Carbohydrates

The name Carbohydrate comes from early studies that gave an empherical formula Cx(H₂O)_y for the monomer units obtained from the polymeric carbohydrate molecules. They appeared to be hydrates of carbon. They are also called Saccharides (from the Greek word sakcharon for sugar). The common usage is the word Sugars, coming from the most popular member Sucrose, which was called sugar from the early days of civilization. Its glorious past could be traced to the shores of Bengal. The high commercial demand for this class of compounds is mainly for natural sweeteners such as sucrose, glucose and different forms of fructose preparations from sugar cane and beet. In addition, natural and modified fibres from cotton and other natural fibres constitute a very large market.

In biology, carbohydrates have several functions. Carbohydrates have derived notoriety due to their association with a disease called diabetics. A diabetic is a condition when the blood sugar level is not maintained between 70 & 115-mg/100 ml of blood. When food is digested, glucose from the digested food is passed on into the blood stream. This triggers signals for the release of insulin (a peptide hormone) from the pancreas beta cells. Insulin hormone promotes the storage of excess glucose in the liver as glycogens, a polymer of glucose. It also binds to many cells and promotes the uptake of glucose. Thus, the level of excess glucose in the blood is controlled. During fasting, the pancreatic alpha cells secrete a hormone glycogon, which inhibits the uptake of glucose by various cells and promotes release of glucose from glycogen in the liver. This hormone also promotes the biosynthesis of glucose from amino acids.

Note

That is why parents advise you not to 'fast" for long periods of time. Starving depletes the level of glucose that is essential for functioning of brain and also removes the amino acids away from the more important purpose of building enzymes and proteins need for the function of brain and all other cells. The healthy level of “carbs” (a commercial acronym for carbohydrates) is also needed for the smooth function of other cells in organs like kidney, liver and heart. That is why you are told to eat ‘healthy’ food at frequent intervals.

Thus, the level of glucose in the blood is maintained. In diabetics, the production / release of insulin are affected, necessitating the need of drug intervention.

Carbohydrates also play a key role in cell recognition processes, which is an important initial step in recognition of guest / host binding. Dietary fibres (that are polysaccharides from plant sources) play active as well as passive rolls in the large intestine. These fibres come in soluble and insoluble varieties, playing different rolls in digestion. Such biological importance has naturally attracted research in this area. New carbohydrate based diabetic drugs, antiviral drugs, antibiotics and hormone modulators for several diseases such as Alzheimer's disease and HIV are in various stages of development.

Carbohydrate molecules are interesting starting materials for synthetic chemists as well. In these polyhydroxy sugars, we find economical chiral pools that lead to the synthesis of chiral synthons (intermediates) for the synthesis of chiral drugs. We would learn this aspect of synthesis at the end of this chapter.

Carbohydrates are classified as Mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, oligo- and polysaccharides depending upon the number of monomer units present in the molecule. Let us look into these classes of carbohydrates in some detail.

Classification & Structure

• Monosaccharides: These are the monomeric units that combine together in different ways to give di-, tri- etc., collectively called Saccharides. In this chapter, we would learn about monosaccharide molecules - their structures and chemistry - in detail.
• Disaccharides: These are dimeric molecules made up of the same monosaccharide or of two different monosaccharide units. Study of these units introduces you to the stereochemistry at the point of joining and their reducing and nonreducing properties that are derived from their structures. These lay the foundation for proper understanding of higher saccharides.
• Larger polymers: These linear and branched polymers provide us a large variety of fibres. Modification of their surfaces provides us fibres with different physical properties that have revolutionized our dress materials as well as the fibres we use in different domestic and industrial applications.

Now let us discuss some of these molecules in details.

Monosaccharides

Classification and structural details:

These molecules have a general formula C_x(H₂0)_y. When x = 1 and y = 1, we get CH₂O, a formula corresponding to formaldehyde (HCHO). The next member C₂(H₂O)₂ would be 2-hydroxyacetaldehyde (OHC-CH₂OH). These two members are not discussed under monosaccharides. The third member C₃(H₂O)₃ would be glyceraldehydes (OHC-CHOH-CH₂OH), a trisaccharide. This has one asymmetric centre, which is of great historical importance. Glyceraldehydes are taken as the first members of the monosaccharide family. We could come back to this important molecule soon.

Tetrasaccharides (C₄(H₂O)₄ give a structural formula OHC-(CHOH)₂-CH₂OH with contiguous asymmetric carbons. As the chain lengthens, the asymmetric centers progressively increase. Note that as the asymmetric centers (R-*CH(OH)-CH₂OH) increase, the number of diastereomers (and therefore enantiomers) increase dramatically, according to the formula 2ⁿ that you are quite familiar with. The larger members of the family (C₈ and beyond) are unstable and are not of importance. Note that, for the sake of simplicity, we have indicated only the aldehydes. We can have a number of monoketones as well. Some of these are important members of the monosaccharide family (e.g., Fructose).

The nomenclature of monosaccharaides is arrived at in a very simple way. We just note the number of carbons (as in tria- for three), drop the last letter ‘a’ and add the suffix -ose. Thus, we have triose, tetrose, pentose, hexose and heptose. When the carbonyl unit is an aldehyde, we call them aldoses (as in aldohexoses). The ketone isomers are called ketoses.

We would now discuss these families in greater details.

Trioses:

The aldoses of triose have one asymmetric center, while the ketose has none. Thus, the aldotriose has (n = 1, 2¹ = 2) one pair of enantiomers.

On the other hand, the ketotriose has no asymmetric center. This molecule is called dihydroxyacetone, a compound of great industrial importance, but has no relevance as in saccharide chemistry.

Note that we are using D/L and not d/l that is normally used to denote optical rotations. This set of D/L nomenclature was specially evolved by Fischer to define carbohydrate structures. It is also used in amino acid chemistry. Fischer made another important decision. He proposed that all natural sugars had D- configuration.

  This tentative rule for D-(+)-Glyceraldehyde (and thereby to all sugars) turned out to be the correct 
  configurations for D-(+) and L-(-)- glyceraldehydes, when X-Ray structures became available several decades later.
  This happy coincidence saved science from a major revision of structures.

An important thing you have to learn in carbohydrate chemistry is the projection formula evolved by L. Fischer.

• You first write the stereo Projection Formula in such a way that the terminal atom with highest oxidation is at the top and the remaining carbons are written vertically down. Number the top carbon as ‘1’ and proceed numbering downwards. Note that in the case of ketoses, the keto- carbon C2 is placed 2nd from the top.

• The substituents to the right and left should project towards you (upwards wedge or thick lines) and the top and bottom carbons should project below the plane of the paper (downwards wedge or dotted or broken line bonds).
• Press the entire drawing flat (to appear as in line drawings).
• To get back the stereo Projection, the horizontal bonds are pulled upwards and the two terminal bonds are pushed downwards.

We would soon return to D/L-glyceraldehydes while studying the structure of glucose.

Tetroses

The aldotetroses have two contiguous asymmetric centers. Therefore they exist as (n = 2, 2² = 4) four enantiomers³. We thus have two pairs of diastereomers shown below. You have already studied this pair of diastereomers while dealing with enantiomers and diastereomers. A ketotetrose could have only one pair of enantiomers, as shown in the figure.

  Note that, unlike tartaric acid, these aldehydes cannot exhibit mirror symmetry.

Pentoses

Pentoses are important members of the monosaccharide family. Ribose is most popular because it is found in RNAs. The DNAs have 3-Deoxyribose units. The names of the members of the aldopentoses are shown below. The D-ketopentoses are also shown for comparison.

Hexoses

These hexoses are of great importance. We would deal with some members of this family in detail. All the aldohexoses are listed below. The D-ketohexoses are shown for comparison.

How could you remember these structures? Scientists have suggested a simple method, which is briefly discussed here. Remember this sentence. All Altruists Gladly Make Gum In Gallon Tanks. Recall this sentence and the corresponding names as discussed below:

  Adopted  from Wikipedia ‘Structural Biochemistry/Carbohydrates/Monosaccharides

Now you are ready to place the -OH groups on the Fischer Formula according to the following order, which is easy to remember.

1. Allose has all - OH groups on the right.
2. Remember that C5 - OH in hexoses (any sugar for that matter) would determine D / L family. In the D family, this - OH is always to the right
3. C4 - OH is to the right for first 4 members (Allose to Mannose).
4. C3 - OH marches as 2 right, 2 left, 2 right, 2 left.
5. C2 - OH marches right, left, right, left, and right, left all the way.

Structure determination of aldoses

  Partly Adopted from http://bama.ua.edu/ ~kshaughn/chem232/handouts/Fischer-proof.PDF and Slide 
 ‘Emil Fischer’s Proof of the Structure of Glucose  - 1891’ , 
  http://chemistry.csudh.edu/faculty/jim/Fisher%20Proof.ppt

Linear Structure

Two decision made by Fischer helped chemists to solve the structures of all aldoses, except the four hexoses highlighted with question marks. With only simple chemistry and an instrument to determine the sign of optical rotation, the structures were established with their stereochemistry. Let us go through Fischer’s suggestions, before we look into the remarkable feat of Fischer. To systematize the way in which sugar structures were written, he made a suggestion that the carbon skeleton be written vertically, with the terminal aldehyde carbon at the top. He also suggested the line-drawing projection formula, now known as Fischer Projection Formula.

1. Glyceraldehydes were tentatively assigned the D- and L- configurations as shown above for Trioses.
2. A very bold suggestion was that all natural sugars had D- configuration at the (n − 1)th carbon, counting aldehyde carbon as C1.

On the foundation of these two suggestions, Fisher attempted to solve the riddle. At the time Fischer took up structure elucidation of hexoses (and glucose in particular) (late 1800s) some degradation studies were already known.

1. Molecular formula determination gave a molecular formula C₆H₁2O₆ for Glucose.
2. When aldohexoses were reduced with conc. HI, 2-lodohexane and n- Hexane were obtained. This suggested a linear arrangement of carbons for hexoses.
3. Since the hexoses gave an oxime, a carbonyl group was assigned.
4. On oxidation with bromine water, a pentahydroxy acid was obtained, suggesting that the carbonyl group was an aldehyde.
5. When treated with acetic anhydride, hexoses gave pentaacetates, indicating 5 -OH groups in the molecule. Since, two -OH groups cannot be placed on one carbon, five carbons had one -OH each.

All these degradative studies suggested a gross structure as follows:

OHC-CH(OH)-CH(OH)-CH(OH)-CH(OH)-CH₂OH.

• The idea of asymmetric carbon was already known. Therefore, this structure suggested an arrangement of 4 asymmetric carbons in a row. That would make 2⁴ = 16 structures (i.e) 8 diastereomeric pairs.

Now let us go through the structure elucidation procedure of monosaccharides. Students should refer to the flow-chart given below for following these discussions. Kiliani-Fischer (KF) chain homologation sequence was extensively used to promote one sugar to its higher homologue. Thus, on chain lengthening by one carbon, D-(+)-Glyceraldehyde gave the tetroses D-(+)-Erythrose and D-(+)-Threose. Since addition of cyanide ion could be from either side of the carbonyl double bond, a mixture of diastereomers were obtained. Though such diastereomers were indeed separable, they could not say which Erythrose was and which Threose was. The sign of rotation was of no help. On nitric acid oxidation, the terminal carbons were oxidized to -COOH groups, thus giving different Tartaric Acids. Since, Threose gave optically active acid (D-(+)-Tartaric Acid), the diacid that had no mirror plane symmetry was assigned the given structure. This assignment led to the structure of D-(+)-Threose. Similar reasoning led to assignment of the structure of D-(+)-Erythrose, which gave an optically inactive diacid meso-Tartaric Acid (had mirror plane symmetry). This process (of KF followed by HNO3 oxidation) was repeated all the way through, up to hexoses, with remarkable success. The problem areas were D-(+)-Glucose / D-(+)-Mannose. and D-(-)-Gulose /D-(+)-Galactose pairs. Since the diacid pairs were all optically active, these four hexoses were problematic.

Structure of Glucose

The carbon skeleton of hexoses had been thus determined and the structural problems had been narrowed down to four hexoses by the time Fischer undertook this task. Emil Fischer determined the stereochemistry of Glucose and published this remarkable chemistry

Note

To put things in perspective, this was just a decade or so after the tetrahedral nature of carbon atom was pronounced by van’t Hoff. No spectroscopic tools were available at that time. Organic chemistry was a developing science. Mechanistic chemistry, as we now know, was about half a century away. The only tool available at that time was the crude (by our standards) polarimeter to ascertain whether the molecule was optically active. This achievement has been acclaimed as an outstanding example of ‘deductive reasoning’ in science. Sources: Modern Methods of Monosaccharide Synthesis from Non-Carbohydrate. Tomas Hudlicky, David A. Entwistle, Kevin K. Pitzer, and Andrew J. Thorpe.

in 1891. Fischer solved this riddle through a series of well-planned experiments. For the purpose of solving this problem he proposed some rules, which have already discussed. By these rules, the part structure that emerged is as shown below.

With this structural frame, he planned the following experiments.

• When (-)-Arabinose was homologated by KF reaction (details of this reaction would be discussed later), it gave a mixture of the diastereomeric hexoses D-(+)-Glucose and D-(+)-Mannose. We do not know which was which, but this tells that all three sugars had the same configuration at three asymmetric carbons. On oxidation with HNO3, both hexoses gave optically active diacids.

This established the relationship between these three sugars.

When Wohl degradation was performed on (+)-Glucose (we would discuss the reaction later), (-)-Arabinose was formed. Oxidation of this product gave a dicarboxylic acid that was optically active.

This identified the configuration at C3 of D-(+)-Glucose.

Let us look at the structure of pentoses again. On oxidation, only two pentoses gave optically active acids (see pentoses for all structures). Hence (-)-Arabinose had to be either 2 or 4 shown below. On KF homologation, (-)-Arabinose gave Glucose and Mannose. On oxidation, both – Glucose and Mannose gave optically active diacids. We could now examine structures 2 and 4 on paper, through the KF Oxidation sequence shown below.

This pencil exercise suggested that structure 2 was in agreement with the results obtained. Since (-)-Arabinose was assigned structure 2, part structure of Glucose would be as shown above. Now we are left with one center that would define the structures of Glucose and Mannose.

Fischer had earlier developed a procedure for interchanging the end groups (-CHO & - CH₂OH). Now look closely at the last assigned structure. One epimer at C2 is D-Glucose and the other is D-Mannose. When D-(+)-Glucose was carried through the end- group exchange, a new L- sugar was obtained. On the other hand, when the procedure was applied to D-(+)-Mannose, the final product was same as D-(+)-Mannose. When we do the pencil exercise of the above transformations on structures A and B and compare with the experimental results, we could assign structure A to D-(+)-Glucose and structure B to D-(+)-Mannose. The new sugar was identified as L-(+)- Glucose.

This remarkable application of deductive reasoning coupled with carefully planned experiments for verification, paved way to completion of the structural problems of hexoses. These developments were the cornerstone for further developments in the chemistry of disaccharides and polysaccharides.

Cyclic Structure for D-(+)-Glucose

This elegant elucidation of the structure of D-(+)-Glucose still left some questions unanswered, thereby leaving the structure problem incomplete.

Though an aldehyde, glucose does not answer all the tests for aldehydes. Scliiff’s Test, a mild test specific to aldehydes, is negative.

Bisulphite addition compound is not obtained.

On reaction with methanol under acidic conditions, aldehydes react with two moles of methanol to give acetals. Under the same conditions, glucose takes up only one mole of methanol to give a stable acetal (called a glycoside). This acetal exists in two isomeric forms.

All these reactions suggested that the aldehyde group was modified. On the basis of an earlier suggestion, the structure assigned by Fischer was a five- membered ring hemiacetal. This assignment was not based on any experiment, but on the basis of the known fact that five membered rings are formed more easily than six membered rings (as in lactones). This structure was later revised on the basis of some degradation studies on glycosides discussed below.

When glucose was reacted with dry HC1 in methanol, a mixture of two glycosides (α- and β-methyl glycosides) was formed. On reaction with dil HCl, one methyl group was lost to give back an aldehyde group. This reaction condition is similar to that of acetal formation reaction for aldehyde. The remaining free -OH groups of the glycosides were all converted to methyl ethers using dimethylsulphate in aq. NaOH. On mild oxidation with aqueous bromine, a pentamethoxy acid (as lactone) was formed. On oxidation with nitric acid, the molecule cleaved to a succinic acid derivative and a glutaric acid derivative. This cleavage reaction suggested that the C5 - OH was free, leading the one C4 - C5 cleavage and one C5 - C6 cleavage.

Thus, the six membered hemiacetal structure was established for glucose. The same technique was soon extended to other pentoses and hexoses to establish their cyclic structures.

     Please note that the cyclic structure is shown here as a chair form. This was indeed a later 
     development. The cyclic structure actually shown at that time was by a representation called 
     Haworth’s structure to be discussed soon. We would return to these conformational drawings soon.

Similar oxidation studies on β-glucopyronaside using HIO4 oxidation studies suggested a 6-membered pyranose ring. When β-Furanoside of glucose was studies in a similar fashion, the cleavage products were different. The fragments were in agreement with the formation of a five membered ring.

All such studies clearly establish the structures of the pyranosides and furanosides.

Given the fact that α- and β- pyranosides and furanosides could be obtained from the same compound, the degradations cannot be taken a proof for the fact that glucose itself exists as pyranose in solution. X-Ray studies have indeed indicated a pyranose structure, but this cannot be taken as proof for such a structure in solution phase. Solution phase NMR studies in D₂0 and DMSO-d₆, provided proof for the existence of α- and β- pyranose structures in solution.

  For more detailed treatment see Organic Chemistry, Vol., 2, by I. L. Finar

Haworth’s Structure:

The cyclic structures discussed above were actually depicted by Haworth as simple pentagons and hexagons. Thus the two isomeric hemiacetals were written as shown below.

The glycoside linkage was called α- when the - CH₂OH and the new -OMe groups were trans-. When these groups were cis-, they structure was called β-. Fischer isolated α- and β- forms of hemiacetals of glucose through crystallization under two different conditions. The α- form of D-glucose was prepared by crystallization from cold aqueous solutions - mp 146°C; Optical Rotation [α]D = +111°. The β- form of glucose was obtained from hot aqueous solution of glucose - mp 148-150°C; Optical Rotation [α]D = +19.2°.

How to convert Fischer Formula into Haworth Formula? There are several suggestions in the literature. The following exercise may be simple for students.

Write down the Fischer projection and number the carbons. Now, convert the vertical structure to horizontal structure (as shown), with the aldehyde to the right.

Bend the chain at C6 end clockwise such that the C5 - OH points to C1and the C6 carbon points upwards.

Now make the hemiacetal bond such that the C1 - OH is either a- or β

Replace the OH groups as in Table below.

Fischer projection	Haworth projection	Configuration	Chair conformer
Right	Down	a	Axial
Left	Up	β	Equatorial

The Haworth formula continues to be popular amongst carbohydrate chemists and other areas of applied chemistry. For trained organic chemists the chair configuration conveys more information than the Haworth formula. Note the way Haworth formula is written. The heteroatom is placed at the top-right and the hemiacetal carbon is placed at the right extreme of the ring. The C2 and C3 atoms are at the front, while the C5 and -O- link are at the rear.

In the Fischer formula, the cyclic structure and α- and β- forms of methyl glucoside are indicated as shown below.

  Do not get confused by this old representation, which is still in use. The acetal  oxygen bond connecting 
  C1and C5 through -O- could be better shown as curved lines (sec Organic Chemistry by Pine). Just be aware 
  of this fact. These 90° bends do not represent carbons as assumed in natural product chemistry.

Mutarotation

The isomeric forms a- and β were unstable in aqueous solutions. On standing in solution, the optical rotation gradually shifted to +52.5° in both cases. In the case of glucose, the equilibrium value corresponds to 38% α and 62% β. This phenomenon is called Mutarotation. The rate of mutarotation is different for different sugars and is characteristic of the sugar. Thus, the sugars could be identified by their rate of mutarotations.

The process of cyclisation introduces a new asymmetric center at Cl. This center is called Anomeric Center, the C1carbon is called anomeric carbon and the substituent, whether -OH, -OMe or any group, is called an anomeric group. This is an important center in saccharide chemistry. An O-Alkyl or O-Aryl linkage at this point is called Glycoside Linkage. Several natural products exist in nature as glycosides. Once the sugar unit is cleaved, the natural product is called an Aglycone.

Conformation and stability of the Pyranose and Furanose rings:

As discussed above, degradation studies on O-methylglycosides and mutarotation studies of D-(+)-glucose indicate that the predominant structure is the pyranose forms. All the three structures being in equilibrium, the population of the open chain structure of Fischer is in very small amount,. On the basis of the well-established stability of the chair form of cyclohexane rings, it is reasonable to expect a chair form of pyranose ring in solution. The solid state structures of several derivatives of glucose were indeed found to be the chair form. The hetero atom in ring would indeed distort the inner bond angles. In addition, the -OH substituents on the ring would also further influence the stability of the pyranose ring.

In the case of D-glucose, one would expect two chair conformations in solution. In line with the Haworth formula, the ether oxygen is placed at the rear right of the ring in both the conformations.

The C1chair, which closely relates to the Haworth Formula is widely used. In the conformational drawings, the process of mutarotation would look as shown below. Note that in these conformational drawings, it is easy to visualize an attack of the C5-OH at the carbonyl carbon. In the chain, rotation at the C1- C2 bond gives two conformations for the aldehyde unit in the open structure. Cyclisations on these conformers would give α and β- epimers.

Since the β- epimer is in larger amounts in this equilibrium, it follows that this epimer is more stable than the α- epimer. A close look at the conformations would convince you that the β epimers has all substituents equatorial, whereas α- epimer has the anomeric -OH in axial orientation, making the latter less stable. What makes the β- epimers revert to the open chain isomer? There are two factors that are typical to pyranose rings. This is generally termed as Anomeric Effect. Let us first look at the dipole- dipole interactions at the anomeric centre shown in the figure below. The epimeric -OR group and the ether oxygen have their dipoles in conflict (cumulative) in the equatorial epimer, whereas in the axial epimer, the dipoles are so oriented that the net dipole is less (compared to the equatorial epimer).

Thus, dipole-dipole repulsion in the equatorial epimers contributes to its instability. This alone would not be sufficient to explain the observed stability of the axial epimer. It has been pointed out that there is a further stabilising factor associated with the axial epimer. As shown in the diagram below, the axial lone pair on the ether oxygen could positively interact with the antibonding back lobe of the polar axial substituent. Such overlap is known as n → σ* interaction. The overall effect of this overlap would be stabilisation of the axial anomer, due to a ‘double bond – no-bond’ resonance, resulting in a shorter bond at C – X.

It should be noted that in all these discussion, we have taken only the pyranose ring isomer. This is because under normal glycoside bond formations conditions, the furanose isomer is a not available (probably due to increased eclipsing strains in this (five membered ring) isomeric form. Normally the envelope conformation of the 5 membered ring would have several eclipsing strain (compared to the chair forms of pyranose) and hence for D-Glucose molecule in solution phase this population is expected to be negligible.

Under certain reaction conditions (as in acetonide protection reactions discussed later), the furanose ring could be exclusively trapped. This is indeed a very valuable path when sugars are viewed as ‘chiral pools’ for the synthesis of enantiomerically pure molecules. We would look at some of these reactions later, under reactions of glucose.

Reactions of Glucose

Reactions at Anomeric Centre:

Since you are already familiar with acetals of monosaccharides, let us begin with reactions at this center. When the anomeric centre bears a free hydroxy group it is called an anomeric -OH. This cyclic hemiacetal is in equilibrium with the open chain tautomer (Ring Chain Tautomerism). The open chain isomer is only in a very small concentration. In the case of D-Glucose this tautomer is < 0.001%). Nonetheless, reactions on aldehyde group (such as reduction reactions, oxime formation with hydroxylamine etc.,) occur on this tautomer. This causes the equilibrium to shift to open chain until all the cyclic

tautomers are consumed. These compounds are of great value as chiral synthons for the chiral synthesis of open chain molecules. The cyclic tautomer could be locked in a furanose ring or a pyranose ring through formation of acetals with aliphatic alcohols. We have seen such reaction before with methanol. As demonstrated by Fischer, the anomeric -OR could be synthesized as a mixture of α- or β - anomers and purified by crystallization (nowadays by chromatography).

The mechanism of glycoside formation is of considerable interest and importance. An outline of the mechanism is presented here. Details in this mechanism appear to be speculative based on various studies. As indicated in this mechanism, elimination of water molecule is facilitated by participation of the lone pair on ether oxygen of C5. With weak nucleophiles such as alcohols, the reaction appears to proceed via a carbonium ion mechanism. The oxonium ion is in resonance with the carbonium ion at the anomeric carbon. The nucleophile could attack this partial double bond from either α- or β- phase. The main deciding factor is the stability of the product due to the developing anomeric effects. Note that this complex equilibrium could be influenced by several factors - solvent polarity, the Lewis acids (you could use other LAs in place of protic acids), the influence of axial substituents (found in other hexoses) and nucleophiles.

Such glycosides are important drugs and natural products. In plants, terpenes, alkaloids and steroids mostly exist as glycosides. During isolation, the glycoside link is cleaved to isolate these compounds as aglycones. Several such glycosides are of interest in industry. Some glycosides of interest are illustrated - Decyl glucoside is a surfactant, arbutins are skin whiteners, Sinigrin and related glycosides are anti-cancer agents.

In view of such diverse interests in the chemistry of the anomeric centre, the formation of glycoside linkage has been investigated in detail. Trans glycolysation has been extensively applied. Several protic acids and Lewis Acids have been used. When the C2 -OR is a nonparticipating group like an alkyl, a carbonium ion is formed. The nucleophile could then attack from either phase as discussed for anomeric -OH groups. When the C2 -OH is protected as an acyl derivative, the acyl carbonyl could ‘participate’ and form a cyclic acyloxonium ion, thus blocking the α- phase. The nucleophile would then exclusively attach from the β- phase to give the β-anomer as the main product. Why is this product not exclusive? This has been attributed to the fact that the acyloxonium ion is in equilibrium with the open carbonium ion, which would then prefer the α- product due to anomeric effects that are operative. This acyl participation is particularly favoured in the furanose ring as seen in the synthesis of DNA nucleosides.

Halide catalysed glycosylation has been extensively investigated. Quaternary ammonium bromides have been used as halide donors. In these reactions, shielding of the bromide ion from the β- phase promotes the attack of the nucleophile mainly from the α- phase. Since it is possible to synthesize C1halides directly from the sugars, these have been extensive used in such glycosylation reactions.

Such Halides at the anomeric position have been synthesized regiospecifically and converted to glycosides and nucleosides.

The cyclic acetals formed by the action of aldehydes and ketones at the other alcohol sites are of special interest. Benzaldehyde reacts with glucose to give the following acetal exclusively in good yield. Note the stable all-chair trans-decalane like structure for this compound, with all the substituents equatorial. On the other hand, acetone gives furanose diacetonide as the exclusive product. We have mentioned earlier that the open chain structure of hexoses have the facility to give pyranose or furanose. The chair conformation of Glucopyranose, with all substituents equatorial (except the -OH at the anomeric centre where anomeric effect is operative) would be most stable. Acetonide formation drives the equilibrium towards the furanoside ring. A pyranose ring formation would have introduced an axial methyl and associated strains.

As we said before, the open chain form of glucose is only a very minor component. Nonetheless, this structure could be trapped as the exclusive product on reaction with thiols. Thus, monosaccharides provide a rich source of chiral precursors for synthesis. The fact that some of these sugars are the cheapest chiral raw materials in the market adds great value to this chemistry.

Protection of the -OH groups:

We have already seen methylation of the -OH groups (other than anomeric –OH) as protecting group for -OH groups in monosaccharides. This is achieved using dimethyl sulphate in aq. sodium hydroxide. Such O-Me groups are not easy to remove. Generally if removal of such protection is desired, benzyl bromide (Bn-Br) is used as the alkylating agent. The O-Bn group could be selectively cleaved by hydrogenolysis reaction. Trimethylsilyl- (TMS-) protection is also a preferred protection for the -OH groups. The bulky silyl- protections and triphenylmethyl (Trityl- / Tr-) protection could be regiospecific for the -CH2OH group. Such regiospecificity is of great value in the synthesis of modified carbohydrate skeletons.

Oxidation reactions

While discussing the structure of monosaccharides, we came across nitric acid oxidation and oxidation with bromine water for the synthesis of diacids and monoacids respectively. Under bromine-water conditions aldehyde carbon (hemiacetal) would be first oxidized to lactone, which would then cleave under the reaction conditions to give the Aldonic acids. This mild reaction is specific to aldoses only. Selective oxidation of the C6

position of glucose would give glucuronic acid (Uronic Acids). However, chemically this is a long synthesis, involving differential protections and deprotections steps. However, in the body glucuronic acid is formed by enzymic oxidation and plays an important role in excretion of toxins and waste phenols as glycosides. The diacids are called Aldiric Acids. All these derivatives are important starting materials for the synthesis of other chiral compounds.

Osazone Formation:

When D-Glucose (aldose) and D-Fructose (ketose) react with three moles of phenylhydrazine, they give the same compound - Glucosazone. This is one more reaction that played a role in the structure determination of D-Glucose and D-Fructose. Similar reactions are observes with all monosaccharides. The mechanism of the reaction is given below. Note that this osazone formation is common to α-hydroxyaldehydes and α-hydroxyketones, α-diketones and α-ketoaldeliydes as well.

The above osazone formation proceeds via., a complex mechanism. Note that Glucose and fructose give the same osazone. In both cases, there is oxidation at α- carbon. The reaction consumes 3 moles of phenylhydrazine. . One mole of aniline and one mole of ammonia are released in this reaction. All these factors are incorporated in the following mechanism. You could write a mechanism for the formation of Fructosazone (which is same as Glucosazone) along the same lines. The first step is the condensation of amine moiety to the carbonyl group to give an imine unit and one mole of water. Details on this step are not shown in this mechanism.

The imine next undergoes an imine-enamine tautomerism, which gives an enol at C2. In the case of Fructose, the enamine would be towards the terminal C1 carbon. The enol, on tautomerism, gives a new carbonyl group, which then reacts with a second mole of phenylhydrazine to give a hydrazone. The mildly basic condition allows abstraction of an acidic proton on -CH2- group to give an anion, which would eliminate a mole of aniline and give an imine. This new imine would then be hydrolyzed to give an aldehyde and ammonia. This new carbonyl group would react with the third mole of hydrazine to give the osazone.

Kiliyani-Fischer Chain Elongation

We have already seen the usefulness of Kiliani-Fischer reaction, which is a chain elongation reaction. This reaction is an early example of Stereo- Differentiation reaction.

Ruff Degradation

This reaction was also extensively used in the structure correlation studies of monosaccharides. This procedure enables chain shortening in a homologous series.

Wohl Degradation

In this procedure for descending in length of a homologous series, the mono-oxime of an aldose is converted to a nitrile. This being a hydroxy- nitrile, it readily reverts to an aldehyde as shown below for D-Glucose.

Ferrier Carbocyclisation

This is a rearrangement first reported in carbohydrate chemistry, involving an enol ether. The mechanism involves a hydration, followed by ring opening and closure as shown below.

In 1988, Adams reported a Pd(II) catalysed rearrangement, in which the metal salt was used in catalytic amounts.

  1) Ferrier. RJ, "Unsaturated carbohydrates. Part 21. A carbocy clic ring closure of a hex-5-cnopyranosidc 
  derivative. J. Chein. Soc.. Perkin Trans. 1, 1455 (1979). 2) Blattncr. RJ; Ferrier, RJ. Direct synthesis
  of 6- oxabicyclo[3.2.1]octane derivatives from deoxvinososcs. Carbohydr. Res 150. 151 (1986). 
  2. Adam, S, Palladium(ll) promoted carbocyclisation of aminodcoxyhcx-5-cnopyranosides. Tetrahedron Lett,
  . 29 (50): 6589 (1988). 3. Das. SK; Mallet, J-M; Sinay, P, Novel Carbocyclic Ring Closure of 
  Hex-5-enopyranosidc,. Angew. Chem. Int. Ed. 36 (5): 493-496 (1997).

Sinaÿ et.al., reported a modified version using AltBu₃ as the Lewis acid. The reaction involves a proposed LA-complex shown below.

Ferrier Rearrangement

This rearrangement is a Lewis Acid catalysed rearrangement of allylic acetate on carbohydrate skeletons. The reaction involves formation of a stabilized allylic carbonium ion followed by introduction of an alkoxy group. The Lewis Acid could be Indium (III) chloride or borantrifluoride etherate. The ratio of α- and β- anomers depends on the Lewis acid and the nucleophile. With triethylsilane (R-H), the reaction yields a 2,3- unsaturated desoxy sugar.

   Fcrricr. Robert J. "Unsaturated Carbohydrates. Part 21. A Carboxylic Ring Closure of a Hcx-5- enopyranosidc 
   Derivative". J. Cheni. Soc.. Perkin Trans. 1: 1455 (1979)..
   Ferrier. Robert J.; Zubkov. O. A. Transformation of Glycals into 2.3-Unsaturaled Glvcosvl Derivatives. 
   Org. React. 62. (200.3).

Lobry-de Bruyn-van Ekenstein Transfromation

An aldose could be isomerised to a ketose via the corresponding enediol tautomer. This reaction could take place in basic, neutral as well a acidic conditions. The isomerisation could proceed down the chain under strong base conditions. In this way, D-Glucose could be epimerised to a mixture of D-Glucose, D-Fructose and D-Mannose.

Amodori Rearrangement

This rearrangement involves a rearrangement of 1-aminosugar to 1- amino-l-deoxyketose. The transformation could be seen in the transformation of D-Mannose to the corresponding open chain ketose.

Tipson-Cohen Reaction

When vis-diol in carbohydrates is converted to tosylates or mesylates, this moiety could be eliminated through an iodide to give unsaturated sugars. This is shown in the following examples. This is called Tipson-Cohen Reaction

   R.S. Tipson and A. Cohen. Carbohydrate Research. 1, 338-340 (1965).

These unsaturated sugars are important intermediates in the conversion of sugars to other optically pure natural products.

Synthesis of Monosaccharides

When sugar molecules are so cheap (as we said before) why would scientists synthesize natural sugars? They would like to accomplish this challenge for three important reasons.

1. Structure elucidation would be considered complete only when the structure is verified by total synthesis. 2. There is a huge demand for unnatural sugars and modified sugars in the area of synthetic drugs. For these reasons, scientists have been investigating efficient methods for their syntheses. 3. All members of the monosaccharide family are not available naturally and therefore routes for their synthesis might yield new interesting molecular materials.

For example, in the hexose family, only L-Altrose exists naturally. It has been isolated from strains of the bacterium Butyrivibrio fibrisolvens. D-Glucose is the most abundant hexose. The second most common hexose is D-Galactose. Other hexoses such as Threose, Lylose, Gulose and Allose are not known in nature. Similarly, D-Arabinose exists widely, but L-Arabinose is less common. Thus, all the unnatural members of the monosaccharide family are known via synthesis only. We would see later that these monosaccharide structures are of interest as Chiral Pools for the synthesis of other compound.

In the process structure elucidation, Fischer and his contemporaries had accomplished the syntheses of all pentoses and hexoses via, Kiliani – Fischer reaction and Wohl Degradation reaction sequences. As discussed earlier, these not only established their structural correlations, but also helped to synthesize all members of the family, whether they existed naturally or not. The first documented total synthesis of monosaccharide came in the form of synthesis of ‘Formose’ by Boutlerow in 1861. The simplicity of the approach attracted several workers to improve upon this approach.

  Boutlerow. M. A. Compt. Rend., 53. 145 (1861)

The racemic forms of Glucose and Fructose were isolates as Osazones by later workers. The first synthesis of D-Fructose from D- Mannitol was documented in 1886.

   Fischer E,  Tafel  J, Ber,  , 23, 2114 (1890).
   Fischer. E, Tafel J. Ber., 20, 1088, 2566, 3384 (1887). 
   Brown A. J. J Chem. Soc., 49, 172 (1886).

As we saw earlier, a systematic study on synthesis of ail the monosaccharides were reported around the same time. Thus, the era of sugar synthesis began. In this chapter we would see two approaches in detail.

R.K. Brown’s school has explores the pyran skeleton of acrolein dimer 2,3-dihydro-2H-pyran-2-carboxaldehyde for the synthesis of several hexoses and their modified structures. They exploited the stereochemical control that is feasible on cyclohexane rings. They first investigated the stereoselective epoxide ring opening in this pyran ring system.

   F. Sweet and R. K. Brown, ‘Synthesis of 1,6-anhydro-4-deoxy-β-DL-xylo-hexapyranose’, Canadian 
   Journal of Chemistry, 46, 2289 (1964).
   U. P. Singh and R. K. Brown, ‘Total Synthesis of DL-Glucose’, Canadian Journal of Chemistry, 48, 1792 (1970).

Epoxidation of the olefin gave α-epoxide almost exclusively. Trans- diaxial ring opening also proceeded well as expected. This chemistry was further exploited for the synthesis of DL-Glucose. Proton abstraction on the above epoxide gave an allylic alcohol regioselectively. Neighbouring group participation of -OH ensured exclusive formation of the α-epoxide,

whose diaxial ring opening set the stereochemistry for Glucose molecule, after the anomeric centre was unlocked. In a subsequent paper, they further explored its extension to other hexapyranose systems. Since they were working with racemic starting materials, all their hexoses were racemic.

   U.P.Singh and H. C.Brown, ‘Total Synthesis of DL-Glucose, 3-0-Methyl-DL-glucose, and 
   3-Deoxy-DL-ribohexopyranose from 1,6-3,4-Dianhvdro-DL-allo-hexopyranosc, a Product Obtained from 
   Acrolein Dimer’, Can. J. Chem., 49, 3342 (1971).

Synthesis of Enantiopure Monosaccharides

The most common approach for enantioselective synthesis has been to select a precursor that has appropriate chirality, which is enantiomerically pure. The reagents are then carefully chosen to avoid racemisation and follow enantio- / diastereo- selective routes to develop the product. This could be described a substrate-control strategy. In this strategy, the developing chiral centers are dependent on the inherent diastereofacial preferences of the substrate. With a host of enantioselective reagents on hand, a new strategy is emerging, which is called reagent-control strategy. In this approach, a common substrate is chosen and the chirality is controlled through appropriate selection of chiral reagents. From the school of Sharpless, enantioselective synthesis of all the 8 L-Hexoses has appeared to demonstrate the utility of this strategy.

   Soo Y. Ko., Albert W.M. Lee, Satoru Masamune, Laurence A. Reed, III, K. Berry Sharpless and
   Frederick J. Walker, ‘Total Synthesis of L-Hexoses’, Tetrahedron, 45, 245 (1990)

The scheme envisages a sequence of four steps reiterated to add two chiral centres at a time. This basic concept is shown below. Each cycle introduces two consecutive chiral centres followed by two more carbons to enable repetition. The first step is a Wittig reaction to provide a double bond stereospecifically, with a suitable functional group to provide a terminal alcohol. The -OH