Regioselective synthesis of 6-amino- and 6-amido-6-deoxypullulans

Hydrophobically modified polysaccharides that contain amine and amide groups possess valuable features for drug delivery and other applications. These chemical groups are known to play a fundamental role in the biological activity of important polysaccharides. Pullulan is known for its non-toxicity and biocompatibility, therefore, we have applied the versatile Staudinger reaction for the synthesis of regioselectively substituted pullulan derivatives containing amine or amide groups with promise for biomedical applications. The synthesis began with the regioselective bromination of pullulan at C-6 with N-bromosuccinimide and triphenylphosphine, providing 6-bromo-6-deoxy-pullulan, which is soluble in a range of organic solvents and therefore is a dynamic intermediate for the synthesis of other pullulan derivatives. Azide displacement of bromide from 6-bromo-6-deoxy-pullulan esters yielded the corresponding 6-azido-6-deoxy-pullulan esters. Staudinger reduction of these azides efficiently and chemoselectively afforded the corresponding amino- or amidopullulans.     

Enzyme-catalyzed transesterification of vinyl esters on cellulose solids

Enzyme-catalyzed transesterification of several cellulose solids in organic media have been investigated. Several protease enzymes were made soluble in organic media through ion-paired enzyme–surfactant complexes. Subtilisin Carsberg was found to be catalytically active in the transesterification of cellulose with vinyl propionate and vinyl acrylate in anhydrous pyridine. The ester carbonyl groups in acylated cellulose derivatives were confirmed by Fourier transform infrared spectroscopy. The surfaces of these cellulose derivatives became hydrophobic as demonstrated by increased water-contact angles. The enzyme-catalyzed transesterification was confirmed to regioselectively target the primary hydroxyl group of cellulose by reactions on specifically substituted cellulose. The cellulose esters from enzyme-catalyzed transesterification could be hydrolyzed partially by the same enzyme in aqueous media, and were thus biodegradable. Surface grafting of cellulose acrylate was demonstrated using azobisisobutyronitrile-initiated polymerization of acrylonitrile in dimethylformamide. Polyacrylonitrile (PAN)-g-cellulose shows a different thermal behavior from cellulose, homopolymer PAN, and PAN/cellulose blends. The grafted PAN on PAN-g-cellulose at a 16% grafting add-on is incapable of cyclization. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1931–1939, 2001     

Highly C6-selective and quantitative modification of cellulose: nucleoside-appended celluloses to solubilize single walled carbon nanotubes

Cellulose derivatives having thymidine and/or trimethylammonium appendages exclusively at C6 positions can be prepared in a convenient manner through C6-selective bromination/azidation on cellulose to afford 6-azido-6-deoxycellulose followed by chemoselective [3 + 2] cycloadditions using Cu⁺ as a catalyst. These cellulose derivatives take unique sheet-like structures and function as “wrapping papers” to effectively disperse single-walled carbon nanotubes in water.     

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 deoxy sugar esters: a chemoenzymatic stereoselective approach affording deoxy sugar derivatives also in the form of aldehyde

A chemoenzymatic synthesis of deoxy sugar esters is described. The synthesis is based on the O-alkylation of carboxylic acid with 2-bromo-5-acetoxypentanal. The method allows treatment of hydroxy carboxylic acids without protection of alcoholic hydroxyl groups. Several stereoisomeric deoxy sugar esters were resolved (up to ee or de > 98%) using a lipase-catalyzed acetylation of hemiacetals that in certain cases afforded deoxy sugar derivatives in the form of aldehydes. The stereochemistry of the reactions was determined by the NMR spectra of mandelic acid derivatives.     

Cellulose esters in drug delivery

Cellulose esters have played a vital role in the development of modern drug delivery technology. They possess properties that are not only well-suited to the needs of pharmaceutical applications, but that enable construction of drug delivery systems that address critical patient needs. These properties include very low toxicity, endogenous and/or dietary decomposition products, stability, high water permeability, high T _g, film strength, compatibility with a wide range of actives, and ability to form micro- and nanoparticles. This suite of properties has enabled the creation of a wide range of drug delivery systems employing cellulose esters as key ingredients. The following is a review of the most important types of these systems, and of the critical roles played by cellulose esters in making them work, focusing on more recent developments.     

Dynamic mechanical thermal analysis transitions of partially and fully substituted cellulose fatty esters

The main transitions of cellulose fatty esters with different degrees of substitution (DSs) were investigated with dynamic mechanical thermal analysis. Two distinct main relaxations were observed in partially substituted cellulose esters (PSCEs). They were attributed to the glass‐transition temperature and to the chain local motion of the aliphatic substituents. The temperatures of both transitions decreased when DS or the number of carbon atoms (n) of the acyl substituent increased. Conversely, all the transitions of fully substituted cellulose esters occurred within a narrow temperature range, and they did not vary significantly with n. This phenomenon was explained by the formation of a crystalline phase of the fatty substituents. The presence of few residual OH groups in PSCEs was responsible for a large increase in the storage bending modulus, and it eliminated the effect of n on damping. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 281–288, 2003     

2,4-Dioxohexahydropyrimidine derivatives V. 5-Bromo-6-alkoxydihydroorotic acids,amides, and esters

The corresponding 5-bromo-6-alkoxydihydroorotic acid derivatives were obtained by reaction of orotic acid, its methyl ester, and amide with bromine in methanol and ethanol. The reaction of methyl and butyl orotates with methyl and ethyl hypobromites gives 5,5-dibromo-6-alkoxydihydroorotic acid esters. Isoorotic acid reacts with methyl hypobromite to give 5,5-dibromo-6-methoxydihydrouracil.     

Haloacetylated enol ethers. 11. Synthesis of 1-methyl- and 1-phenyl pyrazole-3(5)-ethyl esters. A one-pot procedure

A one-pot synthesis of 1-methyl- and 1-phenylpyrazole-3(5)-ethyl esters 2,3a-e by the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones 1a-e with methyl and phenyl hydrazine hydrochloride under mild conditions, is reported. A study using compounds 1a-e with different substituents proved that these are versatile building blocks for the synthesis of pyrazole derivatives, having a 3(5)-ethoxycarbonyl substituent in good yields (60–89%). The hydrazine and β-alkoxyvinyl trichloromethyl ketone substituent effects on the reaction regiochemistry on the formation of the 1,3- and 1,5-isomer were observed.     

Synthesis of methyl esters of 5-amino-4-(substituted amino)-2-methylthio-7H-pyrrolo[2,3d]-pyrimidine-6-carboxylic acids

The optimum route for the synthesis of methyl esters of N-[(4-substituted amino)-5-cyano-2-methylthiopyrimidin-6-yl]amino acids (which are starting materials for preparing the methyl esters of the corresponding 5-amino-4-(substituted amino)pyrrolo[2,3-d]pyrimidine-6-carboxylic acids) is via subsequent reactions of 4,6-dichloro-2-methylthiopyrimidine-5-carbonitrile with amines and methyl glycinate. In some examples, the reaction of methyl N-(4-chloro-2-methylthio-6-pyrimidinyl)aminoacetate with amines occurs to give the corresponding acid amides. The previously unknown synthesized derivatives of pyrimidin-6-yl amino acids and 4,5-diaminopyrrolo[2,3-d]pyrimidine- 6-carboxylic acids possess fungicidal properties.Vilnius University, Vilnius 2006, Lithuania. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 7, pp. 955–961, July, 2000.     

Interaction of 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-α]pyrimidine with methylene-active compounds and acid hydrolysis of its products

Reactions of 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine with sodium derivatives of pentane-2,4-dione, malonodinitrile, Meldrum acid, acetoacetic, cyanoacetic and malonic esters have been shown to give the respective substituted derivatives. Azinyl-ylidene tautomerism has been found to be characteristic of these compounds, the latter existing mainly in the ylidene form. The acid hydrolysis of pentane-2, 5-dione and cyanoacetic and malonic esters derivatives has been investigated.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1957–1961, November, 1993     

Synthesis of 4‐hydroxyquinolin‐2(1H)‐one analogues and 2‐substituted quinolone derivatives

A versatile synthetic method for preparing 4‐hydroxyquinolone and 2‐substituted quinolone compounds from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester synthesis and reductive cyclization. The key intermediates were keto esters 4a‐e , which could be transformed to 4‐hydroxyquinolones 5a,b or 2‐substituted quinolone ethyl esters 6a‐c depending on the reaction conditions. 4‐Hydroxyquinolone analogues were prepared and investigated for N‐methyl‐D‐aspartate (NMDA) activity in vitro. Among these derivatives, 6,7‐difluoro‐3‐nitro‐4‐hydroxyquinolin‐2(1H)‐one ( 9 ) exhibited moderate activity.     

Study of chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronic esters with iridium–PˆN complexes

In this paper we report the first chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronic esters, which constitutes a new route to (α-bromoalkyl)boronic esters. The study demonstrates that excellent chemoselectivities along with full conversions can be obtained for hydrogenation of alkyl substituted derivatives with iridium–PˆN complexes. Moreover, acyclic alkyl derivatives afford (α-bromoalkyl)boronic esters in good enantioselectivities ranging from 64 to 73% ee. A cyclic alkyl derivative was obtained only in a nearly racemic form. The (1-bromo-1-alkenyl)boronic esters appear to be less reactive towards homogenous hydrogenation conditions than their chloro analogues as demonstrated by the higher catalyst loadings required to achieve full conversions for alkyl derivatives and lower conversions observed for the aryl substituted derivatives.     

Synthesis and biological activity of some new 3-and 6-substituted coumarin amino acid derivatives. Part I

The synthesis of 6-nitrocouarrain-3-CO-amino acids and their corresponding methyl esters (II-XVII) and some dipeptide methyl esters (XVIII-XXVI) are described. 6-(N-Tosyl- or N-phthalylaminoacyl)aminocoumarin-3-carboxylic acid methyl esters (XXXIV-XL) and 3-(N-phthalyl- or N-tosylaminoacytyaminocoumarins (XLV-LVI) have been prepared via the carbodiimide and acid chloride methods. Hydrazinolysis of 3- or 6-(N-phthalylaminoacyl)aminocoumarin derivatives in tetraline gave the corresponding 3- and 6-(aminoacyl)aminocoumarins and the carboxylic acid hydrazides (XLI-LVIII), respectively. 3-(N-Tosyl-L-Val-L-Leu-)aminocoumarin (LIX) was synthesized via the azide method. Twenty four of various substituted 3- and 6-aminoacylcoumarin derivatives were found to possess specific antimicrobial activities towards different microorganisms.     

Synthesis and characterization of novel amino cellulose esters

The homogeneous conversion of cellulose dissolved in N-methyl-2-pyrrolidone/LiCl and 1-N-butyl-3-methylimidazolium chloride with N-methyl-2-pyrrolidone, ε-caprolactam, N-methyl-ε-caprolactam, and N-methyl-2-piperidone in the presence of p-toluenesulphonic acid chloride was studied. Depending on the reaction conditions, novel cellulose esters with degree of substitution (DS) values ranging from 0.12 to 1.17 could be prepared. The structure of the amino group containing cellulose esters was elucidated by elemental analysis, FTIR- and NMR spectroscopy. NMR spectroscopy revealed an almost complete esterification of position 6 of the anhydroglucose unit at DS of 1. The conversion can be conducted between room temperature and 40 °C, while side-reactions became predominant at 60 °C. Starting with DS of 0.24, the samples were soluble both in water and dimethyl sulphoxide. The derivatives described are capable of forming polyelectrolyte complexes. The samples were stable at room temperature in aqueous solution at pH 2 and 7. Lower viscosities were found for samples with higher DS in aqueous solution at comparable molar mass.     

Substituted 2-nitrobenzyltrichloroacetate esters for photodirected oligonucleotide detritylation in solid films

Oligonucleotide microarray fabrication by chemical synthesis using photoacid generators in solid films could have advantages over existing methods, but has not matched the accuracy of conventional synthesis where detritylation is performed with acid solutions. To address this problem, we explored the kinetics and equilibria of nucleoside detritylation in solid films, using trichloroacetic acid (TCA) generated by photolysis from its esters with substituted 2-nitrobenzyl alcohols. We synthesised 25 such esters, all alpha-phenyl substituted, and assessed their potential as solid film photoacid generators. They included sets with (i) mono- or dimethoxy-, (ii) 5-halo-, (iii) alkyl- or aryl-substituted 5-amino-, or (iv) 5-aryl-substituents in the 2-nitro- or 2,6-dinitrobenzyl ring. Absorption maxima of their UV spectra ranged from 230 to 410 nm, with quantum yields at 365 nm from < 0.01 to nearly 1.0. The esters formed optically clear solid films on glass slides without added polymer. Kinetics of intrafilm photoacid generation, proton activity changes and detritylation were measured in situ. The most effective esters for light sensitivity and detritylation were 5-chloro-, 5-bromo-, 4,5-dimethoxy-, and 4- or 5-aryl-substituted 2,6-dinitrobenzyl esters. Photoacid-induced increases in proton activity and detritylation were severely inhibited by polymers containing electronegative heteroatoms, but not by polymers lacking them. In solid films, intrafilm detritylation with photogenerated TCA was fast, but stopped at an equilibrium well short of completion. Both experiment and theory emphasise the inadequacy of attempting to force detritylation with high intrafilm acid activity.     

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.     

Novel cellulose derivatives. IV. Preparation and thermal analysis of waxy esters of cellulose

Cellulose esters with linear aliphatic acyl substituents ranging in size from C₁₂ (lauric acid) to C₂₀ (eicosanoic acid) were prepared in homogeneous solution (DMAc/LiCl) using a novel synthetic method based on the use of a mixed p-toluenesulfonic/carboxylic acid anhydride. The resulting waxy cellulose esters had a high degree of substitution (DS), between 2.8 and 2.9, and showed little degradation. Thermal analysis of these cellulose derivatives by differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis (DMTA) revealed a series of transitions that represented motion by both ester substituents and cellulosic main chain. Broad crystallization and melting transitions attributed to side-chain crystallinity were observed in the range between −19 and +55°C; these side-chain T_m and T_c transition temperatures increased by 10°C per carbon atom of the ester substituent. The T_g of these derivatives increased linearly with increasing substituent size from 94°C for C₁₂ (cellulose laurate) to 134°C for C₂₀ (cellulose eicosanoate). Evidence of “main-chain” crystallization was not observed for these samples, except in the case of peracetylated C₁₂ and C₁₄ esters, which had T_m values of 96°C and 107°C, respectively. © 1996 John Wiley & Sons, Inc.     

Synthesis of 6-halo-5-nitroquinoxalines

The 5-nitro derivatives of 6-haloquinoxalines have been efficiently synthesized by condensation of α-dicarbonyls with 4-bromo- or 4-chloro-3-nitro-1,2-benzenediamines. The novel diamines were readily obtained by reductive cleavage of 5-bromo- and 5-chloro-4-nitro-2,1,3-benzoselenadiazoles. As demonstrated by the synthesis of an imidazo-, a selenadiazolo- and a pyrazinoquinoxaline, the reactive halogen atom ortho to the nitro substituent renders the novel quinoxalines versatile intermediates to further heterocycles.     

Pyrimidine derivatives XII. A convenient preparation of 6-formylpyrimidinedione and 2- and 3-formylpyridine derivatives from corresponding nitrooxymethyl derivatives

The convenient preparation of 6-fomylpyrimidinedione derivatives and 2- and 3-formylpyridine are described. Thus, 5-bromo-1,3-dimethyl- ( 1a ), 5-bromo-3-methyl-1-(2-nitrooxyethyl)- ( 1b ), and 5-bromo-3-methyl-1-(3-nitrooxypropyl)-2,4(1H,3H)-pyrimidine-dione ( 1c ) were converted to the corresponding 6-formyl compounds 2a, 2b , and 2c , respectively, in excellent yields by the reaction with triethylamine and 1,4-diazabicyclo[2.2.2]octane. These 6-formylpyrimidinedione derivatives are key intermediates for the preparation of 6-carbon-carbon substituted compounds, which are expected to be potential antitumor and antiviral agents. Similarly, 2-(and 3-)formylpyridine ( 9a (and 9b )) were obtained by the reaction of 2-(and 3)nitrooxymethylpyridine ( 8a (and 8b )) with 1,4-diazabicyclo[2.2.2]octane.