N-benzyloxycarbonyl Group Research Articles

Mild Method for Deprotection of the N-Benzyloxycarbonyl (N-Cbz) Group by the Combination of AlCl3 and HFIP.

Herein, we report our findings on the novel ability of aluminum chloride (AlCl3) in fluorinated solvent 1,1,1,3,3,3-hexafluoroisopropanol [HFIP] to selectively deprotect the N-benzyloxycarbonyl group (N-Cbz). The salient features of this method are good functional group tolerance including other reducible groups, cost-effectiveness, easy-to-handle, safe protocol, amenable to scale-up, high yields, and ambient temperature reactions. The methodology would serve as an excellent alternative to the use of pyrophoric hydrogen gas and metal catalyst reagents that pose severe safety and environmental concerns. The most notable feature of this methodology is the orthogonal deprotection of the N-Cbz group in the presence of O- and N-Bn protecting groups, hence, expanding the scope for designing synthetic routes to target compounds requiring multiple functional group transformations.

Anti-chlamydial activities of cell-permeable hydrophobic dipeptide-containing derivatives

The obligate intracellular bacteria chlamydia is major human pathogen that causes millions of trachoma, sexually transmitted infections and pneumonia worldwide. We serendipitously found that both calpain inhibitors z-Val-Phe-CHO and z-Leu-Nle-CHO showed marked inhibitory activity against chlamydial growth in human epithelial HeLa cells, whereas other calpain inhibitors not. These peptidomimetic inhibitors consist of N-benzyloxycarbonyl group and hydrophobic dipeptide derivatives. Both compounds strongly restrict the chlamydial growth even addition at the 12 h post infection. Notably, inhibitors-mediated growth inhibition of chlamydia was independent on host calpain activity. Electron microscopic analysis revealed that z-Val-Phe-CHO inhibited chlamydial growth by arresting bacterial cell division and RB-EB re-transition, but not by changing into persistent state. We searched and found that z-Leu-Leu-CHO and z-Phe-Ala-FMK also inhibited chlamydial growth. Neither biotin-hydrophobic dipeptide nor morpholinoureidyl-hydrophobic dipeptide shows inhibitory effects on chlamydial intracellular growth. Our results suggested the possibility of some chemical derivatives based on z-hydrophobic dipeptide group for future therapeutic usage to the chlamydial infectious disease.

Anti-cancer, Anti-inflammatory, Cytotoxic and Biochemical Activities of a Novel Phosphonotripeptide Synthesized from Formyl Pyrazolofuran using TUBU as Condensing Agent

A novel and mild protocol for the synthesis of phosphonotripeptide 16 were achieved from novel formylpyrazolofuran 3, benzyl carbamate 5, triphenyl phosphite 6 by Birum-Oleksyszyn reaction using copper (II) trifliate as Lewis acid catalyst in dry dichloromethane at room temperature which synthesis of novel N-benzyloxy-α-aminophosphonate 7 . A mechanism for this condensation reaction is proposed. Cleavage of the N-benzyloxy carbonyl group under acid hydrolysis afford the free α-aminophosphonate 9 in quantitative yield. This in turn, by reaction with N-phthaloylglycine 12 via TUBU to phthalimido group 13.Cleavage of phthalimido group under hydrazinedihydrochloride afford free peptide 14 .the result phosphonotripeptide 16 obtained by the reaction of free peptide with bioactive cyclic moiety-COCl 15. The structures of all new compounds were established by IR,1HNMR and mass spectral data. Also anti-cancer, anti-inflammatory and biochemical activities of all these compounds were reported.

ChemInform Abstract: Enzymic Synthesis of α- and β-D-Glucosides of 1- Deoxynojirimycin and Their Glycosidase Inhibitory Activities.

1-Deoxynojirimycin (1) is a potent inhibitor of mammalian and rice alpha-glucosidase. Several glucosides of 1 were synthesized by use of the native and immobilized enzyme and their effect on various enzymes was investigated. Transglucosylation reactions using rice alpha-glucosidase, yeast alpha- and beta-glucosidases purified from Rhodotorula lactosa were performed with maltose or cellobiose as a glucose donor and N-(benzyloxycarbonyl)-1-deoxynojirimycin (2) as an acceptor. The transglucosylation reaction using native rice alpha-glucosidase afforded 3-O-alpha-D-glucopyranosyl-N-(benzyloxycarbonyl)-1-deoxynojirimycin (4), 4-O-alpha-D-glucopyranosyl-N-(benzyloxycarbonyl)-1-deoxynojirimycin (5), and 2-O-alpha-D-glucopyranosyl-N-(benzyloxycarbonyl)-1-deoxynojirimycin (3) in yields of 40, 13, and 2%, respectively, after 30 min. The transglucosylation reaction using immobilized rice alpha-glucosidase was similar to that using the native enzyme. In the system using native yeast alpha-glucosidase, 3, 5, and 4 were formed in yields of 34, 13, and 6%, respectively, after 15 h. The immobilization of yeast alpha-glucosidase caused a significant decrease in transglucosylation activity. Yeast beta-glucosidase showed a high transglucosylation activity and incubation with the reaction system afforded 2-O-beta-D-glucopyranosyl-N-(benzyloxycarbonyl)-1-deoxynojirimycin (6) and 4-O-beta-D-glucopyranosyl-N-(benzyloxycarbonyl)-1-deoxynojirimycin (7) in yields of 69 and 3%, respectively, after 3 h. The transglucosylation reaction using immobilized yeast beta-glucosidase preferentially afforded 6 in a yield of 73% after 3 h. After removal of N-benzyloxycarbonyl group from the product glucosides, their glycosidase inhibitory activities were measured. 3-O-alpha-D-Glucopyranosyl-1-deoxynojirimycin (9) retained the potent inhibition of 1 against rat intestinal sucrase activity and was more effective than 1 against rice alpha-glucosidase. 4-O-alpha-D-Glucopyranosyl-1-deoxynojirimycin (10) retained the potency of 1 against rat intestinal sucrase and isomaltase. 2-O-alpha-D-Glucopyranosyl-1-deoxynojirimycin (8) was more effective than 1 against trehalases.

Efficient Deprotection of N‐Benzyloxycarbonyl Group from Amino Acids by Hydroxyapatite‐Bound Pd Catalyst in the Presence of Molecular Hydrogen.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Rapid Removal of Benzyloxycarbonyl Groups from 1,4,7,10‐Tetraazacyclododecane Derivatives by Catalytic Transfer Hydrogenation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient deprotection of N-benzyloxycarbonyl group from amino acids by hydroxyapatite-bound Pd catalyst in the presence of molecular hydrogen

Hydroxyapatite-bound Pd catalyst was found to be highly effective for the deprotection of N-benzyloxycarbonyl group from amino acids in the presence of molecular hydrogen. The catalyst was also applicable to the hydrogenolysis of a sterically encumbered core-Z-protected poly(amido amine) dendrimer, affording the dendritic amino compound in 99% yield.

Rapid Removal of Benzyloxycarbonyl Groups from 1,4,7,10-Tetraazacyclododecane Derivatives by Catalytic Transfer Hydrogenation

We report that N-benzyloxycarbonyl groups can be conveniently removed from 1,4,7,10-tetraazacyclododecanes by catalytic transfer hydrogenation with cyclohexene and 5% palladium–carbon catalyst. The process is rapid, selective, inexpensive, and is high yielding.

One-pot conversion of benzyl carbamates into fluorenylmethyl carbamates

A simple one-pot procedure smoothly converted N-benzyloxycarbonyl groups into N-fluorenylmethoxycarbonyl groups via hydrogenation with a poisoned catalyst in the presence of Fmoc-OSu. Functional groups such as t-butyl esters, t-butyl ethers, and N-Boc were stable under the reaction conditions.

Preparation and Characterization of Pseudopoly(trans-4-hydroxy-L-proline ester)

The preparation and characterization of polymers derived from hydroxyproline were investigated. Two new polymers of poly(trans-4-hydroxy-N-benzyloxycarbonyl-L-proline) [poly(N-Z-Hpr-OH)] and poly(trans-4-hydroxy-N-benzyloxycarbonyl-L-proline ester) [poly(N-Z-Hpr-OMe)], with easily removable pendant N-benzyloxycarbonyl group, were prepared. Weight-average molecular weight (Mw) of about 254000 and 33000 were obtained via esterification or transesterification, using stannous octoate as a catalyst, at 140°C under vacuum (20 mmHg) for 16 h. Removal of the N-benzyloxycarbonyl group by catalytic transfer hydrogenation yielded pseudopoly(trans-4-hydroxy-L-proline ester) [poly(Hpr-OMe·HCl)].

Chirospecific synthesis of 1,4-dideoxy-1,4-imino-D-arabinitol and 1,4-dideoxy-1,4-imino-L-xylitol via one-pot cyclisation

The multi-protected compounds 4 and 5 were treated with 20% iodine in methanol to give 1,4-dideoxy-1,4-imino-D-arabinitol 1 and 1,4-dideoxy-1,4-imino-L-xylitol 2 directly. Iodine was an efficient catalyst for deprotection of O-isopropylidene, O-(tert-butyldimethylsilyl), N-(9-phenylfluoren-9-yl) and N-benzyloxycarbonyl groups, resulting in intramolecular cyclisation.

Total synthesis of scopine, pseudoscopine, and nor- derivatives

Scopine and pseudoscopine have been synthesised from cyclohepta-3,5-dienol; the initial 1,4-fuctionalisation of the diene is based on a nitroso- cycloaddition. The use of the N-benzyloxycarbonyl group throughout the scheme allows ultimate reductive deprotection to yield N-methyl or novel NH (nor-) derivatives without damage to the exo-epoxide of the title compounds. Preliminary investigation of nitroso- cycloaddition to 5,6-epoxycyclohepta-1,3-diene is described.

(R)-(+)-3-Amino-2-phenylpropanoic acid: a revised absolute configuration based on an enantioselective synthesis and an X-ray crystal structure of the salt with (1S)-(+)-camphor-10-sulfonic acid

Amidoalkylation of the lithium enolate of (4S,5R)-4-methyl-5-phenyl-3-(phenylacetyl)oxazolidin-2-one 5 by 1-(N-benzyloxycarbonylaminomethyl)benzotriazole 2c, followed by cleavage of the oxazolidinone chiral auxiliary and of the N-benzyloxycarbonyl group, gave (R)-(+)-3-amino-2-phenylpropanoic acid 1, the absolute configuration of which was determined by X-ray crystallography on the salt 8 with (1S)-(+)-camphor-10-sulfonic acid.

Enzymic synthesis of α- and β- d-glucosides of 1-deoxynojirimycin and their glycosidase inhibitory activities

1-Deoxynojirimycin ( 1) is a potent inhibitor of mammalian and rice α-glucosidase. Several glucosides of 1 were synthesized by use of the native and immobilized enzyme and their effect on various enzymes was investigated. Transglucosylation reactions using rice α-glucosidase, yeast α- and β-glucosidases purified from Rhodotorula lactosa were performed with maltose or cellobiose as a glucose donor and N-(benzyloxycarbonyl)-1-deoxynojirimycin ( 2) as an acceptor. The transglucosylation reaction using native rice α-glucosidase afforded 3- O-α- d-glucopyranosyl- N-(benzyloxycarbonyl)-1-deoxynojirimycin ( 4), 4- O- α- d-glucopyranosyl- N-(benzyloxycarbonyl)-1-deoxynojirimycin ( 5), and 2- O-α- d-gluco- pyranosyl- N-(benzyloxycarbonyl)-1-deoxynojirimycin ( 3) in yields of 40, 13, and 2%, respectively, after 30 min. The transglucosylation reaction using immobilized rice α-glucosidase was similar to that using the native enzyme. In the system using native yeast α-glucosidase, 3, 5, and 4 were formed in yields of 34, 13, and 6%, respectively, after 15 h. The immobilization of yeast α-glucosidase caused a significant decrease in transglucosylation activity. Yeast β-glucosidase showed a high transglucosylation activity and incubation with the reaction system afforded 2- O-β- d-glucopyranosyl- N-(benzyloxycarbonyl)-1-deoxynojirimycin ( 6) and 4- O-β- d-glucopyranosyl- N-(benzyloxycarbonyl)-1-deoxynojirimycin ( 7) in yields of 69 and 3%, respectively, after 3 h. The transglucosylation reaction using immobilized yeast β-glucosidase preferentially afforded 6 in the yield of 73% after 3 h. After removal of N-benzyloxycarbonyl group from the product glucosides, their glycosidase inhibitory activities were measured. 3- O-α- d-Glucopyranosyl-1-deoxynojirimycin ( 9) retained the potent inhibition of 1 against rat intestinal sucrase activity and was more effective than 1 against rice α-glucosidase. 4- O-α- d-Glucopyranosyl-1-deoxynojirimycin ( 10) retained the potency of 1 against rat intestinal sucrase and isomaltase. 2- O-α- d-Glucopyranosyl-1-deoxynojirimycin ( 8) was more effective than 1 against trehalases.

ChemInform Abstract: Wittig Reaction with N‐Protected 3‐(Triphenylphosphonio)alaninates: Synthesis of Optically Active E‐(2‐Arylvinyl)glycine Derivatives.

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Wittig Reaction with N-Protected 3-(Triphenylphosphonio) alaninates: Synthesis of Optically Active (E)-(2-Arylvinyl) glycine Derivatives.

(R)-[2-Carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (1) was converted by treatment with anion exchange resin (HCO-3) into the inner salt 13h, which gave a better yield (43%) than 1 in the Wittig reaction with benzaldehyde to afford the [S-(E)]-(2-phenylvinyl)glycine derivative 24. The inner salt 13i bearing an N-benzyloxycarbonyl group was prepared by hydrogenolysis of (R)-[3-benzyloxy-2-[(benzyloxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11e) over palladium on carbon, followed by dehydrochlorination. Hydrogenolysis of 11e over Pearlman's catalyst afforded the unprotected phosphonium chloride 12 (X=Cl). N-tert-Butoxycarbonylation of 12 followed by dehydrochlorination afforded 13j, which was more efficiently prepared through hydrogenolysis of (R)-[3-benzyloxy-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11f).The usefulness of 13h-j as building blocks for the synthesis of configurationally labile (2-arylvinyl)glycine derivatives was exemplified by the Wittig reactions with piperonal, which exclusively afforded the (E)-isomers 18h-j with high optical purity in 28-39% yield.

ChemInform Abstract: BOP Reagent for the Coupling of pGlu and Boc‐His(Tos) in Solid Phase Peptide Synthesis.

The model peptide TRH was successfully synthesized using benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent). The coupling reactions were carried out in N,N-dimethylformamide or N-methylpyrrolidone. These solvents allowed the incorporation of the N-terminal pyroglutamic acid residue into the peptide chain, without using the derivative bearing the N-benzyloxycarbonyl group, which acts as a solubility promoter. A comparative racemization study showed that Boc-His(Tos) can be coupled by means of BOP reagent with less racemization than with DCC when the amount of diisopropylethylamine (DIEA) is kept minimal (same ratio of equivalents as for Boc-His(Tos), i.e. 3 equiv.). However, with the use of a larger amount of DIEA in the coupling mixture (9 equiv.), approximately 3% of epimer was found in the crude product. Our study showed that even under low DIEA conditions, the rate of coupling of the residues with BOP remained comparable to that observed with DCC.

BOP reagent for the coupling of pGlu and Boc‐His(Tos) in solid phase peptide synthesis

The model peptide TRH was successfully synthesized using benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent). The coupling reactions were carried out in N,N-dimethylformamide or N-methylpyrrolidone. These solvents allowed the incorporation of the N-terminal pyroglutamic acid residue into the peptide chain, without using the derivative bearing the N-benzyloxycarbonyl group, which acts as a solubility promoter. A comparative racemization study showed that Boc-His(Tos) can be coupled by means of BOP reagent with less racemization than with DCC when the amount of diisopropylethylamine (DIEA) is kept minimal (same ratio of equivalents as for Boc-His(Tos), i.e. 3 equiv.). However, with the use of a larger amount of DIEA in the coupling mixture (9 equiv.), approximately 3% of epimer was found in the crude product. Our study showed that even under low DIEA conditions, the rate of coupling of the residues with BOP remained comparable to that observed with DCC.

An Improvement of the Anderson Test by the Use of High Performance Liquid Chromatography

Abstract The replacement of the N-benzyloxycarbonyl (Z) group in the Anderson peptide (Z–Gly–l/d–Phe–Gly–OEt) by Z–l-Ala and the subsequent separation of the diastereomers of the resulting tetrapeptide by reversed-phase HPLC offer a more convenient version with higher accuracy to the original Anderson test for studying racemization in peptide synthesis.

One-pot conversion of N-benzyloxycarbonyl group into N- tert-butoxycarbonyl group

An efficient one-pot two stage transformation of the N-Z group into the N- t-Boc group was carried out under the neutral conditions.