Scalable Synthesis of Anomerically Pure Orthogonal-Protected GlcN₃ and GalN₃ from d‑Glucosamine

An improved and scalable synthesis of orthogonally protected d-glucosamine and d-galactosamine building blocks from inexpensive d-glucosamine has been developed. The key reaction is an inversion/migration step providing access to a fully orthogonal protecting group pattern, which is required for microbial oligosaccharide synthesis. The method can be carried out on a multigram scale as several of the reactions can be purified by crystallization to give anomerically pure products

Scalable Synthesis of Anomerically Pure Orthogonal-Protected GlcN₃ and GalN₃ from d‑Glucosamine

An improved and scalable synthesis of orthogonally protected d-glucosamine and d-galactosamine building blocks from inexpensive d-glucosamine has been developed. The key reaction is an inversion/migration step providing access to a fully orthogonal protecting group pattern, which is required for microbial oligosaccharide synthesis. The method can be carried out on a multigram scale as several of the reactions can be purified by crystallization to give anomerically pure products

Rhamnosylation: Diastereoselectivity of Conformationally Armed Donors

The α/β-selectivity of super-armed rhamnosyl donors have been investigated in glycosylation reactions. The solvent was found to have a minor influence, whereas temperature was crucial for the diastereoselectivity. At very low temperature, a modest β-selectivity could be obtained, and increasing temperature gave excellent α-selectivity. The donors were highly reactive, and activation was observed at temperatures as low as −107 °C. Different promoter systems and leaving groups were investigated, and only activation with a heterogeneous catalyst increased the amount of the β-anomer significantly. By introducing an electron-withdrawing nonparticipating group, benzyl sulfonyl, on 2-O, an increase in β-product was observed

Conformationally Armed 3,6-Tethered Glycosyl Donors: Synthesis, Conformation, Reactivity, and Selectivity

The reactivity and selectivity of 3,6-tethered glycosyl donors have been studied using acceptors with different steric and electronic characteristics. Eight (four anomeric pairs) 3,6-bridged-glycosyl donors were synthesized in high yields from their common parent sugars. The glycosylation properties were tested using at least three different acceptors and several promoter systems. Thiophenyl 2,4-di-<i>O</i>-benzyl-3,6-<i>O</i>-(di-<i>tert</i>-butylsilylene)-α-d-glucopyranoside gave α/β mixtures with standard NIS/TfOH mediated activation, whereas the corresponding fluoride was found to be highly β-selective, when using SnCl₂/AgB­(C₆F₅)₄ as the promoter system. Mannosyl donors were highly α-selective despite the altered conformation. Galactosylations using NIS/TfOH were generally α-selective, but more β-selective using the galactosyl fluoride and depending on the acceptor used. Thiophenyl 2-azido-2-deoxy-4-<i>O</i>-benzyl-3,6-<i>O</i>-(di-<i>tert</i>-butylsilylene)-α-d-glucopyranoside was found to be α-selective . The reactivity of the donors was investigated using competition experiments, and some but not all were found to be highly reactive. Generally it was found that the α-thioglycosides were significantly more reactive than the β; this difference in reactivity was not found for 3,6-anhydro-, armed-(benzylated), or the classic super armed (silylated) donors. A mechanism supporting the unusual observations has been suggested

NMR Study of the Hydrolysis and Dehydration of Inulin in Water: Comparison of the Catalytic Effect of Lewis Acid SnCl₄ and Brønsted Acid HCl

Various NMR techniques were employed to study the catalytic performance of the Lewis acid SnCl₄ and the Brønsted acid HCl in the conversion of inulin to value-added compounds by hydrolysis and subsequent dehydration. The hydrolysis of inulin was examined to reveal the catalytic abilities of SnCl₄ besides its intrinsic acidity by in situ ¹H and ¹³C NMR at 25 °C. The dehydration reaction of inulin with SnCl₄ as catalyst was followed by high temperature in situ ¹H NMR at 80 °C. The fructose moieties were dehydrated to 5-(hydroxy­methly)­furfural (5-HMF), but the glucose fragment of inulin was inactive for dehydration reaction under this condition. The formation of 5-HMF and its transformation into formic acid and levulinic acid through a rehydration reaction could be monitored by in situ NMR spectroscopy. Moreover, diffusion ordered spectroscopy NMR revealed that the Lewis acid ion, Sn⁴⁺ interacts with the inulin model compounds, i.e., sucrose and fructose. The synergistic effects of complexation and acidity from the hydrolysis of SnCl₄ results in a higher catalytic ability of this Lewis acid catalyst compared with a Brønsted acid

Influence of O6 in Mannosylations Using Benzylidene Protected Donors: Stereoelectronic or Conformational Effects?

The stereoselective synthesis of β-mannosides and the underlying reaction mechanism have been thoroughly studied, and especially the benzylidene-protected mannosides have gained a lot of attention since the corresponding mannosyl triflates often give excellent selectivity. The hypothesis for the enhanced stereoselectivity has been that the benzylidene locks the molecule in a less reactive conformation with the O6 trans to the ring oxygen (O5), which would stabilize the formed α-triflate and subsequent give β-selectivity. In this work, the hypothesis is challenged by using the carbon analogue (C7) of the benzylidene-protected mannosyl donor, which is investigated in terms of diastereoselectivity and reactivity and by low-temperature NMR. In terms of diastereoselectivity, the C-7-analogue behaves similarly to the benzylidene-protected donor, but its low-temperature NMR reveals the formation of several reactive intermediate. One of the intermediates was found to be the β-oxosulfonium ion. The reactivity of the donor was found to be in between that of the “torsional” disarmed and an armed donor

DOSY NMR: A Versatile Analytical Chromatographic Tool for Lignocellulosic Biomass Conversion

The diffusion ordered NMR spectroscopy (DOSY) protocol for the analysis of reaction mixture of lignocellulosic biomass conversion has been developed and investigated systematically. Model reaction mixtures from cellulose, hemicellulose and lignin conversion, real reaction mixtures of sucrose and glucose dehydration, were facilely separated and assigned in the diffusion dimension without any prior separation or isolation. The shift reagent, EuFOD, was successfully utilized to increase the difference in diffusion and thereby resolution in lignin degradation model. DOSY NMR offers an easy and robust method for the structure identification and reaction mixture separation in biomass conversion

Deep Eutectic Solvents: Green Solvents and Catalysts for the Preparation of Pyrazine Derivatives by Self-Condensation of d‑Glucosamine

Deep eutectic solvents (DESs) exhibit similar physicochemical properties to the ionic liquids. They are inexpensive, renewable, nontoxic, and environmentally benign solvents and have gradually attracted attention in several fields, for example, biorefinery. Here choline chloride-based DESs have been used as solvents and catalysts for the preparation of deoxyfructosazine (DOF) through a self-condensation reaction of d-glucosamine (GlcNH₂). The catalytic performances of a “green cocatalyst”, amino acids, and the reaction mechanism were also studied. The results displayed that choline chloride/urea was capable to convert GlcNH₂ efficiently, with a 13.5% yield of DOF at low temperature and with a short reaction time (100 °C, 150 min). Among the screened amino acids, arginine showed the highest activity and gave the highest yield of DOF (30.1%) under the optimized reaction conditions. Nuclear magnetic resonance (NMR) studies revealed a strong hydrogen bond interaction between GlcNH₂ and arginine. Moreover, a detectable intermediate, namely dihydrofructosazine, in the condensation of GlcNH₂ to DOF/fructosazine (FZ) was captured by in situ NMR technique

Product Distribution Control for Glucosamine Condensation: Nuclear Magnetic Resonance (NMR) Investigation Substantiated by Density Functional Calculations

Selective conversion of glucosamine (GlcNH₂) to deoxyfructosazine (DOF) and fructosazine (FZ) with additives was investigated. Significantly enhanced yield of DOF can be improved to 40.2% with B­(OH)₃ as the additive. Chemical shift titration (via one-dimensional nuclear magnetic resonance (1D ¹H and ¹³C NMR)) and two-dimensional nuclear magnetic resonance (2D NMR) including ¹H–¹³C HSQC and ¹H–¹H COSY are used to investigate intermolecular interactions between B­(OH)₃ and GlcNH₂. Diffusion-ordered NMR spectroscopy (DOSY) was further employed to identify intermediate species. Mechanistic investigation by NMR combined with electron spray ionization–mass spectroscopy (ESI-MS) discloses that a mixed 1:1 boron complex was identified as the major species, shedding light on the promotional effects of B­(OH)₃, which is substantiated by density functional theory (DFT). Boron coordination effects make ring-opening and subsequent dehydration reaction thermodynamically and kinetically more favorable. Dehydration of dihydrofructosazine is a key step in controlling overall process (49.7 kcal/mol). Interestingly, chelating effect results in substantial reduction of this free-energy barrier (31.5 kcal/mol). Notably, FZ was gradually becoming the main product (yield up to 25.3%), with H₂O₂ as the oxidant