Proline reaction mechanism

A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of a-ketoglutarate (Figure 28-11). Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and prohne hydroxylase is also required in formation of osteocalcin and the Clq component of complement. Aspartate P-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease which hydrolyzes activated factor V in the blood clotting cascade. TrimethyUysine and y-butyrobetaine hydroxylases are required for the synthesis of carnitine. 

A full kinetic study of the proline-mediated aldol reaction based on a detailed catalytic reaction mechanism will be published separately. 

Careful inspection of the reported photocatalytic reactions may demonstrate that reaction products can not be classified, in many cases, into the two above categories, oxidation and reduction of starting materials. For example, photoirradiation onto an aqueous suspension of platinum-loaded Ti02 converts primary alkylamines into secondary amines and ammonia, both of which are not redox products.34) ln.a similar manner, cyclic secondary amines, e.g., piperidine, are produced from a,co-diamines.34) Along this line, trials of synthesis of cyclic imino acids such as proline or pipecolinic acid (PCA) from a-amino acids, ornithine or lysine (Lys), have beer. successfuL35) Since optically pure L-isomer of a-amino acids are available in low cost, their conversion into optically active products is one of the most important and practical chemical routes for the synthesis of chiral compounds. It should be noted that l- and racemic PCA s are obtained from L-Lys by Ti02 and CdS photocatalyst, respectively. This will be discussed later in relation to the reaction mechanism. 

A detailed study of the reaction mechanism based on quantum mechanical calculations was reported very recently by Houk and List et al. [96]. In this connection, the ratio of the four stereoisomeric products in the proline-catalyzed dia-stereo- and enantioselective aldol reaction was predicted and excellent agreement... 

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. 

The (S)-(-)-proline catalyzed asyimietric aldol cyclization of the triketone to the optically active bicyclic aldol product, followed by dehydration to the optically active enedione, (+)-(7aS)-2,3,7,7a-tetrahydro-7a-methyl-lH-indene-l,5(6H)-dione, has been described, and two alternative reaction mechanisms have been suggested by the submitters. The exact... 

Both experimental and theoretical studies have contributed significantly to the elucidation of the reaction mechanism. We found that in contrast with earlier proposals (Agami et al. 1984, 1986, 1988 Puchot et al. 1986 Agami and Puchot 1986), proline-catalyzed aldol reactions... 

Proline-catalyzed enantioselective aldol reaction, mechanism of 88BSF499. 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

Macias, A., Alonso, E., Del Pozo, C., Venturini, A., Gonzalez, J. Diastereoselective [2+2]-Cycloaddition Reactions of Unsymmetrical Cyclic Ketenes with Imines Synthesis of Modified Prolines and Theoretical Study of the Reaction Mechanism. J. Org. Chem. 2004, 69, 7004-7012. 

Progress in the study on the reaction mechanisms of proline-catalyzed asymmetric direct aldol reactions 06CJO1463. 

Agami s model was subsequently challenged by List, Lerner, and Barbas III in 2000 [8a], when they proposed a one-proline enamine mechanism for the proline-catalyzed intermolecular aldol reaction between ketones and aldehydes. Shortly afterwards, on the basis of DFT calculations, Houk and co-workers proposed a very similar mechanism for the Hajos-Parrish intramolecular aldol [19]. Using the B3LYP/6-31H-G(2df,p) level of DFT theory, Houk and co-workers [20] have seen that the energy difference between the two possible chair Zimmermann-Traxler-like transition states, which differ in the orientation of the enamine with... 

The similarity in reaction mechanisms between amino acid- and 2-deoxyribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggested to us that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes [38, 39]. In this context, proline catalyzes the direct catalytic asymmetric Mannich reaction between umnodified aldehydes, and A -PMP-protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantio-selectivity (Scheme 4.7) [40]. 

The mechanism of the entry of fructose into the Maillard reaction (a series of sugar/amino acid processes in vivo) has been studied by DFT the order of reactivity for the isomers is predicted as a- > /3- > open-chain. Heyns rearrangement products are most favourable under basic conditions, possible under neutral conditions, but unfeasible at or below glycine s isoelectric point. Kinetic and activation parameters have been reported for the corresponding glucose/proline reaction. ... 

In 2012, Rueping et al. reported the proline-mediated reaction of 1,3-diketones with aldehydes to provide 2-hydroxy-3,4-dihydro-2//-pyran derivatives in good to excellent yields [46]. The reaction mechanism involves a Knoevenagel-Michael addition sequence with subsequent hemiacetalization. The haniacetal was oxidized with TPAP/ NMO or PCC to give the corresponding lactones 96. An enantioselective variant utilizing stoichiometric amounts of an... 

The reaction mechanism most often proposed is a transfer of hydrogen atoms from the amino group and the a-carbon to the flavin, leaving an imino acid, which is thought to hydrolyze spontaneously. While there is no direct evidence for the intermediate formation of an imino acid, support for this hypothesis is found in the requirement for a hydrogen atom on both the nitrogen and a-carbon atoms. W-Monomethyl amino acids and proline are substrates, but neither W-dimethyl compounds nor compounds such as a-aminoisobutyric acid are attacked. Acylated amino acids, including peptides, are not substrates. ... 

Shoeib T, Hopkinson AC, Siu KWM (2001) Collision-induced dissociation of the Ag -l--proline complex fragmentation pathways and reaction mechanisms—a synergy between experiment and theory. J Phys Chem B 105(49) 12399-12409. doi 10.1021/jp012335o... 

The possible reaction mechanism for a cascade olefination-hydrogenation reaction is illustrated in Scheme 1.21. First, the reaction of proline with ciis-isomer 67 generates the iminium cation 68, which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69. A retro-Mannich or base-induced elimination reaction of amine 69 would furnish active olefin 70. The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situ-generated conjugated system or, more precisely, the HOMO-LUMO gap of reactants 65 and 70. 

The reaction mechanism was proposed to have iminium intermediate (Scheme 9.3). The iminium moiety is formed between L-prolinate and enone (intermediates A and B). Then, the malonate attacks the 3-carbon of the enone to afford the asymmetric Michael adduct. For iminium intermediate A, malonate with metal counter cation is located at a suitable position to approach the (3-carbon of the enone from the same side of the armed metal salt Considering about intermediate B, the distance between malonate and P-carbon of the enone is relatively too far for reaction to take place. 

SCHEME 9.3. The reaction mechanism ruhidium L-prolinate catalyzed Michael addition. 

An extensive review of the synthesis of a wide variety of five-membered heterocyclic compounds, via the formal 3-1-2-cycloaddition reactions of aziridines with alkenes, alkynes, nitriles, carbonyl groups, and heterocumulenes, has been presented." Supercritical CO2 has been used as the solvent in the formal 3-1-2-cycloaddition reactions of A-benzyl- and A-cyclohexyl-2-benzoyl-3-phenylaziridines with allenoates to yield pyrrole derivatives." The Lewis acid-catalysed intramolecular formal 3-1-2-cycloaddition reactions of 2-methyleneaziridines with tethered alkenes or alkynes (23) yielded cw-octahydrocyclopenta[c]pyrroles (24) after reductive workup. The reaction mechanism proceeds in a stepwise manner via a 2-aminoallyl cation (Scheme The Cu(I)/DTBM-Segphos-catalysed 1,3-dipolar cycloaddition reactions of a-silylimines and activated alkenes yielded highly enriched 5-unsubstituted a-quaternary proline cycloadducts with excellent diastereo- and enantio-selectivities (73-99% The... 

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