Hydrogen bonding is responsible for the structure of much of the world around us. The unusual and complex properties of bulk water, the ability of proteins to fold into stable three-dimensional structures, the fidelity of DNA base pairing, and the binding of ligands to receptors are among the manifestations of this ubiquitous noncovalent interaction. In addition to its primacy as a structural determinant, hydrogen bonding plays a crucial functional role in catalysis. Hydrogen bonding to an electrophile serves to decrease the electron density of this species, activating it toward nucleophilic attack. This principle is employed frequently by Nature's catalysts, enzymes, for the acceleration of a wide range of chemical processes. Recently, organic chemists have begun to appreciate the tremendous potential offered by hydrogen bonding as a mechanism for electrophile activation in small-molecule, synthetic catalyst systems. In particular, chiral hydrogen-bond donors have emerged as a broadly applicable class of catalysts for enantioselective synthesis. This review documents these advances, emphasizing the structural and mechanistic features that contribute to high enantioselectivity in hydrogen-bond-mediated catalytic processes.

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Asymmetric catalysis by chiral hydrogen-bond donors.

Wasserstoffbrucken bestimmen die Struktur eines grosen Teils der uns umgebenden Materie. Die ungewohnlichen Eigenschaften von flussigem Wasser, die Faltung von Proteinen zu stabilen dreidimensionalen Strukturen, die DNA-Basenpaarung und die Bindung von Liganden an Rezeptoren beruhen auf dieser nichtkovalenten Wechselwirkung. Neben ihrer strukturgebenden Rolle haben Wasserstoffbrucken auch entscheidende Funktionen bei katalytischen Prozessen. Enzyme beschleunigen viele biochemische Reaktionen, indem sie die Elektronendichte eines Elektrophils durch Bildung einer Wasserstoffbrucke verringern und es so fur den nucleophilen Angriff aktivieren. In der organischen Synthese hat man das Potenzial dieser Strategie erkannt, und niedermolekulare Verbindungen, insbesondere chirale Wasserstoffbruckendonoren, wurden als Katalysatoren fur enantioselektive Synthesen entwickelt. Dieser Aufsatz zeigt, welche strukturellen und mechanistischen Merkmale in wasserstoffbruckenvermittelten Katalyseprozessen zu hohen Enantioselektivitaten fuhren.

Asymmetrische Katalyse durch chirale Wasserstoffbrückendonoren

Binding Energy and Catalysis: The Implications for Transition-State Analogs and Catalytic Antibodies.

Chemists have long envied the ability of enzymes to manipulate reaction energetics and specificity through steric confinement and precise functional-group interactions. The enormous rate accelerations that enzymes achieve at modest temperatures may be attributed to their high degree of complexity, and the synthetic chemist is hard pressed to create such well-constructed catalytic scaffolds. Yet in this regard, the utilization of supramolecular chemistry may have an advantage: supramolecular self-assembly facilitates the creation of large, complex structures from relatively simple precursors. Based on reversible weak interactions, such as hydrogen bonding or metal–ligand interactions, synthetic chemists have generated an array of self-assembled structures, diverse in architecture and composition. Some of these synthetic structures bear an internal cavity, and their interior can provide a new and very specific chemical environment, distinctly different from the exterior surroundings. The development of container-like molecules into chemically useful structures is an attractive goal, and their utilization as catalytic reaction chambers can parallel the enzyme function. The rate for a bimolecular Diels–Alder reaction, for example, was reported to be significantly accelerated in the presence of a supramolecular host, owing to the increase of effective concentrations of the two substrates when bound within the same capsule. Major challenges are a) to develop supramolecular systems capable of catalyzing unimolecular reactions, and b) to circumvent catalyst inhibition, a problem that frequently occurs when the cavity binds the reaction product more strongly than the substrate. We report herein the utilization of a supramolecular metal–ligand assembly that is capable of catalyzing a unimolecular rearrangement. Simply by inclusion into a sizeand shape-constrained reaction space these rearrangements are accelerated by up to three orders of magnitude compared to their background rates. Furthermore, the chemical properties of the reacting system provide an effective means of preventing product inhibition, which facilitates catalyst turnover. Raymond and co-workers have composed supramolecular tetrahedral structures of M4L6 stoichiometry through selfassembly of simple metal and ligand components. 11] In these assemblies the metal atoms are located at the vertices of the tetrahedron and six bis-bidentate catechol amide ligands span the edges (Figure 1). The tris-bidentate chelation of the metal centers renders them chiral (D or L), and the mechanical coupling through the rigid ligands results in the formation of exclusively homochiral assemblies (i.e. D,D,D,D or L,L,L,L). By virtue of the 12 overall charge, the assemblies are water soluble, yet they contain a flexible

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Supramolecular catalysis of a unimolecular transformation: Aza-cope rearrangement within a self-assembled host

Antibody molecules elicited with rationally designed transition-state analogs catalyze numerous reactions, including many that cannot be achieved by standard chemical methods. Although relatively primitive when compared with natural enzymes, these catalysts are valuable tools for probing the origins and evolution of biological catalysis. Mechanistic and structural analyses of representative antibody catalysts, generated with a variety of strategies for several different reaction types, suggest that their modest efficiency is a consequence of imperfect hapten design and indirect selection. Development of improved transition-state analogs, refinements in immunization and screening protocols, and elaboration of general strategies for augmenting the efficiency of first-generation catalytic antibodies are identified as evident, but difficult, challenges for this field. Rising to these challenges and more successfully integrating programmable design with the selective forces of biology will enhance our understanding of enzymatic catalysis. Further, it should yield useful protein catalysts for an enhanced range of practical applications in chemistry and biology.

Clardy J

Papers

New insight into the catalytic mechanism of chorismate mutases from structural studies