Targeted glycosyl donor delivery for site-selective glycosylation

[reaction: see text]n-Pentenyl ortho esters (NPOEs) and n-pentenyl glycosides (NPGs) are interconvertible glycosyl donors which are activated by reaction with halonium ions. In a series of cyclic syn-1,3-diols, NPOEs have been found to specifically glycosylate the equatorial-OH while the NPG glycosylates predominantly, but not exclusively, the axial-OH. When the cyclic diol acceptor is presented with equivalent amounts of an NPOE and an NPG in a three-component-reaction, a single, double-glycosylation product is obtained, which conforms to the foregoing preferences, presenting evidence for site-selective glycosylation.     

IPy2BF4-mediated transformation of n-pentenyl glycosides to glycosyl fluorides: a new pair of semiorthogonal glycosyl donors

Bis(pyridinium) iodonium(I) tetrafluoroborate (IPy2BF4), a solid and stable reagent, can be used to transform n-pentenyl orthoesters (NPOEs) and n-pentenyl glycosides (NPGs) into glycosyl fluorides. The latter pair constitutes a new set of semiorthogonal glycosyl donors that can be used in glycosylation strategies, alone or in combination with NPOEs.     

Linker influence on the stereochemical outcome of glycosylations utilizing solid support-bound glycosyl phosphates

[reaction: see text] Glycosyl phosphates can be readily accessed on a solid support via a three-step procedure from support-bound glycals. These resin-bound glycosyl phosphates were successfully used as glycosylating agents for coupling with a series of nucleophiles. The stereochemical outcome of disaccharide formation was dependent on the nature of the linker connecting the saccharide to the polymer. Interestingly, other glycosyl donors such as thioglycosides and trichloroacetimidates did not exhibit such a dependence, indicating a different reaction mechanism for glycosylation.     

Silver(I) tetrafluoroborate as a potent promoter for chemical glycosylation

We have identified silver tetrafluoroborate (AgBF₄) as an excellent promoter for the activation of various glycosyl donors including glycosyl halides, trichloroacetimidates, and thioimidates. Easy handling and no requirement for azeotropic dehydration prior to application makes AgBF₄ especially beneficial in comparison to the commonly used AgOTf. Selective activation of glycosyl halides or thioimidates over thioglycosides or n-pentenyl glycosides, including simple sequential one-pot syntheses, has also been demonstrated. Versatility of glycosyl thioimidates was further explored by converting these intermediates into a variety of other classes of glycosyl donors.     

SYNTHESIS OF 2-(TRIMETHYLSILYL)ETHYL α-d-MANNOPYRANOSIDES REVISITED

Glycosylation of 2-(trimethylsilyl)ethanol with various ethyl 1-thioglycosides, which were activated with N-iodosuccinimide and silver triflate, was studied. The starting thioglycosides, some prepared for the first time, were obtained conventionally from the corresponding α-1-acetates. When β-1-acetates were more readily available, these were converted to the α-anomers by anomerization, prior to the glycosylation. Using ethyl 1-thioglycosides as glycosyl donors, especially those bearing a pivaloyl or a nonparticipating group at O-2, the corresponding 2-(trimethylsilyl)ethyl α-d-mannopyranosides were obtained in excellent yields.     

Synthesis of pennogenyl saponin analogs using three methods

The synthesis of pennogenyl saponins and related compounds using three popular methods of glycosylation has been reported for the first time. Glycosyl halides, glycosyl trichloroacetimidates, and thioglycosides were used as glycosyl donors in the reactions with pennogenin as the glycosyl acceptor. The reactions occur selectively with the C(3)OH group due to the difference in steric accessibility of the hydroxyl groups at the C(3) and C(17) atoms of pennogenin. This makes it possible to synthesize a series of pennogenyl saponins without C(17)OH group protection. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1789–1792, October, 2006.     

Studies on the Selectivity Between Nickel-Catalyzed 1,2-cis-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene N-Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group

The stereoselective synthesis of saccharide thioglycosides containing 1,2-cis-2-amino glycosidic linkages is challenging. In addition to the difficulties associated with achieving high α-selectivity in the formation of 1,2-cis-2-amino glycosidic bonds, the glycosylation reaction is hampered by undesired transfer of the anomeric sulfide group from the glycosyl acceptor to the glycosyl donor. Overcoming these obstacles will pave the way for the preparation of oligosaccharides and glycoconjugates bearing the 1,2-cis-2-amino glycosidic linkages because the saccharide thioglycosides obtained can serve as donors for another coupling iteration. This approach streamlines selective deprotection and anomeric derivatization steps prior to the subsequent coupling event. We have developed an efficient approach for the synthesis of highly yielding and α-selective saccharide thioglycosides containing 1,2-cis-2-amino glycosidic bonds, via cationic nickel-catalyzed glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl aglycon with N-phenyl trifluoroacetimidate donors. The 2-trifluoromethylphenyl group effectively blocks transfer of the anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene donor and can be easily installed and activated. The current method also highlights the efficacy of the nickel catalyst selectively activating the C(2)-benzylidene imidate group in the presence of the anomeric sulfide group on the glycosyl acceptors.     

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.     

An armed-disarmed approach for blocking aglycon transfer of thioglycosides

Thioglycosides are used frequently as glycosyl donors and as mimetics of O-glycosides. While being very useful, thioglycosides are prone to a detrimental side reaction referred to as aglycon transfer. In this letter, it is shown that aglycon transfer can be blocked by matching thioglycoside-containing acceptors with more armed glycosyl donors.     

Synthesis of the Salmonella type E(1) core trisaccharide as a probe for the generality of 1-(benzenesulfinyl)piperidine/triflic anhydride combination for glycosidic bond formation from thioglycosides

A synthesis of a chromogenic glycoside of the Salmonella anatum group E(1) core trisaccharide is presented in which all three glycosidic bonds, a 1,2-cis-equatorial, a 1,2-trans-axial, and a 1,2-trans-equatorial linkage representing three of the four main classes of glycosidic bond, are formed with thioglycoside donors activated under a single set of conditions by the combination of 1-(benzenesulfinyl)piperidine and trifluoromethanesulfonic anhydride. 2,3-O-Carbonyl- and 2,3-O-isopropylidene-alpha-L-rhamnopyranosyl thioglycosides are found to be highly alpha-selective rhamnosyl donors under these conditions.     

Stereoselective synthesis of 2-deoxy-beta-galactosides via 2-deoxy-2-bromo- and 2-deoxy-2-iodo-galactopyranosyl donors

[reaction: see text] A series of 2-bromo- and 2-iodo-galactopyranosyl acetates and trichloroacetimidates were evaluated as glycosyl donors for the synthesis of 2-deoxygalactopyranosides. The best selectivity for the beta-glycosidic linkage was achieved by using 6-deoxy-3,4-carbonate-protected galactosyl donors.     

Some Aspects of Selectivity in the Reaction of Glycosyl Donors*

Some advantages, disadvantages, and anomalies of various donors in glycosidations are discussed. By studying several two‐component donor/acceptor‐diol reactions, it is shown that regiopreferences are not very sensitive to the type of donor used. However, in competitive glycosidations within a given type of donor and between different types of donor, it is shown that regio‐ and chemoselectivities must be indexed to donor reactivity.     

Stereoselective synthesis of aryl 1,2-cis-furanosides and its application to the synthesis of the carbohydrate portion of antibiotic hygromycin A

An efficient methodology for the synthesis of aryl 1,2-cis-furanosidic linkages has been developed with 2-quinolinecarbonyl (Quin) group substituted furanose ethyl thioglycosides as glycosyl donors. The method permits a wide range of phenol acceptors to be used, thus resulting in the formation of structurally diverse phenol furanosides in good to excellent chemical yields with complete 1,2-cis anomeric selectivity. The synthetic utility of the approach has been demonstrated by concise preparation of the carbohydrate portion of antibiotic hygromycin A.     

Stereoselective Synthesis of α‐3‐Deoxy‐D‐manno‐oct‐2‐ulosonic Acid (α‐Kdo) Glycosides Using 5,7‐O‐Di‐tert‐butylsilylene‐Protected Kdo Ethyl Thioglycoside Donors

An efficient methodology for the synthesis of α‐Kdo glycosidic bonds has been developed with 5,7‐O‐di‐tert‐butylsilylene (DTBS) protected Kdo ethyl thioglycosides as glycosyl donors. The approach permits a wide scope of acceptors to be used, thus affording biologically significant Kdo glycosides in good to excellent chemical yields with complete α‐selectivity. The synthetic utility of an orthogonally protected Kdo donor has been demonstrated by concise preparation of two α‐Kdo‐containing oligosaccharides.     

Triflic Anhydride: An Alternative Promoter in Glycosidations

Abstract

The activation of glucosyl halides, trichloroacetimidates and of thioglucosides with triflic anhydride has been investigated showing that triflic anhydride promotes glycos idations with trichloracetimidates as well as with fluorides. There is also some potential for the activation of reactive thioglycosides. The role of triflic anhydride as a Lewis acid is likely.     

Sequential one-pot glycosylations using 1-hydroxyl and 1-thiodonors

[reaction: see text] A novel sequential glycosylation procedure is described that combines the use of 1-hydroxyl and thiodonors. The Ph(2)SO/Tf(2)O-mediated dehydrative condensation of 1-hydroxyl donors with thioglycosides affords in good yield the thiodisaccharides, which in turn can be activated by the same activator system to furnish trisaccharides. The alpha-Gal epitope and a hyaluronan trisaccharide were efficiently assembled in a one-pot procedure.     

Anomeric reactivity-based one-pot synthesis of heparin-like oligosaccharides

A highly efficient one-pot methodology is described for the synthesis of heparin and heparan sulfate oligosaccharides utilizing thioglycosides with well-defined reactivity as building blocks. L-Idopyranosyl and D-glucopyranosyl thioglycosides 5 and 10 were used as donors due to low reactivity of uronic acids as the glycosyl donors in the one-pot synthesis. The formation of uronic acids by a selective oxidation at C-6 was performed after assembly of the oligosaccharides. The efficiency of this programmable strategy with the flexibility for sulfate incorporation was demonstrated in the representative synthesis of disaccharides 17, 18, tetrasaccharide 23, and pentasaccharide 26.     

Solid-Phase Supported Synthesis of the Branched Pentasaccharide Moiety That Occurs in Most Complex Type N-Glycan Chains

Repetitive glycosylation on a sulfanylalkyl-functionalized Merrifield resin leads to the branched, complex pentasaccharide 1 in 20% overall yield in ten steps when appropriately protected O-glycosyl trichloroacetimidates are used as glycosyl donors. A decisive factor here was the tuning of the reaction conditions for the solid-phase glycosylation and the conditions for selective removal of the protecting groups and for cleavage of the samples from the resin for characterization. The subsequent cleavage of the product was achieved with a thiophilic reagent that does not attack the O-glycosidic linkages.     

Solid-Phase Synthesis of Oligosaccharides: Construction of a Dodecasaccharide

Complicated oligosaccharides such as dodecasaccharide 1 can be constructed by a new solid-phase strategy. The attachment to the polymeric support (gray sphere) is through a photolabile linker (structure I ), and thioglycosides serve as carbohydrate donors. Bn=benzyl, Bz=benzoyl.