Degradations and Rearrangement Reactions

Abstract

This section deals with recent reports concerning degradation and rearrangement reactions of free sugars as well as some glycosides. The transformations are classified in chemical and enzymatic ways. In addition, the Maillard reaction will be discussed as an example of degradation and rearrangement transformation and its application in current research in the fields of chemistry and biology.

Overview

Degradation and rearrangement reactions in carbohydrate chemistry are described in the standard organic chemistry textbooks [1,2]. Recent books [3,4,5] contain informative surveys of developments in this area. This chapter dealing with degradation and rearrangement reactions of carbohydrate systems covers literature published in the last few years. Degradation reactions are classified into two main categories: hydrolysis from glycosides or polysaccharides into free sugars, and the degradations from free sugars into useful building blocks or chiral synthons for organic synthesis. The rearrangement reactions described herein are classified into four groups: double bond shifts, ring rearrangements associating with a double bond, ring isomerizations (contraction and expansion), and other processes. Current results on the Maillard reaction initiated by the Amadori reaction, which are so intimately associated with degradation and rearrangement reactions, are also discussed in this chapter.

Hydrolysis of Glycosides and Polysaccharides

Among all the degradation patterns for glycosides and polysaccharides, hydrolysis is the most important process in carbohydrate chemistry, either in nature or in biological systems. Before long, it became a process important in the food industry for production of free sugars and is now gaining more and more attention because of the present energy crisis. This is because petroleum is not an ideal chemical feedstock for industry, due to its intractability, while glycosides and polysaccharides—which are abundant and recyclable—can be utilized in the production of fuel and chiral synthons to be used instead of traditional petroleum [6].

Chemical Hydrolysis

Chemical hydrolysis is a very familiar reaction for the sugar industry. However, it may generate an array of possible degradation products. For example, very low rate constants for the spontaneous hydrolysis of nonactivated methyl β‑d‑glucopyranoside 1 have been determined at 220 ℃ [7], (Fig. 1). At pH > 7, the rate constants approach a constant value. On hydrolysis at pH 10 in the presence of H₂ ¹⁸O, the results show that the reaction occurs almost exclusively by cleavage of the C1/O1 bond. The β‑anomer  1 is roughly twice as reactive as the α‑anomer 2, as are also the anomeric pair of methyl d‑ribofuranosides 3 and 4. Unlike the hydrolysis at pH < 7, the hydrolysis of 1 without catalysts proceeds with a negative entropy of activation. This is consistent with bimolecular attack of water on 1.

Acid hydrolysis of isopropenyl α‑d‑glucopyranoside 5 at pH 3.0 and 25 ℃ occurs by C‑protonation followed by cleavage of the alkenyl ether C/O bond. The α‑anomer 5 is hydrolyzed 4.5‑times faster that its β‑anomer 6. Spectroscopic evidence indicates greater conjugation of O1 with the double bond, and hence a greater basicity of the β‑carbon of the double bond, in 5 compared to 6 [8].

An accelerating effect by the intramolecular nucleophilic catalysis of a phosphate anion upon hydrolysis of the phosphate 7 at 80TT ℃ and pH 6–9, in comparison with the unsubstituted 8 and its 2‑O‑methyl derivatives 9, has been observed [9]. The reaction of 8 is base‐catalyzed down almost to pH 7, while that of 9 is pH‐independent up to pH 9–10 The hydrolysis of 7 proceeds about 100‑times faster than that of 9 at pH ∼9 and 80 ℃. In comparison, the hydrolysis of 10 is pH‐independent down to pH 7 and ∼20‑times slower than that of 7 at pH 9 and 80 ℃ [10].

A kinetic study of the acyl migration reaction of the 1‑O‑acyl β‑d‑glucopyranuronic acid 11, a model drug ester glucuronide, employing a directly coupled stop‐flow HPLC/600 MHz ¹H‑NMR system at pH 7.4 and 25 ℃, has been carried out [11]. The acyl migration rate of the β‑1‑O‑acyl group of 11 is greater than any other regio‐isomers. The simulating mutarotation rates for the 4‑O‑acyl isomers 12 are in good accord with the experimental values.

Figure 1

Glycosidesubstrates for nucleophilic hydrolysis

The fructofuranosyl cation  13 is the first formed product of the acid‐catalyzed melt thermolyses of sucrose 14 (Scheme 1). This reacts with hydroxy nucleophiles co‑existing in the melt to give fructose‐grafted products. Rigorous thermolysis of 14 itself at 170 ℃ furnishes a fructosylglucan with an average dp ∼25 together with the known sucrose thermal oligosaccharides from 14, such as 15 (3.9%) and 16 (4.1%) [12].

Scheme1

-

Mechanistic studies on acid hydrolysis of glycosides often encounter the endo/exo‐cyclic cleavage problem [13]. For instance, the sulfuric acid (1%)‑catalyzed acetolysis of the anomeric ethyl glycoside derivatives 17 and 18 as well as the diastereoisomeric acetal 19 and 20 have been studied kinetically. The time‐dependent distribution of the acetolysis products from 17 and 18 shows that their rapid mutual anomerization precedes their acetolysis to 21 and 22, undoubtedly by way of the endo‐cyclic cleavage product 23, the precursor of 19 and 20 [14] (Fig. 2).

Figure 2

Substrates and intermediates in acetolysis of ethyl glycoside

Sialosides have a distinct mechanism of hydrolysis for its unusual sugar structure of sialic acid. For example, the large β‑dideuterium and small primary ¹⁴C kinetic isotope effects observed at the anomeric carbon and the large secondary ¹⁴C kinetic isotope effect observed at the carboxylate carbon in the acid‐catalyzed solvolysis of CMP‑N‑acetyl neuraminate 24 support an oxocarbenium ion‐like transition state 25 having the ₅S conformation without nucleophilic participation of carboxylate and with the carboxylate anion in a looser environment than in the ground state [15] (Fig. 3). Such a zwitterion structure is consistent with the results from calculations using the COSMO‑AM1 method for aqueous solutions [16].

Figure 3

CMP‑N‑acetyl neuraminic acid and oxocarbenium ion‐like transition state in sialoside hydrolysis

Enzymatic Hydrolysis

Glycoside hydrolase is one of the main categories of hydrolases in nature. Many references have suggested a distorted conformation for the substrate, which accelerated the hydrolytic process dramatically [17,18]. The influenza A sialidase hydrolyzes sialyl glycosides with retention of the anomeric configuration [16], whereas the Salmomella typhimurium sialidase works with inversion, although their protein folds and presumed active site residues are very similar [19,20]. Comparative studies using deuterium‐labeledp‑nitrophenyl N‑acetyl‐α‑neuraminides 26–28 have postulated that the reactive substrate adopts a B₂₅ conformation with significant proton donation to the leaving group for the influenza virus enzyme, whereas the S. typhimurium enzyme works through a single chemical transition state derived from the ground state ²C₅ conformation with little proton donation to the leaving group [13]. The leaving group ¹⁸O isotope effects are higher at pH 6.67 and 60 ℃ than at pH 2.69 and 50 ℃ in the nonenzymatic hydrolysis of 29 (Fig. 4) [21,22]. This indicates that the C/O bond dissociation is complete at the transition state [21].

Figure 4

Deuterium‐labeled p‑nitrophenyl N‑acetyl‐α‑neuraminides

New analytic tools can be helpful in the research of enzymatic processes. For instance, time‐course examination of enzymatic hydrolysis has recently been studied with ¹H‑NMR spectroscopy. Thus, α‑l‑rhamnosyl and α‑d‑galactosyl hydrolysates from Aspergillus fungi have recently been found to be inverting hydrolyses [23,24].

With newly gained knowledge of hydrolytic mechanisms a novel artificial enzyme, the antibody enzyme AbZyme , was designed using the known mimics of the transition states [25]. Antibody Ab24, produced by in vitro immunization using the carrier‐free hapten 30 and spleen cells in culture, catalyzes the hydrolysis of 8 with a k _cat of 0.02 h⁻¹ and K _m of 160 µM (k _cat/k _uncat = 2.2 × 10⁴). Similarly, antibody Ab21 can catalyze the hydrolysis of galactoside 31 with a k _cat of 0.035 h⁻¹ and K _m of 310 µM (k _cat/k _uncat = 2.5 × 10⁴) (Fig. 5) [26].

Figure 5

Hapten and substrate for catalytic antibody Ab24

At the same time, with the progress in development of new separation techniques and biotechnology, more and more enzymes have been found with interesting properties. For instance, the α‑1,4 glucan lyase (EC 4.2.2.-) from Gracilariopsis lemeneiformis is a new class of starch/glycogen degrading enzyme that digests the substrate from the nonreducing end while releasing 1,5‑anhydro‐d‑fructose 32 successively, instead of the usual d‑glucose 33 (Fig. 6) [27,28,29].

Figure 6

1,5‑anhydro‐d‑fructose and d‑glucose

Several recent books review the enzymes used in the conversion of renewable feedstocks such as starch and cellulose [30,31,32]. They provide many examples of the use of enzymes in the resource sector, specifically addressing their use in agriculture, forest products, and pulp and paper; they also address the greater use of agriculture and forestry residues and possible enzymatic modification. One recent example is the use of crude α‑galactosidase from Gibberella fujikuroi to reduce the flatulence‐inducing raffinose family sugars in chickpea flour. Crude enzyme treatment of chickpea flour resulted in complete hydrolysis of sugars of the raffinose family [33,34].

Degradation of Free Sugars

Although the free sugars are important industrial starting materials, they have not been focused upon until the recent findings of their degradation into useful organic resources [35,36].

Thermal Degradations

Thermal degradations in aqueous carbohydrate solutions are well documented [37,38,39]. Innovation of technology for the degradation of phytomass has focused upon the production of pyrolysis oil with high H/C and C/O ratios. Hydrothermal degradation appears to be attractive from this point of view [36,40,41,42]. Early in 1964, Qua and Fagerson tentatively identified furfural 34, dihydroxyacetone 35, glycolic acid 36, glycolaldehyde 37, and 5‑(hydroxymethyl)‐2‑furaldehyde (HMF) 38, and noted the presence of six additional volatile products from glucose 33 heated at 250 ℃ for 1 min in air. Recently, the scientists found that HMF 38 can be utilized as a very important intermediate for the petroleum industry [43,44,45].

Figure 7

Main thermal degradation products from d‑glucose

For example, a problem is the formation of 35 during autoclave sterilization of various solutions for parenteral injection containing 33 as an excipient or a nutritional carbohydrate [46]. Similar degradations occur during food processing, especially in soft‐drink production, with compound l‑ascorbic acid 39 degrading into 34 and 35 [47,48]. Another example includes the roasting of coffee, during which there are many aphilic acids formed by carbohydrate degradation, which contribute to the smell and taste impact for coffee beans [49,50,51].

Scheme2

-

Ab initio molecular dynamics (MD) simulations were also applied in elucidation of xylose and glucose degradation pathways (Scheme 2). In the case of d‑xylose 39, a 2,5‑anhydride intermediate was observed leading to the formation of furfural 34 through elimination of water. This pathway agrees with one of the mechanisms proposed in the literature in that no open chain intermediates were found. In the case of d‑glucose 33, a series of intermediates were observed before forming the 2,5‑anhydride intermediate that eventually leads to HMF 38 (Fig. 7). One of these intermediates was a very short‐lived open‐chain form. Furthermore, two novel side‐reaction pathways were identified, which lead to degradation products other than 38 [52].

Acidic Degradations

Alkyl glycosides are environmentally benign biosurfactants due to their biodegradability and low toxicity [53]. Usually they are produced through Fisher glycosylation using hydrophobic alcohols in acidic media. A practical problem is the control of the degradation reactions of starting free sugars in the acidic Fischer reaction. The situation is more serious in the case of d‑Fructose 40, which degrades into 38 [54,55,56] (Scheme 3). In Fischer reactions of this type, silica‐alumina cracking catalysts effectively catalyze reactions to give the glycosides 41, 42, and 43, without formation of 38 [57]. These results convincingly indicate that both the glycosylation giving the furanosides 41 and 42 and the degradation to 38 proceed via the common cyclic intermediates 13 [54].

Scheme3

-

Alkaline Degradations

Scheme4

-

The alkaline degradation of reducing monosaccharides involves a series of consecutive reactions and gives many kinds of products [58]. For example, the alkaline degradation of 33 in aqueous calcium hydroxide at 100 ℃ results in a complex mixture of more than 50 compounds (Scheme 4). Products obtained by the same degradation of 40 are similar to those from the reaction of 33. Among the degradation products, lactic acid 44 is almost the sole major product in each case [59].

High‐temperature alkaline degradation of 33 forms furaneol (52), an aroma compound, probably because of fragmentation of 49 into the C₃‑fragments 35 and 50 (Scheme 5). Fragment 50 dimerizes into the diketone 51, the precursor of 52 [60].

Scheme5

-

Oxidative Degradations

Oxidative degradation reactions involving the anomeric center are classic processes and are well documented [61,62]. For example, lactose, maltose, cellobiose, and galactose can be degraded selectively in one step and in high yield into the corresponding next lower aldose and formic acid by H₂O₂ in the presence of borate. The selectivity further improves when a small amount of EDTA is added, in order to suppress the influence of transition metal ions, which catalyze the decomposition of H₂O₂ via radical pathways, leading to nonselective oxidative degradation of aldoses. The function of borate in the selective oxidative degradation of aldoses is two‐fold: catalysis of the degradation of the starting aldose and protection of the next lower aldose against oxidation [63].

Scheme6

-

On alkaline oxidation of aldoses with (N‑chloro‐p‑toluenesulfonamido) sodium (CAT), the monosaccharides 33, 40, d‑mannose 54, d‑arabinose 55, and d‑ribose 56, belonging to the 4,5‑ or 3,4‑ethythro‐series, afford the C₄‑acids 59 and 60 in 35 to 49% yields while the yields of glyceric acid are low [64]. Thus, as illustrated in Scheme 6, hexoses are cleaved at the C1/C2 (a) and C2/C3 (b) bonds, whereas pentoses break at the C1/H1 (a) and C1/C2 (b) bonds.

These reactions are governed by the alkaline‐induced slow equilibrium between hexoses and enediol anions and the irreversible, rate‐determining formation of the intermediate 63 (Scheme 7). The latter is transformed into 57 and 58 or 64. In the case of pentose 55, the intermediate 67 gives out 59 and 60 from the intermediate 64.

Scheme7

-

(S)‑ and (R)‑3‑hydroxy‐γ‑butyrolactone (68 and 69, respectively) are two extremely flexible chiral synthons. They can be converted to an extremely large number of useful and important intermediates with a wide range of applications. Earlier synthetic routes to these compounds all relied on structural transformations or selective reductions of malic acid. They can now be obtained in high yield from several carbohydrate raw materials. For example, the (S)‑lactone 68 can readily be prepared by the oxidation of 4‑linked d‑hexose sources such as cellobiose, lactose, maltose, maltodextrins, starch, etc., with hydrogen peroxide and an alkaline or alkaline‐earth hydroxide. Treatment of a 4‑linked hexose 70 with base leads to an isomerization to the 4‑linked ketose, which readily undergoes β‑elimination to form enone, which then tautomerizes to the diketone. The diketone is readily cleaved with hydrogen peroxide to give the salt of (S)‑3,4‑dihydroxybutyric acid and glycolic acid. Acidification and concentration yields the lactone 68 [65]. Similarly, the (R)‑lactone 69 can be synthesized using a 4‑linked l‑hexose source since the chiral center in the product is derived from the 5‑carbon of the hexose. The (R)‑lactone was obtained in high yield from l‑arabinose 71 by the simple strategy of functionalizing the 3‑position by forming a 3,4‑acetal and oxidizing it under similar conditions as those used for the preparation of the other isomer. This oxidation yields the dihydroxy acid and formic acid via the unsaturated aldehyde which tautomerizes to the R‑dicarbonyl compound. The dihydroxy acid is then converted to the lactone 69 by acidification and concentration (Scheme 8) [66].

Scheme8

-

Titanium‐containing zeolites, such as Ti‑BEA, Ti‑FAU, and TS‑1 have been tested as catalysts for the Ruff oxidative degradation of calcium d‑gluconate 72 to d‑arabinose 55 using diluted hydrogen peroxide as the oxidant. Only large‐pore zeolites Ti‑BEA and Ti‑FAU were found to be active. It was shown, in particular, that a very rapid leaching of titanium occurred and that the titanium species present in the solution were responsible for the catalytic activity observed [67,68].

Applying H₂O₂/CuO in alkaline solution, degradation of the carbohydrate‐rich biomass residues results with formic, acetic and threonic acids as the main products. Gluconic acid was formed instead of glucaric acid throughout. Reaction of a 10% H₂O₂ solution with sugar beet molasses generated mainly formic and lactic acids. Important advantages of the microwave application were lower reaction times and reduced reagent demands [69].

Enzymatic Degradations

1,2,4‑Butanetriol is an important intermediate in organic synthesis, for instance in the production of d,l‑1,2,4‑butanetriol trinitrate. Commercial synthesis of d,l‑1,2,4‑butanetriol employs NaBH₄ reduction of esterified d,l‑malic acid. For every ton of 1,2,4‑butanetriol synthesized, multiple tons of byproduct borates are generated. d,l‑malic acid can also be hydrogenated over various catalysts (Cu–Cr, Cu–Al, Ru–Re) at 2900–5000 psi of H₂ and 60–160 ℃ reaction temperatures. Yields of 1,2,4‑butanetriol range from 60 to 80%. A variety of byproducts are also formed during high‐pressure hydrogenation. These byproducts are not generated when esterified malic acid is reduced using NaBH₄. d,l‑malic acid is synthesized from the n‑butane component of liquefiable petroleum gas via the intermediacy of maleic anhydride. The new synthesis of 1,2,4‑butanetriol has been established with microbes. Enzymes from three different microbes are recruited to create biosynthetic pathways by which d‑1,2,4‑butanetriol 73 and l‑1,2,4‑butanetriol 74 are derived from d‑xylose 39 and l‑arabinose 55, respectively [70] (Scheme 9).

Scheme9

-

The use of ethanol as an alternative automobile fuel has been steadily increasing around the world for a number of reasons [71]. Domestic production and use of ethanol for fuel can decrease dependence on foreign oil, reduce trade deficits, create jobs in rural areas, reduce air pollution, and reduce global climate change carbon dioxide buildup. Ethanol, unlike gasoline, is an oxygenated fuel that contains 35% oxygen, which reduces particulate and NOx emissions from combustion. Ethanol can be made synthetically from petroleum or by microbial conversion of biomass materials through fermentation. In 1995, about 93% of the ethanol in the world was produced by the fermentation method and about 7% by the synthetic method. The fermentation method generally uses three steps: (1) the formation of a solution of fermentable sugars, (2) the fermentation of these sugars to ethanol, and (3) the separation and purification of the ethanol, usually by distillation. Ethanol‐from‐cellulose (EFC) holds great potential due to the widespread availability, abundance, and relatively low cost of cellulosic materials. However, although several EFC processes are technically feasible, only recently have cost‐effective EFC technologies begun to emerge, which are quite important for rapidly developing countries such as China and Canada [72].

Rearrangement with Double Bond Shifts

[2,3]-Sigmatropic Rearrangements

Double bond rearrangements in carbohydrate systems lead to various kinds of sugar transformations. The [2,3]‑Wittig rearrangements [73] initiated by deprotonation and followed by migration of an anionic substituent are illustrated in Scheme 10. The stereochemistry at C1 is well transformed to C3 and/or C4 [74,75]. The [1,2]‑Wittig rearrangement without a double bond shift occurs in dependence on the conditions.

Scheme10

-

The [2,3]‑Witting rearrangement has been employed in synthetic work on the tetrahydrofuran acetogenins from Annonaceous species starting from furanoid glycals [76]. The rearrangement of 75 is induced by a base to generate an anionic species, which rearranges into 76 and its epimer. In this case, erythro-2 predominates. Under the same conditions, 77 with a silyl‐protecting group mainly gives the [1,2]‑Witting rearrangement product 78 (Scheme 11).

Scheme11

-

A [2,3]‑sigmatropic rearrangement of a sulfoxide has been employed in the total synthesis of calicheamicin g [77]. The thioglycoside 79 is oxidized to give the sulfoxide intermediate, which spontaneously undergoes a suprafacial sigmatropic shift to the β‑position to move the double bond towards the anomeric center. The resulting sulfinate is treated with a secondary amine to afford the desired rearranged glycal derivative 80 (Scheme 12).

Scheme12

-

Recently, the C‑analogue of sulfatide  83 was synthesized through a [2,3]‑Wittig sigmatropic rearrangement (Scheme 13) [78].

Scheme13

-

[3,3]-Sigmatropic Rearrangements

Overman Rearrangement and Related Reactions

An allylic system that is easy to rearrange is a useful tool in a variety of synthetic methods. Allylic alcohol is readily converted into the corresponding trichloroacetimidate by brief treatment with trichloroacetonitrile in the presence of an appropriate base and usually results in high yields. Simple heating of the imidate of the allylic alcohol system induces the rearrangement reaction [79,80] (Scheme 14).

Scheme14

-

For example, on heating at 160 ℃ in 1,2‑dichlorobenzene, the allylic trichloroacetimidate  84 smoothly rearranges into the corresponding 2‑amino‐2‑deoxy sugar 85 [81]. The suprafacial rearrangement from C2 to C4 is similarly performed to obtain the 4‑amino‐4‑deoxy sugar derivative 87 [82] (Scheme 15).

Scheme15

-

Under dehydrating conditions, the allylic carbamate 88 generates the allyl cyanate which, in turn, rearranges into the reactive allyl isocyanate and then reacts with nucleophiles [83] (Scheme 16). The allylic carbamate is prepared by treatment of the allylic alcohol with trichloroacetyl isocyanate in dichloromethane at 0 ℃ and chemoselective removal of the alkali‐labile trichloroacetyl group by mild reaction with cold methanolic potassium carbonate without affecting the carbamate linkage at all. The obtained carbamate 88 is dehydrated by the triphenyl phosphine/tetrabromomethane system under very mild conditions. This leads to the reactive isocyanate via spontaneous rearrangement. The isocyanate thus generated is trapped with a nucleophile such as pyrrolidine to furnish the aminosugar derivative 89.

Scheme16

-

In the recent total synthesis of sphingofungin E (90), Overman rearrangement of an allylic trichloroacetimidate derived from diacetone‐d‑glucose 91 generated tetra‐substituted carbon with nitrogen (94), and subsequent Wittig olefination afforded the highly functionalized part in sphingofungin E stereoselectively [84] (Scheme 17).

Scheme17

-

Modified Claisen Rearrangements

Modifications of the Claisen rearrangement have been widely used in a variety of synthetic chemistry reactions [85] (Scheme 18).

Scheme18

-

The simple Claisen rearrangement itself has been employed in the transformation of the vinylglycal 95 into carbocyclic compounds [86] (Scheme 19). On heating at 240 ℃ in o‑dichlorobenzene in a sealed tube for 1 h, the desired rearrangement of 95 proceeds in the expected direction to give the unsaturated carbocyclic system bearing an aldehyde function in 84% yield. This is a useful synthetic intermediate for a variety of pseudosugars.

Scheme19

-

Aromatic Claisen rearrangements in 2,3‑unsaturated sugar systems are useful for the stereocontrolled synthesis of aryl‐branched sugars [87] (Scheme 20). The α‑anomer 97 is much less reactive in comparison to the β‑anomer 99. This thermal rearrangement is carried out by refluxing in N,N‑diethylaniline. The efficiency of the reaction is almost independent of the nature of the p‑substituent in the phenyl group.

Scheme20

-

Hetero-Cope Rearrangements

Cationic aza‑Cope/Mannich tandem reactions  [88,89,90,91] have been applied to the asymmetric synthesis of homochiral proline derivatives (azafuranosides) [92]. The β‑amino alcohol 101 reacts with glyoxal at room temperature to generate a cyclic aminoacetal, which undergoes spontaneous dehydration to give rise to the ene‑iminium intermediate (Scheme 21). Through an aza‑Cope reaction, this cationic species transforms into the bond‐rearranged exo‐methylene intermediate. Then a Mannich-type cyclization takes place to give the homochiral proline derivative 102 quantitatively.

Scheme21

-

This protocol was later employed for the synthesis of (−)‑α‑allokainic acid [93]. Tandem aza‑Cope/Mannich reactions of this type have also been employed to construct the framework of (−)‑preussin [90]. On refluxing in trifluoroacetic acid, the protonated and functionalized oxazolidine 103 changes into the ene‑iminium intermediate, which equilibrates with the bond‐rearranged enol compound through an aza‑Cope process (Scheme 22). This is followed by cyclization through the Mannich reaction to give the functionalized pyrrole 104 in 78% yield with 86% ee. To proceed to (−)‑preussin, a retro‐Mannich fragmentation‐Mannich cyclization of 104 is needed to establish the desired configuration of the pendants on the pyrrolidine ring.

Scheme22

-

A neutral, metal‐free rearrangement, formally a suprafacial [1,3]‑sigmatropic migration, of the hydroxy group has been reported [94] (Scheme 23). The direct migration of the hydroxy group is thermally forbidden. This rearrangement reaction probably proceeds by way of an intermediate formate, which undergoes an oxy‑Cope rearrangement. Diethylaminosulfur trifluoride (DAST) is considered to react with the solvent DMF to generate the reactive quaternary amine salt, which rapidly converts 105 into the corresponding formate. The hypothetical 4‑O‑formate would then undergo acyloxy group migration accompanied by a double bond shift through an oxy‑Cope rearrangement to give the 2‑O‑formate. Thus, the net results are suprafacial 1,3‑shifts of the hydroxy group from the C4 to the C2 position. No substitution reaction of the hydroxy group with the fluoride ion seems to occur during this reaction.

Scheme23

-

As an artificial enzyme, AbZyme was applied in a similar [3,3]‑sigmatropic rearrangement [95,96]. The substrate 107 is prepared from a diacetone‐d‑mannitol through conventional synthetic transformations. On exposure to the artificial polychronal antibody in the presence of 2‑(N‑morpholino)ethanesulfonic acid and sodium chloride at 37 ℃, with a molar ratio of 100:1 of the hexadiene 107 to the antibody, 107 is completely converted into the product 108 in 20 h (Scheme 24).

Scheme24

-

Double Bond Inducing Ring-Closing Rearrangements

There are a variety of examples of ring‐closing rearrangements with exhausting double and/or triple bonds and some recent examples are shown here. Pd(0)‑complexes catalyze reactions of the unsaturated amine 109 to give the azasugar 110, an intermediate in the synthesis of SS20846A 111 [97,98,99,100] (Scheme 25).

Scheme25

-

Besides the conventional methods, the metallo‐carbene route to access cyclic compounds has become a versatile tool in sugar chemistry. Synthesis of stavudine 112, an antiviral nucleoside, from an allyl alcohol [101] is realized by a Mo(CO)₅‑mediated cyclization reaction (Scheme 26). Molybdenum hexacarbonyl smoothly reacts with the triple bond of 113 to generate the intermediate Mo‑carbene, which undergoes a clean cyclorearrangement to yield the furanoid glycal 114. Alkynol isomerization is effected by group‑6 transition metal carbonyl complexes [102].

Scheme26

-

Ring Isomerizations

Ring transformations are useful reactions in synthetic carbohydrate chemistry [103].

Ring Contractions

Nucleophilic displacement reactions of the sulfonyloxy group or its equivalents in the sugar ring are known to induce unexpected ring‐contraction reactions [104]. However, the first target‐oriented ring‐contraction reaction of the sulfonate 115 (Scheme 27) in the stereoselective total synthesis of (−)‑rosmarinecine from d‑glucosamine impressively demonstrated the novel utility of this kind of reaction [105]. Ring‐contraction reactions of carbohydrates have now become a useful tool for syntheses of various types of compounds [103].

Scheme27

-

Epoxy sugars are good starting materials for the preparation of ring‐contracted products. Various 2,3‑epoxypyranosides such as 117 can be converted into furanosides directly by simple heating under reflux in toluene containing lithium bromide and N,N‑tetramethylurea (TMU) [106] (Scheme 28). Usually, the more stable 3‑C‑formyl derivatives are formed. In the case of the C‑glycoside 119, however, the mode of reaction changes to yield mainly the 2‑C‑formyl compound 120.

Scheme28

-

Zr‑mediated ring‐contraction reactions using vinyl sugars are useful to synthesize carbocycles [107,108]. This method was later employed successfully for aza‑sugar synthesis. The functionalized morpholine 121 is transformed into the pyrrolidine 122 with excellent stereoselectivity. The stereochemistry at the junction of the main product is cis. This protocol has been applied to the synthesis of inositol phosphate analogs using the 5‑C‑vinyl glycoside derivative 123 [109] (Scheme 29).

Scheme29

-

The O‑benzyl derivative of the glycal 126 undergoes stereoselective ring contractions on treatment with thallium(III) nitrate [110] (Scheme 30).

Scheme30

-

Triflates of aldonolactones are a productive source of ring‐contraction reactions. Compound 128 contracts its ring under acidic and basic conditions to give C‑furanosides [111,112] (Scheme 31). Triflates of glycosides occasionally yield ring‐contracted products [113]. Another paper has provided an additional example of a ring‐contraction reaction of a sugar triflate on reaction with tetrabutylammonium nitrite in moist toluene; the triflate yields a ring‐contracted byproduct [114]. It has been found that the ring‐contraction reactions of the triflate in the presence of pyridine depend on the acidity of the solvent; in the acidic solvent 1,1,1,3,3,3‑hexafluoro‐2‑propanol (HFIP), ring‐contraction of 130 proceeds smoothly. Oxygenophilic silyl protection of the 2‑O‑triflate of aldonolactone 131 prohibits ring contraction so that the reaction results in the formation of the silyl‐migrated epoxide 132 [115].

Scheme31

-

Mitsunobu conditions smoothly effect clean ring‐contraction reactions of thiosugars [116] (Scheme 32). From the thioheptanoid 134, the thiopyranoid 135 is obtained. Mild sulfonation induces a spontaneous ring‐contraction of the azaheptanoid 136 to afford the azapyranoside 137 [117].

Scheme32

-

Some rare, four‐membered sugar rings have been synthesized by ring‐contraction reactions [103]. Similar to 2‑O‑triflates, which easily undergo ring‐contraction reactions [118]. DAST‐treatment of the thiopentofuranose derivative 138 affords the ring‐contracted product 139 having a thietane framework (Scheme 33). DAST‑assisted ring‐contraction has been found in the fluorination reaction of the thiosugar furanose 138 [119]. It is known that the sulfur(IV) fluoride/hydrogen fluoride system also promotes such ring‐contraction reactions [120]. On Friedel–Craft reaction of the thiopentosyl bromide 140, a ring‐contraction process occurs [121]. The per‑O‑alkylated glycoside 142 is converted into the δ‑lactone 143 with concomitant ring‐contraction to furnish product 144 [122].

Scheme33

-

The Chan rearrangement was effectively used to build up the furanoid structure on the way to taxol [123,124] (Scheme 34).

Scheme34

-

Scheme35

-

In the syntheses of staurosporin congeners, ring‐contraction reactions have been used effectively [125,126]. Novel stereoselective Beckmann‐type rearrangement of TAN‑1030A 147 produces the K‑252 analog 148 via a hypothetical hemiacetal intermediate [127]. Oxidation of the model compound 149, the staurosporin analog, results in ring contractive benzilic acid rearrangement to give a furanoid 150 possessing the framework of K252a [128] (Scheme 35).

The protected oxyaminoglucoside 151 rearranges to the azafuranose form under deprotecting conditions [77] (Scheme 36).

Scheme36

-

The mild reaction of the thioureido derivative 153 with methanol produces the compound 154 with migration of the acetyl group. On heating, this compound isomerizes into the cis‑fused cyclic 155 [129] (Scheme 37).

Scheme37

-

Epimerization at C2 of l‑gulose 156 on reaction with KCN in buffered aqueous solution is thought to proceed by way of the open‐chain intermediate. Free sugars produce cyclic products directly on reaction with the Wittig reagent. Thus, 159 is converted into 160 on prolonged heating with the reagent (Scheme 38).

Scheme38

-

Ring Expansions

The cyclopropane system is a tool for inserting a methylene unit into a ring system to form a larger ring structure. Even densely functionalized pyranoids such as 161 [130,131] and cyclohexanes [132] expand into heptanoids and cycloheptanes, respectively. 1,2‑C‑dibromomethylene sugar 163 expands its pyranose ring to give oxepine 164 [133] (Scheme 39).

Scheme39

-

α‑Hydroxyfurans expand to pyranoids via sequential epoxyalcohol rearrangements. Epoxidation of the α‑hydroxyfuran 165 with meta‐chloroperoxybenzoic acid (m‑CPBA) induces a cationic rearrangement, followed by dehydration, to form a pyranoid on the way to (+)‑resineferatonin [134] (Scheme 40). Dimethyldioxirane (DMDO), apparently more sensitive to the steric circumstances than m‑CPBA, has been used for the selective epoxidation of the furan 167 [135]. The monoepoxide rearranges followed by hemiacetalization to afford the pyranoid intermediate 165 of the total synthesis of the eleuthesides. α‑Aminofurans similarly expand into azapyranoids [136]. Racemic 169 is kinetically resolved to give (S)‑169 and the rearranged (2R, 6R)‑170 with modified Sharpless epoxidation . Compound (S)‑169 is transformed into (2S, 6S)‑170 on treatment with m‑CPBA.

Scheme40

-

The reaction of the bicyclic thiosugar 171 with N6‑benzoyladenine in the presence of moist tin(IV) chloride furnishes the ring‐rearranged nucleoside product 172 instead of the normal glycosylation product [137]. On heating mesylate 173 under reflux in the presence of a nucleophile, the thermal ring‐expanding reaction occurs [138] (Scheme 41).

Scheme41

-

Scheme42

-

Scheme43

-

The key compound on the way to the debranched nagstatin 175 has been synthesized from the l‑ribose derivative 176 by employing ring‐chain interconversion involving addition of trityl imidazole, selective sulfonylation, and warm acetylation which causes detritylation with cyclization [139] (Scheme 42).

Scheme44

-

The glycosylamine 179 transforms to the piperidinone 180 on reductive amination [140]. Sequential deprotection to regenerate hemiacetal OH and amino groups from 181 induces ring interconversion and reduction to give the azasugar  182 [141]. Similarly, the azidodeoxyketose derivative 183 can be converted to the piperidine derivative 184 by reductive aminocyclization [142]. Reduction of 185 affords the bicyclic azasugar 186 on intramolecular reductive cyclization , which is not a stable system and forms an equilibrium mixture with the monocyclic imine 187 [143]. Reactions of this type are also of use for the synthesis of the branched‐chain 1‑N‑iminosugars such as 189, which have been the subject of continuous attention as glycosidase inhibitors [144,145,146,147,148,149,150,151,152] (Scheme 43).

On deprotection, followed by neutralization, the acetal 190 rearranges spontaneously to the azasugar 191 [153], an analog of the indolizine alkaloids for which synthetic approaches starting from carbohydrates [154] have recently been described [155] employing the olefin metathesis protocol [156,157,158,159]. Under basic conditions, silyl‐group shifts occur in a 6‑deoxy‑6,6,6‑trifluorosugar 192 and form a pyranoside derivative [160]. Acetolysis of the methyl glycoside 194 mainly affords the piperidine 195 [161]. Azasugar ethyl thioglycoside 197, a new type of azasugar derivative, can be stereoselectively prepared from suitable glycosylenamine 196, through anhydroazasugar derivatives. The thioethoxy group is introduced through a highly stereoselective substitution. The attack of EtSH was 100% stereoselective [162,163] (Scheme 44).

Scheme45

-

Scheme46

-

Scheme47

-

The protected 5‑ulose derivative 198 can be converted into the piperidine 199 by reductive amination [164]. The 5‑O‑sulfonyllactol 200 is reductively transformed into the azasugar 201 by way of oxime formation [165]. Reductive deprotection of the aminodeoxylactol derivative 202 affords the N‑substituted piperidine 203 [166]. The unsaturated alcohol, readily obtained from the lactol 204 and Grignard reagent, cyclizes into the C‑glycoside 206 [167]. The lactol 207 is converted into the unsaturated dithioacetal, which cyclizes slowly to give 208 on storage [168] (Scheme 45).

Ring Transformation

Additive ring‐opening of 209, followed by Swern oxidation and aminocyclization, affords the aza‑C‑nucleoside 210 [169], belonging to an attractive class of C‑glycosides [170,171,172,173,174,175]. The glycosylamine 211 is converted to the azasugar 212 via an alkylative ring‐opening reaction [176,177]. The aminoaldehyde derivative generated from the unsaturated aminocyclitol 213 cyclizes to give 214 [178] (Scheme 46). Descending oxidative aminocyclization of 215 affords the lactam 216 [179].

Ring-Opening Rearrangements

A fragmentation ring‐opening rearrangement reaction of 217 using a Grignard reagent has been reported [180]. The combined reagent acetyl chloride/sodium iodide induces a ring‐opening rearrangement of the bicyclic ketal 219 [181]. The iodide ion serves to promote the reaction [182] (Scheme 47).

Scheme48

-

Scheme49

-

Scheme50

-

Miscellaneous Reactions

Ferrier Carbocyclization and Related Reactions

The Ferrier II reaction, a carbocyclization reaction, is of widespread use as a tool for the conversion of glycosides into cyclitols [183,184,185]. Newer examples for the utilization of the reaction conducted under catalytic conditions [186,187] have appeared in the recent literature. Compound 221 is converted into cyclohexanone  222 on the way to (−)‑mesembranol [188] (Scheme 48). Compound 223 is transformed to the enone 224, the precursor of several new cyclitol derivatives [189,190,191].

The Pd‐catalyzed carbocyclization affects good control on the orientation of the newly formed OH group [192] (Scheme 49). Thus, 225 and 227 afford the corresponding cyclitols with almost complete selectivity. In the rearrangement of 227, the stereoselectivity is controlled by the bulky silyl ether‐protecting group, which effects the conformational change. This protocol can be applied to the 6‑O‑acetyl‐5‑enopyranoside 229 with good efficiency and the utility is well demonstrated by the synthesis of the d‑myo‑inositol phosphate, IP3 [193,194].

Scheme51

-

Scheme52

-

Compound 231 is converted to the Ferrier product 232, the precursor of novel aminoglucosides [183] (Scheme 50). Carbocyclization of the glycoside 233 gives the cyclohexane 234, from which tetrazoline analogs can be synthesized [195]. The Ferrier cyclization found new utility in the synthetic chemistry of Amaryllidaceae alkaloids [196]. Thus, the glycoside 235 is transformed to the Ferrier‑II product 236, the logical intermediate to 7‑deoxypancratistatin.

A novel reductive carbocyclization of hex‑5‑enopyranosides retains the substituent at the anomeric center and the ring oxygen remains as the new hydroxy group [197]. The stereochemistry at the anomeric centers is retained as exemplified by the conversion of 237 to 238 (Scheme 51). A more efficient cyclization also retains the aglycone; the glycoside 239 affords the cyclohexanone 240. The cyclic acetal 241 is converted to the pyran 242 reductively [198,199,200].

Scheme53

-

The enol acetate 243 affords the Ferrier product 244, a key compound to l‑chiro‐inositol polyphophates [201]. The Ferrier cyclization of 245 is useful for the preparation of the key intermediate to glycosylphophetidylinositols [202] (Scheme 52).

Combination of the Ferrier‑II and the Baeyer–Villiger reactions leads to the stereoselective synthesis of rare 5‑deoxyfuranosiduronic acids [203]. As exemplified, the oxidation of the Ferrier II product 246, followed by hydrolysis, gives the acid 248 [204] (Scheme 53).

The evolution of SmI₂ as a reagent in synthesis has been one of the exciting recent developments in organic chemistry. The construction of highly functionalized carbocycles from carbohydrates promoted by SmI₂ is currently receiving significant interest and a series of carbocyclization strategies have been described in the literature. Treatment of the lactol 249 with the Wittig reagent readily gives the olefins, which undergo radical‐induced cyclization [205]. Cyclization of the (Z)‑isomer 250 under the action of SmI₂ is more stereoselective than that of the (E)‑isomer 251 [206]. In the case of 252, the diastereomeric excess of the products significantly depends on the choice of the reducing agents (Scheme 54).

Scheme54

-

Scheme55

-

Stepwise conversion of the iodoglycoside 253 via Grob–Vasella fragmentation and cyclorearrangement induced by SmI₂ furnishes the carbocycles 255 and 256 with a trans‐junction [207,208]. This reaction can be carried out in a one‑pot manner whereby SmI₂ induces the fragmentation of the iodoglycoside [209]. While the iodoglycoside 258 mainly affords the carbocycle 259 with a cis‑junction, the reaction of 253 only gives the quinovoside 257 (Scheme 55).

The glycoside 260 is converted into the cyclopentenone 261 on reaction with dimethyl methanephosphonate and base [210] (Scheme 56). The tandem β‑fragmentation‐cycloisomerization of the unsaturated lactol 262 gives the carbocycle 263 [211].

Scheme56

-

Scheme57

-

Anomerization and Related Rearrangements

Anomerization is a characteristic reaction of sugar [212,213]. The well‐known reagent, Pascu's TiCl₄ for the anomerization of acetylated glycoside, rapidly anomerizes the benzyl‐protected glucoside 264 [214,215] (Scheme 57). The results from inhibition experiments indicate that TiCl₄ might coordinate with O5 and O6 to form a ring‐opened intermediate. The use of catalytic amounts of TiBr₄ combined with MgBr₂·OEt₂ allows us to carry out longer reactions: the disaccharide 266 anomerizes to 267 completely. It has been reported that β‑glycosides such as 268 anomerizes quantitatively [216]. Although the acetylated glycoside 270 is anomerized in polar nitromethane containing BF₃·OEt₂, the bromide 272 is practically inert [217] (Scheme 57).

The silylated ketose 274 slowly anomerizes in the presence of TASF by way of the keto‑form [218]. The thioglycoside 276 anomerizes in the presence of a catalytic amount of IDCP [219]. Under PTC conditions, the β‑chloride 278 also anomerizes [220]. Anomerization of 280 to the α‑form 281 via an open‐chain zwitterionic intermediate has been suggested [221] (Scheme 58).

Scheme58

-

Figure 8

Anomeric equilibrium of glycosides and reverse anomeric effect

Scheme59

-

Scheme60

-

An investigation of the time course of the anomerization of β‑iodide 282 has been carried out using ¹H‑NMR spectroscopy [222]. The NMR titration method to measure the shift of the anomeric equilibrium on protonation of 283 and 284 reveals that the protonated imidazoyl group has a small but distinct preference for the axial disposition than does the unprotonated group; which is the opposite of what the reverse anomeric effect predicts [223,224,225]. Compounds 285 and 286 increase the proportion of their ¹C₄ conformers on N‑protonation but not when the polarity of the solvent is increased as predicted by the reverse anomeric effect [226]. In solution, the α‑glycosylpyridinium salt 287 adopts the ¹C₄ conformation and the β‑mannosyl compound 288 has the ⁴C₁ form; both of them have positively charged groups in an equatorial position at the anomeric center, indicating the manifestation of the reverse anomeric effect [227] (Fig. 8).

Aryl C‑glycosides such as 289 and 291 undergo α‑ to β‑anomerization in the presence of an acid by way of open‐chain intermediates [228,229]. Under basic conditions, 293 isomerizes into 295 through 294 [230] (Scheme 59).

The glycosylamine 296 anomerizes in methanolic solution. The spirohydantoins 298 and 299 form an equilibrium mixture under basic conditions [231] (Scheme 60.

A possibility for the α‑ to β‑anomerization of C‑glycosides 300 and 302 by way of open‐chain intermediates generated under basic conditions has been discussed [232,233]. Isomerization of pure 303 to 304 and vice versa probably occurs by way of open‐chain isomerization through the linear intermediate [234] (Scheme 61).

Aromatization of Sugars

Sequential elimination reactions, most of them being dehydration, involving the reaction at the anomeric center often produce various aromatic compounds [235] especially furans which have diverse use [236,237]. Explorations have been continued to open a new route to aromatics based on renewable biomass in place of fossilized material.

Scheme61

-

Oxidation of 5‑hydroxymethylfuraldehyde  38 with hydrogen peroxide catalyzed by chloroperoxidase, a hemeperoxidase from Caldariomyces fumago, proceeds with good selectivity to furnish 306 [238] (Scheme 62). The 6‑aminodeoxyglycal derivative 307 is similarly converted into the furan 308 [239]. The dithiane 309 gives the oxacyclohexadiene 310, on acid treatment [240]. Treatment of 311 with TMSOTf produces the pyrylium salt 312 [241].

The phenylosazone from d‑xylose 39 can be converted into the pyrazoles 313 [242] . Isomaltulose 314 affords the glycosylated aromatic compound 315 [243]. On acidic acetylation the ulosonic acid ester 316 forms concomitantly the glycal derivative 317 and the furanoic acid derivative 318 [244] (Scheme 63).

Scheme62

-

Scheme63

-

Even on mild C‑glycosylation using the TMSCN/TMSOTf system, a notable amount of the d‑psicofuranose derivative 319 degrades to the furan 321 [245]. On reaction with Ph₂Hg, the chloride 322 gives the furan 323 exclusively [246]. The bromohydrin 324 degrades into furan 325 on heating with a base [247] (Scheme 64).

Scheme64

-

The Maillard Reaction

The Maillard reaction is a complex group of degradation/rearrangement reactions initiated by reactions of free sugars and amines [248,249,250,251]. The reaction is of major interest for food processing [252,253,254,255,256,257] and life sciences [258,259,260,261,262,263,264,265]. Degeneration of amine drugs in the presence of reducing sugars as excipients and deterioration of sugar artifacts are also related to the reaction [266,267].

The nonenzymatic reaction between reducing sugars and long-lived proteins in vivo results in the formation of glycation and advanced glycation end products, which alter the properties of proteins including charge, helicity, and their tendency to aggregate. Such protein modifications are linked with various pathologies associated with the general aging process such as Alzheimer disease and the long‐term complications of diabetes . Although it has been suggested that glycation and advanced glycation end products altered protein structure and conformation, little structural data and information currently exist on whether or not glycation does indeed influence or change local protein secondary structure [268]. For example, in the blood, d‑glucose can react with an NH₂ group of hemoglobin to form an imine that subsequently undergoes an irreversible rearrangement to a more stable a‑aminoketone known as hemoglobin‐AIc \index{hemoglobin‐AIc}%  [269].

Diabetes results when the body does not produce sufficient insulin or when the insulin it produces does not properly stimulate its target cells. Because insulin is the hormone that maintains the proper level of glucose in the blood, diabetics have increased blood glucose levels. The amount of hemoglobin‐AIc formed is proportional to the concentration of glucose in the blood, so diabetics have a higher concentration of hemoglobin‐AIc than nondiabetics. Thus, measuring the hemoglobin‐AIc level is a way to determine whether the blood glucose level of a diabetic is being controlled [270,271].

Cataracts, a common complication in diabetics, are caused by the reaction of glucose with the group of proteins in the lens of the eye. It is thought that the arterial rigidity common in old age may be attributable to a similar reaction of glucose with the NH₂ group of proteins [250,272].

Mechanism of the Maillard Reaction

As illustrated in Scheme 65, 33 reacts with an amine to give an imine 326 that isomerizes into an aminoketose 327 (Amadori product), existing as an equilibrium mixture of cyclic hemiacetals, whereas 40 affords, by way of 328, the hexosamine derivatives 329 and 330 (Heyns products), also in cyclic form. The Amadori–Heyns compounds \index{Amadori–Heyns compounds}% are at the head of the complex sequences of the Maillard reaction. The crystal structure of the Amadori product 331 between 33 and glycine has been determined more than three decades after the first proposal of its structure. Alternative preparations and X‑ray analyses of Heyns products 332 and 333 have been reported [273,274].

The Amadori product from d‑glucose 33 and l‑proline decomposes at 130 ℃ in DMF to afford 33 and d‑Mannose 54, indicating the reversibility of the Amadori reaction. A kinetic study using 33 and phenylalanine indicates that the Schiff's base formation is the rate‐determining step of the Maillard reaction [275,276].

Maltol 337 is one of the degradation products in monosaccharide solutions with amino acids forming Amadori compounds but not in the solution of monosaccharides alone. Heated solutions of monosaccharides yield 335, the logical precursor of 337, but not 337 itself. On the basis of the molecular mechanics calculation indicating that 335 adopts the conformation unfavorable for dehydration into 337, a possible route via the dehydrated product 336, an ortho‐elimination product, has been postulated as a more favorable alternate reaction pathway [277].

Scheme65

-

Scheme66

-

Chemistry of Biologically Significant Maillard Products

In biological systems, Amadori products formed from aldoses and the amino group in peptides, decompose to release reactive sugar derivatives that are irreversibly consumed in the production of the advanced glycation end products (AGEs). In this sense, 338 is one of the key substances in the Maillard reaction [278]. A new specific assay of 338 has been developed using diaminonaphelene [279]. The dicarbonyl compounds 338 and 339, the suggested intermediates in the degradation of the Amadori compound 331, had been trapped with aminoguanidine [280,281]. The role of 338 generated in the Maillard cascade as a cross‐linker of proteins has been emphasized [282]. Oxygen and metal cations accelerate the degradation of Amadori products to d‑glucosone (340), a precursor of glyoxal 341 [283,284] (Scheme 66).

Figure 9

Maillard products having strand‐breaking activities to DNA

It is known that some Maillard products have strand‐breaking activities to DNA . Many compounds found in foodstuffs are α,β‑unsaturated ketones [285,286]. Compounds 53, 342, 343, and 335 (Fig. 9) cleave DNA single strands by generating hydroxyl radicals and other active oxygen radicals in the presence of Fe³⁺ and oxygen [287,288,289,290,291,292]. For example, the key hydrolyzate 344 generates hydroxyl radicals and the oxidation products 345 and 346. An organic hydroperoxide 347, presumably formed via direct oxidation of 339 or stepwise from 348, the precursor of 335, has been isolated [293,294,295,296,297] (Scheme 67).

Scheme67

-

Scheme68

-

The major intermediate of the Maillard reaction 38, having an allylic system, seems to furnish a cytotoxic ester on metabolic sulfonation [298]. In contrast to the above findings, some Amadori products, such as pyrazines have antimutagenicity [299,300,301]. Enkastines , the Amadori products of 33 and dipeptides, beneficially prolong the action of enkephaline by inhibiting enkephalinase [302].

Reactive small sugars and related acids appear to play a role in forming AGEs including cross‐linked proteins in the aged body as well as inactivation of human Cu,Zn‐superoxide dismutase [282,303,304]. Reaction of 33 with n‑propylamine in phosphate‐buffered, neutral solution generates several derivatives of small sugars [305,306], namely, C₂ and C₃ sugar derivatives. The 3‑deoxyulose 349, a hemiacetal form of 338, yields 351, the hydrate of methylglyoxal (352), as well as the Schiff's base 350 which is thought to be the precursor of the C₃‑products [307,308,309] (Scheme 68).

N ^ε‑(carboxymethyl)lysine (357), is a main AGE product found in vivo [310,311]. About 50% of 357 seems to be formed via oxidative degradation of the Amadori product 356. The reduced compounds 358 and 359 also form 356 under aerobic physiological conditions [282]. Reactive 352 combines reversibly with lysine and cysteine residues and irreversibly with arginine residue [312] (Scheme 69).

Scheme69

-

Scheme70

-

l‑threose (362), the degradation product of 360 degrades in the presence of N ^α‑acetyl‐l‑lysine (369) at pH 7 into 3‑deoxy‐tetros‐2‑ulose (365) [313,314]. Only at pH 7 does retro‐aldolization of 362 occur to give glyceraldehyde (363). Under physiological conditions, the AGE product 364 is formed from 362 and 369, apparently via condensation of the Amadori compounds 365 and 366 [315,316,317]. On heating at 100 ℃, a hood‐processing temperature, in methanol in a sealed vessel, 39 and 369 form an amine 368 [318] (Scheme 70).

Some of the heterocyclic compounds among the Maillard products, for example, pentosidine 370 and pyrraline 371, are AGEs in the skin of diabetic patients as well as in the brain of Alzheimer patients [319,320,321,322,323,324,325,326,327,328,329]. The observation that the aldehyde 372, the Maillard product of 33 and n‑propylamine, reacts with the amine and 369 to give 373 and 374, respectively, led to the assumption that pyrrole aldehydes might also be precursors of the lysine side chain of proteins [320,330,331,332] (Scheme 71).

Scheme71

-