The Pd-catalyzed intermolecular enantioselective aza-Heck reaction

项目摘要 通过催化分子间过程， 在过渡金属催化领域中，简单的稳健方法仍然是一个长期的挑战。特别是 胺和其它亲核试剂加成到未活化的内烯烃上的进展已被证明是 特别具有挑战性。西格曼小组的初步研究最近发现了一些条件， 完成了Pd催化的胺的分子间对映选择性加成的第一个实例， 未活化的烯丙醇通过使用氧化还原中继赫克反应策略。这其中的一个主要目标 我们的建议是了解支配这一令人兴奋的新转变的因素，以便将其扩展到 更广泛的N-H亲核试剂和更具挑战性的烯烃。为了实现这一目标，我将提出一系列 的机制问题，以更好地了解的因素，是至关重要的反应的成功。第一、 我将合成一个系统的底物库，并将其提交给反应，以开发 定量构效关系有了这些数据，预测模型将通过使用 西格曼小组最近开发的相关技术。此外，我将承诺 机制研究，以确定关键的氨基钯化事件是否通过顺式或反式 途径，一个因素，显着影响该方法的发展和应用。根据 在这些实验中，我计划将这种方法扩展到更高度取代的N-H亲核试剂（如 伯酰胺和氨基甲酸酯）和更宽范围的烯烃。转化非手性胺的能力， 将烯烃转化为对映体纯的手性胺是一个重大的进步， 天然产物和手性药物中最常见的结构基序。

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.