Synthesis of (±)-Muscone from Ethyl 6-Methyl-8-oxopentadecanedioate

(±)-Muscone (3-methylcyclopentadecanone) (8) was synthesized from ethyl 6-methyl-8-oxopentadecanedioate (1) in a 31.9% over-all yield. Ethylene ketal (2) of 1 was cyclized to the acyloin mixture (3) by the acyloin condensation. Reduction of 3 gave 9,9-ethylenedioxy-7-methylcyclopentadecane-1,2-diol (4) which afforded 1,2-ditosyloxy derivative (5). By detosylation according to the Tipson-Cohen procedure, 5 was converted to 9,9-ethylenedioxy-7-methylcyclopentadec-1-ene (6) which was hydrogenated to 8.     

Nucleosides Having Quinolone Derivatives as Nitrogenated Base: Regiospecific and Stereospecific Ribosylation of 3-Carbethoxy-1,4-dihydro-4-oxoquinolines

Abstract

Ribosylation reactions of previously silylated 3-carbethoxy-8-methyl-1,4-dihydro-4-oxoquinoline (6a) and 3-carbethoxy-6-methyl-1,4-dihydro-4-oxoquinoline (6b) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (7), under Lewis acid catalysis, were studied. The method using hexamethyldisilazane (HMDS)/trimethylchlorosilane (TMCS) mixture for silylation and anhydrous stannic chloride as catalyst for ribosylation failed to give any nucleoside product. On the other hand, the protected nucleoside 3-carbethoxy-6-methyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,4-dihydro-4-oxoquinoline (8b) was obtained in good yields using bis(trimethylsilyl)trifluoroacetamide (BSTFA) containing 1% of TMCS and the same catalyst. Compound 8b was more easily isolated in higher yields with an improvement of the later method by replacing stannic chloride with trimethylsilyl trifluoromethanesulfonate (TMSOTf).

De-O-benzoylation of 8b with methanolic sodium hydroxide solution afforded the free riboside 3-carbomethoxy-6-methyl-1-β-D-ribofuranosyl-1,4-dihydro-4-oxoquinoline (9b). The structures of the obtained products were confirmed by their LTV, MS, IR, ¹H and ¹³C-NMR data.     

Synthesis of 2-Hydroxy-3-p-tolyl-2-cyclopentenone and Its Application to Isolaurene

2-Hydroxy-3-p-tolyl-2-cyclopentenone (7), a potential starting material for synthesis of isolaurene (1), was prepared by photolysis of 2-p-toluenesulfonyloxy-2-cyclopentenone (6). Conversion of 7 into 2,5-dimethyl-2-p-tolyl-cyclopentanone (14) was carried out as follows. Methylation of 7 with methyl iodide gave 2-methoxy-3-p-tolyl-2-cyclopentanone (9), and the treatment of (9) with methyl magnesium iodide afforded 2-methyl-5-p-tolyl-2-cyclopentenone (11). This compound was allowed to react with methyl iodide in the presence of sodium methoxide to yield 2,5-dimethyl-2-p-tolyI-4-cyclopentenone (13), the hydrogenation of which over palladium charcoal gave 14.     

Synthesis and in vitro antimicrobial activities of 2-hydroxy-6-methyl-7-(arylamino)-1,7-dihydropurin-8-ones

A number of 2-hydroxy-6-methyl-7-(arylamino)-1,7-dihydropurin-8-ones have been synthesized. 3-Oxo-2-(arylhydrazono)butyric acid ethyl ester were acetylated and treated with triethyl amine and formamide in presence of 1,4-dioxane to yield N-(5-acetyl-4-ethoxy-2-oxo-2,5-dihydro-imidazol-1-yl)-N-arylacetamide, which on refluxation with urea and freshly prepared sodium ethoxide yielded the title compound. All the newly synthesized compounds have been characterized by spectroscopic and elemental analysis data. The synthesized compounds were screened against a representative panel of susceptible and resistant Gram-positive and Gram-negative bacteria using a standard antibiotic drug purinthol as control. Quantitative structure-activity relationship has also been interpreted in terms of correlation of biological activity with molecular refractive index parameters (M(R)) and Hammett substituent constant (sigma).     

An Efficient Synthesis Of Acyclic N7- and N9-Adenine Nucleosides Via Alkylation With Secondary Carbon Electrophiles to Introduce Versatile Functional Groups At the C-1 Position of Acyclic Moiety

The introduction of versatile functional groups, allyl and ester, at the C-1 position of the acyclic chain in acyclic adenine nucleosides was achieved for the first time directly by alkylation of adenine and N⁶-protected adenine. Thus, the C-1′-substituted N⁹-adenine acyclic nucleoside, adenine-9-yl-pent-4-enoic acid ethyl ester (11), was prepared by direct alkylation of adenine with 2-bromopent-4-enoic acid ethyl ester (6), while the corresponding N⁷-regioisomer, 2-[6, (dimethylaminomethyleneamino)-purin-7-yl]-pent-4-enoic acid ethyl ester (10), was obtained in one step by the coupling of N,N-dimethyl-N′- (9H-purin-6-yl)-formamidine (9) with 2-bromopent-4-enoic acid ethyl ester (6). The functional groups, ester and allyl, were converted to the desired hydroxymethyl and hydroxyethyl groups, and subsequently to phosphonomethyl derivatives and corresponding pyrophosphorylphosphonates.     

Inhibitory effect of the compounds from the water extract of Curcuma longa on the production of PGE2 and NO in a macrophage cell line stimulated by LPS

ABSTRACT

We wished to search for the compounds contributing to the anti-inflammatory effects of the water extract of Curcuma longa (WEC). WEC was fractioned and the fractions were evaluated with regard to their inhibitory effect on the production of nitric oxide (NO) from the macrophage cell line stimulated by lipopolysaccharide. Compounds in the active fractions were isolated and identified. One isolated compound was identified as new: (6S)-2-methyl-5-hydroxy-6-(3-hydroxy-4-methylphenyl)-2-heptene-4-one (1). Four isolated compounds were identified as known: (6S)-2-methyl-6-(4-hydroxyphenyl)-2-heptene-4-one (4), bisabolone-4-one (5), curcumenone (6), and turmeronol A (8). Three isolated compounds were not identified their stereostructures but their planar structures: 2-methyl-6-(4-hydroxymethyl-phenyl)-2-heptene-4-one (2), 2-methyl-6-(2,3-epoxy-4-methyl-4-cyclohexene)-2-heptene (3), and 4-methylene-5-hydroxybisabola-2,10-diene-9-one (7). Compounds 1, 4, 7 and 8 inhibited production of prostaglandin E2 and NO. Others inhibited NO production only. These results (at least in part) show the active compounds contributing to the anti-inflammatory effects of WEC, and may be useful for elucidating its various beneficial physiologic effects.     

Synthesis and antidiabetic activity of some new chromonyl-2,4-thiazolidinediones

A series of chromonyl-2,4-thiazolidinediones/imidazolidinediones/2-thioxo-imidazolidine-4-ones (IIIa–i, IVa–i) was prepared by Knoevenagel reaction of 2,4-thiazolidinedione/2,4-imidazolidinedione/2-thioxo-imidazolidine-4-one (IIa–c) with 2/3-formyl chromone (Ia–b) and then alkylation with methyl/ethyl iodide. The prepared compounds were tested for their insulinotropic activities in INS-1 cells. Compounds ?Vb and ?Vc (at lower concentration, 1?μg/mL) were able to increase insulin release in the presence of 5.6?mmol/L glucose.” should be written as “Compounds IVb and IVc (at lower concentration, 1?µg/mL) and also IIId and IIIg (at higher concentration) were able to increase insulin release in the presence of 5.6?mmol/L glucose. Compounds ?Vb and ?Vc (at lower concentration, 1?μg/mL) were able to increase insulin release in the presence of 5.6?mmol/L glucose.     

The synthesis of α-isomalto-oligosaccharide derivatives and their protein conjugates

2-[4-(p-Toluenesulfonamido)phenyl]ethyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside was condensed with 2,3,4-tri-O-benzyl-6-O-(N-phenylcarbamoyl)-1-O-tosyl-D-glucopyranose to give 2-[4-(p-toluenesulfonamido)phenyl]ethyl 2,3,4,2′,3′,4′-hexa-O-benzyl-6′-O-(N-phenylcarbamoyl)α-isomaltoside. The disaccharide was decarbanilated in ethanol with sodium ethoxide. The sequence of coupling with the 1-O-tosyl-glucose derivative followed by decarbanilation was repeated to form the tri- and tetra-saccharide derivatives. The di-, tri-, and tetra-oligo-saccharides, were deblocked with sodium in liquid ammonia to give the 2-(4-aminophenyl)ethyl α-isomalto-oligosaccharides, which were diazotized with sodium nitrite in acid, and then coupled to bovine serum albumin and edestin to give the protein conjugates.     

Synthesis of (E)-5-(2-cIOdovinyl)-3′-0-(1-Methyl-1,4-Dihydropyridyl-3 -Carbonyl)-2′-Fluoro-2′-Deoxyuridine (Ivfru-Cds) for Brain Targetted Delivery of Ivfru,an Antiviral Nucleoside

Abstract

(E)-5-(2-lodovinyl)-2′-fluoro-3′-0-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11) was synthesized for future evaluation as a lipophilic, brain-selective, pyrimidine phosphorylase-resistant, antiviral agent for the treatment of Herpes simplex encephalitis (HSE). Treatment of (E)-5-(2-iodovinyl)-2′-fluoro-2′-deoxyuridine (6) with TBDMSCI in the presence of imidazole in DMF yielded the protected 5′-O-t-butyldimethylsilyl derivative (7). Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded (E)-5-(-2-iodovinyl)-2′-fluoro-3′-O-(3-pyridylcarbonyl)-5′-O-t-butyldimethylsily-2′-deoxyuridine (8). Deprotection of the silyl ether moiety of 8 with n-Bu₄N⁺F^? and quaternization of the resulting 3′-O-(3-pyridylcarbonyl) derivative 9 using iodomethane afforded the corresponding 1-methylpyridinium salt 10. The latter was reduced with sodium dithionite to yield (E)-5-(2-iodovinyl)-2′-fluoro-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11).     

Synthesis and Biological Evaluation of 2-Oxo/Thioxoquinoxaline and 2-Oxo/Thioxoquinoxaline-Based Nucleoside Analogues

Several O- and S-quinoxaline glycosides have been prepared by glycosidation of 3-methyl-2-oxo(thioxo)-1,2-dihydroquinoxalines 1a,b with α-D-glucopyranosyl, α-D-galactopyranosyl, and α-D-lactosyl bromide in the presence of K₂CO₃ followed by deacetylation with Et₃N/H₂O. Furthermore, alkylation of 1a,b with 4-bromobutyl acetate, 2-acetoxyethoxymethyl bromide, and 3-chloropropanol afforded the corresponding O- and S-acycloquinoxaline nucleosides. Reaction of 1b with chloroacetic acid followed by condensation with sulfacetamide and sulfadiazine in the presence of Et₃N/THF and ethyl chloroformate gave the corresponding sulfonamide derivatives 14 and 15, respectively. The structures of new compounds were confirmed by using IR, ¹H, ¹³C NMR spectra and microanalysis. Some of these compounds were screened in vitro for antitumor and antifungal activities.     

An atom efficient, solvent-free, green synthesis and antimycobacterial evaluation of 2-amino-6-methyl-4-aryl-8-[(E)-arylmethylidene]-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitriles

An atom efficient, green protocol for the synthesis of fifteen 2-amino-6-methyl-4-aryl-8-[(E)-arylmethylidene]-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitriles in quantitative yields from the reaction of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones with malononitrile in presence of solid sodium ethoxide under solvent-free condition is described. The compounds were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant tuberculosis (MDR-TB), and Mycobacterium smegmatis using agar dilution method. 2-Amino-4-[4-(dimethylamino)phenyl]-8-(E)-[4-(dimethylamino)phenyl]methylidene-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridine-3-carbonitrile was found to be the most potent compound (MIC: 0.43microM) against MTB and MDR-TB, being 100 times more active than standard, isoniazid against MDR-TB.     

Novel regioselective hydroxyl-alkylation of 4,5-diphenylimidazole-2-thione and a competitive intramolecular ring closure of the S-hydroxyalkyl-imidazoles to imidazo[2,1-b]thiazines and thiazoles. Role of catalyst, microwave irradiation, and solid support

Under both conventional method (CM) and microwave (MW) irradiation (MWI) conditions, alkylation of 4,5-diphenylimidazole-2-thione (1) with halogeno-alkanols 2 or 5, chloroglycerol 11 and 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (8) in presence of sodium ethoxide or sodium acetate in alcohol afforded regioselectively the corresponding S-alkylated analogues 3, 6, 9, and 12; they also were obtained using MW in absence and presence of bentonite as solid support with no change in regioselectivity. In the presence of potassium carbonate in DMF, the bisalkylated analogues 4, 7, 10, and 13 were obtained except in case of compound 13 where it was accompanied with the imidazothiazine 14. A convenient approach for imidazo-[2,1-b]thiazines and thiazoles 14-16 could be achieved by intramolecular dehydrative ring closure of the S-hydroxyalkylated imidazoles 3, 6, and 12 using potassium carbonate in DMF under both conventional and microwave methods. Isopropylidenation of 12 and 13 and deprotection of 9 and 10 also were investigated.     

The utility of 1-[18F]fluoro-3-iodopropane for the synthesis of certain dopamine D-1 and benzodiazepine receptor radioligands

No-carrier-added (NCA) R(+)-7-chloro-8-hydroxy-3-(3′-[¹⁸F]fluoropropyl)-1-phenyl-2,3,4,5-tetrahydro-3-benzazepine (2b) (an analog of dopamine D-1 receptor ligand SCH 23390), ethyl 8-fluoro-5,6-dihydro-5-(3′-fluoropropyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (4b) and 3′-[¹⁸F]fluoropropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (6b) (analogs of the benzodiazepine RO 15-1788) were synthesized by alkylation of the corresponding nor-compound with NCA 1-[¹⁸F]fluoro-3-iodopropane in 10–15% yield (EOB) in ~110min and with a mass of 2–3nmol. Compound 2 is less potent (~ 12–14 times) than SCH 23390 in binding to rat striatal membranes in vitro. Compounds 2b, 4b and 6b exhibit no specific anatomical distribution to mouse brain. These results suggest that the substituent at position 3 of SCH 23390, and position 5 and carboxylate group of RO 15-1788 are critical determinants both of affinity and selectivity for receptor binding, and underscores the evaluation necessary when even minor changes (C1 to C3) are made in bioactive compounds.     

Synthesis of 1-Hydroxy-10-methyl-pyrimido [1, 6-C][1, 3]oxazine and the Oxazepine Derivative,Structural Mimicry of Anti-Constrained Acyclic Thymidine

Abstract

A number of pyrimido[1, 6-c][1, 3]oxazine and -oxazepine derivatives, mimicry analogs of anti-constrained acyclic thymidine, have been prepared via treatment of lithiated 5, 6-dimethyl-2, 4-dimethoxypyrimidine with benzylchloromethyl ether or oxiran to furnish 2, 4-dimethoxy-6-(1-benzyloxyethyl)-S-methylpyrimidine (2) and 2, 4-dimethoxy-6-(1-hydroxypropyl)-5-methylpyrimidine (8), respectively. Debenzylation of 2 afforded 2, 4-dimethoxy-6-(1-hydroxyethyl)-5-methylpyrimidine (3). Chloromethylation of 3 and 8 with paraformaldehyde and gaseous hydrogen chloride produced reactive chloromethyl ether intermediates which were converted to the cyclized products 9-methyl-(1H, 2H, 4H, 7H)-pyrimido[1, 6-c][1, 3]-oxazine (5) and -oxazepine (9)-6, 8-dione, respectively. By using selenium dioxide, allylic oxidation of 5 and 9 afforded the target compounds, a racemic mixture of (±)1-hydroxy-9-methyl-(1H, 2H, 4H, 7H)-pyrimido[1, 6-c][1, 3]-oxazine (6) and -oxazepine (10)-6, 8-dione, respectively. Compounds 5, 6, 7, 9, and 10 were evaluated for activity against human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). All of these compounds were inactive.     

Stereoselective Approach to the Z-Isomers of Methylenecyclopropane Analogues of Nucleosides: A New Synthesis of Antiviral Synguanol

Stereoselective synthesis of antiviral synguanol (1) is described. Reaction of 6-benzyloxy-2-(dimethylaminomethyleneamino)purine (10) with ethyl (cis,trans)-2-chloro-2-(chloromethyl) cyclopropane-1-carboxylate (2c) under the conditions of alkylation-elimination gave (Z)-6- benzyloxy-2-formylamino-9-[(2-carbethoxycyclopropylidene)methyl]purine (11) but no E,N⁹-isomer. Minor amounts of (Z)-6-benzyloxy-2-formylamino-7-[(2-carbethoxy-cyclopropylidene)methyl]purine (13) were also obtained. Hydrolysis of compounds 11 and 13 in 80% acetic acid afforded (Z)-9-[2-(carbethoxycyclopropylidene)methyl]guanine (14) and (Z)-7-[2-(carbethoxy- cyclopropylidene)methyl]guanine (15). Reduction of 14 furnished synguanol (1). Reaction of N⁴-acetylcytosine (7) with ester 2c led to (Z,E)-1-(2-carbethoxycyclopropropylidenemethyl)cytosine (8, Z/E ratio 6.1:1). Basicity of purine base, lower reactivity of alkylation intermediates as well as interaction of the purine N³ or cytosine O² atoms with the carbonyl group of ester moiety seem to be essential for the observed high stereoselectivity of the alkylation-elimination. The Z-selectivity is interpreted in terms of E1cB mechanism leading to a transitory “cyclic” cyclopropenes which undergo a cyclopropene-methylenecyclopropane rearrangement.     

Synthesis and Anti-HBV Activity of Thiouracils Linked via S and N-1 to the 5-Position of Methyl β-D-Ribofuranoside

Abstract

Reverse nucleoside derivatives of 2-(methylsulfanyl)uracils 6a-d were prepared by treating of the sodium salt of 2-(methylsulfanyl)uracils (5a-d) with methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-β-D-ribofuranoside (2). The alkylation of 2-thiouracils 4a-d with methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3) afforded the corresponding S-ribofuranoside derivatives 8a-d. Deisopropylidenation of 6a-d and 8a-d afforded the corresponding deprotected derivatives 7a-d and 9a-d, respectively. The Anti-HBV activity of selected compounds was studied.     

1′, 2′-Seco-2′,3′-Dideoxynucleoside Analogues: Synthesis and Antiviral Evaluation of Racemic Trans-[1′, 5′-Dihydroxy 3′, 4′-methylenylpent-2′-oxy)methyl] Nucleosides

Abstract

Reaction of (±)but-3-en-1,2-diol (3) with ethyl diazoacetate afforded two cyclopropyl compounds (5) and (6). Their relative trans stereochemistry at C-2 and C-3 has been determined by high-field and computational NMR spectroscopy. (±)Trans-1-(1′,5′-dihydroxy-3′,4′-methylenyl-pent-2′-oxy)methyl]thymine (1d) or -cytosine (1b) and (±)trans-9-(1′,5′-dihydroxy-3′,4′-methylenylpent-2′-oxy)-methyl]adenine (la) or -guanine (1c) have been obtained through a regiospecific alkylation procedure and their antiviral evaluation is reported.     

Synthesis and Evaluation of Antimicrobial Activity of Some Pyrimidine Glycosides

Reaction of ethyl 4-thioxo-3,4-dihydropyrimidine-5-carboxylate derivatives 1a,b and ethyl 4-oxo-3,4-dihydropyrimidine-5-carboxylate 1c with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in KOH or TEA afforded ethyl 2-aryl-4-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosylthio or/ oxy)-6-methylpyrimidine-5-carboxylate 6a-c. The glucosides 6a and 6b were obtained by the reaction of 1a and 1b with peracetylated glucose3 under MW irradiation. Mercuration of 1a followed by reaction with acetobromoglucose gave the same product 6a. The reaction of 1a-c with peracetylated ribose 4 under MW irradiation gave ethyl 2-aryl-4-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosylthio)-6-methylpyrimidine-5-carboxylate 8a–c. The deprotection of 6a–c and 8a–c in the presence of methanol and TEA/H₂O afforded the deprotected products 7a–c and 9a–c. The structure were confirmed by using ¹H and ¹³CNMR spectra. Selected members of these compounds were screened for antimicrobial activity.     

MDPSCL2: A New Protecting Group for Chemoselective Synthesis of 2′-O-Alkylated Guanosines

Abstract

An improved strategy for the synthesis of 2′-O-methyl-guanosine (6) and 2′-MOE-guanosine (8) is reported. The regioselectivity of the alkylation was attained using a novel silicon-based protecting group, methylene-bis (diisopropyl-silylchloride) (MDPSCl₂, 2). The alkylation proceeded in a chemoselective manner using NaHMDS as the base and MeCl or MOE-Br as the appropriate electrophiles.     

Synthesis of trans-4-Amino-1-hydroxy-2-methyl-2-butene from Isoprene

A novel synthetic pathway to trans-4-amino-1-hydroxy-2-methyl-2-butene (7), a useful synthetic intermediate of zeatin, is presented here. On selective monophthalimide formation, the trans-1, 4-dibromo-2-methyl-2-butene (10) prepared from isoprene (1) predominantly gives trans-1-bromo-2-methyl-4-phthalimido-2-butene (11). The compound (11) is converted to 7 via trans-1-acetoxy-2-methyl-4-phthalimido-2-butene (6). The overall yield of 7 from 1 is 33.6%. Base-catalyzed hydrolysis of 11 also gives 7 directly. Zeatin can be prepared by the condensation of 7 with 6-chloropurine.