This work describes novel, effective hydrogen-bond (HB) donor catalysts based on a known bifunctional tertiary amine-thiourea, a privileged structure, which has been proven to be one of the most widely used organocatalysts. These HB donor catalysts derived from quinazoline and benzothiadiazine were initially synthesized as novel HB donors with their HB-donating abilities being measured by analytical methods. They were found to be effective for a variety of asymmetric transformations including Michael reactions of a, b-unsaturated imides and hydrazination reactions of 1,3-dicarbonyl compounds. Thiourea catalysts that have an additional functional group are also described. Specifically, thioureas that bear a hydroxyl group were synthesized and subsequently used as novel bifunctional organocatalysts for catalytic, asymmetric Petasis-type reactions involving organoboronic acids as nucleophiles. These addition reactions were difficult to achieve using existing organocatalysts. One of the developed catalytic methods can be applied to the synthesis of biologically interesting peptide-derived compounds possessing unnatural vinyl glycine moieties. These findings introduce new criteria required for the development of organocatalysts for asymmetric reactions, thus making a significant contribution to the field of organocatalysis.

This thesis focuses on the first synthesis and application of planar-chiral [2.2]paracyclophane- derived hydrogen-bond donor catalysts, thereby inducing a unique chiral motif into the emerging field of thiourea organocatalysis. Reaction acceleration through hydrogen-bond catalysis has made a significant impact on the field, rendering the development of potent catalyst structures extremely valuable. Based on the [2.2]paracyclophane scaffold, mono- and bi-functional thiourea catalysts were prepared. The rigidity of the [2.2]paracyclophane structure leads to a unique setup of the substituents. In pseudo-geminal position to the thiourea moiety, a hydroxy group was selected and introduced as the second functionality. In a 12-step synthesis, the enantiopure hydroxy- substituted [2.2]paracyclophanylene thiourea was obtained. Furthermore, efficient access to enantiopure pseudo-geminally substituted 13-amino-4- bromo[2.2]paracyclophane was developed. The aminobromide was employed in cross- coupling reactions to yield arylated amino[2.2]paracyclophanes, exhibiting a broad range of electronic and steric features useful for organocatalytic applications. The developed catalysts were applied in asymmetric organic transformations and proved most useful in the transfer hydrogenation reaction. The hydroxy-substituted thiourea catalyst particularly exhibited catalytic activity and stereoselectivity. To shed light on the mode of action of this class of hydrogen-bond catalysts, various analytic methods were conducted. Through extensive crystallographic and NMR complexation experiments, the binding properties of the catalysts were investigated in terms of their interaction with hydrogen-bond- accepting functional groups. Furthermore, quantum chemical DFT and ab initio calculations were undertaken to explore the favored conformations of [2.2]paracyclophane-derived thioureas. The combined findings revealed substrate-dependent activation via single or double hydrogen bonding between the NH groups of the thiourea and the respective substrate. Furthermore, a class of readily accessible hydrogen-bond thiourea catalysts was developed, derived from amino acids. Their steric and electronic features were modulated by their degree of substitution at the carbinol carbon center. All catalysts were applied in the asymmetric transfer hydrogenation of nitroolefins, furnishing the products in up to 99% yield and 87% enantiomeric excess.

The synthesis and study of organosilanols can lead to the development of effective hydrogen-bonding catalysts and chiral ligands for Lewis acid catalysis. This dissertation discusses the development of 1,3-disiloxanediols and incompletely condensed polyhedral oligomeric silsesquioxanes as novel hydrogen-bonding catalysts, with insight into hydrogen-bonding properties. Chiral silanol-containing ligands have also been developed with applications in Lewis acid catalysis. Mechanistic studies to better understand how silanol-containing catalysts activate substrates will also be presented. The introduction discusses relevant silicon chemistry including the unique properties of silicon that are utilized to make effective catalysts. Previous literature in the areas of silanol hydrogen-bonding catalysts and silanol-containing ligands for metal-catalysis is highlighted. The importance of mechanistic studies to learn about the activation mode of organocatalysts is emphasized with recent literature examples. Chapter one describes the synthesis and investigation of the hydrogen-bonding ability of 1,3-disiloxanediols. The synthetic route to access novel disiloxanediol structures with a variety of steric and electronic effects is presented. 1H NMR spectroscopy binding studies with both anionic and neutral Lewis basic binding partners were conducted to examine hydrogen-bonding properties. Diffusion-ordered spectroscopy studies were used to assess self-association of disiloxanediols in solution and demonstrate that concentration dependent self-association is observed. Chapter two outlines the use of 1,3-disiloxanediols as effective hydrogen-bonding and anion-binding organocatalysts. The catalytic activity of 1,3-disiloxanediols is compared to other silanol catalysts to understand the features of 1,3-disiloxanediols that enhance their catalytic ability relative to silanol catalysts. I describe an in-depth kinetic study that was performed for the indole addition to nitrostyrene catalyzed by a 1,3-disiloxanediol catalyst to elucidate information about the mode of activation of 1,3-disiloxanediols. Chapter three describes the use of 31P NMR spectroscopy to evaluate and quantify the hydrogen-bond activation for a wide variety of organocatalysts including phenols, benzoic acids, silanol-containing compounds and boronic acids. Hydrogen-bond donors with a variety of steric and electronic effects were utilized to understand factors that contribute to hydrogen-bond activation. The measured hydrogen-bond activation was compared to relative rate in a Friedel-Crafts reaction and the 31P NMR probe was found to be an excellent predictor of reactivity; especially when compared to traditional metrics including pK[subscript a]. Chapter four discusses the use of incompletely condensed polyhedral oligomeric silsesquioxanes (POSS-silanols) as hydrogen-bonding catalysts. Hydrogen-bonding properties of POSS-silanols were investigated using both 1H and 31P NMR binding studies. A kinetic study was performed on the indole addition to nitrostyrene catalyzed by POSS-silanols where an intriguing concentration effect was observed, and indicated a change in reaction mechanism depending on the POSS-silanol concentration. Chapter five presents the synthesis and investigation of silanol-containing chelating ligands with applications in asymmetric catalysis. A modular synthetic route that allows for steric and electronic modifications has been developed to access various silanol-oxazoline (SiOX) ligands. Mass spectrometry and 1H NMR binding studies were used to identify metals that should be investigated for catalytic activity with SiOX ligands. Preliminary enantioselectivity in a [3 +2] silver-catalyzed intramolecular cycloaddition reaction is also discussed.

This first comprehensive overview of the rapidly growing field emphasizes the use of hydrogen bonding as a tool for organic synthesis, especially catalysis. As such, it covers such topics as enzyme chemistry, organocatalysis and total synthesis, all unified by the unique advantages of hydrogen bonding in the construction of complex molecules from simple precursors. Providing everything you need to know, this is a definite must for every synthetic chemist in academia and industry.

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.

The Organic Chemistry of Enzyme-Catalyzed Reactions is not a book on enzymes, but rather a book on the general mechanisms involved in chemical reactions involving enzymes. An enzyme is a protein molecule in a plant or animal that causes specific reactions without itself being permanently altered or destroyed. This is a revised edition of a very successful book, which appeals to both academic and industrial markets. Illustrates the organic mechanism associated with each enzyme-catalyzed reaction Makes the connection between organic reaction mechanisms and enzyme mechanisms Compiles the latest information about molecular mechanisms of enzyme reactions Accompanied by clearly drawn structures, schemes, and figures Includes an extensive bibliography on enzyme mechanisms covering the last 30 years Explains how enzymes can accelerate the rates of chemical reactions with high specificity Provides approaches to the design of inhibitors of enzyme-catalyzed reactions Categorizes the cofactors that are appropriate for catalyzing different classes of reactions Shows how chemical enzyme models are used for mechanistic studies Describes catalytic antibody design and mechanism Includes problem sets and solutions for each chapter Written in an informal and didactic style