Amadori rearrangement mechanism

Fig. 6.25. Simplified mechanism of two degradation reactions between peptides and reducing sugars occurring in solids, a) Maillard reaction between a side-chain amino (or amido) group showing the formation of an imine (Reaction a), followed by tautomerization to an enol (Reaction b) and ultimately to a ketone (Reaction c). Reaction c is known as the Amadori rearrangement (modified from [8]). b) Postulated mechanism of the reaction between a reducing sugar and a C-terminal serine. The postulated nucleophilic addition yields an hemiacetal (Reaction a) and is followed by cyclization (intramolecular condensation Reaction b). Two subsequent hydrolytic steps (Reactions c and d) yield a serine-sugar conjugate and the des-Ser-peptide...

The mechanism proposed by Hodge in 1953 U) for the early stages of the Maillard reaction, involving the Amadori rearrangement as a key step, has been accepted over a quarter of a century as a most apt description. Here, we propose a new mechanism... 

Knowledge about the chemical structure of the antioxidative MRP is very limited. Only a few attempts have been made to characterize them. Evans, et al. (12) demonstrated that pure reductones produced by the reaction between hexoses and secondary amines were effective in inhibiting oxidation of vegetable oils. The importance of reductones formed from amino acids and reducing sugars is, however, still obscure. Eichner (6) suggested that reductone-like compounds, 1,2-enaminols, formed from Amadori rearrangement products could be responsible for the antioxidative effect of MRP. The mechanism was claimed to involve inactivation of lipid hydroperoxides. 

Some uncertainty exists whether the Amadori Rearrangement follows a concerted pathway, in which case no formal charge is formed during the reaction, or whether its course runs via the formation of a carbonium ion (Scheme 3). The latter proposition is commonly accepted in the literature, but the actual mechanism probably is a mixture of the two proposals depending on the reaction conditions. 

It may be concluded that the mechanism of the "early phase" of the Maillard reaction is not dramatically changed by the addition of phosphate. It is therefore clear that the phosphate did not act as a nucleophile in the reaction, giving a reactive intermediate, in the rate-limiting step of a typical phosphate-dependent mechanism, but acts as a basic catalyst during the Amadori rearrangement. 

An example of the Amadori rearrangement is shown in the following equation. Suggest a mechanism for this reaction. 

The formation of the pyridinol is prevented if, in the step 19 to 20, no anion can be eliminated from C-3 this is the case with 5-amino-3,5-dideoxy-l,2-0-isopropylidene-a-D-er /thro-pentofuranose, which, on acid hydrolysis, afFords only the Amadori rearrangement product and no pyridine derivative. The reaction then proceeds, according to the above mechanism, in only one direction from 19. The 3-deoxypentose is prepared, in a manner analogous to the formation of 15, from 3-deoxy-l,2-0-isopropylidene-a-D-riho-hexofuranose through catalytic reduction of the phenylhydrazone of its periodate-oxidation product. ... 

No extensive study of the reaction mechanism of the Amadori rearrangement has been made. As the isomerization is usually conducted, about half of the amount of aldose orN-siibstitutedaldosylamiiie originally present is not accounted for at the end of the reaction. The intermediates and byproducts of the decomposition have not been identified or extensively investigated. Consequently, any conclusions now drawn on the course and mechanism of the reaction are speculative. In this Section, the limited number of positive and negative experimental results which bear upon the reaction mechanism will be presented first, and then their implications for the reaction mechanism will be discussed. 

The Amadori rearrangement has some features of the Lobry de Bruyn-Alberda van Ekenstein transformation, as can be seen from the ammono analogy to sugar enolization formulated in Part 2 of this Section. Both reactions occur in basic media, and each doubtless involves 1,2-enolization of the sugar. However, the Amadori rearrangement proceeds by acceptance of a proton from the acid catalyst, whereas the Lobry de Bruyn Alberda van Ekenstein transformation proceeds by delivery of a proton to the base catalyst. Aside from what may be argued as to the enolization mechanism, there are other important differences. 

Weygand has suggested two possible mechanisms for osazone formation which depend on the occurrence of an Amadori rearrangement after initial condensation of the hydrazine with the carbonyl group.Both routes were presented and reviewed by Percival in Volume 3 of this Series. Since that time, Weygand s theory has remained valid. Criticism by Ruggli and Zeller was satisfactorily answered by Weygand and Reckhaus, who showed that... 

As indicated previously, primary and secondary amines can also react with carbonyl compounds to form a mixture of compounds containing small molecules and polymers. The small molecule compounds obtained from an aldose and an amine have the common name Amadori products because the Amadori rearrangement is involved in their formation. The compounds generated from ketoses and amines are known as Heyns products (although the differentiation Amadori/Heyns is not always considered). The mechanism for the reaction of primary amines with a reducing sugar can be formulated as follows ... 

A mechanistic proposal for this reaction is outlined in Fig. 8. The pro-S proton at C-1 of 38 is derived from nicotinamide. This excludes an alternate mechanism involving an Amadori rearrangement [26]. 

According to Micheel, osazone formation starts from an aldose and requires an Amadori rearrangement, so that his scheme may not account for the reaction in the ketose series. It may be concluded that the Fischer mechanism is not valid, and that further studies are needed in order to solve the problem of interaction between ketoses and substituted phenyl-hydrazines. 

Bloink and Pausacker suggested a mechanism similar to that of Braude and Forbes, in which the hydrazonium salt, instead of oxidizing the hydroxyl group, oxidizes the hydrazino hydrazone formed by the action of phenyl hydrazine on the phenylhydrazone by way of (7). The hydrazino hydrazone is also an intermediate in the Weygand scheme B (see p. 145) for ketoses, where it is produced by an Amadori rearrangement. 

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