The development of brønsted acid catalysis technologies andudmechanistic investigations therein

摘要

The enantioselective reductive amination of ketones with Hantzsch ester has been achieved through Brønsted acid catalysis. A novel triphenylsilyl substituted BINOL-derivedudphosphoric acid catalyst has been developed for this transformation, imparting high levels of selectivity when used with methyl ketones and aromatic amines. Audstereochemical model for the observed selectivity based on torsional effects has been developed through molecular modeling and is further supported by a single crystal x-rayudstructure of an imine-catalyst complex. ududMechanistic studies have revealed the importance of catalyst buffering and drying agent on reaction efficiency while a Hammett analysis of acetophenone derivatives offersudinsight into the key factors involved in the enantiodetermining step. Kinetic studies have shown that imine reduction is rate-determining and follows Michaelis-Menten kinetics. Determination of the Eyring parameters for the imine reduction has also been accomplished and suggests that the phosphoric acid catalyst behaves in a bifunctional manner by activating both the imine electrophile and the Hantzsch ester nucleophile.ududThe intermolecular addition of vinyl, aromatic, and heteroaromatic potassium trifluoroborate salts to non-activating imines and enamines can also be accomplishedudthrough Brønsted acid activation. This analog of the Petasis reaction shows a wide substrate scope and is amenable to use with a variety of carbamate protected nitrogen electrophiles in the first example of metal-free 1,2-additions of trifluoroborate nucleophiles. The mechanistic underpinnings of benzyl trifluoroborate addition has also been explored and, in contrast to what is seen with π-nucleophilic species, appears to proceed through an intramolecular alkyl-transfer mechanism.