Glycosyl halide

The application of glycosyl halides in glycosylation, as developed by Koenigs and Knorr [10], had been, for a long time, the only available method for the stereospecific synthesis of 1,2-trans-glycosides. Today, they are still widely used in the syntheses 

FIGURE 3.1 Typical glycosyl donors and their corresponding promoters or activating reagents. DTBMP, 2,6-di-ferf-butyl-4-methylpyridine TMS, trimethylsilyl Tf, triflyl. 

SCHEME 3.7 Koenigs-Knorr glycosylation promoted by insoluble silver salts. 

2- ris-glycosides. Other factors such as solvent participation and temperature may also play a role in the stereocontrol of the glycosylation reaction. 

Despite its wide application in glycoside synthesis, the Koenigs-Knorr reaction suffers from several disadvantages (i) the glycosyl halides are unstable, (ii) excess toxic heavy metals are needed to activate the donor, and (iii) a desiccant (to absorb any liberated water) and an acid acceptor (to absorb the liberated hydrogen halide and can be a promoter itself) are often needed to increase the yield and suppress side reactions. 

Several methods have been reported for the preparation of glycosyl fluorides7 but the most common procedure is treatment of a thioglycoside with NBS (iV-bromosuccinimide) and (diethylamino)sulfur trifluoride (DAST)8 or the reaction of a lactol with DAST or 2-fluoro-l-methylpyridinium p-toluenesulfohate.7 9 An alternative and interesting method is the treatment of a 1,2-anhydro-pyranoside with tetra-n-butylammonium fluoride (TBAF). 

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan toshima applc.keio.ac.jp 

Glycosylation Glycosyl donor Glycosyl halide Glycosyl bromide Glycosyl chloride Glycosyl iodide Glycosyl fluoride 

Glycosylation of glycosyl bromide or chloride using heavy metal KO ROH O 

The stereochemistry of the addition of chlorine to 3,4-dihydro-2/f-pyran has been found to be influenced by the polarity of the solvent in which the reaction is conducted. Stereoselective syn addition occurred in non-polar solvents e.g. n-pent-ane) to give a mixture of cis- and rrans-2,3-dichlorotetrahydropyrans in the ratio of ca. 4 1, whereas the ratio was 1 2 in polar solvents e.g. dichloromethane). cis-2,3-Dichlorotetrahydropyran yielded exclusively trans-products with various nucleophiles (N3, MeO, PhS, and AcO ) in DMF with inversion of configuration at C-2, whereas trans-2,3-dichlorotetrahydropyran yielded the cis-product with the thiophenate anion and a mixture of cis- and trans-products with the other anions. Hydrogen chloride and hydrogen bromide added to 3,4-di-O-acetyl-L-fucal (134) and -rhamnal (135) to give adducts (136) and (137), respectively, possessing the a-L configuration.  

Reagents i, ClCH COCl-sym-trimethylpyridine ii, AcjO-py iii, H iv, AcCI-py v,(NH2)jCS-H20 vi, HBr-AcOH 

D-Mannofuranosyl halide derivatives are referred to in the following section, while references to other glycosyl halides appear in Chapters 3, 10, 12, and 17. 

Reagents i, BzCl-py ii, N, iii, BzCl-py iv, AC2O-H2SO4 v, TiBr vi, EtiN+Cl  

Peracetates of mono- and di-saccharides e.g. a-D-glucopyranose and j8-lactose) were treated with dichloromethyl methyl ether and tin(iv) chloride at room temperature to give the more stable acetylated glycosyl chlorides in high yields, and this and other uses of this reagent in carbohydrate chemistry 

Re-investigation of the chlorination of the hydroxyglycal tetrabenzoate (95) has shown that the cw-adducts (96) and (97) are formed in the ratio of 3 7. Chlorination of (95) at low temperatures furnished the orthoacid chloride 

Pedersen, and R. Rasmussen, Acta Chem. Scand. S), 1976, 29, 185. 

Glycosyl halides used in the synthesis of glycosides have been mentioned in Chapter 3. 

Prolonged treatment of 1,2,3,5-tetra-O-benzoyl-jS-D-xylofuranose with anhydrous hydrogen fluoride gave, after aqueous work-up and benzoylation, principally 

5-tri-0-benzoyl-o -D-lyxofuranosyl fluoride, whereas similar treatment of D-xylo-furanosyl and -pyranosyl and D-lyxo-furanosyl and -pyranosyl tetraacetates yielded complex mixtures. The reaction of 1,3,4,6-tetra-O-benzoyl-2-0-methyl- -D-glucopyranose with anhydrous hydrogen fluoride yielded initially the a-glycopyranosyl fluoride, which reacted further to give, after aqueous work-up and benzoylation, the anomeric furanosyl fluorides (88).  

6- Tri-C -acetyl-2-0-raethyl-j8-D-mannofuranosyl fluoride (40%) and the corresponding a-anomer (11%) were obtained following prolonged treatment of 

6- tetra-0-acetyl-2-0-methyl-j3-D-mannopyranose with anhydrous hydrogen fluoride, aqueous work-up, and acetylation. Similar ring-contractions were observed with 1,3,4,6-tetra-0-acetyl-2-bromo(chloro)-2-deoxy-j8-D-glucopyranose. A mixture of 1,2,3,4,6-penta-O-acetyl-a- and -)8-D-fructofuranose gave the 

6- tetra-O-acetyl-a- and -]S-D-fructofuranosyl fluorides when treated briefly with anhydrous hydrogen fluoride. The acetylated a- and /3-D-fructofuranosyl fluorides were separated by chromatography on silica gel and appear to adopt 2 or and or 7i conformations, respectively, in chloroform- /. 

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In the case of indazoles the reaction of indazole, 5-nitroindazole or 6-nitroindazole with glycosyl halides and mercury(n) cyanide gives exclusively 2-glycosylindazoles (670), (673) and (675) (7QJHC1435). Similarly, the reaction of 1-trimethylsilyl derivatives of indazole, 3-cyanoindazole, 4-nitroindazole, 5-nitroindazole and 6-nitroindazole with 2,3,5-tri-O-acetyl-D-ribofuranosyl bromide gives only, or preferentially, the 2-ribofuranosyl derivatives (670)-(674) 7QJHC117, 70JHC1329). 

Compounds in which the anomeric hydroxy group is replaced by a halogen atom are named as glycosyl halides. Pseudohalides (azides, thiocyanates etc.) are named similarly. 

From Acylated Glycosyl Halides by Reaction with Thiolate Anion. 181... 

IV. In situ Generation of Glycosyl Halides from Thioglycosides. 184... 

In the Koenigs-Knorr method and in the Helferich or Zemplen modifications thereof, a glycosyl halide (bromide or chloride iodides can be produced in situ by the addition of tetraalkylammonium iodide) is allowed to react with a hydrox-ylic compound in the presence of a heavy-metal promoter such as silver oxide, carbonate, perchlorate, or mercuric bromide and/or oxide,19-21 or by silver triflu-oromethanesulfonate22 (AgOTf). Related to this is the use of glycosyl fluoride donors,23 which normally are prepared from thioglycosides.24... 

In the halide-assisted method,25 a glycosyl halide (normally bromide) with a nonparticipating 2-substituent and with the thermodynamically more stable axial orientation at C-l is treated with an excess of the corresponding halide anion by the addition of a soluble tetraalkylammonium salt. This sets up an equilibrium between the axial and the (much less stable) equatorial glycosyl halide. The lat-... 

In this classic41 and general method, an acylated glycosyl halide reacts with a thiolate anion to produce a 1-thioglycoside, usually with 1,2-trans configuration. With alkyl thiolates, re-acylation is normally required following this treatment. 

An acylated glycosyl halide, such as a 2,3,4,6-tetra-O-acetyl derivative, is treated with thiourea. The resulting pseudothiouronium salt is hydrolyzed with aqueous potassium carbonate to give the 2,3,4,6-tetra-0-acetyl-l-thio-(3-D-glucopyranose,48 which then is alkylated. 

Fischer projection of acyclic form, 56-57 glycosides, 132-135 C-glycosyl compounds, 139-140 N-glycosyl derivatives, 137-139 glycosyl halides, 136-137 glycosyl residues, 125 isotopic substitution and isotopic labelling, 91 me so forms, 59 optical rotation, 59 parent structure choice, 53... 

Because of the high C - F bond energy, glycosyl fluorides are stable in comparison to the other glycosyl halides, and this character has attracted much attention. They have been prepared in many different ways. One of them, rather classical, is through addition of the elements of HF (for example, HF in benzene ), BrF, or IF to per-O-acylated glycals. ... 

Glycosylations utilizing the aforedescribed glycosyl fluorides are described next. In 1981, Mukaiyama and coworkers attempted to prepare 1,2-cw-glycosides by utilizing the relatively stable (as compared with other glycosyl halides) 2,3,4,6-tetra-0-benzyl-)8-D-glucopyranosyl fluoride (47)5)... 

Tetramethylguanidinium azide, an azide salt that is readily soluble in halogenated solvents, is a useful source of azide ions in the preparation of azides from reactive halides such as a-haloketones, a-haloamides, and glycosyl halides.74... 

The /3-d configuration was assigned40 to 82 on the basis of the trans rule,83 as exemplified by the reaction of glycosyl halides with heavy-metal salts of heterocyclic bases.833 Unambiguous chemical proof was secured from the transformation of the nitrile into the corresponding acid (21). 

Glycosyl halides, a very important group of carbohydrate derivatives, are commonly prepared14 from per-O-acylated sugars by reaction with hydrogen halides or halides of aluminum or titanium. The selection of the method depends mainly on the anomeric configuration of the substrate, the kind of its O-acyl groups, and the stability of the product to be prepared. 

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