Chemical glycosylation
Encyclopedia
A chemical glycosylation reaction involves the coupling of a sugar to a glycosyl acceptor
forming a glycoside
. If the acceptor is another sugar, the product is an oligosaccharide
. The reaction involves coupling a glycosyl donor
to a glycosyl acceptor
via activation utilizing a suitable activator. The reactions often result in a mixture of products due to the creation of a new stereogenic centre at the anomeric position
of the glycosyl donor
. The formation of a glycosidic linkage allows for the synthesis of complex polysaccharides which may play important roles in biological processes and pathogenesis
and therefore having synthetic analogs of these molecules allows for further studies with respect to their biological importance.
An activator is commonly a Lewis acid
which enables the leaving group at the anomeric position to leave and results in the formation of the oxocarbenium ion.
Below it can be seen that having an acetyl protecting group at position 2 allows for the formation for an acetoxonium ion intermediate that blocks attack to the bottom face of the ring therefore allowing for the formation of the β-glycoside predominantly.
Alternatively, the absence of a participating group at position 2, allows for either attack from the bottom or top face. Since the α-glycoside product will be favoured by the anomeric effect
, the α-glycoside usually predominates.
such as the benzyl group, are found to increase the reactivity of the donor/acceptor and are therefore called "arming" groups.
although were often considered too reactive for synthetic use. Recently several research groups have shown these donors to have unique reactive properties and can differ from other glycosyl chlorides or bromides with respect to reaction time, efficiency, and stereochemistry
. Glycosyl iodides may be made under a variety of conditions, one method of note is the reaction of a 1-O-acetylpyranoside with TMSI.
Iodide donors may typically be activated under basic conditions to give β-glycosides with good selectivity. The use of tetraalkylammonium iodide salts such as tetrabutylammonium iodide (TBAI) allows for in-situ anomerization of the α-glycosyl halide to the β-glycosyl halide and provides the α-glycoside in good selectivity.
and since then have been explored constantly allowing for the development of numerous protocols for their preparation.
The advantage of using thioglycosides is their stability under a wide range of reaction conditions allowing for protecting group manipulations. Additionally thioglycosides act as temporary protecting groups at the anomeric position allowing for thioglycosides to be useful as both glycosyl donors as well as glycosyl acceptors.
Thioglycosides are usually prepared by reacting per-acetylated sugars with BF3•OEt2 and the appropriate thiol.
Thioglycosides used in glycosylation reactions as donors can be activated under a wide-range of conditions, most notably using NIS/AgOTf.
in 1980 and since then have become very popular for glycoside synthesis. The use of trichloroacetimidates provides many advantages including ease of formation, reactivity and stereochemical outcome.
O-Glycosyl trichloroacetimidates are prepared via the addition of trichloroacetonitrile (Cl3CCN) under basic conditions to a free anomeric hydroxyl group.
Typical activating groups for glycosylation reactions using trichloroacetimidates are BF3•OEt2 or TMSOTf.
Glycosyl acceptor
A glycosyl acceptor is any suitable nucleophile-containing molecule that will react with a glycosyl donor to form a new glycosidic bond. By convention, the acceptor is the member of this pair which did not contain the resulting anomeric carbon of the new glycosidic bond...
forming a glycoside
Glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme...
. If the acceptor is another sugar, the product is an oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
. The reaction involves coupling a glycosyl donor
Glycosyl donor
A glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new glycosidic bond...
to a glycosyl acceptor
Glycosyl acceptor
A glycosyl acceptor is any suitable nucleophile-containing molecule that will react with a glycosyl donor to form a new glycosidic bond. By convention, the acceptor is the member of this pair which did not contain the resulting anomeric carbon of the new glycosidic bond...
via activation utilizing a suitable activator. The reactions often result in a mixture of products due to the creation of a new stereogenic centre at the anomeric position
Anomer
In carbohydrate chemistry, an anomer is a special type of epimer. It is one of two stereoisomers of a cyclic saccharide that differs only in its configuration at the hemiacetal or hemiketal carbon, also called the anomeric carbon. Anomerization is the process of conversion of one anomer to the other...
of the glycosyl donor
Glycosyl donor
A glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new glycosidic bond...
. The formation of a glycosidic linkage allows for the synthesis of complex polysaccharides which may play important roles in biological processes and pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
and therefore having synthetic analogs of these molecules allows for further studies with respect to their biological importance.
Terminology
The glycosylation reaction involves the coupling of a glycosyl donor and a glycosyl acceptor via initiation using an activator under suitable reaction conditions.- A glycosyl donorGlycosyl donorA glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new glycosidic bond...
is a sugar with a suitable leaving group at the anomeric position. This group, under the reaction conditions, is activated and via the formation of an oxocarbeniumOxocarbeniumAn oxacarbenium ion is a canonical form of a carbocation, real or hypothetical, which places a formal positive charge on an oxygen atom. They are common transition states for the hydrolysis of glycosidic bonds, and are a commonly used strategy for chemical glycosylation...
is eliminated leaving an electrophilic anomeric carbon. - A glycosyl acceptorGlycosyl acceptorA glycosyl acceptor is any suitable nucleophile-containing molecule that will react with a glycosyl donor to form a new glycosidic bond. By convention, the acceptor is the member of this pair which did not contain the resulting anomeric carbon of the new glycosidic bond...
is a sugar with an unprotected nucleophilic hydroxyl group which may attack the carbon of the oxocarbenium ion formed during the reaction and allow for the formation of the glycosidic bond.
An activator is commonly a Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
which enables the leaving group at the anomeric position to leave and results in the formation of the oxocarbenium ion.
Stereochemistry
The formation of a glycosidic linkage results in the formation of a new stereogenic centre and therefore a mixture of products may be expected to result. The linkage formed may either be axial or equatorial (α or β with respect to glucose). To better understand this, the mechanism of a glycosylation reaction must be considered.Neighbouring group participation
The stereochemical outcome of a glycosylation reaction may in certain cases be affected by the type of protecting group employed at position 2 of the glycosyl donor. A participating group, typically one with a carboxyl group present, will predominantly result in the formation of a β-glycoside. Whereas a non-particiapting group, a group usually without a carboxyl group, will often result in an α-glycoside.Below it can be seen that having an acetyl protecting group at position 2 allows for the formation for an acetoxonium ion intermediate that blocks attack to the bottom face of the ring therefore allowing for the formation of the β-glycoside predominantly.
Alternatively, the absence of a participating group at position 2, allows for either attack from the bottom or top face. Since the α-glycoside product will be favoured by the anomeric effect
Anomeric effect
In organic chemistry, the anomeric effect or Edward-Lemieux effect is a stereoelectronic effect that describes the tendency of heteroatomic substituents adjacent to a heteroatom within a cyclohexane ring to prefer the axial orientation instead of the less hindered equatorial orientation that would...
, the α-glycoside usually predominates.
Protecting groups
Different protecting groups on either the glycosyl donor or the glycosyl acceptor may affect the reactivity and yield of the glycosylation reaction. Typically, electron-withdrawing groups such as acetyl or benzoyl groups are found to decresase the reactivity of the donor/acceptor and are therefore termed "disarming" groups. Electron-donating groupsPolar effect
The Polar effect or electronic effect in chemistry is the effect exerted by a substituent on modifying electrostatic forces operating on a nearby reaction center...
such as the benzyl group, are found to increase the reactivity of the donor/acceptor and are therefore called "arming" groups.
Glycosyl iodides
Glycosyl iodides were first introduced for use in glycosylation reactions in 1901 by Koenigs and KnorrKoenigs-Knorr reaction
The Koenigs–Knorr reaction in organic chemistry is the substitution reaction of a glycosyl halide with an alcohol to give a glycoside. It is one of the oldest and simplest glycosylation reactions...
although were often considered too reactive for synthetic use. Recently several research groups have shown these donors to have unique reactive properties and can differ from other glycosyl chlorides or bromides with respect to reaction time, efficiency, and stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
. Glycosyl iodides may be made under a variety of conditions, one method of note is the reaction of a 1-O-acetylpyranoside with TMSI.
Iodide donors may typically be activated under basic conditions to give β-glycosides with good selectivity. The use of tetraalkylammonium iodide salts such as tetrabutylammonium iodide (TBAI) allows for in-situ anomerization of the α-glycosyl halide to the β-glycosyl halide and provides the α-glycoside in good selectivity.
Thioglycosides
Thioglycosides were first reported in 1909 by FischerHermann Emil Fischer
Hermann Emil Fischer, Emil Fischer was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He developed the Fischer projection, a symbolic way of drawing asymmetric carbon atoms.-Early years:Fischer was born in Euskirchen, near Cologne,...
and since then have been explored constantly allowing for the development of numerous protocols for their preparation.
The advantage of using thioglycosides is their stability under a wide range of reaction conditions allowing for protecting group manipulations. Additionally thioglycosides act as temporary protecting groups at the anomeric position allowing for thioglycosides to be useful as both glycosyl donors as well as glycosyl acceptors.
Thioglycosides are usually prepared by reacting per-acetylated sugars with BF3•OEt2 and the appropriate thiol.
Thioglycosides used in glycosylation reactions as donors can be activated under a wide-range of conditions, most notably using NIS/AgOTf.
Trichloroacetimidates
Trichloroacetimidates were first introduced and explored by SchmidtSchmidt
Schmidt may refer to:* Schmidt , including list of people with the surname* Schmidt * Schmidt , a crater on Mars* Schmidt , in Kamchatka...
in 1980 and since then have become very popular for glycoside synthesis. The use of trichloroacetimidates provides many advantages including ease of formation, reactivity and stereochemical outcome.
O-Glycosyl trichloroacetimidates are prepared via the addition of trichloroacetonitrile (Cl3CCN) under basic conditions to a free anomeric hydroxyl group.
Typical activating groups for glycosylation reactions using trichloroacetimidates are BF3•OEt2 or TMSOTf.
Notable synthetic products
Below are a few examples of some notable targets obtained via a series of glycosylation reactions.See also
- GlycosylationGlycosylationGlycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
- Glycosyl transferase
- GlycorandomizationGlycorandomizationGlycorandomization, which literally means “diversification of sugar-containing compounds”, is a tool currently used in the pharmaceutical industry to modify the sugar residues of the glycosylated natural products by using unique glycosylation strategies...
- GlycationGlycationGlycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
- Carbohydrate chemistryCarbohydrate chemistryCarbohydrate chemistry is a subdiscipline of chemistry primarily concerned with the synthesis, structure, and function of carbohydrate structures. Due to the general structure of carbohydrates, their synthesis is often preoccupied with the selective formation of glycosidic linkages and the...
- OligosaccharideOligosaccharideAn oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
- CarbohydrateCarbohydrateA carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...