Carbohydrate synthesis

Last updated

Carbohydrate synthesis is a sub-field of organic chemistry concerned with generating complex carbohydrate structures from simple units (monosaccharides) through natural or unnatural processes. The generation of carbohydrate structures involves linking glycosyl groups like monosaccharides or oligosaccharides through glycosidic bonds is called glycosylation. Carbohydrate synthesis aims to generate the polysaccharides with controlled structures through atomically economic methods. Therefore, it is important to construct glycosidic linkages that have optimum molecular geometry (stereoselectivity) and the stable bond (regioselectivity) at the reaction site (anomeric centre). [1]

Contents

Simplified mechanism of glycosylation Generalized glycosylation.png
Simplified mechanism of glycosylation



Background

Generally speaking, carbohydrates can be classified into two groups, simple sugars, and complex carbohydrates. Simple sugars, also called monosaccharides, are carbohydrates that cannot be further broke down by hydrolysis. When glycosidic linkages connect two or more monosaccharide units, complex carbohydrates are formed. Complex carbohydrates, according to the different number of monosaccharide units, can be classed into three groups, disaccharides, oligosaccharides, and polysaccharides. A disaccharide is formed from two monosaccharides. When a carbohydrate contains 3-10 monosaccharides, [2] it is called a oligosaccharide. Higher oligosaccharides with more than 10 monosaccharides are polysaccharides.

So far, there has not been a unified synthetic strategy of consistent oligosaccharide production because of the nuances in the anomeric effects of monomers and the complexity in the carbohydrate structures. [3] [4] The facile procedures such as the one-pot and solid phase synthesis which ensures atom economy [5] [3] are used. However, further developments in those synthetic approaches are needed since still not fully controlled and automated. [5]  

Significance

Glycoconjugate is the covalently bonded product of oligosaccharides to the biomolecules such as proteins and lipids. [6] They play indispensable role in the biological activities of mammalian cells from energy generation to cell signalling. [6] [7] [8] These glycoconjugates with short oligosaccharide structures are important for the characterization and purification in the course glycoconjucate vaccine developements. [9] Therefore, research in the engineering of the glycosyl precursors that create oligosaccharides with controlled size is important in carbohydrate synthesis.

Oligosaccharide synthesis

Oligosaccharides have diverse structures. The number of monosaccharides, ring size, the different anomeric stereochemistry, and the existence of the branched-chain sugars all contribute to the amazing complexity of the oligosaccharide structures. The essence of the reducing oligosaccharide synthesis is connecting the anomeric hydroxyl of the glycosyl donors to the alcoholic hydroxyl groups of the glycosyl acceptors. Protection of the hydroxyl groups of the acceptor with the target alcoholic hydroxyl group unprotected can assure regiochemical control. Additionally, factors such as the different protecting groups, the solvent, and the glycosylation methods can influence the anomeric configurations. This concept is illustrated by an oligosaccharide synthesis in Scheme 1. Oligosaccharide synthesis normally consists of four parts: preparation of the glycosyl donors, preparation of the glycosyl acceptors with a single unprotected hydroxyl group, the coupling of them, and the deprotection process.

Scheme1(Lu).gif

Building blocks

Common donors in oligosaccharide synthesis are glycosyl halides, glycosyl acetates, thioglycosides, trichloroacetimidates, pentenyl glycosides, and glycals. Of all these donors, glycosyl halides are classic donors, which played a historical role in the development of glycosylation reactions. Thioglycoside and trichloroacetimidate donors are used more than others in contemporary glycosylation methods. When it comes to the trichloroacetimidate method, one of the advantages is that there is no need to introduce heavy metal reagents in the activation process. Moreover, using different bases can selectively lead to different anomeric configurations. (Scheme 2) As to the thioglycosides, the greatest strength is that they can offer temporary protection to the anomeric centre because they can survive after most of the activation processes. [10] Additionally, a variety of activation methods can be employed, such as NIS/ AgOTf, NIS/ TfOH, IDCP (Iodine Dicollidine Perchlorate), iodine, and Ph2SO/ Tf2O. Furthermore, in the preparation of 1, 2-trans glycosidic linkage, using thioglycosides and imidates can promote the rearrangement of the orthoester byproducts, since the reaction mixtures are acidic enough.

Scheme2(Lu).gif

Stereoselectivity

The structures of acceptors play a critical role in the rate and stereoselectivity of glycosylations. Generally, the unprotected hydroxyl groups are less reactive when they are between bulky protecting groups. That is the reason why the hydroxyl group at OH-4 in pyranosides is unreactive. Hyperconjugation is involved when OH-4 is anti-periplanar to the ring oxygen, which can also reduce its reactivity. (Scheme 3) Furthermore, acyl protecting groups can reduce the reactivity of the acceptors compared with alkyl protecting groups because of their electron-withdrawing ability. Hydroxyl group at OH-4 of N-acetylglucosamine derivatives is particularly unreactive. [11]

Scheme3(Lu).gif

The glycosidic bond is formed from a glycosyl donor and a glycosyl acceptor. There are four types of glycosidic linkages: 1, 2-trans-α, 1, 2-trans-beta, 1, 2-cis-α, and 1, 2-cis-beta linkages. 1, 2-trans glycosidic linkages can be easily achieved by using 2-O-acylated glycosyl donors (neighboring group participation). To prevent the accumulation of the orthoester intermediates, the glycosylation condition should be slightly acidic.

Challenging linkages

When connecting the monosaccharides, the oligosaccharides need to be reducing in order to sequentially connect the glycosyl units. The monosaccharides, in nature prefer ɑ-linkages due to anomeric effect, [12] but the disaccharides with ɑ-linkages are non-reducing thus deactivating the consequent connection of the monosaccharides. [13] In order to make the process of glycosylation continuous and automated, the glycosidic linkages must maintain beta so to keep the structure open to coupling with more glycosyl groups.

It is somewhat more difficult to prepare 1, 2-cis-β-glycosidic linkages stereoselectively. Typically, when non-participating groups on O-2 position, 1, 2-cis-β-linkage can be achieved either by using the historically important halide ion methods, or by using 2-O-alkylated glycosyl donors, commonly thioglycosides or trichloroacetimidates, in nonpolar solvents.

In the early 1990s, it was still the case that the beta mannoside linkage was too challenging to be attempted by amateurs. However, the method introduced by Crich (Scheme 4), with 4,6-benzylidene protection a prerequisite and anomeric alpha triflate a key intermediate leaves this problem essentially solved. The concurrently developed but rather more protracted intramolecular aglycon delivery (IAD) approach [14] is a little-used but nevertheless stereospecific alternative.

Scheme4(Lu).gif

See also

Related Research Articles

<span class="mw-page-title-main">Carbohydrate</span> Organic compound that consists only of carbon, hydrogen, and oxygen

A carbohydrate is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 and thus with the empirical formula Cm(H2O)n, which does not mean the H has covalent bonds with O. However, not all carbohydrates conform to this precise stoichiometric definition, nor are all chemicals that do conform to this definition automatically classified as carbohydrates.

<span class="mw-page-title-main">Disaccharide</span> Complex sugar

A disaccharide is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, lactose, and maltose.

A glycosidic bond or glycosidic linkage is a type of ether bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate.

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

Glycosylation 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 order to form a glycoconjugate. In biology, glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation may refer to a non-enzymatic reaction.

<span class="mw-page-title-main">Glycoside</span> Molecule in which a sugar is bound to another functional group

In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme hydrolysis, which causes the sugar part to be broken off, making the chemical available for use. Many such plant glycosides are used as medications. Several species of Heliconius butterfly are capable of incorporating these plant compounds as a form of chemical defense against predators. In animals and humans, poisons are often bound to sugar molecules as part of their elimination from the body.

<span class="mw-page-title-main">Amino sugar</span>

In organic chemistry, an amino sugar is a sugar molecule in which a hydroxyl group has been replaced with an amine group. More than 60 amino sugars are known, with one of the most abundant being N-acetyl-D-glucosamine, which is the main component of chitin.

<span class="mw-page-title-main">Reducing sugar</span> Sugars that contain free OH group at the anomeric carbon atom

A reducing sugar is any sugar that is capable of acting as a reducing agent. In an alkaline solution, a reducing sugar forms some aldehyde or ketone, which allows it to act as a reducing agent, for example in Benedict's reagent. In such a reaction, the sugar becomes a carboxylic acid.

Glycal is a name for cyclic enol ether derivatives of sugars having a double bond between carbon atoms 1 and 2 of the ring. The term "glycal" should not be used for an unsaturated sugar that has a double bond in any position other than between carbon atoms 1 and 2.

An Endoglycosidase is an enzyme that releases oligosaccharides from glycoproteins or glycolipids. It may also cleave polysaccharide chains between residues that are not the terminal residue, although releasing oligosaccharides from conjugated protein and lipid molecules is more common.

<span class="mw-page-title-main">Glycosyltransferase</span> Class of enzymes

Glycosyltransferases are enzymes that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar to a nucleophilic glycosyl acceptor molecule, the nucleophile of which can be oxygen- carbon-, nitrogen-, or sulfur-based.

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 glycosylation reactions. It is named after Wilhelm Koenigs (1851–1906), a student of von Baeyer and fellow student with Hermann Emil Fischer, and Edward Knorr, a student of Koenigs.

Carbohydrate chemistry is a subdiscipline of chemistry primarily concerned with the detection, synthesis, structure, and function of carbohydrates. Due to the general structure of carbohydrates, their synthesis is often preoccupied with the selective formation of glycosidic linkages and the selective reaction of hydroxyl groups; as a result, it relies heavily on the use of protecting groups.

A chemical glycosylation reaction involves the coupling of a glycosyl donor, to a glycosyl acceptor forming a glycoside. If both the donor and acceptor are sugars, then the product is an oligosaccharide. The reaction requires activation with a suitable activating reagent. 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.

Oligosaccharides and polysaccharides are an important class of polymeric carbohydrates found in virtually all living entities. Their structural features make their nomenclature challenging and their roles in living systems make their nomenclature important.

Intramolecular aglycon delivery is a synthetic strategy for the construction of glycans. This approach is generally used for the formation of difficult glycosidic linkages.

<span class="mw-page-title-main">Armed and disarmed saccharides</span>

The armed/disarmed approach to glycosylation is an effective way to prevent sugar molecules from self-glycosylation when synthesizing disaccharides. This approach was first recognized when acetylated sugars only acted as glycosyl acceptors when reacted with benzylated sugars. The acetylated sugars were termed “disarmed” while the benzylated sugars were termed “armed”.

The Crich β-mannosylation in organic chemistry is a synthetic strategy which is used in carbohydrate synthesis to generate a 1,2-cis-glycosidic bond. This type of linkate is generally very difficult to make, and specific methods like the Crich β-mannosylation are used to overcome these issues. The technique takes its name from its developer, Professor David Crich.

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 resulting reaction is referred to as a glycosylation or chemical glycosylation.

Pierre Sinaÿ, born on April 11, 1938, in Aulnay-sous-Bois (Seine-et-Oise), is a French organic chemist.

References

  1. ↑ Tiwari, Vinod Kumar (October 26, 2023). Synthetic Strategies in Carbohydrate Chemistry (1st ed.). Elsevier. pp. 3–7. ISBN   9780323986496.{{cite book}}: CS1 maint: date and year (link)
  2. ↑ Laurentin, A.; Edwards, C. A. (2013-01-01), "Fiber: Resistant Starch and Oligosaccharides", in Caballero, Benjamin (ed.), Encyclopedia of Human Nutrition (Third Edition), Waltham: Academic Press, pp. 246–253, ISBN   978-0-12-384885-7 , retrieved 2024-04-13
  3. 1 2 Seeberger, Peter H.; Werz, Daniel B. (April 2007). "Synthesis and medical applications of oligosaccharides". Nature. 446 (7139): 1046–1051. Bibcode:2007Natur.446.1046S. doi:10.1038/nature05819. ISSN   1476-4687. PMID   17460666.
  4. ↑ Boltje, Thomas J.; Buskas, Therese; Boons, Geert-Jan (2009-11-01). "Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research". Nature Chemistry. 1 (8): 611–622. Bibcode:2009NatCh...1..611B. doi:10.1038/nchem.399. ISSN   1755-4330. PMC   2794050 . PMID   20161474.
  5. 1 2 Xu, Han; Shen, Baoxing; Qiao, Meng; Linhardt, Robert J.; Zhang, Xing (2021-04-15). "Recent advances on the one-pot synthesis to assemble size-controlled glycans and glycoconjugates and polysaccharides". Carbohydrate Polymers. 258: 117672. doi:10.1016/j.carbpol.2021.117672. ISSN   1879-1344. PMID   33593549.
  6. 1 2 Shivatare, Sachin S.; Shivatare, Vidya S.; Wong, Chi-Huey (2022-10-26). "Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments". Chemical Reviews. 122 (20): 15603–15671. doi:10.1021/acs.chemrev.1c01032. ISSN   0009-2665. PMC   9674437 . PMID   36174107.
  7. ↑ Chandel, Navdeep S. (January 2021). "Carbohydrate Metabolism". Cold Spring Harbor Perspectives in Biology. 13 (1): a040568. doi:10.1101/cshperspect.a040568. ISSN   1943-0264. PMC   7778149 . PMID   33397651.
  8. ↑ Daniel E. Levy & Péter Fügedi.; The organic chemistry of sugars; Taylor & Francis: 2006, pp 181-197
  9. ↑ Stefanetti, Giuseppe; MacLennan, Calman Alexander; Micoli, Francesca (2022-09-29). "Impact and Control of Sugar Size in Glycoconjugate Vaccines". Molecules. 27 (19): 6432. doi: 10.3390/molecules27196432 . ISSN   1420-3049. PMC   9572008 . PMID   36234967.
  10. ↑ Robert V. Stick.; Carbohydrates: The Sweet Molecules of Life.; Academic Press.; 2001, pp 113-177
  11. ↑ Crich, D.; Dudkin V. J. Am. Chem. Soc.2001, 123, 6819-6825
  12. ↑ Tiwari, Vinod Kumar (October 26, 2023). Synthetic Strategies in Carbohydrate Chemistry (1st ed.). Elsevier. pp. 3–7. ISBN   9780323986496.{{cite book}}: CS1 maint: date and year (link)
  13. ↑ academic.oup.com https://academic.oup.com/glycob/article/21/1/23/1988274 . Retrieved 2024-04-13.{{cite web}}: Missing or empty |title= (help)
  14. ↑ Garegg, P. J. Chemtracts-Org. Chem., 1992, 5, 389
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.