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.

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.

My work on computing complex catalyzed organic transformations reveals that only a few subtle chemical factors, e.g. non-classical hydrogen bonding, (hyper)conjugation and steric effects, common across different catalyst manifolds are critical for catalysis and selectivity. Rational manipulation and exploitation of these factors has led to improved catalyst designs, which has previously been an oft-promised but rarely delivered endeavor. Hydrogen bonding is critical to stabilizing structures in both the ground and transition state across many branches of chemistry and life. C-H bonds polarized through either hybridization or proximity to a developing or full positive charge can provide stabilization through interaction with negatively charged atoms in a C-H···O non-classical hydrogen bond (NCHB). In the transition state, where a molecule experiences temporarily amplified polarization, these hydrogen bonds can serve to stabilize the structures and differentiate between diastereomeric TSs A joint experimental and computational investigation on a diaryl prolinol silyl ether-catalyzed Michael cascade reaction to complex furanyl/pyranyl products uncovered the synergistic relationship between catalyst and substrate beyond the basic enamine activation and steric control. NCHBs were discovered to stabilize the transiently polar transition state. The kinetic resolution of addition products was afforded by virtue of the conformation of the substrate preventing or allowing hyperconjugation. An N-heterocyclic carbene-catalyzed dynamic kinetic resolution of [beta]-ketoesters was discovered to display an unusual resolution mechanism. Rapid substrate epimerization early in the aldol mechanism allowed routing through the lowest energy diastereomeric pathway, which also differs in mechanism from the other diastereomeric TSs. Facial control arises from the presence or absence of a single chiral NCHB donor stabilizing the developing alkoxide. Diastereocontrol is afforded by the configuration of the epimerizable [beta]-stereocenter hydrogen affecting the conjugative ability of the keto aryl group. This same control arises in the rapid and enantioselective retro-[2+2] decarboxylations of the product bicyclic [beta]-lactones to cyclopentenes. A study on the origins of enantioselectivity of an NHC-catalyzed homoaldol with acylphosphonates uncovered stereodifferentiating pockets of NCHB akin to an oxyanion hole between the catalyst aryl groups and the phosphonyl (P=O) oxygen. Computations predicted an increase of selectivity by blocking the sites stabilizing the minor transition state. Synthesis and test of the catalyst verified computational predictions. A chiral bifunctional aminothiourea has been developed for the Michael addition of acrylates to [alpha]-ketones to generate asymmetric all-carbon quaternary centers. This catalyst both activates the nucleophile via enamine catalysis and employs hydrogen bonding catalysis to activate the carbonyl-bearing electrophile. A joint experimental and computational study reveals the mechanism of this process and seeks to uncover the origins of selectivity. Computations predict that deletion of the catalyst [beta]-phenyl group would increase selectivity; however, experimental synthesis and test led to unforeseen catalyst decomposition.

Summarizing the emerging field of N-heterocyclic carbenes used in organocatalysis, this is an excellent overview of the synthesis and applications of NHCs focusing on carbon-carbon and carbon-heteroatom bond formation. Alongside comprehensive coverage of the synthesis, characteristics and applications, this handbook and ready reference also includes chapters on NHCs for polymerization reactions and natural product synthesis.

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 book, unique in its field, is a comprehensive description of all the methodologies reported for carrying out conjugate addition reactions in a stereoselective way, using small chiral organic molecules as catalysts (organocatalysts). In the last 3-4 years, this has been a rapidly growing field in organic chemistry, and many papers have appeared reporting excellent protocols for carrying out these highly efficient transformations that compete well with other classical approaches using transition metal catalysts. A particularly attractive feature of this transformation relies upon the fact that the conjugate addition (Michael and Hetero-Michael reactions) is an extraordinarily effective means to initiate cascade processes which result in the formation of complex molecules from very small and simple starting blocks. The book, written by noted experts, covers all recent advances in this hot topic, and provides a good state-of-the-art review for organic chemists working in this field and all those who wish to start projects in this area.