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.

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.

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.

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.

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.