Executive Summary : | Chiral alkyl amines are ubiquitous in numerous drugs and pharmaceuticals. Most of the common methods to prepare such molecules are the asymmetric catalytic hydrogenation of imines or organometallic reagent addition to imines bearing a chiral auxiliary. Despite great progress made in the last decades, there is a lack of a general method that can circumvent the current chemical limitations. Compared to umpolung of carbonyls, umpolung of imines remains underdeveloped. Our goal is to develop an efficient method for the preparation of non-racemic chiral amines by enantioselective nickel catalysis through umpolung of imines. The reaction will be triggered by a 1,2-aza-Brook rearrangement to generate an α-aminoalkyl-Ni intermediate that can be leveraged in the cross-coupling with a variety of alkyl electrophiles. At first, we will investigate the cross-coupling of imines with various non-activated alkyl halides to obtain chiral alkyl amines. Furthermore, highly abundant alkyl carboxylic acids and alkyl amines feedstocks can be used as alternatives to alkyl halides in such cross-coupling. This will certainly allow us to increase structural diversity in many drugs and natural products through late-stage functionalization which is an important aspect of drug discovery. Then we will investigate the diastereoselective enantioconvergent cross-coupling reaction between imines and racemic secondary alkyl electrophiles. The stereoselective coupling of two secondary alkyl fragments is highly challenging. A series of high-end functionalities such as amide, ester, polyfluoro-alkyl, alkyne, aryl, silyl, boryl, amine, and alcohol along with a pendant chiral alkyl amine group can be introduced in the C(sp³)-skeletons with a high level of enantio- and diastereo-control. Various alkyl carboxylic acids and amines containing drugs and peptides could also be well accommodated in such an enantioconvergent coupling process through redox activation. Moreover, by judicious choice of various chiral ligands, the method will allow us to access all four stereoisomers which will open a new horizon in stereodivergent synthesis. By taking advantage of our developed methods, we will be able to synthesize several drugs and alkaloids bearing at least a chiral alkyl amine moiety. For example, sitagliptin (anti-diabetic drug), darunavir (antiretroviral medication to treat and prevent HIV-AIDS), amprenavir (protease inhibitor to treat HIV infection), and atazanavir (HIV medications for infants) can be synthesized by using our methodology. Two key intermediates to coniine and coniceine alkaloids can also be prepared from the reaction of corresponding imines and primary alkyl iodides. Overall, by using readily available and stable imines as nucleophiles and mild conditions, our method will allow the synthesis of a diverse set of chiral alkyl amines bearing densely functionalized alkyl fragments with notable applications in drug synthesis. |