Synthesis of 1-beta-O-acyl glucuronides of diclofenac, mefenamic acid and (S)-naproxen by the chemo-selective enzymatic removal of protecting groups from the corresponding methyl acetyl derivatives

Using a straightforward chemo-enzymatic procedure, 1-beta-O-acyl glucuronides of three non-steroidal anti-inflammatory drugs, diclofenac (DF) 5, mefenamic acid (MF) 6 and (S)-naproxen (NP) 7, were prepared. Caesium salts of these carboxylic acid drugs reacted with commercially available methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate 4 to give exclusively the corresponding 1-beta-O-acyl glucuronides 8-10 in moderate yields. The protecting acetyl (for -OH group) and methyl ester (for -CO2H group) groups of each sugar moiety were easily removed to provide the corresponding free 1-beta-O-acyl glucuronides 1-3 in high yields. Deprotection was achieved through effective enzyme-catalysed chemo-selective hydrolyses of the acetyl groups using lipase AS Amano (LAS), and of the methyl ester group using esterase from porcine liver (PLE).     

Electrocatalytic haloform reaction - conversion of methyl ketones to methyl esters of carboxylic acids

An electrocatalytic haloform reaction is accomplished. Methyl ketones are converted to the corresponding carboxylic acid methyl esters in a diaphragmless electrolyzer in methanol in the presence of catalytic quantities of NaBr. The methyl ester of 3-phenylpropanoic acid is formed from benzyl methyl ketone under these conditions via electrochemically induced Favorskii rearrangement.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 122–126, January, 1991.     

Phosphonic-Acid Analogues of the N-Acetyl-2-deoxyneiiraniinic Acids: Synthesis and Inhibition of Vibrio cholerae Sialidase

The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N-acetyl-2-deoxyneuraminic acids 5 and 6 . Thus, hydrogenation and benzylation of methyl N-acetyl-2,3-didehydro-2-deoxyneuraminate (1MeNeu2en5Ac; 7) gave a mixture of the fully O-benzylated benzyl and methyl esters 9 and 10 , the partially O-benzylated benzyl and methyl esters 11 and 12 , and the fully O-and N-benzylated benzyl and methyl esters 13 and 14 (Scheme 1). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15 . Oxidative decarboxylation of 15 with Pb(OAc)₄ gave a 1:9 mixture of the α-and β-D-glycero-D-galacto-acetates 16 and 17 . Phosphonoylation of 17 with P(OMe)₃ and Me₃SiOTf gave a 1.3:1 mixture of the phosphonates 18 and 19 , which were deprotected to give the (4-acetamido-2,4-dideoxy-D-glycero-α-and β-D-galacto-octopyranosyl)phosphonic acids 3 and 4 , respectively. The acid 6 was obtained by epimerization of the tert-butyl ester 23 with lithium N-cyclohexylisoproylamide and deprotection. The phosphonic acids 3 (K_i 5.5 10_-5 M) and 4 (K_i 2.3.10^?4 M ) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N-acetyl-2-deoxyneuraminic acids 5 (K_i 2.3 10^?3 M ) and 6 . Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carboxylic acid 5 , possessing an equatorial COOH group is an inhibitor.     

Chemoenzymatic Synthesis of (R)- and (S)-4-Amino-3-Methylbutanoic Acids

(R)- and (S)-4-Amino-3-methylbutanoic acids were synthesized in high yields via initial enantioselective hydrolysis of dimethyl 3-methylglutarate to methyl (R)-3-methylglutarate with pig liver esterase. The ester group was converted to an amine to give (R)-4-amino-3-methylbutanoic acid; the carboxylic acid was converted to an amine to give (S)-4-amino-3-methylbutanoic acid.     

Determination of N-acetyl-S-(N-alkylthiocarbamoyl)-L-cysteine, a principal metabolite of alkyl isothiocyanates, in rat urine

A simple and rapid analytical procedure is described for N-acetyl-S-(N-alkylthiocarbamoyl)-L-cysteine (alkyl = benzyl, allyl, methyl, ethyl or n-butyl), a mercapturic acid with an unstable dithiocarbamic acid ester structure, which is found in rat urine as the principal metabolite of the corresponding alkyl isothiocyanate. Because such mercapturic acids decompose at pH values greater than 5 to N-acetylcysteine and alkyl isothiocyanate, the free isothiocyanate is converted with n-butylamine into the corresponding disubstituted thiourea, and, after extraction, measured by high-performance liquid chromatography using an ultraviolet detector. The recovery is ca. 100% and the precision is very good. The lower limit of detection is ca. 0.5 microgram of thiourea. The 24-h renal excretion of these mercapturic acids was determined in rats after administration of benzyl, allyl, methyl, ethyl or n-butyl isothiocyanate.     

Decarboxylative elimination of enol triflates as a general synthesis of acetylenes

The enol trifluoromethanesulfonates 4, 8, 12, 17 and 20 of tert-butyl beta-ketodiesters and beta-ketoesters can be hydrolysed to the corresponding carboxylic acids by dissolution in trifluoroacetic acid. The dicarboxylic acids undergo mild decarboxylative elimination to give the acetylenic acids 4 and 9 in aqueous sodium bicarbonate solution at room temperature. Similarly, the monocarboxylic acids give the terminal and mid-chain acetylenes 13, 18, 21, and 24 by refluxing in acetone with potassium carbonate. One of the substituents on the acetylenes can be methyl, primary alkyl, secondary alkyl or ethynyl, and the other can be a carboxylic acid, hydrogen or primary alkyl, but the enol trifluoromethanesulfonates could not be prepared when one of the substituents was tert-butyl, nor when both substituents on the precursor to the acetylene were secondary alkyl.     

Simultaneous gas chromatographic determination of aliphatic C2−C20 n-carboxylic acids and their methyl esters using SE-30 and OV-351 quartz capillary columns

Summary Simultaneous determination of aliphatic C₂–C₂₀ carboxylic acids and their methyl esters was carried out using SE-30 and OV-351 quartz capillary columns with temperature programming. Complete resolution of all 36 components was achieved. On SE-30 the methyl ester and the corresponding free acid are eluted in turn, whereas on OV-351 acetic acid eluted after methyl octanoate, after which the C_n methyl ester and C_n-6 carboxylic acid (n>9) are eluted one after the other. A non-polar SE-30 column is better for long-chain acids giving sharp peaks without tailing, the analysis time of the mixture being less than 16 minutes. The weight response correction factors for compounds under optimum operating conditions are given.     

（R）—N—乙酰四氢噻唑—2—硫酮—4—羧酸与醇的反应

（Ｒ）－Ｎ－乙酰四氢噻唑－２－硫酮－４－羧酸与醇反应，在ＳＯＣｌ２存在下得到乙酸酯及四氢噻唑－２－硫酮－４－羧酸酯；在碳酸钾存在下得到乙酸酯及四氢噻唑－２－硫酮－４－羧酸；在二环己基碳二亚胺（ＤＣＣ）存在下得到缩水产物Ｎ－乙酰四氢噻唑－２－硫酮－４－羧酸酯。     

Electrocarboxylation of benzyl halides through redox catalysis on the preparative scale

The electrocarboxylation of benzyl halides to the corresponding carboxylic acids through homogeneous charge-transfer catalysis was investigated both theoretically and experimentally to determine the influence of the operative parameters on the yield of the process and on the catalyst consumption. Theoretical considerations, based on fast kinetics of redox catalysis, were confirmed by the electrocarboxylation of 1-phenyl-1-chloroethane catalyzed by 1,3-benzenedicarboxylic acid dimethyl ester performed at a carbon cathode under different operative conditions. We obtained high yields of the target carboxylic acid and experienced a low catalyst consumption by operating with optimized [RX]bulk/[CO2]bulk and [RX]bulk/[catalyst] ratios.     

Aerobic oxidation under visible light irradiation of a fluorescent lamp with a combination of carbon tetrabromide and triphenyl phosphine

A combination of CBr₄–Ph₃P, a non-metal method, enables us to carry out aerobic photo-oxidation of alcohols and aromatic methyl groups to the corresponding carboxylic acids under irradiation of vis from a general-purpose fluorescent lamp. Aliphatic primary- and secondary alcohols, benzyl alcohols, and methyl groups at the aromatic nucleus generally afforded the carboxylic acids directly in good to high yield.     

Simultaneous determination of C2-C22 non-esterified fatty acids and other metabolically relevant carboxylic acids in biological material by gas chromatography of their benzyl esters

A method for the simultaneous determination of non-esterified short-, medium- and long-chain fatty acids and other types of metabolically relevant carboxylic acids such as hydroxy, keto, aromatic and dicarboxylic acids in biological material by capillary gas chromatography of benzyl ester derivatives is described. Sample preparation avoiding incomplete isolation of carboxylic acids consisted of deproteinization and extraction with ethanol, fixation of carboxylic acids as carboxylates, removal of interfering compounds such as neutral lipids by hexane extraction and amino acids, acyl carnitines and other cations by cation-exchange chromatography, derivatization of keto groups of ketocarboxylic acids into O-methyl oximes and benzyl ester formation by reaction of the potassium carboxylates with benzyl bromide via crown ether catalysis. The sample preparation conditions were investigated, showing the usefulness of this method for quantitative determinations. Chromatograms obtained from human serum, human urine and rat heart ventricle and concentrations of carboxylic acids in these specimens are presented.     

Solid-phase synthesis of 1-substituted tetrahydroisoquinoline derivatives employing BOC-protected tetrahydroisoquinoline carboxylic acids

Compounds containing the tetrahydroisoquinoline ring system were prepared using solid-supported ester derivatives on a nucleophile-sensitive resin, starting from the corresponding BOC-protected amino acids. The key heterocyclic intermediates were obtained from the Pictet-Spengler reaction between ethyl glyoxylate or methyl 4-formylbenzoate and dopamine or 3-hydroxyphenethylamine. After the resulting amino esters were converted to the BOC derivatives, the phenolic hydroxyl groups were alkylated with a series of alkyl halides to afford the corresponding ethers. Ester hydrolysis afforded the BOC-protected tetrahydroisoquinoline carboxylic acid scaffolds, which were then attached to (4-hydroxyphenyl)sulfide resin (Marshall linker) as the corresponding ester. The BOC group was removed under acidic conditions, and the resulting support-bound amine hydrochlorides were converted to the corresponding amides using a set of carboxylic acids. The support-bound amides were liberated with amines to produce the desired tetrahydroisoquinoline carboxamides. Optimization of the resin loading conditions is described in addition to the identification of impurities observed during the development of the optimum conditions for solid-phase synthesis.     

Syntheses of (-)-Isocitric Acid Lactone and (-)-Homoisocitric Acid. A New Method of Conversion of Alkynylsilanes into the Alkynyl Thioether and Corresponding Carboxylic Acids

A simple, stereoselective synthesis of natural isocitric and homoisocitric acids from a common alkynylsilane correlates the stereochemistry of these acids. Starting with dimethyl D-malate dianion, methyl 2-hydroxy-3-carbomethoxy-6-(trimethylsilyl)-5-hexynoate (6a) was prepared with a good stereoselectivity (threo/erythro 90/10). Oxidative cleavage of the triple bond provided isocitric acid lactone (8') in 15% overall yield starting from D-malic acid diester 1. The synthesis of homoisocitric acid relied on a new method of conversion of alkynylsilane to alkynyl thioether, which is converted to the carboxylic acid of the same chain length. Addition of benzenesulfenyl chloride to (trimethylsilyl)alkyne 6b and elimination of trimethylsilyl chloride gave the corresponding thioether 10, which by acid hydrolysis gave homoisocitric acid (11) in a 24% yield from D-malic acid ester. This novel method of conversion of alkynylsilane to the corresponding acid was illustrated with several other alkynyltrimethylsilanes.     

Enantiomeric separation of enzymatic hydrolysis products of dihydropyrimidinone methyl ester with cationic cyclodextrin by capillary electrophoresis

The achiral separation of dihydropyrimidinone (DHP) methyl ester and its corresponding carboxylic acid and the chiral separation of their respective enantiomers were achieved in a single analysis using capillary electrophoresis (CE) with quaternary ammonium-beta-cyclodextrin (QA-beta-CD) as a chiral buffer additive. Separation of the DHP methyl ester from the corresponding carboxylic acid was achieved because the acid was negatively charged at pH 8.3 of the running buffer and the ester is neutral. Upon the addition of QA-beta-CD, the enantiomers of the acid and ester were well resolved before and after the electroosmotic flow, respectively. In addition, the minor DHP methyl ester enantiomer (R isomer) was well separated from several impurities. This CE system was used to monitor the progress of a bioresolution reaction that utilizes an enzyme to convert the R isomer of the ester to its corresponding acid. The quantities of all four enantiomers can be determined using a single set of CE conditions. In addition, it is demonstrated that samples can be directly injected into the capillary without sample pretreatment due to the fact that the coating of the cationic CD on the capillary surface prevents adsorption of the positively charged enzyme. The effects of other experimental parameters such as type of CDs, concentration of CDs, pH, temperature, and the preconditioning of capillary were also studied.     

Mild, efficient and selective hydrolysis of polymer-supported methyl esters using trimethyltin hydroxide

An efficient and selective procedure for a rapid access to polymer-supported carboxylic acids from their corresponding methyl esters using trimethyltin hydroxide is described. Silyl and benzyl ether, and Rink amide linkers are stable to the reaction conditions.     

An Easy Access to Construct Some Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H )‐one ( 1 ) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4 , 5 , 6 , which incorporating 1,2,4‐triazine nucleus was achieved. Moreover, compound 1 was subjected to react either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3 , or thiadiazine 7 . However, the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1 . In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.     

An Easy Access to Construct Some New Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H )‐one ( 1 ) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4 , 5 , 6 , which incorporating 1,2,4‐triazine moiety was achieved. Moreover, compound 1 was subjected to reaction either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3 or thiadiazine 7 . However, while the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1 . In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.     

A facile one-pot benzylation of sodium enolates using trifluoromethanesulfonic anhydride and diphenyl sulfoxide

A facile one-pot C-benzylation of various sodium enolates derived from methyl malonate, beta-ketoesters, a beta-cyanoester, a beta-cyanosulfone, ketones and a carboxylic ester is reported. Reaction of alkoxydiphenylsulfonium salts formed by treating various benzyl alcohols with diphenyl sulfide bis(trifluoromethanesulfonate) (derived from trifluoromethanesulfonic anhydride and diphenyl sulfoxide) proceeded smoothly, and the corresponding C-benzylated products were afforded in good to high yields.     

An improved chemo-enzymatic synthesis of 1-beta-O-acyl glucuronides: highly chemoselective enzymatic removal of protecting groups from corresponding methyl acetyl derivatives

An improved and widely applicable chemo-enzymatic method for the synthesis of a series of 1-beta-O-acyl glucuronides 5a-f has been developed from the corresponding methyl acetyl derivatives 3a-f, which were stereospecifically synthesized from cesium salts of carboxylic acids 1a-f and methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate (2). Chemoselectivity of lipase AS Amano (LAS) in the hydrolytic removal of O-acetyl groups of 3a-f to provide methyl esters 4a-f was influenced by the nature of their 1-beta-O-acyl groups; high selectivity was evident only for 3b and 3f. Carboxylesterase from Streptomyces rochei (CSR), newly screened as an alternative to LAS, showed much greater chemoselectivity toward the O-acetyl groups than LAS; 3a, 3d, and 3e were chemoselectively hydrolyzed only by CSR. The combination of CSR with LAS yielded better results in the hydrolysis of 3c and 3f than did single usage of CSR. Final deprotection of the methyl ester groups of 4a-f to provide 5a-f was chemoselectively achieved by using lipase from Candida antarctica type B (CAL-B) as well as esterase from porcine liver (PLE), although CAL-B possessed higher chemoselectivity and catalytic efficiency than did PLE. CSR also exhibited high chemoselectivity in the synthesis of (S)-naproxen 1-beta-O-acyl glucopyranoside (7) from its 2,3,4,6-tetra-O-acetyl derivative 6.     

Thermal decomposition of a sulfoximide in the presence of a carboxylic acid; an interesting rearrangement

5-Hexyl-7-(S-methylsulfonimidoyl)xanthone-2-carboxylic acid 1a , when heated above its melting point gives a number of products including the corresponding methyl ester 1b , which arises by a novel methyl group transfer. A similar methyl transfer reaction is observed when the sulfoximide and carboxylic acid groups are present in different molecules.