Heterocyclic N-glycosyl derivatives—XIII: Reaction of 6-chloropurine and benzotriazoles with acetylated glycals

Acid-catalysed reactions of tri-O-acetyl-D-glucal with benzotriazole, 5,6-dimethylbenzotriazole, 5,6-dichlorobenzotriazole and 6-chloropurine have been found to give anomeric mixtures of the corresponding 2′,3′-unsaturated N-glycosyl derivatives with the α-anomers preponderating. When tri-O-acetyl-D-galactal was used the 3′,4′,6′-tri-O-acetyl-α- and β-D-lyxo-hexopyranosyl nucleoside analogs were obtained. The conformation and anomeric configuration of all the N-glycosyl compounds obtained were assigned by NMR studies.     

The Thorpe-Ziegler-type reaction of 3-cyanopyridine-2(1H)-thiones with Biginelli 6-bromomethyl-3,4-dihydropyrimidin-2(1H)-ones: cascade assembling of tetra- and pentacyclic heterocyclic scaffolds

3-Cyanopyridine-2(1H)-thiones have been shown to react with Biginelli-type ethyl 4-aryl-6-(bromomethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates upon heating in DMF giving rise to ethyl 4-aryl-6-{[(3-cyanopyridin-2-yl)thio]methyl}-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates. The latter upon treatment with an excess of NaH or t-BuOK in boiling DMF undergo a tandem Thorpe-Ziegler-type heterocyclization to give pyrido[3″,2″:4′,5′]thieno[2′,3′:5,6]pyrido[4,3-d]pyrimidine derivatives in good yields. Selected compounds were tested for antibacterial and antifungal activity.     

A novel and efficient one-pot synthesis of furo[3′,4′:5,6]pyrido[2,3-c]pyrazole derivatives using organocatalysts

A novel approach to one-pot synthesis of dihydrofuro[3′,4′:5,6]pyrido[2,3-c]pyrazole and indeno[2′,1′:5,6]pyrido[2,3-c]pyrazole derivatives have been investigated using organocatalysts that are recyclable. This new protocol has the advantages of environmental friendliness, higher yield, low cost, as well as convenient operation. The catalytic efficiency of various small organocatalysts such as l-proline, trans-4-hydroxy-l-proline, l-thiaproline, cinchonidine, (+)-cinchonine, and dl-2-phenylglycine has also been studied.     

Synthesis of 4-N-alkyl and ribose-modified AICAR analogues on solid support

Herein, we report the solid-phase synthesis of several 5-aminoimidazole-4-(N-alkyl)carboxamide-1-ribosides (4-N-alkyl AICARs) and the corresponding 2′,3′-secoriboside derivatives. The method uses the N-1-dinitrophenyl-inosine 5′-bonded to a solid support. This inosine derivative has the C-2 of the purine base strongly activated towards the attack of N-nucleophiles thus allowing the preparation of several N-1 alkylated inosine supports from which a small library of 4-N-alkyl AICAR derivatives has been synthesized. A set of new 4-N-alkyl AICA-2′,3′-secoriboside derivatives have also been obtained in high yields by solid-phase cleavage of the 2′,3′-ribose bond.     

3′-Selective modification of a 4′,5′-didehydro-5′-deoxy-2′,3′-epoxyuridine using nucleophiles

1-(2,3-Anhydro-5-deoxy-4,5-didehydro-α-l-erythro-pent-4-enofuranosyl)uracil 4 was obtained by the treatment of 5′-iodo-2′,3′-epoxyuridine 5 with LiHMDS in excellent yield. The pyrimidine nucleoside 4 possesses quite unique vinyl epoxide moiety within the molecules. The reactions of 4 with a variety of nucleophiles gave 3′-substituted pyrimidine nucleosides without the formation of the corresponding 2′-substituted isomers. In the case of NaN₃ or PhSH, the corresponding 5′-adduct was obtained as a minor product together with the expected 3′-adduct.     

Efficient synthesis of 3,3′,5,5′-tetra(p-X-phenylethynyl)biphenyl (X: NMe2; OMe) by homocoupling of 1-bromo-3,5-di(p-X-phenylethynyl)benzene or by heterocoupling of 3,3′,5,5′-tetraethynylbiphenyl with p-X-phenylbromobenzene with nickel or palladium complexes, respectively

The conjugated 3,3′,5,5′-tetra(p-X-phenylethynyl)biphenyl derivatives were efficiently obtained by homocoupling of 1-bromo-3,5-di(p-X-phenylethynyl)benzene mediated by zero-valent nickel complexes.The 1-bromo-3,5-di(p-X-phenylethynyl)benzene was previously prepared by heterocoupling between 1-bromo-3,5-di(ethynyl)benzene and p-X-iodobenzene (X: NMe₂; OMe) catalysed by the palladium/copper system in good yield. The necessary 1-bromo-3,5-di(ethynyl)benzene was obtained by heterocoupling between 1,3,5-tribromobenzene and 2-methyl-3-butyn-2-ol catalysed by palladium and successive treatment with sodium hydroxide in dry toluene, in good yield.The same 3,3′,5,5′-tetra(p-X-phenylethynyl)biphenyl (X: NMe₂; OMe) derivatives were alternatively synthesised in highest yield by heterocoupling between 3,3′,5,5′-tetra(ethynyl)biphenyl and p-X-bromobenzene (X: NMe₂; OMe) catalysed by palladium in excellent yields. Previously, 3,3′,5,5′-tetra(ethynyl)biphenyl was obtained in practically quantitative yield by homocoupling of 1-bromo-3,5-di[4-(2-methyl-3-butyn-2-ol)] benzene mediated by the zero-valent nickel complex to the 3,3′,5,5′-tetra{di[4-(2-methyl-3-butyn-2-ol)]}biphenyl followed the treatment with sodium hydroxide.     

Pyrazolo[2′,3′:3,4][1,3]oxazino[5,6-b]quinoxaline, a novel tetracyclic ring system

Reaction of 2-chloro-3-(3-chloro-1H-pyrazol-5-yl)quinoxaline and aldehydes does not afford the corresponding N-(α-hydroxyalkylated) derivatives but results in a cyclisation reaction to give a derivative bearing the hitherto undescribed pyrazolo[2′,3′:3,4][1,3]oxazino[5,6-b]quinoxaline system.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Heterocyclic N-glycosyl derivatives—XIX : Glycal nucleosides. their relationship with 2',3'-unsaturated nucleosides and their utilization in the synthesis of 1',3'-two base nucleosides

The acid catalized reaction of tri-0-acetyl-D-glucal with benzotriazole or 6-methylthiopurine in acetonitrile gave a mixture of 1',2'- and 2',3'-unsaturated nucleosides, the former predominating. The relationship between these unsaturated nucleosides is studied and an allylic carbonium ion is proposed as an intermediate for these isomerizations. The acid catalized reaction of 1',2'-unsaturated nucleosides with more benzotriazole or 6-methylthiopurine gave 1',3'-two base nucleosides. The conformation and anomeric configuration of the N-glycosyl compounds obtained were assigned by NMR spectroscopy.     

Synthesis, structure, and isomerism of N-2,4-dinitrophenylbenzotriazoles

Both isomers of N-(2′,4′-dinitrophenyl)benzotriazole, the 1(3)- and the 2-substituted, have been characterized and their reciprocal isomerism was studied. Cross-experiments in the presence of 5(6)-nitro-1H-benzotriazole proved that the isomerization of 2-(2′,4′-dinitrophenyl)-2H-benzotriazole into the 1-isomer occurs by an intermolecular mechanism. The reported reaction of 5(6)-nitro-1H-benzotriazole with 1-chloro-2,4-dinitrobenzene has been reexamined discovering that there is an error in the proportions of N-substituted isomers. A possible explanation for the observed isomerizations was proposed. Identification of all compounds by multinuclear magnetic resonance, including solid-state studies, has been achieved.     

Au(I)/Ag(I)-catalyzed annulation of sugar aldehyde tethered with 3-phenylprop-2-yn-1-yl ether with aryl amines for the pyrano[4,3-b]quinoline derivatives

Aryl amines undergo smooth annulation with O-phenylpropynyl sugar aldehyde in the presence of the Ph₃PAuCl (10 mol %)/AgSbF₆ (10 mol %) catalytic system to afford the corresponding tetrahydro-3aH-spiro[[1,3]dioxolo[4″,5″:4′,5′]furo[3′,2′:5,6]pyrano[4,3-b]quinoline-2,1′-cyclohexane] derivatives in good yields and selectivity.     

New pyrano[3,4-b]indoles from 2-hydroxymethylindole and l-dehydroascorbic acid

2-Hydroxymethylindole reacts with l-dehydroascorbic acid under mild conditions to give (3R,3aR,10cS)-3-[(1S)-1,2-dihydroxyethyl]-3a,10c-dihydroxy-3a,5,6,10c-tetrahydrofuro[3′,4′:5,6]pyrano[3,4-b]indol-1(3H)-one. Its tosyl derivative undergoes cyclization to form a pentacyclic ketal derivative.     

A rapid access to indolo[2,1-a]pyrrolo[4′,3′:4,5]pyrano[5,6-c]coumarin/[6,5-c]chromone derivatives by domino Knoevenagal intramolecular hetero Diels-Alder reactions

Knoevenagal condensation of indole-2-carbaldehyde containing an internal dienophile with coumarins, followed by domino intramolecular hetero Diels-Alder reaction, provides polycyclic heterocycles. Different approaches for stereo- and chemoselective synthesis of indolo[2,1-a]pyrrolo[4′,3′:4,5]pyrano[5,6-c]coumarin and indolo[2,1-a]pyrrolo[4′,3′:4,5]pyrano[6,5-c]chromone derivatives are described.     

2-Amidinylindole-3-carbaldehydes: synthesis of new tetracyclic compounds containing the pyrrolo[1,2-c]1,4-diazepine ring

2-Amidinylindol-3-carbaldehydes bearing an α-alkoxycarbonyl substituent on the cyclic-tertiary amine moiety were prepared. Pyrolysis of these amidines in diethylenglycol-monoethyl ether produced mainly a pyrrolo[1′,2′-1,2]-1,4-diazepino[5,6-b]indol-7,11-dione. A similar result was obtained starting from 2-amidinylbenzofuran-3-carbaldehyde.     

Synthesis of spiro-fused (C5)-pyrazolino-(C6)-triazinones, a new heterocyclic system

Reaction of 4-hydrazinoquinazoline with 2,4-diketoesters gives the corresponding 3-acylmethyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones in a one-step procedure via cyclocondensation-Dimroth-like rearrangement. Spectroscopic studies as well as X-ray analysis reveal that the obtained triazinoquinazolines exist in their ketoimine tautomeric form. Treatment of these compounds with hydrazine hydrate affords 3′-(2-aminophenyl)-3-(het)aryl-spiro[pyrazoline-5,6′(1′H)-1,2,4-triazin]-5′(4′H)-ones or 5-(het)arylpyrazole-3-carboxylic acid hydrazides depending on the reaction conditions. The structure of the spiro-heterocycles was elucidated by means of single-crystal X-ray analysis and confirmed by spectroscopic investigations.     

Stereoselective synthesis of new glycooxathiecinone using vic-cyclic thionocarbonate haloalkylation and ring closing metathesis as key steps

Herein, we describe the first glycoconjugate macrocyclic thiolcarbonate namely (Z)-10(S)-[3′-O-acetyl-1′,2′-O-isopropylidene-4′-deoxy-d-erythrofuranose]-4,7,9-trihydro-10H-8-thia-1,3-oxathiecin-2-one (17a) using a strategy based on two key steps synthesis: (i) a haloalkylation of vic-diol via their cyclic thionocarbonate derivatives; (ii) a macrocyclisation using ring closing metathesis reaction. Detailed here is a newly developed extension of vic-diol halogenation via the cyclic thionocarbonate function but using a range of alkyl halides other than the customarily used MeI. For example, with 1,2-O-isopropylidene-5,6-O-thionocarbonate-d-glucose (1) and allyl bromide, the 5-allylthiolcarbonate-6-bromo-6-deoxy-d-glucose derivative 6 was obtained in good yield. The later submitted to 6-allythioetherification and ring closing metathesis (RCM) with Grubbs second generation gave stereoselectively the target oxathiecinone 17a in 75% yield for the RCM step.     

A simple entry to novel spiro dihydroquinoline-oxindoles using Povarov reaction between 3-N-aryliminoisatins and isoeugenol

An easy, fast, and cheap way for the synthesis of the new 4′-(4-hydroxy-3-methoxyphenyl)-3′-methyl-3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-ones using BF₃ OEt₂-promoted imino Diels-Alder cycloaddition between ketimine-isatin derivatives and trans-isoeugenol.     

A new synthetic procedure to spiro[cyclohexane-1,3′-indoline]-2′,4-diones

A new synthetic pathway to spiro[cyclohexane-1,3′-indoline]-2′,4-diones was found starting from 3-chloromethylene-2-indolones 1 and Danishefsky's diene 2. Their synthesis consists of several steps involving the formation of the cycloadducts, the 6-chloro-4-trimethylsilyloxy-2-methoxyspiro[cyclohex-3-en-1,3′-indolin]-2′-one derivatives, transformed into spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones via 6-chloro-spiro[cyclohex-2-en-1,3′-indoline]-2′,4-dione intermediates. The reduction of spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones gave spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. Using a ‘one pot reaction’, starting from 1 and 2, compounds 7 were obtained in satisfactory overall yield.     

Further monoterpene chromane esters from Peperomia obtusifolia: VCD determination of the absolute configuration of a new diastereomeric mixture

A reinvestigation of the monoterpene chromane ester enriched fraction from Peperomia obtusifolia using chiral chromatography led to the identification of a minor peak, which was elucidated by NMR and HRMS as fenchyl-3,4-dihydro-5-hydroxy-2,7-dimethyl-8-(3″-methyl-2″-butenyl)-2-(4′-methyl-1′,3′-pentadienyl)-2H-1-benzopyran-6-carboxylate, the same structure assigned to two other fenchyl esters described previously, pointing out a stereoisomeric relationship among them. Further NMR analysis revealed that it was actually a mixture of two compounds, whose absolute configurations were determined by VCD measurements. Although, almost no vibrational transitions could be assigned to the chiral chromane, the experimental VCD spectrum was largely opposite to that obtained for the average experimental VCD [(2S,1?R,2?R,4?S + 2R,1?R,2?R,4?S)/2] for fenchol derivatives. These results allowed us to assign the putative compounds as a racemic mixture of the chiral chromane esterified with the monoterpene (1S,2S,4R)-fenchol, which had not been identified in our early work.     

Synthesis, resolution and assignment of absolute configuration of trans 3-amino-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (POAC), a cyclic, spin-labelled β-amino acid

Racemic trans 3-(9-fluorenylmethyloxycarbonylamino)-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (Fmoc-POAC-OH), prepared by conventional methods, was resolved upon esterification with (aR)-2,2′-dihydroxy-1,1′-binaphthyl. Separation of the obtained diastereomeric monoesters Fmoc-(±)-trans-POAC-O-(aR)-binaphthol by crystallization/chromatography, and removal of the chiral auxiliary by saponification of the aryl ester function furnished both enantiomers (+)-(3R,4R)-Fmoc-POAC-OH and (−)-(3S,4S)-Fmoc-POAC-OH. The absolute configuration of the asymmetric C³, C⁴ carbons of POAC were assigned from the induced circular dichroism of a flexible biphenyl probe present in the terminally protected dipeptide derivatives Boc-Bip-(+)-POAC-OMe and Boc-Bip-(−)-POAC-OMe (Bip, 2′,1′:1,2;1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid). This assignment was confirmed by X-ray diffraction analysis of the diastereomeric monoester Fmoc-(+)-trans-POAC-O-(aR)-binaphthol, shown to be (aR,3R,4R). Solution synthesis of peptides to the hexamer level, based on the (3R,4R)-POAC enantiomer combined with (1S,2S)-2-aminocyclopentane-1-carboxylic acid, was carried out to examine coupling conditions at both C- and N-termini of the POAC residue, in view of further syntheses and 3D-structural investigations.