Hydrogenolysis Of Benzyl Ethers Research Articles

Chemoenzymatic Synthesis of Select Intermediates and Natural Products of the Desferrioxamine E Siderophore Pathway.

The NIS synthetase family of enzymes responsible for the biosynthesis of siderophores is increasingly associated with bacterial virulence. Proteins in this class represent outstanding potential drug targets, assuming that basic biochemical and structural characterizations can be completed. Towards this goal, we have mated an improved synthesis of the non-commercial amino acid N-hydroxy-N-succinylcadaverine (HSC, 6) with an isothermal titration calorimetry (ITC) assay that profiles the iterative stages of HSC trimerization and macrocyclization by NIS synthetase DesD from Streptomyces coelicolor. HSC synthesis begins with multigram-scale Gabrielle and tert-butyl N-(benzyloxy)carbamate alkylations of 1-bromo-5-chloropentane following prior literature, but the end-game reported herein has two advantages for greater material throughput: (1) hydrogenolysis of benzyl ether and Cbz blocking groups is best accomplished with Pearlman’s catalyst at 40 psi of H2 and (2) purification of neutral (zwitterionic) HSC is effected by simple flash chromatography over silica gel in MeOH. HSC is subsequently shown to be a substrate for NIS synthetase DesD, which catalyzes three successive amide bond syntheses via adenyl monophosphate ester intermediates. We quantify and present the iterative and overall enzyme kinetic constants associated with formation of the cyclotrimeric siderophore desferrioxamine E (dfoE, 1).

Synthesis of oligomers of β-l-arabinofuranosides of (4R)-4-hydroxy-l-proline relevant to the mugwort pollen allergen, Art v 1.

An efficient, convergent solution phase synthesis of monomer, dimer, trimer and tetramer of the β-l-arabinofuranosylated hydroxyproline (β-l-Araf-Hyp) glycocluster is described. This motif constitutes the carbohydrate-specific epitope of Art v 1, the major allergen of mugwort pollen. While a single monomeric unit was proposed at the outset, poor yields for the seemingly trivial steps of end-capping to replace protecting groups with N-terminal acetamides and C-terminal methyl amides led to the introduction of N-terminal, central and C-terminal β-l-Araf-Hyp building blocks. Dimer 2 was obtained in 60% yield by coupling of two monomers, followed by hydrogenolysis of benzyl ether protecting groups. Trimer 3 was obtained in 35% yield via a [2 + 1] coupling and tetramer 4 in 15% yield via a [2 + 2] fragment condensation. Circular dichroism spectra show that monomer 1 displays no organized structure, whereas compounds 2-4 show a strong negative band at 200 nm and a weak positive band at ∼220 mn, as is characteristic of the polyproline II helix.

Palladium-catalyzed hydrogenation with use of ionic liquid bis(2-hydroxyethyl)ammonium formate [BHEA][HCO2] as a solvent and hydrogen source

We designed ionic liquid bis(2-hydroxyethyl)ammonium formate [BHEA][HCO2] for use as a solvent and hydrogen donor for hydrogenation. Catalytic hydrogenation of aromatic ketones, nitro groups, and olefins with PdCl2 in [BHEA][HCO2] generated the corresponding reduction products. Selective reduction of aromatic ketones over aliphatic ketones was observed. Hydrogenolysis of benzyl ethers and benzyl amines also proceeded. All these reactions were successfully carried out in good to excellent yields under mild and nonflammable conditions. In addition, the ionic liquid and Pd source can be reused several times.

FerriBRIGHT: A Rationally Designed Fluorescent Probe for Redox Active Metals

The novel catechol-BODIPY dyad, 8-(3,4-dihydroxyphenyl)-2,6-bis(ethoxycarbonyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (FerriBRIGHT) was rationally designed with the aid of computational methods. FerriBRIGHT could be prepared by standard one-pot synthesis of BODIPY fluorophores from 3,4-bis(benzyloxy)benzaldehyde (1) and 3,5-dimethyl-4-(ethoxycarbonyl)pyrrole (3); however, isolating the dipyrrin intermediate 8-[3,4-bis(benzyloxy)phenyl]-2,6-bis(ethoxycarbonyl)-1,3,5,7-tetramethyl-4,4-diaza-s-indacene (7) prior to reaction with excess BF(3).OEt(2) led to marked improvements in the isolated overall yield of the desired compound. In addition to these improvements in fluorophore synthesis, microwave-assisted palladium-catalyzed hydrogenolysis of benzyl ethers was used to reduce reaction times and catalyst loading in preparation of the desired compound. When FerriBRIGHT is exposed to excess FeCl(3), CuCl(2), [Co(NH(3))(5)Cl]Cl(2), 2,3-dichloro-5,6-dicyanobenzoquinone, or ceric ammonium nitrate in methanol, a significant enhancement of fluorescence is observed. FerriBRIGHT-Q, the product resulting from the oxidation of the pendant catechol to the corresponding quinone, was found to be the emissive species. FerriBRIGHT-Q was synthesized independently, isolated, and fully characterized to allow for direct comparison with the spectroscopic data acquired in solution. Biologically relevant reactive oxygen species, such as H(2)O(2), (*)OH, (1)O(2), O(2)(*-), and bleach (NaOCl), failed to cause any changes in the emission intensity of FerriBRIGHT. In accordance with the quantum mechanical calculations, the quantum yield of fluorescence for FerriBRIGHT (Phi(fl) approximately 0) and FerriBRIGHT-Q (Phi(fl) = 0.026, lambda(ex)/lambda(em) = 490 nm/510 nm) suggests that photoinduced electron transfer between the catechol and the BODIPY dye is attenuated upon oxidation, which results in fluorescence enhancement. Binding studies of FerriBRIGHT with Ga(NO(3))(3), a redox-inactive analogue of Fe(III), provided conditional binding constant log beta(12)' = 13.3 +/- 0.2 for a [Ga(FerriBRIGHT)(2)](-) complex. A 2.8-fold enhancement of fluorescence intensity upon addition of Ga(III) to FerriBRIGHT suggests the possibility of metal ion sensing with this new class of compounds.

Hydroxyl Group Deprotection Reactions with Pd(OH)2/C: A Convenient Alternative to Hydrogenolysis of Benzyl Ethers and Acid Hydrolysis of Ketals.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Hydroxyl group deprotection reactions with Pd(OH) 2/C: a convenient alternative to hydrogenolysis of benzyl ethers and acid hydrolysis of ketals

Benzyl ethers, ketals and orthoformates were cleaved with Pd(OH) 2/C in methanol, to generate the corresponding alcohol; carboxylic acid esters were stable under these reaction conditions. Pd(OH) 2/C in methanol was used for the deprotection of hydroxyl groups during the preparation of sequoyitol via myo-inositol orthobenzoate. This method of deprotection has the potential to be useful in the synthesis of different classes of organic compounds since the reaction conditions do not involve strong acids, bases or hydrogen.

Development of Large-Scale Preparations of Indole Derivatives: Evaluation of Potential Thermal Hazards and Studies of Reaction Kinetics and Mechanisms

Hydrogenation of (E)-2-nitropyrrolidinostyrene in the presence of the doped rhodium catalyst is safe, scalable, and highly effective for the preparation of 6-benzyloxyindole. Reaction kinetics with/without additives also were examined using in situ IR for the first time. Results showed that the additives decelerate the hydrogenolysis of benzyl ethers, while simultaneously accelerating the de-oxygenation of N-oxy-intermediates.

Selective Hydrogenolysis of Benzyl Ethers in the Presence of Benzylidene Acetals with Raney Nickel.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Studies on the hydrogenolysis of benzyl ethers

Selective hydrogenolysis of benzyl ethers can be achieved by the appropriate choice of the catalyst, solvent, and concentration, which facilitates the design of O-benzyl based protecting group strategies for the synthesis of natural products.

Selective hydrogenolysis of benzyl ethers in the presence of benzylidene acetals with Raney nickel

A simple method to remove selectively a benzyl group protecting a hydroxyl function in the presence of a benzylidene acetal by catalytic hydrogenolysis with Raney nickel is reported. This method was successfully applied to the synthesis of the C1–C14 fragment of dolabelides.

Microwave‐Promoted Synthesis of Amino‐Substituted 2‐Pyridone Derivatives via Palladium‐Catalyzed Amination Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Microwave-promoted synthesis of amino-substituted 2-pyridone derivatives via palladium-catalyzed amination reaction

A rapid and efficient synthesis of amino-substituted 2-pyridones was demonstrated by palladium-catalyzed amination reaction under microwave irradiation. This high-speed synthesis provided a number of amino-substituted 2-pyridones from the corresponding bromo-2-benzyloxypyridines via palladium-catalyzed amination followed by hydrogenolysis of benzyl ether.

Bis-benzyl protected 6-amino cyclitols are poisonous to Pd/C catalysed hydrogenolysis of benzyl ethers

Pd/C and Pd(OH)2/C catalysts are both poisoned by bis-benzyl protected 6-aminocyclitols thereby inhibiting the hydrogenolysis of benzyl ethers but removing N-Cbz groups chemoselectively. This outcome was unaltered by the use of different hydrogen donors. Replacement of the C-6 nitrogen atom by oxygen resulted in the starting materials being fully deprotected under similar conditions. These findings add cyclitolamines to the list of amines/bases that are poisonous to Pd/C catalysts during hydrogenolysis.

Mild catalytic multiphase hydrogenolysis of benzyl ethers

A preliminary study was conducted on the multiphase (aqueous KOH–isooctane–Aliquat® 336) hydrogenolysis of benzyl methyl ether using Pd/C, Pt/C and Raney-Ni as catalysts, under mild conditions (T = 50 °C, pH2 = 1 atm). Using ethanol as solvent, the Pd/C system is very efficient, while the same catalyst under multiphase conditions is almost inactive. With Pt/C, the reaction is always sluggish, and ring hydrogenation kicks in under multiphase conditions. The Raney-Ni system has an opposite behavior, while debenzylation is slow in ethanol, under multiphase conditions the reaction is quite fast. Other O-benzyl protected substrates undergo debenzylation with Raney-Ni as well, with varying chemoselectivity.

5-Benzyloxy-1-phenyltetrazole: catalytic transfer hydrogenolysis of benzyl ethers

In contrast to the earlier reported inertness of 5-benzyloxy-1-phenyltetrazole, (1a), and 3-benzyloxy-1,2-benzisothiazole 1,1-dioxide, (2a), towards catalytic transfer hydrogenolysis in toluene/water solvent systems, it is now shown that simply changing the solvent to tetrahydrofuran/water leads to their rapid hydrogenolysis with formation of toluene. Compound (1a), C 14 H 12N4O , has a short C-O ether bond to the tetrazole ring [1.3261 (15) A] and a particularly long C-O bond to the benzyl group [1.4676 (16) A], consistent with an activation of this longer bond by the strongly electronegative tetrazole unit.

Synthetic antigenic determinants of the Brucella A polysaccharide: A disaccharide thioglycoside for block synthesis of pentasaccharide and lower homologues of α1,2-linked 4,6-dideoxy-4-formamido-α-D-mannose

Methyl glycosides 13, 18, and 22, which represent potential antigenic determinants of the Brucella A polysaccharide, are the first synthetic analogues of this antigen. Their synthesis was necessitated by crystallographic studies of a Fab combining site obtained from a monoclonal antibody that binds the Brucella A antigen and synthetic pentasaccharide. Monosaccharide synthon 3 and disaccharide 7, S-ethyl glycoside derivatives of 4-azido-4,6-dideoxy-D-mannose, have been used successfully as key intermediates in a convergent strategy to synthesize α1,2-linked homo-oligosaccharides of 4,6-dideoxy-4-formamido-D-mannose. The disaccharide thioglycoside 7 was activated by methyl triflate in the presence of selectively protected mono- or trisaccharide alcohols 1, 6, or 10 to give α1,2-linked tri- and pentasaccharides 8, 9, and 19. Despite the non-participating glycosyl substituent at position two of the thioglycoside, 1,2-trans glycosidic products appeared to be formed exclusively. Conversion of 3 to the glycosyl bromide 5 by bromine under mild conditions provided routes to both the disaccharide building block 7 and a tetrasaccharide 15 using conventional silver triflate promoted glycosylation reactions. Deprotection was accomplished by transesterification, hydrogen sulphide reduction of azido groups, followed by N-formylation and finally hydro-genolysis of benzyl ethers. Keywords: Brucella A antigen, pentasaccharide synthesis, thioglycosides, oligosaccharide building units, 4,6-dideoxy-4-formamido-D-mannose, antibody combining sites.

Reduction of carbon-carbon double bonds and hydrogenolysis by sodium hypophosphite

Sodium hypophosphite plus palladium-charcoal is a mild, economical, selective system for the reduction of carbon-carbon double bonds and hydrogenolysis of benzyl ethers and benzyl carbonates.