The Sulfur Reaction

Thioglycosides are useful glycosyl donors widely used in the preparation of O-glycosides. An example of their applicability for the preparation of saccharide synthesis is represented in Figure 2.33. Thus, the synthesis of trisaccharide intermediate was obtained by combining the thioglycoside donor with a monosaccharide acceptor in the presence of methyltriflate, to provide the target trisaccharide in 72 yield.33 A convergent synthesis of the trisaccharide unit belonging to an antigen...

Ray Diffraction of Nucleosides

A number of N-glycosides and C -glycosides has been solved by X-ray analysis, presenting as common features space group P212121orP21, the furanoside ring in the twist conformation, and symmetric system monoclinic or orthor-hombic. For instance, the hypermodified nucleoside queuosine presents a space group P212121, cell dimensions a 26.895, b 7.0707, c 23.883 A, and symmetric system orthorhombic (Figure 9.7). The three-dimensional structure determined by X-ray has been also helpful to understand...

T

N-glycoside formation via sulfur glycosyl donor. for C-C bond formation and consists in the coupling of an aryl halide with activated olefin in the presence of palladium (0) as catalyst (Figure 3.32).41 More recently, other palladium-mediated reaction have been developed with great potential for heterocycle coupling reaction with furanosides, to produce an interesting variety of nucleosides. The group of reactions includes the Suzuki Figure 3.30. The Mitsunobu reaction for the...

Selective Protections

I) CH2 CHCH2OCO2Et, Pd2(dba)3, THF, 65oC, 4h, 70 . i) CH2 CHCH2OCO2Et, Pd2(dba)3, THF, 65oC, 4h, 70 . Figure 1.76. Miscellaneous selective protections i) 4-CH3OC6H5OH, THF, DEAD, Ph3P, 80oC, 82 . i) Ph3CCl, DMAP, DMF, 25oC, 12h, 88 . i) Me3SiCl, Et3N, THF, 25oC, 8h, 90 . i) Pancreatin, vinyl acetate, THF, TEA 95 . i) CH2 C(CH3)OCH3, DMF, TsOH. 0oC, 95 i) aq. H2O2 (33 ), AcOH, NaOAc, 80oC, 8h. i) TIBS-Cl, Imidazole. ii) Bu2SnO, BnBr, TBAI, 67 i) a) 1eq. NaOMe MeOH. b) 1.2 eq. Ac2O, 12h, 91 ....

Selective Deprotections

MPM p-Methoxybenzyl ether p-MeOC6H4CH2OR i) CAN or NBS, CH2Cl2, H2O. i) LiAlH4, AlCl3, Et2O, CH2Cl2, heat Figure 1.77. Miscellaneous selective deprotections. i) a) SnCl4, CH2Cl2, -78oC. b) Bu4NOH, 90 . i) NaBH3CN. b) TFA, DMF. ii) a) NaBH3CN. b) TMSCl, CH3CN. iii) CAN, CH3CN-H2O (9 1), 95 . i) Pd(0Ac)2, (o-biphenyl)P('Bu)2, PhN(H)Me, NaO'Bu, 80oC. ii) SnCl4, 84 .

General Methods

When a monosaccharide (or sugar fragment of any size) is condensed with either an aliphatic or aromatic alcohol, or another sugar moiety through an oxygen, a glycoside bond is formed. General examples of O-glycosides are shown in Figure 2.1. The most common coupling reaction methodologies used for preparing the vast majority of O-glycosides known thus far are1

The Michael Reaction

Examples of O-glycosides. Figure 2.1. Examples of O-glycosides. This pioneering methodology for O-glycosylation consists of the condensation reaction between 2,3,4,6-Tetraacetyl-a-D-glucopyranosyl chloride and potassium phenoxide to generate the acetylated derivate that undergoes basic hydrolysis to give phenyl-p-D-glucopyranoside (Figure 2.2). Since its original methodology, some modifications have been introduced especially for aromatic glycosides. Some of the main features...

The Fusion Reaction

I) Hg(II)CN2, CaSO4 dioxane, PhH. ii) MeONa MeOH. iii) AcOH. iv) H2, Pd-C. Figure 2.19. Synthesis of a kanamacin A derivative. Figure 2.20. Synthesis of Epirubicine. i) Hg(II)CN2, CaSO4, PhH. ii) MeONa MeOH. iii) H2, Pd-C. Figure 2.21. Synthesis of Rafinose derivative. Figure 2.21. Synthesis of Rafinose derivative. Figure 2.22. Helferich conditions for the preparation of sialic disaccharide. This is a process that is mainly used for preparing aromatic glycosides, and generally consists of the...

Miscellaneous Leaving Groups 21101 Fluoride Glycosyl Donors

CH2Cl2, -25 C CH2Cl2,0 C Fluorine is considered a poor leaving group, and its use for glycoside bond formation has been more restricted than chlorine and bromine, although display higher thermal and chemical stability. Nonetheless several O-glycoside synthesis involving glycosyl donors with fluorine as leaving group has been described, specially for the preparation of a-O -glycosides with high stereoselectivity.55 Based in the use of fluorine glycosyl donors, the synthesis of the...

Conversion of Pentose to Furfural

Pentoses subjected to high acid concentrations can be transformed to furfural in quantitative yields. The sequence involves a tautomeric keto-enol equilibrium, dehydration and intramolecular nucleophilic addition of the primarily alcohol to the aldehyde to generate furfural (Figure 1.16). Figure 1.14. The Kiliani-Fischer synthesis. Figure 1.16. Conversion of pentoses to furfural.

Enzymatic Synthesis

Likewise, carbocyclic nucleosides aristeromycin and neplanocin A can be biosyn-thetically prepared by using a mutant strain of S. citricolor as is observed in Figure 4.59. The cyclopropylamino carbocyclic nucleosides (-)-Abacavir is a potent anti-HIV drug with promising results on clinical trials.103 An improved synthesis has been described by Crimmins et al.104 involving the treatment of key carbocyclic 2-amino-6-cloropurine intermediate with cyclopropilamine producing Abacavir along its...

It

I) UDP-NeuAc aldolase. ii) CMP-NeuAc synthetase. iii) pyruvate kinase. iv) adenylate kinase. Figure 2.72. Synthesis of CMP-N-acetylneuraminic acid. Figure 2.73. Glycosynthase-catalyzed oligosaccharide synthesis. 2.1.11.1 Enzymatic Synthesis of Oligosaccharides Figure 2.73. Glycosynthase-catalyzed oligosaccharide synthesis. 2.1.11.1 Enzymatic Synthesis of Oligosaccharides Mutated glycosidase also known as glycosynthase AbgGlu358Ala in combination with activated glycosyl donors and suitable...

Enediol Rearrangement

This transformation occurs at basic medium and allows the conversion of epimers, defined as isomeric forms that differ in the position of the hydroxyl group at C-2. In this way it is possible to transform through the enediol intermediate glucose to mannose and vice versa (Figure 1.12). Another important isomerization process through the enediol rearrangement is the interconversion of glucose and fructose. Thus, the enolization proceeds by migration of proton at position 2, to carbon at 1...

The Leaving Groups

As mentioned above, the anomeric hydroxyl group can be replaced under suitable conditions with a good leaving group. Initially, the use of halogens such as fluorine, chlorine, and bromine was the strategy of choice, and particulary the last since it presents the best balance between reactivity and stability and this is why it has been extensively used for preparing glycosides. However, halides are in most cases labile and undergo decomposition. Consequently a number of other leaving groups have...

Benedict and Fehling Test

The test consists in the use of a cooper citrate (Benedict reagent) or cooper tar-trate complex (Fehling reagent), which upon treatment with the sugar under study produces the glucuronide ion along with cooper (I) oxide which is detected as brick-red precipitate (Figure 1.9). Based on the Tollens, Benedict or Fehling test, the sugars are classified into reducing when positive or non-reducing sugars if negative. Reducing sugars are hemiacetals in equilibrium with small amounts of the open forms....

The Glycal Reaction

The glycals are unsaturated sugars with a double bond located between C1 and C2. These useful intermediates were discovered by Fischer and Zach in 191342 and their utility in the preparation of building blocks for oligosaccharide synthesis is increasingly important. Different routes for the preparation of triacetyl glycals have been examined by Fraser-Reid et al.,43 involving the Ferrier rearrangement. Moreover, a suitable one-pot preparation of glycals has been more recently described,...

The Fischer Reaction

Michael approach for preparation umbellyferyl- O -glycoside. Figure 2.4. Michael approach for preparation umbellyferyl- O -glycoside. This straightforward strategy is used specially for the preparation of simple O -glycosides. The advantage of this methodology is that it does not require the use of protecting groups and simply by combining the free sugar with an alcohol under acidic condition we furnish the corresponding O-glycoside. However, contrary to the previous method, this...

III iiN

I) a) LMPT. b) Bu3SnCl. ii) R-X, Pd, cat FIGURE 4.8. Cross-coupling reactions for purine modification. i) EtOH H2O, A. ii) Ac2O, n-Pr3N, 100oC. iii) DBU, CH3CN, 25oC 81 FIGURE 4.9. Synthesis of 7-deazapurine analogs. FIGURE 4.10. Anti-AIDS 2'3'-dideoxy nucleosides. FIGURE 4.10. Anti-AIDS 2'3'-dideoxy nucleosides. A strategy for preparing D- and L-2'-fluoro-2'3 -unsaturated nucleosides has been described and their anti-HIV activity evaluated. This approach requires as key starting material,...

Y

I) Candida antarctica lipase (CAL), 90 . ii) Pseudomona sp. lipase (PS), 92 . iii) Mucor javanicus lipase (M), 42 . Figure 3.8. Regioselective acyl protection by lipase. i Subtillisin or PPL, organic solvent, phosphate buffer, pH 7. Figure 3.9. Selective enzymatic 5'-acetyl deprotection. i) WGL, phosphate buffer, 29 . or PLE, phosphate buffer, 31 . Figure 3.10. Lipase-catalyzed deacetylation of anomeric nucleoside. Regioselective protections and deprotections is often a critical step especially...

References

Robyt, Essentials of Carbohydrate Chemistry, Springer, NY (1998). 2. H.S. Khadem, Carbohydrate Chemistry, Academic Press, NY (1988). 3. E. Fischer, Ber. 23, 2114 (1890). 4. G. Casiraghi, F. Zanardi, G. Rassu, and P. Spanu, Chem. Rev. 95, 1677 (1995) 5. T.-H. Chan, and C-J. Li J. Chem. Soc. Chem. Commun. 747 (1992) 6. J. Gao, R. H rtner, D.M. Gordon, and G.M. Whitesides, J. Org. Chem. 59, 3714 (1994). 7. R.H. Prenner, W.H. Binder, and W. Schmid, Liebigs Ann. Chem. 73 (1994). 8. K.-I. Sato,...

R

Two general approaches for immobilized solid-phase oligosaccharide synthesis. Figure 2.85. Enzymatic-solid phase glycosylation reaction. Figure 2.85. Enzymatic-solid phase glycosylation reaction. 4. the ring opening of cyclodextrins followed by oligosaccharide chain elongation and cycloglycosylation (Figure 2.86). Despite the significant advances observed in cyclic oligosaccharide synthesis, their preparation is time-consuming, producing the target compounds with low regio- and...

The Helferich Reaction

I AgOTf, TMU, CH2Cl2. ii MeONa MeOH C6H12. iii H2, Pd C, EtOH-H2O. Figure 2.16. Synthesis of tetrasaccharide. i AgOTf, TMU, CH2Cl2. ii MeONa MeOH C6H12. iii H2, Pd C, EtOH-H2O. Figure 2.16. Synthesis of tetrasaccharide. This methodology is considered a modification of the previous one, and the main change being the use of mercury and zinc salts instead of silver. Also, more polar solvents are used such as acetonitrile or nitromethane Figure 2.18 . The yields reported for this reaction are up to...

The Imidate Reaction

Naphtyl O-glycosides and Phenyl S-glycosides. BF3-OEt2 CH2Cl2 or MeCN, -20 C This is a more recent procedure attributed to Schmidt and coworkers21 -0 who introduced trichloroacetimidate as a good leaving group for preparation of O -glycosides. A significant number of simple and complex O-glycosides involving the imidate coupling reaction have been described. This strategy involves the use of trichloroacetonitrile that in the presence of a base is incorporated on the anomeric...

Synthesis of Carbohydrates Mimetics 161 Iminosugars

This class of isosteric sugars also recognized as azasugars have been the subject of intense study because their significant activity as a-glycosidase inhibitors, which is a promising strategy in the treatment against diabetes mellitus type II and other glycosidase associated disorders. It is believed that the mechanism for glycosidase inhibition and to some extent for glycosyltransferases involves the binding of the aza sugars to the active site by charge-charge and hydrogen bond...

Classification of Glycocoproteins

Based on the type of the glycosidic bond formed between the sugar and the protein residues, glycoproteins are divided in N- and O -glycans. The first type involved the glycosidic linkage between asparagine and N-acetylglucosamine and the second involves an O-glycosidic linkage between the sugar residue fucose, galactose, N-acetylgalactosamine, and N-acetylglucosamine and the oxygen in the side chain serine, threonine, or hydroxyl lysine. It is known that N-linked glycans contain the...

Protecting Groups

An important additional requirement for achieving glycosidic coupling reactions, besides the fact that a good leaving group should be present, is the appropriate use of protecting groups. Their function is to shield those groups particularly heteroatoms that are wanted to keep unaltered during the coupling reaction and then release them under mild conditions that do not affect the glycosidic bond Figure 1.63 . A significant number of protecting groups75 have been used and combined for pursuing...

Nucleosides

These modified nucleosides are structurally distinct to their counterparts N-nucleosides because of the presence of a C-C linkage instead of C-N between i DMDO, CH2Cl2, -30oC. ii Me3Al 3 eq. , CH2Cl2,-30oC, 2h. FIGURE 4.25. Ring opening of 4',5'-epoxynucleosides. i C0Cl 2, DMSO, Et3N, CH2Cl2. ii CBr4, PPh3, CH2Cl2. iii n-BuLi, THF. iv n-BuLi, THF, then Et3SiCl. v a 70 AcOH, TFA. b Ac20, Py. vi N,0-bis trimethylsilyl acetamide, thymine, CH2Cl2, reflux, 1h, 96 . FIGURE 4.26. Synthesis of...

Acidic Hydrolysis

When a glycoside is subjected to acid conditions, a process called acetolysis takes place. This phenomenon is more clearly seen on O-glycosides, where even weak acid conditions can be sufficient for O-glycoside breakage. Some simple glycosides such as 3 methyl-2,3,4,6-tetra- O-methyl-D-glucopyranose are hydrolyzed under diluted HCl conditions to yield a Likewise ethyl-glucopyranose is hydrolyzed to a mixture of anomers Figure 7.1 . In general, -glycosides are more resistant than their...

Glycosyl Donors

This term is used to define a glycosidic moiety that contains a leaving group at the anomeric position. When a glycosyl donor is reacted in the presence of a catalyst also known as promoter with a free alcohol called glycosyl acceptor, it will produce an O-glycosidic linkage. The first glycosyl donors developed and used specifically for glycoside formation were the glycoyl halides. As mentioned above, glycosyl bromide and chloride are the most widely used halides, and are the glycosyl donors...