Anhydrides of aldoses

The chemistry of the 2,5-anhydrides of aldoses subsequently entered a prolonged lull, and Peat s review21 of 1946 in this Series does not report on any work later than 1925. The experimental basis of the deamination of amino sugars with nitrous acid was, nevertheless, established. The progress afterwards made in the conformational analysis of sugars made it possible for Shafizadeh22 to draw a parallel with the nitrous acid deamination of the aminocyclohexanols, and to rationalize the whole of these results. 

During the same period of time, the use of chromatography, together with developments in physical methods for the determination of structure, permitted reaction mixtures to be studied more thoroughly. Many investigations revealed the formation of 2,5-anhydrides of aldoses during reactions where such anhydrides were not anticipated. 

The purpose of this article is to attempt a rationalization among the numerous methods for access to 2,5-anhydrides of aldoses and, from the mass of scattered, and frequently fragmentary, information in the literature, to single out sugar derivatives in this class from the viewpoint of their properties and their utilization. 

The reactivity of the 2,5-anhydrides of aldoses is determined by two essential structural features that do not exist in the sugars, namely, the presence of an oxolane ring and of a carbonyl group (most frequently, free) a to the ring-oxygen atom. These two characteristics make the 2,5-anhydroaldoses closer to tetrahydro-2-furaldehyde than to the aldoses, where only in exceptional cases is the carbonyl group not masked by the formation of an intramolecular, five- or six-membered, hemiacetal ring. 

An article on the anhydrides of polyhydric alcohols appeared in Volume 5 of this Series,1 and it is the purpose of the present article to bring the subject up to date. Wiggins article1 was limited to the anhydrides of the pentitols and hexitols the present article will include the anhydrides of tetritols and of alditols higher than the hexitols. However, anhydrides having the three-membered (oxirane) ring will not be considered, as they are discussed elsewhere in this Volume.13 2,5-Anhydrides of aldoses are also treated in this Volume.lb... 

In this Chapter, only anhydrides of aldoses and ketoses are included. Anhydrides of acyclic carbohydrates, for example, alditols, aldonic acids, and intermolecular anhydrides are not discussed. 

Trifluoroacetates have been applied to the analysis of sugars in the same way as acetates. Imanari et al. [445] analysed aldoses after a prior reduction, as follows. A 0.5-ml volume of 1% NaBH4 in water was added to 0.5 ml of an aqueous solution containing 100-500 pg of a mixture of aldoses. The solution was allowed to stand at room temperature for 30 min and the excess of borohydride was decomposed by adding 0.5 ml of Amberlite CG-120 (H+). The resin was removed by filtration and the filtrate was evaporated to dryness. Borate was removed by the three-fold addition of 1 ml of methanol and subsequent evaporation. The residue was vacuum dried and dissolved in 0.1 ml of ethyl acetate and 0.1 ml of TFA anhydride. After 30 min at room temperature, 1—2 pi were taken for analysis. The resulting derivatives were more volatile than acetates and provided symmetric peaks on a column packed with 2% of XE-1105 (see Fig. 5.30). 

Protection of aldoses at the non-anomeric positions makes it possible to use many of the common procedures in organic chemistry for oxidizing lactols as shown with mannofura-nose 1 and glucopyranose 3 (O Table 1). The reactions can be divided into three main categories oxidations mediated by activated dimethyl sulfoxide (DMSO), oxidations with chromi-um(VI) oxides, and oxidations catalyzed by ruthenium oxides. The DMSO-mediated oxidations of alcohols can be promoted by several activators [27]. With the partially protected aldoses the activation has mainly been achieved with acetic anhydride and oxalyl chloride. Competing /3-elimination does usually not occur unless the eliminating group is an ester, e. g., an acetate or a benzoate [27]. 

No acetolyses appear to have been performed on methylene acetals of aldoses or aldosides. The use of the trifluoroacetic anhydride-acetic acid sequence would be one way of protecting a primary hydroxyl group and freeing a particular secondary one. 

Anomerization of aldose peracetates in acetic anhydride and acetic acid in the presence of an acid catalyst such as zinc chloride or sulfuric acid has long been known, and is of synthetic value. The preponderant product is normally the (more stable) -(d or l) anomer. For example, with sulfuric... 

Peracetates of aldoses, disaccharides, and methyl glycosides have been obtained in good yields by reaction of the trimethylsilylated sugars with iron(III) chloride-acetic anhydride without change in their stereochemistry. The same reaction on ketoses produced dehydration products only. 

Reductive amination of aldoses with chiral l-(—)-a-methylbenzylamine in the presence of sodium cyanoborohydride, carried out overnight at room temperature, followed by acetylation with acetic anhydride in pyridine (100°C, Ih) gives diastereoiso-meric l-(N-acetyl-a-methylbenzylamino)-l-deoxyalditol acetates. LC of these derivatives on silica gel permits resolution of enantiomeric pairs, which are detected by UV photometry at 230 nm. 

In a study of the deacetylation of acetylated sugar osazones it has been shown that under alkaline conditions and depending upon the substrate, either an external nucleophile fe.a.. Na, MeO , NH3) can be incorporated at C-3 or a 3,6-anhydride can be formed. The 3-methoxy-epimers (49) were thus formed from the L-ervthro-pentose osazone triacetate presumably by formation and 1,4-addition to a phenylazo-ene intermediate." The 2-acetoxy group of aldose diphenylformazan peracetates is also readily displaced. 2-Deoxy-D-arabino-hexose diphenylformazan (50) was thus formed when penta-Q-acetyl-D-glucose or -D-mannose H H diphenylformazan was treated with sodium borohydride." ... 

Conversion of the aldehyde into a nitrile is accomplished by treatment of an aldose with hydroxvlamine to give an oxime (Section 19.8), followed by dehydration of the oxJme with acetic anhydride. The Wohl degradation does not give particularly high yields of chain-shortened aldoses, but the reaction is general for all aldopentoses and aldohexoses. For example, D-galactose is converted by Wohl degradation into n-lyxose. 

An intramolecular ether (commonly called an intramolecular anhydride), formally arising by elimination of water from two hydroxy groups of a single molecule of a monosaccharide (aldose or ketose) or monosaccharide derivative, is named by attaching the (detachable) prefix anhydro- preceded by a pair of locants identifying the two hydroxy groups involved. 

Excessive activity of the enzyme aldose reductase sometimes accompanies diabetes. The net result is often accumulation of reduced sugars such as galactose in the lens of the eye and ensuing cataract formation. A1 restatin (43), an aldose reductase inhibitor, is one of the first agents found that holds promise of preventing diabetes-induced cataracts. The compound, actually used as its sodium salt, is prepared in straightforward manner by imide formation between 1,8-naphthalic anhydride (41) and glycine. ... 

Wohl prepared the acylated nitriles of the aldonic acids by heating the aldose oximes with a mixture of sodium acetate and acetic anhydride. With careful control of the reaction, this method may be used for preparative work with fairly good results. 

In the case of the oximes of the aldose sugars, the situation is more complicated because of the possibility of both open-chain and cyclic structures. That aldose oximes can react in the open-chain form follows from the formation of the nitriles and from the isolation of acylated open-chain aldose oximes as secondary products in preparation of nitriles. For example, Wolfrom and Thompson, by the action of sodium acetate-acetic anhydride on n-glucose oxime, not only obtained pentaacetyl-D-glucononitrile, in 40% yield, but also isolated a small amount of hexaacetyl-oWeAydo-D-glucose oxime (V) identical with that prepared by mild acetylation of pentaacetyl-aWe%do-D-glucose oxime (IV) whose structure was assured by its formation from pentaacetyl-aldehydo-D-glucoae (III). 

Acetylated aldose oximes with a ring structure have also been obtained during the preparation of the nitriles, both with sodium acetate-acetic anhydride and with pyridine-acetic anhydride. Thus it appears that under these conditions at least a certain amount of the oxime is present in the ring form. 

Reaction of phthalic anhydride (70-1) with the ylide from ethyl triphenylphos-phoniumacetate leads to the condensation product (70-2), which in effect consists of a cyclic enol anhydride. Treatment of this product with hydrazine leads to the hydrazone-hydrazide (70-3). Alkylation of the anion from removal of the hydrazide proton with the substituted benzyl bromide (70-4) affords the alkylation product (70-5). Saponification then leads to the aldose reductase inhibitor ponalrestat (70-6) [79]. 

Attempts to use a Lewis acid to anomerize the ester linkage at C-l from /3 to a have thus far been mostly unsuccessful however, application of Bonner s249 procedure, involving anomerization of acetylated aldoses in an acid anhydride containing an acid catalyst, was found246 to be applicable to the acetylated D-glucopyranuronate series also. Thus, /3 —> a anomerization of methyl tri-0-acetyl-l-0-propanoyl-/3-D-glucopyranuronate (prepared by the silver salt method) was achieved... 

If steric strain due to repulsions between substituents in the chair ring is the chief factor deciding the stability of 1,6-anhydroaldopyranoses, it is possible to calculate that, as the configuration of the aldose is varied, the amount of anhydride present at equilibrium in dilute acidic solutions should decrease in the following orcjpr of configurations,... 

---