Nouveaux types de sucres acétyléniques. Communication préliminaire

Novel types of acetylenic sugars The coupling, following Cadiot's procedure, of a 6-bromo-5,6-dideoxy-1,2-O-isopropylidène-3-O-methyl-α-D -xylo-hex-5-yno-1, 4-furanose (1) with phenylacetylene, 2-propyn-1-ol or terminal acetylenic sugars gave with excellent yields the expected diynes (an enediyne when the terminal acetylene was the 3,5, 6-trideoxy-1,2-O-isopropylidene-α-D -glycero-hex-3-en-5-yno-1,4-furanose 7 ). The chloro analogue 8 of 1 on treatment with lithium thiophenate gave the corresponding phenylthio-acetylenic sugar 9 . An acetylene was also formed by reacting the gem-difluoro-olefinic sugar 10 with butyllithium whereas the same olefinic sugar and its 3-O-benzyl analogue 11 gave only a gem-fluoro-arylthio-olefinic sugar (13–15) as a mixture of the Z and E isomers (Z/E > 4) when treated with the conjugate base of an arylmercaptan.     

Dérivés du C-méthyl-3-xylofurannose

3-C-Methylxylofuranose Derivatives 3′-C-methyladenosine has been known for almost ten years whereas its 3′-epimer is still to be prepared, because of the difficulty of synthesizing the 3-C-methylxylo-furanose. In this communication, the synthesis of 1,2-O-isoproypylidene acetal 9 and its derivatives is described. Vicinal dihydroxylation of 5-O-benzoyl-3-deoxy-1,2-O-isopryopylidene-3-C-methylidene-α-D -erythro-pentofuranose ( 6 ) led to the branchedchain sugar derivative 7 which was selectively tosylated to 8 whose reduction gave 9 . These reactions, as well as the derivatizations of 7 , 8 and 9 , took place with good to excellent yields.     

Dérivés C-Glycosyliques XXXII. Synthèse de dérivés spiro-C-glycosylidéniques par cyclisation nucléophile. Communication préliminaire

C -Glycosylic derivatives XXXII. Synthesis of spiro-C -glycosylidenic derivatives via nucleophilic cyclization. On treatment with compounds bearing two nucleophilic groups as ethylenediamine, o-phenylenediamine or their monooxa or monothia analogues, 1,2:5, 6-di-O-isopropylidene-α-D -ribo-hexofuranos-3-ulose gave with excellent yields the corresponding spiro-C-glycosylidenic derivative; for example, when using o-phenylenediamine, a spirobenzimidazoline ( 5 ) was obtained. The latter compound underwent, on oxidation, a ring expansion to a morpholinobenzimidazole ( 8 ). Spirobenzodiazepines, spirobenzooxazepines and spirobenzothiazepines were formed when applying the same type of cyclization reaction to 3-C-acetylmethylene-3-deoxy-1,2:5,6-di-O-isopropylidene-α-D -ribo- and α-D -xylo-hexofuranoses.     

Synthèse de spiro-pyrazolines par cycloaddition du diazométhane sur des sucres insaturés ramifiés. Influence de l'isomérie géométrique sur l'orientation de la réaction Communication préliminaire

The orientation of the cycloaddition of diazomethane on unsaturated branchedchain sugars has been studied. For 3-C-cyanomethylidene-3-deoxy-1,2-O-isopropylidene-α-D-glycero-tetrofuranose the orientation was ‘normal’ and did not depend on the configuration at the double bond. The same situation prevailed with derivatives of 3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-methylidene-α-D-xylo-hexofuranose. For the 3-C-acylmethylidene- and the 3-C-cyanomethylidene-3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranoses, the trans-(H–C(3′)–C(2))-isomer gave the ‘normal’ cycloadduct whereas the cis-isomer gave predominantly the αabnormal spiro-pyrazoline. This observation represents the first instance where the regioselectivity of a cycloaddition reaction is affected by the geometrical isomerism of the dipolarophile. The most probable explanation of the phenomenon is the conformational perturbation about the C(4)--C(5) bond of the unsaturated sugars induced by a change in the configuration at C(3). The consequence of that ‘conformational transmission’ of a difference in configuration at C(3) is that the steric crowding on the cis- than in the trans-isomer. Several novel examples of a new series of C-glycosylidenic derivatives, the spiro-pyrazolines, are described.     

Esters phosphoriques cycliques ou non cycliques de quelques O-isopropylidène-1,2-α-D-pentofurannoses. Communication préliminaire

Cyclic and acyclic phosphate esters of some 1,2-O-isopropylidene-α-D -pentofuranoses When treated with monophenyl phosphorodichloridate, 1,2-O-isopropylidene-α-D -xylofuranose gave the two possible, isolable isomers of the corresponding 3,5-cylic phenylphosphate. Upon phosphorylation of the same sugar derivative using bis (2,2,2-trichloroethyl) phosphorochloridate only one isomer was formed. The same situation obtained when preparing 1,2-O-isopropylidene-α-D -ribofuranose-3,5-cyclic phenylphosphate. The synthesis of a new kind of sugar phosphate with a branched-chain unsaturated sugar moiety namely the trans-3-deoxy-3-C-cyanomethylene-1,2-O-isopropylidene-D -erytho-pentofuranose 5-bis(2,2,2-trichloroethyl) phosphate is also described.     

Application de la réaction de Wittig à la synthèse de dérivés de bromoénosuloses et d'esters bromoénuroniques. Note de laboratoire

Use of the Wittig reaction for the synthesis of derivatives of bromoenosuloses and bromoenuronic esters Treatment of 3-O-benzyl (or 3-O-methyl)-1, 2-O-isopropylidene-α-D -xylo-pentodialdo-1, 4-furanoses ( 2 or 1 ) with acetylbromomethylidenetriphenylphosphorane ( 3 ), benzoylbromomethylidenetriphenylphosphorane ( 4 ) or bromoethoxycarbonylmethylidenetriphenylphosphorane ( 5 ) gave in good to excellent yields the expected enose ( 6--11 ). In all cases but one ( 8 where some 10% of the E-isomer was formed) the reaction led to the exclusive formation of the Z-isomer whose configuration was established by NMR.     

A practical synthesis of ethyl 1,2,4-triazole-3-carboxylate and its use in the formation of chiral 1′,2′-seco-nucleosides of ribavirin

A practical and efficient synthesis of ethyl 1,2,4-triazole-3-carboxylate ( 6a , R' = H) from ethyl carboethoxyformimidate hydrochloride ( 7 ) is described. Alkylation of this heterocycle with the chloromethyl ethers of 1,3-O-dibenzylbutane-1,2R,3S-triol ( 8a ) and 1,3,4-O-tribenzylbutane-1,2R,3S,4-tetrol ( 8b ), followed by conversion of the ester function to the amide and deprotection, furnished the chiral 1′,2′-seco-nucleosides of ribavirin, 11a and 11b , respectively.     

Etude de la décomposition thermique d'azido dithiényl-1,2 éthènes et éthanes

Thermal decomposition of azido-1,2-dithienylethenes 1 gave thienyl 4H-thieno[3,2-b]pyrroles 3 . For the 3,4-disubstituted thiophene derivatives 2 , the same reaction led to the amino-1,2-dithienylethenes 4 . In contrast, only azido-1,2-dithienylethanes 7 led to thienyl-5,6-dihydro-4H-thieno[3,4-b]pyrroles 8 . The structure of the obtained derivatives was established on the basis of ¹H nmr, ir, and mass spectral data.     

Synthèse et réactions de didésoxy-5,6-halogéno-6-α-D-xylo-hepténo-5-furannurononitriles. Communication préliminaire

Synthesis and reactions of 5,6-dideoxy-6-halogeno-α-D-xylo-hept-5-eno-furanurononitriles The 5,6-dideoxy-6-chloro-, 6-iodo- and 6-fluoro-3-O-methyl-α-D -xylo-hept-5-eno-furanurononitriles have been prepared, their properties described as well as the methods used for the assignment of the configuration of the geometrical isomers. Some new reactions of the 6-bromo analog ( 1 ) of these compounds are reported. For example, when reacted with 2-mercaptoethanol or N,N′-dimethyl-ethylenediamine in the presence of NaOH, 1 gave the corresponding six-membered ring, stereo-isomers of an oxathiane or of a perhydrodiazine respectively. When the base used was Et₃N and the binucleophile the N-methyl-ethanolamine or the N,N′-dimethyl-ethylene-diamine the major product was a cyano-enamine which could be hydrolysed to a β-cyanoketone or cyclized to a five-membered ring, an oxazolidine or an imidazolidine respectively.     

Un nouvel analogue synthétique de l'adénosine: La désoxy-3′-C-dibromométhylidène-3′-adénosine

A novel synthetic analog of adenosine: the 3′-deoxy-3′-C-dibromomenthylidene-adenosine The title compound ( 7 ) has been prepared by a sequence of classical synthetic steps from 3-deoxy-3-C-dibromomethylidene-1,2: 5,6-di-O-isopropylidene-α-D -ribo-hexofuranose ( 1 ). The β-configuration of the nucleoside was established by formation of a cyclonucleoside. 7 is very slowly deaminated by adenosine deaminase. In contrast with its dichloro analog, it does not inhibit the growth of Escherichia coli.     

Etude par spectrométrie de masse de la fragmentation du désoxy-3-di-O-isopropylidène-1,2: 5,6-méthylidène-3-α-D-hexofurannose et de quelques analogues substitués en C(3′)

Electron Impact Mass Spectrometry of the 3-Desoxy-1,2: 5,6-di-O-isopropylidene-3-methylidene-δ-D -hexofuranose and Some C(3′)-Substituted Analogues The mass spectra of the 3-desoxy-1,2:5, 6-di-O-isopropylidene-3-methylidene- α-D -ribo-hexofuranose and of some C(3′)-mono- and -disubstituted derivatives have been investigated. Deuterium labelled molecules allow fragmentation modes to be proposed.     

Syntheses of 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one,an isostere of oxanosine,and the guanosine analog 6-amino-1-(β-d-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one via ring closure of pyrazole-5-thioureido intermediates

6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 4 ), an isostere of the nucleoside antibiotic oxanosine has been synthesized from ethyl 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxylate ( 6 ). Treatment of 6 with ethoxycarbonyl isothiocyanate in acetone gave the 5-thioureido derivative 7 , which on methylation with methyl iodide afforded ethyl 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-ethoxycarbonyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxylate ( 8 ). Ring closure of 8 under alkaline media furnished 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 10 ), which on deisopropylidenation afforded 4 in good yield. 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 5 ) has also been synthesized from the AICA riboside congener 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxamide ( 12 ). Treatment of 12 with benzoyl isothiocyanate, and subsequent methylation of the reaction product with methyl iodide gave 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-benzoyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxamide ( 15 ). Base mediated cyclization of 15 gave 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 14 ). Deisopropylidenation of 14 with aqueous trifluoroacetic acid afforded 5 in good yield. Compound 4 was devoid of any significant antiviral or antitumor activity in culture.     

Novel and Stereospecific Synthesis of (2S)‐3‐(2,4,5‐Trifluorophenyl)propane‐1,2‐diol from D‐Mannitol

A stereospecific synthesis of (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol from D ‐mannitol has been developed. The reaction of 2,3‐O‐isopropylidene‐D ‐glyceraldehyde with 2,4,5‐trifluorophenylmagnesium bromide gave [(4R)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl](2,4,5‐trifluorophenyl)methanol in 65% yield as a mixture of diastereoisomers (1 : 1). The Ph₃P catalyzed reaction of the latter with C₂Cl₆ followed by reduction with Pd/C‐catalyzed hydrogenation gave (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol with >99% ee and 65% yield.     

Synthesis of some 6-S-heterocyclic derivatives of 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose

We applied nucleophilic substitution to 6-O-tosyl-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose using sulphur nucleophiles and obtained 6-S-derivatives of 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose. We present the physical and spectroscopic characterization of these heterocyclic compounds as well as other related compounds obtained by substitution, using other substrates. The conformational studies of all products are presented and discussed.     

Synthesis and epimerization of 10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-(11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione

The reaction of the 1,2:3,4-di-O-isopropylidene-6-O-tosyl-α-d-galactopyranose 2 with (11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione 1, prepared from l-proline and isatoic anhydride, gave two products which were previously reported as conformational isomers. In this work, an X-ray crystallographic study showed these to be the diastereomeric pair (11aS)- and (11aR)-10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones as a consequence of C(11a) epimerization in the benzodiazepine moiety during glycosylation under basic reaction conditions. The hydrosolubility of the deprotected products were compared with those of the analogous benzodiazepine derivatives.     

Action du cyanure mercurique sur quelques halogénures de désoxy-3-trifluoroacétamido-3-D-ribofurannosyle. Note de laboratoire

Reactions of Some 3-Deoxy-3-trifluoroacetamido-D -ribofuranosyl Halides with Mercuric Cyanide The expected 2,5-anhydro-D -allononitrile 11 was obtained when the 2-O-benzoyl-3-deoxy-3-trifluoroacetamido-D -ribofuranosyl bromide reacted with mercuric cyanide, whereas the isomeric 1,2-O (1-cyanoethylidene) derivative was formed from the 2-O-acetylated halide; no reaction occurred when the halide was 2-O-p-nitrobenzoylated.     

Thiosucres. III. Réactions du substituant (benzylthio)-acétyle. Communication préliminarie

Thiosugars. III. Some reactions of the (benzylthio)-acetyl substituent Preliminary Communication The (benzylthio)-acetyl substituent as found in 6-benzylthio-6-deoxy-1, 2-O-isopropylidene-3-O-methyl-α-D-xylo-hexofuranos-5-ulose ( 1 ) constitutes and useful synthon which can be transformed into ‘second generation’ synthons as, for example, the sulfylidene 10 or the chlorinated derivative 14 . S-Debenzylating C-acylation of 10 leading to 11 is described as well as the ring-forming condensation of 10 with the sulfene 12 . Depending on the nature of the nucleophile reacted with 14 , one can obtain the product of the substitution of the chlorine atom or of the chlorine atom and the benzylthio group or reactions taking place at both the carbonyl group and the terminal carbon atom, among them binucleophilic cyclizations. Some reactions of the conjugate base of 14 are also described.     

Un nouvel exemple de nucléoside à sucre ramifié insaturé: la désoxy-3′-méthylidène-3′-adénosine

A Novel Example of Unsaturated Branched-chain Sugar Nucleoside: 3′-Deoxy-3′-methylidene-adenosine Starting from 5-O-benzoyl-3-C-methylidene-3-deoxy-1,2-O-isopropylidene-α-D -erythro-pentofuranose ( 11 ) the title compound 8 has been prepared. Its α-anomer ( 9 ) and the acyclic sugar nucleoside 10 have been obtained as by-products. Adenosine deaminase slowly deaminated 8, 9 being not affected. Compound 8 exhibited no antiviral activity, whereas one of its saturated analogues ( 13 ) inhibited the multiplication of the herpes-1 (HF) virus.     

Compounds with bridgehead nitrogen. 42—1H NMR and stereochemistry of isomeric 6a-methylperhydroindolo[3,2,1-i,j]benzoxazines and the position of conformational equilibrium in perhydropyrrolo[1,2-c][1,3]oxazine

The ¹H NMR parameters of the NCH₂O protons in the spectrum of perhydropyrrolo[1,2-c][1,3]oxazine show its existence in solution at room temperature in the O-inside cis-fused conformation. rel-(3aS,6aS,6bR,10aS,11aS)-6a-Methylperhydroindolo[3,2,1-i,j]benzoxazine and rel-(3aS,6aS,6bS,10aR,11aS)-6a-methylperhydroindolo[3,2,1-i,j]benzoxazine are shown to adopt cis- and trans-fused conformations, respectively, for the corresponding bicyclic moiety.     

A Practical Synthesis of 3′-Thioguanosine and of Its 3′-Phosphoramidothioite (a Thiophosphoramidite)

Starting from guanosine, an efficient method for the synthesis of 3′-thioguanosine (see 13 ) and of its 3′-phosphoramidothioite (see 23 ), suitable for automated incorporation into oligonucleotides, was developed. Reaction of 5′-N²-protected guanosine with 2-acetoxyisobutyryl bromide afforded stereoselectively the 2′-O-acetyl-3′-bromo-β-D -xylofuranosyl derivative 3 , which was converted to a 7 : 3 mixture of the S-acyl ribofuranosyl intermediates 5 or 6 and the 3′,4′-unsaturated by-product 4 . The S-acylated nucleosides 5 and 6 were then converted in three steps to 5′-O-(4,4′-dimethoxytrityl)-3′-S-(pyridin-2-ylthio)-3′-thioguanosine ( 11 ), which served as a common intermediate for the preparation of free 3′-thionucleoside 13 and 3′-thionucleoside 3′-phosphoramidothioite 23 .