O-benzyl Ethers Research Articles

Lipophilicity Study of 1-(Benzofuran-2-yl)ethan-1-one Oxime and its Substituted O-Benzyl Ethers

Heterocyclic oxime ethers play a significant role in organisms due to their biological activity. Lipophilicity is an important parameter that may affect biological activity of the compounds 1-(benzofuran-2-yl)ethan-1-one oxime and its nine biologically active ethers. The relationship between the structure and lipophilicity parameters (log kw values) of the ten compounds is here described. Reversed phase high performance liquid chromatography (RP-HPLC) method was used having methanol, 2-propanol and acetonitrile as organic modifiers of the mobile phases. Both experimental (log kw) and calculated (log P) parameters showed to be strongly positively correlated. The weakest correlation with all the data was for the log kw methanol. For all of analyzed compounds, log kw values are smaller than 5 (except for analyses carried out in methanol), and this result corresponds to the Lipinski’s rule in the range of lipophilicity. Therefore, in the case of their use as drugs, they will be probably active after oral application.

ChemInform Abstract: Oxidative Debenzylation of N‐Benzyl Amides and O‐Benzyl Ethers Using Alkali Metal Bromide.

The oxidative debenzylation of N-benzyl amides and O-benzyl ethers was promoted with high efficiency by a bromo radical formed through the oxidation of bromide from alkali metal bromide under mild conditions. This reaction provided the corresponding amides from N-benzyl amides and carbonyl compounds from O-benzyl ethers in high yields.

Oxidative debenzylation of N-benzyl amides and O-benzyl ethers using alkali metal bromide.

The oxidative debenzylation of N-benzyl amides and O-benzyl ethers was promoted with high efficiency by a bromo radical formed through the oxidation of bromide from alkali metal bromide under mild conditions. This reaction provided the corresponding amides from N-benzyl amides and carbonyl compounds from O-benzyl ethers in high yields.

Enantioselective reduction of ketoxime ethers with borane–oxazaborolidines and synthesis of the key intermediate leading to (S)-rivastigmine

The reduction of representative alkyl aryl (E)-ketoxime O-benzyl ethers with borane catalyzed by terpene oxazaborolidines, derived from (1R)-nopinone and (1R)-camphor, gave the corresponding amines with 82–99% ee. Oxazaborolidines derived from (1S)-2-carene and (1S)-3-carene were less selective. (S)-1-(3-Methoxyphenyl)ethanamine (94% ee) the key intermediate in the synthesis of (S)-rivastigmine, was obtained by the reduction of (E)-1-(3-methoxyphenyl)ethanone O-benzyl oxime with borane/oxazaborolidine generated from (S)-valinol.

Reliable and Safe, Gram-Scale Hydrogenation and Hydrogenolysis of O-Benzyl Ether Groups with In Situ Pd0/C Catalyst

Hydrogenation of alkenes, alkynes, and hydrogenolysis of O-benzyl ethers with Pd-0/C catalyst generated in situ can be readily scaled up under safer conditions than with traditional procedures. The precise control of the palladium loading and the mild conditions developed allow the formation of a very active and reliable Pd-0/C catalyst, leading to highly reproducible results.

Iodine–sodium cyanoborohydride-mediated reductive ring opening of 4,6- O-benzylidene acetals of hexopyranosides

A quick, efficient and convenient method for the regiospecific reductive ring opening of 4,6- O-benzylidene acetals of O-/ S-alkyl/aryl glycosides of mono- and disaccharides, leading to the exclusive formation of the corresponding 6- O-benzyl ethers, using sodium cyanoborohydride in the presence of molecular iodine, is reported. It has been observed that common protecting groups such as ethers and esters are well tolerated under the conditions studied. The reaction was proved unsuccessful when applied to a glucosamine-derived benzylidene acetal.

A Useful, Reliable and Safer Protocol for Hydrogenation and the Hydrogenolysis ofO‐Benzyl Groups: The In Situ Preparation of an Active Pd0/C Catalyst with Well‐Defined Properties

A simple, highly reproducible protocol for the hydrogenation of alkenes and alkynes and for the hydrogenolysis of O-benzyl ethers has been developed. The method features the in situ preparation of an active Pd(0)/C catalyst from Pd(OAc)(2) and charcoal, in methanol. The mild reaction conditions (25°C) and low catalyst loading required (0.025 mol%), as well as the absence of contamination of the product by palladium residues (<4 ppb), make this a sustainable, useful process for organic chemists. Alternatively, the protocol can be carried out under microwave activation, to shorten the reaction times, with cyclohexene as the hydrogen source.

Regio- and chemoselective reductive cleavage of 4,6- O-benzylidene-type acetals of hexopyranosides using BH 3·THF–TMSOTf

Benzylidene-type cyclic acetals of carbohydrates undergo efficient reductive ring opening using BH 3·THF and a catalytic amount of TMSOTf at room temperature. 4,6- O-Benzylidene-hexopyranosides afford the corresponding 4- O-benzyl ethers exclusively, in high yields. Other benzylidene-type acetals, such as naphthylmethylene and 4-methoxybenzylidene acetals are also cleaved with the same reagent. The conversions are highly regio- and stereoselective and afford benzyl-type ethers in excellent yields.

Solid-Phase Synthesis of α-Glucosamine Sulfoforms with Fragmentation Analysis by Tandem Mass Spectrometry

Sulfated epitopes of alpha-glucosamine (GlcN sulfoforms) were prepared by solid-phase synthesis as models of internal glucosamines within heparan sulfate. An orthogonally protected 2'-hydroxyethyl GlcN derivative was immobilized on a trityl resin support and subjected to regioselective deprotection and sulfonation conditions, which were optimized with the aid of on-resin infrared or Raman analysis. The sulfoforms were cleaved from the resin under mild Lewis acid conditions without affecting the O- or N-sulfate groups and purified by reversed-phase high-performance liquid chromatography (HPLC). The alpha-GlcN sulfoforms and their 4- O-benzyl ethers were examined by electrospray ionization tandem mass spectrometry (ESI-MS/MS), with product ion spectra produced by collision-induced dissociation (CID). ESI-MS/MS revealed significant differences in parent ion stabilities and fragmentation rates as a function of sulfate position. Ion fragmentation by CID resulted in characteristic mass losses with strong correlation to the positions of both free hydroxyl groups and sulfate ions. Most of these fragmentation patterns are consonant with elimination pathways, and suggest possible strategies for elucidating the structures of glucosamine-derived sulfoforms with identical m/ z ratios. In particular, fragmentation analysis can easily distinguish GlcN sulfoforms bearing the relatively rare 3- O-sulfate from isomers with the more common 6- O-sulfate.

Asymmetric synthesis of N-substituted N-hydroxyureas

Asymmetric synthesis of ( S)- N-(1-arylethyl)- N-hydroxyureas, ( S)- N-(6-methoxy)- and ( S)- N-(6-benzyloxy-2,3-dihydrobenzofuran-3-yl)- N-hydroxyurea— lipoxygenase inhibitor, is described. Three approaches to the formation of the N-hydroxyurea moiety at the stereogenic center have been used. The first one, via the reaction of ( R)-6-benzyloxy-2,3-dihydrobenzofuran-3-ol with N, O-bis(phenoxycarbonyl)hydroxylamine under Mitsunobu conditions, leads to a partially racemized product. Alternatively, the enantioselective reduction of oximes O-benzyl ethers of acetophenone, 4-methoxy- and 4-benzyloxyacetophenone, 6-methoxy- and 6-benzyloxy-2,3-dihydrobenzofuran-3-one with borane/oxazaborolidines can be controlled to produce either the corresponding hydroxylamine O-benzyl ethers or primary amines which have been transformed into N-substituted N-hydroxyureas in 57% to 99% ee.

Use of methanesulfonic acid in the reductive ring-opening of O-benzylidene acetals

Methanesulfonic acid was shown to be an efficient and convenient substitute for ethereal HCl in reductive 4,6- O-benzylidene acetal ring-opening reaction with sodium cyanoborohydride in THF. Normal regioselectivity was observed, the 6- O-benzyl ethers with free 4-OH group being the major products of the reaction.

Stereoselective synthesis of musclides A1, A2 and B

An expedient method for the stereoselective preparation of musclide A1, A2 and B, cardiotonic-potentiating principles from musk, has been achieved. The key step is the addition of the O-benzyl ethers of prop-2-yn-1-ol and ( R)-but-3-yn-2-ol to aldehydes mediated by zinc triflate, Et 3N, and (+)- or (−)- N-methylephedrine. In some cases, the partial reduction of the resulting alkynols to Z-olefins has allowed us to remove the minor stereoisomer easily by chromatography to afford highly stereoenriched precursors of musclides.

N-Heterocycles from Oxime and Oxime O-Benzyl Ethers via Electrophile Induced - Ring Formation. Route to Cyclic and Bicyclic Amine and Hydroxylamine

N-Heterocycles from Oxime and Oxime O-Benzyl Ethers via Electrophile Induced - Ring Formation. Route to Cyclic and Bicyclic Amine and Hydroxylamine

Stereoselective electrophile-induced mono- and bis-cyclisation–fragmentation reactions of alkenyl oxime O-allyl and O-benzyl ethers. Synthesis of dihydropinidine

Phenylseleny bromide-induced cyclisation of γ- and δ-unsaturated aldoxime and ketoxime O-allyl and O-benzyl ethers is followed by a slow fragmentation of the resultant oxyiminium ions furnishing cyclic iminium salts which are readily reduced to pyrrolidines, piperidines or tetrahydroisoquinolines by sodium borohydride; dialkenyl oximes yield indolizidines and quinolizidines by an analogous sequence terminating in a mercury(II)-induced cyclisation.

An alternative approach to ( S)- and ( R)-2-methylglycidol O-benzyl ether derivatives

This report describes the gram scale synthesis of ( S)- and ( R)-2,2,4-trimethyl-4-(hydroxymethyl)-1,3-dioxolanes using the Sharpless asymmetric dihydroxylation (AD) of the Weinreb amide of 2-methyl-2-propenoic acid. The 2-methylglycerol acetonides resultant from protection of the AD products were used as starting materials in the synthesis of O-benzyl ethers of the valuable C4-chiral building blocks ( S)- and ( R)-2-methylglycidol.

A selective ring opening reaction of 4,6- O-benzylidene acetals in carbohydrates using trialkylsilane derivatives

Reductive ring opening reactions of 4,6- O-benzylidene-protected carbohydrates to the corresponding benzyl ethers using trialkylsilane derivatives were examined. When Et 3SiH(or PS-DES™)-TfOH was used, 6- O-benzyl ethers with 4-hydroxy unsubstituted were obtained, while, when Et 3SiH(or PS-DES™)-PhBCl 2 was used, 4- O-benzyl ethers with 6-hydroxy unsubstituted were obtained in quantitative yield with excellent selectivity.

A concise synthesis of the 6- o- and 6′- o-sulfated analogues of the sialyl lewis X tetrasaccharide

The octyl glycoside of the sialyl Lewis X tetrasaccharide and its 6- O-sulfated and 6′- O-sulfated analogues were chemically synthesized in a concise manner starting from readily accessible monosaccharide intermediates. The synthesis involved formation of an orthogonally protected tetrasaccharide intermediate from which all three materials were prepared. A selective catalytic hydrogenolysis of four O-benzyl ethers in presence of a 4,6- O-benzylidene group was the key step in the synthetic scheme.

Regioselective reduction of 4,6- O-benzylidenes using triethylsilane and BF 3·Et 2O

The 4,6-di- O-benzylidene acetals of glucose, mannose, glucosamine, and galactose were regioselectively reduced by triethylsilane in the presence of BF 3·Et 2O to yield the 6- O-benzyl ethers in good to excellent yields.

Electrophile-induced cyclisation–fragmentation reactions of oxime O-allyl and O-benzyl ethers

Phenylselenyl bromide-induced cyclisation of γ- and δ-unsaturated aldoxime and ketoxime O-allyl and O-benzyl ethers is followed by a slow fragmentation furnishing cyclic imines which are readily reduced to pyrrolidines, piperidines or tetrahydroisoquinolines by sodium borohydride; dialkenyl oximes yield quinolizidines by an analogous sequence terminating in a mercury(II)-induced cyclisation.

C-glycofuranosides via tandem Wittig-Michael sequence using a thiazole-armed phosphorane. A route to C-furanosyl α-hydroxy propanals and propionic acids

The reactions of 2-thiazolylcarbonylmethylenetriphenylphosphorane with five protected D-furanoses (manno, ribo, arabino, xylo, and lyxo) in refluxing toluene lead to mixtures of α- and β-1-C-(2-thiazolacyl)-glycosides (66 – 93 % overall yield). The β-linked C-glycosides derived from 2,3:5,6-di-O-isopropylidene- D-mannnofuranose was reduced to (R) and (S) akohols which after protection as O-benzyl ethers were transformed to α-alkoxy aldehydes by thiazole-to-formyl conversion; the aldehydes were oxidized to the corresponding α-alkoxy acids.