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editCarbohydrate 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].
Background[edit]
editGenerally 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].
Steric Challenges[edit]
editWhen connecting the monosaccharides the substrate needs to be reducing in order to sequentially connect the monosaccharide units. The monosaccharides, in nature prefer ɑ-linkages due to anomeric effect [6], but the disaccharides with ɑ-linkages are non-reducing thus deactivating the consequent connection of the monosaccharides[7]. 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 is a little-used but nevertheless stereospecific alternative.
Application[edit]
editGlycoconjugate is the covalently bonded product of oligosaccharides to the biomolecules such as proteins and lipids[8]. They play indispensable role in the biological activities of mammalian cells from being the substrates for energy generation to cell signalling[8][9]. These glycoconjugates are prone to associated with short oligosaccharide structures[10].
Significance
editGlycoconjugate is the covalently bonded product of oligosaccharides to the biomolecules such as proteins and lipids[11]. They play indispensable role in the biological activities of mammalian cells from being the substrates for energy generation to cell signalling[11][12]. These glycoconjugates are prone to associated with short oligosaccharide structures[13].
Oligosaccharide synthesis[edit]
editOligosaccharide 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. 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. Reducing oligosaccharide synthesis is important since the non-reducing units are no longer activate for the glycosidic linkage. The essence the 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.
References
edit- ^ 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) - ^ Laurentin, A.; Edwards, C. A. (2013-01-01), Caballero, Benjamin (ed.), "Fiber: Resistant Starch and Oligosaccharides", Encyclopedia of Human Nutrition (Third Edition), Waltham: Academic Press, pp. 246–253, ISBN 978-0-12-384885-7, retrieved 2024-04-13
- ^ a b Seeberger, Peter H.; Werz, Daniel B. (2007-04). "Synthesis and medical applications of oligosaccharides". Nature. 446 (7139): 1046–1051. doi:10.1038/nature05819. ISSN 1476-4687.
{{cite journal}}: Check date values in:|date=(help) - ^ 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. doi:10.1038/nchem.399. ISSN 1755-4330. PMC 2794050. PMID 20161474.
- ^ a b 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.
- ^ 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) - ^ academic.oup.com https://academic.oup.com/glycob/article/21/1/23/1988274. Retrieved 2024-04-13.
{{cite web}}: Missing or empty|title=(help) - ^ a b 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.
- ^ Chandel, Navdeep S. (2021-01). "Carbohydrate Metabolism". Cold Spring Harbor Perspectives in Biology. 13 (1): a040568. doi:10.1101/cshperspect.a040568. ISSN 1943-0264. PMC 7778149. PMID 33397651.
{{cite journal}}: Check date values in:|date=(help) - ^ 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.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b 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.
- ^ Chandel, Navdeep S. (2021-01). "Carbohydrate Metabolism". Cold Spring Harbor Perspectives in Biology. 13 (1): a040568. doi:10.1101/cshperspect.a040568. ISSN 1943-0264. PMC 7778149. PMID 33397651.
{{cite journal}}: Check date values in:|date=(help) - ^ 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.
{{cite journal}}: CS1 maint: unflagged free DOI (link)