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

Abstract

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-β-thioglycosides from glycals. While the 1 H 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 solvationinsusceptible, cationic [TTBPyH] + and on the observed reactivity.

Cl–···H–N Interaction Assisted Addition of Sulfonamides to Enol Ethers: Synthesis of 2-Deoxy and 2,6-Dideoxy Sulfonamido Glycosides

“…23 Given the significance of the sulfonamides, it is important to develop other milder methods for the direct synthesis of 2-deoxysulfonamidoglycosides. After successfully utilizing the bulky pyridine catalysis for O-and S-glycocosylation reactions, 8,9,10 here, in the current work, we present this mild and unique anion based activation catalyzed synthesis of 2-deoxy glycosylsulfonamides in a highly efficient and stereoselective fashion. Our attempts started by using 3,4,6-tri-O-(p-methylbenzyl)-D-galactal 1c and orthotoluenesulfonamide 2c as starting materials and the chloride salt 3a as the catalyst in dichloroethane as the solvent.…”

“…However, the IR experiments, along with the control experiments and the optimization studies with various salts, point to an anion-directed activation similar to the O-and S-glycosylation reactions. 9,10 The anions associated with the sterically bulky Template for SYNLETT Thieme ). The applicability of current mild catalysis for the sulfonamidoglycosylation protocol towards large scale synthesis was also investigated.…”

“…However, the IR experiments, along with the control experiments and the optimization studies with various salts, point to an anion-directed activation similar to the O - and S -glycosylation reactions. 9 10 The anions associated with the sterically bulky 2,4,6-tri- tert -butylpyridinium, due to the strain within the ion pair is imparted with unusual reactivity and can polarize the N–H bond of the sulfonamido group. The thus mildly acidic N–H proton protonates the glycals forming an oxocarbenium ion which undergoes a nucleophilic addition leading to the observed N-glycosylated products (Figure 1, b ).…”

“…9 The mild activation conditions have been exploited in the stereoselective synthesis of O - and S -glycosylation reactions from glycals. 9 10 In this work we show the ability of the TTBPy·HCl salt to activate the aliphatic and aro­matic sulfonamides via frustrated Brønsted pair catalysis to synthesize the biologically important 2-deoxysulfonamidoglycosides.…”

“…8 We hypothesized that due to the weakening of the cation–anion interactions in the sterically bulky TTBPy salts owing to the steric bulk, the anions show increased reactivity in organic solvents and can activate any third molecule, which we call as frustrated Brønsted pair reactivity. 9 The mild activation conditions have been exploited in the stereoselective synthesis of O - and S -glycosylation reactions from glycals. 9 10 In this work we show the ability of the TTBPy·HCl salt to activate the aliphatic and aro­matic sulfonamides via frustrated Brønsted pair catalysis to synthesize the biologically important 2-deoxysulfonamidoglycosides.…”