Aldose shift

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

D-xylose was converted into 2-furaldehyde in acidified, tritiated water, no carbon-bound isotope was detected. This suggested that the 1,2-enediol (2) reacted immediately, as otherwise, tritium would have been detected at the aldehydic carbon atom of 2-furaldehyde, as a result of aldose-ketose interconversion.An acidic dehydration performed with d-[2- H]xylose showed that an intramolecular C-2-C-1 hydrogen transfer had actually occurred. Thus, these data indicated that an intramolecular hydride shift is more probable than the previously accepted step involving a 1,2-enediol intermediate. 

Scheme 9.—Isomerization of Aldose to Ketose with a Hydride Shift.

These reactions are typical of the —CHO group. The Schiff and bisulfite reactions are reversible, and the equilibrium favors unreacted hemiacetal. Since osazone and Fehling reactions are irreversible, equilibrium is shifted to restore the low concentration (0.02%) of open-chain aldehyde as soon as some reaction occurs, and eventually all the aldose reacts. 

C. A. Collyer, K. Henrick, and D. M. Blow, Mechanism for aldose-ketose interconversion by D-xylose isomerase involving ring opening followed by a 1,2-hydride shift, J.Mol.Bid. 1990, 212, 211-235. 

The H and NMR chemical shifts of the aldose reductase inhibitor 4(A)-2,3-dihydro-6-fluoro-2(R)-methylspiro-[chroman-4,4 -imidazoline]-2, 5 -dione (methylsorbinil, 66, Figure 17) and its seven synthetic intermediates have been completely assigned on the basis of DEPT, COSY, g-HSQC and g-HMBC. All the/-values for C-F (1 bonds), H-F (1 bonds), and H-H (3 bonds) have been determined <2005MRC1008>. 

Most imidazoline, imidazolone, and imidazole derivatives are stable ring structures and usually exist only in the cyclic forms. For example, in the reaction of methyl 2-deoxy-2-isothiocyanato-a-D-glucopyranoside 149 with D-glucosamine 148, a-deoxy-2-(3-substituted thioureido)-D-aldose, 150, is presumably the reaction intermediate. However, the ring-chain tautomeric equilibrium of 150 shifts towards the cyclic form to yield 151 which is the only detectable form by NMR analysis (Scheme 41) <1999TA3011>. 

M. J. King-Morris and A. S. Serianni, 13C NMR studies of [l-13C]aldoses Empirical rules correlating pyranose ring configuration and conformation with 13C chemical shifts and 13C-13C spin couplings, J. Am. Chem. Soc., 109 (1987) 3501-3508. 

Non-enzymic aldose-ketose isomerisations that are acid catalysed appear to involve a 1,2-hydride shift. During acid-catalysed rearrangement of glucose to fructose, the label of [2- H]glucose substrate is retained in the [l- H]fructose product, distributed equally between the proR and proS positions." In the reverse sense retention of the label of tritiated fructose in the glucose and mannose products was not complete. Similar observations were made for the xylose-xylulose interconversion." With an appropriate sugar configuration (ribose), even the base-catalysed reaction proceeds partly with retention of label, presumably by the same mechanism as with trioses. 

The Bilik reaction applied to 2-ketoses yield 2-hydroxymethyl aldoses in which the tertiary carbon originates from C2 of the ketose and the C2 hydroxyl is on the opposite side to the C3 hydroxyl of the ketose (in the Fischer projection). Thus, o-fructose yield o-hamamelose. The position of equilibrium, however, lies towards the straight-chain sugar, although it can be pulled over somewhat towards the branched-chain aldose by the addition of borate. The mechanism in Figure 6.9 again explains the main reaction, but not the formation of sorbose as a by-product, which probably arises from a metal ion-promoted hydride shift, as there is no isotope exchange with solvent. The Bilik reaction can be applied to the production of l-deoxy-o-xylulose from 2-C-methyl-D-erythrose the reaction is particularly clean and only the two... 

An enzymic counterpart of these complex base-catalysed rearrangements of sugars may be the reaction catalysed by 4-phospho-3,4-dihydroxy-2-butanone synthetase. The enzyme catalyses the formation of the eponymous intermediate in secondary metabolism from ribulose 5-phosphate. Labelling studies indicated that C1-C3 of the substrate became C1-C3 of the product, that H3 of the substrate derived from solvent and that C4 was lost as formate. X-ray crystal structures of the native enzyme and a partly active mutant in complex with the substrate are available. The active site of the enzyme from Met ha-nococcus jannaschii contains two metals, which can be any divalent cations of the approximate radius of Mg " or Mn ", the two usually observed. Their disposition is very reminiscent of those in the hydride transfer aldose-ketose isomerases, but also to ribulose-5-phosphate carboxylase, which works by an enolisation mechanism, so the enolisation route suggested by Steinbacher et al. is repeated in Figure 6.14, as is the Bilik-type alkyl group shift, for which an equivalent reverse aldol-aldol mechanism cannot be written. 

ISOMERIZATION REACTIONS Isomerization reactions involve the intramolecular shift of atoms or groups. One of the most common biochemical isomerizations is the interconversion between aldose and ketose sugars (Figure 1.19). 

Another mechanism of formation starts from the bisamino derivative (q) to the tautomeric aldoses (k) and (m) by way of (p) and carbonium ion (o). The diamino compound may be formed from the D-fructosylamine by opening of the ring and addition of a second amine molecule. Compound (s), a possible Erickson product, may be formed by this same route. Whether the factor responsible is a proton shift or a proton exchange is still unknown, so that differentiation between sequence (f-e-e -k and m) or (q-p-o-m-e ) has not yet been made. 

Sugar isomerases catalyze the interconversion between aldose and ketose. Tautomerases catalyze a keto-enol tautomerization. A-Isomerases catalyze the shift of a double bond. The reactions catalyzed by these enzymes proceed through intramolecular oxidation and reduction. 

In addition to its acceptance of unnatural substrates, several other characteristics make NeuAc aldolase a useful synthesis catalyst. The cloning of the enzyme has reduced its cost and offers the potential to produce large quantities of new proteins with improved stability or with altered stereoselectivity. This approach could be used to extend the chain of a variety of aldoses by two carbon units. Although the optimal pH for activity of NeuAc aldolase is near pH 7.5 at 37 °C, the enzyme is active at pH 7-9.82.83 TTie protein is stable in the presence of oxygen and does not require added cofactors. - One drawback is that an excess of pyruvate (the less expensive reagent) must be used in synthetic reactions to shift the equilibrium towards the formation of product approximately 7 equiv. of pyruvate are needed to attain 90% conversion of ManNAc to NeuAc at equilibrium. It may be possible to avoid the need for an excess of pyruvate by coupling the synthesis of NeuAc to a more thermodynamically favored process. 

Mechanism of Sugar-Borate Complexation It has been suggested that borate leads to a shift in the equilibrium isomerization because of the binding of tetrahydroxyborate ions to aldose and ketose sugars. At near neutral pH, tetrahydroxyborate ions can be formed by hydrolysis of borax (Na2B4O5(OH)4-8H20) [44] ... 

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