Pyridazine C-nucleosides have been synthesized by [4+2] cycloaddition of alkynyl C-nucleosides with substituted tetrazines. These pyridazines on extrusion of a nitrogen atom afforded novel pyrrole C-nucleosides with good yields. The results of electrochemical and chemical reduction are compared. (C) 2003 Elsevier Ltd. All rights reserved.

The synthesis of monoglycosyl imidazoles and 1,1′-di-O-glycosides is described by direct glycosylation process from reducing sugar in the presence of 1,1′-thiocarbonyldiimidazole. Novel anomeric groups as 1-O-(imidazolyl)thiocarbonyl and 1-O-(imidazolyl)carbonyl are presented as potent glycosidic activators.

The syntheses of thiazinone, thiazinedione and thiazolinone base modified nucleoside analogues have been discussed in both the deoxy- and ribosyl series. Both inter- and intramolecular N-glycosylations were evaluated.

The synthesis of galactosides thiolate and thioester is described by direct S-glycosylation process from 1-O-(thio-p-nitrobenzoyl)thiocarbonyl galactoside. Three novel anomeric groups are presented as potent glycoside activators: O-(thio-p-nitrobenzoyl)thiocarbonyl, O-(imidazolyl)thiocarbonyl and S-thio-p-nitrobenzoyl.

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The electrochemical two electron reduction of pyridazines, substituted by electron withdrawing groups, primarily lead to their corresponding 1,2-dihydro-derivatives. Depending on the nature of the ring substitution, these intermediates can either rearrange into 1,4-dihydro-pyridazines, or undergo electrochemical reduction to give rise to activated pyrroles by a ring contraction reaction with extrusion of nitrogen. Another way of access to the latter has been achieved by a disproportionation reaction of 1,2-dihydro-pyridazines, leading directly to the expected pyrroles and recovery of 50% of pyridazines.

Two studies, concerning the synthesis of original nucleoside analogs regarded as an application of heterochemistry on thiaazaheterocycle systems from thiaazabutadienes are discussed. The preparation of new N- and C-nucleosides is presented. In the second part, the discovery of aromatic polycyclic derivatives as inhibitors of Tat protein is exposed. The work presented takes into account the participation of African partners in further synthetic research programs carried out in collaboration with the laboratory of Nantes.

The bielectronic electrochemical reduction of pyridazines, substituted by electron-withdrawing groups, leads to their corresponding 1,2-dihydro derivatives. Depending on the nature of the ring substitution, these intermediates can either rearrange into 1,4-dihydropyridazine isomers or be further electrochemically reduced into activated pyrroles.

The synthesis of 3'-O2-(azaheterocycle)-thymidines is presented from 1-thia-3-aza- 1,3-butadiene precursors (N-thioacylamidines). A variety of heterocycles is accessible using the dienic, the electrophilic or the nucleophilic reactivity of these thia-azabutadiene systems. 3'-O2-(azaheterocycle)-thymidine analogues are regarded as potential substrates to interfere with the DNA-polymerization process.

The preparation of 2-phenyl-4-dimethylamino-1-aza-, 1-oxa-, 1-thia-, 1-selena-3-azabuta-1,3-dienes as well as their 4-methyl derivatives is described following a new heteroatom interchange reaction process. Heteronucleophilic attack at one particular reactive site of bis-electrophilic amidinium salts is the key feature of the process. In addition, we also disclose that the substituted 1-oxa-3-aza- and 1,3-diazabuta-1,3-dienes can be obtained by a reactional transformation cascade initiated by either silver acetate addition or tosyl azide [3+2] cycloaddition onto the CS or CSe double bonds of the 1-thia- and 1-selena-3-azabuta-1,3-diene analogues.

A new synthesis and the reactivity of stable selenaazadienes are discussed. Their dienic, electrophilic and nucleophilic character are used to prepare five and six membered selenoheterocycles. The easy access to selenazine, selenazinone, selenopyran, selenazoline, selenazole and selenophene heterocycles from N-selenoacylamidines is described. An interpretation of the reactivity of the selenaazadiene systems, experimentaly compared to their thia analogues, is based on their physico-chemical parameters and correlated to the theoretical calculations of their frontier molecular orbital energy levels.

An original synthesis of substituted formyl selenophene heterocycles is described via selenoamide vinylogue from N-selenoacylamidines. The access of mono and his-substituted 1,3-dithiol-2-ylidene selenophenes, potential pi-conjugated precursors of selenafulvalene analogs, was achieved using Wittig olefination.

The behaviour of endo selective diene 4 in kinetically controlled hetero Diels-Alder cycloadditions is in marked contrast with that of its exo selective aza analogue 1.

Electrochemical behaviour of triactivated thiopyrans has been investigated in protic medium. Electroreduction of 4-dimethylamino-2,3,5-trimethoxycarbonyl-4H-thiopyran I first led to 2,3, 5-trimethoxy-carbonyl-2H-thiopyran IV, with elimination of dimethylamine; further reduction at more negative potential gives equimolar mixture of 2,3,6-trimethoxycarbonyl-3,6-dihydro-2H-thiopyran V and 2,3, 6-trimethoxycarbonyl-5,6-dihydro-2H-thiopyran VI. The same mixture is obtained by reduction of either 4-dimethylamino-3,5,6-trimethoxycarbonyl-3,4-dihydro-2H-thiopyran II or 3,5,6-trimethoxycarbonyl-2H-thiopyran III. Intermediate formation of a delocalised carbanion is postulated in order to explain these results.

Electroreduction of tetraactivated 4H-thiopyrans leads selectively to diastereoisomers of dihydrothiopyrans. The relative percentages depend on the experimental conditions (electrolysis in sulfuric medium, ammoniacal buffer). The preferred conformations of the end-products are determined in solid state by X-ray crystallography and in solution by H-1 NMR spectroscopy, then compared with molecular modelling results. The relative conformations of the diastereoisomers and their ratio are established by H-1 NMR spectroscopy.

Dipole moments of selenobenzamide, of eight N′-thio (oxo or seleno) acylamidines and of two N′-thioacyliminoethylidenetriphenylphosphoranes in carbon tetrachloride, benzene or dioxane solutions were measured or examined. Calculations of molecular moments for the sp (CS and NC on the same side) and ap conformations and for the canonical structures implied by conjugation were performed according to a recently proposed method. A comparison between the calculated and the experimental values shows that only strong conjugations with significant statistical percentages ps(±) of the 1,5 (or 1,6) zwitterionic forms (X−CN−CN+ or X−CNCCP+ with X  O, S or Se) can explain observed moments. The μ differences between compounds are related to ps(±) variations which can give information about the molecular structures and their relationship with reactivities.

New 2-aza-1,3-dienes bearing 1 and 3-donor substituents are prepared from N-thioacylacetamidines through deprotonation of N-ylidene acetamidinium iodides. The 2-aza-3-(dimethylamino)-1-(methylthio)-1-phenylbutadiene (3) is trapped in situ by the residual precursor salt acting as a heterodienophile to give the pyrimidine 5. Substituted 2-aza-1-(dimethylamino)-3-(methylthio) analogues react readily with a variety of electron-deficient dienophiles to yield pyridine or pyrimidine derivatives. The stereochemistry of the hetero Diels-Alder reaction in the cases of dimethyl fumarate and acrylonitrile has been assigned by X-ray diffraction analyses of the resulting tetrahydropyridines and corresponds to an exo selectivity. The number and nature of cycloadducts in the cases of dimethyl acetylenedicarboxylate and phenyl isothiocyanate depend on C-4 substitution. The results obtained from the C-4 unsubstituted azabutadiene 8 are explained by an allylic rearrangement involving the 1,3-migration of dimethylamino group in the primary [4+2] adduct.

Magnesium bromide mediated hetero Diels-Alder cycloaddition of diene 1 (R(1) = Ph) to chiral N-acryloyl-2-oxazolidinone 4b leads to 5b as the sole adduct formed. Chiral auxiliary removal leads to enantiomerically pure 5,6-dihydro-4H-1,3-thiazine 3 (R(2) = Bn). The selectivity of the cycloaddition is reversed under thermal or high pressure activation. The predominant diastereomeric adduct 6b is isolated in pure form after flash chromatography.