An efficient glycosylation protocol with glycosyl ortho-alkynylbenzoates as donors under the catalysis of Ph3PAuOTf

A new and powerful glycosylation protocol with glycosyl ortho-alkynylbenzoates as donors and Ph₃PAuOTf as a promoter is disclosed. The donors are readily available and stable; the glycosidic coupling yields are generally excellent; the promotion system is catalytic, neutral, and orthogonal to the known glycosylation conditions.     

A Catalytic and Stereoselective Glycosylation with β‐Glycosyl Fluorides

A catalytic and stereoselective glycosylation of several glycosyl acceptors with β‐D ‐glycosyl fluoride was successfully performed in the presence of a catalytic amount of trityl tetrakis(pentafluorophenyl)borate (TrB(C₆F₅)₄) or trifluoromethanesulfonic acid (TfOH). When TrB(C₆F₅)₄ was used as a catalyst in the solvent pivalonitrile/(trifluoromethyl)benzene 1 : 5, the glycosylation proceeded smoothly to afford the glycosides in high yields with high β‐D ‐stereoselectivities (see Table 3). Further, the glycosylation by the armed‐disarmed strategy in the presence of this catalyst was established (see Table 4). Similarly, glycosylation catalyzed by the strong protic acid TfOH afforded the corresponding β‐D ‐glycosides in good‐to‐excellent yields on treating β‐D ‐ glycosyl fluorides having a 2‐O‐benzoyl group with various glycosyl acceptors including thioglycosides (see Tables 6 and 7).     

Towards the preparation of 2″-deoxy-2″-fluoro-adenophostin A. Study of the glycosylation reaction

The synthesis of 2″-deoxy-2″-fluoro-adenophostin A framework starting from tri-O-acetylglucal and adenosine is described. The key steps are the formation of the 2-deoxy-2-fluoroglycosyl donor by electrophilic fluorination of tri-O-acetylglucal and the stereoselective glycosylation of a suitable adenosine derivative. The glycosylation reaction was optimized affording the desired 2″-deoxy-2″-fluoroglycoside with excellent α-stereoselectivity and in good yields, taking into account that glycosylations using nucleosides as glycosyl acceptors do not usually give excellent results. In that sense, an improvement of the glycosylation step with respect to that of the reported adenophostin synthesis, using adenosine derivatives as glycosyl donors, has been made.     

A Highly Efficient Glycosidation of Glycosyl Chlorides by Using Cooperative Silver(I) Oxide–Triflic Acid Catalysis

Following our discovery that silver(I) oxide-promoted glycosylation with glycosyl bromides can be greatly accelerated in the presence of catalytic TMSOTf or TfOH, we report herein a new discovery that glycosyl chlorides are even more effective glycosyl donors under these reaction conditions. The developed reaction conditions work well with a variety of glycosyl chlorides. Both benzoylated and benzylated chlorides have been successfully glycosidated, and these reaction conditions proved to be effective in coupling substrates containing nitrogen and sulfur atoms. Another convenient feature of this glycosylation is that the progress of the reaction can be monitored visually; its completion can be judged by the disappearance of the characteristic dark color of Ag₂O.     

Stereoselective glycosylation of endo-glycals by microwave- and AlCl3-assisted catalysis

α-2-Deoxyglycosides were synthesized in good to excellent yields by microwave-assisted reaction of endo-glycals with various O-nucleophiles in the presence of catalytic amount of AlCl₃. These glycosyl additions occurred with high α-stereoselectivity and were complete in 5-35 min in 65-93% yield.     

Lithium Triflate as a New Promoter of Glycosylation Under Neutral Conditions 1

Abstract

The glycosyl donors 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl trichloroacetimidate and 3,4,6-tri-O-benzyl-α-D-fucopyranosyl trichloroacetimidate were activated under neutral conditions with a catalytic amount (0.05 equiv) of lithium triflate and reacted with a series of alcohols including an acid sensitive sugar to give the corresponding glycosides in high yields. The stereoselectivity of the glycosylation was improved by introducing a participating group next to the anomeric position.

     

O-Glycosyl trichloroacetimidates bearing Fmoc as temporary hydroxy protecting group: a new access to solid-phase oligosaccharide synthesis

Different O-glycosyl trichloroacetimidates bearing base sensitive Fmoc protected hydroxy groups were efficiently prepared with CCl(3)CN using a catalytic amount of sodium hydride. The resulting glycosyl donors were engaged in glycosylation reactions both in solution and on solid support with a new ester-type linker with good results. In both approaches, Fmoc groups were afterward quantitatively cleaved using mild basic conditions.     

The application of chiral phosphine-Schiff base type ligands in silver(I)-catalyzed asymmetric vinylogous Mannich reaction of aldimines with trimethylsiloxyfuran

Catalytic asymmetric vinylogous Mannich (AVM) reactions of readily available aldimines with trimethylsiloxyfuran in the presence of catalytic amount of AgOAc and chiral phosphine-Schiff base type ligands are described, affording the corresponding products in up to 91% yield, anti/syn >99:1 and 81% ee.     

Syntheses of N-aryl-protected glucosamines and their stereoselectivity in chemical glycosylations

N-Aryl-protecting groups were introduced in glucosamines to achieve β-selective glycosylation. Various N-aryl aminosugars were synthesized via Buchwald–Hartwig reaction. Glycosylation using glycosyl trichloroacetimidates of N-aryl aminosugars smoothly proceeded in the presence of trimethylsilyl trifluoromethanesulfonate. Use of a glycosyl donor comprising an electron-donating 2,4-dimethoxyphenyl (DMP) group led to the glycosylation proceeding with high β selectivity. This stereoselectivity seemed to be derived from the formation of an aziridine intermediate. The DMP-protecting group can be removed immediately by using ammonium hexanitratocerate (IV).     

Armed-disarmed effect of remote protecting groups on the glycosylation reaction of 2,3-dideoxyglycosyl donors

The armed-disarmed effect of remote protecting groups at the C-4 and/or C-6 position(s) on the glycosylation reactions of 2,3-dideoxyglycosyl donors was investigated. It was found that under various glycosylation conditions, 4- or 6-O-Bn 2,3-dideoxyglycosyl donors were much more reactive than the corresponding 4,6-di-O-Bz 2,3-dideoxyglycosyl donors. Based on these results, an effective and chemoselective glycosylation reaction using 4,6-di-O-Bn glycosyl acetate and 4-OH-6-O-Bz glycosyl acetate was realized, producing a 2,3-dideoxydisaccharide in good yield with high α-stereoselectivity.     

Toward the total synthesis of vineomycin B2: application of an efficient glycosylation methodology using 2,3-unsaturated sugars

The application of an efficient glycosylation methodology using 2,3-unsaturated sugars to synthesize critical precursors required for the total synthesis of an antibiotic, vineomycin B₂ (1), was demonstrated. The required disaccharide, the acurosyl rhodinose derivative of 1, was prepared by chemoselective glycosylation using a 2,3-saturated glycosyl acetate corresponding to the rhodinose moiety and a 2,3-unsaturated glycosyl acetate corresponding to the acurose portion. Further, the right-hand side chain of 1, consisting of β-oxo-tert-alcohol and rhodinose, was constructed by a powerful glycosylation approach using a 2,3-unsaturated glycosyl acetate in an ionic liquid under reduced pressure.     

Synthesis of a pentasaccharide repeating unit of the O-antigen of enteroadherent Escherichia coli O154 strain

A straightforward linear synthetic strategy has been developed for the synthesis of the pentasaccharide repeating unit of the cell wall O-antigenic polysaccharide of enteroadherent Escherichia coli O154 strain. Newly developed glycosylation conditions using glycosyl trichloroacetimidate derivatives as glycosyl donors and nitrosyl tetrafluoroborate as the glycosylation activator have been used in all of the glycosylation reactions throughout the synthetic scheme. The stereochemical outcomes of the glycosylations were excellent and the yields were very good.     

A novel method for the formation of N-glycosides using hydroxamate

Direct formation of Asn-linked carbohydrate by N-glycosylation has been difficult, because of the lack of nucleophilicity of carboxamide nitrogen. We report here the novel N-glycosylation using Asn hydroxamate as a glycosyl acceptor. Reaction with glycosyl fluoride or glycosyl trichloroacetimidate afforded N-glycoside and subsequent reduction with SmI₂ gave Asn-linked glucose. Carbamate derived hydroxamates proved to have even enhanced reactivity to give N-glycosides in high yields.     

Stereoselectivity investigation on glycosylation of oxazolidinone protected 2-amino-2-deoxy-d-glucose donors based on pre-activation protocol

Diverse 2,3-oxazolidinone protected 2-amino-2-deoxy-d-glucose thioglycosides were prepared and studied as glycosyl donors at low temperature by BSM/Tf₂O pre-activation protocol before the addition of glycosyl acceptors. The stereochemistry outcomes of a series of glycosylations were investigated. Different stereoselectivities of the coupling reactions were obtained, arising from the different protecting groups in the oxazolidinone donors. 4,6-Di-O-benzyl-N-benzyl-oxazolidinone protected thioglycoside donor 1c underwent glycosylation with general β-anomeric selectivity and the stereoselectivity could be also affected by glycosylation conditions.     

Efficient synthesis of kaempferol 3,7-O-bisglycosides via successive glycosylation with glycosyl ortho-alkynylbenzoates and trifluoroacetimidates

Selective glycosylation of the 3-OH of 5,4′-di-O-acetyl-kaempferol was achieved with glycosyl ortho-alkynylbenzoates as donors under the catalysis of Ph₃PAuNTf₂, and subsequent glycosylation of the remaining 7-OH with glycosyl trifluoroacetimidates under the catalysis of BF₃·OEt₂, after global deprotection, afforded the kaempferol 3,7-O-bisglycosides conveniently.     

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.     

Hydrogen bond activated glycosylation under mild conditions

Herein, we report a new glycosylation system for the highly efficient and stereoselective formation of glycosidic bonds using glycosyl N-phenyl trifluoroacetimidate (PTFAI) donors and a charged thiourea hydrogen-bond-donor catalyst. The glycosylation protocol features broad substrate scope, controllable stereoselectivity, good to excellent yields and exceptionally mild catalysis conditions. Benefitting from the mild reaction conditions, this new hydrogen bond-mediated glycosylation system in combination with a hydrogen bond-mediated aglycon delivery system provides a reliable method for the synthesis of challenging phenolic glycosides. In addition, a chemoselective glycosylation procedure was developed using different imidate donors (trichloroacetimidates, N-phenyl trifluoroacetimidates, N-4-nitrophenyl trifluoroacetimidates, benzoxazolyl imidates and 6-nitro-benzothiazolyl imidates) and it was applied for a trisaccharide synthesis through a novel one-pot single catalyst strategy.

A mild glycosylation system was developed using glycosyl imidate donors and a charge-enhanced thiourea H-bond donor catalyst. The method can be used for the effective synthesis of O-, C-, S- and N-glycosides and chemoselective one-pot glycosylation.     

Microwave-assisted stereoselective α-2-deoxyglycosylation of hex-1-en-3-uloses

α-2-Deoxyglycosides were successfully synthesized by means of microwave-assisted glycosylation. Hex-1-en-3-uloses were treated with a catalytic amount of AlCl₃ and various O-nucleophiles including alcohols and sugars under microwave conditions. The desired α-2-deoxy-ulosides products were obtained in good to excellent yields with high stereoselectivity (α/β ? 88/12).     

Preparation of linear oligosaccharides by a simple monoprotective chemo-enzymatic approach

A monoprotective approach, involving acetyl ester as unique protective group in oligosaccharides synthesis, has been developed. Starting from peracetylated monosaccharides and glycals, by using an efficient and selective chemo-enzymatic ‘one-pot’ strategy (a regioselective hydrolysis catalyzed by immobilized lipases followed by a chemical acyl migration), different carbohydrate acceptors, only protected with acetyl ester, can be achieved. If combined with the use of an acetylated glycosyl donor, the glycosylation reaction with these glycosyl acceptors leads to peracetylated oligosaccharides. These compounds can be directly used as intermediates for the synthesis of glycopeptides used as antitumoral vaccines and, at the end of the process, can be easily fully deprotected in only one step. Thus, these key building blocks have been successfully used in glycosylation reactions for an efficient construction of peracetylated disaccharides, such as the biological relevant lactosamine, in multigram scale. Subsequently, glycosylation with the 3OH-tetraacetyl-α-d-galactose, used as carbohydrate acceptor, allowed the synthesis of a peracetylated N-trisaccharidic precursor of the lacto-N-neo-tetraose antigen. Extending this strategy to a 3OH-di-acetyl galactal, one peracetylated precursor of the T tumor-associated carbohydrate antigen has been synthesized.This efficient approach, characterized by the use of the acetyl ester as only protecting group during all the synthetical steps expected, represents an easy and efficient alternative to the classical synthetic methods in carbohydrate chemistry that involve several protecting group manipulation.     

Direct,stereoselective thioglycosylation enabled by an organophotoredox radical strategy

While strategies involving a 2e⁻ transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or S_N side reactions of commonly used, labile glycosyl donors. Here we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-cis-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp² and sp³ sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed.

Organophotoredox mediated HAT catalysis is developed for achieving high anomerically selective thioglycosylation of glycosyl bromides.