Asymmetric enamine catalysis.

Small-molecule H-bond donors in asymmetric catalysis.

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.

The use of secondary amines as asymmetric catalysts in transformations of carbonyl compounds has seen tremendous development in recent years. Going from sporadic reports of selected reactions, aminocatalysis can now be considered as one of the methods of choice for many asymmetric functionalizations of carbonyl compounds—primarily of aldehydes and ketones. These functionalizations have been published at a breathtaking pace over the last few years—during the “golden age” and “gold rush” of organocatalysis. This tutorial review will firstly sketch the basic developments in organocatalysis, focussing especially on the use of secondary amines as catalysts for the functionalization of aldehydes and α,β-unsaturated aldehydes, with emphasis on the mechanisms of the transformations and, secondly, outline recent trends within central areas of this research topic. Lastly, we will present our guesses as to where new developments might take organocatalysis in the years to come.

Organocatalysis--after the gold rush.

Catalysis with chiral secondary amines (asymmetric aminocatalysis) has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalization of carbonyl compounds. In the last eight years alone, this field has grown at such an extraordinary pace that it is now recognized as an independent area of synthetic chemistry, where the goal is the preparation of any chiral molecule in an efficient, rapid, and stereoselective manner. This has been made possible by the impressive level of scientific competition and high quality research generated in this area. This Review describes this "Asymmetric Aminocatalysis Gold Rush" and charts the milestones in its development. As in all areas of science, progress depends on human effort.

Asymmetric aminocatalysis--gold rush in organic chemistry.

Ever since Pasteur noticed that tartrate crystals exist in two non-superimposable forms that are mirror images of one another--as are left and right hands--the phenomenon of chirality has intrigued scientists. On the molecular level, chirality often has a profound impact on recognition and interaction events and is thus important to biochemistry and pharmacology. In chemical synthesis, much effort has been directed towards developing asymmetric synthesis strategies that yield product molecules with a significant excess of either the left-handed or right-handed enantiomer. This is usually achieved by making use of chiral auxiliaries or catalysts that influence the course of a reaction, with the enantiomeric excess (ee) of the product linearly related to the ee of the auxiliary or catalyst used. In recent years, however, an increasing number of asymmetric reactions have been documented where this relationship is nonlinear, an effect that can lead to asymmetric amplification. Theoretical models have long suggested that autocatalytic processes can result in kinetically controlled asymmetric amplification, a prediction that has now been verified experimentally and rationalized mechanistically for an autocatalytic alkylation reaction. Here we show an alternative mechanism that gives rise to asymmetric amplification based on the equilibrium solid-liquid phase behaviour of amino acids in solution. This amplification mechanism is robust and can operate in aqueous systems, making it an appealing proposition for explaining one of the most tantalizing examples of asymmetric amplification-the development of high enantiomeric excess in biomolecules from a presumably racemic prebiotic world.

Thermodynamic control of asymmetric amplification in amino acid catalysis

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200453997

Amplification of Enantiomeric Excess in a Proline-Mediated Reaction†

Kinetic investigations show that the proline-mediated alpha-amination of aldehydes exhibits autoinductive rate behavior and amplification of product enantiomeric excess. Further experiments highlight the role of product, offering suggestions for the design of catalysts of improved efficiency for such transformations. The unusual characteristics exhibited by these reactions implicate amino acid catalysis in rationalizations of the origin of biological homochirality.

In situ catalyst improvement in the proline-mediated alpha-amination of aldehydes.

A new catalytic cycle involving only soluble proline complexes or adducts is proposed for the reactions in eq 1 based on kinetic observations and molecular modeling studies. This reaction pathway circumventing free proline and incorporating hydrogen-bonded reaction product helps to rationalize the observations of accelerating reaction rate in both the α-aminooxylation and α-amination reactions.

Suju P. Mathew

Papers

Thermodynamic control of asymmetric amplification in amino acid catalysis

Amplification of Enantiomeric Excess in a Proline-Mediated Reaction†

In situ catalyst improvement in the proline-mediated alpha-amination of aldehydes.

Probing the active catalyst in product-accelerated proline-mediated reactions.

Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalysis Based on Phase Behavior