Synthesis of Monosaccharide Glycosides

The syntheses of the methyl D-fructofuranosldes from 1,3,, 6-tetra- -benzoyl-D-fructose have been developed, and hence a large range of derivatives with amino, azldo, bromo, chloro, deoxy and 

Acidified methanolic treatment of 3-deoxy-D-arablno-2-heptulo-sonlc acid gave the methyl ester methyl glycoside (7) which was 

Several syntheses have involved the direct substitution of anomerlc hydroxy groups. 2,3,, 6-Tetra-O-benzyl-a-D-glucose condensed with alcohols in the presence of methanesulphonlc acid, cobalt dlbromide and tetraethylammonium perchlorate gave 

Reageats l. NaH-ROTf , NlaH-ROTf Crown Ether 

Various derivatives of C-1 hydroxy compounds have been used in 

1 Synthesis of Monosaccharide Glycosides.- A monograph on the stereo- and regio-control of synthesis in carbohydrate chemistry has covered several glycosidation procedures, while a second review 

Treatment of the diethyl dithioacetal of D-fucose with mercury(II) salts in methanol at 0° gave the 3-D-furanoslde in 93% yield, whereas at 65° 20 of the a-anomer was produced. Similar proportions of this compound were also obtained following anomeriza-tlon of methyl trl- -benzyl- -D-fucofuranoside. 

Acid-catalysed alcoholysis of D-fructose with 2-chloroethanol affords the crystalline B-pyranoside (1) in 90% yield, and an extensive range of further derivatives have been reported. For example, treatment of (1) with ethoxide anion gave the spiro-product (2), and the dlsulphonate (3) afforded the tricyclic epoxide 

A short synthesis of the natural cerebroslde (5) involved the use of the trichloroacetimldate method applied to either the 

Glycal derivatives continue to be used for the preparation of glycosides, and the N-iodosuccinimide procedure has afforded a route to steroidal glycosides of deoxy sugars. In some cases, 

1 Synthesis of Monosaccharide Glycosides.- Reviews on this topic have dealt with Issues Involved In the synthesis of 1,2-cls-related 

Compounds (1) and (2), readily prepared from 2-amlno-2-deoxy-D-glucose, gave mainly the a-pyranoslde (3) on treatment with methanollc HCl but also the 6-anomer and minor amounts of the CHoOH 

The anomeric selectivity observed in the synthesis of glucosides (including disaccharides) by reaction of 1-0-metallated 2,3, -tri- -benzyl-D-glucose compounds with alkyl triflates is dependent upon the substituent at 0-6. Good g-selectivity was observed for the 6-benzyl ether, while for the monomethoxytrltyl derivatives, the a 6 ratio was dependent upon the triflate employed.The 0-xylosyl serine derivative (9) has been made using the trlchloro- 

B-D-glucosides of pregnenolone. Treatment of the copper(I) bromide complex of the amldophosphlte (10) (R PNEtj) with butanol gave the furanoslde (11) in 12% yield, while the phosphate (12) (R s P(0)NEt2) reacted with less anomeric selectivity. 

A racemic anthracycllnone derivative has been resolved by treat- 

Attention will now be given to the methods which are used in glycoside synthesis and then to the types of glycosides produced. 

Carbohydrate Chemistry, Volume 30 The Royal Society of Chemistry, 1998 

2-deoxyglycosides, whereas sodium borohydride/cerium chloride in methanol gave the arabino-epimers  

Usual activation of the Kahne phenyl sulfoxide glycosylation method is by use of triflic anhydride, trimethylsilyl triflate, or triflic acid and methyl propiolate. This, however, has been found to be unsatisfactory in cases of glycosylating agents which do not have 2-deoxy groups. It has now been reported that triethyl phosphite with catalytic amounts of triflic acid cause the reaction to give disaccharide products in variable yields.  

1 Synthesis of Monosaccharide Glycosides.- A very useful review has appeared on newer methods for glycoside formation, particularly those based on 0-alkylation and on the use of glycosyl trichloro-acetimidates, sulphonium salts and fluorides. A shorter paper has 

Phase transfer reaction of unsubstituted anomeric hydroxy compounds with dimethyl sulphate gives o,6-ratios of methyl glycosides which are determined by the relative acidities of the anomeric 

1-Thio compounds continue to attract attention as glycosylating agents. Thioglycosides can be activated under mild conditions by use of copper(II) bromide and catalytic tert-butyl ammonium bromide to give high yields of either 1,2-cis- or 1,2-trans-glycosides from 

A review has appeared on the synthesis of fluorinated carbohydrates including glycosyl fluorides and their use in the pre- 

Both anomers gave a-linked dlsaccharlde products with secondary 

1 Synthesis of Monosaccharide Glycosides.-Conversions of secondary alcohols 1 into their tetra-O benzoyl-P-D-glucopyranosides have the effects shown (on the 8-values) of the relevant protons, while the effects on these protons in the diastereoisomers produced from the enantiomers of 1 (R=H) are similar in magnitude but opposite in sign. The method, therefore, can be used for determining absolute configtirations of such alcohol centres.  

Full details have appeared on the use of 0-protected glycosyl phosphites for Lewis acid-catalysed glycosidation (cf. Synlett, 1993, 115). Again anomeric mixtures were produced, but reasonable yields resulted - especially when O-benzyl protection was employed with glucosyl, galactosyl and mannosyl donors and with 0-acetylated sialic acid donor. 

Sugars protected at all hydroxyl position other than the anomeric can be used in a variety of other ways for the synthesis of glycosides. Tetra-O-methyl-glucose and -mannose have been examined in alkane and aprotic solvents using methyl iodide in the presence of sodium hydride. Good selectivities were claimed depending upon the conditions used.  

Extended interest has been shown in porphyrins carrying glycosyloxy substituents (cf. Vol 27, p 18) which can be made by condensation of glycosyloxy benzaldehydes with pyrrole. Compounds with the carbohydrate substituents in the ortho positions have phenyl rings which do not have freedom of rotation with respect to the prophyrin rings, and studies have now been undertaken on the interconversion of the various rotomer forms of the compound. The all-cfr 

Related glycosylated macrocyclic compounds are the calix-4-arene derivatives 18, with R= O-substituted D-mannofurano l, D-galactopyranosyl or D-glucopyranosyl units which were made using Mitsunobu conditions with sugars O-protected other than at the anomeric centre. Di- and tetra-glycosylated compounds were also reported.  

1 Synthesis of Monosaccharide Glycosides.-A further review on recent progress in methodological aspects of glycoside synthesis has appeared.  

Fraser-Reid and coworkers have reviewed the group s work on the use of pentenyl glycosides and have included some useful experimental details. In a related paper issues associated with matched and mis-matched glycosyl donors and acceptors and consequent effects on a, /3-product ratios are considered.  

Tetra-O-acetyl-a-D-glucosyl trifluoroacetate in the presence of boron trifluoride or trimethylsilyl triflate, gives -glucosides as expected. A related method of preparing /3-glucosides with high stereoselectivity involves the use of 2,3,4,6-tetra-6 -pivaloyl-/3-D- 

6-Tetra-O-benzoyl-a-D-fructofuranose, on treatment with DEAD, triphenylphosphine and alcohols, phenols and arylamines, gives access to the corresponding a-furanosyl products, the stereo-chemistry, it is presumed, being controlled by the intermediacy of a benzoxonium ion at C-2, C-3.  

Salt 3 is obtainable crystalline in 56% yield from tetra-O-acetyl-a-o-glucopyranosyl bromide, tetra-AT-methylurea and silver triflate. In methanol it afforded the /5-glycoside, and in dichlorometheme it condensed with methyl 2,4,6-tri-0-benzyl-/3-D-glucopyranoside to give the 3-0-linked disaccharide in good yield.  

1 Synthesis of Monosaccharide Glycosides.- A review with 168 references has appeared (in Japanese) of recent developments in the synthesis of 0 -glycosides. The acid-catalyzed formation of D-fructosides and 2-thio-D-fructosldes in DMSO is believed to proceed by way of the cyclic carbonlum ions, and furanoslde-pyranoside isomerization by way of the bicyclic 2,6-anhydro-3-D-fructofuranose 

Kinetic methanolysls of arablnose to give the furanosides has been used to obtain the furanosyl acetates which were subsequently produced by acetolysis reactions. It was claimed that in the initial reaction substantial proportions of hemiacetals were produced this is not in accord with previous observations, and the conclusion may have followed from an irregularity in the analytical procedures 

1-Thioglycosldes have received further attention as precursors of 0-glycosldes. Phenyl 1-thioglycosldes, activated by use of NBS (in the presence of molecular sieve to remove water) and treated with alcohols, yield glycosides in a mild procedure which is applicable with complex alcohols. Yields were in the 60-80% range 

The same two pentose triethers have also been used as 

Resulting dlastereolsomers were separated and the fluorescent mannosyl diglycerlde (11) has also been reported by the same 

1 Synthesis of Monosaccharide Glycosides.- A new procedure for glycosylating unreactive alcohols or phenols involves the treatment of perbenzylated S-phenyl 1-thioglycoside sulphoxides with triflic anhydride followed by the hydroxy compounds at -78 C. The a,p ratios depend strongly on the solvent, and the procedure appears to be the first to allow the direct M-glycosylating of amides.  

Reo ervfcS- t, MsCL Et3N ii, NH3,MeOH Ui, Brj, EtsN, McOH liv, Pr OH 

2- Chloro-l,l,2-trifluoroethyl o-D-glucopyranoside was prepared and found to inhibit yeast a-glucosidase irreversibly, probably because the released 2-chloro-l,l,2-trifluoroethanol 

2-deoxy-D-Jjfxo-hexopyranosides from ulosonic acid glycosides is mentioned below. 

In the field of glycosides of 2-amino-2-deoxy sugars Mootoo and Fraser-Reid have found an ingenious method for controlling the 

1 Synthesis of Monosaccharide Glycosides.—Sinay has written a review on recent advances in glycosylation procedures which include one-electron transfer reactions in the synthesis of 3-linked oligosaccharides, the use of 2-azido-2-deoxy-D-galactopyranosyl xanthates, and methods for synthesizing KDO- containing disaccharides.  

The macrocycle (1) complexes with free sugars (frivouring 2-deoxyribose, ribose erythrose, arabinose glucose, mannose xylose, lyxose) and enables them to be solubilized in carbon tetrachloride from aqueous solution and hence converted to their glycosides with the furanosides being favoured. The preparation of methyl a-D-[U C]glucopyranoside (from the labelled free sugar) has been reported.  

With 2,3,5-tri-O-benzyl-D-ribose and trimethylsilylated alcohols, furanosides with a 0 

Several alcohols, including monosaccharide alcohols, were used since the reactions did not proceed with 4-pyridyl carboxylates, chelation of the metals seems a probable component of the activation process. 

Reoi0en.tS i, MgBi. OEt2 (NoHCOjjTHF,reflux,uitmsound, ii, SOaPh 

1 Methods of synthesis of glycosides. - The 2-(dimethyloctylsilyl)ethyl group can be used at a hydrophobic aglycon which allows the use of reversed phase adsorbants for easy product isolation following enzymic glycosylation.  

Unsaturated compounds continue to be of value in glycoside synthesis - see some examples given in Chapter 13. 

A full account of the use of 2,6-anhydro-2-thio sugars for the stereo-controlled synthesis of 2,6-dideoxy-a- and 3-glycosides has appeared, and the method has been applied to the synthesis of erythromycin A and olivomycin A trisac-charide.  

1 Synthesis of Monosaccharide Glycosides.- A review has been published on the synthesis of glycopeptides which covers aspects of glycoside formation and the linkage between sugars and serine or serine-containing peptides.  

Cytotoxic aldehydes which cannot themselves be used clinically because of binding to proteins can be administered in the acetal-glycosidic form. The amlnated compounds (2), (R=( CH ) j NH2, R =Me, n=l-i ) have been made by acetal exchange from (1) via the m-bromides and azides, giving potential 3-glucosidase Inhibitors. The amines were resistant to enzymolysls while their synthetic precursors - 

The potentially useful observation has been made that while treatment of methyl a-D-glucopyranoslde with benzoic acid, trl-phenylphosphlne and diethyl azodlcarboxylate is known to give the 6-benzoate, similar treatment of the g-anomer afforded, after 

Considerable attention has been paid to the further development of routes to glycosides of 2-ulosonic acids. Treatment of the alkene (7) with m-chloroperbenzolc acid gave (8) as the only glycoside formed ( 5 ),  

Alternatively, S-glycosldes have been obtained using the dlbromlde (13), the second bromine atom of which prevented elimin- 

A highly efficient synthesis of 1,2-rrafw-glycosides which can be applied with acid-labile alcohols employs benzoyl protected glycopyranosyl P,F-diphenyl-A -tosylphosphinimidates- (eg 1) as glycosylating agents. On the other hand, mainly 1,2-cis-ribofuranosides were obtained on treatment of the phosphonium salt (2) with alcohols.  

A very simple procedure for 0-glycosidation without the need for metal salts involves heating perbenzylglycosyl chlorides and alcohols in dichloromethane in the presence of tetramethylurea. Cholesterol and tetra-O-benzyl-a-D-glucopyranosyl chloride gave 92% of the glycosides (a 0, 60 40). In the case of the a-L-rhamnosyl chloride only a-products were obtained.  

D-Lyxose, treated with ethyl(dimethoxy)borane in the presence of acid, gave the glycoside ester (3) from which methyl a-D-lyxofuranoside was obtained in 80% yield. In related fashion methyl a-D-mannofuranoside was obtained in similar yield. Alternatively, a wide range of 3-D-lyxofuranosides can be made by way of the 5-O-acetyl-a-glycofuranosyl bromide of (3).  

Very interestingly, D-ribose complexed within the resorcinol-dodecylidene cyclotetramer (4) in carbon tetrachloride underwent highly efficient and selective conversion to methyl 3-D-ribofuranoside. Several methyl 0-furanoside derivatives of L-e/yt/jfo-pentulose have been described following synthesis from the commercially available sugar. The a- and /3-septanosides (5) were obtained in 43% combined yield on treatment of methyl 4,6-0-isopropylidene-a-D-glucopyranoside with anhydrous pyridinium chloride.  

Fischer, Koenigs-Knorr and Schmidt methods have been used to obtain a- and /3-D-glucopyranosides of alcohols of chain lengths with and without cationic 

Not surprisingly, trifluoromethanesulphonic acid can be used effectively as catalyst for the Fischer glycosidation of free sugars, and phosphorus oxychloride catalyses the reaction between sugar peracetates and alcohols. For aryl, alkyl and aralkyl D-glucoside esters /9-anomers (the kinetic products) are favoured if the reactions are carried out in benzene solution, whereas the more stable o-products predominate if no solvent is used. ° 

Good -selectivity (a as high as 1 16) was found on reaction of 4-Q-acetyl-6-deoxy-2,3-di-Q-methyl-/9-D-allopyranosyl fluoride (D-mycinosyl fluoride) with alcohols in the presence of silver perchlorate and bis(cyclopentadienyl)zirconium dichloride in benzene,and in related fashion a desosamine fluoride has been used to produce -glycosides under mild conditions involving a hafnium complex and the methods have been combined in a total synthesis of the macrocyclic glycoside mycinamycin IV. 

In the area of ulosonic acids, condensation of D-mannose with oxalacetic acid gave 3-deoxv-D-alycero-D-aalacto-2-nonulopyranosonic acid from which a protected glycosyl bromide and hence glycosides e.g. (7) were prepared,and the phenylthioglycosides (8), made from tri-Q-benzyl-D-glucal, can be converted into Q-glycosides.  

Considerable effort has gone into the synthesis of aminoacid glycosides mainly because of their significance in glycopeptide chemistry. Reaction of the dimer of tri-Q-acetyl-2-deoxy-2-nitroso-a-D-glucopyranosyl chloride with methyl M substituted-L-serinate (and L-threoninate and L-tyrosinate) gave mixed anomers of the oximes (9), and their deacylated products on deoximation, reduction and reacetylation afforded the corresponding q-d- 

A similar copolymer was made from the corresponding a-glycoside of H-acetylneuraminic acid. 

The stereoselectivity of the uncatalysed 0-1 methylation of free sugars with diazomethane has been correlated with the preferred conformations of the thermodynamically favoured anomers. More specific studies of methyl glycosides relate to the acid-catalysed methanolysis of a-D-glucofuranose 1,2 3,5-bis(phenylboronate), which gives the a- and 3-glucofuranosides in the ratio of 

Transglucosylation, using different enzymes, from maltose and cellobiose to the enantiomers of trans-cyclohexane-l,2-diol gave stereochemically discrete a- and jS-monoglycosides. 

Jary and M. Marek, Collect. Czech. Chem. Commun., 1980, 45, 3571. 

Several glycosylations of cyclitol derivatives are referred to in Chapter 18. 

Krasavina, M. M. Vigdorchik, K. F. Turchin, and N. N. Suvorov, Tezisy Dokl. Sov.-Indiiskii Simp. Khim. Prir. Soedin., 5th, 1978, 42 Chem. Abstr., 1980, 93, 186 704). 

Reagents i, (Ph3P)3RhCI, Bu Li ii, ROH, NIS, AgOTf, base iii, MeOTf, base 

A review on the use of triflic anhydride in organic chemistry has surveyed the activation of glycosyl donors with this reagent.  

1 Methods of Synthesis of Glycosides. Much material in this section overlaps reports in the synthesis of disaccharides, Section 1.4. 

Hanessian and Lou have reviewed the remote activation concept applied with 0-unprotected glycosyl donors e.g. 1 which, with methyl triflate, give access to a-glucosides. This approach can also be used to make glycosyl carboxylates. 

5-Tri-Obenzyl-D-ribose together with trimetiiylsilylated alcohols, [catechoIato(2-)- 

Vasella s group has reported a series of new glycosylidene diazirines, for example 8, which undergo thermolysis in methanol to give methyl glycosides. Kinetic studies indicate the importance of 

Dimethoxybenzyl glycosides, for example 9, on treatment with DDQ in the presence of an alcohol in acetonitrile, degrade oxidatively to give the corresponding benzaldehyde compound and a carbocation which results in the formation of glycosides. Yields are in the 60-95% range, but the stereoselectivity is not high.  

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Synthesis of Monosaccharide Glycosides - Three reviews have dealt with this important subject. ... 

Synthesis of Monosaccharide Glycosides.- Compound (1), prepared from tartaric acid, offers a useful general means of obtaining a-L-threofuranosides (2) (Scheme 1). Simple glycosides were produced... 

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