Small-molecule H-bond donors in asymmetric catalysis.

Stronger Brønsted acids

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.

After an initial period of validating asymmetric organocatalysis by using a wide range of important model reactions that constitute the essential tools of organic synthesis, the time has now been reached when organocatalysis can be used to address specific issues and solve pending problems of stereochemical relevance. This Review deals with selected studies reported in 2006 and the first half of 2007, and is intended to highlight four main aspects that may be taken as testimony of the present status and prospective of organocatalysis: a) chemical efficiency; b) discovery of new substrate combinations to give new asymmetric syntheses; c) development of new catalysts for specific purposes by using mechanistic findings; and d) applications of organocatalytic reactions in the asymmetric total synthesis of target natural products and known compounds of biological and pharmaceutical relevance.

Asymmetric Organocatalysis: From Infancy to Adolescence

The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Bronsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.

Lewis Base Catalysis in Organic Synthesis

The efficient and novel bifunctional organocatalyst for the enantioselective aza-Morita-Baylis-Hillman (aza-MBH) reaction has been established with (S)-3-(N-isopropyl-N-3-pyridinylaminomethyl)BINOL for the first time. The reaction proved to be deeply influenced by the position of the Lewis base attached to BINOL. The acid-base-mediated functionalities for the activation of the substrate and the fixing of conformation of the organocatalyst are harmoniously performed to promote the reaction with high enantiocontrol.

Bifunctional organocatalysts for enantioselective aza-Morita-Baylis-Hillman reaction.

( S )-3-( N -Isopropyl- N -3-pyridinylaminomethyl)BINOL has been established as an efficient asymmetric bifunctional organocatalyst for the aza-MBH reaction. The acid–base functionalities cooperate in substrate activation and fixing of the organocatalyst conformation to promote the reaction with high enantiocontrol.

Conformational lock in a Brønsted acid–Lewis base organocatalyst for the aza-Morita–Baylis–Hillman reaction

Enantioselective Morita–Baylis–Hillman (MBH) reaction promoted by a heterobimetallic complex with a Lewis base

Powerful bifunctional organocatalysts, (S)-3-(N-isopropyl-N-3-pyridinylaminomethyl) BINOL (6a) and (S)-3-[2-(diphenylphosphino) phenyl] BINOL (10a), for the aza-Morita-Baylis-Hillman (aza- MBH) reaction, were developed. In these catalysts, chiral Bronsted acid units are connected with a Lewis base unit via a spacer. The acid-base moieties act cooperatively as an enzyme-mimetic catalyst to activate substrates in the carbon-carbon bond forming reaction between a, α, β-unsaturated carbonyl compounds and N-tosylimines with high enantioselectivity.

Bifunctional Organocatalysts for Enantioselective aza-Morita-Baylis-Hillman (aza-MBH) Reactions

(S)-3-[2-(Diphenylphosphino)phenyl]BINOL has been established as an efficient asymmetric bifunctional organocatalyst for the aza-Morita-Baylis-Hillman (aza-MBH) reaction. The Bronsted acid and Lewis base functionalities cooperate in substrate activation to promote the reaction with high enantiocontrol.

Katsuya Matsui

Papers

Bifunctional organocatalysts for enantioselective aza-Morita-Baylis-Hillman reaction.

Conformational lock in a Brønsted acid–Lewis base organocatalyst for the aza-Morita–Baylis–Hillman reaction

Enantioselective Morita–Baylis–Hillman (MBH) reaction promoted by a heterobimetallic complex with a Lewis base

Bifunctional Organocatalysts for Enantioselective aza-Morita-Baylis-Hillman (aza-MBH) Reactions

A Brønsted Acid and Lewis Base Organocatalyst for the Aza-Morita-Baylis-Hillman Reaction