Enamine mechanism

Wagner, J., Lerner, R. A., and Barbas, C. F., Ill, 1995. Efficient adolase catalytic antibodies that use tlie enamine mechanism of natural enzymes. Science 270 1797-1800. See also tlie discussion entitled Aldolase antibody in Science 270 1737. 

Like many other antibodies, the activity of antibody 14D9 is sufficient for preparative application, yet it remains modest when compared to that of enzymes. The protein is relatively difficult to produce, although a recombinant format as a fusion vdth the NusA protein was found to provide the antibody in soluble form with good activity [20]. It should be mentioned that aldolase catalytic antibodies operating by an enamine mechanism, obtained by the principle of reactive immunization mentioned above [15], represent another example of enantioselective antibodies, which have proven to be preparatively useful in organic synthesis [21]. One such aldolase antibody, antibody 38C2, is commercially available and provides a useful alternative to natural aldolases to prepare a variety of enantiomerically pure aldol products, which are otherwise difficult to prepare, allovdng applications in natural product synthesis [22]. 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

Mechanistically it seems that the reactions follow an enamine mechanism, in which the enamine derived from the ketone and proline reacts with the imine formed in situ from the aldehyde and p-anisidine. 

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... 

Zhong rationalized the enantioselectivity by proposing an enamine mechanism which proceeds via the chair transition state shown in Figure 7.1 [11]. In this transition state, the Si face of an E enamine formed from the aldehyde and the catalyst L-proline approaches the less-hindered oxygen atom of nitrosobenzene leading to the chiral product with (R) configuration. This mechanism is in accordance with the proposed reaction mechanism for the aldol reaction (see chapter 6.2). 

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. 

Scheme 7. Proposed enamine mechanism of the proline-catalyzed direct aldol addition reaction of acetone [25].

Other aromatic aldehydes provided products with similar enantiomeric excess. Although a-unbranched aldehydes such as pentanal did not yield any significant amount of the desired aldol products, the reaction of isobutyraldehyde gave the corresponding aldol product in 97% yield and 96% ee. The reaction is considered to proceed via an enamine mechanism. The enantioselectivity of the reaction can be explained in terms of a metal-free version of a six-membered transition state... 

In contrast to primary amine catalysis, the enamine mechanism has been ruled out for D—H exchange in isobutyraldehyde catalysed by secondary amines. Catalytic rate constants were explained by considering only the... 

Silverman and associates explored a variety of potential inactivators for GABA [y-aminobutyric acid, H3T (CH2)3COOH] transaminase, another pyridoxal-dependent enzyme. In the reaction of the enzyme with 4-amino-5-fluoropentanoic acid, Silverman and Invergo wrote the mechanism in equation 25 for the covalent interaction of the enzyme with the inactivator161. The mechanism, dubbed the enamine mechanism, was earlier suggested by Metzler s group162, who had also proposed, as a test, alkaline treatment of the inactivated enzyme that would result in the release of the coenzyme-bound modified inactivator. 

It was shown thereafter by Silverman and George that such an enamine mechanism is not universal, since 4-amino-2-fluorobut-2-enoic acid inactivated the same enzyme by a Michael-type reaction between an enzymic nucleophile and the bound isomerized inactivator163. 

Clemente FR, Houk KN (2004) Computational evidence for the enamine mechanism of intramolecular aldol reactions catalyzed by praline. Angew Chem Int Ed Engl 43 5766-5768... 

C.F. (1995) Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes. Science, 270,1797-1800. 

C. Thus, computation indicates that the Hajos-Parrish-Wiechert-Eder-Sauer reaction proceeds by the carboxylic-acid-catalyzed enamine mechanism D, which is consistent with all of the computations for intermolecular proline-catalyzed aldol examples. 

Silverman RB, Invergo BJ. Mechanism of inactivation of y-aminobutyrate aminotransferase by 4-amino-5-fluoropentanoic acid. Eirst example of an enamine mechanism for a y-amino acid with a partition ratio of 0. Biochemistry 1986 25 6817-6820. 

Figure 42 Michael addition mechanism (reaction a) and enamine mechanism (reaction b) of inactivation of GABA-AT by...

Figure 43 Enamine mechanism of inactivation of GABA-AT by (D,L)-c/s-3-aminocyciohex-4-ene-1 -carboxyiic acid. ...

Wagner, J. Lemer. R.A. Barbas. C.F.. III. Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzyme. Science 1995. 270. 1797-1800. Arnold. F.H. Combinatorial and computational challenges for biocatalyst design. Nature 2001, 409. 253-257. Penning, T.M. Jez, J.M. Enzyme redesign. Chem. Rev. 2001. 101. 3027-3046. 

Early work by Tomioka and coworkers [39] described a two-component Michael/ aldol process to cyclopentenes. Furthermore, rhodium-assisted Michael/aldol processes to cyclopentanes and cyclohexanes have also been reported [40]. Later, a Michael addition reaction in combination with an adehyde a-alkylation reaction was reported for the highly stereoselective formation of y-nitroaldehydes 50 [41]. In this publication, a series of aliphatic aldehydes 49 (at Rj) and ( )-5-iodo-l-nitropent-1-ene 48 were reacted in the presence of the organocatalyst 1 and benzoic acid in dimethyl sulfoxide (DMSO) to afford the resulting cyclopentene ring system 50 (Scheme 7.9). The diastereo- and enantioselective process follows the proposed mechanism beginning with enamine activation of the aldehyde to 51 by the catalyst 1 (blocking the re face), and Michael addition of 48 occurs at its more accessible si face. The full enamine-enamine mechanism, illustrated in Scheme 7.9, provided... 

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