Exploiting the Strained Ion-Pair Interactions of Sterically Hindered Pyridinium Salts Toward SN2 Glycosylation of Glycosyl Trichloroacetimidates.

We demonstrate here that strained and sterically hindered protonated 2,4,6-tri-tert-butylpyridinium (TTBPy) tetrafluoroborate, a crystalline, bench stable salt serves as a mild and efficient organocatalyst for the SN2 type displacement of glycosyl trichloroacetimidates toward the stereoselective synthesis of both α- and ß-glycosides. The strained ion-pair interactions between the sterically hindered pyridinium cation and the tetrafluoroborate anion infuse unusual reactivity to the ions resulting in the unique anion assisted activation of alcohol. This mild activation of alcohol facilitates the SN2 type displacement of glycosyl α-trichloroacetimidates into ß-glycosides in a highly diastereoselective manner. These unique interactions were established based on extensive infrared and 1H, 19F, 11B NMR studies and theoretical studies.

Regio- and Stereoselective C-Glycosylation of Indoles Using o-[1-(p-MeO-Phenyl)vinyl]benzoates (PMPVB) as Glycosyl Donors under Brønsted Acid Catalysis.

The alkene-based o-[1-(p-MeO-phenyl)vinyl]benzoates (PMPVB) donors that can be remotely activated under catalytic Brønsted acidic conditions have been utilized to synthesize the C-linked indolyl glycosides in a regio- and stereoselective manner. The highly reactive glycosyl donors allow the usage of the poorly nucleophilic N-Boc and N-acetyl indole derivatives, leading to the indolyl glycosides in excellent yields and stereoselectivities. Also, conditions were developed for recycling the byproduct, which significantly improves the potential of these donors.

Influence of Various Silyl Protecting Groups on Stereoselective 2-Deoxyrhamnosylation.

The influence of various silyl protecting groups on 2-deoxyrhamnosylation using 2-deoxyrhamnosyl acetates, thioglycosides, and (p-methoxyphenyl)vinylbenzoate (PMPVB) donors has been presented. C-Glycosylation reactions reveal that tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and tert-butyldiphenylsilyl (TBDPS) silyl protected rhamnosyl oxocarbenium ions have no facial selectivity except for the conformationally (4H3) locked tetraisopropyldisiloxane (TIPDS) protected rhamnose donor, which provides complete α-selectivity. However, TBDPS protected rhamnosyl donors are found to be superior protecting groups for α-stereoselective O-glycosylation reactions with various acceptors. The observed results are found consistent across donors and donor activation conditions. Most importantly, the study was conducted at room temperature unlike the other energy-intensive low-temperature studies and was bound to have more practical utility. The outcomes have been explained using kinetic and thermodynamic analyses.

ortho-[1-(p-MeOPhenyl)vinyl]benzoate PMPVB as a recyclable auxiliary for C-O and C-S bond formation reactions under Brønsted acid catalysis.

A practically simple and useful method is reported for the synthesis of ethers and thioethers via Brønsted acid-catalyzed activation of ortho-[1-(p-MeOphenyl)vinyl]benzoate (PMPVB) donors derived from alcohols. The mechanism of action is based on the remote activation of an active alkene followed by intramolecular 5-exo-trig cyclization leading to a reactive intermediate that can react via a substrate dependent SN1 or SN2 mechanism with alcohols and thiol nucleophiles providing facile access to ether and thioether functionalities, respectively.

Glycosyl o-[1-(p-MeO-Phenyl)vinyl]benzoates (PMPVB) as Easily Accessible, Stable, and Reactive Glycosyl Donors for O-, S-, and C-Glycosylations under Brønsted Acid Catalysis.

Methods suitable for the synthesis of both O- and S-glycosylations are relatively rare because commonly used promoters like halonium sources or gold catalysts are incompatible with thiols as nucleophiles. Here, we present (p-MeO)phenylvinylbenzoates (PMPVB) as easily accessible, stable, and reactive alkene-based glycosyl donors that can be activated with catalytic amounts of a Brønsted acid. This activation protocol not only allows us to synthesize O-glycosides but also can successfully provide S- and C-linked glycosides. The armed and disarmed donors lead to product formation in 5 min, showcasing the high reactivity of the donors. Competitive experiments show that the PMPVB donors are much more reactive than the corresponding PVB donors even under NIS/TMSOTf conditions, whereas PVB donors are not reactive enough to be efficiently activated under Brønsted acid conditions. The potential of the catalytic glycosylation protocol has also been showcased by synthesizing trisaccharides. The Brønsted acid activation of PMPVB donors also allows access to C-glycosides in a stereoselective fashion. The easy accessibility of the donor aglycon on a multigram scale in just two steps makes the PMPVB donors highly attractive alternatives.

Catalytic stereoselective synthesis of 2-deoxy α-glycosides using glycosyl ortho-[1-(p-MeOPhenyl)Vinyl]Benzoate (PMPVB) donors.

2-Deoxy glycosyl ortho-[1-(p-MeOPhenyl)Vinyl]Benzoates (PMPVB) have been presented as stable, reactive glycosyl donors for the synthesis of 2-deoxy α-glycosides. The donors react under Brønsted acid conditions to provide the 2-deoxy-α-glycosides with very high stereocontrol. The observed high stereoselectivities were discussed with respect to the relative free energy differences between the anomeric reactive intermediates.

Influence of Anion-Binding Schreiner's Thiourea on DMAP Salts: Synergistic Catalysis toward the Stereoselective Dehydrative Glycosylation from 2-Deoxyhemiacetals.

Amines are used as additives to facilitate or increase the host-guest chemistry between the thiourea and the anions of Bronsted acids. However, we here demonstrate, for the first time, the synergistic effect of the combination of DMAP/HCl/Schreiner's thiourea in catalyzing dehydrative glycosylation. The variations in the electronic effects of the cationic Bronsted acid part (the protonated DMAP) in the presence of chloride binding Schreiner's thiourea have been discussed using NMR and X-ray crystallographic techniques.

Sterically Strained Brønsted Pair Catalysis by Bulky Pyridinium Salts: Direct Stereoselective Synthesis of 2-Deoxy and 2,6-Dideoxy-ß-thioglycosides from Glycals.

A sterically strained ionic Brønsted pair complex obtained from a sterically bulky base 2,4,6-tri-tert-butylpyridine and hydrochloric acid imbues unusual reactivity to the anionic chloride. The complete shielding of the cationic [N-H]+ by the bulky ortho-tert-butyl groups weakens the possible hydrogen-bonding interactions with the chloride anion, and the [N-H]+···Cl- distance is unusually longer (3.10 Å). This results in strained/frustrated electrostatic interactions between the ion-pair, thus infusing an increased reactivity in both of the ions, which results in the activation of a third molecule like thiol via hydrogen-bonding. This intriguing weak interaction-based reactivity has been utilized to develop an organocatalytic synthesis of 2-deoxy-ß-thioglycosides from glycals. While the 1H NMR studies showcase the diamagnetic activation of thiols in the presence of the catalyst, the electron paramagnetic resonance (EPR) studies reveal the generation of a radical species that suggests a possible frustrated radical pair catalysis. Besides, IR spectroscopic studies explain the intriguing influence of size/charge density of the anion on the solvation-insusceptible, cationic [TTBPyH]+ and on the observed reactivity.

Expedient Synthesis of Core Disaccharide Building Blocks from Natural Polysaccharides for Heparan Sulfate Oligosaccharide Assembly.

The complex sulfation motifs of heparan sulfate glycosaminoglycans (HS GAGs) play critical roles in many important biological processes. However, an understanding of their specific functions has been hampered by an inability to synthesize large numbers of diverse, yet defined, HS structures. Herein, we describe a new approach to access the four core disaccharides required for HS/heparin oligosaccharide assembly from natural polysaccharides. The use of disaccharides rather than monosaccharides as minimal precursors greatly accelerates the synthesis of HS GAGs, providing key disaccharide and tetrasaccharide intermediates in about half the number of steps compared to traditional strategies. Rapid access to such versatile intermediates will enable the generation of comprehensive libraries of sulfated oligosaccharides for unlocking the "sulfation code" and understanding the roles of specific GAG structures in physiology and disease.

Secondary amine salt catalyzed controlled activation of 2-deoxy sugar lactols towards alpha-selective dehydrative glycosylation.

A new organocatalytic glycosylation method exploiting the lactol functionality has been disclosed. The catalytic generation of glycosyl oxacarbenium ions from lactols under forcible conditions via weakly Brønsted-acidic, readily available secondary amine salts affects the diastereoselective glycosylation of 2-deoxypyranoses and furanoses. This operationally simple iminium catalyzed activation of 2-deoxy hemi-acetals is a potential alternative to the existing cumbersome methods that need specialized handling. The mechanisms for this unique transformation and kinetic/thermodynamic effects have been discussed based on both experimental evidence and theoretical studies.

Probing the influence of protecting groups on the anomeric equilibrium in sialic acid glycosides with the persistent radical effect.

A method for the investigation of the influence of protecting groups on the anomeric equilibrium in the sialic acid glycosides has been developed on the basis of the equilibration of O-sialyl hydroxylamines by reversible homolytic scission of the glycosidic bond following the dictates of the Fischer-Ingold persistent radical effect. It is found that a trans-fused 4O,5N-oxazolidinone group stabilizes the equatorial glycoside, i.e., reduces the anomeric effect, when compared to the 4O,5N-diacetyl protected systems. This effect is discussed in terms of the powerful electron-withdrawing nature of the oxazolidinone system, which in turn is a function of its strong dipole moment in the mean plane of the pyranose ring system. The new equilibration method displays a small solvent effect and is most pronounced in less polar media consistent with the anomeric effect in general. The unusual (for anomeric radicals) poor kinetic selectivity of anomeric sialyl radicals is discussed in terms of the planar π-type structure of these radicals and of competing 1,3-diaxial interactions in the diastereomeric transition states for trapping on the α- and ß-faces of the radical.

Synthesis of chiral functional polyhydroxylated arenes via Mukaiyama aldol reaction from Perlin aldehydes.

Functionalized aryl polyhydroxylated compounds could be of great synthetic value for natural product synthesis. However, the synthesis of such compounds usually requires multi-step synthesis or the usage of sensitive reagents. We present here a practically simple route for the synthesis of such functionalized arylpolyols from glycal derived α,ß-unsaturated 2,3-dideoxy aldehyde as well as α,ß-saturated 2,3-dideoxy aldehyde (Perlin aldehydes) via Mukaiyama cross aldol condensation in the presence of silyl enol ether and TiCl4. It was observed that the nature of the electronic substitution of the silyl enol ether does not play any role in the yield of the desired products. Further functionalization of the products has also been shown.

Triple Role of Proton Sponge (DMAN) in the Palladium-Catalyzed Direct Stereoselective Synthesis of C-Aryl Glycosides from Glycals.

The triple role of 1,8-bis(dimethylamino)naphthalene (proton sponge) as a reductant, ligand precursor, and organic base in the palladium-catalyzed Heck-type coupling reaction of glycals with aryl iodides affords the rapid and stereoselective synthesis of 2',3'-unsaturated α-C-aryl glycosides in excellent yields. The role of the proton sponge in reducing palladium(II) to (0) has been studied using cyclic voltammetry, UV-vis, HRMS, and other spectroscopic techniques. This is the first example of a palladium proton sponge complex utilized in coupling reactions. The method is observed to be tolerant of various functional groups, as demonstrated by the huge substrate scope. Moreover, the 2',3'-unsaturated α-C-aryl glycosides were also converted to 3-keto-ß-C-glycosides under sterically hindered pyridinium salt catalysis via a ring-opening and -closing mechanism.

Influence of side chain conformation and configuration on glycosyl donor reactivity and selectivity as illustrated by sialic acid donors epimeric at the 7-position.

Two N-acetyl 4O,5N-oxazolidinone-protected sialyl thioglycosides epimeric at the 7-position have been synthesized and their reactivity and stereoselectivity in glycosylation reactions have been compared. It is demonstrated that the natural 7S-donor is both more reactive and more α-selective than the unnatural 7R-isomer. The difference in reactivity is attributed to the side chain conformation and specifically to the proximity of O7 to the anomeric center. In the natural 7S-isomer, O7 is closer to the anomeric center than in its unnatural 7R-epimer and, therefore, better able to support incipient positive charge at the locus of reaction. The difference in selectivity is also attributed to the side conformation, which in the unnatural 7R-series is placed perpendicularly above the α-face of the donor and so shields it to a greater extent than in the 7S-series. These observations are consistent with earlier conclusions on the influence of the side chain conformation on reactivity and selectivity derived from conformationally locked models in the glucose and galactose series and corroborate the suggestion that those effects are predominantly stereoelectronic rather than torsional. The possible relevance of side chain conformation as a factor in the influence of glycosylation stereoselectivity by remote protecting groups and as a control element in enzymic processes for glycosidic bond formation and hydrolysis are discussed. Methods for assignment of the anomeric configuration in the sialic acid glycosides are critically surveyed.

Synthesis of 2-nitroglycals from glycals using the tetrabutylammonium nitrate-trifluoroacetic anhydride-triethylamine reagent system and base-catalyzed Ferrier rearrangement of acetylated 2-nitroglycals.

A reagent system comprising tetrabutylammonium nitrate-trifluoroacetic anhydride-triethylamine has been developed for the synthesis of 2-nitroglycals from various protected glycals. The base-catalyzed Ferrier rearrangement on tri-O-acetylated 2-nitroglycals has been reported for the first time. Reactivity of these nitroacetates and associated selectivity has been examined, and some of the products have been converted into 2,3-diamino-2,3-dideoxyglycosides and methyl N-acetyl-D-lividosaminide.

Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars.

Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors.

Dissecting the influence of oxazolidinones and cyclic carbonates in sialic acid chemistry.

At a moment's notice: Thermal equilibration of 1 and mass spectral analysis of sialyl phosphates suggest that the 4O,5N-oxazolidinone and the 4,5-O-carbonate systems influence the anomeric effect and the mechanisms of sialidation by virtue of their dipole moment in the mean plane of the pyranose ring. The electron-withdrawing effect destabilizes 2 and promotes associative glycosylation mechanisms. TEMPO = 2,2,6,6-tetramethylpiperidine N-oxide.

TfO-···H-O-H Interaction-Assisted Generation of a Silicon Cation from Allylsilanes: Access to Phenylallyl Ferrier Glycosides from Glycals.

We demonstrate here that the strained and bulky protonated 2,4,6-tri-tert-butylpyridine (TTBPy) triflate salt serves as a mild and efficient organocatalyst for the diastereoselective C-Ferrier glycosylation of various glycals. The importance of the role of the 1/2 H2O molecule trapped in the catalyst has been disclosed. The mechanism of action involves unique anionic triflate and H2O hydrogen-bond interactions that assist the activation of allylsilanes, providing unprecedented access to diastereoselective phenylallyl Ferrier glycosides.

Acetyl chloride-silver nitrate-acetonitrile: a reagent system for the synthesis of 2-nitroglycals and 2-nitro-1-acetamido sugars from glycals.

A new reagent system comprising acetyl chloride, silver nitrate, and acetonitrile has been developed for the synthesis of 2-nitroglycals from the corresponding glycals. Under certain conditions, the formation of 2-nitro-1-acetamido sugars has also been observed. In addition, a few other non-carbohydrate-derived olefins also gave the corrresponding conjugated nitroolefins.

Reductive Alkylation of Quinolines to N-Alkyl Tetrahydroquinolines Catalyzed by Arylboronic Acid.

A boronic acid catalyzed one-pot tandem reduction of quinolines to tetrahydroquinolines followed by reductive alkylation by the aldehyde has been demonstrated. This step-economcial synthesis of N-alkyl tetrahydroquinolines has been achieved directly from readily available quinolines, aldehydes, and Hantzsch ester under mild reaction conditions. The mechanistic study demonstrates the unique behavior of organoboron catalysts as both Lewis acids and hydrogen-bond donors.