chemical glycosylation

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.

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.

File:MechChemGlycosylation.gif

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.

File:NGPAcetoxoniumIon.gif

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.

File:NGPBenzylExample.gif

Different protecting groups on either the glycosyl donor or the glycosyl acceptor{{Cite journal|last1=Vorm|first1=Stefan van der|last2=Hansen|first2=Thomas|last3=Hengst|first3=Jacob M. A. van|last4=S. Overkleeft|first4=Herman|last5=Marel|first5=Gijsbert A. van der|last6=C. Codée|first6=Jeroen D.|date=2019|title=Acceptor reactivity in glycosylation reactions|journal=Chemical Society Reviews|language=en|volume=48|issue=17|pages=4688–4706|doi=10.1039/C8CS00369F|pmid=31287452|doi-access=free|hdl=1887/79489|hdl-access=free}}{{Cite journal|last1=Vorm|first1=S. van der|last2=Hansen|first2=T.|last3=S. Overkleeft|first3=H.|last4=Marel|first4=G. A. van der|last5=C. Codée|first5=J. D.|date=2017|title=The influence of acceptor nucleophilicity on the glycosylation reaction mechanism|journal=Chemical Science|language=en|volume=8|issue=3|pages=1867–75|doi=10.1039/C6SC04638J|pmid=28553477|pmc=5424809}} 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|Armed and disarmed saccharides}}

Glycosyl iodides were first introduced for use in glycosylation reactions in 1901 by Koenigs and Knorr{{cite journal

| title = Ueber einige Derivate des Traubenzuckers und der Galactose (p )

| first1=Wilhelm |last1=Koenigs |first2=Edward |last2=Knorr

| journal = Berichte der deutschen chemischen Gesellschaft

| volume = 34

| issue = 1

| pages = 957–981

| year = 1901

| url = https://zenodo.org/record/1425998

| doi = 10.1002/cber.190103401162 }}{{cite journal |first=E. |last=Fischer |title=Ueber die Glucoside der Alkohole |journal=Ber. Dtsch. Chem. Ges. |volume=26 |issue= 3|pages=2400–12 |date=1893 |doi=10.1002/cber.18930260327 |url=https://zenodo.org/record/1425724}} 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.{{cite journal |last1=Gervay |first1=J. |last2=Hadd |first2=M. J. |title=Anionic Additions to Glycosyl Iodides: Highly Stereoselective Syntheses of β C-, N-, and O-Glycosides1|journal=J. Org. Chem. |volume=62 |issue=20 |pages=6961–67 |date=1997 |doi=10.1021/jo970922t |url=}}{{cite journal |last1=Hadd |first1=M.J. |last2=Gervay |first2=J. |title=Glycosyl iodides are highly efficient donors under neutral conditions |journal=Carbohydr. Res. |volume=320 |issue=1–2 |pages=61–69 |date=1999 |doi=10.1016/S0008-6215(99)00146-9 |url=}}{{cite journal |last1=Miquel |first1=N. |last2=Vignando |first2=S. |last3=Russo |first3=G. |last4=Lay |first4=L. |title=Efficient Synthesis of O-, S-, N- and C-Glycosides of 2-Amino-2-Deoxy-d-Glucopyranose from Glycosyl Iodides |journal=Synlett |volume=2004 |issue=2 |pages=341–3 |date=2004 |doi=10.1055/s-2003-44978 |url=}}{{cite journal |last1=van Well |first1=R.M. |last2=Kartha |first2=K.P.R. |last3=Field |first3=R.A. |title=Iodine Promoted Glycosylation with Glycosyl Iodides: α-Glycoside Synthesis |journal=J. Carbohydr. Chem. |volume=24 |issue=4–6 |pages=463–474 |date=2005 |doi=10.1081/CAR-200067028 |s2cid=86329924 |url=}} Glycosyl iodides may be made under a variety of conditions, one method of note is the reaction of a 1-O-acetylpyranoside with TMSI.{{cite journal |last1=Gervay |first1=J. |last2=Nguyen |first2=T.N. |last3=Hadd |first3=M.J. |title=Mechanistic studies on the stereoselective formation of glycosyl iodides: first characterization of β-d-glycosyl iodides |journal=Carbohydr. Res. |volume=300 |issue= 2|pages=119–125 |date=1997 |doi=10.1016/S0008-6215(96)00321-7 |url=}}

File:GlycosylIodideFormation.gif

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.{{cite journal |vauthors=Zhu X, Schmidt RR |title=New principles for glycoside-bond formation |journal=Angew Chem Int Ed Engl |volume=48 |issue=11 |pages=1900–34 |date=2009 |pmid=19173361 |doi=10.1002/anie.200802036 }}{{cite journal |vauthors=Lam SN, Gervay-Hague J |title=Efficient route to 2-deoxy beta-O-aryl-d-glycosides via direct displacement of glycosyl iodides |journal=Org Lett |volume=5 |issue=22 |pages=4219–22 |date=October 2003 |pmid=14572289 |doi=10.1021/ol035705v }}{{cite journal |vauthors=Du W, Gervay-Hague J |title=Efficient synthesis of alpha-galactosyl ceramide analogues using glycosyl iodide donors |journal=Org Lett |volume=7 |issue=10 |pages=2063–5 |date=May 2005 |pmid=15876055 |doi=10.1021/ol050659f }}{{cite journal |vauthors=Du W, Kulkarni SS, Gervay-Hague J |title=Efficient, one-pot syntheses of biologically active alpha-linked glycolipids |journal=Chem Commun |volume=23 |pages=2336–8 |date=June 2007 |issue=23 |pmid=17844738 |doi=10.1039/b702551c }}

File:IodideGlycosylationExamples.gif

Thioglycosides were first reported in 1909 by Fischer{{cite journal |last1=Fischer |first1=E. |last2=Delbrück |first2=K. |title=Über Thiophenol-glucoside |journal=Ber. Dtsch. Chem. Ges. |volume=42 |issue= 2|pages=1476–82 |date=1909 |doi=10.1002/cber.19090420210 |url=}} 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 {{chem|BF|3|•OEt|2}} and the appropriate thiol.{{cite journal |vauthors=Tai CA, Kulkarni SS, Hung SC |title=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 |journal=J Org Chem |volume=68 |issue=22 |pages=8719–22 |date=October 2003 |pmid=14575510 |doi=10.1021/jo030073b }}{{cite journal |vauthors=Agnihotri G, Tiwari P, Misra AK |title=One-pot synthesis of per-O-acetylated thioglycosides from unprotected reducing sugars |journal=Carbohydr Res |volume=340 |issue=7 |pages=1393–6 |date=May 2005 |pmid=15854611 |doi=10.1016/j.carres.2005.02.027 }}{{cite journal |vauthors=Hasegawa JY, Hamada M, Miyamoto T, Nishide K, Kajimoto T, Uenishi J, Node M |title=The application of phenylmethanethiol and benzenethiol derivatives as odorless organosulfur reagents in the synthesis of thiosugars and thioglycosides |journal=Carbohydr Res |volume=340 |issue=15 |pages=2360–8 |date=October 2005 |pmid=16143318 |doi=10.1016/j.carres.2005.07.011 }}

File:ThioglycosidePrep.gif

Thioglycosides used in glycosylation reactions as donors can be activated under a wide range of conditions, most notably using NIS/AgOTf.{{cite journal |last1=Veeneman |first1=G.H. |last2=van Leeuwen |first2=S.H. |last3=van Boom |first3=J.H. |title= 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|journal=Tetrahedron Lett. |volume=31 |issue= 9|pages=1331–4 |date=1990 |doi=10.1016/S0040-4039(00)88799-7 |url=}}

File:SampleThioglycoside.gif

Trichloroacetimidates were first introduced and explored by Schmidt in 1980{{cite journal |last1=Schmidt |first1=R.R. |last2=Michel |first2=J. |title=Einfache Synthese von α-und β-O-Glykosylimidaten; Herstellung von Glykosiden und Disacchariden |journal=Angew. Chem. |volume=92 |issue=9 |pages=763–4 |date=1980 |doi=10.1002/ange.19800920933 |bibcode=1980AngCh..92..763S |url=}}{{cite journal |last1=Schmidt |first1=R.R. |last2=Michel |first2=J. |title=Facile Synthesis of α- and β-O-Glycosyl Imidates; Preparation of Glycosides and Disaccharides |journal=Angew. Chem. Int. Ed. Engl. |volume=19 |issue=9 |pages=731–2 |date=1980 |doi=10.1002/anie.198007311 |url=}} 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 ({{chem|Cl|3|CCN}}) under basic conditions to a free anomeric hydroxyl group.

File:TCAPrep.gif

Typical activating groups for glycosylation reactions using trichloroacetimidates are {{chem|BF|3|•OEt|2}} or TMSOTf.{{cite journal |vauthors=Kale RR, McGannon CM, Fuller-Schaefer C, Hatch DM, Flagler MJ, Gamage SD, Weiss AA, Iyer SS |title=Differentiation between structurally homologous Shiga 1 and Shiga 2 toxins by using synthetic glycoconjugates |journal=Angew Chem Int Ed Engl |volume=47 |issue=7 |pages=1265–8 |date=2008 |pmid=18172842 |doi=10.1002/anie.200703680 }}

File:TCAexample1.gif

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.{{Cite journal|last1=Heuckendorff|first1=Mads|last2=Jensen|first2=Henrik H.|date=2017|title=Removal of some common glycosylation by-products during reaction work-up|url=http://www.sciencedirect.com/science/article/pii/S000862151630550X|journal=Carbohydrate Research|volume=439|pages=50–56|doi=10.1016/j.carres.2016.12.007|pmid=28107657 }}

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

[[File:Docosanasaccharide.png|centre|thumb|400px|A polyfuranoside.{{cite journal |vauthors=Joe M, Bai Y, Nacario RC, Lowary TL |title=Synthesis of the docosanasaccharide arabinan domain of mycobacterial arabinogalactan and a proposed octadecasaccharide biosynthetic precursor |journal=J Am Chem Soc |volume=129 |issue=32 |pages=9885–901 |date=August 2007 |pmid=17655235 |doi=10.1021/ja072892+ }}

]]

File:TetraMan.gif

• Glycosylation
• Glycosyl transferase
• Glycorandomization
• Glycation
• Carbohydrate chemistry
• Oligosaccharide
• Carbohydrate

{{reflist|30em}}

• {{cite book |first=Marco |last=Brito-Arias |title=Synthesis and Characterization of Glycosides |publisher=Springer |edition=3rd |date=2022 |isbn=978-3-030-97854-9 |doi=10.1007/978-3-030-97854-9|s2cid=248302952 }}

Category:Carbohydrates

Category:Carbohydrate chemistry