Wikipedia

Chemical glycosylation

A chemical glycosylation reaction involves the coupling of a glycosyl donor, to a glycosyl acceptor forming a glycoside.[1][2][3] 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.

Terminology

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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 donor 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 oxocarbenium is eliminated leaving an electrophilic anomeric carbon.
  • A glycosyl acceptor 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 which enables the leaving group at the anomeric position to leave and results in the formation of the oxocarbenium ion.

Stereochemistry

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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

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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-participating 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, the α-glycoside usually predominates.

 

Protecting groups

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Different protecting groups on either the glycosyl donor or the glycosyl acceptor[4][5] may affect the reactivity and yield of the glycosylation reaction. Typically, electron-withdrawing groups such as acetyl or benzoyl groups are found to decrease the reactivity of the donor/acceptor and are therefore termed "disarming" groups. Electron-donating groups such as the benzyl group, are found to increase the reactivity of the donor/acceptor and are therefore called "arming" groups.

Main article: Armed and disarmed saccharides

Current methods in glycoside synthesis

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Glycosyl iodides

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Glycosyl iodides were first introduced for use in glycosylation reactions in 1901 by Koenigs and Knorr[6][7] 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.[8][9][10][11] Glycosyl iodides may be made under a variety of conditions, one method of note is the reaction of a 1-O-acetylpyranoside with TMSI.[12]

 

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.[13][14][15][16]

 

Thioglycosides

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Thioglycosides were first reported in 1909 by Fischer[17] 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.[13] Thioglycosides are usually prepared by reacting per-acetylated sugars with BF
3•OEt
2 and the appropriate thiol.[18][19][20]

 

Thioglycosides used in glycosylation reactions as donors can be activated under a wide range of conditions, most notably using NIS/AgOTf.[21]

 

Trichloroacetimidates

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Trichloroacetimidates were first introduced and explored by Schmidt in 1980[22][23] 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.[13] O-Glycosyl trichloroacetimidates are prepared via the addition of trichloroacetonitrile (Cl
3CCN) under basic conditions to a free anomeric hydroxyl group.

 

Typical activating groups for glycosylation reactions using trichloroacetimidates are BF
3•OEt
2 or TMSOTf.[24]

 

Column chromatographic purification of the reaction mixture can sometimes be challenging due to the trichloroacetamide by-product. This can, however, be overcome by washing the organic layer with 1 M NaOH solution in a separatory funnel prior to chromatography. Acetyl protecting groups were found to be stable during this procedure.[25]

Notable synthetic products

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Below are a few examples of some notable targets obtained via a series of glycosylation reactions.

 
A polyfuranoside.[26]
 
A polypyranoside.[27]

See also

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References

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  1. ^ Boons, Geert-Jan; Karl J. Hale (2000). Organic synthesis with carbohydrates. Blackwell. ISBN 978-1-85075-913-3.
  2. ^ Crich, D.; Lim, L. (2004). "Glycosylation with Sulfoxides and Sulfinates as Donors or Promoters". Org. React. 64: 115–251. doi:10.1002/0471264180.or064.02. ISBN 0471264180.
  3. ^ Bufali, S.; Seeberger, P. (2006). "Glycosylation on Polymer Supports". Org. React. 68: 115–251. doi:10.1002/0471264180.or068.02. ISBN 0471264180.
  4. ^ Vorm, Stefan van der; Hansen, Thomas; Hengst, Jacob M. A. van; S. Overkleeft, Herman; Marel, Gijsbert A. van der; C. Codée, Jeroen D. (2019). "Acceptor reactivity in glycosylation reactions". Chemical Society Reviews. 48 (17): 4688–4706. doi:10.1039/C8CS00369F. hdl:1887/79489. PMID 31287452.
  5. ^ Vorm, S. van der; Hansen, T.; S. Overkleeft, H.; Marel, G. A. van der; C. Codée, J. D. (2017). "The influence of acceptor nucleophilicity on the glycosylation reaction mechanism". Chemical Science. 8 (3): 1867–75. doi:10.1039/C6SC04638J. PMC 5424809. PMID 28553477.
  6. ^ Koenigs, Wilhelm; Knorr, Edward (1901). "Ueber einige Derivate des Traubenzuckers und der Galactose (p )". Berichte der deutschen chemischen Gesellschaft. 34 (1): 957–981. doi:10.1002/cber.190103401162.
  7. ^ Fischer, E. (1893). "Ueber die Glucoside der Alkohole". Ber. Dtsch. Chem. Ges. 26 (3): 2400–12. doi:10.1002/cber.18930260327.
  8. ^ Gervay, J.; Hadd, M. J. (1997). "Anionic Additions to Glycosyl Iodides: Highly Stereoselective Syntheses of β C-, N-, and O-Glycosides1". J. Org. Chem. 62 (20): 6961–67. doi:10.1021/jo970922t.
  9. ^ Hadd, M.J.; Gervay, J. (1999). "Glycosyl iodides are highly efficient donors under neutral conditions". Carbohydr. Res. 320 (1–2): 61–69. doi:10.1016/S0008-6215(99)00146-9.
  10. ^ Miquel, N.; Vignando, S.; Russo, G.; Lay, L. (2004). "Efficient Synthesis of O-, S-, N- and C-Glycosides of 2-Amino-2-Deoxy-d-Glucopyranose from Glycosyl Iodides". Synlett. 2004 (2): 341–3. doi:10.1055/s-2003-44978.
  11. ^ van Well, R.M.; Kartha, K.P.R.; Field, R.A. (2005). "Iodine Promoted Glycosylation with Glycosyl Iodides: α-Glycoside Synthesis". J. Carbohydr. Chem. 24 (4–6): 463–474. doi:10.1081/CAR-200067028. S2CID 86329924.
  12. ^ Gervay, J.; Nguyen, T.N.; Hadd, M.J. (1997). "Mechanistic studies on the stereoselective formation of glycosyl iodides: first characterization of β-d-glycosyl iodides". Carbohydr. Res. 300 (2): 119–125. doi:10.1016/S0008-6215(96)00321-7.
  13. ^ a b c Zhu X, Schmidt RR (2009). "New principles for glycoside-bond formation". Angew Chem Int Ed Engl. 48 (11): 1900–34. doi:10.1002/anie.200802036. PMID 19173361.
  14. ^ Lam SN, Gervay-Hague J (October 2003). "Efficient route to 2-deoxy beta-O-aryl-d-glycosides via direct displacement of glycosyl iodides". Org Lett. 5 (22): 4219–22. doi:10.1021/ol035705v. PMID 14572289.
  15. ^ Du W, Gervay-Hague J (May 2005). "Efficient synthesis of alpha-galactosyl ceramide analogues using glycosyl iodide donors". Org Lett. 7 (10): 2063–5. doi:10.1021/ol050659f. PMID 15876055.
  16. ^ Du W, Kulkarni SS, Gervay-Hague J (June 2007). "Efficient, one-pot syntheses of biologically active alpha-linked glycolipids". Chem Commun. 23 (23): 2336–8. doi:10.1039/b702551c. PMID 17844738.
  17. ^ Fischer, E.; Delbrück, K. (1909). "Über Thiophenol-glucoside". Ber. Dtsch. Chem. Ges. 42 (2): 1476–82. doi:10.1002/cber.19090420210.
  18. ^ Tai CA, Kulkarni SS, Hung SC (October 2003). "Facile Cu(OTf)2-catalyzed preparation of per-O-acetylated hexopyranoses with stoichiometric acetic anhydride and sequential one-pot anomeric substitution to thioglycosides under solvent-free conditions". J Org Chem. 68 (22): 8719–22. doi:10.1021/jo030073b. PMID 14575510.
  19. ^ Agnihotri G, Tiwari P, Misra AK (May 2005). "One-pot synthesis of per-O-acetylated thioglycosides from unprotected reducing sugars". Carbohydr Res. 340 (7): 1393–6. doi:10.1016/j.carres.2005.02.027. PMID 15854611.
  20. ^ Hasegawa JY, Hamada M, Miyamoto T, Nishide K, Kajimoto T, Uenishi J, Node M (October 2005). "The application of phenylmethanethiol and benzenethiol derivatives as odorless organosulfur reagents in the synthesis of thiosugars and thioglycosides". Carbohydr Res. 340 (15): 2360–8. doi:10.1016/j.carres.2005.07.011. PMID 16143318.
  21. ^ Veeneman, G.H.; van Leeuwen, S.H.; van Boom, J.H. (1990). "Iodonium ion promoted reactions at the anomeric centre. II an efficient thioglycoside mediated approach toward the formation of 1,2-trans linked glycosides and glycosidic esters". Tetrahedron Lett. 31 (9): 1331–4. doi:10.1016/S0040-4039(00)88799-7.
  22. ^ Schmidt, R.R.; Michel, J. (1980). "Einfache Synthese von α-und β-O-Glykosylimidaten; Herstellung von Glykosiden und Disacchariden". Angew. Chem. 92 (9): 763–4. Bibcode:1980AngCh..92..763S. doi:10.1002/ange.19800920933.
  23. ^ Schmidt, R.R.; Michel, J. (1980). "Facile Synthesis of α- and β-O-Glycosyl Imidates; Preparation of Glycosides and Disaccharides". Angew. Chem. Int. Ed. Engl. 19 (9): 731–2. doi:10.1002/anie.198007311.
  24. ^ Kale RR, McGannon CM, Fuller-Schaefer C, Hatch DM, Flagler MJ, Gamage SD, Weiss AA, Iyer SS (2008). "Differentiation between structurally homologous Shiga 1 and Shiga 2 toxins by using synthetic glycoconjugates". Angew Chem Int Ed Engl. 47 (7): 1265–8. doi:10.1002/anie.200703680. PMID 18172842.
  25. ^ Heuckendorff, Mads; Jensen, Henrik H. (2017). "Removal of some common glycosylation by-products during reaction work-up". Carbohydrate Research. 439: 50–56. doi:10.1016/j.carres.2016.12.007. PMID 28107657.
  26. ^ Joe M, Bai Y, Nacario RC, Lowary TL (August 2007). "Synthesis of the docosanasaccharide arabinan domain of mycobacterial arabinogalactan and a proposed octadecasaccharide biosynthetic precursor". J Am Chem Soc. 129 (32): 9885–901. doi:10.1021/ja072892+. PMID 17655235.
  27. ^ Wu X, Bundle DR (September 2005). "Synthesis of glycoconjugate vaccines for Candida albicans using novel linker methodology". J Org Chem. 70 (18): 7381–8. doi:10.1021/jo051065t. PMID 16122263.

Books

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