“Reverse chromophore” of actinomycin d. Synthesis of 2-substituted 7-amino-8H-8-oxo-oxazolo[4,5-b] phenoxazine ring system

The synthesis and physico-chemical properties of a new 7-amino-8H-8-oxo-oxazolo[4,5-b]-phenoxazine ring system (8a and 8b) are reported. These tetracyclic heteroaromatic rings posses an extra oxazolo ring fused to the phenoxazinone chromophore observed in actinomycin D (1b). These tetracyclic compounds (8a-8b) possess a structure in which the orientation of the A and B rings in 1b are “reversed”. Since DNA binding and the resulting specificity of the antitumor antibiotic 1b is believed to depend on the spatial orientation of P(α) and P(β) relative to the functions on the B ring of 1b , these new compounds represent a novel approach for investigating AMD-DNA interactions.     

Heterodiamantane und strukturell verwandte Verbindungen II. Pentacyclische Diäther der C10-Reihe: 5,12-Dioxapentacyclo-[6.4.0.02,6.04,9]dodecan und 4,12-Dioxapentacyclo[6.3.1.02,7.03,10.05,9]- dodecan

In connection with studies on heterodiamantanes and structurally related compounds the two novel pentacyclic diethers 9 and 10 were prepared starting from the photo-dimer 8 of cyclopentadienone. All three compounds have as common features a central carbocyclic 6membered ring with four axial alkyl substituents and two oxygen function in 1,4-position. The diether 9 was obtained on the one hand from the intermediate tetracyclic unsaturated alcohol 23 by intramolecular addition, catalyzed either by acid or base (scheme 3), and on the other hand from the tetracyclic diol 32 or the dibromoketones 34 (via 38 ) and 35 (via 39 ) by intramolecular substitution (schemes 4 and 5). The synthesis of the isomeric diether 10 was achieved by intramolecular substitution of the tetracyclic diol 33 (scheme 4). Diether 9 is thermodynamically more stable than 10 . The latter was easily isomerized to the former on treatment with concentrated sulfuric acid in benzene.     

Research on nitrogen containing heterocyclic compounds. XX. Synthesis of 8H-Imidazo[5,1-c]pyrrolo[1,2-a][1,4]benzodiazepine and its 6-derivatives

Starting from 1H-1-(2-aminomethylphenyl)pyrrole the synthesis of 8H-imidazo[5,1-c]pyrrolo[1,2-a][1,4]ben-zodiazepine, a novel nitrogen containing tetracyclic ring, has been performed by two routes involving a three-step and a six-step sequence, respectively. The more complex sequence offers the advantage to obtain also 3-alkyl and 3-aryl derivatives of the parent nucleus. The three step sequence involves the use of toluene-4-sulfonylmethylisocyanide (TosMIC) as a synthon.     

Research on nitrogen containing heterocyclic compounds. XVII. Synthesis of 8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine,a novel tetracyclic ring of pharmaceutical interest

The synthesis of 8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine 6 , a novel nitrogen-containing tetracyclic ring, is reported starting from 5H-imidazo[2,1-c][1,4]benzodiazepine 7. Reaction of this compound with nitromethane and subsequent reduction of the obtained nitromethyl derivative 8 afforded 11-aminomethyl-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine 9. Treatment of the latter compound with formaldehyde led to 1,2,3,3a-tetrahydro-8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine 10 , which was then oxidized to the title compound.     

Total Synthesis of Spiroalkaloids Lycibarbarines A–C

The concise and efficient synthesis of tetrahydroquinoline alkaloids lycibarbarines A−C has been accomplished in four steps from a common intermediate derived from commercially available 2-deoxy-D-ribose and 8-hydroxyquinoline. For the synthesis of the unique tetracyclic spiro-heterocycle skeleton we employed a synthetic strategy that features two key transformations: iodomethyllithium-based homologation of lactone / N-alkylation to access tetracyclic spiro-heterocycle skeleton in one step and one-pot acetonide deprotection, hemiacetal formation, and spirocyclization cascade process.     

Heterocyclic compounds. VII. Synthesis of thiadiazasteroid analogs

The synthesis of a number of β-northiadiaza steroid analogs has been described. Suitable o-aminonitriles were acylated with γ-chlorobutyryl chloride. These amidonitriles were cyclized to substituted γ-lactams and subsequently to the tetracyclic products. To functionalize the “17-position” in these steroids, the intermediate γ-lactams were converted to arylidene derivatives before cyclization to the tetracyclic derivatives.     

Unusual dihydrazone formation in the fischer-indole cyclization. The synthesis of novel nonclassical annulated 2,4-Diamino-pyrrolo[2,3-d]pyrimidine antifolates

The synthesis of seven novel tetracyclic 2,4-diaminopyrrolo[2,3-d]pyrimidines as conformationally restricted nonclassical antifolates was achieved via an unusual Fischer-indole cyclization of dihydrazones. An attempted synthesis of 2,4-diamino-6-hydrazinopyrimidine afforded 2-amino-4,6-dihydrazinopyrimidine which when reacted with appropriate ketones gave the dihydrazones. The dihydrazones in turn under Fischer-indole cyclization conditions afforded target conformationally restricted tetracyclic products.     

Versuche zur enantiomerenreinen Synthese des Chatancins, 1. Mitt. Synthese von (1R,2S,6S,7R,8S,3′S)-2-(4′-Benzyloxy-3′-methylbutoyl)-7-hydroxy-8-isopropyl-1-methylbicyclo [4.4.0]decan-4-on

Summary Our first target on the way towards the synthesis of enantiomerically pure chatancin is the preparation of the title compound. The cycloadduct of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene and thymoquinone is stereo- and regioselectively reduced to the tricyclic ketoalcohol4, which by nucleophilic cyclisation and reductive removal of the keto group as well as the chlorine atoms yielded a tetracyclic dimethoxyketal. Acidic hydrolysis freed the keto group, which now was treated with a chiral lithium alkyl compound derived from methyl (R)-2-methyl-3-hydroxypropionate in few steps. The resulting stereomeric tertiary alkohols were fragmented and the decalinones thus obtained separated. X-ray analysis permitted the determination of the absolute configuration of these decalinone derivatives.

     

Efficient synthesis of onoceranediol from 12-hydroperoxy-8α,12-epoxy-11-bishomodrimane

An efficient one-step synthesis of the diacetate of the tetracyclic triterpenoid onoceranediol (4) by radical cleavage of the readily available 12-hydroperoxy-8α,12-epoxy-11-bishomodrimane is described. Drim-9(11)-en-8α-yl acetate (7) is formed in this reaction as a byproduct. Onoceranediol diacetate 4 is converted into onoceranediol on treatment with LiAlH₄, and acetate 7 is transformed into drim-9(11)-en-8α-ol on saponification. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2571–2573, November, 2005.     

Copper‐Catalyzed Aerobic Oxidative Ring Expansion of Isatins: A Facile Entry to Isoquinolino‐Fused Quinazolinones

A copper‐catalyzed aerobic oxidative ring expansion reaction of isatins with 1,2,3,4‐tetrahydroisoquinoline for the synthesis of tetracyclic quinazolinones has been developed. This reaction is performed smoothly under simple conditions to give the corresponding products in moderate to good yields with good functional group tolerance. The capacity of the resultant 5H‐isoquinolino[1,2‐b]quinazolin‐8(6H)‐one for a range of palladium‐catalyzed directing C—H activation has been further demonstrated, thus giving a broader access to diverse tetracyclic quinazolinones.     

Synthesis of (+)-(4S, 8R)hyphen;8hyphen;Epi- and (−)-(4R, 8S)-4-Epi-β-bisabolol

The first total enantioselective synthesis of (+)-(4S, 8R)-8-epi-β-bisabolol(+)- 1 and of (?)-(4R, 8 S )-4-epi-β-bisabolol ((?))? 1 ) is reported. The key step in the synthesis is the kinetic resolution of (±)? 5 by means of the Sharpless epoxidation yielding (?)- and (+}? 6 , respectively. Reduction of the epoxides with LiAlH₄ gave the diols (+)-and(?)? 7 which were transformed into (+)- and (?)? 8 , respectively, via the corresponding mesylate. Reaction of these epoxides with the Grignard reagent derived from homoprenylbromide, assisted by Li₂CuCl₄, finished the synthesis of the target compounds 1 with high diastereo- and enantioselectivity.     

A one-pot synthesis of novel sugar derived 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones: an entry towards highly functionalized sugar-heterocyclic hybrids

An efficient and practical one-pot method for the synthesis of novel diversified sugar derived dihydro-quinazolino[4,3-b]quinazolin-8-ones has been reported. Various protected sugar hemiacetals were used to synthesize the hybrid tetracyclic ring system. The one-step reductive transformation of 2-(2-nitrophenyl)-3H-quinazolin-4-one with different sugar hemiacetals furnished the desired tetracyclic product in good yields and with high purity.     

Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp3)H and C(sp2)H Functionalization Reactions

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C? H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp³)? H functionalization followed by a Catellani reaction, including C(sp²)? H functionalization. A one‐pot reaction involving both C(sp³)? H and C(sp²)? H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.     

Synthesis of ecdysone. 3. On insect hormones. Syntheses of 2-beta, 3-beta, 14-alpha-trihydroxy-6-keto-delta-7-A-B-cis-steroids

The synthesis of the tetracyclic skeleton of ecdysone with correct stereochemistry and substitution is described. 22,25-Didehydroxy-ecdysone and methyl (20S)-2β,3β-dihydroxy-6-oxo-5β-pregn-7-ene-20-carboxylate have been prepared. The latter is a key intermediate in the synthesis of ecdysone.     

Inhaltsstoffe des Osmanthus-Absolues. 5. Mitteilung. (8E)-4, 7-Epoxymegastigma-5(11),8-dien

Constituents of Osmanthus absolute, 5th communication. (8 E )-4,7-Epoxymegastigma-5(11),8-diene The title compound 1 has been identified as trace constituent in Osmanthus absolute. The synthesis of 1 was performed by reaction of α-ionone-epoxide ( 4 ) with aluminum tri (isopropylate) in 2-propanol at 130°. Besides 1 we found another bicyclic ether 5 in the lower boiling part of the reaction mixture, and ten further substances with interesting structural features from the less volatile part. Formation mechanism as well as some spectral particularities are discussed in more detail.     

New heterocyclic compounds derived from 1,4-dihydro-3(2H)-cinnolinone. Cyclic hydrazides. Note I

The question concerning the synthesis of the 1,4-dihydro-3(2H)cinnolinone was solved and some new tetracyclic derivatives are described. The structure and the synthesis of the two isomers 2-(2-carbomethoxymethylphenyl)phthalazine-1(2H),4(3H)dione and 1-(2-carbomethoxybenzoyl)-1,2-dihydrocinnolin-3(4H)one are discussed.     

Potential antitumor agents. III. Synthesis of pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine and 1H-pyrazolo[3,4-e]indolizine derivatives

The preparation of 5-dimethylaminoethyl-4,6-dioxo-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]pyrrolo-[3,4-g]indolizine, a derivative of the still unknown tetracyclic parent ring pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine, is reported starting from 1-phenyl-5-(1-pyrryl)pyrazole-4-acetonitrile by PPA catalyzed double cyclization of the related oxalylcyanomethyl derivative and subsequent alkylation. The synthesis of 4,5-bis(isopro-pylaminocarbonyloxymethyl) and 4,5-bis-(cyclohexylaminocarbonyloxymethyl) derivatives of 1-phenyl-1H-pyrazolo[3,4-e]indolizine is also described. The new tricyclic and tetracyclic derivatives were tested as potential antitumor agents.     

A novel synthetic approach for the synthesis of pyridocarbazole alkaloids

The synthesis of 11‐methyl‐6H‐pyrido[4,3‐b]carbazole‐1(2H)‐one (5), which can be important for the synthesis of other pyridocarbazole alkaloids and especially 1‐substituted ellipticines, is described. Construction of the tetracyclic structure was achieved by a new route and two important precursor compounds (4a and 4b) for the synthesis of pyridocarbazole alkaloids and also many new tetrahydrocar‐bazole derivatives (7, 8, 9, 10, 11, 12, 13) were synthesized.     

Ein neuer Zugang zum tetracyclischen Grundgerüst des Cyclohepta (def)fluorens

A New Synthetic Way to the Tetracyclic Skeleton of Cyclohepta (def)fluorene The synthesis of 2-Methyl-4, 5, 6, 8, 9, 10-hexahydrocyclohepta (def)fluorene 2 is described starting with the reduction of the ketone 3 by a (1:1)-mixture of LiAlH₄/AlCl₃ to the hydrocarbon 4 . After metallation with butyllithium 4 was allowed to react with bromoacetic acid to yield 5 . The cyclization of this compound was performed with p-toluenesulfonic acid to give the tetracyclic ketone 6 which was converted to the tetracyclic hydrocarbon 2 by reduction with LiAlH₄/AlCl₃.     

Synthesis of pyrazole analogues of isoaptazepine

The synthesis of the novel tetracyclic rings 5 and 6 is described starting from 4-cyano-1-methyl-5(1H-pyrrol-1-yl)-1H-pyrazole and its 3-(1H-pyrrol-1-yl)- isomer, respectively. The pathway employed is based on a one-pot double annelation reaction involving the transformation of 13 into the required tetracyclic derivative 16 . Lithium aluminum hydride/sulfuric acid reduction of the last compound furnished 5 . A similar way was used for the synthesis of 6 by cyclization of 20 .