Glycosides

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Basic structure of a glycoside, here with D - glucose as the sugar part

Glycosides , also known as glycosides , are organic chemical compounds with the general structure R – O – Z. An alcohol (R – OH) is linked to a sugar (Z) via a glycosidic bond . Glycosides are therefore full acetals of sugars . The alcohol OR can be any other sugar or any other hydroxy compound , but not an acyl radical .

If a thioacetal R – S – Z or selenoacetal R – Se – Z is present instead of an acetal , one speaks of a thioglycoside or selenoglycoside.

N -Glycosyl compounds R – NR' – Z, on the other hand, are called glycosylamines or amino sugars. C -Glycosyl compounds R – CR'R '' - Z are glycosyl derivatives . In laboratory jargon, only “ C- glycoside” or “ N- glycoside” is often said instead , but this is misleading because glycosylamines and glycosyls behave chemically differently.

The sugar part Z is generally referred to as glycon (glycon). If it is in R-OH according to IUPAC - Nomenclature is a non-sugar, it is called aglycone (aglycone).

The glycosidic bond

The chemical bond between the anomeric carbon atom of a sugar and the heteroatom of the aglycone or with a second sugar is called a glycosidic bond (see figure). Glycosides are also substances with bonds to other heteroatoms such as sulfur , selenium , nitrogen and phosphorus . The glycosidic bond is hydrolytically cleavable, the reaction equilibrium being on the part of the cleavage products. The bond is kinetic but quite stable. It is formed by a condensation reaction with little energy expenditure, with elimination of water . In nature, the formation known as glycosylation takes place enzymatically via an activated saccharide, in the laboratory by special activation methods or by the reaction of a sugar with a large excess of the alcohol under acid catalysis.

In the case of a glycoside, the aldehyde function of the aldoses (e.g. glucose ) or the keto function of the ketoses (e.g. fructose ) is a cyclic full acetal. An acetal is the condensation product of an aldehyde or ketone and one or two alcohols (hemiacetal or full acetal). Full acetals are stable to basic and neutral to weakly acidic aqueous solutions, but hydrolyze in the presence of strong acids.

Stereochemistry and nomenclature

The formation of the full glycosidic acetal makes the prochiral carbonyl function chiral , i.e. That is, a new stereocenter is formed , the so-called anomeric carbon atom or anomeric center . The two resulting diastereomers (anomers) are called α- and β-glycosides. The glycosides are named by adding the ending -id to the root of the glycone, e.g. B. fructoside for a glycoside of fructose or glucoside for a glycoside of glucose .

If the sugar forms a five-membered ring, it is a glycofuranoside (derived from furan ). If it forms a six-membered ring, one speaks of a glycopyranoside (derived from pyran ).

See also Glycosidic Bond # nomenclature and examples
Definition α and β: glycosidic bond

Glycosylation and hydrolysis

What the peptide bond is in the case of amino acids , the glycosidic bond is in the case of carbohydrates, as it enables a stable link to other sugars or a wide variety of alcohols through a slightly reversible condensation reaction. This results in an enormous structural diversity for the carbohydrates, which by far make up the largest part of the biomass. Both the enzymatic and the non-enzymatic synthesis of a glycoside is referred to as glycosylation .

Enzymes

In biological systems, glycosides are hydrolyzed to free sugar and aglyconic alcohol by glycosidases . These glycosidases are more or less specific for certain sugars and one of the anomeric shapes and ring sizes. Thus, an α-mannopyranose-specific glycosidase, an α-mannosidase, cannot hydrolyze galactoside . An α-galactosidase can not only cleave α-galactopyranosides, but sometimes also similar glycosides, such as β-arabinopyranosides. Glycosyltransferases, on the other hand, are highly specific enzymes that catalyze the transfer of activated carbohydrates (UDP sugars) to an alcohol with the formation of a glycosidic bond.

Chemical syntheses

The formation of glycosidic bonds is one of the most important components of carbohydrate chemistry. There are now a large number of different enzymatic and non-enzymatic glycosylation methods that are used in the laboratory through to industrial production.

Fischer Glycosylation: Simple Alkyl Glycosides and Alkyl Polyglycosides

Example of an APG based on glucose (m = 1 to 5 and n = 11 to 15).

The glycosidic bond is stable to a basic to weakly acidic environment, but sensitive to strongly acidic conditions, possibly under the supply of energy or increased pressure. The proximity of the ring oxygen promotes solvolysis by stabilizing the cyclic carboxonium ion formed . In aqueous solution this leads to the hydrolysis of a glycoside to aglycon and the free sugar. In an alcoholic solution, the alkyl glycoside corresponding to the alcohol is formed instead, e.g. B .:

Equilibrium composition (%) of some methyl glycosides in 1% CH 3 OH / HCl
Monosaccharide Me-α-pyr Me-β-pyr Me-α-fur Me-β-fur
glucose 66 32.5 0.6 0.9
Mannose 94 5.3 0.7 -
Galactose 58 20th 6th 16
Arabinose 24 47 22nd 7th

It should be noted that this Fischer glycosylation, named after Emil Fischer , is a complex equilibrium reaction with the free sugar as the thermodynamic product. In order to obtain a quantitative yield of alkyl glycoside, anhydrous alcohol is used, usually with HCl g or a strongly acidic ion exchanger as a catalyst. The resulting water in the reaction can, for. B. be withdrawn dynamically in a Soxhlet apparatus by molecular sieve .
On the glycoside side, both the α- and β-glycopyranosides and furanosides are formed. The equilibrium mixture of the glycosides with the exclusion of water is individually different for each saccharide, but mostly the α-glycopyranosides are the main product (see table). These can then often be kept very pure by crystallization. This works very well for simple alcohols up to butanol. However, if the desired aglycone is less polar, you get a phase problem. The sugar is no longer soluble in the alcohol and the reaction cannot take place, or very high temperatures or pressure are required. For some years now, the alkyl polyglycosides (APG) in the sense of renewable raw materials have gained industrial importance as surfactants , especially in high-quality cosmetics. Since the glycosides of long-chain and non-polar fatty alcohols are of interest for this, one has the phase problem described. Therefore, starting from starch, a butanolysis is first carried out and the resulting butyl polyglycosides are re-glycosylated with the fatty alcohols:

Anomeric effect

The increased thermodynamic stability of the axial anomeric position (mostly α) is called the anomeric effect and is the subject of controversial discussions. How strong the anomeric effect is depends on the configuration of the sugar and, among other things, on the polarity of the solvent. It plays an important role in carbohydrate chemistry and can be used in synthesis.

Activation of protected glycosyl donors

In a glycosylation reaction, the sugar is called the glycosyl donor and the aglycon is called the glycosyl acceptor. The aim of such a synthesis is usually the introduction of a sensitive aglycone or the synthesis of oligosaccharides. The simple alkyl glycosides are usually obtained by Fischer glycosylation (mainly or purely α after crystallization) or from peracetylated sugars (β, see below).

  • Protective groups: In order to obtain a selective glycosylation, considerable additional effort has to be made because of the high degree of functionalization of the saccharides. A variety of protecting groups are used to mask the hydroxy groups. The most important protecting groups are acetates , benzoates and benzyl ethers .
  • Neighboring group effect : 2- O -acylated glycosyl donors selectively produce β-glycosides (or α in the case of mannose, among others), since the ester carbonyl oxygen shields the α position. In contrast, 2- O -alkylated donors give predominantly or under very special conditions exclusively the thermodynamically more favorable α-glycosides (also applies to mannose).
    In the case of the neighboring group effect, the formation of an orthoester as a competitor to the glycoside can prove to be disturbing .

In order to obtain a full glycosyl donor, a suitable leaving group must be introduced in the anomeric position. At this point, only a few important donors and their activation in the presence of alcohol are briefly described:

  • Sugar halides: One of the best-known glycosylation methods is the activation of sugar halides by silver salts, known as the Koenigs-Knorr method , for example acetobromoglucose by silver carbonate (note that β is selectively formed here by the neighboring 2-OAc group):

Koenigs-Knorr.png

  • Trichloroacetimidates: Sugars – O– (C = NH) –CCl 3 are activated by catalytic amounts of Lewis acid.
  • Thioglycosides: Sugar-SR are activated by electrophilic reagents such as Br + .
  • 1- O -Acetates: Sugar-OAc are activated by an excess of Lewis acid. They are used as peracetylated compounds for the synthesis of alkyl-β-glycosides and -thioglycosides, as well as protected 1-OH-free sugars and sugar halides.

Biology and pharmacy

Glycosides are widespread in nature. They have a wide range of biological functions. When differentiating according to the aglycone belonging to a certain chemical substance group, extensive subclasses arise, which are often similar in terms of toxicity , suitability as medicinal substances or other properties. In biochemistry and pharmacology , this is the most common classification.

In the human body, polar and non-polar alcoholic toxins are often made water-soluble and excreted as glucuronides by binding to glucuronic acid .

Some special glycosides are phytochemicals . The synthesis of glycosides allows the plant u. a. to store toxic substances in a non-toxic form. The glycoside is z. B. stored in a vacuole , which is used to compartmentalize the respective glycosidase. Come the glycoside and the associated glycosidase, e.g. B. by destroying the plant cell together, the glycoside is hydrolytically split and the toxin is released and can develop its effect.

Glycosides are very different in their effect as medicinal substances or in their toxicology. In biochemistry and pharmacy, they are divided into the following subgroups, depending on the aglycon:

Anthocyanin glycosides

The anthocyanin glycosides are a group of compounds found in many plants as colorants.

Coumarin glycosides

The coumarin glycosides (for example rutarin ) are derived from the coumarin used as a fragrance . Many of these glycosides have a pharmacological effect.

Cyanogenic Glycosides

As their name suggests, cyanogenic glycosides split off the highly toxic hydrocyanic acid HCN when they decompose .

Flavonoids

In the group of flavonoids , the aglycon is a flavone . Similar to the anthocyanin glycosides, this large group contains many vegetable dyes which, as natural polyphenols, are also pharmacologically active. Examples are hesperidin , naringin and rutin .

Cardiac glycosides

Cardiac glycosides are around 300 substances that have a pharmacologically inotropic effect on the heart muscles . They come in some plants such as foxgloves Digitalis or lily of the valley Convallaria majalis ago and consist of three relatively rare deoxy sugars and a steroid alcohol as aglycone. Today only digoxin and digitoxin are of clinical importance. Because of their special properties, they are distinguished from the related saponins. As we now know, our body can produce cardiac glycosides from cholesterol itself, but the importance of endogenously synthesized cardiac glycosides is still unknown.

Iridoid glycosides

Iridoid glycosides such as aucubin and catalpol are used to ward off plants' predators.

Phenolic glycosides or phenyl glycosides

Phenyl glycosides (also phenol glycosides ) are a group of glycosides in which a phenol is linked to a carbohydrate via a glycosidic bond. Since many anthraquinones and flavonoids are also phenols, these groups partially overlap. Phenyl glycosides are widespread in nature; these include B .:

Saponins

Saponins (Latin “ Sapo ” = “soap”) form soap-like mixtures when mixed and shaken with water. The respective aglycon belongs to the class of sapogenins , which is usually associated with D- glucose or D - galactose . Sapogenins are either steroids , steroid alkaloids (nitrogen-containing steroids), or triterpenes . Many plants use saponins such as digitonin or solanin as defensive or defense substances.

Mustard oil glycosides

Mustard oil glycosides or glucosinolates are glycosides that are bridged by a sulfur atom, i.e. S- glycosides or thioglycosides. These also contain nitrogen and give many cruciferous vegetables and capers such as radish , mustard , cress and cabbage a bitter and pungent taste. If the plant tissue is damaged, the mustard oil glycosides are broken down into partly toxic products.

Classic proof

Carbohydrates (sugars) are polyhydroxycarbonyl compounds, i. That is, they have several functional alcohol groups and are therefore usually in the form of an energetically very favorable cyclic hemiacetal, i.e. they react with themselves to form rings. The former carbonyl oxygen atom forms an exocyclic OH group, the oxygen of the hydroxyl group forms the endocyclic ring oxygen. Since the hemiacetal form of the aldoses in aqueous solution is in equilibrium with the open-chain aldehyde form, a glucose solution reduces Fehling's solution . With a wide variety of alcohols R-OH, sugars form a cyclic full acetal with an exocyclic OR substituent instead of an exocyclic hydroxyl group. Such a full acetal is stable in aqueous solution and therefore does not reduce Fehling's solution unless the aglycon itself has a reducing effect, e.g. B. if it is again a sugar. In a strongly acidic aqueous solution, glycosides are split into one or more monosaccharide (s) and the alcohol. The classic detection criterion for a glycoside is therefore the resistance to Fehling's solution without prior hydrolysis and reduction of Fehling's solution after acidic hydrolysis. In the presence of a reducing aglycone, e.g. B. another sugar, this criterion does not apply. Since the first investigations of pharmaceutical herbal formulations (formulation = dosage form) were carried out with these classic investigation methods, the herbal active ingredients listed below are referred to as glycosides in pharmacy, although the glycosides have a meaning that goes far beyond this small group.

Individual evidence

  1. ↑ Entry on glycosides . In: IUPAC Compendium of Chemical Terminology (the “Gold Book”) . doi : 10.1351 / goldbook.G02661 Version: 2.2.
  2. ↑ Jochen Lehmann, Carbohydrates: Chemistry and Biology , 2nd revised. and exp. Ed., Stuttgart New York, Thieme 1996, page 82.

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