The Development of Brønsted Acid Catalysis Technologies and Mechanistic Investigations Therein

Author: Carrera, Diane Elizabeth

Year: 2010

Degree: Dissertation (Ph.D.)

Advisor: MacMillan, David W. C.

Committee Members: Barton, Jacqueline K.; Dervan, Peter B.; Stoltz, Brian M.; MacMillan, David W. C.

Option: Chemistry

DOI: 10.7907/ZGS8-QT92

Abstract

The enantioselective reductive amination of ketones with Hantzsch ester has been achieved through Brønsted acid catalysis. A novel triphenylsilyl substituted BINOL-derived phosphoric acid catalyst has been developed for this transformation, imparting high levels of selectivity when used with methyl ketones and aromatic amines. A stereochemical model for the observed selectivity based on torsional effects has been developed through molecular modeling and is further supported by a single crystal x-ray structure of an imine-catalyst complex.

Mechanistic studies have revealed the importance of catalyst buffering and drying agent on reaction efficiency while a Hammett analysis of acetophenone derivatives offers insight 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.

The intermolecular addition of vinyl, aromatic, and heteroaromatic potassium trifluoroborate salts to non-activating imines and enamines can also be accomplished through 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.

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