使用氧化还原-继而Heck反应策略。这样做的一个主要目标是 提案的目的是了解支配这一令人兴奋的新转型的因素，以便将其扩展到 更广泛的N-H亲核剂和更具挑战性的烯烃。为了实现这一点，我将发表一系列 以更好地理解对反应成功至关重要的因素。首先， 我将合成一个系统的底物文库，并将它们提交给反应，以便开发 定量构效关系。有了这些数据，预测模型将通过使用 西格曼团队最近开发的相关技术。此外，我还将承诺 机制研究，以确定关键的氨基转移事件是否通过同步性或反转性发生 路径，这是一个对这一方法的发展和应用产生重大影响的因素。在此基础上 在这些实验中，我计划将这种方法扩展到更高取代度的N-H亲核分子(例如 伯胺和氨基甲酸酯)和更广泛的烯烃。将无手性胺和无手性胺 将烯烃转化为对映体手性胺是一项重大的进展，它将使一些 在天然产物和手性药物中发现的最常见的结构基序。