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.
The goal of this research project is to develop an intermolecular enantioselective aza-Heck reaction, which allows for the synthesis of enantioenriched chiral amines from simple alkene starting materials. In order to achieve this goal, a detailed mechanistic analysis will be carried out to determine the factors that are critical for achieving high enantioselectivity, and the efficient combination of a variety of amines and alkenes to form enantioenriched amines. This reaction has recently been expanded to acidic N?H nucleophiles such as carbamates and will be further developed through the use of a mixture of computational and experimental studies in order to enable the rapid construction of complex chiral amines from simple alkene starting materials.
