Propargyl/methyl furanosides as potential glycosyl donors

Transfuranosylations are not well studied though many similar studies exist for transpyranosylation; herein, we report that propargyl/methyl D-ribf- and D-lyxf- give only 1,2-trans glycosides whereas D-araf- and D-xylf- result in a mixture of 1,2-trans and 1,2-cis glycosides; observed facts are rationalised by computational studies.     

Iron(III) chloride as an efficient catalyst for stereoselective synthesis of glycosyl azides and a cocatalyst with Cu(0) for the subsequent click chemistry

A highly efficient and mild method for azido glycosylation of glycosyl β-peracetates to 1,2-trans glycosyl azides was developed by using inexpensive FeCl(3) as the catalyst. In addition, we demonstrated, for the first time, that FeCl(3) in combination with copper powder can promote 1,3-dipolar cycloaddition (click chemistry) of azido glycosides with terminal alkynes. Good to excellent yields were obtained with exclusive formation of a single isomer in both glycosyl azidation and subsequent cycloaddition processes.     

1,2-migration of 2'-oxoalkyl group and concomitant synthesis of 2-C-branched O-, S-glycosides and glycosyl azides via 1,2-cyclopropanated sugars

Treatment of 2'-oxoalkyl 2-O-Ms(Ts)-alpha-C-mannosides (4, 5, and 6) with base resulted in 1,2-cyclopropanation via an intramolecular SN2 reaction due to their 1,2-trans-diaxial configurations. The 1,2-cyclopropanated sugars (10 and 13) were reacted with various alcohols, thiols, and sodium azide to produce 2-C-branched O- and S-glycosides and glycosyl azides (11, 14-28) in good to excellent yields. In contrast, 1,2-cis 2'-oxoalkyl 2-O-Ms(Ts)-alpha-C-glucoside 9 formed an acyclic conjugated aldehyde (31) under basic conditions, which occurred by 1'-enolation followed by beta-elimination. An intramolecular Michael addition from 31 produced 2-O-Ms-beta-C-glucoside 30 as a major product. However, due to the electron-withdrawing effect exerted by 2-O-Ms compound 31 also undergoes a C2 epimerization to form 32. Thereafter, the intramolecular Michael addition led to the formation of both 1,2-trans 2'-oxoalkyl 2-O-Ms-alpha-C-mannoside 4 and its beta-anomer (33). Because beta-elimination/Michael addition and C2 epimerization are reversible reactions, equilibriums among 9, 31, 30, 32, 33, and 4 were established, which included the transformation of 1,2-cis C-glucoside 9 into 1,2-trans C-mannoside 4. The subsequent 1,2-cyclopropanation of 4 was an irreversible reaction yielding 1,2-cyclopropanated 10 and further conversion to 1,2-migration products (11 and 12).     

Propargyl 1,2-orthoesters as glycosyl donors: stereoselective synthesis of 1,2-trans glycosides and disaccharides

Propargyl 1,2-orthoesters are identified as glycosyl donors. Various glycosides and disaccharides were synthesized in a stereoselective manner using AuBr₃ as the promoter. AuBr₃ may activate the alkyne resulting in the formation of a 1,2-dioxolenium ion and also behaves as a Lewis acid to facilitate the attack of the glycosyl acceptor. The versatility of the protocol was demonstrated using a panel of aglycones comprising aliphatic, alicyclic, steroidal and sugar alcohols.     

Synthesis of glycosyl phosphates from 1,2-orthoesters and application to in situ glycosylation reactions

[reaction: see text] A series of glycosyl phosphates were prepared in high yield by treatment of the corresponding 1,2-orthoesters with dibutyl phosphate. Glycosyl phosphates are efficient glycosylating agents even when used in crude form or when generated in situ. The immunodominant epitope trirhamnoside of group B Streptococcus was prepared to demonstrate the synthetic utility of the method.     

Gold mediated glycosylations: selective activation of propargyl 1,2-orthoesters in the presence of aglycones containing a propargyl moiety

Selective activation of propargyl 1,2-orthoesters in the presence of propargyl glycosides and propargyl ethers was studied; a catalytic amount of AuBr(3) activated the propargyloxy group of the 1,2-orthoester thereby giving access to disaccharides with the propargyl group at the reducing end; furthermore, propargyl ethers were unaffected under the reaction conditions.     

Efficient and direct synthesis of saccharidic 1,2-ethylidenes, orthoesters, and glycals from peracetylated sugars via the in situ generation of glycosyl iodides with I2/Et3SiH

Peracetylated sugars can be efficiently converted into the corresponding 1,2-ethylidenes, -orthoesters, and -glycals via the in situ generation of glycosyl iodides promoted by I₂/Et₃SiH. The approach is straightforward and avoids isolation of the sensitive iodinated intermediates.     

Use of fluorobenzoyl protective groups in synthesis of glycopeptides: beta-elimination of O-linked carbohydrates is suppressed

Fluorobenzoyl groups have been investigated as alternatives to acetyl and benzoyl protective groups in carbohydrate and glycopeptide synthesis. D-Glucose and lactose were protected with different fluorobenzoyl groups and then converted into glycosyl bromides in high yields (>80% over two steps). Glycosylation of protected derivatives of serine with these donors gave 1,2-trans glycosides in good yields (approximately 60--70%) and excellent stereoselectivity without formation of ortho esters. The resulting glycosylated amino acid building blocks were then used in solid-phase synthesis of two model O-linked glycopeptides known to be unusually sensitive to beta-elimination on base-catalyzed deacylation. When either a 3-fluoro- or a 2,5-difluorobenzoyl group was used for protection of each of the two model glycopeptides the extent of beta-elimination decreased from 80% to 10% and from 50% to 0%, respectively, as compared to when using the ordinary benzoyl group. Fluorobenzoyl groups thus combine the advantages of the benzoyl group in formation of glycosidic bonds (i.e., high stereoselectivity and low levels of ortho ester formation) with the ease of removal characteristic of the acetyl group.     

Propargyl glycosides as stable glycosyl donors: anomeric activation and glycoside syntheses

The advantages of stable glycosyl donors for saccharide coupling are many, and we describe herein the utility of propargyl glycosides for anomeric activation and glycoside synthesis exploiting the alkynophilicity of AuCl3. Various aglycones were reacted with propargyl glycosides, resulting in the formation of an alpha,beta-mixture of glycosides and disaccharides in good yields.     

Synthesis and use of glycosyl phosphates as glycosyl donors

Differentially protected glycosyl phosphates prepared by a straightforward synthesis from glycal precursors are used as powerful glycosyl donors. Activation of beta-glycosyl phosphates by TMSOTf at -78 degrees C achieves the selective formation of beta-glycosidic linkages in excellent yields with complete stereoselectivity. Reaction with thiols results in the conversion of glycosyl phosphates into thioglycosides in nearly quantitative yield. An orthogonal coupling strategy using glycosyl phosphate donors and thioethyl glycoside acceptors allows for the rapid synthesis of a trisaccharide.     

One-pot synthesis of sialo-containing glycosyl amino acids by use of an N-trichloroethoxycarbonyl-beta-thiophenyl sialoside

We describe an efficient synthesis of 2,6- and 2,3-sialyl T antigens linked to serine in a one-pot glycosylation. We first investigated the glycosidation of thiosialosides by varying the N-protecting group. Modification of the C-5 amino group of beta-thiosialosides into the N-9-fluorenylmethoxycarbonyl, N-2,2,2-trichloroethoxycarbonyl (N-Troc), and N-trichloroacetyl derivatives enhanced the reactivity of these compounds towards glycosidation. Addition of a minimum amount of 3 A molecular sieves was also effective in improving the yield of alpha-linked sialosides. Next, we conducted one-pot syntheses of the glycosyl amino acids by using the N-Troc sialyl donor. The N-Troc derivative can be converted into the N-acetyl derivative without racemization of the amino acids. Branched-type one-pot glycosylation, initiated by regioselective glycosylation of the 3,6-dihydroxy galactoside with the N-Troc-beta-thiophenyl sialoside, provided the protected 2,6-sialyl T antigen in good yield. Linear-type one-pot glycosylation, initiated by chemoselective glycosylation of galactosyl fluoride with the N-Troc-beta-thiophenyl sialoside, afforded the protected 2,3-sialyl T antigen in excellent yield. Both protected glycosyl amino acids were converted into the fully deprotected 2,6- and 2,3-sialyl T antigens linked to serine in good yields.     

Stereoselective assembly of complex oligosaccharides using anomeric sulfonium ions as glycosyl donors

The development of selectively protected monosaccharide building blocks that can reliably be glycosylated with a wide variety of acceptors is expected to make oligosaccharide synthesis a more routine operation. In particular, there is an urgent need for the development of modular building blocks that can readily be converted into glycosyl donors for glycosylations that give reliably high 1,2-cis-anomeric selectivity. We report here that 1,2-oxathiane ethers are stable under acidic, basic, and reductive conditions making it possible to conduct a wide range of protecting group manipulations and install selectively removable protecting groups such as levulinoyl (Lev) ester, fluorenylmethyloxy (Fmoc)- and allyloxy (Alloc)-carbonates, and 2-methyl naphthyl ethers (Nap). The 1,2-oxathiane ethers could easily be converted into bicyclic anomeric sulfonium ions by oxidization to sulfoxides and arylated with 1,3,5-trimethoxybenzene. The resulting sulfonium ions gave high 1,2-cis-anomeric selectivity when glycosylated with a wide variety of glycosyl acceptors including properly protected amino acids, primary and secondary sugar alcohols and partially protected thioglycosides. The selective protected 1,2-oxathianes were successfully employed in the preparation of a branched glucoside derived from a glycogen-like polysaccharide isolated form the fungus Pseudallescheria boydii , which is involved in fungal phagocytosis and activation of innate immune responses. The compound was assembled by a latent-active glycosylation strategy in which an oxathiane was employed as an acceptor in a glycosylation with a sulfoxide donor. The product of such a glycosylation was oxidized to a sulfoxide for a subsequent glycosylation. The use of Nap and Fmoc as temporary protecting groups made it possible to install branching points.     

Orthoesters versus 2-O-acyl glycosides as glycosyl donors: theorectical and experimental studies

n-Pentenyl orthoesters (NPOEs) undergo routine acid catalyzed rearrangement into 2-O-acyl n-pentenyl glycosides (NPGs). The reactant and product can both function as glycosyl donors affording 1,2-trans linked glycosides predominantly. However, both donors differ in their rates of reactions, the yields they produce, and the nature of their byproducts, indicating that the NPOE/NPG pair may not be reacting through the same intermediates. We have therefore applied quantum chemical calculations using DFT methods and MP second order perturbation theory to learn more about orthoesters and their 2-O-acyl glycosidic counterparts. The calculations show that in the case of a manno NPG and NPOE pair, each donor goes initially to a different cationic intermediate. Thus, the former goes to a high-energy oxocarbenium ion before descending to a trioxolenium ion in which the charge is distributed over the pyrano ring oxygen, as well as the carbonyl and ether oxygen atoms of the putative C2 ester. On the other hand, ionization of the NPOE produces a dioxolenium ion lying slightly above the more stable trioxolenium counterpart. For the gluco pair, the NPG also goes to a very high-energy oxocarbenium ion, which also descends to a trioxolenium ion. However, unlike the manno analogue, the gluco NPOE does not give a dioxolenium ion; indeed, the dioxolenium is not energetically distinguishable from the trioxolenium counterpart. The theoretical observations have been tested experimentally. Thus, it was found that with manno derivatives, the orthoester is a more reactive donor than the corresponding NPG donor, whereas, for gluco derivatives, there is no advantage to using one over the other, unless one resorts to carefully selected promoters.     

Neighboring-group participation by C-2 ether functions in glycosylations directed by nitrile solvents

Ether-protecting functions at C-2 hydroxy groups have been found to play participating roles in glycosylations when the reactions are conducted in nitrile solvent mixtures. The participation mechanism is based on intramolecular interaction between the lone electron pair of the oxygen atom of the C-2 ether function and the nitrile molecule when they are positioned in a cis configuration. A 1,2-cis glycosyl oxazolinium intermediate is formed. This participation, in conjunction with the anomeric effect of the glycosyl donor, confers high 1,2-trans selectivities on glycosylations. Further application of this concept has led to efficient preparations of α-(1→5)-arabinan oligomers.     

Efficient synthesis of core 2 class glycosyl amino acids by one-pot glycosylation approach

We describe the one-pot synthesis of core 2 class branched oligosaccharides initiated by chemo-selective glycosylation of silyl ether. Glycosylation of 6-O-silyl-4-benzyl-2-azido-thiogalactoside with glycosyl fluoride provided selectively 6-glycosylated thioglycoside without both O-glycosylation at the 3 position and S-glycosylation. Subsequent coupling of galactosyl fluoride and amino acids afforded the protected branched oligosaccharides in good yields.     

A new efficient glycosylation method employing glycosyl pentenoates and PhSeOTf

The PhSeOTf promoted glycosylations of various glycosyl acceptors with mannosyl pentenoates and glucosyl pentenoates as glycosyl donors afforded corresponding disaccharides in high yields. And the present glycosyl pentenoates/PhSeOTf method showed that the complete -selective mannosylation of secondary alcohol acceptors was achieved with 2,3,4,6-tetra-O-benzyl-d-mannopyranosyl pentenoate to give -disaccharides in good yields.     

From solution phase to "on-column" chemistry: trichloroacetimidate-based glycosylation promoted by perchloric acid-silica

[reaction: see text] Activation of ester-protected glycosyl trichloroacetimidate donors by perchloric acid immobilized on silica afforded 1,2-trans disaccharides in 60-90% yields. Applying this approach to one-pot sequential glycosylation resulted in efficient syntheses of the N-linked glycan trimannoside and Le(X) and Le(A) trisaccharides in very good yield (76%, 62%, and 59% yields, respectively). Solution phase reactions were also translated to a solid phase format; priming the top of a standard silica chromatography column with perchloric acid immobilized on silica facilitated "on-column" glycosylation with subsequent "in situ" purification of products. Coupling yields from this approach were comparable to those obtained from the corresponding solution-phase disaccharide couplings. A series of glycosylated amino acids were also synthesized in high yield with use of the on-column approach.     

A variable concept for the preparation of branched glycosyl phosphatidyl inositol anchors

A variable concept for the synthesis of branched glycosyl phosphatidyl inositol (GPI) anchors was established. Its efficiency could be shown by the successful synthesis of the GPI anchor of rat brain Thy-1 and of the scrapie prion protein both in the water soluble 1c and lipidated form 1a. Retrosynthesis led to building blocks 2-6 of which 5 could be further disconnected to building blocks 7-9. Trichloroacetimidate 5 was built up in a straightforward manner starting from glycosyl acceptor 9 using known glycosyl donors 7 and 8. The carbohydrate backbone was then assembled by glycosylation of pseudodisaccharide acceptor 6 with donor 5. To ensure high stereoselectivity and good yields in the glycosylation reactions, anchimeric assistance was employed. Successive deprotection and introduction of the various phosphate residues gave the fully protected GPI anchors. Catalytic hydrogenation and acid-catalyzed cleavage of the Boc protecting groups afforded the target molecules, which could be fully structurally assigned.     

Efficient one-pot synthesis of glycosyl disulfides

Methodology for the efficient and facile synthesis of glycosyl disulfides is reported. A one-pot procedure employing mild conditions using diethyl azodicarboxylate is described to synthesise a series of glycosyl disulfides in excellent yields.     

How the arming participating moieties can broaden the scope of chemoselective oligosaccharide synthesis by allowing the inverse armed-disarmed approach

A new method for stereocontrolled glycosylation and chemoselective oligosaccharide synthesis has been developed. It has been determined that complete 1,2-trans selectivity can be achieved with the use of a 2-O-picolyl moiety, a novel neighboring group that is capable of efficient participation via a six-membered intermediate. The application of the picolyl concept to glycosidations of thioimidoyl, thioglycosyl, and trichloroacetimidoyl glycosyl donors is demonstrated. The picolyl moiety also retains the glycosyl donor in the armed state, as opposed to conventional acyl participating moieties. We name this new approach the "inverse armed-disarmed" strategy, because it allows for the chemoselective introduction of a 1,2-trans glycosidic linkage prior to other linkages. In the context of the oligosaccharide synthesis, the strategy provides trans-trans and trans-cis patterned oligosaccharides as opposed to classic Fraser-Reid's armed-disarmed approach leading to cis-trans and cis-cis linkages.