O-alkyl Derivatives Research Articles

Computerized optimization of selectivity for direct capillary gas chromatographic multicomponent separations of enantiomers

A computer-assisted procedure was elaborated for optimization of selectivity of two capillary columns coupled in series for direct gas chromatographic multicomponent separations of enantiomers. Two fused-silica capillary columns (column A coated with permethyl-β-cyclodextrin (ChirasilDex) and column B coated with a mixture of heptakis(6- O-tert.-butyl-dimethylsilyl-2,3- O-diacetyl)-β-cyclodextrin and polysiloxane OV-1701 in 1:1 ratio (TBDMSDAC) were coupled in series via a T-piece. Each column was placed in an independently heated oven. Selectivity was tuned by variation of temperatures of the two columns ( T A, T B) and carrier gas pressure in the column coupling point ( p m) under a constant inlet and outlet pressure. The chromatograms were recorded under working conditions ( T A, T B and p m) calculated using the Doehlert experimental design. Optimization procedure was based on mathematical models. A new threshold criterion for optimization of selectivity suitable for multicomponent sample separation was introduced. The elaborated optimization procedure was verified by separating d- and l-enantiomers of N-trifluoroacetyl/ O-alkyl derivatives of alanine, valine, 2-aminobutanoic acid and proline.

Synthesis of 4 H-[1,2,3]triazolo[4,5- c][1,2,5]oxadiazole 5-oxide and its N- and O-alkyl derivatives

The synthetic route to the fused 1,2,3-triazole 2-oxide systems via intramolecular cyclization of N-nitroso and azido groups is described. The title compounds are characterized by 1H, 13C, 14N, 15N and 17O NMR spectroscopy.

Photochemistry in microemulsions: Fluorescence quenching of naphthols and their O-alkyl derivatives by CCl 4

The fluorescence characteristics of 1- and 2-naphthols and their O-alkyl derivatives in presence of carbon tetrachloride have been studied in hexane and in sodium lauryl sulphate (NaLS)-isobutanol-hexane-water microemulsions. The fluorescence quenching of the fluorophore by CCl 4 obeys the linear Stern-Volmer equation in most of the cases except in oil-in-water microemulsion. A quenching sphere of action model has been proposed for the deviation and the number of quenchers present in the quenching sphere of action has been calculated. The dielectric constant of the water-in-oil and oil-in-water microemulsion surface has been evaluated to be 27.36 and 34.31, respectively.

Hydroxoundecahydro-closo-dodecaborate(2-) as a Nucleophile. Preparation and Structural Characterization of O-Alkyl and O-Acyl Derivatives of Hydroxoundecahydro-closo-dodecaborate(2-).

The syntheses, solid state structures, and spectral properties of O-alkyl and O-acyl derivatives of hydroxoundecahydro-closo-dodecaborate(2-), 1, are described. Alkylation of 1 with ethyl iodide was achieved in dimethyl sulfoxide using potassium hydroxide as a base, leading to [N(n-C(4)H(9))(4)](2)[CH(3)CH(2)O-B(12)H(11)(2-)], 2, bis(tetrabutylammonium) ethoxyundecahydro-closo-dodecaborate(2-) [monoclinic P2(1)/n, a = 1192.4(9) pm, b = 1253.9(4) pm, c = 3049.1(10) pm, beta = 92.69(4) degrees, Z = 4, R1 = 0.0693, wR(2) = 0.1517]. Alkylation with 1,5-dibromopentane afforded the cyclic oxonium salt [PPN][C(5)H(10)O-B(12)H(11)(1-)], 3, (&mgr;-nitrido)bis(triphenylphosphorus)(1+) tetrahydropyrane-undecahydro-closo-dodecaborate(1-) [monoclinic P2(1)/c, a = 1938.1(2) pm, b = 1329.7(10) pm, c = 1944.0(2) pm, beta = 108.82(10) degrees, Z = 4, R1 = 0.0484, wR(2) = 0.0833]. Acylation of 1 in acetonitrile with acyl chlorides in the presence of pyridine yielded [N(n-C(4)H(9))(4)](2)[C(6)H(5)CO(2)-B(12)H(11)(2-)], 4, bis(tetrabutylammonium) undecahydrobenzoyl-closo-dodecaborate(2-) [monoclinic P2(1)/c, a = 1812.0(4) pm, b = 1711.9(3) pm, c = 1685.0(3) pm, beta = 114.03(3) degrees, Z = 4, R1 = 0.0915, wR(2) = 0.2093], and [N(n-C(4)H(9))(4)](2)[CH(3)CO(2)-B(12)H(11)(2-)], 5, bis(tetrabutylammonium) acetoxyundecahydro-closo-dodecaborate(2-) [monoclinic P2(1)/n, a = 1190.5(2) pm, b = 1243.0(10) pm, c = 3078.4(4) pm, beta = 92.76(10) degrees, Z = 4, R1 = 0.0642, wR(2) = 0.1462]. All crystal structures showed distortion of the pseudoicosahedral geometry of the boron cluster. The boron-oxygen distances varied from 144.2(5) pm for 2, 148.5(3) pm for 5, 149.4(12) pm for 4, to 152.8(4) pm for 3. The 3-fold coordinated oxygen of oxonium salt 3 is nearly planar.

Synthesis and Antitumor Activities of 5'-O-Aminoacyl-3'-O-benzyl Derivatives of 2'-Deoxy-5-fluorouridine and Related Compounds.

Various O-alkyl derivatives of 2'-deoxy-5-fluorouridine (FUdR) were synthesized and their antitumor activities in mice bearing sarcoma 180 (s.c.-p.o.) were evaluated in terms of the ED50 values (mg/kg/d). Most of these compounds were superior to FUdR in antitumor activity. In particular, the antitumor activity of 3'-O-(p-chloro-benzyl)-FUdR (3e) (ED50 = 0.87 mg/kg/d) was as much as 100 times that of FUdR (ED50 = 84 mg/kg/d). Further, various 5'-O-aminoacyl derivatives of 3e were synthesized and evaluated in terms of ED50 value and therapeutic index (T.I.). Both the ED50 value (0.41 mg/kg/d) and the T.I. (4.18) of 3'-O-(p-chlorobenzyl)-5'-O-glycyl-FUdR hydrochloride (6a) were significantly improved, compared with those of 3e and FUdR. FUdR plasma concentration after a single p.o. dosing of 6a was maintained for as long as 24 h.

Building Blocks for Ribozyme Mimics: Conjugates of Terpyridine and Bipyridine with Nucleosides

The incorporation of the 2,2‘:6‘,2‘‘-terpyridyl (terpy) complex of Cu(II) into a deoxyoligonucleotide has led to a functional mimic of ribozymes. The resulting mimic can cleave target RNA in a sequence-directed manner by a hydrolytic mechanism. Here we describe the synthesis and characterization of four modified nucleoside phosphoramidite reagents (7, 10, 14, and 18) that contain pendant 2,2‘-bipyridine or terpy ligands. The ligands are attached either to the nucleobase (7, 10) or to the sugar (14, 18). Nucleobase modification was carried out at the C-5 position of 2‘-deoxyuridine (dU). One route to sugar modification was performed by synthesis of 18, a 1‘-functionalized analog of dU based on 1-[3-deoxy-β-d-psicofuranosyl]uracil. Another route to sugar functionaliztion resulted in 14, a 2‘-O-alkyl derivative of adenosine. These modified nucleosides are building blocks for ribozyme mimics. They are designed to deliver hydrolytically active metal complexes across either the major groove (7, 10) or the minor groove (14, 18) of an RNA/DNA duplex.

Synthetic substrate analogues for UDP-GlcNAc: Man alpha 1-3R beta 1-2-N-acetylglucosaminyltransferase I. Substrate specificity and inhibitors for the enzyme.

UDP-GlcNAc:Man alpha 1-3R beta 1-2-N-acetylglucosaminyltransferase I (GlcNAc-T I; EC 2.4.1.101) catalyses the conversion of [Man alpha 1-6(Man alpha 1-3)Man alpha 1-6][Man alpha 1-3]Man beta-O-R to [Man alpha 1-6(Man alpha 1-3)Man alpha 1-6] [GlcNAc beta 1-2Man alpha 1-3]Man beta-O-R (R = 1-4GlcNAc beta 1-4GlcNAc- Asn-X) and thereby controls the conversion of oligomannose to complex and hybrid asparagine-linked glycans (N-glycans). GlcNAc-T I also catalyses the conversion of Man alpha 1-6(Man alpha 1-3)Man beta-O-octyl to Man alpha 1-6(GlcNAc beta 1-2Man alpha 1-3)Man beta-O-octyl. We have therefore tested a series of synthetic analogues of Man"alpha 1-6(Man'alpha 1-3)Man beta-O-octyl as substrates and inhibitors for rat liver GlcNAc-T I. The 2"-deoxy and the 3"-, 4"- and 6"-O-methyl derivatives are all good substrates confirming previous observations that the hydroxyl groups of the Man"alpha 1-6 residue do not play major roles in the binding of substrate to enzyme. In contrasts, all four hydroxyl groups on the Man'alpha 1-3 residue are essential since the corresponding deoxy derivatives either do not bind (2'- and 3'-deoxy) or bind very poorly (4'- and 6'-deoxy) to the enzyme. The 2'- and 3'-O-methyl derivatives also do not bind to the enzyme. However, the 4'-O-methyl derivative is a substrate (KM = 2.6 mM) and the 6'-O-methyl compound is a competitive inhibitor (Ki = 0.76 mM). We have therefore synthesized various 4'- and 6'-O-alkyl derivatives, some with reactive groups attached to an O-pentyl spacer, and tested these compounds as reversible and irreversible inhibitors of GlcNAc-T I. The 6'-O-(5-iodoacetamido-pentyl) compound is a specific time dependent inhibitor of the enzyme. Four other 6'-O-alkyl compounds showed competitive inhibition while the remaining compounds showed little or no binding indicating that the electronic properties of the attached O-pentyl groups influence binding.

ChemInform Abstract: Synthesis and Conformational Studies of Calixarene‐Analogous Trihydroxy(3.3.3)metacyclophanes and Their O‐Alkylated Derivatives.

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6-Substituted Derivatives of Carbovir: Anti-HIV Activity

Abstract A series of 6-alkoxy and 6-alkylamino carbovir derivatives were synthesized in order to evaluate prodrug approaches to increased bioavailability of the anti-HIV agent, carbovir. All of the compounds were active against HIV with the N-alkyl derivatives less active than the corresponding O-alkyl derivatives. The adenosine deaminase inhibitor, EHNA, had no effect on the anti-HIV activity of 6-propoxycarbovir, while the adenylic acid deaminase inhibitor, 2′-deoxycoformycin, significantly decreased antiviral activity. These observations suggest that the 6-alkoxycarbovirs are metabolized directly to the monophosphates and are subsequently converted to carbovir monophosphate via adenylic acid deaminase

Regioselectivity of alkylation of cyclomaltoheptaose (β-cyclodextrin) and synthesis of its mono-2- O-methyl, -ethyl, -allyl, and -propyl derivatives

Mono-2- O-methyl-, -2- O-ethyl-, and -2- O-allyl-cyclomaltoheptaose were prepared by alkylations of cyclomaltoheptaose in dilute aqueous alkali, and mono-2- O-propylcyclomaltoheptaose was obtained by hydrogenation of the allyl derivative. All the 2- O-alkyl derivatives were less soluble in water than was cyclomaltoheptaose. All formed inclusion complexes with toluene in aqueous solution, but only the methyl ether was less soluble in the water-toluene system than in water. The solubilities of the other ethers in water were enhanced by the addition of toluene. Partial methylation of cyclomaltoheptaose with 13C-enriched dimethyl sulfate in dilute aqueous alkali yielded mixtures of products. The substitution patterns were analyzed by GLC-MS of the alditol acetates, prepared by hydrolysis, reduction, and acetylation, and by 13C NMR after complete permethylation with nonenriched reagent. The results showed that methylation at O-2 is a predominant but not an exclusive reaction; as expected, the regioselectivity decreases with increasing degree of methylation.

5′-O-Alkyl and Acyl Prodrugs of 1-β-D-Arabinofuranosyl-E-5-(2-Bromovinyl)Uracil

5′- O-Alkyl derivatives of 1-β-D-arabinofuranosyl- E-5-(2-bromovinyl)uracil (BV-araU) were synthesized by selective alkylation and deprotection of 2′,3′-bis- O-tetrahydropyranyl BV-araU to enhance metabolic stability and evaluated for efficacy as oral prodrugs of BV-araU. For comparison, their acyl congeners, and 3′- O- and 2′- O-ethyl BV-araU, were also prepared by direct acylation of BV-araU and by selective protection, alkylation, and deprotection, respectively. The 5′- O-alkyl prodrugs were stable in acidic solutions, whereas the 5′- O-acyl analogues were unstable under the same conditions. When incubated with enterobacteria, the 5′- O-acyl derivatives resulted in the formation of BV-uracil through non-enzymatic hydrolysis of BV-araU, but the 5′- O-alkyl prodrugs did not. 5′- O-Short-chain aliphatic alkyl (not longer than butyl) and generally acyl prodrugs gave higher blood concentrations of BV-araU than the aromatic derivatives. Plasma concentrations of BV-araU were equal or slightly higher than those after equivalent oral doses of BV-araU. 5′- O-Ethyl BV-araU was effective against intracerebral, intraperitoneal, and cutaneous infections with herpes simplex virus type 1 in mice. 5′- O-Short-chain aliphatic alkyl derivatives may prove to be useful oral prodrugs of BV-araU because of increased metabolic stability.

News on Inositol Liquid Crystals1

Abstract A greater number of selected, partially O-alkylated derivatives of three (myo-, scyllo-, and chiro-) inositols, stereoisomers of 1,2,3,4,5,6-hexahydroxycyclohexane, as well as of hexahydroxybenzene and tetrahydroxy-l,4-benzoquinone were synthesized and characterized by usual methods. From the study of the various liquid crystalline target compounds (long-chained alkyl ethers) by polarizing microscopy and differential scanning calorimetry it emerges that the occurrence, type, and stability of their meso-phases are clearly determined by the number, the position, and the stereochemical arrangement of both the hydroxyl groups and the alkoxy chains on the cyclohexane ring which is discussed in detail. Here, unsaturated six-membered ring units—for example quinoic or aromatic in character—as carriers of the numerous hydroxyl functions have been proved damaging to the exhibition of mesophases; our mul-tihydroxy model compounds of this type have not been found liquid crystalline. In general, it was found ...

Synthesis of Ellagic Acid O-Alkyl Derivatives and Isolation of Ellagic Acid as a Tetrahexanoyl Derivative from Fragaria ananassa

Ellagic acid [1] is a gallic acid dimer that occurs in plants, fruits, and nuts, either in its free form, or in a series of ellagitannins, or as a glucoside. It has been shown to inhibit cancer induced by several types of chemical carcinogens including polycyclic aromatic hydrocarbons, N-nitrosamines, aflatoxin, and aromatic amines. It has been extracted from a number of fruits, including strawberries; however, its presence in the extracts was determined only by hplc connected with a diode array detector. In the present report, ellagic acid was isolated as a tetrahexanoyl derivative 2 from Fragaria ananassa and identified by 13C and 1H nmr and ms. The 13C-nmr shifts of the aromatic carbons adjacent to a hexanoyloxy group were assigned using two new synthetic model compounds: 3,3'-dihexanoyloxydiphenic-2,2',6,6'-dilactone [3] and 4,4'-dihexanoyloxydiphenic-2,2',6,6'-dilactone [4]. Two new derivatives of ellagic acid [1],3,3'-di-beta-D-glucopyranosylellagic acid decaacetate [5] and 3,3'-di-n-octyl-4,4'-dihexanoylellagic acid [7], were also synthesized. Both derivatives were less effective as inhibitors of benzo[a]pyrene tumorigenesis in the lungs of strain A/J mice than ellagic acid.

Studies on the Alkylation of 5′-CMP under Alkaline Conditions

The reaction of 5′-CMP with methyl, ethyl, n-propyl and isopropyl iodides gave predominantly ribose alkylated products. Various alkylated derivatives have been characterized using UV spectroscopy, paper electrophoresis, 1H NMR and FAB (negative) mass spectroscopic techniques. Under strongly alkaline conditions the 2′-O-alkylated derivatives are synthesized in maximal yields. Isopropylation reaction gave only a small yield of the 3′-O-isopropyl derivative, this could be explained on the basis of steric hindrance offered to the bulky isopropyl group at the 2′-OH position by the heterocyclic base of the nucleotide.

クラリスロマイシンの開発研究

A series of O-alkylated derivatives of erythromycin (EM) has been prepared and their biological properties were evaluated. Among them, clarithromycin (CAM, 6-O-methylerythromycin) exhibits most potent in vitro and in vivo antibacterial activities, higher acid-stability than EM and favorable pharmacokinetic properties as an antibiotic. CAM was originally synthesized via methylation of 2'-O,3'-N-bis(benzyl-oxycarbonyl)-N-demethylerythromycin in low yield, because of the less selectivity of 6-O-methylation. The selective 6-O-methylation was achieved using the erythromycin 9-oxime derivative as a key intermediate. By the further investigation on the protective groups of 9-oxime and desosamine moiety, the production process of CAM on an industrial scale has been established via methylation of 2',4''-O-bis(trimethylsilyl)erythromycin 9-[O-(1-isopropoxycyclohexyl)oxime] in more than 45% overall yield. CAM has the same antibacterial spectra as EM and is active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, Mycoplasma and Chlamydia. The activity of CAM against clinical isolates was 1 to 16 times higher than that of EM. The efficacies of CAM were 6 to 15 times superior to those of EM against systemic infections due to Gram-positive bacteria in mice. CAM also showed more potent therapeutic efficacies than EM against respiratory tract infections caused by S. pneumoniae and H. influenzae. CAM was well absorbed after oral administration, and its distribution to various tissues was significantly higher than that of EM in animals. The level of CAM in the lung was extremely high, which accounted 69 times that of EM. CAM was found to be distributed predominantly in the alveolar wall, especially in the alveolar epithelial cells, by microautoradiography. After oral administration in human, the serum level and urinary excretion of CAM were 5 and 20 times higher than those of EM, respectively. The major and active metabolite of CAM in human, (14R)-14-hydroxyclarithromycin, existed in significant quantity in the serum and urine, suggesting that the metabolite contributes to the excellent clinical efficacy of CAM. This paper describes the synthesis, structure-activity relationships, antibacterial activities, metabolism and clinical efficacies of CAM, a new macrolide antibiotic.

Differentiation of substituent effects from hydrogen bonding and protonation effects in carbon-13 NMR spectra of pyridine N-oxides

Aromatic 13C chemical shifts are reported for 4-substituted and 3-substituted pyridine N-oxides measured in deuteriochloroform, deuterium oxide, perchloric acid (60% in D2O) and dichloroacetic acid (80% in CDCl3), and also for O-alkylated derivatives in (CD3)SO and D2O. The substituent chemical shift (SCS) data show systematic non-additivity in comparison with monosubstituted benzenes. Data for the position para to the variable substituent were analysed by means of the dual substituent parameter equation. For this position multiple substituent interactions are responsible for the non-additive shifts; interactions have both an inductive (polar) and a resonance component. Hydrogen bonding and protonation effects were differentiated from the substituent effect. It is shown that the relative 13C chemical-shift difference [(Δ3–Δ4)/Δ3] is a measure of the hydrogen bond and protonation effects and is not subject to substituent effects. 3-Dimethylaminopyridine N-oxide is protonated at the dimethylamino group, but 4-dimethylaminopyridine N-oxide at the oxygen.

Chemical modification of erythromycins. II. Synthesis and antibacterial activity of O-alkyl derivatives of erythromycin A.

A series of O-alkyl erythromycin A derivatives have been synthesized and their antibacterial activities compared with those of erythromycin A (1) and 6-O-methylerythromycin A (3). Methylation of the hydroxyl groups of erythromycin A analogue proceeded stepwise by the two main pathways beginning at the C-6 and C-11 positions, individually. O-Alkylation, other than methylation, took place at the C-11 hydroxyl group exclusively. Among O-alkyl derivatives, 6,12-di-O-methylerythromycin A (5) showed comparable in vitro antibacterial activity to those of 1 and 3. 11-O-Methylerythromycin A (8) was slightly less active than 1. O-Methylation at the C-4" position resulted in a decrease of antibacterial activity.

A new procedure for the preparation of 3′- o-alkyl derivatives of 2′-deoxyribonucleosides

2′-Deoxy-2′-mercaptouridine ( 7 ) has been converted, via its 2′- S, 3′- O-alkylidene derivatives ( 8 ), into the corresponding 3′- O-alky1-2′-deoxyuridines ( 9 ).

Alkylation of cyclomalto-oligosaccharides (cyclodextrins) with dialkyl sulfate-barium hydroxide: Heterogeneity of products and the marked effect of the size of the macrocycle

The alkylation of cyclomalto-oligosaccharides (cyclodextrins, CDs) with dialkyl sulfate-barium hydroxide has been claimed to yield 2,6-di- O-alkyl derivatives. Re-investigation by plasma desorption-m.s. of the products of laboratory methylation of αCD, βCD, or γCD and ethylation of βCD and several commercial preparations revealed them to be mixtures with broad and roughly symmetrical distributions of the degree of substitution. Recrystallization separated the components only partially. Analysis of the product of methylation of a mixture of CDs established the order of reactivity γ ⪢ α ⩾ β. The reactivity of γCD thus resembles that of amylose.

Mass spectral analysis of phenprocoumon andO-alkyl phenprocoumons

Electron impact mass spectra of the oral coumarin anticoagulant phenprocoumon and its 4-O-alkyl and 2-O-alkyl (methyl and ethyl) derivatives (including deuterium and 13C-labelled compounds) have been analysed using accurate mass measurements and B/E and B2/E constant linked-scan techniques; fragmentation routes have been proposed which are different from those for simple coumarins and other oral coumarin anticoagulants. All compounds showed an ethyl group migration from the phenylpropyl side chain to the coumarin ring; the O-alkyl derivatives presented additionally a rearrangement with bond formation between a C atom of the O-alkyl group and the phenyl ring of the side chain. Previous literature reports about fragment ion structures for methylated phenprocoumon have been revised.