Acid catalysis, bifunctional cooperative

So far, most approaches to enzyme-like activity have used just one of the functional groups which are present in enzymes. However, many enzymes only operate by a cooperation of functional groups (see for instance the catalytic triade in peptidases). There, the enzyme s functional groups perform a multifunctional catalysis. Therefore in (organo) catalysis, bifunctional catalysis has been developed, too. In the field of concave reagents, first bifunctional catalysts have been constructed (Figure 7.28), and future will tell how capable they are to catalyse reactions with their acidic and basic functionalities. 

Abstract The concept of bifunctional acid catalysis is very helpful for inventing new catalytic asymmetric reactions. Compared with single functional acid catalysts, cooperative effect of two acid components has the potential to fine tune the reactivity as well as the selectivity of desired reaction pathways. This chapter focuses on some representative examples on the recent developments of bifunctional acid catalysis, including combined acid catalysis and other cooperative acid catalysis. 

Keywords Asymmetric synthesis Bifunctional acid catalysis Combined acid catalysis Cooperative acid catalysis Designer acid... 

Beyond the concept of combined acid catalysis, there are also many other bifunctional acid catalysts interacting with nucleophiles and electrophiles simultaneously, and thus benefiting through such cooperative effect. Selected examples on Lewis acid/hydrogen bonding cooperative catalysis and Lewis acid/transition-metal... 

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

Artificial enzymes with metal ions can also hydrolyze phosphate esters (alkaline phosphatase is such a natural zinc enzyme). We examined the hydrolysis of p-nitro-phenyfdiphenylphosphate (29) by zinc complex 30, and also saw that in a micelle the related complex 31 was an even more effective catalyst [118]. Again the most likely mechanism is the bifunctional Zn-OH acting as both a Lewis acid and a hydroxide nucleophile, as in many zinc enzymes. By attaching the zinc complex 30 to one or two cyclodextrins, we saw even better catalysis with these full enzyme mimics [119]. A catalyst based on 25 - in which a bound La3+ cooperates with H202, not water - accelerates the cleavage of bis-p-nitrophenyl phosphate by over 108-fold relative to uncatalyzed hydrolysis [120]. This is an enormous acceleration. 

Later, Lectka et al. reported a detailed synthetic and mechanistic study of unusual [4 + 2] cycloaddition of ketene enolates and o-quinones by the bifunctional catalysis of cinchona alkaloids BQD la (or BQN lb) and Lewis adds. The undertaken investigations based on the integration of experimental and calculated data itself demonstrated a surprising cooperative LA/LB interaction on a ketene enolate. It showed that the reaction of o-quinone undergoes a mechanistic switch in which the mode of activation changes from Lewis acid (LA) complexation of the quinone to metal complexation of the chiral ketene enolate. 

Just a few reviews on this quickly developping field a) D. H. Pauli, C. J. Abraham, M. T. Scerba, E. Alden-Danforth, T. Lectka, Bifunctional asymmetric catalysis cooperative lewis acid/base systems, Acc. Chem. Res., 2008,41, 655-663 b) M. Kanai, N. Katob, E. Ichikawab, M. Shibasaki, Power of cooperativity Lewis acid-Lewis base bifimctional asymmetric catalysis, Synlett, 2005, 1491-1508, c) M. Shibasaki, M. Kanai K. Funabashi, Recent progress in asymmetric two-center catalysis, Chem. Commun., 2002, 1989-1999. 

The cobalt(III)-promoted hydrolysis of amino acid esters and peptides and the application of cobalt(III) complexes to the synthesis of small peptides has been reviewed. The ability of a metal ion to cooperate with various inter- and intramolecular acids and bases and promote amide hydrolysis has been investigated. The cobalt complexes (5-10) were prepared as potential substrates for amide hydrolysis. Phenolic and carboxylic functional groups were placed within the vicinity of cobalt(III) chelated amides, to provide models for zinc-containing peptidases such as carboxypeplidase A. The incorporation of a phenol group as in (5) and (6) enhanced the rate of base hydrolysis of the amide function by a factor of 10 -fold above that due to the metal alone. Intramolecular catalysis by the carboxyl group in the complexes (5) and (8) was not observed. The results are interpreted in terms of a bifunctional mechanism for tetrahedral intermediate breakdown by phenol. 

Besides doping, co-doping in where two or more elements are present on the G sheet is also interesting from the point of view of using Gs as catalysts. One case that could be of interest is the presence of electron deficient atoms such as B and heteroatoms with excess of electrons such as N. In a certain way the simultaneous presence of B and N could be similar to the introduction of acid and basic Lewis sites. The concept of bifunctional acid-base solid catalyst has found wide application in heterogeneous catalysis of solids such as aluminophosphates containing NH groups (ALPONs) due to the cooperative activity of both sites in the reaction mechanism. 

Acyl Transfer Blfunctlcfnal Catalysis- Many mechanisms for enzjrme cataly-sls postulate cooperative ("push-pull") catalysis by an acid-base pair in the active site. The analogous bifunctional intramolecular catalysis has been widely sought the evidence presented generally consists of a maximum rate at a pH sufficiently acidic for the acid-catalytic function to be pro-tonated yet sufficiently basic for the base-catalytic function to be free. The hydrolysis of hexachlorophene monosuccinate (14). for example, exhibits such a rate maximum at pH 6.8 (between pK 5.20 for Che carboxyl group and... 

Pauli DH, Abraham CJ, Scerba MT, Alden-Danfrath E, Lectka T (2008) Bifunctional asymmetric catalysis cooperative Lewis acid/base systems. Acc Chem Res 41(5) 655-663. doi 10.1021/ ar700261a... 

In this chapter, we have successfully developed bifunctional chiral rhodium complexes bearing chiral phebox ligands that can be used in catalytic asymmetric reactions. The N,C,N meridional geometry with the rhodium-carbon covalent bond is the key character in the phebox complexes. The metal-phebox cooperative bifunctionality significantly contributes reactivity and selectivity in the catalytic asymmetric reactions. Furthermore, the prototype of the bifunctional catalyst can be explained to a wide range of asymmetric catalytic reactions promoted by the Lewis acids, hydrides, enolates, and bory active species. Their diversity further broadens the range of opportunities for asymmetric catalysis. 

Chen et al. [26] reported the use of a bifunctional thiourea catalyst 61 during the organocatalyzed thia-Michael addition of thiophenol to unsaturated imide 58c (Scheme 3.29). Michael adduct 60c was obtained in 60% ee and 97% yield by conducting the reaction in dichloromethane at -78°C. The authors speculated that while the tertiary amine of the bifunctional catalyst 61 would act as a proton shuttle according to a Brpnsted acid/base catalysis, the presence of the thiourea moiety might possibly cooperate in the stabilization of the more stable Z-enolate intermediate via hydrogen bond formation as illustrated in Scheme 3.31. 

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