Aldol condensation antibodies

Antibody-catalyzed aldol condensation was demonstrated in a [bmim][PFg] solvent system by Kitazume and co-workers (Fig. 17). They tested recyclable use of antibody catalyst in the solvent system and, very interestingly, found that the chemical yield was increased for the second cycle (89%) over the initial run (21%). 

Examples of highly enantio- and regio-selective aldol condensation reactions have featured in a review of organic synthesis and catalytic antibodies.188... 

Reymond and Chen88 have investigated the same set of antibodies for their ability to catalyze bimolecular aldol condensation reactions. The antibodies were assayed individually at pH 8.0 for the formation of aldol 111 from aldehyde 109 and acetone. None catalyzed the direct reaction, but in the presence of amine 110 three anti-52a and three anti-52b antibodies showed modest activity. In analogy with natural type I aldolase enzymes, the reaction is believed to occur by formation of an enamine from acetone and the amine, followed by rate-determining condensation of the enamine with the aldehyde. As in the previous example, the catalyst, which was characterized in detail, is not very efficient in absolute terms ( cat = 3 x 10-6 s 1 for the anti-52b antibody 72D4), but it is approximately 600 times more effective than amine alone. Moreover, the reactions with the antibody are stereoselective The enamine adds only to the si face of the aldehyde to give... 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

Scheme 4.7 Antibodies generated against hapten 15 promote diverse aldol condensations through enamine chemistry.

An alternate complementary approach toward catalytic antibody generation that could overcome the entropic disadvantage of preorganization of the amine cofactor with the Ab catalyst was investigated. A phosphinate (Scheme 5.64) was designed to mimic the expected transition state for the addition of a pheny-lacetone derived enolate to the carbonyl of benzaldehyde. An Ab raised against this hapten was expected to catalyze the aldol condensation of benzylacetone and benzaldehyde by both proximity and electrostatic effects. However, while... 

Aldol condensation reactions are catalyzed by amines and the active sites of many aldolases contain an essential lysine residue. Using a strategy of reactive immunization with a 1,3-diketone (18 in Fig. 5.8), Wagner et al. were able to generate antibodies with aldolase activity. These were shown to possess a highly reactive lysine residue in... 

Keywords Catalytic antibody. Hapten, Enantiofacial, Enantioselective, Diels-Alder cycloaddition, Cationic reactions, Aldol condensation. Disfavored cyclization... 

Initial catalytic antibodies were developed to bind a primary amine cofactor as a mimic of the type I aldolases. The hapten designed mimicked the transition state the iminium ion, resulting in the production of an antibody that catalyzed the aldol condensation of acetone and aldehyde acceptors (Fig. 14.1-36)(2091. Even though no stereochemical information was built into the transition-state mimic, the antibody catalyzed stereoselective addition to the si face of the aldehyde. 

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

Because many important chemical transformations, inclnding aldol condensations, Sn2 substitutions, E2 eliminations are sensitive to solvent microenvironment, this strategy is likely to be increasingly exploited in the development of a wide variety of catalytic antibodies. 

The catalysis of carbon-carbon bond formation remains as one of the most active areas of research in catalytic antibody technology and organic synthesis [18]. Mosbach and coworkers reported the preparation and evaluation ofavinylpyridine-styrene-divinylbenzene copolymer imprinted with an aldol condensation reactive intermediate analog (Scheme 13). Dibenzoylmethane (DMB, 28) was chosen as the imprinted template based on molecular modeling studies for the cobalt (II) ion-mediated aldol condensation of acetophenone, 29, and benzaldehyde, 30, to produce chalcone, 31. 

See The Chemistry of... Antibody-catalyzed Aldol Condensations in WileyPLUS for a method that uses the selectivity of antibodies to catalyze aldol reactions. 

Antibodies 38C2 and 33F12 also catalyzed self-aldol condensations of pro-pionaldehyde and provided the aldol-elimination product 26, and the antibodies did not catalyze the consecutive aldol reaction of 26 with propionalde-hyde (Scheme 6.3). The antibodies did not catalyze the self-aldol reactions of aldehydes bearing a longer alkyl chain (> valeraldehyde, for example, aldehydes 3, 12, and 13). It might not be possible for the antibody to accept two... 

Synthetic peptide dendrimers, catalytic antibodies, RNA catalysts, peptide foldamers as well as other native or modified enzymes with completely different fxmctions were discovered to catalyze carbon-carbon bond formation [15]. 4-Oxalocrotonate tau-tomerase (4-OT) catalyzes in vivo the conversion of 2-hydroxy-2,4-hexadienedioate (136) to 2-oxo-3-hexenedioate (137) (Scheme 10.33a), and it belongs to the catabolic pathway for aromatic hydrocarbons in P. putida mt-2 [200]. This enzyme carries a catalytic amino-terminal proline, which could act as catalyst in the same fashion as the proline mediated by organocatalytic reactions. Initial studies demonstrate that this enzyme was able to catalyze aldol condensations of acetaldehyde to a variety of electrophiles 138 (Scheme 10.33b) [200]. This enzyme was also examined as a potential catalyst for carbon-carbon bond forming Michael-type reactions of acetaldehyde to nitroolefins 139 (Scheme 10.33c) [201,202]. 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

Antibody Catalysis. Recent advances in biocatalysis have led to the generation of catalytic antibodies exhibiting aldolase activity by Lemer and Barbas. The antibody-catalyzed aldol addition reactions display remarkable enantioselectivity and substrate scope [18]. The requisite antibodies were produced through the process of reactive immunization wherein antibodies were raised against a [Tdiketone hapten. During the selection process, the presence of a suitably oriented lysine leads to the condensation of the -amine with the hapten. The formation of enaminone at the active site results in a molecular imprint that leads to the production of antibodies that function as aldol catalysts via a lysine-dependent class I aldolase mechanism (Eq. 8B2.12). 

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