Catalytic asymmetric addition of stabilized nucleophiles to acyl imines

The enclosed work focuses on development of asymmetric bond formation reactions employing the use of imines. The first portion discusses the bifunctional, organocatalytic activation of nucleophiles for addition to acyl imines in the Mannich and Aza-Henry reaction. The second portion investigates cycloaddition reactions of imines with isonitriles to synthesize complex heterocycles.;Two important and useful organic reactions are the Mannich and aza-Henry additions of carbon nucleophiles to electrophilic acyl imines. Utilizing dicarbonyls and nitroalkanes as nucleophiles, these reactions allow for the formation of secondary amine adducts, which are easily converted to a variety of synthetically useful alpha- and beta-amino acids, and 1,2-diamines. Herein, we present the asymmetric Mannich reaction of beta-ketoesters with aryl acyl imines catalyzed by cinchona alkaloids. The reaction generated products in high enantioselectivity. We expanded the scope of the reaction to include cyclic alpha-substituted beta-ketoesters and beta-diketones. The reaction provides an organocatalytic route towards the construction of cyclic beta-aminoesters with alpha-quaternary carbon centers with excellent levels of enantio- and diastereoselectivity. The methodology is applicable towards nitroalkanes in an organocatalytic, asymmetric aza-Henry reaction.;Through a select choice of catalysts employed in a reaction, other mechanistic modalities of acyl imines were explored in cycloaddition reactions. The synthesis of multi-substituted aminooxazoles and enantiopure imidazolines highlights the utility of imines in new methodology development. Using the different activation modalities of acyl imines with isonitriles, two reaction methodologies are developed. The first procedure is a novel Bronsted acid-promoted construction of tri-substituted aminooxazoles from the addition of isonitriles to acyl imines. Overall, this methodology highlights a one-pot route towards formation of 2,4-subsitituted 5-aminooxazoles under a simple Bronsted-acid promoted Ugi-like mechanism. The second procedure involves the use of acyl imines with isonitriles to afford chiral dihydroimidazoles catalyzed by silver(I) complexes. No current methodology employs the use of a chiral silver-ligand complex to activate isocyanoacetates for an enantioselective cycloaddition to acyl imines. Both novel reactions are complementary processes that use similar starting materials affording completely different hetero-products. Catalyst development and optimization studies will be discussed.