O-benzyl Derivatives Research Articles

Novel (+)-Neoisopulegol-Based O-Benzyl Derivatives as Antimicrobial Agents.

Discovery of novel antibacterial agents with new structures, which combat pathogens is an urgent task. In this study, a new library of (+)-neoisopulegol-based O-benzyl derivatives of aminodiols and aminotriols was designed and synthesized, and their antimicrobial activity against different bacterial and fungal strains were evaluated. The results showed that this new series of synthetic O-benzyl compounds exhibit potent antimicrobial activity. Di-O-benzyl derivatives showed high activity against Gram-positive bacteria and fungi, but moderate activity against Gram-negative bacteria. Therefore, these compounds may serve a good basis for antibacterial and antifungal drug discovery. Structure–activity relationships were also studied from the aspects of stereochemistry of the O-benzyl group on cyclohexane ring and the substituent effects on the ring system.

Synthesis and Investigation of Pinane-Based Chiral Tridentate Ligands in the Asymmetric Addition of Diethylzinc to Aldehydes

A library of pinane-based chiral aminodiols, derived from natural (−)-β-pinene, were prepared and applied as chiral catalysts in the addition of diethylzinc to aldehydes. (−)-β-Pinene was reacted to provide 3-methylenenopinone, followed by a reduction of the carbonyl function to give a key allylic alcohol intermediate. Stereoselective epoxidation of the latter and subsequent ring opening of the resulting oxirane with primary and secondary amines afforded aminodiols. The regioselectivity of the ring closure of the N-substituted secondary aminodiols with formaldehyde was examined and exclusive formation of oxazolidines was observed. Treatment of the allylic alcohol with benzyl bromide provided the corresponding O-benzyl derivative, which was transformed into O-benzyl aminodiols by aminolysis. Ring closure of the N-isopropyl aminodiol derivative with formaldehyde resulted in spirooxazolidine. The obtained potential catalysts were applied in the reaction of both aromatic and aliphatic aldehydes to diethylzinc providing moderate to good enantioselectivities (up to 87% ee). Through the use of molecular modeling at an ab initio level, this phenomenon was interpreted in terms of competing reaction pathways. Molecular modeling at the RHF/LANL2DZ level of theory was successfully applied for interpretation of the stereochemical outcome of the reactions leading to display excellent (R) enantioselectivity in the examined transformation.

A convenient method for palladium-catalyzed reductive deuteration of organic substrates using deuterated hypophosphite in D2O.

A convenient method for the deuteration of organic substrates using deuterated hypophosphite as the deuterium source was investigated. Transfer deuteration of organic substrates, such as aromatic halides, alkenes, alkynes, epoxides, and O-benzyl derivatives, in the presence of palladium on carbon in deuterium oxide proceeded efficiently to give the corresponding deuterated products in excellent yields with high deuterium contents.

Palladium-catalyzed transfer hydrogenation of organic substrates by hypophosphite in water containing a nonionic surfactant

Palladium-catalyzed transfer hydrogenation of some organic substrates in water containing a nonionic surfactant was examined using sodium hypophosphite as a hydrogen source. Hydrogenation of organohalides such as polychloroarenes, alkenes, alkynes, nitro compounds, aromatic aldehydes, and O-benzyl and N-benzyl derivatives efficiently proceeded to give the corresponding reduction products. The addition of a nonionic surfactant, such as Tween 20, proved to be effective in obtaining satisfactory results in most cases.

A Mild, Room-Temperature Protection of Ketones and Aldehydes as 1,3-­Dioxolanes under Basic Conditions

Protection of ketones or aldehydes as 1,3-dioxolane derivatives proceeds within minutes at room temperature in the presence of N-hydroxybenzenesulfonamide, its O-benzyl derivative, or the tosyl analogue, in the absence of strong protonic acids, and in the presence of base (Et3N). Acid-sensitive groups such as O-THP, O-TBS, or N-Boc are unaffected.

Regioselective ring opening of exo- and endo-3,4-benzylidene acetals of arabinopyranoside derivatives with Lewis acids and reducing agents

Dioxolane type 3,4-benzylidene acetals of benzyl β- l-arabinose either as a mixture or pure exo- and endo-isomers cleavaged with BF 3·OEt 2/Et 3SiH in dichloromethane or acetonitrile regioselectively, provided the 4- O-benzyl-3-hydroxy derivative. The reaction with TiCl 4/Et 3SiH or Cu(OTf) 2/Et 3SiH provided a mixture of 3- and 4- O-benzyl derivatives whereas with Cu(OTf) 2/BH 3·THF gave only hydrolyzed product. The regioselectivity of the reaction was proved to be directed by the acetyl substitution at C-2. Benzyl substitution provided a mixture of 3- and 4- O-benzyl derivatives in 1:1 ratio whereas non-substitution yielded the same mixture in 2:1 ratio.

Regioselective ring opening of benzylidene acetal protecting group(s) of hexopyranoside derivatives by DIBAL-H

The reductive ring-opening reaction of benzylidene-protected glucosides and mannosides such as methyl 2,3-di- O-benzyl-4,6- O-benzylidene-α- d-glucoside ( 1) and methyl 2,3-di- O-benzyl-4,6- O-benzylidene-α- d-mannoside ( 4) by using a toluene stock solution of DIBAL-H and a dichloromethane stock solution of DIBAL-H gives mainly or selectively the corresponding 2,3,4-tri- O-benzyl derivatives ( 2, 5) and 2,3,6-tri- O-benzyl derivatives ( 3, 6), respectively, although that of methyl 2,3-di- O-benzyl-4,6- O-benzylidene-α- d-galactoside ( 7) gives methyl 2,3,6-tri- O-benzyl-α- d-galactoside ( 9) selectively irrespective of the solvent of the stock solution of DIBAL-H. Similarly, the reaction of the exo-isomer of methyl 2,3:4,6-di- O-benzylidene-α- d-mannopyranosides ( exo- 10) with a toluene stock solution and dichloromethane stock solutions of DIBAL-H selectively gives methyl 3- O-benzyl-4,6- O-benzylidene-α- d-mannoside ( 12) and methyl 2- O-benzyl-4,6- O-benzylidene-α- d-mannoside ( 11), respectively, although that of endo- 10 selectively affords 11, irrespective of the solvent of the stock solution of DIBAL-H.

2-Diphenylphosphino-2′-hydroxybiphenyl-based P-ligands and their platinum(II) complexes

2-Diphenylphosphino-2′-hydroxybiphenyl ( 2), become readily available via a ring opening reaction of a dibenzo[ c. e][1,2]oxaphosphorine, was utilized as P-ligand in complexation with dichlorodibenzonitrile platinum to give a Cl 2Pt 2 2 complex ( 4) with trans geometry. The O-benzyl derivative ( 5) could not be involved in complexation. A bidentate P-ligand ( 7) obtained by the interaction of hydroxy-diphenylphosphinobiphenyl 2 with chloro-dibenzo[ c. e][1,2]oxaphosphorine ( 1) formed an 8-ring transition metal complex (Cl 2Pt 7 = 9) in reaction with PtCl 2(PhCN) 2. Under the conditions of chromatography, separation of the diastereomers of 7 was not possible due to a partial isomerisation by rotation around the biphenyl axis of the molecule that is justified by the average barrier height of 6.0 kcal/mol. The stereostructure of P-ligands 2 and 7, as well as platinum complexes 4 and 9 was evaluated by B3LYP quantum chemical calculations.

Facile synthesis of sulfonium ion derivatives of 1,5-anhydro-5-thio- l-fucitol as potential α- l-fucosidase inhibitors

Five sulfonium ion derivatives with 1,5-anhydro-5-thio- l-fucitol as a core structure were efficiently synthesized as potential α- l-fucosidase inhibitors. The key unit, the tri- O-benzyl derivative of l-fucitol, was readily synthesized from methyl α- d-mannopyranoside. Alkylation with methyl iodide or 5-methoxycarbonyl-1-pentyl iodide in acetonitrile containing AgBF 4 afforded the corresponding alkylated sulfonium tetrafluoroborates. Alternatively, ring opening of three 1,3-cyclic sulfates in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) containing K 2CO 3 afforded the corresponding zwitterionic sulfonium sulfates.

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino- d-galactitol derivatives

The readily available 3- O-benzoyl-4- O-benzyl-1,2- O-isopropylidene-5- O-methanesulfonyl-β- d-fructopyranose ( 5 ) was straightforwardly transformed into its d- psico epimer ( 8 ), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4- O-benzyl-5-deoxy-1,2- O-isopropylidene-α- l-tagatopyranose ( 9 ) that was transformed into the related 3,4-di- O-benzyl derivative 10 . Cleavage of the acetonide in 10 to give 11 , followed by regioselective 1- O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2 R,3 S,4 R,5 S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′- O-pivaloylpyrrolidine ( 13 ). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14 . Total deprotection of 14 gave 2,5-imino-2,5-dideoxy- d-galactitol ( 15 , DGADP).

Novel neuroprotective effects with O-benzyl derivative of pralidoxime in soman-intoxicated rodents

Pharmacological properties of oxime reactivators, not related to its ability to regenerate or reactivate nerve agent-inhibited acetylcholinesterase located at nerve synapses, have been reported to be important in protecting against poisoning by the nerve agent soman. Such non-reactivation effects have thus far been associated only with bispyridinium oximes. This study investigated the possibility of creating similar non-reactivation therapeutic effects in the mono-pyridinium ring oxime, pralidoxime (2-PAM) through attachment of alkyl groups of increasing chain length to the oxime functional group. Of the 4 derivatives investigated, only the O-benzyl derivative displayed strong sedative effects in mice and mitigated the development of motor convulsions following soman challenge (1.8 × LD 50, subcutaneous). Anticonvulsant effects of this compound were enhanced by co-administration of a non-anticonvulsant dose of atropine sulfate. Administration of equivalent amount of other O-derivatives of pralidoxime failed to elicit similar anticonvulsant actions. Electroencephalographic (EEG) and histopathological studies using the rat model, intoxicated with a lethal dose (1.6 × LD 50, s.c.) of soman, confirmed O-benzyl derivative neuroprotective capabilities when used as a pretreatment drug. Microdialysis studies revealed that its neuroprotective effect is related to its ability to attenuate soman-induced increase in acetylcholine.

Glycosylation of acid sensitive acceptors. Synthesis of (2,3-epoxy-1-propyl) glycosides

Treatment of O-benzylated derivatives of glycosyl N-allyl thiocarbamate with racemic or enantiomerically pure glycidol and bromine provides the 1,2- cis-glycidyl glycosides. This protocol was mild, highly stereoselective and efficient.

Stereoselective synthesis of alpha- and beta-L-C-fucosyl aldehydes and their utility in the assembly of C-fucosides of biological relevance.

An efficient synthesis of O-benzylated derivatives of the title sugar aldehydes via thiazole addition to tri-O-benzyl-l-fuconolactone followed by highly stereoselective deoxygenation of the resulting thiazolylketose and thiazole to formyl transformation is described. Wittig olefination of these aldehydes with galactopyranose and glucopyranose 6-phosphoranes and reduction of the resulting alkenes afforded alpha- and beta-linked (1-->6)-L-C-fucosyl disaccharides, namely, beta-L-C-Fuc-(1-->6)-alpha-D-Gal, alpha-L-C-Fuc-(1-->6)-alpha-D-Gal, and alpha-L-C-Fuc-(1-->6)-alpha-d-Glc. The alpha-anomer of the above C-fucosyl aldehydes was transformed into a C-fucosylmethyl triphenylphosphonium iodide from which the corresponding C-fucosylmethylene phosphorane was generated upon treatment with BuLi. This phosphorane reacted with the Garner aldehyde (N-Boc D-serinal acetonide) and its one-carbon higher homologue to give alkenes whose reduction and unveiling of the glycinyl group from the oxazolidine ring afforded C-fucosyl alpha-amino acids, namely alpha-L-linked C-fucosyl serines and C-fucosyl asparagines. As a final test of the synthetic utility of the title aldehydes, the beta-anomer was employed as starting material in the stereoselective synthesis of both R- and S-epimer L-C-fucosyl phenylhydroxy acetates. One epimer was obtained by reaction of the sugar aldehyde with phenylmagnesium bromide, oxidation of the resulting alcohol to ketone, addition of 2-lithiothiazole to the latter, and transformation of the thiazole ring into the carboxyl group through an aldehyde intermediate. The other epimer was obtained by the same procedure and inverting the timing of phenyl and thiazolyl group addition. In both routes, the key step establishing the configuration of the quaternary carbon atom of the aliphatic chain was the highly stereoselective addition of the organometal to the ketone intermediate.

Introduction of a Benzyl Group onto the 2′‐OH of 6‐Chloropurine 3′‐O‐Benzoylriboside

AbstractFor Abstract see ChemInform Abstract in Full Text.

Introduction of a Benzyl Group onto the 2′-OH of 6-Chloropurine 3′-O-Benzoylriboside

A new method to introduce a benzyl group onto the 2′-OH of purine ribonucleoside is described. Thus, 6-chloropurine 3′-O-benzoylriboside and its 5′-O-trityl congener were condensed with benzyl alcohol using the Mitsunobu reaction to give the 2′-O-benzyl derivative. The yields were varied from 4.6 to 62.9% depending on the solvent. The product was converted to adenosine, indicating that the stereochemistry at C-2′ is retained.

A New Method for the Synthesis of 2′-O-Benzyladenosine Using Mitsunobu Reaction.

For Abstract see ChemInform Abstract in Full Text.

Synthesis and activity of novel glutathione analogues containing an urethane backbone linkage

The new GSH analogues H–Glo(–Ser–Gly–OH)–OH ( 5), its O-benzyl derivative 4, and H–Glo(–Asp–Gly–OH)–OH ( 9), characterized by the replacement of central cysteine with either serine or aspartic acid, and containing an urethanic fragment as isosteric substitution of the scissile γ-glutamylic junction, have been synthesized and characterized. Their ability to inhibit human GST P1-1 (hGST P1-1) in comparison with H–Glu(–Ser–Gly–OH)–OH and H–Glu(–Asp–Gly–OH)–OH, which are potent competitive inhibitors of rat GST 3-3 and 4-4, has been evaluated. In order to further investigate the effect of the isosteric substitution on the binding abilities of the new GSH analogues 4, 5 and 9, the previously reported cysteinyl-containing analogue H–Glo(–Cys–Gly–OH)–OH has been also evaluated as a co-substrate for hGSTP1-1.

A New Method for the Synthesis of 2′-O-Benzyladenosine Using Mitsunobu Reaction

A new method to introduce a benzyl group onto the 2′-OH of purine ribonucleoside is described. Thus, 6-chloropurine 3′-O-benzoylriboside and its 5′-O-trityl congener were condensed with benzyl alcohol using the Mitsunobu reaction to give the 2′-O-benzyl derivative. The yields were varied from 4.6 to 62.9% depending on the solvent used. The product was converted to adenosine, indicating that the stereochemistry at C-2′ is retained.

The presence of water improves reductive openings of benzylidene acetals with trimethylaminoborane and aluminium chloride

The acidic reagent formed in situ from anhydrous AlCl 3 and H 2O in 3:1 ratio is much more efficient for the reductive openings of the cyclic benzylidene acetals with Me 3N·BH 3 in tetrahydrofurane than the AlCl 3 alone. Under proposed conditions, the dioxane-type 4,6- O-bezylidene acetals of hexopyranosides give regioselectively the corresponding 4-hydroxy,6- O-benzyl derivatives in excellent yields. Reductive openings of the dioxolane-type 3,4- O-benzylidene acetals of galactopyranoside are also very efficient and regioselective and give either 3- O-benzyl derivative (from 3,4- O- exo-benzylidene acetal) or 4- O-benzyl derivative (from 3,4- O- endo-benzylidene acetal) depending on the configuration of the acetal carbon atom.

Stereoselective allylations of erythrulose derivatives under anhydrous conditions

We have investigated a number of nucleophilic additions of allylating reagents to several α,α′,β-trioxygenated ketones ( O-protected erythrulose derivatives). Reagents based on lithium, magnesium, copper and titanium gave low to medium stereoselectivities and did not display any recognizable trend in the sense of stereoselection. In contrast, reactions involving silicon and tin derivatives were highly stereoselective and gave rise to essentially a single diastereoisomer, the structure of which depended on the type of protecting group. Thus, α,β-di- O-benzylated derivatives experienced almost exclusive addition to the carbonyl Si side, whereas α,β- O, O-alkylidene derivatives (dioxolane acetals) yielded the opposite diastereoisomers as a result of addition to the Re side. These results suggest the intermediacy of α-chelates in the additions of silicon and tin reagents to the di- O-benzylated derivatives. In contrast, the opposite stereoisomers, formed in the reactions of dioxolanes, are believed to be formed through Felkin–Anh transition states, pointing again to the reluctance of acetal oxygens to participate in chelated intermediates.