THE SYNTHESIS OF SOME C-4 AND C-9 SUBSTITUTED DERIVATIVES OF KDN2EN METHYL ESTER

The synthesis of a number of C-4 and C-9 substituted derivatives of KDN2en methyl ester 2 is reported. 9-Deoxy-9-iodo, 9-azido-9-deoxy and 9-O-methyl derivatives of 2(compounds 5, 7and 9) were prepared from the corresponding 9-O-tosylate, methyl 2,6-anhydro-3-deoxy-9-O-p-toluenesulfonyl-D-glycero-D-galacto-non-2-enonate (3). These compounds have been fully characterised as the peracetates 6, 8 and 10. Treatment of 3 with KSAc gave the 9-thioacetyl derivative which was isolated as the peracetate 11. 4-C-Ethenyl-4-deoxy (14), 4-C-phenyl-4-deoxy (15) and 4-C-[1-(methoxycarbonyl)ethenyl]-4-deoxy (16) derivatives of 2were prepared via the palladium-catalysed coupling of the 4-epi-chloride, methyl 5,7,8,9-tetra-O-acetyl-2,6-anhydro-4-chloro-3,4-dideoxy-D-glycero-D-talo-non-2-enonate (12) with the appropriate organostannanes.     

Rogiolol Acetate: A Novel β-Chamigrene-Type Sesquiterpene Isolated from a Marine Sponge

The marine sponge Spongia zimocca SCHMIDT , 1862, collected in front of the torrent II Rogiolo, south of Livorno, contains the sesquiterpene rogiolol acetate (= (+)-(2R,3S,6R,8R,9R)-2,8-dibromo-9-chloro-1,1,9-trimethyl-5-methylidenespiro[5.5]undec-3-yl acetate; (+)- 3a ), which represents the first chamigrane isolated from a sponge. Although compounds of this class are common in red seaweeds of the genus Laurencia, and our sponge actually contains 9-bromochamigrene and a variety of other metabolites of nearby growing Laurencia sp., (+)- 3a is unique to our sponge.     

1, 3-dipolar cycloaddition of diazomethane to azolopyridazines. The synthesis of 8-methyl-8H- and 9-methyl-9H-pyrazolo[3, 4-d]-s-triazolo[4, 3-b]pyridazine and 1-methyl-1H- and 2-methyl-2H-imidazo[1, 2-b]pyrazolo[3, 4-b]pyridazine derivatives

The transformations of 7-methyl-7H- and 8-methyl-8H-pyrazolo[4, 3-d]tetrazolo[1, 5-b]pyridazines 1, 2, 9 and 10 into 8-methyl-8H- and 9-methyl-9H-pyrazolo[3, 4-H]-s-triazolo[4, 3-b]pyridazines 7 and 8 , and 1-methyl-1H-and 2-methyl-2H-imidazo[1, 2-b]pyrazolo[3, 4-d]pyridazines 13 and 14 are described.     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

Synthesis of some functional derivatives ofo- andm-carboranes

Amides, amines, and alcohols were synthesized from 9-o- and 9-m-carboranecarboxylic chlorides. It follows from comparison of the¹H NMR spectra ofN,N-dimethyl-1-o- and-1-m-carboranecarboxamides andN,N-dimethyl-9-o- and -9-m-carboranecarboxamides that -bonding of the carborane polyhedron with the carbonyl group in 1-carboranyl dimethylamides is stronger than that in 9-carboranyl dimethylamides. Oxidation of 9-hydroxymethyl-m-carborune with pyridinium chlorochromate gives 9-m-carboranylmethyl 9-m-carboranecarboxylate.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 719–721, March, 1996.     

Heterocyclic fused tropylium ions VII. On the synthesis of 9H-dithieno[2,1 -b:4,5-c′]tropylium fluoborate and 4H-dithieno[1,2-b:4,5-c′]tropylium fluoborate

9H-Dithieno[2,1 -b:4,5-c′]tropylium ion (III) and 4ii-dithieno[1,2-b:4,5-c′]tropylium ion (IV) have been synthesized by ring-closure of 1-(4-carboxy-3-thienyl)-2-(3′-thienyl)ethane (IX) and 1-(4-carboxy-3-thienyl)-2-(2′-thienyl)ethane (XVI), respectively, followed by bromination-debrom-ination to 9H-cyclohepta[2,1-b:4,5-c′] dithiophen-9-one (XI) and 4H-cyclohepta[1,2-b:4,5-c′]-dithiophen-4-one (XVIII), and finally by reduction and hydride transfer. The tropylium ions III and IV were less stable than the [b,b′]-fused isomers previously studied.     

Unexpected Recyclization of 1H-δ-Carbolines to Pyrrolo[1,2-a]indoles

When 1H-2-methyl-1-p-nitrophenyl-3-ethoxycarbonylpyrido[3,2-b]indole (1) is heated in alcoholic solutions of ammonia, we observe a previously unknown recyclization leading to formation of 2-alkoxycarbonyl-3-methyl-9-p-nitrophenylimino-9H-pyrrolo[1,2-a]indoles (3,6).     

Research on nitrogen containing heterocyclic compounds. XVIII. Synthesis of 9H-pyrrolo[2,1-c]-s-triazolo[4,3-a][1,4]benzodiazepine,a novel tetracyclic ring of pharmaceutical interest

Reaction of di-4-morpholinylphosphinic chloride on 5,10-dihydro-9H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one 9 afforded 11-(di-4-morpholinylphosphinyloxy)-5H-pyrrolo[2,1-c][1,4]benzodiazepine 10 . Displacement of di-4-morpholinylphosphinyloxy group of 10 by formylhydrazine with concomitant intramolecular cyclization led directly to 9H-pyrrolo[2,1-c]-s-triazolo[4,3-a][1,4]benzodiazepine 7, a novel nitrogen heterocyclic ring of pharmaceutical interest. A new procedure for the synthesis of 9 is also described.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo [4,3-b] pyridazine,III

s-Triazolo[4,3-b]pyridazine (I) reacted photochemieally with bieyélo[2.2.1] hepla-2,5-diene, 1,5-cyclooctadiene, 1,3-cyclooctadiene, methylene cyclohexane, diethyl cis-1,2,3,6-tetrahydro-phthalate and ethyl 2-cyclopentene-1-acetate to givt: the following products: the endo and exo isomers of 4a, 5, 8a, 9-tetrahydro-9-rnethylene-5,8-rnethano-8H-s-triuzolo[1, 5-a]indole (II) and the endo and exo-9-cyanometliyl products (III and IV) from bicyclo[2.2.1] hepta-2,5-diene; 4a,5,-9, 10, 10a, 11-huxahydro-11-methylene-6H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole (V) and the 11-cyanomethyl product VI from 1,5-cyclooctadiene: 4a,7,8,9,10,10a-hexahydro-11 -inethylene-11H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole(VII),4a, 5, 7, 8, 10a, 11-hexahydro-11-methylene-6H-cycloocta[4,5]pyrroIo[1,2-b]-s-triazole (VIII) and their respective 9-cyanomethyl products (X and 1X) from 1,3-cyclooctadiene; 6′, 7′ -dihydro-7′ -methylenespiro[cyclohexane-1, 5′-[5H] pyr-rolo[1,2-b]-s-triazole] (XI), 6′, 7′-dihydro-7′-meth) lene. spiro cyclohexane-1, 6′-[5H]pyrrolo[1,2-b]-s-triazole] (XII) and their respective 7 -eyanomethyl products (XIII and XIV) from melhylene cyclohexane; 6,7-dicarbethoxy-9-cyanomelhyl-4a, 5, 7, 8, 8a, 9-hexahydro-6H-s-triazolo[1,5-a]indole (XV) from diethyl cis-1, 2, 3, 6-tetrahydrophlhalate: and 5-earl)elhoxymethyl-8-eyanomethyl-4a, 5, 6, 7, 7a, 8-hexahydrocyclopenta[4,5]pyrrolo( 1, 2-b]-s-triazole (XVI) from ethyl 2, 2-cyclo-pentene-1-acetate. Many other alkenes, particularly the phenyl ethylenes, did not react with compound 1. In general, more than one product was isolated for each reaction except in the case of the two ester alkenes where a single eyanomethyl product was observed.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo[4,3-b]pyridazine (II)

s-Triazolo[4,3-b Jpyridazine (I) photochemically reacted with dihydropyran; 2,3-dihydro-p-dioxin; 2,5-dihydrofuran; 2,5-dimethoxy-2,5-dihydrofuran; and 1,3-dioxep-5-ene to give a new series of substituted pyrrolo[1,2-b]-.s-triazoles (II-IX). In most reactions, two or more products were formed. The following compounds have been prepared from I: 9-methylene-4a,5,6,7,8a,9-hexahydropyrano[2,3 :4,5]pyrrolo[1,2-b]-s-triazole (Ha), the corresponding 9-cyanomethyl product (III), and 9-methylene-4a,7,8,8a-tetrahydro-6H,9H-pyrano[3′,2′:4,5]pyrrolo[1,2-b]-s-triazole (IIb) from dihydropyran; 9-methylene-4a,6,7,8a-tetrahydro-9H-p-dioxino[2′,3′:4,5]-pyrrolo[1,2-6]-s-triazole (IV) from 2,3-dihydro-p-dioxin; 8-methylene-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]pyrrolo[1,2-b]-s-triazole (V) and the corresponding 8-cyanomethyl product (VI) from 2,5-dihydrofuran; 8-cyanomethyl-5,7-dimethoxy-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]-pyrrolo[1,2-6]-s-lriazole (VII) from 2,5-dimethoxy-2,5-dihydrofuran; and 10-methylene-4a,5,9a,10-tetrahydro-9H-[1,3]dioxepino[5′,6′:4,5]pyrrolo[1,2-b]-s-triazole (VIII) and the corresponding 10-cyanomethyl product (IX) from 1,3-dioxep-5-ene. The addition of several other compounds (1,2,3,6-tetrahydropyridine, 1-acetylimidazole, 3-sulfolene, 2,3-dihydro-p-dithiin, and vinylene carbonate) was attempted, but no reactions were observed.     

Preparation of two triflate precursors for <Emphasis Type="Italic">O</Emphasis>-(2-[<Superscript>18</Superscript>F] fluoroethyl)-<Emphasis Type="Italic">L</Emphasis>-tyrosine used in positron emission tomography (PET)

Two novel triflate precursors for radiolabelling of L-tyrosine in positron emission tomography (PET) for tumor imaging, O-(2-trifluoromethanesulfonyloxyethyl)-N-(tert-butoxycarbonyl)-L-tyrosine methyl ester 9a and O-(2-trifluoromethanesulfonyloxyethyl)-N-(tert-butoxycarbonyl)-L-tyrosine tert-butyl ester 9b, are synthesized. The triflate agent, 9a or 9b, is prepared by esterification of methanol or transesterification of tert-butyl acetate with L-tyrosine, protection of the amine group with di-tert-butyl dicarbonate, alkylation with chlorohydrin, and triflation with trifluoromethanesulfonic anhydride in four steps with overall yields of 30% and 15%, respectively.     

The synthesis and transformations of 9H-imidazo[1,2-b]pyrazolo[4,3-d]-pyridazine and 9H-pyrazolo[4,3-d]-s-triazolo[4,3-b]pyridazine derivatives

The nucleophilic and electrophilic substitutions of 6-substituted 9,9-dimethyl-9H-imidazo[1,2-b]pyrazolo- [4,3-d]pyridazines 2 , nucleophilic substitutions of 6-substituted 9,9-dimethyl-9H-pyrazolo[4,3-d]-s-triazolo- [4,3-b]pyridazines 7 and some other transformations to give compounds 3 and 8 , respectively, were studied. It was shown that both heterocyclic systems are stable under the conditions employed in these transformations.     

Synthesis of 2H-benzo[2,3-g]pyridazino-[4,5-d,e]quinolin-3-one derivatives

Summary Condensation-cyclization of hydrazine with 4-methoxycarbonylbenzo[g]quinolinequinone or its corresponding carboxylic acid afforded 7-hydrazino-2H-benzo[2,3-g]pyridazino[4,5-d,e]-quinolin-3-one. Starting with the 9-hydroxy derivative, a similar double condensation of the nucleophile was observed, whereas its 6-hydroxylated regioisomer gave 2H-benzo[2,3-g]pyridazino-[4,5-d,e]quinolin-3,7-dione.

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Synthese von 2H-Benzo[2,3-g]pyridazino[4,5-d,e]chinolin-3-on-Derivaten

Zusammenfassung Die Kondensation/Zyklisierung von Hydrazin mit 4-Methoxycarbonylbenzo-[g]chinolinchinon bzw. mit der entsprechenden Carbonsäure ergab 7-Hydrazino-2H-benzo[2,3-g]-pyridazino[4,5-d,e]chinolin-3-on. Ausgehend vom 9-Hydroxy-Derivat, wurde in analoger Weise doppelte Kondensation des Nucleophils beobachtet, wohingegen das 6-Hydroxy-Regioisomer zu 2H-Benzo[2,3-g]pyridazino[4,5-d,e]chinolin-3,7-dion reagierte.

     

Synthesis of substituted 3-amino[6,5-b]triazinoindoles

4-[(9-Methyl-as-triazino[6,5-b]indol-3-yl)amino]-2-methyl-2-butanol ( 13 ) and the corresponding 2-methyl-3-imino derivative 12 were synthesized and tested in vitro against Rhino 2 virus. The two compounds were more active than the known triazino[5,6-b]indole 4 . 2,9-Dimethyl-3-methoxy-9H-as-triazino[6,5-b]indolium tosylate ( 21 ) and the related 3-methylthio compound 9 were prepared. Quaternary 21 formed a pseudo base, 22a , whereas quaternary 9 did not form a pseudo base.     

Hexafluoroacetone as Protecting and Activating Reagent. Glycosylated Malic, Citramalic, and Thiomalic Acid Derivatives, New Glycosylated Building Blocks for Drug Design [1]

Summary. Glycosylated -hydroxy and -mercapto acids have been synthesized starting from malic/citramalic/thiomalic acid and Ac₄--D-Glc-NH₂/Bzl₄--D-Glc-NH₂ using hexafluoroacetone as protecting and activating reagent.Dedicated to Prof. Dr. Horst Wilde on the occasion of his 65^th birthday     

Rhodathiaboranes with `anomalous' electron counts: synthesis, structure and reactivity

Analysis of the structures of 8,8-(PPh₃)₂-8,7-nido-RhSB₉H₁₀ and 9,9-(PPh₃)₂-9,7,8-nido-RhC₂B₈H₁₁ by RMS misfit calculations has confirmed that these rhodaheteroboranes possess nido 11-vertex cluster geometries in apparent contravention of Wade's rules. However, examination of the molecular structures of both species shows that the {RhP₂} planes are inclined by ca. 66° with respect to the metal-bonded SB₃ or CB₃ faces, and that two weak ortho-CHRh agostic interactions occupy the vacant co-ordination position thereby created. As a consequence of these agostic bonds the Rh atom, and hence the overall cluster, is provided with an additional electron pair, meaning that their nido structures are now fully consistent with Wade's rules. The chelated diphosphine compound 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ is similar to the PPh₃ compound in showing the same agostic bonding. Attempts to prepare a bis-P(OMe)₃ analogue result in ligand scavenging and the formation of 8,8,8-{P(OMe)₃}₃-8,7-nido-RhSB₉H₁₀. Similarly, reaction between Cs[6-arachno-SB₉H₁₂] and RhCl(dmpe)CO does not result in CO loss but in formation of 8,8-(dmpe)-8-(CO)-8,7-nido-RhSB₉H₁₀, shown to exist as a mixture of two of three possible rotamers. Deprotonation of 8,8-(PPh₃)₂-8,7-nido-RhSB₉H₁₀ and 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ with MeLi yields the anions [1,1-(PPh₃)₂-1,2-closo-RhSB₉H₉]⁻ and [1,1-dppe-1,2-closo-RhSB₉H₉]⁻, respectively, with octadecahedral cage structures. It is argued that anion formation causes the agostic bonding to be `switched-off' and results in the cluster adopting the closo architecture predicted by Wade's rules. This structural change is fully reversible on reprotonation, and if reprotonation of [1,1-(dppe)-1,2-closo-RhSB₉H₉]⁻ is carried out in MeCN, the product 8,8-(dppe)-8-(MeCN)-8,7-nido-RhSB₉H₁₀ forms. Interestingly, 8,8-(dppe)-8-(MeCN)-8,7-nido-RhSB₉H₁₀ reconverts to 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ on standing in CDCl₃, suggesting that the agostic bonding is sufficiently strong to displace co-ordinated MeCN. All new compounds are fully characterised by multinuclear NMR spectroscopy and, in many cases, by single crystal X-ray diffraction.     

Presence of an N-6 acetate group shifts the alkylation site of the ambident nucleophile sodium 1-N-methylisoguanide

Inclusion of an N-6 acetate into the ambident nucleophile, sodium 1-N-methylisoguanide, resulted in a shift in alkylation preference from N-9 to N-3. The preparation of the N-6 acetate of 1-N-methylisoguanine, 9-N-acetyl-1-N-methylisoguanine (4) , and related acetate analogs are described and evidence presented for their structural determination. Analysis of long range ¹³C-¹H coupling data facilitated the structural elucidation of the predominant alkylation products and provided evidence for the unusual N-7 hydrogen tautomeric form in one of them, 3-N-benzyl-6-N-acetyl-1-N-methylisoguanine (8).     

A new synthetic route to 2-substituted naphtho[2,3-b]furan-4,9-dione2-Substituted Naphtho[2,3-b]furan-4,9-dione

4,9-Dimethoxynaphtho[2,3-b]furan 9 was obtained in 91% yield via the reductive methylation of naphtho[2,3-b]furan-4,9-dione 2 . After treatment of 9 with butyllithium, the mixture was allowed to react with N,N-dimethylacetamide, followed by oxidization with cerium(IV) diammonium nitrate to give 2-acetylnaphtho[2,3-b]furan-4,9-dione 1 . 2-Formylnaphtho[2,3-b]furan-4,9-dione 13 and 2-trimethylsilyl-naphtho[2,3-b]furan-4,9-dione 14 were also obtained from 9 by a similar method. The halodesilylations of 14 easily gave 2-iodonaphtho[2,3-b]furan-4,9-dione 16 , 2-bromonaphtho[2,3-b]furan-4,9-dione 17 , and 2-chloronaphtho[2,3-b]furan-4,9-dione 18 in 82%, and 93% and 83% yield, respectively. Furthermore, the nitrodesilylation of 14 gave 2-nitronaphtho[2,3-b]furan-4,9-dione 3 in 77% yield.     

Azaindoles. V. Pyrido(4,3-b]indoles (γ-carbolines) fonctionnalisés sur leur sommet 4: Synthèse en une seule étape

In boiling diphenylether phenylhydrazine reacts with 1,2-dihydro-2-oxo-4-hydroxypyridines to give 3,4-dihydro-4-oxo(9H)-pyrido[4,3-b]indoles (γ-carbolines) in one step. Nucleophilic displacement of their 4-chloro derivatives by secondary amines affords both 3,4-disubstituted γ-carbolines and chlorination of 2,3-dimethyl-4-oxo(9H)pyrido[4,3-b]indoles, as well as methylation of 2-methyl-4-chloro-(9H)pyrido[4,3-b]indole leads to derivatives in the (3H)4-substituted pyrido[4,3-b] indole series.     

Structure elucidation and NMR assignment of two new eudesmane derivatives from Merremia yunnanensis

Two new eudesmane derivatives, 1α,6β,9β-trihydroxy-eudesm-3-ene-1-O-β-d -glucopyranoside ( 1 ) and 1α,6β,9β-trihydroxy-eudesm-3-ene-1-(6-cinnamoyl)-O-β-d -glucopyranoside ( 2 ) were discovered from Merremia yunnanensis. The structures were elucidated by analysis of their spectroscopic data including HR-ESI-MS, 1D, and 2D NMR. It should be noted that this is the first report about structure elucidation and NMR assignment of compounds from M. yunnanensis.