UC Berkeley

The development of new catalysts for asymmetric organic transformations is a broad and important research goal in modern synthetic organic chemistry. The use of chiral ligands as a source of asymmetric induction in metal-catalyzed reactions has been a traditional focus of this field. One class of chiral ligands is those which incorporate enantiomerically pure sulfinamides. Chapter 1 provides an overview of this area of research. Also included are examples of sulfinamide-based ligands for reactions involving stoichiometric metals, as well as a few examples of sulfinamide-based organocatalysts that have been reported in the literature. The literature reviewed serves as an important foundation for the research described in Chapters 2 and 3.

Asymmetric organocatalysis, the use of chiral small molecules as metal-free catalysts, has developed into an area of intense research in the past decade. One mode of substrate activation by organocatalysts is hydrogen bonding. The urea/thiourea scaffold is one of the most effective and well developed types of hydrogen bonding organocatalysts. The acidity (and corresponding strength of the hydrogen bonding interaction) of the hydrogen bond donor is an important consideration for the development of efficient catalysts. Chapter 2 details the development of organocatalysts that incorporate an N-sulfinyl urea as a hydrogen bond donor. In these catalysts, the sulfinyl substituent serves both to acidify the urea N-H bond and to act as a source of asymmetric induction by virtue of the sulfur-based chirality that is presented proximal to the hydrogen bond donor. The application of these catalysts to two different nucleophilic addition reactions is described.

Organocatalysts that incorporate a nucleophilic amine have also been developed extensively in recent years. One of the earliest reported examples of this type of catalysis was the use of proline as a catalyst for the enantioselective intermolecular aldol reaction via a nucleophilic enamine intermediate. While the amine may be considered the primary catalytic site, the carboxylic acid has also been implicated in the catalytic cycle, and is proposed to provide a key hydrogen bonding interaction in the enantiodetermining step of the reaction. Chapter 3 describes the development of an N-sulfinyl proline amide as a novel and superior catalyst for the aldol reaction, again demonstrating the utility a sulfinyl N-H as a chiral hydrogen bond donor.