Synthesis of steroid 24,20-lactones by means of phenylselenolactonization

A synthesis of (20 R)- and (20 S)-3β-methoxy-5-cholen-24,20-lactones (7a and 7b) from 3β-methoxy-5-androsten-17-one (2) is described. The 17-ketone 2 was treated with isopropenyllithium to give 3β-methoxy-17α-(prop-l'-en-2'-ylo)-5-androsten-17β-ol (3). Compound 3 on reaction with ethyl orthoacetate and Claisen rearrangement of intermediate 17β-orthoester furnished ethyl esters of (E)- and (Z)-3β-methoxy-chol-5,17(20)-diene-24-acids (4b and 4a). Hydrolysis of ester groups in 4a and 4b and phenylselenolactonization afforded stereospecifically and regioselectively unsaturated (20 R)- and (20 S)-3β-methoxy-chol-5,16-diene-24, 20-lactones(6a and 6b), respectively. Reduction of double bond 16-17 in 6a and 6b gave the final products 7a and 7b. The phenylselenolactonization of(E)- and (Z)-3β-methoxy-chol-5,17(20)-diene-24-acids (5b and 5a) and spontaneous elimination of phenylselenyl moiety was investigated and compared with iodolactonization of the same unsaturated acids.     

Cycloadditionsreaktionen des tetrachlor-o-benzochinons mit fulvenen

Tetrahloro-o-benzoquinone (1) reacts with 6,6-diphenyl- and 6,6-bis (p-methoxyphenyl)fulvene resp. (2a, b) forming [π4 + π2]-cycloadducts of the dihydrobenzodioxin type (4a, b); besides 6,6-dimethyl- and 6,6-pentamethylenefulvene (2c, d) yield dimeric 1:1-adducts (7c, d; 8c, d), which originated from primarily formed [π4 + π6]-cycloadducts of the dihydrobenzo [b]cyclopenta [e] [1·4]dioxepin type (6c, d) through a Diels-Alder reaction. The structures of 7c, d and 8c have been clarified through X-ray crystallography. Some investigations concerning the mechanism are reported.     

Pyrimidines-19: Ring transformation of 5-nitrouracil into nitroresorcinols

The first intermolecular right transformation of a uracil derivative into the benzene system is reported. Treatment of 1,3-dimethyl-5-nitrouracil (1) with acetone in NaOMe/MeOH afforded 6-acetonyl-5,6-dihydro-1,3-dimethyl-5-nitrouracil (6) which was converted into 4-nitroresorcinol (5) upon treatment with NaOEt/EtOH at reflux. Reaction of1 with butanone gave two major products, 3-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)butanone (7) and the 1-(uracil-6-yl)butanone isomer (8). Prolonged treatment of7 with NaOEt/EtOH afforded 4-methyl-6-nitro-resorcinol (9) whereas8 was converted into 2-methyl-4-nitro-resorcinol (10). Treatment of1 with diethyl acetonedicar?ylate in NaOEt/EtOH afforded diethyl-2-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)-acetonedicar?ylate (2). Prolonged treatment of2 with NaOEt/EtOH at reflux afforded (5,6-dihydro-1,3-dimethyl-6-nitrouracil-6-yl)-acetate (3). Apparently,2 underwent a retroClaisen reaction to give3. Reaction of1 with ethyl acetoacetate in NaOEt/EtOH gave adduct isomers4 which underwent transformation reaction to give eventually 6-nitroresorcinol (5).     

Synthesis of carbazomycin B by radical arylation of benzene

Iodination of 2-methoxy-3,4-dimethyl-5-nitrophenol followed by acetylation yields (6-iodo-2-methoxy-3,4-dimethyl-5-nitrophenyl) acetate. Reduction with iron and acetic acid followed by reaction with methyl chloroformate then provides N-methoxycarbonyl-3-acetoxy-2-iodo-4-methoxy-5,6-dimethylaniline. Treatment of this substance in benzene at reflux with tributyltin hydride and a catalytic quantity of diphenyl diselenide leads to the formation of N-methoxycarbonyl-3-acetoxy-2-(2,5-cyclohexadienyl)-4-methoxy-5,6-dimethylaniline which on exposure to phenylselenenyl bromide affords a phenylselenenyl tetrahydrocarbazole. Oxidation deselenation and rearomatization are achieved by heating with tert-butylhydroperoxide finally affording carbazomycin B after saponification.     

Design and synthesis of an aminobenzo-15-crown-5-labeled estradiol tethered with disulfide linkage

A novel measuring method (electroimmunoassay) of 17β-estradiol (E₂) in urine or blood was proposed on the basis of a competition between E₂ and a labeled E₂ against an immobilizing antibody. To evaluate the principle, 3-{4-[17β-hydroxy-1,3,5(10)-estratrien-3-yloxy]butyldisulfanyl}-N-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxabenzocyclopentadecen-2-yl) succinamic acid (1) was designed and synthesized as a novel aminobenzo-15-crown-5-containing E₂ tethered with disulfide linkage. Two thiol-intermediates 5b and 19c were efficiently synthesized from mercaptosuccinic acid 7 and 4,4′-dithiodibutyric acid 12, respectively. Formations of disulfide linkages from less reactive thiols were examined and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) could be employed for the formation of an unsymmetrical disulfide 20c from 5b and 19c. Then, removal of TMS- and allyl-protecting groups in 20c successfully afforded the crown ether-containing E₂1.     

Some new ring-D seco steroids

The Beckmann fragmentation product, 3-methoxy-17-oxo-16,17-secoestra-1,3,5(10)-trien-16-nitrile (2) has been reduced by LAH giving the expected 3-methoxy-17-hydroxy-16,17-secoestra-1,3,5(10-trien-16-amine hydrochloride (3) and 3-methoxy-17-oxa-D-homoestra-1,3,5(10)-trien-16-ol (4), by a presumed neighbouring group participation of 17-OH group in the intermediary formed 16-imino derivative (A). The structure of 4 has been proved by an alternative synthetic route by reducing 3-methoxy-17-oxa-D-homoestra-1,3,5(10)-trien-16-one (7) with di-iso-butylaluminium hydride.     

Voltammetric behavior,biocidal effect and synthesis of some new nanomeric fused cyclic thiosemicarbazones and their mercuric(II) salts

New nanomeric 3-thioxo-5-methoxy-4,5-dihydro-6-methyl-9-unsubstituted/substituted-1,2,4-triazino[5,6-b]indoles (2a–c) and 3-thioxo-5-methoxy-4,5-dihydro-6,7-dihydroxy-1,2,4-triaino[5,6]-cyclobut-6-ene (3) were prepared via reaction of thiosemicarbazide with 5-unsubstitutedand/substituted-indol-2,3-diones and/or 3,4-dihydroxycyclobutane-1,2-dione in methanol–concentrated HCl at room temperature. A series of mercury(II)–ligand salts e.g. compound 4b and Hg(II) complexes 5a,b and 6 of cyclic Schiff base were prepared. Structures of these compounds were established by elemental analysis and spectral measurements. The redox characteristics of selected compounds were studied for use as chelating agents for stripping voltammetric determination of mercuric(II) ions in aqueous media. The compounds were also screened for their use as molluscicidal agents against Biomophalaria Alexandrina Snails responsible for Bilhariziasis.     

Tetracyclic 1,6-methano-[10]annulenes a novel class of steroidal annulenes

Reaction of 19-hydroxyandrosta-4,6-diene-3,17-dione (8b) and the corresponding Δ⁷-compound (8c) with diethyl-(2-chloro-1,1,2-trifluoroethyl)-amine affords 5β,19-cyclo-Δ^1,6- and 5β,19-cyclo-Δ^1,7-3-ketones (4b) and (4c) respectively. Solvolysis experiments with the 19-tosylates of the 19-hydroxy-Δ^4,6- and Δ^4,7-3-ketones (8b) and 8c) are described as alternate approaches to (4b) and (4c). Exposure of 5β,19-cyclo compounds (4b) and (4c) to acetic anhydride-acetic acid-p-toluenesulfonic acid yields the respective 3-acetoxycycloheptatrienes (5a) and (6a). The latter substance (6a) is converted into the novel tetracyclic 1,6-methano-[10]annulene (2a) on exposure to N-bromosuccinimide in boiling carbon tetrachloride. Synthesis of the corresponding 3-methoxy- and 3-desoxy-1,6-methano-[10]annulenes (2b) and (2c) are also described. The NMR spectra of (2a), (2b) and (2c) and related intermediates are discussed.     

Some new ring- seco steroids

The Beckmann fragmentation product, 3-methoxy-17-oxo-16,17-secoestra-1,3,5(10)-trien-16-nitrile (2) has been reduced by LAH giving the expected 3-methoxy-17-hydroxy-16,17-secoestra-1,3,5(10-trien-16-amine hydrochloride (3) and 3-methoxy-17-oxa- -homoestra-1,3,5(10)-trien-16-ol (4), by a presumed neighbouring group participation of 17-OH group in the intermediary formed 16-imino derivative (A). The structure of 4 has been proved by an alternative synthetic route by reducing 3-methoxy-17-oxa- -homoestra-1,3,5(10)-trien-16-one (7) with di-iso-butylaluminium hydride.     

Acid catalyzed rearrangement of β-ionone epoxide

Rearrangement of β-ionone epoxide with aqueous formic acid gave 1,2-dihydro-1,1,6-trimethylnaphthalen (2), 1-(1,2,2-trimethylcyclopent-1-yl)-2-penten-1,4-dione (3), 4-(5,5-dimethyl-2-acetyl-1-cyclopenten-1-yl)-2-butanone (5), 4-(1,3,3-trimethyl-2-cyclohexanon-1-yl)-3-buten-2-one (6), 4-(2,3,6-trimethylphenyl)-2-butanone (7) and 6,6-dimethyl-2,5-10-undecatrione (8). NMR assignments are made for each compound while a computer assisted analysis of the A₂B₂ portion of 7 has been completed. Possible mechanistic pathways leading to these compounds are discussed.     

Strukturelle Abwandlungen an Nukleotiden,Nukleosiden und Nukleosidbasen mit β-Acylvinylphosphoniumsalzen

β-Acetylvinyl-triphenylphosphonium bromide1 reacts with CMP to form the 3,N⁴-etheno-derivative {[6-(5′-phosphoribofuranosyl)-2-methyl-5-oxo-imidazo [1.2-c]pyrimidin-3-yl]-methyl}triphenyl-phosphonium bromide (2). Guanine affords mainly the lin. condensation product [(6-methyl-9-oxo-imidazo[1.2-a]-purin-7-yl)-methyl]triphenylphosphonium bromide (3) and the angular tricyclic product [(6-methyl-9-oxo-imidazo[2.1-b]purin-5-yl)-methyl]-triphenylphosphonium bromide (4). For comparison we synthesized the angular condensed heterocycle5, (6.8-dimethyl-9-oxo-imidazo[2.1-b]purin-5-yl)-methyl]triphenylphosphonium bromide, by reaction of 1-methylguanine with1, and the corresponding linear derivative6 [(4.6-dimethyl-9-oxo-imidazo[1.2-a]purin-7-yl)-methyl]-triphenylphosphoniumbromide from 3-methylguanine and1. AHofmann-type degradation of3 with the anion of diethyl malonate led to7, diethyl (6-methyl-9-oxo-imidazo[1.2-a]purin-7-yl)-methylmalonate, a compound whose structure resembles some Y-bases in t-RNA.Wittig reaction of the silylated nucleoside derivative8 a {[2-methyl-5-oxo-6-(2′.3′.5′-tris-trimethylsilyl)-ribofuranosyl-imidazo[1.2-c]pyrimidin-3-yl]methyl}-triphenylphosphonium bromide, with C₆H₅CHO resulted in the 2-methyl-3(ω-styryl)-6[2′.3′.5′-tris-(trimethylsilyl)]ribofuranosyl-imidazo[1.2-c] pyrimidin-5-one (9).     

Synthesis and unusual beckmann fragmentation reaction of syn-3-Methoxy-6α,17β-Dihydroxyestra-1,3,5(10)-trien-7-one oxime

Sodium borohydride reduction of anti-3-methoxy-17β-hydroxyestra-1,3,5(10)-trien-6,7-dione 7-oxime (4a) afforded syn-3-methoxy-6α,17β-dihydroxyestra-1,3,5(10)-trien-7-one oxime (5), which in thionyl chloride at −18 °C undenvent Beckmann fragmentation reaction to the unexpected 3-methoxy-6-oxo-17β-hydroxy-6.7-secoestra-1.3.5(10)-trien-7-nitrile (6). A mechanism of this fragmentation process was proposed.     

Cyclisation acido catalysee en serie labdane-II: Influence d'un groupe carbonyle en position 15

Cyclisation in formic acid of 4β-carbomethoxy labda-8(17),13 diene 14 al 1c leads to a mixture of two aldehydes, 5b et 6b, of the pimaric and isopimaric series, in contrast with known behaviour of the related methyl ester (dimethyl agathate). Similar results have be found for the cyclisation of the corresponding methyl ketone 1b.     

Synthesis of Enol Methyl Ethers of 3-Acetyl-6,6-dimethyltetrahydrothiopyran-2,4-dione and Their Reactions with Amines

The reaction of 3-acetyl-6,6-dimethyltetrahydrothiopyran-2,4-dione with diazomethane furnishes a mixture of 3-acetyl-6,6-dimethyl-4-methoxy-5,6-dihydro-2H-thiopyran-2-one and 3-acetyl-6,6-dimethyl- 2-methoxy-5,6-dihydro-2H-thiopyran-4-one in 2:3 ratio, whereas in reaction with dimethyl sulfate in the presence of potassium carbonate forms a mixture of the same products in 9:1 ratio. In both reactions the overall yield of ethers amounts to 50%. Treating of regioisomeric enol methyl ethers with pyrrolidine, o-toluidine, and allylamine provides the corresponding endocyclic enaminodiketones.     

New analogs of steroid estrogens

Aiming at the investigation of the mechanism of functioning of steroid estrogens a series of compounds with unnatural rings junction was synthesized. All investigated compounds exhibit a reduced uterotropic activity. It was established applying the NMR spectroscopy that 7α-methyl-3-methoxy-D-homo-6-oxa-8α,14β-estra-1,3,5(10)-trien-17a-one existed in solution in two conformations distinguished by the structure of the rings B, C, and D simultaneously. The reaction of 17-methylidene-3-methoxy-6-oxa-8α-estra-1,3,5(10)-triene with hydrobromic acid in acetic acid promotes a rearrangement with the migration of a methyl group into the position 17 resulting in the formation of 17,17-dimethyl-6-oxa-8α-gona-1,3,5(10),13(14)-tetraene derivatives.     

Synthesis of 5,6-Dimethylbenz[a]phenazine

5,6-Dimethylbenz[a]phenazine ( 4 ), an aza analogue of the carcinogenic 5,6-dimethylbenz-[c]acridine has been obtained by a 1,1-dehydration-rearrangement (Wagner-Meerwin type) from 5,5-dimethyl-6-hydroxy-5,6-dihydrobenz[a]phenazine ( 3 ). The alcohol 3 was obtained from the hydrogenation of the corresponding ketone 2 which was prepared in two ways: Method A, the oxidation of 5,5-dimethyl-5,6-dihydrobenz[a]phenazine ( 1 ); Method B, the hydrolysis of the 6,6-dibromo derivative 5 of 1.     

A new phenanthro [2,3-b] furan from Pleione bulbocodioides

A novel phenanthro[2,3-b]furan 1,named(3-hydroxy-9-(4′-hydroxy-3′-methoxypheny1)-11-methoxy-5,6,9,10-tetrahydro- phenanthro[2,3-b]furan-10-yl)methyl acetate,and two known phenolic compounds were isolated from the tubers of Pleione bulbocodioides(Franch.)Rolfe.Their structures were elucidated by spectroscopic methods.     

Bis-aminoquinolines as potential antimalarial agents and a novel fused ring system,pyrano[3,2-c:5,6-c′]diquinoline

3,3′(1,3-Ethyliminodimethylene)bis(4-hydroxy-6-methoxy-2-methyl)quinoline ( 2c ) and related compounds were synthesized. 3,3-Methylenebis(4-hydroxy-6-methoxy-2-methyl)quinoline ( 5 ) was prepared and upon treatment with phosphorus oxychloride gave 1,13-dimethyl-5,9-dimethoxy-14H-pyrano[3,2-c:5,6-c′]diquinoIine (6), a novel ring system.     

14-methyl steroids. Part 3. Synthesis of (±)-14α-methyl-9β-estradiol and related 14α-methyl-19-norsteroids

Catalytic hydrogenation of a totally synthetic mixture of (±)-3-methoxy-14-methyl-14α-estra-1,3,5( 10), 9(11)-tetraen-17-one(1) and the corresponding 1,3,5(10),8-tetraen-17-one (2) gives a mixture of 14α-methyl-8β,9β-, -8α,9α-, and -8β,9α-estrones, which is converted into the 17β-hydroxy-mixtures. t-Butylation gives a separable mixture of the three isomers, of which (±)-17β-t-butoxy-3 methoxy-14-methyl-9β,14α-estra-1,3,5(10)-triene(6) is the major component. The corresponding 14α-methylestradiols are prepared. A practical synthesis of (±)-14-methyl-14α-estra-1,3,5(10), 6,8-pentaene-3,17β-diol(25) is described, and it is shown that DDQ dehydrogenation of 1,3,5(10),9(11)-tetraenes in this series leads exclusively to the corresponding 1,3,5(10),6,8,11-hexaenes, whereas that of 1,3,5(10),8-tetraenes gives only 1,3,5(10),6,8-pentaenes.     

Steroidal analogues of unnatural configuration—VII : Total synthesis of 17β-hydroxy-9-methyl-9β, 10α-oestr-4-en-3-one,a novel retrotestosterone isomer

Conjugate methylation of 17β-hydroxy-des-a-oestr-9-en-5-one (1) and the derived 4,5-seco-steroid (6b) afforded the respective 9β-methyl compounds. Base-catalysed alkylation of 17β-hydroxy-9-methyl-des-a-9/gb-oestran-5-one (3a) resulted in attack at C(6); this result was used to prepare the anthrasteroid (5). Ring closure of the 9β-methyl-4,5-seco-steroid (8) derived from 6b afforded 17β-hydroxy-9-methyl-9β,10α-oestr-4-en-3-one (9a). Conjugate methylation of 17β-hydroxyoestra-4,9-dien-3-one (11) resulted in 1,4-addition to the dienone system.