Monosaccharides

It is generally accepted that monosaccharides, or simple sugars, may have three to nine carbon atoms in a linear chain. Thus the nomenclature aldotriose, aldotetrose, aldopentose, etc., or ketotetrose, ketopentose, etc. The vast majority of naturally occurring sugars contain five or six carbon atoms. These saccharides are classified as D- or L- if they can be derived from D- or L- glyceraldehyde, respectively, or the four carbon ketoses (Fig. 2). The determining asymmetric center is that farthest from the carbonyl group—projection of the hydroxyl group to the right is D. As the chain length increases, new asymmetric centers are introduced. Accordingly, there are four aldotetroses, eight aldopentoses, four ketopentoses, eight ketohexoses, etc. (Fig. 3).

Figure 3 Structures of aldoses and ketoses up to six carbons in length. Monosaccharides with up to nine carbons are present in nature.

Fischer recognized that sugars such as glucose existed in a ring form (i.e., a hemiacetal or hemiketal formed by addition of a hydroxyl group to the carbonyl carbon). Based on his knowledge of lactones, he assigned the participating hydroxyl to C-4 in the case of glucose, thus forming a five-membered (furanose) ring. The thermodynamics, however, show that the six-membered (pyranose) ring is the more stable form and that is the one predominating in solution. Note that the internal addition reaction at C-1 causes that carbon to become asymmetric and, therefore, two new isomeric structures are formed. To distinguish this asymmetry from that present at the other asymmetric centers, the term anomer is employed with the designation α or β reflecting projection of the newly formed hydroxyl group on the same or opposite side of the ring, respectively (Fig. 4).

Figure 4 Alpha- and beta-forms of D-glucose.

The ring structures (aldopyranose for the six-membered rings and aldofuranose for the five-membered rings) are, in aqueous solution, in ready equilibrium with the openchain, free aldehyde form. Thus, a solution of glucose in water contains five species: free aldehyde, two furanoses, and two pyranoses (Fig. 5). The aldehyde form represents about 0.025% of the total, with the bulk made up of the two pyranoses (the beta form predominates; see below). Although the six-membered ring is the energetically preferred form, the predominant ketohexose, D-fructose, is found in the furanose form in combined structures (sucrose, for example) although it too prefers the six-membered ring when free in aqueous solution. Other commonly occurring furanosides include ribose and deoxyribose as components of RNA and DNA (Fig. 6); galactose is also found as a furanoside in several plant and microbial polysaccharides.

Figure 5 Equilibrium mixture of D-glucose in aqueous solution.

Figure 6 Structures of D-ribose (left) and 2-deoxy-D-ribose (right).

A key property of the free monosaccharides is their ability to be readily oxidized (initially via the available aldehydo function), especially in alkaline solution. This characteristic was used as an analytical tool for many years, and the term reducing sugar was employed to designate saccharides with a free (or potentially free, in aqueous solution) carbonyl function. Prior to the advent of specific enzymatic methods, this was the standard procedure for measurement of blood glucose levels (i.e., reducing sugar).

Monosaccharides that differ fromoneanother at a single asymmetric center other than the one derived from the carbonyl carbon are termed epimers (D-galactose is the 4-epimer of D-glucose, and D-mannose is the 2-epimer,

Figure 8 Interconversion of glucose forms in aqueous solution. The optical rotation is initially reflective of the starting material (alpha or beta) and changes (mutarotates) until equlibrium is achieved.

for example; Fig. 7). Mirror-image structures are termed enantiomers.

Figure 7 Relationship between D-glucose and D-galactose (4-epimer), and D-mannose (2-epimer).

An important and characteristic feature of saccharides is their ability to interact with plane-polarized light. Thus, each sugar has a characteristic optical rotation that is a complex function of the asymmetric centers, their polarizability, solvent interactions, etc. The sign (+ or dextrorotatory, − or levorotatory) and magnitude cannot be determined a priori. Nor is it true that all sugars of the same configuration (D- or L-) will have the same sign of optical rotation. Thus, D-glucose is dextrorotatory, whereas D-fructose is levorotatory. Since monosaccharides tend to crystallize in a single anomeric form rather than as mixtures, dissolving them in water results in a change in the optical rotation from that of the pure anomer (either alpha or beta) to that of the thermodynamically defined equilibrium mixture. This phenomenon is termed mutarotation (Fig. 8).

As the principles of conformational analysis became known, it was rapidly realized that the pyranose form of sugars adopted a chair structure analogous to that of cyclohexane (Fig. 9). In this spatial arrangement, equatorial hydroxyl groups are thermodynamically more stable (energy differences of about 1.5 kcal) than axial ones with the exocyclic hydroxymethyl group having a much larger effect. It is not surprising, therefore, that β-D-glucose, the allequatorial structure, is themost prevalent natural sugar and the most prevalent organic compound on earth (Fig. 10). As a philosophical aside, it may be inferred that the choice between D- and L-glucosewas made very early and on a basis we do not understand since they are conformationally equivalent. It is also expected that other naturally occurring sugars such as D-mannose or D-galactose would have only a single axial hydroxyl. Of the 16 possible aldohexoses, D-glucose, D-mannose, and D-galactose are widely distributed in nature while the remainder are of laboratory interest only. Parenthetically, idose (three axial hydroxyls in the classic conformer) has never been obtained in crystalline form. Additional widely distributed sugars include D-xylose (alL-equatorial aldopentose), D-ribose, and 2- deoxy-D-ribose (backbone components of RNA and DNA, respectively). A large number of other sugars are present in nature. The vast majority of naturally occurring saccharides exist other than as free monosaccharides (only D-glucose and D-fructose are widely found free) and are present in disaccharides and complex oligomeric and polymeric structures in both plants and animals. About a dozen different sugars are present in mammals, all but glucose in combined form. Plants and microorganisms have very diverse saccharides, again all in combined forms.

Figure 9 Conformational structure of pyranose rings.

Figure 10 AlL-equatorial structure of β-D-glucose.