Novel 3-mono-<Emphasis Type="Italic">O</Emphasis>-hydroxyethyl cellulose: synthesis and structure characterization

The synthesis of 3-mono-O-hydroxyethyl cellulose using orthogonal protecting groups was realized. The reaction of 2,6-di-O-thexyldimethylsilyl cellulose with 2-(2-bromoethoxy)tetrahydropyran leads to a completely functionalized cellulose derivative. The complete removal of the protecting groups was possible by split off of the TDMS functions with tetrabutylammonium fluoride trihydrate and subsequently the tetrahydropyran moieties with hydrochloric acid. The structure of 3-mono-O-hydroxyethyl cellulose was confirmed by applying one and two-dimensional NMR spectroscopy. The novel polymer is soluble in water and does not show thermoreversible gelation.     

Hot Topics in Polysaccharide Chemistry – Selected Examples

Summary: The paper highlights recent developments in polysaccharide chemistry. Cellulose tert-butyl- and thexyldimethylsilyl ethers with degree of substitution up to 2 were accessible and comprehensively characterized by means of NMR spectroscopy. These derivatives enable the preparation of 3-O-functionalized cellulose ethers. Especially the allyl ether as protecting group at position 3 can be used for the synthesis of 2,6-di-O-methyl cellulose. Nucleophilic displacement reactions of cellulose p-toluenesulfonic acid esters with amines afforded deoxyamino celluloses that form stable monolayers on different substrates. Based on 6-deoxy-6-azido cellulose, dendrons with a focal alkyne moiety were bound via the copper(I) catalyzed Huisgen reaction. Moreover, dextran derivatives were synthesized that form stable nanoparticles useful, e.g., for the determination of the pH value in biological systems.     

Hydrogen bonds in regioselectively substituted cellulose derivatives

Formation of hydrogen bonds in various cellulose derivatives, 2,3-di-O- and 6-O-substituted cellulose ethers, were characterized by FTIR and solid-state CP/MAS¹³C-NMR. The polymers were synthesized by regioselective substitution of hydroxyl groups and had a uniform structure. Since their three hydroxyl groups (OH) are selectively blocked, the cellulose derivatives appeared to form specific inter- and intramolecular hydrogen bonds. The characteristic OH stretching frequencies in IR spectra and the C-1 chemical shift in CP/MAS spectra of 6-O-substituted cellulose derivatives indicated existence of two equivalent intramolecular hydrogen bonds between ether oxygen and OH groups at 3-OH-O5′ and O6-HO-2′ [Figure 3(C)]. Influence of the substituents at the C-6 position on the formation was not significant except trityl group. Behavior of the hydrogen bonds in 6-O-tritylcellulose were also discussed. © 1994 John Wiley & Sons, Inc.     

Regioselectively Modified Cellulose and Chitosan Derivatives for Mono- and Multilayer Surface Coatings of Hemocompatible Biomaterials

In this study different synthetic strategies were developed and applied to introduce solely or in combination heparin/heparansulfate-like functional groups such as N-sulfo, O-sulfo, N-acetyl, and N-carboxymethyl groups into chitosan and cellulose with highest possible regioselectivity and completeness and defined distribution along the polymer chain. Completely substituted 6-amino-6-deoxycellulose and related derivatives were prepared from tosylcellulose (DS 2.02; C₆ 1.0) by nucleophilic substitution with azido groups only in the 6-position at 50 °C with subsequent reduction to amino groups and completely removing tosyl groups in the 2,3-position. 2,6-Di-O-sulfocellulose was prepared using the reactivity difference between C-2, C-6 and C-3 of cellulose. The reactivity difference between amino groups and hydroxyl groups was used to prepare various N-substituted derivatives. Partially 2,6-di-O-sulfated cellulose was obtained from trimethylsilylcellulose by the insertion of sulfurtrioxide into the Si–O ether linkage. Partially 3-O-sulfocellulose was synthesized by protecting C-2 and C-6 with trifluoroacetyl groups. A copper–chitosan complex was used to synthesize 6-O-sulfochitosan with a DS of 1.0 at C-6 and various partially 6-O-desulfonated products are possible. Using the phthalimido group to increase the solubility of chitosan in DMF, the regioselectivity of 3-O-sulfo groups was improved by regioselective 6-O-desulfonation of nearly complete 3,6-O-disulfochitosan. The platelet adhesion properties of immobilized regioselectively modified water-soluble derivatives on membranes have been tested in vitro. Some regioselectively modified chitosan and cellulose derivatives are potential candidates for the surface coatings of biomaterials if the regioselective reactions are somewhat further optimized.     

Synthesis of regioselectively brominated cellulose esters and 6-cyano-6-deoxycellulose esters

The control of regiochemistry in the synthesis of polysaccharide derivatives is one of the most significant scientific challenges in the field. Its importance is only further highlighted by the individual successes in synthesis of regioselectively substituted derivatives, in particular cellulose esters and ethers, over the last 20 years. The availability of these samples and studies of their properties versus randomly substituted analogs has shown clearly that properties like solubility, aggregation phenomena, and optical properties depend heavily on the regiochemistry of substitution. We report here on the one-pot synthesis of novel 6-bromo-6-deoxy-2,3-O-acylcellulose derivatives, which as more organic soluble derivatives of 6-bromo-6-deoxycellulose should allow broader exploitation of the highly regioselective cellulose 6-bromination chemistry. We illustrate the potential of these new derivatives by conversion to 6-cyano-6-deoxycellulose esters.     

Syntheses of 2,6-O-alkyl celluloses: influence of methyl and ethyl groups regioselectively introduced at O-2 and O-6 positions on their solubility

2,6-Di-O-ethyl (2E6E) (1), 2-O-ethyl-6-O-methyl (2E6M) (2), and 6-O-ethyl-2-O-methyl (6E2M) (3) celluloses were synthesized via ring-opening polymerization of glucose orthopivalate derivatives. 2,6-Di-O-methyl cellulose (2M6M) was insoluble in any common solvents, though it was not expected. On the other hand, cellulose derivative 1 (2E6E) was soluble in chloroform. Introduced positions of alkyl groups on cellulose affected solubilities of cellulose derivatives. Their solubility in chloroform decreased in the order: polymer 1 (2E6E) > polymer 2 (2E6M) > polymer 3 (6E2M) ≫ 2M6M.     

Modifications at the 6-O-position of 1-deoxynojirimycin: facile and efficient synthesis of 6-O-alkylated-N-octyl-1-deoxynojirimycin derivatives

A straightforward synthesis of N-alkylated 1-deoxynojirimycin derivatives modified at the 6-O-position has been described. The key intermediate in the synthesis of target compounds was 2,3,4-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol, which was prepared from 2,3,4,6-tetra-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol. Optimal conditions have been established for the synthesis of the key intermediate by varying reaction parameters. Reductive amination and subsequent alkylation of the 6-O-position followed by hydrogenolysis were the main reaction steps, which gave target compounds 6-O-ethyl-N-octyl-1,5-dideoxy-1,5-imino-D-glucitol and 6-O-butyl-N-octyl-1,5-dideoxy-1,5-imino-D-glucitol. This synthetic route is flexible and can be useful for the synthesis of other lipophilic iminosugar derivatives.     

Silylation of Cellulose and Starch – Selectivity, Structure Analysis, and Subsequent Reactions

The silylation of cellulose and starch under different starting conditions is reviewed. The control of the degree of substitution (DS) and regioselectivity in dependence of the reaction pathway are discussed in detail. The synthesis of trimethylsilyl cellulose (TMSC) in the system hexamethyldisilazane (HMDS)/ammonia leads to partially and completely silylated products controlled by the amount of the components. Hydrolytic desilylation of TMSC in tetrahydrofuran (THF)/ammonia gives the partially desilylated products. The desilylation proceeds statistically along the polymer chains. The reaction of cellulose dissolved in N,N-dimethylacetamide (DMA)/LiCl with bulky thexyldimethylchlorosilane (TDSCl) in the presence of imidazole leads to 2,6-di-O-TDS cellulose. The silylation of starch dissolved in dimethylsulfoxide (DMSO) with TDSCl/pyridine results in the formation of regioselectively 2-O and 6-O functionalized silyl ethers with DS values up to 1.8. 6-O Silyl ethers of cellulose and starch were synthesized with TDSCl highly activated in the reaction system N-methylpyrrolidone (NMP)/ammonia. Two- dimensional NMR techniques after subsequent modifications of the remaining OH groups have been established as important methods for the characterization of the substitution pattern of the described silyl ethers. In the case of starch, the distribution of the substituents could be detected not only in the anhydroglucose units (AGU) but also in the non-reducing end groups (NEG).     

Phosphorylated cellulose propionate derivatives as thermoplastic flame resistant/retardant materials: influence of regioselective phosphorylation on their thermal degradation behaviour

Cellulose ester derivatives having phosphoryl side-chains were synthesized by phosphorylation of two types of cellulose propionate (CP); the difference between the two CPs was whether the primary hydroxyl group at C6 had been fully propionylated or not. Dimethyl phosphate, dimethyl thiophosphate, diethyl phosphate, or diethyl thiophosphate was introduced into the residual hydroxyl positions of the CPs. Chemical composition of the respective derivatives was characterized by elemental analysis and a combined use of saponification and HPLC quantification of the released propionic acid. Their thermal properties were investigated by DSC and TGA, and an intermediate residue of the pyrolysis was also examined by FT-IR spectroscopy. From the thermal degradation measurements using TGA, the C6-O phosphorylation was found to noticeably prevent the CP derivatives from weight loss in the pyrolysis process under dynamic air, i.e., providing them with a flame-resistance functionality, whereas the C2-O and C3-O phosphorylation did not give rise to such an appreciable resistance effect. A discussion was focused on the difference in pyrolysis mechanism between the phosphorylated CPs. However, most samples of the CP derivatives showed a clear T _g considerably lower than the onset temperature of the thermal degradation. Thus we suggest that it is possible to design thermoplastic flame resistant/retardant materials based on cellulose, by controlling the substitution distribution of the phosphoryl and propionyl groups introduced.     

Synthesis and Configuration of Some Hydroxymilbemycin Derivatives Including 22,23-Dihydroavermectin B1b Aglycone

The synthesis of several configurationally defined hydroxymilbemycin derivatives is described. One of these allylic alcohols is the known 5-O-[(tert-butyl)dimethylsilyl]-13α-hydroxymilbemycin D (= 5-O-[(tert-butyl)-dimethylsilyl]-22,23-dihydroavermectin B _1b, aglycone; 15D ), the synthesis of which represents LI conversion of the milbemycin to the avermectin series of natural products. The configurations at C(13), C(14), and C(15) of the new milbemycin derivatives were determined by NMR experiments and force-field calculations.     

Synthesis of 6-O-Hexadecyl- and 6-O-Octylsucroses and Their Self-Assembling Properties Under Aqueous Conditions

This paper reports the synthesis and self-assembling properties of 6-O-hexadecyl- and 6-O-octylsucroses. Mono-etherification of 2,3,4,1′,3′,4′-hexa-O-benzylsucrose with the corresponding alkyl bromides predominantly took place at the glucose 6-position and the products were isolated by silica gel column chromatography. Benzyl groups in the isolated products were cleaved to yield the target derivatives. The SEM, TEM, XRD, and DLS results indicated that 6-O-alkylsucroses formed vesicle-type particles via formation of lamellar-like planes under aqueous conditions, which were further merged by fusion of the planes to construct larger aggregates. The self-assembling properties of the materials were different from those of the previously reported 6-O- and 6’-O-hexadecylsucroses mixture.     

Introduction of a New Class of Ligands for the Metal-Catalyzed Enantioselective Synthesis

Protected thiosugars were prepared as ligands for the metal-catalyzed enantioselective synthesis. The protecting groups in these ligands were varied to test a proposed new concept for the metal-catalyzed enantioselective synthesis. This new concept centres on the use of a stair-like ligand with a large substituent on one side and a small substitutent on the other rather than the commonly employed ligands which have C₂ symmetry (see Fig.3). In such a ligand, both substituents should have a major influence on the coordination of a prochiral substrate. To test this proposal, 3-thio-α-D -glucofuranose derivatives with the following substituents were synthesized: 1,2-O-isopropylidene-5,6-O-methylidene (see 24 ), 1,2:5,6-di-O-isopropylidene (see 2 ), 5,6-O-cyclohexylidene-1,2-O-isopropylidene (see 23 ), 1,2-O-cyclohexylidene-5,6-O-isopropylidene (see 14 ), 1,2:5,6-di-O-cyclohexylidene (see 13 ), 5,6-O-(adamantan-2-ylidene)-1,2-O-isopropylidene (see 21 ), and 1,2:5,6-di-O-(adamantan-2-ylidene) (see 25 , Table 2). As a representative of the allofuranoses, 1,2:5,6-di-O-isopropylidene-3-thio-α-D -allofuranose ( 6 ) was chosen. The following derivatives of 1,2-O-isopropylidene-α-D -xylofuranose were also synthesized: 1,2-O-isopropylidene-5-deoxy-3-thio-α-D -xylofuranose ( 29 ), 1,2-O-isopropylidene-3-thio-α-D -xylofuranose ( 28 ) and 5-O-[(tert-butyl)-diphenylsilyl]-1,2-O-isopropylidene-3-thio-α-D -xylofuranose ( 15 , see Table 2). The proposed concept was tested using the copper-catalyzed 1,4-addition of BuMgCl to cyclohex-2-en-1-one. The enantioselectivity was very dependent on the ligand used and was up to 58%.     

Preparation and Characterization of 6-<Emphasis Type="Italic">O</Emphasis>-(4-stearyloxytrityl)Cellulose acetate Langmuir–Blodgett Films

Multilayer films of 2,3-di-O-acetyl-6-O-(4-stearyloxytrityl)cellulose (ASTC) were prepared and investigated. The fairly high surface pressure (π)–area (A) isotherms (36– 47 mN/m) suggest that the balky and hydrophobic trityl group contribute to form a condensed monolayer. The cellulose derivative formed a homogeneous monolayer at 10 mN/m. The monolayer on the water surface was transferred successfully at 10 mN/m onto various substrates by modifying the preparation methods, to form Z-type multilayer films. The ultraviolet–visible (UV–Vis) absorbance was independent of the number of layers, indicating that each layer is made of definite number of anhydroglucose unit (AGU). The monolayer thickness determined from atomic force microscope (AFM) and ellipsometry was calculated to be about 1.9 nm, suggesting that the long alkyl chain in the film has a so-called hairy-rod type structure. This is the first paper about the Z-type LB film prepared from cellulose derivatives having long mono-alkyl chain only at 6-O-position.     

Water solubility of regioselectively 2,3-O-substituted carboxymethylcellulose

A series of 2,3-O-carboxymethylcelluloses (CMC's), which are regioselectively substituted at the C-2 and C-3 position, were prepared and their water solubility was examined. It was found that the lower limit for the degree of substitution (DS) value of water-soluble 2,3-O-CMC is about 0.3. This value was almost the same as that of CMC prepared in a slurry of isopropyl alcohol/water with isopropyl chloroacetate and sodium hydroxide, showing that the uniform alkylation is rather important to convert cellulose into water-soluble derivatives.     

A Convenient Synthesis of Type IV Glycosyl Donors from Type I Disaccharides

ABSTRACT

The synthesis of 4,6-di-O-acetyl-3-O-(tetra-O-acetyl-ß-D-galactopyranosyl)-2-deoxy-2-phthalimido-α,ß-D-galactopyranosyl chloride 1 4 and its 6-O -benzyl derivative 1 2 was achieved in a 5-step sequence starting from the readily available type I disaccharide derivative 3. The key step in the synthesis involved the preparation of trifluoromethanesulfonate (triflate) derivatives 7 and 9 and their subsequent SN₂ displacement by acetate ion for conversion of 2-deoxy-2-phthalimido-ß-D-glucopyranosyl moiety to the corresponding galacto configuration.     

Dérivés du C-méthyl-3-xylofurannose

3-C-Methylxylofuranose Derivatives 3′-C-methyladenosine has been known for almost ten years whereas its 3′-epimer is still to be prepared, because of the difficulty of synthesizing the 3-C-methylxylo-furanose. In this communication, the synthesis of 1,2-O-isoproypylidene acetal 9 and its derivatives is described. Vicinal dihydroxylation of 5-O-benzoyl-3-deoxy-1,2-O-isopryopylidene-3-C-methylidene-α-D -erythro-pentofuranose ( 6 ) led to the branchedchain sugar derivative 7 which was selectively tosylated to 8 whose reduction gave 9 . These reactions, as well as the derivatizations of 7 , 8 and 9 , took place with good to excellent yields.     

Semisynthetic β-Rhodomycins: A New Approach to the Synthesis of 4-O-Methyl-β-Rhodomycins

ABSTRACT

Syntheses of 4-O-methyl-β-rhodomycins are described. Glycosylation (trimethylsilyl triflate, dichloromethane-acetone 10:1, -30 °C) of 4-O-methyl-10-O-p-nitrobenzoyl-β-rhodomycinone, obtained from β-rhodomycinone (βRMN) in a 6-step synthesis, with 1-O-tert-butyl(dimethyl)silylated derivatives of 4-O-acetyl- or 4-O-p-nitrobenzoyl-2,3,6-tri-deoxy-3-trifluoroacetylamino-β-L-arabino- and lyxo-hexopyranoses or 2,6-di-O-acetyl-2,6-dideoxy-β-L-lyxo-hexopyranose afforded 7-O-α-L-glycosyl-β-rhodomycinones. Removal of the O- and N-acyl groups with 0.1M and 1M NaOH gave the 7-O-(3-amino-2,3,6-trideoxy-α-L-arabino- and lyxo-hexopyranosyl)-4-O-methyl-β-rhodomycinones and 7-O-(2,6-dideoxy-α-L-lyxo-hexopyranosyl)-4-O-methyl-β-rhodomycinone.     

Synthesis of (5R)- and (5S)-5-Methyl-5, 6-dihydrouridine Derivatives

The hydrogenation of 2′, 3′-O-isopropylidene-5-methyluridine (1) in water over 5% Rh/Al₂O₃ gave (5 R)- and (5 S)-5-methyl-5, 6-dihydrouridine (2) , separated as 5′-O-(p-tolylsulfonyl)- (3) and 5′-O-benzoyl- (5) derivatives by preparative TLC. on silica gel and ether/hexane developments. The diastereoisomeric differentiation at the C(5) chiral centre depends upon the reaction media and the nature of the protecting group attached to the ribosyl moiety. The synthesis of iodo derivatives (5 R)- and (5 S)- 4 is also described. The diastereoisomers 4 were converted into (5 R)- and (5 S)-2′, 3′,-O-isopropylidene-5-methyl-2, 5′-anhydro-5, 6-dihydrouridine (7) .     

SYNTHESIS OF 2′-DEOXY-2′-FLUORO- 1-β-d-ARABINOFURANOSYL URACIL DERIVATIVES: A METHOD SUITABLE FOR PREPARATION OF [18F]-LABELED NUCLEOSIDES

ABSTRACT

N-glycosylation of 2,4-bis-O-(trimethylsilyl)-pyrimidine bases with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-1-(Br, OBz)-α-d-arabinose derivatives are reported. 1-Bromo-arabinose provides high yield and a favorable anomeric ratio (β/α) of pyrimidine nucleoside in either MeCN or CH₂Cl?CH₂Cl. This method should be suitable for the synthesis of 2′-deoxy-2′-[¹⁸F]fluoro-1-β-d-arabinofuranosyluracil derivatives.     

Self-Assembling Properties of 6-O- and 6′-O-Alkylsucrose Mixtures Having Different Chain Lengths Under Aqueous Conditions

The self-assembling properties of the 6-O- and 6′-O-alkylsucrose mixtures with different chain lengths including octyl, decyl, dodecyl, and tetradecyl under aqueous conditions were studied and compared with those of the 6-O- and 6′-O-hexadecylsucrose mixture previously reported. The title compounds were synthesized from sucrose in five steps. The results of scanning and transmission electron microscopes, powder X-ray diffraction, and dynamic light scattering measurements indicated that the self-assembling properties of octyl, decyl, and dodecyl derivatives were completely different from those of the 6-O- and 6′-O-hexadecylsucrose mixture. The three derivatives reported here primarily formed lamellar planes, which further induced the formation of vesicle-type particles under aqueous conditions, whereas the previous derivatives primarily formed spherical micelles in water, which further assembled according to face-centered cubic organization by a drying process from the aqueous dispersion. It was also found that the 6-O- and 6′-O-tetradecylsucrose mixture showed concentration-induced micelle-lamellar transition behavior in an aqueous dispersion. Furthermore, the mixing of a regioisomer, 6′-O-hexadecylsucrose, with 6-O-hexadecylsucrose induced different self-assembling properties from that of 6-O-hexadecylsucrose alone, but this effect did not appear in the self-assembling of the 6-O- and 6′-O-octylsucrose mixture.