Aldolase mimics

Antibodies produced by this procedure were screened for their ability to react with the hapten to form the vinylogous amide 6, which has a convenient UV chromophore near 318nm, clear of the main protein absorption. Two antibodies selected in this way catalysed the expected aldol reaction of acetone with aldehyde 7 by way of the enamine 8 (Scheme 3) the remainder did not. These two effective aldolase mimics have been studied in some detail, and a crystal structure is available for (a Fab fragment of) one of them.126,281... 

In a follow-up to this report, Zeidan et al. [22] prepared materials containing acid and base groups using weaker acid groups (phosphonic, carboxylic) with the primary amines (Fig. 23.4d,e). The activity in these aldolase mimics was found to increase as... 

The role of metal ions in catalysis is well documented. Matsui etal. [115] used a co-ordinating Co2+ ion in a transition state analogue imprinting procedure to prepare synthetic class II aldolase mimics as catalysts of the aldol condensation (Figure 6.30). 

Cyclodextrins with two imidazole groups on the primary hydroxyl side can enhance the enolate formation [86] of a simple bound ketone by bifunctional acid-base catalysis and accelerating the intramolecular aldol condensation of bound ketoaldehyde and dialdehyde. The aldolase mimics which catalyzed crossed aldol condensations were obtained by the assembly of (i-CD and various amino moieties as Schiff base [87]. 

Furthermore, this methodology can provide highly sophisticated polymeric materials, in which unique functions of metal complexes (catalysis, electron-transfer, and others) are combined with the molecule-recognizing activity of the polymer. For example, aldolase-mimic... 

The use of L-proline as an aldolase mimic has produced extraordinary results in cross-aldol reactions of acetone and aldehydes and of dissimilar aldehydes, giving p-hydroxyketones with ee s > 80%. From limited results it appears that L-proline is as active or more active than the catalysts mentioned above (below ambient temperatures, with good yields in <24 h), and exhibits consider-... 

Calixarenes have used for many different purposes that are the subject of several of the following chapters of this book. The original motivation of David Gutsche for developing the calixarene chemistry was their use as a concave platform for aldolase mimics and this idea has also been explored extensively by others. Part of this chemistry is described by Casnati et al. in Chap. 26 and by Yilmaz in Chap. 27. 

Class 1 aldolase mimics consist of amino acid catalysts that presumably activate the donor via enamine formation and the acceptor through a hydrogen bond with an acid functionality. Repotted hrst by Wiechert et al. and then by Hajos and Parrish,-proline was found to catalyze intramolecular asymmetric aldol reactions. However, the... 

Class II aldolase mimics (Scheme 10.4) were the first small-molecule catalysts that were reported for the direct intermolecular aldol reaction. These catalysts are characterized as bimetallic complexes that contain both Lewis acidic and Brpnsted basic sites. Shibasaki et al. first reported on the use of such a catalyst in the aldol reaction in 1997, demonstrating its potential with the reaction of various acetophenones 52 and aldehydes 53 (Scheme 10.13). Aldols 55 were obtained in good yields and enantioselectivities. A similar approach was used in the direct catalytic asymmetric aldol-Tishchenko reaction.Nevertheless, for the moment, this method does not provide access to true polypropionate fragments. ... 

Furthermore, the GPO procedure can also be used for a preparative synthesis of the corresponding phosphorothioate (37), phosphoramidate (38), and methylene phosphonate (39) analogs of (25) (Figure 10.20) from suitable diol precursors [106] to be used as aldolase substrates [102]. In fact, such isosteric replacements of the phosphate ester oxygen were found to be tolerable by a number of class I and class II aldolases, and only some specific enzymes failed to accept the less polar phosphonate (39) [107]. Thus, sugar phosphonates (e.g. (71)/(72)) that mimic metabolic intermediates but are hydrolytically stable to phosphatase degradation can be rapidly synthesized (Figure 10.28). 

Kimura and co-workers have synthesized a series of alkoxide complexes with the alcohol functionality as a pendent arm.447 674 737 A zinc complex of l-(4-bromophenacyl)-l, 4,7,10-tetraaza-cyclododecane was also synthesized by the same workers to mimic the active site of class II aldolases. The X-ray structure shows a six-coordinate zinc center with five donors from the ligand and a water molecule bound. The ketone is bound with a Zn—O distance of 2.159(3) A (Figure 12). Potentiometric titration indicated formation of a mixture of the hydroxide and the enolate. Enolate formation was also independently carried out by reaction with sodium methoxide, allowing full characterization.738... 

Sugiyama, M., Hong, Z., Whalen, L.J., Greenberg, W.A. and Wong, C.-H., Borate as a phosphate ester mimic in aldolase-catalyzed reactions practical synthesis of L-fructose and L-iminocyclitols. Adv. Synth. Catal. 2006, 348, 2555 - 2559. 

Efforts to overcome the Dff AP dependence of aldolases have involved the in situ formation of arsenate [9] or borate [10] complexes with dihydroxyacetone (DHA), which could mimic a phosphate ester (Scheme 4.3). 

For a distinction in the binding mode of substrate constitutional isomers, we first focused on the synthesis of the structurally related anhydroalditol derivatives 7 and 8 as potential inhibitors of FucA that lack the anomeric hydroxyl group of the natural substrate 5 and thus ehminate the possibility for ring opening and cleavage [12] (Scheme 2.2.5.3). Fucitol 1-phosphate 10 was included in the study as a potential mimic of the open-chain form. From kinetic data it became obvious that the aldolase binds preferentially a cyclic substrate, and selectively the more abundant P-anomer of the natural substrate that correlates with 7. 

Deprotonation of 1 at C3 yields an ene-diolate intermediate to which phospho-glycolohydroxamate (PGH) 9 bears a close structural resemblance (Scheme 2.2.5.3). In collaboration with J. V. Schloss, 9 was found to be a potent inhibitor not only of FucA, but indeed also of all currently accessible Class 11 aldolases with Ki in the nanomolar range [12]. Obviously, the hydroxamate mimics very effectively an advanced catalytic intermediate or transition state that is shared by these enzymes, and seems to be bound by all Zn -dependent aldolases in a very similar fashion. Interestingly, when the active-site Zn is replaced by Co ions, catalytic activity is restored and actually becomes higher than with native zinc cofactor. However, the RhuA Co complex catalyzes an oxygenase reaction that consumes... 

Several DHAP aldolases having different stereospecificities were tested for their acceptance of this phosphonomethyl substrate mimic as the aldol donor, individual enzymes belonging to both Glass 1 and 11 types were found to catalyze the stereoselective addition of 14 to various aldehydes, providing bio-isosteric non-hydrolyzable analogues of sugar 1-phosphates in high yields (for example, 16/17 Scheme 2.2.5.7) [25, 26]. 

Scheme 7 Schematic representation of the imprinting and catalytic approach used to prepare the Aldolase II mimic...

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

The mechanism similarities to enzymatic processes In principle, L-proline acts as an enzyme mimic of type I metal-free aldolases. Similar to this enzyme, L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of type I aldolases has been found. The close similarity of... 

In principle, L-proline acts as an enzyme mimic of the metal-free aldolase of type I. Similar to this enzyme L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of the aldolase of type I was found. The close relation of the reaction mechanisms of the aldolase of type 1 [5b] and L-proline [4] is shown in a graphical comparison of both reaction cycles in Scheme 3. In both cases the formation of the enamines Ila and lib, respectively, represents the initial step. These reactions are carried out starting from the corresponding ketone and the amino functionality of the enzyme or L-proline. The conversion of the enamine intermediates Ha and lib, respectively, with an aldehyde, and the subsequent release of the catalytic system (aldolase of type I or L-proline) furnishes the aldol product. 

For the proline- and proline congener-catalyzed aldol reaction [23, 24], a mechanism based on enamine formation is proposed [25], Scheme 7. The catalytic process starts with condensation of the secondary amino group of proline with a carbonyl substrate leading to a nucleophilic enamine intermediate, which mimics the condensation of the active-site lysine residue with a carbonyl substrate in type I aldolases. The adjacent carboxylic acid group of the enamine intermediate... 

In the chemical synthesis of complex natural products, the concept of bidirectional chain synthesis has also been shown effective for the bi-directional backbone extension, as implemented by DHAP-dependent aldolases.37 As such, highly complex carbohydrate mimics may be obtained in a single pot... 

The development of the concept of reactive immunization yielded more effective antibody aldolases.119-120 In this new approach, rather than raise antibodies against an unreactive hapten designed to mimic the transition state, the antibodies were raised against a reactive moiety. Specifically, a p-diketone that serves as a chemical trap to imprint a lysine residue in the active site of the Ab (Scheme 5.65) was used.340 A reactive lysine is a requirement of the type I aldolase mechanism. By this method two aldolase catalytic antibodies, 38C2 and 33F12 were identified.119... 

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