Syntheses and oxidative transformations of 6-(1-methylethylidene)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one and its precursors

Proceeding from the [2+2]-adduct of dichloroketene and dimethylfulvene a synthesis was developed of 6-(1-methylethylidene)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one, and further transformations of the latter were carried out aiming at the oxidative cleavage of the isopropylidene double bond and preparation of the corresponding cyclopentenone blocks.     

A simple and efficient synthesis of enantiomeric (3aRS,4RS,6aSR)-4-hydroxy-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-ones

Diastereomeric amides produced via the cleavage of easily available (±)-7,7-dichloro-4-exo-trimethylsilylbicyclo[3.2.0]hept-2-en-6-one by treatment with (+)-α-methylbenzylamine were transformed into bicyclic lactam-aminals, which can easily be separated by column chromatography on SiO₂. The latter products lead to enantiomeric (3a,6a)-4-hydroxy-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-ones after the removal of the chiral auxiliary and epoxidation.     

New chiral block for cyclopentanoids synthesis

Hydroxymethylation of bicyclic allylsilane, (3aR,6R,6aS)-3,3a,6,6a-tetrahydro-6-(trimethylsilyl)-cyclopenta[c]furan-1-one with formaldehyde by Prins reaction proceeds via S_E2' mechanism with the formation of anti-addition product. Some reactions of obtained (3aS,4S,6aR)-4-(hydroxymethyl)-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-one were investigated.     

Enantioselective syntheses of isoprostane and iridoid lactones intermediates by enzymatic transesterification

Crude Pseudomonas cepacia lipase (Amano PS-30) is a suitable biocatalyst for the kinetic resolution of the 1,2-cis-disubstituted cyclopentanoid building block (3aR*,4R*,6aS*)-(±)-4-hydroxymethyl-3,3a,4,6a-tetrahydrocyclopenta[b]furan-2-one through enantioselective transesterification. Enantiomerically enriched acetic acid (3aS,4S,6aR)-(+)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-4-yl methyl ester was utilized in a formal synthesis of the iridoids (+)-isoiridomyrmecin and (−)-teucriumlactone.     

Chiral blocks for the synthesis of cyclopentanoids from [2 + 2]-cycloadduct of dichloroketene and dimethylfulvene

Opening of the α,α-dichlorocyclobutanone ring in the [2 + 2]-cycloadduct of dichloroketene and dimethylfulvene with (+)-α-methylbenzylamine gave diastereoisomeric 2-dichloromethyl-5-isopropylidene-N-(α-methylbenzyl)cyclopent-3-ene-1-carboxamides, and hydrolysis of the latter at the dichloromethyl group afforded the corresponding bicyclic aminals which can be readily separated by chromatography on silica gel. The subsequent removal of the α-methylbenzylamine fragment via reduction and hydrolysis resulted in the formation of enantiomerically pure (-)- and (+)-6-(1-methylethylidene)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]-furan-1-ones.     

Reaction of alicyclic reformatsky reagents with 2,5-bis(arylmethylidene)cyclopentanones

Reformatsky reaction of methyl 1-bromocyclobutane-, 1-bromocyclopentane-, 1-bromocyclohexane-, and 1-bromocycloheptanecarboxylates with 2,5-bis(arylmethylidene)cyclopentanones gave the corresponding 4??-aryl-7??-arylmethylidene-4??,5??,6??,7??-tetrahydro-2??H-spiro[cycloalkane-1,3-cyclopenta[b]pyran]-2??-ones.     

[3 + 2]-Cycloaddition of azomethine ylide at 1,3-dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e][1,3]thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-diones

[3 + 2]-Cycloaddition of azomethine ylide generated from formaldehyde and sarcosine at the double bond of 1,3-dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5e][1,3]thiazolo[3,2-b][1,2,4]triazine-2,7(1H,6H)-diones occurs stereospecifically at the face opposite to the phenyl substituents. Product 3a crystallizes as a conglomerate.     

Efficient synthesis and resolution of novel 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one by lipase Pseudomonas cepacia

Lipase Pseudomonas cepacia catalyzed acylation of (±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one using vinyl acetate as the acyl donor in acetone gave (−)-(R)-2-acetoxy-2-(methyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one and (+)-(S)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one with high enantiomeric excess. Enantiomerically pure 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one are useful intermediates for the preparation of Ramelteon, an FDA approved drug for the treatment of insomnia.     

A study of the catalytic reductive products of 2,3-dihydro-6-methoxy-3-(6-nitroveratrylidene)-4H-benzopyran-4-one. Part II

Although the previously reported (1,2) chemical reduction of 2,3-dihydro-3-(6-nitroveratry-lidene)-4H-benzopyran-4-one with stannous chloride occurred with cyclization to the 6H-[1]-benzopyrano [4,3-b]quinoline ring system, the present study of the catalytic (palladium/carbon) reduction of 2,3-dihydro-6-methoxy-3-(6-nitroveratrylidene)-4H-benzopyran-4-one ( 1 ) (3) has indicated that other products in addition to the expected benzopyranoquinoline ( 3 ) may be isolated, depending upon the conditions of the reduction. The products of the reduction of 1 , isolated and structurally determined, include 2,9,10-trimethoxy-6H-[1]benzopyrano-[4,3-b]quinoline(3),2,9,10-trimethoxy-6a,7,12,12a-tetrahydro-6H-[1]benzopyrano[4,3-b]-quinoline (2), the N-oxide of 3 (6 ), and 6-hydroxy-2,9,10-trimethoxy-6H-[l]benzopyrano-[4,3-b Jquinoline ( 8 ).     

Intramolecular amidation: synthesis of novel imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole fused diazepinones

Novel heterocyclic systems 2-alkyl/aryl-9-(2-hydroxybenzylidene)-7,9-dihydro-8H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-d][1,2]diazepin-8-one and 9-(2-hydroxy-benzylidene)-3,3-dimethyl-3,4,7,9-tetrahydro-2H-11-thia-4b,6,7,10-tetraazaindeno[1,2-a]azulene-1,8-dione are synthesized via an intramolecular amidation reaction. An interesting ring opening and cyclization of 2-alkyl/aryl-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde and 6,6-dimethyl-8-oxo-2-(2-oxo-2H-chromen-3-yl)-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-3-carbaldehyde are discussed.     

Chemoenzymatic route to optically active dihydroxy cyclopenta[b]naphthalenones; precursors for decalin-based bioactive natural products

The development of an efficient chemoenzymatic route for the synthesis of optically active dihydroxy cyclopenta[b]naphthalenones; (+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-10 and (+)-1,8a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-11 is described. Different lipases and esterases were tested in the enzymatic hydrolysis of the corresponding acetates (±)-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-8, (±)-8a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-9, CRL (Candida Rugosa Lipase) and PLE (Pig Liver Esterase) were found to be the most effectual enzymes; for (?)-8 by 47% ee with the corresponding dihydroxy; (+)-10 by 98% ee in the presence of CRL; whereas, (?)-8 was obtained with 40% ee with the corresponding dihydroxy, (+)-10 with 58% ee in the PLE hydrolysis. It was concluded that CRL was the best biocatalyst for the substrate (±)-8. Moreover, enzymatic resolution in the presence of CRL yields, (?)-9 with 46% ee with the corresponding dihydroxy derivative; (+)-11 with 98% ee; however, in the presence of PLE, yields (?)-9 with 36% ee as well as the related dihydroxy derivative; (+)-11 with 49% ee respectively. The study concluded that CRL is the best biocatalyst for compounds (±)-8 and (±)-9.     

Synthesis,S-alkylation,and fungicidal activity of 4-(benzylideneamino)thioglycolurils

A series of 1,3-disubstituted 4-benzylideneamino-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-ones (thioglycolurils) was synthesized via the reaction of 5,7-disubstituted 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with hydroxy-, alkoxy-, and fluorocontaining benzaldehyde derivatives. An alkylation of the obtained thioglycolurils with methyl iodide or 4-bromobenzyl bromide provided the corresponding 6-benzylideneamino-5-alkylsulfanyl-3,3a,6,6a-tetrahydroimidazo[4,5-d]imidazol-2(1H)-ones. The fungicidal activity of some synthesized compounds against pathogens causing diseases of agricultural crops was studied.     

Synthesis of spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones,spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones and spiro[benzofuran-2,1′-isobenzofuran]-3,3′-diones via transannular reactions of eight membered ring intermediates

An auto oxidation-rearrangement product 4 was isolated from a high dilution reaction of ninhydrin with 3,4,5-trimethoxyaniline in water. A general synthesis of this compound and its derivatives 4–6 was devised by oxidation of tetrahydroindeno[1,2-b]indol-10-ones 1–3 with sodium periodate to give isoindolo[2,1-a]-indole-6,11-diones 4–6 in good yield. Compounds 4–6 can be easily transformed into spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones 8–10 , spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones 11–13 and isoindole[1,2-a:2′,1′-b]pyrimidine-5,15-diones 15, 16 in high yields. Analogous reactions were performed on 3-amino-5a, 10a-dihydroxybenzo[b]indeno[2,1-d]furan-10-one ( 17 ) to give a dibenzoxocintrione 18 , spiro-[benzofuran-2,1′-isobenzofuran]-3,3′-dione 19 and an isoindol-1-one 20 .     

Synthesis and Properties of Brominated 6,6'-Dimethyl-[2,2'-bi-1H-indene]-3,3'-diethyl-3,3'-dihydroxy-1,1 '-diones

Photochromic 6‐bromomethyl‐6′‐methyl‐[2,2′‐bi‐1H‐indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 2 ), 6,6′‐ bis(bromomethyl)‐[2,2′‐bi‐1H‐indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 3 ) and 6,6′‐bis(dibromomethyl)‐[2,2′‐ bi‐1H‐indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 4 ) have been synthesized from 6,6′‐dimethyl‐[2,2′‐bi‐1H‐ indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 1 ). The single crystal of 4 was obtained and its crystal structure was analyzed. The results indicate that in crystal 4 , molecular arrangement is defective tightness compared with its precursor 1 . Besides, UV‐Vis absorption spectra in CH₂Cl₂ solution, photochromic and photomagnetic properties in solid state of 2 , 3 and 4 were also investigated. The results demonstrate that when the hydrogen atoms in the methyl group on the benzene rings of biindenylidenedione were substituted by bromines, its properties could be affected considerably.     

Synthesis of novel spiro[indole-3,3′-pyrrolidin]-2(1H)-ones

Diastereoselective [3+2] cycloaddition of azomethine ylide to 1,3-dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-[1,2,4]triazine-2,7(1H,6H)-dione yields hitherto unknown 1,1′,3-trimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydrodispiro(imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indole)-2,2″,7(1H,1″H)-triones.     

Synthesis of quaternary 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazolium salts

The reaction of dihydroimidazole-2-thiol with N-(3-chloro-2-oxopropyl)phthalimide gave 2-[3-(4,5-dihydroimidazol-2-ylsulfanyl)-2-oxopropyl]-1,3-dioxo-1H-isoindole which underwent intramolecular heterocyclization to dihydroimidazothiazole system by the action of a dehydrating agent. Treatment of 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazole with concentrated hydrochloric acid led to the formation of dihydroimidazo[2,1-b]thiazol-3-ylmethanamine. Water-soluble quaternary 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazolium salts were obtained by alkylation of 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazole with alkyl halides.     

Cross-recyclization of 4-aryl-2,6-diamino-4<Emphasis Type="Italic">H</Emphasis>-thiopyran-3,5-dicarbonitriles with 1-morpholino-1-cyclopentene: New route to 4-aryl-2-thioxo-2,5,6,7-tetrahydro-1<Emphasis Type="Italic">H</Emphasis>-[1]pyrindine-3-carbonitriles and their derivatives

Reaction of 4-aryl-2,6-diamino-4H-thiopyran-3,5-dicarbonitriles with 1-morpholino-1-cyclopentene led to the formation of 4-aryl-2-thioxo-2,5,6,7-tetrahydro-1H-[1]pyrindine-3-carbonitriles used in the synthesis of substituted 2-alkylsulfanyl-4-aryl-6,7-dihydro-5H-[1]pyrindine-3-carbonitriles and 3-amino-4-aryl-6,7-dihydro-5H-cyclopenta[bthieno[3,2-e]pyridines.     

Domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylalkylidene)malononitriles: synthesis of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans and a rare case of [1,5] sigmatropic shift of the nitro group

A variety of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans were easily synthesized in good yields under mild conditions by a domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylethylidene)- and 2-(1-phenylpropylidene)malononitriles. In the latter case, intermediate 7-amino-10-methyl-10-nitro-9-phenyl-6-(trifluoromethyl)-10,10a-dihydro-6H-benzo[c]chromene-8-carbonitriles were isolated as a result of a rare [1,5] sigmatropic shift of the nitro group.     

Bicyclic isothioureas for conjugation with tubulin targeted anticancer agents

Two bicyclic annulated isothiourea derivatives were synthesized using as a key stage either the reaction of isothiocyanate halide with sodium sulfide or cyclization of unsaturated thiourea in the presence of bromine. X-ray molecular structure of N-[(3aSR,7aRS,Z)-hexahydro-1,3-benzothiazol-2(3H)-ylidene]glycine was determined. The conjugate of colchicine with [(3aR,5S,6aS)-2-(tert-butylamino)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]thiazol-5-yl]methanol obtained demonstrated pronounced cytotoxic effect on cancer cells.     

Cyclocondensation of lower aliphatic aldehydes with arylamines and cyclopentadiene

Three-component condensation of lower aliphatic aldehydes (C₁-C₃) with arylamines and cyclopentadiene (the Povarov reaction) gave 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]-quinolines. Ozonization of their N-trifluoroacetyl derivatives afforded the corresponding ozonides. Cyclocondensation of 4-fluoroaniline with formaldehyde and cyclopentadiene gave earlier unknown 2-fluoro-3b,6,6a,7,9,9a,10,12a-octahydrobenzo[i,j]dicyclopenta[b,g]quinolizine.