Carbohydrate synthesis

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Carbohydrate synthesis is a sub-field of organic chemistry concerned with generating complex carbohydrate structures from simple units (monosaccharides). The generation of carbohydrate structures usually involves linking monosaccharides or oligosaccharides through glycosidic bonds, a process called glycosylation. 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

Carbohydrates can generally be classified into one of two groups, monosacharides, and complex carbohydrates. Monosacharides (also called "simple sugars") are the simplest single units of any carbohydrate; the most common monosaccharides are five and six carbon compounds such as glucose, fructose, and galactose. [2] Complex carbohydrates are combinations of monosaccarides linked together through connections called glycosidic bonds, the product of these linkages can be further categorized according to their size. Two monosaccharides linked together produce a disaccharide such as lactose. Three to ten monosaccharide units linked together are referred to as oligosaccharides. Anything larger than ten monosacharide units is called a polysaccharide, this broad category includes very large molecules such as starch, a plant glucose polymer which can contain millions of glucose residues. [2]

The synthesis of carbohydrates is very important to the study of biochemistry and certain kinds of synthetic chemistry since carbohydrates play important roles in many biological systems. In nature, monosaccharides are synthesized biologically from raw materials through the processes of photosynthesis in plants and certain prokaryotes, or by gluconeogenesis in animals. [2] Laboratory processes also exist for the artificial synthesis of monosaccharides, such as the Kiliani-Fischer synthesis which can sequentially build large simple sugars from smaller monomers. [3]

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. [4] [5] The facile procedures such as the one-pot and solid phase synthesis which ensures atom economy [6] [4] are used. However, further developments in those synthetic approaches are needed since still not fully controlled and automated. [6]

Significance

The glycoconjugate is the product formed by oligosaccharides covalently bonding to other biomolecules such as proteins and lipids. [7] They play indispensable roles in the biological activities of mammalian cells from energy generation to cell signalling. [7] [8] [9] These glycoconjugates with short oligosaccharide structures are important for the characterization and purification in the course glycoconjucate vaccine developments. [10] Therefore, research in the engineering of the glycosyl precursors that create oligosaccharides with controlled size is important in carbohydrate synthesis.[ citation needed ]

Biological Synthesis

Glycolysis Pathway Glycolysis pathway 2.png
Glycolysis Pathway

Mammals begin carbohydrate synthesis with monosaccharides, which come from either gluconeogenesis or the breakdown of complex carbohydrates. [11] Gluconeogenesis begins with pyruvate, which comes from alanine and α-ketoglutarate amino acids. [12] This process only begins when glycogen storages are near depletion due to the higher ATP cost of metabolising proteins into amino acids. [12]

Conversely, plants undergo the Calvin Cycle to photosynthesize glucose-3-phosphate from CO2 and H2O in the presence of light; the phosphate is quickly hydrolyzed into glucose. [12]

Glucose to Glycogen Pathway Glucose to Glycogen R.png
Glucose to Glycogen Pathway

Digestion of complex carbohydrates allows glucose molecules to be re-polymerized into a form that is recognized by enzymes. [12] In mammals, glucose molecules polymerize into glycogen stores or glycogenin. [12] The reformation of carbohydrates is essential for converting them into forms that can be more easily transported to cells with higher glucose requirements. [12]

Both mammals and plants use the same mechanisms to convert glucose into complex carbohydrates; the only difference is the enzymes used to catalyze the mechanisms. Mammals require glycogen synthase and glycogenin to synthesize glycogen [12] . Plants synthesize amylose with starch synthase and amylopectin with starch-branching enzymes. [12]

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 which anomer is formed.

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. [13] 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. [14]

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, [1] but the disaccharides with ɑ-linkages are non-reducing thus deactivating the consequent connection of the monosaccharides. [15] 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.[ citation needed ]

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 David 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 [16] 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.

<span class="mw-page-title-main">Polysaccharide</span> Long carbohydrate polymers such as starch, glycogen, cellulose, and chitin

Polysaccharides, or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with water (hydrolysis) using amylase enzymes as catalyst, which produces constituent sugars. They range in structure from linear to highly branched. Examples include storage polysaccharides such as starch, glycogen and galactogen and structural polysaccharides such as hemicellulose and chitin.

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">Maltose</span> Chemical compound

Maltose, also known as maltobiose or malt sugar, is a disaccharide formed from two units of glucose joined with an α(1→4) bond. In the isomer isomaltose, the two glucose molecules are joined with an α(1→6) bond. Maltose is the two-unit member of the amylose homologous series, the key structural motif of starch. When beta-amylase breaks down starch, it removes two glucose units at a time, producing maltose. An example of this reaction is found in germinating seeds, which is why it was named after malt. Unlike sucrose, it is a reducing sugar.

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">Glycosyl</span> Molecular substituent derived from cyclic monosaccharides

In organic chemistry, a glycosyl group is a univalent free radical or substituent structure obtained by removing the hydroxyl group from the hemiacetal group found in the cyclic form of a monosaccharide and, by extension, of a lower oligosaccharide. Glycosyl groups are exchanged during glycosylation from the glycosyl donor, the electrophile, to the glycosyl acceptor, the nucleophile. The outcome of the glycosylation reaction is largely dependent on the reactivity of each partner. Glycosyl also reacts with inorganic acids, such as phosphoric acid, forming an ester such as glucose 1-phosphate.

<span class="mw-page-title-main">Glycolipid</span> Class of chemical compounds

Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connections that allow cells to connect to one another to form tissues. Glycolipids are found on the surface of all eukaryotic cell membranes, where they extend from the phospholipid bilayer into the extracellular environment.

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.

Nucleotide sugars are the activated forms of monosaccharides. Nucleotide sugars act as glycosyl donors in glycosylation reactions. Those reactions are catalyzed by a group of enzymes called glycosyltransferases.

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.

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.

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. Since the nucleophilic atom of the acceptor is typically an oxygen atom, this can be remembered using the mnemonic of the acceptor is the alcohol. A glycosyl acceptor can be a mono- or oligosaccharide that contains an available nucleophile, such as an unprotected hydroxyl.

<i>N</i>-linked glycosylation Attachment of an oligosaccharide to a nitrogen atom

N-linked glycosylation is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom, in a process called N-glycosylation, studied in biochemistry. The resulting protein is called an N-linked glycan, or simply an N-glycan.

References

  1. 1 2 Tiwari, Vinod Kumar (October 26, 2023). Synthetic Strategies in Carbohydrate Chemistry (1st ed.). Elsevier. pp. 3–7. ISBN   9780323986496.
  2. 1 2 3 Pratt, Charlotte W.; Cornely, Kathleen (2014). Essential biochemistry (3rd ed.). Hoboken, NJ: Wiley. ISBN   978-1-118-08350-5.
  3. ↑ Parikh, Arun; Parikh, Hansa; Parikh, Khyati (2006). Name reactions in organic synthesis. New Delhi: Foundation Books. ISBN   978-81-7596-829-5.
  4. 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.
  5. ↑ 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.
  6. 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.
  7. 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.
  8. ↑ 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.
  9. ↑ Daniel E. Levy & Péter Fügedi.; The organic chemistry of sugars; Taylor & Francis: 2006, pp 181-197
  10. ↑ 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.
  11. ↑ Pratt, Charlotte W.; Cornely, Kathleen (2014). Essential biochemistry (3rd ed.). Hoboken, NJ: Wiley. ISBN   978-1-118-08350-5.
  12. 1 2 3 4 5 6 7 8 Nelson, D. L., & Cox, M. M. (2017). Lehninger Principles of Biochemistry (7th ed.). W.H. Freeman and Sapling Learning, 1636-1638, 1671-1675.{{cite book}}: Missing or empty |title= (help)CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  13. ↑ Robert V. Stick.; Carbohydrates: The Sweet Molecules of Life.; Academic Press.; 2001, pp 113-177
  14. ↑ Crich, D.; Dudkin V. J. Am. Chem. Soc.2001, 123, 6819-6825
  15. ↑ Sharma, Alok; Vijayan, Mamannamana (January 2011). "Influence of glycosidic linkage on the nature of carbohydrate binding in β-prism I fold lectins: An X-ray and molecular dynamics investigation on banana lectin–carbohydrate complexes". Glycobiology. 21 (1): 23–33. doi:10.1093/glycob/cwq128. PMID   20729346.
  16. ↑ Garegg, P. J. Chemtracts-Org. Chem., 1992, 5, 389
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