Bifunctional Asymmetric Catalysis: Cooperative Lewis Acid/Base Systems

Abstract

In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction. These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature's catalysts, enzymes. In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners. For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles. Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increases the reaction rates and yields, without any detectable influence on the outstanding enantioselectivities inherent to these reactions. To place our results in perspective, many important contributions to this emerging field are highlighted and our own reports are chronicled. PAULL et al.

Structures, Mechanisms, and Results in Bifunctional Catalysis and Related Species Involving Proton Transfer

“…For about 10 years [2,3] our group has studied combining the ability of a transition metal to move electrons with ligands capable of proton transfer, examples in the wider field of bifunctional catalysis. For reviews of bifunctional catalysts, see [4][5][6][7][8][9][10][11][12]. Here we describe some fundamental studies of bifunctional catalysts and related complexes, with a focus on phosphines bearing an imidazolyl or pyridyl group and the roles the basic nitrogen substituent can play.…”

“…In the case of 4b, the 15 N chemical shift is 21.6 ppm upfield that in species 9, showing the effects of hydrogen bonding in 4b. Even more useful information comes from observing 11-( 15 N) 2 at -100°C: one 15 N resonance at -63.6 ppm indicates a normal pyridylphosphine with no hydrogen bonding or other interaction at the nitrogen, whereas a second resonance centered at -146.7 ppm is consistent with N-protonation (11) rather than a nitrogen accepting hydrogen bond (12). The fact that the N-protonated nitrogen of 11 resonates near -146.7 ppm rather than near -188.5 ppm as in model pyridinium salt 13 suggests perturbation by hydrogen bonding.…”

Development of Atom-Economical Catalytic Asymmetric Reactions under Proton Transfer Conditions: Construction of Tetrasubstituted Stereogenic Centers and Their Application to Therapeutics

“…Compared with conventional catalysts, cooperative catalysts usually exhibit an enhanced catalytic activity and a higher level of stereodifferentiation under mild reaction conditions, thereby attracting much attention as the next-generation catalysts for prospective practical applications. [4][5][6][7][8][9][10][11] Nature harnesses the power of bifunctional catalysis in a number of vital enzymatic reactions, showing the effectiveness of such a strategy for chemical transformations under remarkably mild conditions.…”

Diastereoselective allylation and crotylation of N-tert-butanesulfinyl imines with allylic alcohols

“…2 Among the stereoselective methodologies, the catalytic enantioselective allylations 3 rely on the use of chiral Lewis acids or chiral Lewis bases. In addition, double activation could be also achieved by using chiral bifunctional catalysts 4 by the simultaneous activation of both electrophilic and nucleophilic reaction partners through a cooperative action of different functionalities of the ligand. However, and in spite of the rapid evolution of catalytic methods in recent years, the use of stoichiometric reagents (including substrates and/or allylic organometallic partners) is still the favourite choice of organic chemists in the synthesis of key intermediates of natural products.…”