Benzyl Protection Research Articles

Synthesis and Characterization of Poly(ε‐caprolactone‐co‐δ‐ valerolactone) with Pendant Carboxylic Functional Groups

AbstractIn this paper, aliphatic polyesters functionalized with pendant carboxylic groups were synthesized via several steps. Firstly, substituted cyclic ketone, 2‐(benzyloxycarbonyl methyl)cyclopentanone (BCP) was prepared through the reaction of enamine with benzyl‐2‐bromoacetate, and subsequently converted into the relevant functionalized δ‐valerolactone derivative, 5‐(benzyloxy carbonylmethyl)‐δ‐valerolactone (BVL) by the Baeyer‐Villiger oxidation. Secondly, the ring‐opening polymerization of BVL with ε‐caprolactone was carried out in bulk using stannous octoate as the catalyst to produce poly(ε‐caprolactone‐co‐δ‐valerolactone) bearing the benzyl‐protected carboxyl functional groups [P(CL‐co‐BVL)]. Finally, the benzyl‐protecting groups of P(CL‐co‐BVL) were effectively removed by H2 using Pd/C as the catalyst to obtain poly(ε‐caprolactone‐co‐δ‐valerolactone) bearing pendant carboxylic acids [P(CL‐co‐CVL)]. The structure and the properties of the polymer have been studied by Nuclear Magnetic Resonance (NMR), Fourier Infrared Spectroscopy (FT‐IR) and Differential Scan Calorimetry (DSC) etc. The NMR and FT‐IR results confirmed the polymer structure, and the 13C NMR spectra have clearly interpreted the sequence of ε‐caprolactone and 5‐(benzyloxycarbonylmethyl)‐δ‐valerolactone in the copolymer. When the benzyl‐protecting groups were removed, the aliphatic polyesters bearing carboxylic groups were obtained. Moreover, the hydrophilicity of the polymer was improved. Thus, poly(ε‐caprolactone‐co‐δ‐valerolactone) might have great potential in biomedical fields.

ChemInform Abstract: A Stereoselective Synthesis of 2,6-Dideoxy-6,6,6-trifluoro-arabino-hexoses via an Asymmetric Diels-Alder Strategy.

The enantioselective syntheses of each enantiomer of ethyl 2,6-dideoxy-6,6,6-trifluoro-β-arabino-hexopyranoside (3) and of 2,6-dideoxy-6,6,6-trifluoro-arabino-hexose (4) are described. The key step in the approach is the inverse electron demand Lewis acid catalysed Diels–Alder reaction of the heterodiene (E)-1,1,1-trifluoro-4-[(1R)-1- phenylethoxy]but-3-en-2-one (5) and either ethyl vinyl ether (7a) or benzyl vinyl ether (7b). The titanium(IV) chloride catalysed cycloadditions at low temperature displayed high endo-selectivity and modest diastereofacial selectivity. Hydroboration of the mixture of the cis-cycloadducts (8a) afforded the separable diastereoisomers (9a) and (10a). Hydrogenolysis of (9a) gave ethyl 2,6-dideoxy-6,6,6-trifluoro-β-L-arabino-hexopyranoside (+)-(3), and of (10a) gave the corresponding D-glycoside (−)-(3). Similarly, hydroboration of the cis-cycloadducts (8b) gave the protected benzyl glycosides (9b) and (10b). Hydrogenolysis of each gave 2,6-dideoxy-6,6,6-trifluoro-L-arabino-hexopyranose (−)-(4) and the corresponding D-sugar (+)-(4) respectively. The absolute configurations of fluorinated carbohydrates (+)- and (−)-(3) were determined by comparison of their molar rotations with those of the parent glycosides. These assignments were confirmed by an X-ray crystallographic structure determination of the glycoside (9a).

PH-dependent self-assembly of amphiphilic poly(l-glutamic acid)-block-poly(lactic-co-glycolic acid) copolymers

A novel biodegradable AB-type diblock copolymer poly(L-lactic- co-glycolic acid)-block-poly(l-glutamic acid) (PLGA-b-PGA) was synthesized by a macromolecular coupling reaction between carboxyl-terminated PLGA and amino-terminated poly(γ-benzyl-glutamate) (PBLG) and the subsequent elimination of the protecting benzyl group. The structures of PLGA–PGA and its precursors were confirmed by Fourier transform infrared spectroscopy (FT-IR), 1H nuclear magnetic resonance (1H NMR) spectroscopy and gel permeation chromatography (GPC). This synthetic strategy simplified a former synthesis process of polypeptide-poly(l-lactic acid)(PLA); by using this new synthetic route the molecular weight and block ratio of PLGA–PGA could be easily controlled by adjusting the chain length of PLGA/PGA. The pH sensitivity and self-assembly behavior of PLGA–PGA copolymer were investigated by environmental scanning electron microscopy (ESEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). The results showed that the copolymer exhibited high pH responses, and the morphologies of the copolymer aggregates underwent four stages orderly with the pH increase (pH = 3–9): a disorganized form, micelles, semi-vesicles with thick walls and vesicles. Such a pH-dependent self-assembly process of the copolymer is promising for drug control release and bio-applications.

Synthesis of Oligosaccharide‐Branched Ribofuranan by Ring‐Opening Polymerization of a New Anhydroribo Trisaccharide Monomer

A new anhydroribotrisaccharide monomer, A2B3LR (1), was synthesized and ROP was carried out to elucidate the polymerizability and to obtain oligosaccharide-branched polysaccharides with defined structures. The new trisaccharide monomer was found to be polymerized readily with BF(3) . OEt(2) as a catalyst at -40 degrees C to give a lactose-branched polymer. Copolymerization with ADBR gave the corresponding copolymers in good yields. After removal of protective benzyl groups, D-lactose-branched ribofuranans with free hydroxyl groups were obtained in good yields. The structure of polymers was analyzed by (1)H, 13C, and two-dimensional NMR measurements, suggesting that D-lactose-branched ribofuranans had (1 --> 5)-alpha stereoregularity.

Simultaneous Removal of Benzyl and Benzyloxycarbonyl Protective Groups in 5′-O-(2-Deoxy-α-D-Glucopyranosyl)Uridine by Catalytic Transfer Hydrogenolysis

Synthesis of N 3,2′,3′-O-tris-(benzyloxycarbonyl)uridine and its use in the synthesis of 5′-O-(2-deoxy-α-d-glucopyranosyl)uridine is described. Simultaneous removal of benzyl and benzyloxycarbonyl groups was accomplished by catalytic transfer hydrogenolysis in the presence of Pearlman's catalyst without competing side reactions.

Large-Scale Asymmetric Synthesis of the 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazole BYK 405879: A Promising Candidate for the Treatment of Acid-Related Diseases

A process for the synthesis of the potassium-competitive acid blocker BYK 405879 (8) was established based on the approach used in medicinal chemistry (asymmetric hydrogenation of prochiral ketone 15 and Mitsunobu cyclization of the resulting alcohol 34). Several critical reaction steps were optimized. The synthesis of prochiral ketones was accomplished using ethyl 3-(2-methylphenyl)-3-oxopropanoate instead of 1-[1-(2-methylphenyl)vinyl]pyrrolidine, a reagent that was difficult to prepare and possesses limited shelf life. The catalyst loading of the asymmetric hydrogenation step was reduced significantly from a S/C ratio of 100:1 to a S/C ratio of 2500:1 by benzyl protection of ketone 15. After the Mitsunobu cyclization, the removal of byproduct was easily accomplished through acid−base extraction, and pure BYK 405879 (8) was then obtained by means of crystallization in the presence of succinic acid.

ChemInform Abstract: Benzyl Protection of Phenols under Neutral Conditions: Palladium‐Catalyzed Benzylations of Phenols.

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 of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Nitrile Biotransformations for the Synthesis of Highly Enantioenriched β‐Hydroxy and β‐Amino Acid and Amide Derivatives: A General and Simple but Powerful and Efficient Benzyl Protection Strategy to Increase Enantioselectivity of the Amidase.

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 of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir

An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.

Nitrile Biotransformations for the Synthesis of Highly Enantioenriched β-Hydroxy and β-Amino Acid and Amide Derivatives: A General and Simple but Powerful and Efficient Benzyl Protection Strategy To Increase Enantioselectivity of the Amidase

Biotransformations of a number of racemic beta-hydroxy and beta-amino nitrile derivatives were studied using Rhodococcus erythropolis AJ270, the nitrile hydratase and amidase-containing microbial whole cell catalyst, under very mild conditions. The overall enantioselectivity of nitrile biotransformations was governed predominantly by the amidase whose enantioselectivity was switched on remarkably by an O- and a N-benzyl protection group of the substrates. While biotransformations of beta-hydroxy and beta-amino alkanenitriles gave low yields of amide and acid products of very low enantiomeric purity, introduction of a simple benzyl protection group on the beta-hydroxy and beta-amino of nitrile substrates led to the formation of highly enantioenriched beta-benzyloxy and beta-benzylamino amides and acids in almost quantitative yield. The easy protection and deprotection operations, high chemical yield, and excellent enantioselectivity render the nitrile biotransformation a useful protocol in the synthesis of enantiopure beta-hydroxy and beta-amino acids.

Benzyl Protection of Phenols under Neutral Conditions: Palladium-Catalyzed Benzylations of Phenols

Benzyl protection of phenols under neutral conditions was achieved by using a Pd(eta3-C3H5)Cp-DPEphos catalyst. The palladium catalyst efficiently converted aryl benzyl carbonates into benzyl-protected phenols through the decarboxylative etherification. Alternatively, the nucleophilic substitution of benzyl methyl carbonates with phenols proceeded in the presence of the catalyst, yielding aryl benzyl ethers.

A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

AbstractThe kinetic resolution of 3‐aminopyrrolidine (3AP) and 3‐aminopiperidine (3APi) with ω‐transaminases was facilitated by the application of a protecting group concept. 1‐N‐Cbz‐protected 3‐aminopyrrolidine could be resolved with >99% ee at 50% conversion, the resolution of 1‐N‐Boc‐3‐aminopiperidine yielded 96% ee at 55% conversion. The reaction rate was up to 50‐fold higher by using protected substrates. Most importantly, enantioselectivity increased remarkably after carbamate protection compared to the unprotected substrates (86 vs. 99% ee). Surprisingly, benzyl protection of 3AP had no influence on enantioselectivity. A possible explanation for this observation could be the different flexibility of the benzyl‐ or carbamate‐protected 3AP as confirmed by NMR spectroscopy.

Dimeric Assemblies from 1,2,3-Triazole-Appended Zn(II) Porphyrins with Control of NH-Tautomerism in 1,2,3-Triazole

Cu(I)-catalyzed 1,3-dipolar cycloaddition of meso-ethynyl Zn(II) porphyrin with benzyl azide efficiently provides meso-1-benzyl-1H-1,2,3-triazolyl Zn(II) porphyrin, which assembles to form a slipped cofacial dimer by the complementary coordination of the triazole nitrogen atom at the 3-position to the zinc center of a second porphyrin moiety both in the solid and solution states. Removal of the benzyl protection and introduction of a 2-ethoxycarbonylphenyl moiety greatly stabilize the dimeric assembly through an additional hydrogen bonding interaction between the NH proton of 2H-1,2,3-triazole and the carbonyl oxygen.

Synthesis, degradability, and cell affinity of poly (DL‐lactide‐co‐RS‐hydroxyethyl‐β‐malolactonate)

Poly(DL-lactide-co-RS-hydroxyethyl-beta-malolactonate) (PLMAH), a novel functionalized polylactide with hydroxyl arms, was synthesized by a two-step reaction. DL-lactide (DLLA) and RS-benzyloxyethyl-beta-malolactonate were first copolymerized by ring-opening polymerization with Sn(Oct)(2) as catalyst to generate poly(DL-lactide-co-RS-benzyloxyethyl-beta-malolactonate) (PLMAB); next the benzyl protective groups of PLMAB were removed by the hydrogenation reaction catalyzed by Pd/C to generate the final polymer PLMAH. The composition and structure of PLMAB and PLMAH were characterized by (1)H and (13)C NMR. In vitro degradation experiments of PLMAH copolymers showed that the more RS-hydroxyethyl-beta-malolactonate (MAHE) content in the copolymer film, the faster the degradation occurred. The results of human umbilical vein endothelial cells (ECV-304) cultivated on PDLLA and PLMAH films suggested that among all the films, the PLMAH film containing 9.4 mol % MAHE had the highest cell attachment efficiency.

Synthesis and characterization of functionalized biodegradable poly(DL‐lactide‐co‐RS‐β‐malic acid)

Amorphous poly(DL-lactide-co-RS-beta-malic acid) (PDLLMAc) was synthesized by hydrogenolysis of poly(DL-lactide-co-RS-beta-malolactonate) (PDLLMA), which was obtained from the ring-opening polymerization of DL-lactide (DLLA) and RS-beta-benzyl malolactonate (MA) using stannous octoate as the catalyst. The amount of malolactonate (MA) in the feeding dose was varied from 0 to 8.0 mol %. The copolymers were characterized by 1H NMR, FTIR, GPC, and DSC. The tensile properties and water uptake of the copolymers were measured. The protective benzyl groups in PDLLMA were completely removed in hydrogenolysis to produce PDLLMAc. The molecular weight (M(n)) of the copolymers decreased with increasing MA content. However, with low feed MA content of 0.6 and 1.0%, high molecular weight PDLLMAc with M(n) of 63 and 35 kDa, respectively, were obtained; these copolymers exhibited good tensile yield stress and modulus of 17-23 MPa and 1.1-1.4 GPa, which are comparable to PDLLA homopolymer. The corresponding protected PDLLMA have tensile yield stress/modulus of 2.0-2.4 MPa and 11-42 MPa. The malic acid comonomer in PDLLMAc significantly improves the tensile strength and modulus compared to the protected PDLLMA. Further, the functionalizable PDLLMAc (with 0.6 mol % feed MA) was grafted with bioactive RGD peptide. The culture of primary umbilical artery smooth muscle cells was investigated. Methylthiazoletetrazolium results showed that both the RGD- and COOH-functionalized (0.6 mol %) PDLLMAc copolymers were significantly more biocompatible than the control PDLLA and could potentially be employed as tissue engineering scaffolds.

PREPARATION AND CELL COMPATIBILITY OF FUNCTIONALIZED BIODEGRADABLE POLY(DL-LACTIDE-co-RS-β-MALIC ACID)

In order to create a functionalized biodegradable polymer for vascular tissue engineering application, poly(DL-lactide-co-RS-β-malic acid) (PDLLMAc) was synthesized. PDLLMAc was obtained after hydrogenolysis of poly(DL-lactide-co-RS-β-benzyl malolactonate) (PDLLMA), which was from the ring-opening polymerization of DL-lactide (DLLA) and RS-β-benzyl malolactonate (MA) using stannous octoate as catalyst. The copolymers were characterized by 1H-NMR, FTIR, GPC and DSC. The tensile strength and water uptake of the copolymers were measured. In copolymerization, the proportion of MA in the derived copolymers was lower than that in the feeding dose, a consequence of its lower reactivity. The molecular weight of the copolymers decreased with increasing MA content. The protective benzyl groups were completely removed in hydrogenolysis. The glass transition temperature (Tg) of the protected copolymers decreased with increasing MA content. The mechanical strength test showed that the tensile strength of PDLLMA decreased while elongation increased with MA content increasing, and the tensile strength increased and elongation decreased with increasing malic acid content in PDLLMAc for the formation of hydrogen bonding. The water uptake showed that more hydrophilic malic acid adsorbed more water in PDLLMAc. In order to test the reactivity of functional pendant groups, bioactive RGD peptide was immobilized on the functionalized polymer film surface and smooth muscle cells (SMCs) were cultured on it. The results showed that the functionalized copolymer was biocompatible and could be potentially applied in vascular tissue engineering.

Approach to a Facile and Selective Benzyl‐Protection of Carbohydrates Based on Silyl Migration

AbstractA convenient and selective benzyl protection of carbohydrates has been investigated on the basis of the silyl migration under the conventional benzylation conditions, developing a facile and short synthesis of methyl 2,3,6‐tri‐O‐benzyl‐α‐D‐glucopyranoside.

Synthesis of 2′,3′-Dideoxyinosine via Radical Deoxygenation

A synthetic method for 2 ′,3 ′-dideoxyinosine (ddI) from inosine was established via radical deoxygenation of N1,5 ′-O-diprotected-2 ′,3 ′-bis-S-methyl dithiocarbonate of inosine derivatives. The radical deoxygenation proceeded smoothly to give the desired dideoxy compounds in good yields using 1-ethylpiperidinium hypophosphite and triethylborane. Benzyl or p-methoxybenzyl protection of inosine at the N1, 5 ′-O-positions were effective for the ddI synthesis.

Microwave assisted hydroaminomethylation of alkenes

Hydroaminomethylation of terminal alkenes can be regioselectively carried out in less than 30 min with secondary amines in EtOH under MW irradiation using (PPh 3) 3RhCO(H) and Xantphos or Biphephos as ligands. When primary amines were employed, the corresponding enamines were obtained in good yields. Tris-benzyl allylglycine was transformed into different (basic) benzylated α-amino acids. Moreover, the benzyl protection was removed in few minutes under MW irradiation with Pd(OH) 2 under H 2 atmosphere.

Selective Hydrogenolysis of Benzyl‐Protected 1‐Hydroxy‐3‐hydroxyimino‐2‐pyrrolidinones.

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.