Regio- and stereoselective additions to azomethines: Free radical cyclizations and chiral Bronsted acid catalyzed reactions of imines

The value of imines in organic synthesis is exemplified by their role in such carbon-carbon bond forming transformations as the Mannich, Strecker and Pictet-Spengler reactions. Enantioselective additions of carbon nucleophiles to imines provide straightforward routes to synthetically useful, optically pure amines and amino acids. Demand for inexpensive, robust and environmentally friendly catalysts to affect these transformations with high stereocontrol continues to drive the development of novel chiral catalyst systems. With this motivation, a Bronsted acid catalyst called the chiral proton was developed which relies upon polar ionic hydrogen bonding for substrate activation and as a primary control element for enantioselection. The chiral proton complex, composed of a charge-neutral bisamidine (BAM) ligand and a Bronsted acid, was shown to control the absolute and relative stereochemistry in the addition of silyl nitronates to Boc-protected imines. It was further demonstrated that nitroalkanes could be used in place of silyl nitronates (aza-Henry reaction), eliminating the need for preformation of the nucleophile. In the latter reaction, the amount of catalyst could be reduced to as low as 1 mol% without loss of enantioselectivity, attesting to the BAM ligand's ability to sequester protons from bulk solvent.; The chiral BAM-protic acid complexes were further applied to the stereoselective intramolecular hetero-Diels-Alder reactions of azadienes. These catalysts were found to influence both the endo/exo selectivity, as well as the facial selectivity of the [4+2] cycloadditions. The azadienes used in this study were modeled after the putative Diels-Alder precursors in the biosynthesis of the brevianamide class of natural products.; Complementary to nucleophilic additions, carbon centered radical additions to imines have emerged as a mild route to amine generation. Although radicals generally add to the carbon of azomethines, a free radical-mediated vinyl amination methodology was developed which cyclizes vinyl radicals in a 5- exo fashion regioselectively onto the nitrogen atom. The rate of cyclization was significantly faster than that of direct radical reduction, as only trace amounts of alkene were detected in each case. This chemistry offers a mild, pH-neutral route to a variety of architecturally diverse N,N-dialkyl enamines.