Bifunctional Catalysts

In the search for more active and enantioselective catalysts and taking inspiration from enzymes, whose efficiency is often due to the presence of multiple catalytic sites working in synergistic fashion, some interest has been shifted toward the development of bifunctional systems for the simultaneous activation of both partners of a given reaction. Contrary to conventional asymmetric catalysts, that

Ph yMe3 Lewis base i activation


i) (R)-48a (9% mol) Bu3PO (36% mol) CH2Cl2, -40 °C

Ph yMe3 Lewis base i activation kp*0..2;cn____________

Vy Lewis acid O^^x activation



Scheme 2.28 Transition-metal bifunctional catalysts with BINOL-derived ligands

Ph activate one reactant by a Lewis acid or base group present in their molecular structure, bifunctional systems are designed to have two different functionalities with complementary features in order to promote in concert electrophilicity and nucleophilicity in reactive partners and concentrate them in the proximity of catalyst chiral environment, so that enhanced activity and level of stereodifferentiation in milder conditions can be expected.

Among selected examples of transition-metal based bifunctional catalysts, heterobimetallic complexes 47, containing three BINOL units, three alkali metals and a lanthanide metal, were reported by Shibasaki's group as versatile platform for a variety of asymmetric reactions. Good to excellent performances were achieved through cooperative action of BINOLate moieties as Bronsted base sites and rare earth metal as Lewis acid center [169]. The evolution of such scaffold has led to the development of BINOL ligands 48, functionalised with Lewis basic phosphine oxide or sulphoxide groups, that have been applied for Al(III)-promoted cyanide addition to aldehydes, imines (Strecker reaction) and quinolines (Reissert reaction) [170]. Other useful ligands have been prepared by joining two BINOL units or BINOL-achiral biphenyls units through a heteroatom and the application of their Ga(III)- or Zn(II)- complexes in Michael and Mannich additions has been recently reviewed [171] (Scheme 2.28).

Salen-type Schiff bases 50 bearing additional phenolic substituents have been designed as effective ligands in controlling the position of two different metals


NHBoc rV



Scheme 2.29 Bimetallic salen-complexes in bifunctional catalysis

through selective complexation of a transition metal into the inner N2O2-cavity, meanwhile an oxophilic rare earth metal with larger ionic radius can be accommodated in the outer O2O2-cavity. In a screening of metal combinations for syn-selective nitro-Mannich reaction, Cu(OAc)2 and Sm(O-iPr)3 gave optimal results and substrate scope and enantioselectivity were further improved by addition of 4-tBu-phenol that promoted dissociation of less selective oligomeric species. In the proposed mechanism the Sm-OAr moiety of the catalyst would act as Bronsted base favouring the Sm-nitronate formation while Cu would function as Lewis acid for imine activation [172]. Interestingly, the Pd/La combination enabled to reverse the diastereoselectivity in the related nitroaldol reaction [173] (Scheme 2.29a-b). Changing the substituent on diimine bridge with the more rigid

R = alkyl toluene, rt

Scheme 2.30 Thiourea-based bifunctional organocatalysts

binaphtyl unit also metals with smaller ionic radius can be held into the O2O2-cavity and the bench-stable complex 50c with two Ni atoms showed higher performances in Mannich addition of different nucleophiles to imines with respect to the corresponding mononuclear complex, so confirming the importance of cooperative activation [174] (Scheme 2.29c).

The concept of dual activation is also applicable to organocatalysis and the simplest examples of bifunctional organocatalysts are represented by proline and related prolinol derivatives, that are able to activate one reactive partner through the formation of a covalent enamine intermediate and the other one by non-covalent interactions with the carboxylate or hydroxyl substituent on the catalyst [175]. Thiourea derivatives bearing an additional nitrogen substituent form the main group of effective bifunctional organocatalysts and exert dual activation and stereocontrol by means of a network of hydrogen bonds with the reagents in a strong oriented transition state resulting from the proximity of acid and basic functionalities on the same chiral framework.

In most cases one of the substituents on thiourea moiety is the electron-withdrawing 3,5-trifluorophenyl group, that increases NH acidity and conformational rigidity of the molecule through additional H-bonding interaction with the sulphur

Bronsted base

Bronsted acid

Bronsted base

Bronsted acid

Ar = (3,5-trifluoromethyl)phenyl

R = v








PPh2 (S)-53b

MTBE, rt

H Ph aCO2Me




Scheme 2.31 BINOL-derived bifunctional organocatalysts

atom, while basic amine functionality derives from a variety of chiral scaffolds as trans-cyclohexanediamine, pyrrolidine, binaphtyldiamine, indanol and Cinchona-alkaloids. The resulting catalysts gave excellent results in Michael addition of different nucleophiles to chalcones or nitroolefins, in Morita-Baylis-Hillman reaction of cyclohexenone with a range of aldehydes [176] (Scheme 2.30) as well as in the methanolytic desymmetrization of cyclic anhydrides [177], a process recently broadened in scope by using BINOL-related catalyst 52 with a bifunctional thiophosphoramide group (Scheme 2.31a) [178]. Other BINOL derivatives with aminic or phosphine substituents acting as Lewis basic centres have been designed as valuable alternatives to bifunctional thiourea catalysts for aza-MBH reaction [179] (Scheme 2.31b).

In summary, the conceptual evolution of catalyst design has led to effective systems for a large variety of asymmetric reactions. Organization of substrates in the chiral environments of catalysts is an essential requisite for asymmetric induction and it has been achieved by coordination with transition metals, formation of covalently bonded intermediates or through a network of H-bonding or electrostatic interactions. Simultaneous activation of both the reaction partners by using bifunctional catalysts has often resulted in higher chemical and optical yield of the products. Some asymmetric transformations have been yet applied to the synthesis of chiral biologically active compounds and their extension to large-scale preparation can be reasonably envisaged.

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