Cyclic Forms

Toward the end of the nineteenth century, it was realized that the free sugars exist as cyclic hemiacetals or hemiketals. Individual sugars react with methanol under acid catalysis to give stable products termed methyl glycosides, which are mixed full acetals. These have a new asymmetric center at the original carbonyl atom and were thus isolated as pairs of isomers that were designated as the a and p forms, later termed anomers. In the d series, the a anomer was defined as the one having the more-positive specific rotation, and in the l series, the a anomer has the more-negative specific rotation. The phenomenon of mutarotation, discovered in 1846 by Dubrunfaut, wherein the specific rotation of a free sugar in water solution changes with time, was now interpreted as being due to equilibration of the anomeric hemiacetals formed through reaction of one of the chain hydroxyl groups with the carbonyl group. Emil Fischer assumed the cyclic form to be a five-membered ring, which Tollens designated by the symbol <1,4>, while the six-membered ring received the symbol <1,5>. The a anomers of D-glucose in these two ring forms are here depicted in the Fischer projection (Scheme 6).

HCOH HCOH

HCOH

ch2oh a-d-Glucofuranose

HCOH HCOH

HOCH HCOH

HCO-"

CH2OH a-d-Glucopyranose

Scheme 6 Fischer projection of a-d-glucofuranose and a-d-glucopyranose.

In the 1920s, Haworth and his school (14) proposed the terms "furanose" and "pyranose" for the two forms, and introduced what became known as the "Haworth depiction" for writing structural formulas, a convention that was soon widely followed (Scheme 7).

HCOH 1

HCOH

HOCH

CH2OH

HCOH 1

HCOH

HOCH HC-CH2OH

HOCH

HOCH

H OH

H OH

Fischer projection

Haworth projection

Scheme 7 Relationship of the Fischer and Haworth projection formulas illustrated for P-l-arabinofuranose.

The Haworth projection formula presents a nominally planar ring with planes of substituents above and below the ring, whereas the Haworth conformational formula depicts the actual shape of the molecule with tetrahedral bond angles (Scheme 8). The Mills formula also depicts the ring arbitrarily as a plane, with substituents respectively above and below the plane. All three types of representation remain widely in use.

CHnOH

ho\oh yOH H OH

Haworth projection formula

H OH

H OH

Haworth conformational formula a-D-Glucopyranose Scheme 8 Cyclic representations of a-d-glucopyranose.

hoch2

OH Mills formula

OH Mills formula

The question of ring size in the common glycosides and the free sugars remained controversial in the early part of the twentieth century, with polarimetric studies leading Hudson (15) to support Fischer's suggestion of a five-membered ring, but Haworth provided decisive evidence based on methylation studies (16) that Fischer's "a-methylglucosid" has a six-membered ring, and today it would be named methyl a-D-glucopyranoside. Strong evidence for the six-membered ring form in the free aldoses was also provided by Isbell (17) from studies on their oxidation to 1,5-lactones by bromine water. Subsequently, Jackson and Hudson applied Malaprade's glycol-cleavage reaction by periodate (18) to several related glycosides, and Hudson accepted (19) that Haworth's pyranoside formulation had been correct. In extending the periodate method, Jackson and Hudson (20) also were able to show that the glucose monomeric units in starch and cellulose likewise had the pyranose ring structure.

These two classic methods for structure determination in the carbohydrate field, methylation linkage-analysis and periodate oxidation, have remained key tools up to the present day in applications with numerous polysaccharides and gly-coconjugates. The methylation reaction to introduce acid-stable methyl ether groups, originally performed with methyl iodide-silver oxide (21) or dimethyl sulfate-sodium hydroxide (22), is now more effectively conducted on a microscale by use of powerful deprotonating agents and dipolar aprotic solvents prior to acid hydrolysis of the permethylated carbohydrate (23,24). Analysis of the partially methylated products as their alditol acetates by gas-liquid chromatography-mass spectrometry is a rapid and routine technique (25). Likewise, the fragmentation of complex carbohydrates by periodate glycol cleavage (26) is a standard tool for structural analysis, especially when combined with reduction of the "dialdehydes"

initially produced to the alditols followed by mild acid hydrolysis to cleave open-chain acetal groups [Smith degradation (27)].

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