Synthèses dans la série des bis-indéno-fluorènes V [1]. Dihydro-13, 15–11 H-bis-indéno[2, 1-b; 1′, 2′-h]fluorène et dihydro-13, 15–5H-bis-indéno[1, 2-a; 1′, 2′-h]fluorène

Starting from cyclohexene and 2, 2′, 4, 4′-tetramethylbiphenyl the linear bis-indenofluorene 13, 15-dihydro-11 H-diindeno [2, 1-b; 1′, 2′-h] fluorene (X) has been synthetised in 5 steps (overall yield 30%). As an intermediate product the 11, 13, 15-trioxo-derivative IX was obtained. By a side way the 13-oxo-derivative of X and the already known monoangular bis-indenofluorene 13, 15-dihydro-5 H-diindeno [1, 2-a; 1′, 2′-h] fluorene (XIX) were also obtained.     

Synthèses dans la série des bis-indéno-fluorènes,VI [1] Dihydro-12, 15–6H-bis-indéno[1. 2-b; 2′.1′-h]fluorène et dihydro-14, 15–8H-bis-indéno[2. 1-a; 2′. 1′-h]fluoréne

Starting from cyclohexene and 2, 2′, 5, 5′-tetramethylbiphenyl the linear bisindenofluorene 12, 15-dihydro-6H-diindeno [1.2-b; 2′.1′-h] fluorene (XX) has been synthesized in 5 steps (overall yield 27%). As an intermediate product the 6, 12, 15-trioxo-derivative XIX (greyish green crystals, blue alcaline vat) was obtained. By a side way, the 6-oxo-derivative of XX and the already known monoangular bis-indenofluorene 14, 15-dihydro-8H-diindeno [2.1-a; 2′.1′ -h] fluorene (XXVII) were also obtained. XX can also be prepared in several steps starting from 3-methyl-fluorene or fluorene.     

Synthèses dans la série des bis-indéno-fluorénes III [1]. Dihydro-14, 15-13H-bis-indéno[2,1-a;1′,2′,-i]fluorène et dihydro-14, 15-8H-bis-indéno [2, 1-a;2′,1′-h]fluorène

Starting from 2-bromo-9-oxo-fluorene-1-carboxylic acid the biangular bis-indenofluorene 14, 15-dihydro-13H-diindeno[2, 1-a; 1′, 2′-1]fluorene (VIII) and the monoangular 14, 15-dihydro-8H-diindeno[2, 1-a; 2′, 1′-h]fluorene (XI) have been synthesised in 6 resp. 7 steps (overall yield 22% resp. 18%). As intermediate compounds the 14-oxoderivatives of VIII and XI were also obtained.     

Synthesis of 5′-halo-2′,3′-lyxo-epoxy and 2′,3′-unsaturated thieno[3,2-d]pyrimidine nucleosides

A series of thieno[3,2-d]pyrimidine-2,4-dione nucleosides modified in the carbohydrate moiety has been synthesized. In the first part, synthetic routes are described for the replacement of 5′-hydroxyl group in preformed 1-(β-D-ribofuranosyl)thieno[3,2-d]pyrimidine-2,4-dione I by fluoro, iodo or chloro atoms. Reduction of the 5′-iodo substituent of VI was then carried out catalytically using palladium on carbon as catalyst to give the expected 5′-deoxy derivative VIII. The lyxo-epoxide derivative XII was then synthesized by sequential treatment of the 5′-deoxy-5′-chloro derivative X with methanesulfonyl chloride and with sodium hydroxide. In the second part, most of attention has been devoted to apply different methods reported in the literature that allow access to 2′,3′-olefinic derivatives from the corresponding 2′,3′-dihydroxy precursor. The 5′-O-silyl protected bisxanthate XIV either on reduction with tri-n-butyltin hydride or by reductive elimination of the haloacetate XVI afforded the free 2′,3′-olefin nucleoside after removal of the 5′-protecting group. However none of the compounds in this series exhibited significant antiviral activity against HIV at the doses tested.     

Synthèses dans la série des bis-indéno-fluorènes I. Le dihydro-13, 15-5H-bis-indéno[1, 2-a;1′, 2′-h]fluorène

The synthesis of 13,15-dihydro-5H-diindeno[1,2-a;1′,2′-h] fluorene in six steps starting from flourenone 4-carboxylic acid and 2,4-dichlorotoluene is described. As an intermediate product the 5, 13, 15-trioxo-derivative is obtained.     

Syntheses and Reactions of 1′,2′-Unsaturated 2′,3′-Seconucleoside Analogues

The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18 , respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to H? C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr₂ in dry CH₂Cl₂ was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→ 19 ), nucleophilic displacement of the tosyl group by azide (→ 20 ), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21 . The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine ( 22 ) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).     

8-Aza-7-deaza-2′,3′-dideoxyguanosine: Deoxygenation of its 2′deoxy-β-D-ribofuranoside

The synthesis of 6-amino-1-(2′,3′-dideoxy-β-D -glycero-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( =8-aza-7-deaza-2′,3′-dideoxyguanosine; 1 ) from its 2′-deoxyribofuranoside 5a by a five-step deoxygenation route is described. The precursor of 5a, 3a , was prepared by solid-liquid phase-transfer glyscosylation which gave higher yields (57%) than the liquid-liquid method. Ammonoloysis of 3b furnished the diamino nucleoside 3c . Compound 1 was less acid sensitive at the N-glycosydic bond than 2′,3′-dideoxyguanosine ( 2 ).     

Nucleotides. Part XXXV. Synthesis of 3′-deoxyadenylyl-(2′–5′)-3′-deoxyadenyIyl-(2′–ω)-9-(ω-hydroxyalkyl)adenines

Via the phosphotriester approach, new structural analogs of (2′–5′)oligoadenyiates, namely 3′-deoxyadenylyl-(2′–5′)-3′-dcoxyadenylyl-(2′–ω)-9-(ω-hydroxyalkyl)adenines 18 – 21 , have been synthesized (see Scheme) which should preserve biological activity and show higher stability towards phosphodiesterases. The newly synthesized oligonucleotides 18 – 21 have been characterized by ¹H-NMR spectra, TLC, and HPLC analysis.     

(6′RS,8′RS,2E)- und (6′RS,8′SR,2E)-3-Methyl-3-(2y,2′,6′-trimethyl-7′-oxabicyclo[4.3.0]non-9′-en-8′-yl)-2-propenal ([(5RS,8RS)- und (5RS,8SR)-5,8-Epoxy-5,8-dihydro-ionyloinden]acetaldehyd): Synthese und Röntgenstrukturanalyse

Synthesis and X-Ray Structure of (6′RS,8′RS,2E)- and (6′RS,8′SR,2E)-3-Methyl-3-(2′,2′,6′-trimethyl-7′-oxabicyclo[4.3.0]non-9′-en-8′-yl)-2-propenal ([(5RS,8RS)- and (5RS,8SR)-5,8-Epoxy-5,8-dihydro-ionylidene]acetaldehyde) To check our previous spectroscopic assignments of the structures of trans- and cis-substituted furanoid end groups of carotenoid-5,8-epoxides, we now have synthesized the title compounds. An X-ray structure determination of a single crystal of the trans-isomer (±)- -10A is in agreement with the ¹ H-NMR spectroscopic arguments: isomers with Δδ (H? C(7), H? C(8)) = 0.15–0.22 ppm and J > 1.4 for H? C(7) belong to the cis-series; Δδ in trans-compounds is < 0.07 ppm, and H? C(7) appears as a broad singulett.     

1,2-Fused pyrimidines. III. Derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline,a novel heterocyclic system

Reactivities of 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones and 4-amino-2H-pyrido[1,2-a]pyrimidin-2-ones, both N,N-dialkyl and (N-alkyl, N-phenyl)substituted, when treated with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier-Haack reagent XII were compared. Starting from 2-[(N-alkyl, N-phenyl)amino] compounds IXa,b , the expected XVIa,b and XVIIa,b were obtained, which are derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline, a novel heterocyclic system. When 2-(phenylamino) compound IXc was used a mixture of 3-formylderivative XVIII and 12H-pyrido-[1′,2′:1,2]pyrimido[4,5-b]quinolin-12-one ( XIX ) resulted from the reaction. On the other hand, 2-(dialkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones IIIa-c plainly afforded high yields of 3-formylderivatives XIVa-c. In contrast, no significant reaction occurred when 4-(dialkylamino) and 4-[(N-alkyl,N-phenyl)amino] compounds IIa-c and VIIIa,b were treated with the reagent XII , under the same as well as more severe conditions. A clear difference in the nucleophilic reactivity of C-3 position between these two classes of isomers is pointed out by the above summarized results.     

8-Aza-2′-deoxyguanosine and Related 1,2,3-Triazolo[4,5-d]pyrimidine 2′-Deoxyribofuranosides

The synthesis of 8-azaguanine N⁹-, N⁸-, and N⁷-(2′-deoxyribonucleosides) 1–3 , related to 2′-deoxyguanosine ( 4 ), is described. Glycosylation of the anion of 5-amino-7-methoxy-3H-1,2,3-triazolo[4,5-d]pyrimidine ( 5 ) with 2-deoxy-3,5-di-O-(4-toluoyl)-α-D -erythro-pentofuranosyl chloride ( 6 ) afforded the regioisomeric glycosylation products 7a/7b, 8a/8b , and 9 (Scheme 1) which were detoluoylated to give 10a, 10b, 11a, 11b , and 12a . The anomeric configuration as well as the position of glycosylation were determined by combination of UV, ¹³C-NMR, and ¹H-NMR NOE-difference spectroscopy. The 2-amino-8-aza-2′-deoxyadenosine ( 13 ), obtained from 7a , was deaminated by adenosine deaminase to yield 8-aza-2′-deoxyguanosine ( 1 ), whereas the N⁷- and N⁸-regioisomers were no substrates of the enzyme. The N-glycosylic bond of compound 1 (0.1 N HCl) is ca. 10 times more stable than that of 2′-deoxyguanosine ( 4 ).     

Synthesis and 1H-NMR spectra of halogenated spiro[isobenzofuran-1(3H),9′(9H)-6′-(methylcyclohexylamino)-3′-methyl-2′-anilinoxanthene]-3-ones

Reaction of spiro[isobenzofuran-1(3H).9′(9H)-6′-(methylcyclohexylamino)-3′-methyl-2′-anilinoxanthene]-3-one ( 1 ), which is typical leuco fluoran dye, with N-bromosuccinimide and N-chlorosuccinimide leads to halogenated derivatives 2a–2c and 3 , respectively. Their structures were established by two-dimensional proton-proton (COSY) experiment and their thermal properties examined by means of DSC and compared with commercially available 1 .     

1,2-Epoxycarotinoide. 6. Mitteilung. Isolierung von 1′,2′-Epoxy-1′,2′-dihydro-ε,ψ-carotin aus der ‘Delta-Mutanten’-Tomate

1,2-Epoxycarotenoids Isolation of 1′,2′-Epoxy-1′,2′-dihydro-ε,ψ-carotene from a ‘Delta Mutant’ Tomato From ‘Delta Mutant’ tomatoes, optically active 1′,2′-epoxy-1′,2′-dihydro-ε,ψ-carotene ( 7 ) was isolated. According to the CD data, the configuration is 6R and presumably 2′S.     

Nucleoside und Nucleotide. Teil 16. Verhalten von 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyrimidinon-5′-triphosphat, 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)pyridinon-5′-triphosphat und 4-Amino-1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyridinon-5′-triphosphat gegenüber DNA-Polymerase

Nucleosides and Nucleotides. Part 16. The Behaviour of 1-(2′-Deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidinone-5′-triphosphate, 1-(2′-Deoxy-β-D -ribofuranosyl-2(1H))-pyridinone-5′-triphosphate and 4-Amino-1-(2′-desoxy-β-D -ribofuranosyl)-2(1H)-pyridinone-5′-triphosphate towards DNA Polymerase The behaviour of nucleotide base analogs in the DNA synthesis in vitro was studied. The investigated nucleoside-5′-triphosphates 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone-5′-triphosphate (pppM_d), 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppII_d) and 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppZ_d) can be considered to be analogs of 2′-deoxy-cytidine-5′-triphosphate. However, their ability to undergo base pairing to the complementary guanine is decreased. When pppM_d, pppII_d or pppZ_d are substituted for pppC_d in the enzymatic synthesis of DNA by DNA polymerase no incorporation of these analogs is observed. They exhibit only a weak inhibition of the DNA synthesis. The mode of the inhibition is uncompetitive which shows that these nucleotide analogs cannot serve as substrates for the DNA polymerase.     

New heterocyclic derivatives of 1′- and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones

The preparation of 1′-and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones (IIIa and IIIb) is described, by reduction of the low temperature nitration products of 5′,6′,7′,8′-tetrahydro-2′-acetonaphtone (I). The structures of the nitro isomers (IIa and IIb), and the reduction products, IIIa and IIIb, were elucidated spectroscopically. By known reactions, a series of new heterocyclic compounds prepared from the o-aminoketones, IIIa and IIIb, resulted in two series of new heterocyclic compounds.     

Synthesis and characterization of di‐n‐butyltin(IV) complexes with 4′/2′‐nitrobiphenyl‐2‐carboxylic acids: X‐ray crystal structures of [{(n‐C4H9)2Sn(OCOC12H8NO2−4′)}2O]2 and (n‐C4H9)2Sn{OCOC12H8NO2−4′}2

Reactions of di‐n‐butyltin(IV) oxide with 4′/2′‐nitrobiphenyl‐2‐carboxylic acids in 1 : 1 and 1 : 2 stoichiometry yield complexes [{(n‐C₄H₉)₂Sn(OCOC₁₂H₈NO₂?4′/2′)}₂O]₂ ( 1 and 2 ) and (n‐C₄H₉)₂Sn(OCOC₁₂H₈NO₂?4′/2′)₂ ( 3 and 4 ) respectively. These compounds were characterized by elemental analysis, IR and NMR (¹H, ¹³C and ¹¹⁹Sn) spectroscopy. The IR spectra of these compounds indicate the presence of anisobidentate carboxylate groups and non‐linear C? Sn? C bonds. From the chemical shifts δ (¹¹⁹Sn) and the coupling constants ¹J(¹³C, ¹¹⁹Sn), the coordination number of the tin atom and the geometry of its coordination sphere have been suggested. [{(n‐C₄H₉)₂Sn(OCOC₁₂H₈NO₂?4′)}₂O]₂ ( 1 ) exhibits a dimeric structure containing distannoxane units with two types of tin atom with essentially identical geometry. To a first approximation, the tin atoms appear to be pentacoordinated with distorted trigonal bipyramidal geometry. However, each type of tin atom is further subjected to a sixth weaker interaction and may be described as having a capped trigonal bipyramidal structure. The diffraction study of the complex (n‐C₄H₉)₂Sn(OCOC₁₂H₈NO₂?4′)₂ ( 3 ) shows a six–coordinate tin in a distorted octahedral frame containing bidentate asymmetric chelating carboxylate groups, with the n‐Bu groups trans to each other. The n‐Bu? Sn? n‐Bu angle is 152.8° and the Sn? O distances are 2.108(4) and 2.493(5) Å. The oxygen atom of the nitro group of the ligand does not participate in bonding to the tin atom in 1 and 3 . Crystals of 1 are triclinic with space group P1 and of that of 3 have orthorhombic space group Pnna. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of nitrogen‐containing heterocycles 9. Preparation and carbon‐carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]‐triazolo[1′,5′‐a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N‐cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,‐a][1′,3′‐5′]triazine] derivatives 7–12 in moderate to high yields. Ring‐opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2‐methyl‐7‐methylthio[1,2,4]‐triazolo[1,5‐a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2‐methylpropane from the potential precursor, 2‐tert‐butyl‐2‐methyl‐7‐methylthio[1,2,4]triazolo[1,5‐a]‐[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one‐step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.     

Etude Conformationnelle par Résonance Magnétique Nucléaire Protonique des Dérivés de la O-Isopropylidène-2′,3′ Adénosine

Conformational analysis using ¹H n.m.r. data (δ, ³J and NOE) has been carried out on several derivatives of 2′,3′,-O-isopropylideneadenosine bearing various substituents at positions C-5′, C-8 and N-6. Conformational modifications are assigned to specific interactions between the sugar and purine moieties and also to solvent effects.     

Synthèses dans la série des-indéno-fluorénes,VII. Le trioxo-5,12,13-dihydro-12,13-5H-bis-indéno[2.1-a; 2′.1′-g] fluoréne

Starting from 9-oxo-fluorene-1-carbaldehyde, the title compound, XII, a trioxoderivative of a new biangular diindenofluorene system, has been synthesized in 5 steps (overall yield 37,5%). The corresponding hydrocarbon could not be obtained by reduction of XII. Attempts to synthesize the isomer XX of the trioxoderivative XII are described.