A convenient method for the stereoselective preparation of 3-hydroxy-2-substituted propionaldehyde derivatives, C-terminal precursors for the synthesis of trans-alkene dipeptide isosteres

Summary (S)-3-hydroxy-2-substituted propionaldehyde dimethyl or diethyl acetals 3, which are versatile synthons in dipeptide isostere synthesis, were synthesized in 54–95% enantiomeric excess by reduction of (S,R)-acetalized acyloxazolidinones 7 with LiAlH₄.     

SYNTHESIS AND BIOLOGICAL ACTIVITIES OF (Z) AND (E) α-ETHENYL ACYCLONUCLEOSIDES

Synthesis of Z and E ethenyl acyclonucleosides (6a-e and 7a-e) via Michael addition of nucleobases with the diethyl acetylenedicarboxylate is described. The structures of compounds have been confirmed by spectral data. New compounds were found to be inactive against DNA and RNA viruses.     

Methods for syntheses of <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="Italic">DL</Emphasis>-aspartic acid derivatives

Summary. A novel practical method for the synthesis of N-methyl-DL-aspartic acid 1 (NMA) and new syntheses for N-methyl-aspartic acid derivatives are described. NMA 1, the natural amino acid was synthesized by Michael addition of methylamine to dimethyl fumarate 5. Fumaric or maleic acid mono-ester and -amide were regioselectively transformed into beta-substituted aspartic acid derivatives. In the cases of maleamic 11a or fumaramic esters 11b, the α-amide derivative 13 was formed, but hydrolysis of the product provided N-methyl-DL-asparagine 9 via base catalyzed ring closure to DL-α-methylamino-succinimide 4, followed by selective ring opening. Efficient methods were developed for the preparation of NMA-α-amide 13 from unprotected NMA via sulphinamide anhydride 15 and aspartic anhydride 3 intermediate products. NMA diamide 16 was prepared from NMA dimethyl ester 6 and methylamino-succinimide 4 by ammonolysis. Temperature-dependent side reactions of methylamino-succinimide 4 led to diazocinone 18, resulted from self-condensation of methylamino-succinimide via nucleophyl ring opening and the subsequent ring-transformation.     

Synthesis of d‐mannitol‐based crown ethers and their application as catalyst in asymmetric phase transfer reactions

A few new d ‐mannitol‐based monoaza‐15‐crown‐5 type chiral lariat ethers and 18‐crown‐6 type macrocycles were synthesized. These crown compounds were used as phase transfer catalysts in asymmetric Michael addititons and in a Darzens condensation under mild conditions to afford the corresponding products in a few cases in good to excellent enantioselectivities. In the Michael addition of diethyl acetoxymalonate to trans‐chalcone, in the addition of diethyl acetamidomalonate to ß‐nitrostyrene, in the reaction of diethyl bromomalonate with benzylidene malononitriles, in the cyclopropanation reaction of diethyl bromomalonate and 2‐benzylidene‐1,3‐indandione, and in the Darzens condensation of α‐chloroacetophenone with benzaldehyde, maximum enantioselectivities of 39%, 65%, 99%, 56%, and 62%, respectively, were obtained in the presence of the d ‐mannitol‐based macrocycles as the catalysts.     

Synthesis of bis-amino acid derivatives by Suzuki cross-coupling,Michael addition and substitution reactions

Several bis-amino acids were prepared using a bis-Suzuki coupling (compounds 4–8, 10), a sequential Michael addition and bis-Suzuki coupling (compounds 12, 13) and a Michael addition followed by a substitution reaction (compounds 18, 19). Thus, the pure stereoisomer of the methyl esters of N-(tert-butoxycarbonyl)-β-bromodehydroaminobutyric acid and dehydrophenylalanine and of N-benzyloxycarbonyl-β-bromodehydroaminobutyric acid were reacted with 1,4-phenylene-bis-boronic acid or 9,9-dioctyl-9H-fluorene-2,7-bis-boronic acid using modified Suzuki coupling conditions. The corresponding bis-dehydroamino acid derivatives were obtained in good to high yields maintaining the stereochemistry of the starting materials. This reaction was also applied successfully to a brominated dehydrodipeptide and 1,4-phenylene-bis-boronic acid showing that it could be used to create cross-links in peptide chains. An N,N-diacyldehydroalanine derivative was used in a sequential Michael addition and bis-Suzuki coupling giving a p-terphenyl bis-amino acid and a fluorenyl bis-amino acid in good yields. Two bis-α,β-diamino acids were obtained by a Michael addition of 1,2,4-triazole to the methyl esters of N-(4-toluenesulfonyl), N-(tert-butoxycarbonyl) dehydroamino acids followed by treatment with ethylenediamine.     

Synthesis of l‐threitol‐based crown ethers and their application as enantioselective phase transfer catalyst in Michael additions

A few new l ‐threitol‐based lariat ethers incorporating a monoaza‐15‐crown‐5 unit were synthesized starting from diethyl l ‐tartrate. These macrocycles were used as phase transfer catalysts in asymmetric Michael addition reactions under mild conditions to afford the adducts in a few cases in good to excellent enantioselectivities. The addition of 2‐nitropropane to trans ‐chalcone, and the reaction of diethyl acetamidomalonate with β‐nitrostyrene resulted in the chiral Michael adducts in good enantioselectivities (90% and 95%, respectively). The substituents of chalcone had a significant impact on the yield and enantioselectivity in the reaction of diethyl acetoxymalonate. The highest enantiomeric excess (ee ) values (99% ee ) were measured in the case of 4‐chloro‐ and 4‐methoxychalcone. The phase transfer catalyzed cyclopropanation reaction of chalcone and benzylidene‐malononitriles using diethyl bromomalonate as the nucleophile (MIRC reaction) was also developed. The corresponding chiral cyclopropane diesters were obtained in moderate to good (up to 99%) enantioselectivities in the presence of the threitol‐based crown ethers.     

Stereoselective Reactions OF 1-(4,6-O-Benzylidene-2,3-Didehydro-2,3-dideoxy-3-nitro-β-D-hexopyranosyl)uracil with some Nucleophiles¶

Abstract

Michael addition of benzylamine, piperidine, morpholine, pyrrolidine, cyclohexylamine, allylamine and dimethylmalonate to the nitroolefin (5) generated in situ from 1-(4,6-O-benzylidene-3-deoxy-3-nitro-β-D-glucopyranosyl)uracil (4b) gave the corresponding 2-(substituted-amino)-3-deoxy-3-nitro-β-D-glucopyranosides (6a-f and 6h). Reaction of 4b with N,N-carbonyldiimidazole directly gave 6g. Compound 4b was converted into the 2-deoxy analogue (8), which was reduced to the 3-amino (9) and 3-hydroxylamino analogue (10).

     

Facile Synthesis of 8, 2′-S-Cyclopurine Nucleoside

Abstract

This paper describes the synthesis of 8,2 -anhydro-8-mercapto-9-(β-D-arabinofuranosyl)purine (8,2′-S-cyclopurinenucleoside, 1) via the shorter route from 3′,5′-di-O-acectyl-8,2′-S-cycloadenosine (6) and by direct reductive deamination with n- pentyl nitrite in tetrahydrofuran (THF) and deacetylation. The preparation of 8,2′-S-cycloadenosine (2) was achieved in good yield by the cyclization of the protected 8-mercaptoadenosine with triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF at room temperature, under Mitsunobu reaction conditions.     

α,β-unsaturated 4-oxo acids in heterocyclic synthesis

3-(1,1-Dioxadibenzothien-4-oyl)acrylic acid (1) was condensed with compounds containing active methylene groups under Michael reaction conditions to furnish the Michael adducts (lactones,2a–c, lactams,3a–c, ketones4a, b). The behavior of these adducts toward the action of hydrazine hydrate were investigated. The compounds were tested for their biological properties. 1st part of this series:Egypt. J. Chem. 42, 309 (1999).     

Gas chromatographic—mass spectrometric determination of plasma 5-fluorouracil after administration of 1-hexylcarbamoyl-5-fluorouracil to dogs and humans

A simple, sensitive and specific method for determining 5-fluorouracil (5-FU) in plasma after the administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) was developed using gas chromatography—mass spectrometry. Thymine was used as the internal standard. After removal of interfering substances with chloroform, diethyl ether and Amberlite XAD-2 resin, 5-FU and thymine were extracted with 16% n-propanol in diethyl ether and methylated with trimethylanilinium hydroxide. Fragment ions at m/e 158 and 154, the molecular ion of the dimethyl derivatives of 5-FU and thymine, respectively, were used to monitor 5-FU and thymine. The sensitivity of the method is 10 ng/ml, which is sufficient to determine the 5-FU levels in plasma after the administration of therapeutic doses of HCFU to patients.     

SYNTHESIS OF PYRAZOLO[4,3-C]PYRIDINE C-RIBONUCLEOSIDES VIA AN EFFECTIVE TETRAZOLE TO PYRAZOLE TRANSFORMATION

Abstract

Methyl 2-[4-methoxycarbonyl-5-(β-D-ribofuranosyl)-1H-pyrazolyl-3]-acetate (7a) obtained from ribofuranosyltetrazole 3 by conjugative addition to dimethyl 1,3-allenedicarboxylate or dimethyl 3-chloro-2-pentenedioate after electrocyclization of 2-propenyltetrazole 5 was used as a suitable intermediate to provide pyrazolo [4,3-c]pyridine C-ribonucleosides 1 and 2 related to 7-substituted 3-deazaxanthosine and -guanosine analogs.     

Ruthenium(III) dimethyl sulfoxide pyridinehydroxamic acid complexes as potential antimetastatic agents: synthesis,characterisation and in vitro pharmacological evaluation

Reaction of 3-pyridinehydroxamic acid and 4-pyridinehydroxamic acid (3-pyha and 4-pyha) with either [NBu₄][RuCl₄(dmso-S)₂] or [(dmso)₂H][RuCl₄(dmso-S)₂] (dmso is dimethyl sulfoxide) in acetone afforded three new ruthenium(III) dimethyl sulfoxide pyridinehydroxamic acid complexes: [NBu₄][trans-RuCl₄(dmso-S)(4-pyha)]·CH₃COCH₃ (1), [3-pyhaH][trans-RuCl₄(dmso-S)(3-pyha)] (2) and [4-pyhaH][trans-RuCl₄(dmso-S)(4-pyha)] (3). The solid-state structure of [NBu₄][trans-RuCl₄(dmso-S)(4-pyha)]·CH₃COCH₃ (1) was determined by X-ray crystallography. 2 and 3 were pharmacologically evaluated for their in vitro cytotoxicity, their ability to inhibit cell invasion and their gelatinase activity. 2 and 3 were devoid of cytotoxicity against the cell lines tested. 2 inhibited invasion of the highly invasive MDA-MB-231 cells to a much greater extent than 3. Contrary to expectations, neither 2 nor 3 had any inhibitory effect on matrix metalloproteinase (MMP) production and/or activity and in fact 3 was found to enhance the production and/or activity of both MMP-2 and MMP-9.     

Induction of Abnormal Cell Division in Euglena gracilis by Glutamic Diethyl Ester*

SYNOPSIS. Glutamic diethyl ester inhibited the growth of Euglena gracilis and induced abnormal cell division. A variety of amino acid esters inhibited growth in both Euglena and Astasia, but only glutamic diethyl ester and, to a lesser extent, glutamic dimethyl ester, interfered with cell division, and only in Euglena. Glutamic acid potentiated the growth inhibitory effect of glutamic diethyl ester but antagonized the formation of aberrant division forms. The mitotic process appeared to proceed normally thru the stages of formation of the reservoir, gullet and flagellum, but cytokinesis stopped during the unwinding process which leads to the separation of the daughter cells, thus leading to the formation of doublets. Doublets could then continue their life cycles, forming triplets or quadruplets and, occasionally, octuplets.     

Photochemical Synthesis of Phosphonopyrimidine and Phosphonopurine Ribonucleosides

Abstract

Photochemical reaction of 2′,3′-di-O- or 2′,3′, 5′-tri-O-protected 5-bromouridine (1), 8-bromoadenosine (4) and 8-bromoguanosine (10) with triethyl phosphite in a mixture of dimethyl formamide (DMF) and acetonitrile, followed by deprotection, provided the corresponding diethyl phosphonate derivatives (3, 7 and 12).     

Synthesis of orthogonally protected l-threo-β-ethoxyasparagine

Orthogonally protected l-threo-β-ethoxyasparagine (Fmoc-EtOAsn(Trt)-OH, 1) was synthesized from diethyl (2S,3S)-2-azido-3-hydroxysuccinate 2 in eight steps as a building block for solid-phase peptide synthesis. The starting material is easily available in multi-gram scale from d-diethyltartrate. The transformation steps reported here are robust and scalable. Thus, a significant amount of 1 (1.8 g) was obtained in 21% overall yield. The synthesis reported is also expected to be useful for the preparation of other O-substituted l-threo-β-hydroxyasparagine derivatives.     

Induced mutation in tomatillo (Physalis ixocarpa Brot.)

To induce mutation in tomatillo (Physalis ixocarpa Brot.) commonly grown for its fruit value, seeds were treated with three alkylating agents (dimethyl sulphate, diethyl sulphate and methyl ethane sulphonate) and gamma rays. Seven viable and five chlorophyll mutant types were screened both from M₁ and M₂ generations. The isolated mutant lines are described and evaluated with reference to their beneficial value.     

Novel Types of N6,2′-Cyclonucleosides

Abstract

Upon oxidation followed by treatment with hydroxylamine, the 3′,5′-diblocked uridine 1 gave the expected oxime 2 together with the N⁶,2′.cyclonucleoside 3 formed by nucleophilic attack of hydroxylamine at both C-6 and C-2′ positions. Reduction of 2 took place predominantly from the α face and the major D-arabino compound obtained gave the cyclonucleosides, 7 via Michael type addition. The structures of the novel cyclonucleosides, particularly their configuration at C-6 were established by X-ray diffraction.     

Stereoselective synthesis of (1-alkoxyalkyl) α- and β-d-glucopyranosiduronates (acetal-glucopyranosiduronates): A new approach to specific cytostatics for the treatment of cancer

The reaction of methyl 2,3,4,6-tetra-O-acetyl-1-O-trimethylsilyl-β- (5) and -α-d-glucopyranuronate (6) severally with the dimethyl or diethyl acetals of formaldehyde, bromoacetaldehyde, propionaldehyde, 3-benzyloxypropionaldehyde, 5-carboxypentanal, and 2-bromohexanal in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate at −78° gave the corresponding (1-alkoxyalkyl) α- and β-glycosides (acetal-glucopyranosiduronates) with retention of configuration at C-1 in yields of 41–91%. Instead of the dialkyl acetals, the corresponding aldehydes and alkyl trimethylsilyl ether can be used. Deacetylation gave the corresponding methyl (acetal-β- and -α-d-glucopyranosid)uronates in good yield. De-esterification of methyl [(1R)-1-methoxybutyl β-d-glucopyranosid]uronate with esterase gave the acetal-β-d-glucopyranosiduronic acid which was an excellent substrate for β-d-glucuronidase.     

Facile Synthesis of 1,2: 5,6-Di-O-cyclohexylidene-d-mannitol and 2,3-O-Cyclohexylidene-d-glyceraldehyde

The reaction of cyclohexanone diethyl acetal with d-mannitol yielded quantitatively 1,2: 5,6-di-O-cyclohexylidene-d-mannitol (1) and its isomer (2). From 1, 2,3-O-cyclohexylidene-d-glyceraldehyde (3) was obtained in a quantitative yield without racemization.     

Characterization of a novel thermostable carboxylesterase from thermoalkaliphilic bacterium Bacillus thermocloaceae

A novel thermostable carboxylesterase (Est5250) of thermoalkaliphilic bacterium Bacillus thermocloaceae was heterologously expressed in Escherichia coli and its biochemical properties were investigated. Est5250 showed optimum esterase activity at 60 °C and pH 8.0. The enzyme was highly thermostable at 60 °C, interestingly, the thermostability was enhanced in the presence of Ca²⁺, retaining more than 60% of its original activity after 12 h of pre-incubation. Est5250 was active in the presence of 1% (v/v) of organic solvents and 0.1% (v/v) of non-ionic detergents. The enzyme activity was significantly enhanced up to 167% and 159% in the presence of 2-mercaptoethanol and dithiothreitol, respectively. Est5250 showed high substrate specificity for short-chain p-nitrophenyl-esters. Kinetic constants, K_m and k_cat, for p-nitrophenyl-acetate were 185.8 μM and 186.6 s^?1, respectively. Est5250 showed outstanding thermostability and tolerance to various organic solvents under thermoalkaliphilic conditions, suggesting that it would be a highly suitable biocatalyst for various biotechnological applications.

Abbreviations: B. thermocloaceae sp.: Bacillus thermocloaceae; E. coli: Escherichia coli; NP: nitrophenyl; DMSO: dimethyl sulfoxide; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; DMF: dimethyl formamide; EGTA: ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid; CTAB: cetrimonium bromide; PMSF: phenylmethylsulfonyl fluoride; DEPC: diethyl pyrocarbonate; 2-ME: 2-mercaptoethanol; DTT: dithiothreitol