Three structures of dispirooxindole derivatives generated in situ through a three‐component one‐pot strategy with complete regio‐ and stereoselectivity

The challenging molecular architecture of spirooxindoles is appealing to chemists because it evokes novel synthetic strategies that address configurational demands and provides platforms for further reaction development. The [3+2] cycloaddition of the carbonyl ylide with arylideneoxindole via a five‐membered cyclic transition state gave a novel class of dispirooxindole derivatives, namely tert‐butyl 4′‐(4‐bromophenyl)‐1′′‐methyl‐2,2′′‐dioxo‐5′‐phenyl‐4′,5′‐dihydrodispiro[indoline‐3,2′‐furan‐3′,3′′‐indoline]‐1‐carboxylate, C₃₆H₃₁BrN₂O, (Ia), 5′‐(4‐bromophenyl)‐1,1′′‐dimethyl‐4′‐phenyl‐4′,5′‐dihydrodispiro[indoline‐3,2′‐furan‐3′,3′′‐indoline]‐2,2′′‐dione, C₃₂H₂₅BrN₂O₃, (Ib), and tert‐butyl 1′′‐methyl‐2,2′′‐dioxo‐4′‐phenyl‐5′‐(p‐tolyl)‐4′,5′‐dihydrodispiro[indoline‐3,2′‐furan‐3′,3′′‐indoline]‐1‐carboxylate, C₃₇H₃₄N₂O₅, (Ic). Crystal structure analyses of these dispirooxindoles revealed the formation of two diastereoisomers selectively and confirmed their relative stereochemistry (SSSR and RRRS). In all three structures, intramolecular C—H...O and π–π interactions between oxindole and dihydrofuran rings are the key factors governing the regio‐ and stereoselectivity, and in the absence of conventional hydrogen bonds, their crystal packings are strengthened by intermolecular C—H...π interactions.     

Different nucleobase orientations in two cyclic 2′,3′‐phosphates of purine ribonucleosides: Et3NH(2′,3′‐cAMP) and Et3NH(2′,3′‐cGMP)·H2O

The crystal structures of triethyl­ammonium adenosine cyclic 2′,3′‐phosphate {systematic name: triethyl­ammonium 4‐(6‐amino­purin‐9‐yl)‐6‐hydroxy­methyl‐2‐oxido‐2‐oxoperhydro­furano[3,4‐c][1,3,2]dioxaphosphole}, Et₃NH(2′,3′‐cAMP) or C₆H₁₆N⁺·C₁₀H₁₁N₅O₆P⁻, (I), and guanosine cyclic 2′,3′‐phosphate monohydrate {systematic name: triethyl­ammonium 6‐hydroxy­methyl‐2‐oxido‐2‐oxo‐4‐(6‐oxo‐1,6‐dihydro­purin‐9‐yl)perhydro­furano[3,4‐c][1,3,2]dioxaphosphole monohydrate}, [Et₃NH(2′,3′‐cGMP)]·H₂O or C₆H₁₆N⁺·C₁₀H₁₁N₅O₇P⁻·H₂O, (II), reveal different nucleobase orientations, viz. anti in (I) and syn in (II). These are stabilized by different inter‐ and intra­molecular hydrogen bonds. The structures also exhibit different ribose ring puckering [₄E in (I) and ³T₂ in (II)] and slightly different 1,3,2‐dioxaphospho­lane ring conformations, viz. envelope in (I) and puckered in (II). Infinite ribbons of 2′,3′‐cAMP⁻ and helical chains of 2′,3′‐cGMP⁻ ions, both formed by O—H⋯O, N—H⋯X and C—H⋯X (X = O or N) hydrogen‐bond contacts, characterize (I) and (II), respectively.     

Two stereoisomeric pentacyclic oxin­dole alkaloids from Uncaria tomentosa: uncarine C and uncarine E

The chloro­form solvate of uncarine C (pteropodine), (1′S,3R,4′aS,5′aS,10′aS)‐1,2,5′,5′a,7′,8′,10′,10′a‐octa­hydro‐1′‐methyl‐2‐oxospiro­[3H‐indole‐3,6′(4′aH)‐[1H]­pyrano­[3,4‐f]indolizine]‐4′‐carboxyl­ic acid methyl ester, C₂₁H₂₄N₂O₄·CHCl₃, has an absolute configuration with the spiro C atom in the R configuration. Its epimer at the spiro C atom, uncarine E (isopteropodine), (1′S,3S,4′aS,5′aS,10′aS)‐1,2,5′,5′a,7′,8′,10′,10′a‐octahydro‐1′‐methyl‐2‐oxospiro[3H‐indole‐3,6′(4′aH)‐[1H]pyrano[3,4‐f]indolizine]‐4′‐carboxylic acid methyl ester, C₂₁H₂₄N₂O₄, has Z′ = 3, with no solvent. Both form intermolecular hydrogen bonds involving only the ox­indole, with N?O distances in the range 2.759 (4)–2.894 (5) Å.     

Synthesis of spiro[indoline‐3,3′‐pyrrolizines] by 1,3‐dipolar reactions between isatins,l‐proline and electron‐deficient alkenes

Two spiro[indoline‐3,3′‐pyrrolizine] derivatives have been synthesized in good yield with high regio‐ and stereospecificity using one‐pot reactions between readily available starting materials, namely l ‐proline, substituted 1H‐indole‐2,3‐diones and electron‐deficient alkenes. The products have been fully characterized by elemental analysis, IR and NMR spectroscopy, mass spectrometry and crystal structure analysis. In (1′RS ,2′RS ,3SR ,7a′SR )‐2′‐benzoyl‐1‐hexyl‐2‐oxo‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizine]‐1′‐carboxylic acid, C₂₈H₃₂N₂O₄, (I), the unsubstituted pyrrole ring and the reduced spiro‐fused pyrrole ring adopt half‐chair and envelope conformations, respectively, while in (1′RS ,2′RS ,3SR ,7a′SR )‐1′,2′‐bis(4‐chlorobenzoyl)‐5,7‐dichloro‐2‐oxo‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizine], which crystallizes as a partial dichloromethane solvate, C₂₈H₂₀Cl₄N₂O₃·0.981CH₂Cl₂, (II), where the solvent component is disordered over three sets of atomic sites, these two rings adopt envelope and half‐chair conformations, respectively. Molecules of (I) are linked by an O—H…·O hydrogen bond to form cyclic R ₆⁶(48) hexamers of (S ₆) symmetry, which are further linked by two C—H…O hydrogen bonds to form a three‐dimensional framework structure. In compound (II), inversion‐related pairs of N—H…O hydrogen bonds link the spiro[indoline‐3,3′‐pyrrolizine] molecules into simple R ₂²(8) dimers.     

Purine 3′:5′‐cyclic nucleotides with the nucleobase in a syn orientation: cAMP,cGMP and cIMP

Purine 3′:5′‐cyclic nucleotides are very well known for their role as the secondary messengers in hormone action and cellular signal transduction. Nonetheless, their solid‐state conformational details still require investigation. Five crystals containing purine 3′:5′‐cyclic nucleotides have been obtained and structurally characterized, namely adenosine 3′:5′‐cyclic phosphate dihydrate, C₁₀H₁₂N₅O₆P·2H₂O or cAMP·2H₂O, (I), adenosine 3′:5′‐cyclic phosphate 0.3‐hydrate, C₁₀H₁₂N₅O₆P·0.3H₂O or cAMP·0.3H₂O, (II), guanosine 3′:5′‐cyclic phosphate pentahydrate, C₁₀H₁₂N₅O₇P·5H₂O or cGMP·5H₂O, (III), sodium guanosine 3′:5′‐cyclic phosphate tetrahydrate, Na⁺·C₁₀H₁₁N₅O₇P⁻·4H₂O or Na(cGMP)·4H₂O, (IV), and sodium inosine 3′:5′‐cyclic phosphate tetrahydrate, Na⁺·C₁₀H₁₀N₄O₇P⁻·4H₂O or Na(cIMP)·4H₂O, (V). Most of the cyclic nucleotide zwitterions/anions [two from four cAMP present in total in (I) and (II), cGMP in (III), cGMP⁻ in (IV) and cIMP⁻ in (V)] are syn conformers about the N‐glycosidic bond, and this nucleobase arrangement is accompanied by C_rib—H…N_pur hydrogen bonds (rib = ribose and pur = purine). The base orientation is tuned by the ribose pucker. An analysis of data obtained from the Cambridge Structural Database made in the context of syn–anti conformational preferences has revealed that among the syn conformers of various purine nucleotides, cyclic nucleotides and dinucleotides predominate significantly. The interactions stabilizing the syn conformation have been indicated. The inter‐nucleotide contacts in (I)–(V) have been systematized in terms of the chemical groups involved. All five structures display three‐dimensional hydrogen‐bonded networks.     

Regio‐ and stereospecific assembly of dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidines] from simple precursors using a one‐pot procedure: synthesis,spectroscopic and structural characterization,and a proposed mechanism of formation

The synthesis and characterization of three new dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine] compounds are reported, together with the crystal structures of two of them. (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐Chlorophenyl)‐1‐hexyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₈H₃₀ClN₃O₂S₂, (I), (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐1‐benzyl‐5‐methyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₃₀H₂₆ClN₃O₂S₂, (II), and (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐5‐fluoro‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₂H₁₇ClFN₃O₂S₂, (III), were each isolated as a single regioisomer using a one‐pot reaction involving l ‐proline, a substituted isatin and (Z)‐5‐(4‐chlorobenzylidene)‐2‐sulfanylidenethiazolidin‐4‐one [5‐(4‐chlorobenzylidene)rhodanine]. The compositions of (I)–(III) were established by elemental analysis, complemented by high‐resolution mass spectrometry in the case of (I); their constitutions, including the definition of the regiochemistry, were established using NMR spectroscopy, and the relative configurations at the four stereogenic centres were established using single‐crystal X‐ray structure analysis. A possible reaction mechanism for the formation of (I)–(III) is proposed, based on the detailed stereochemistry. The molecules of (I) are linked into simple chains by a single N—H…N hydrogen bond, those of (II) are linked into a chain of rings by a combination of N—H…O and C—H…S=C hydrogen bonds, and those of (III) are linked into sheets by a combination of N—H…N and N—H…S=C hydrogen bonds.     

Structural consequences of weak interactions in dispirooxindole derivatives

Spiro scaffolds are being increasingly utilized in drug discovery due to their inherent three‐dimensionality and structural variations, resulting in new synthetic routes to introduce spiro building blocks into more pharmaceutically active molecules. Multicomponent cascade reactions, involving the in situ generation of carbonyl ylides from α‐diazocarbonyl compounds and aldehydes, and 1,3‐dipolar cycloadditon with 3‐arylideneoxindoles gave a novel class of dispirooxindole derivatives, namely 1,1′′‐dibenzyl‐5′‐(4‐chlorophenyl)‐4′‐phenyl‐4′,5′‐dihydrodispiro[indoline‐3,2′‐furan‐3′,3′′‐indoline]‐2,2′′‐dione, C₄₄H₃₃ClN₂O₃, (I), 1′′‐acetyl‐1‐benzyl‐5′‐(4‐chlorophenyl)‐4′‐phenyl‐4′,5′‐dihydrodispiro[indoline‐3,2′‐furan‐3′,3′′‐indoline]‐2,2′′‐dione, C₃₉H₂₉ClN₂O₄, (II), 1′′‐acetyl‐1‐benzyl‐4′,5′‐diphenyl‐4′,5′‐dihydrodispiro[indoline‐3,2′‐furan‐3′,3′′‐indoline]‐2,2′′‐dione, C₃₉H₃₀N₂O₄, (III), and 1′′‐acetyl‐1‐benzyl‐4′,5′‐diphenyl‐4′,5′‐dihydrodispiro[indoline‐3,2′‐furan‐3′,3′′‐indoline]‐2,2′′‐dione acetonitrile hemisolvate, C₃₉H₃₀N₂O₄·0.5C₂H₃N, (IV). All four compounds exist as racemic mixtures of the SSSR and RRRS stereoisomers. In these structures, the two H atoms of the dihydrofuran ring and the two substituted oxindole rings are in a trans orientation, facilitating intramolecular C—H...O and π–π interactions. These weak interactions play a prominent role in the structural stability and aid the highly regio‐ and diastereoselective synthesis. In each of the four structures, the molecular assembly in the crystal is also governed by weak noncovalent interactions. Compound (IV) is the solvated analogue of (III) and the two compounds show similar structural features.     

TiO2 Nanoparticles Immobilized on Carbon Nanotubes: An Efficient Heterogeneous Catalyst in Cyclocondensation Reaction of Isatins with Malononitrile and 4-Hydroxycoumarin or 3,4-Methylenedioxyphenol under Mild Reaction Conditions

TiO₂ nanoparticles supported on carbon nanotubes (TiO₂-CNTs) as an efficient heterogeneous catalyst was used for the synthesis of spiro[3,4′]1,3-dihydro-2H-indol-2-one-2′-amino-5′-oxo-4'H,5'H-pyrano[3′,2′-c]chromen-3′-yl cyanides and spiro[3,8′]1,3-dihydro-2H-indol-2-one-6′-amino-8'H-[1′,3′]dioxolo[4′,5′-g]chromen-7′-yl cyanides via the cyclocondensation reaction of isatins with malononitrile and 4-hydroxycoumarin or 3,4-methylenedioxyphenol in aqueous media at room temperature. This reaction offers several sustainable and economic benefits such as high yields of products, convenient operation, and use of non-toxic catalyst in water media.     

Cinerin C: a macrophyllin‐type bicyclo[3.2.1]octane neolignan from Pleurothyrium cinereum (Lauraceae)

The structure of naturally‐occurring cinerin C [systematic name: (7S,8R,3′R,4′S,5′R)‐Δ^8′‐4′‐hydroxy‐5,5′,3′‐trimethoxy‐3,4‐methylenedioxy‐2′,3′,4′,5′‐tetrahydro‐2′‐oxo‐7.3′,8.5′‐neolignan], isolated from the ethanol extract of leaves of Pleurothyrium cinereum (Lauraceae), has previously been established by NMR and HRMS spectroscopy, and its absolute configuration established by circular dichroism measurements. For the first time, its crystal strucure has now been established by single‐crystal X‐ray analysis, as the monohydrate, C₂₂H₂₆O₇·H₂O. The bicyclooctane moiety comprises fused cyclopentane and cyclohexenone rings which are almost coplanar. An intermolecular O—H...O hydrogen bond links the 4′‐OH and 5′‐OCH₃ groups along the c axis.     

Carbon-13 nuclear magnetic resonance study of a new ring-chain tautomerism of some pyridazine derivatives

The ¹³C NMR spectra of a number of pyridazine derivatives have been recorded in DMSO-d₆ solution and analysed. Examination of the most diagnostic resonances, with particular emphasis on those arising from the pyridazine ring system, enabled the ready establishment of the presence of a ring-chain tautomerism in 5-(o-aminophenylcarbamoyl)pyridazine-4-carboxylic acid, methyl 5-(o-aminophenylcarbamoyl)pyridazine-4-carboxylate, 5-(o-aminophenylcarbamoyl)-3,6,-dimethylpyridazine-4-carboxylic acid and 5-(2-amino-1,2-dicyanovinylenecarbamoyl)pyridazine-4-carboxylic acid. This gave rise to 3′,4′-dihydro-3′-oxospiro[pyridazine-5(2H),2′(1H)-quinoxaline]-4-carboxylic acid, methyl 3′,4′-dihydro-3′oxospiro[pyridazine-5(2H),2′(1′H)-quinoxaline]-4-carboxylate, 3′,4′-dihydro-3′-oxo-3,6-dimethylspiro[pyridazine-5(2H), 2′(1′H)-quinoxaline]-4-carboxylic acid and 5-oxo-2,3-dicyano-1,4,8,9-tetraazaspiro[5.5]undeca-2,7,10-triene-11-carboxylic acid, respectively.     

Synthese von diastereo- und enantio-selektiv deuterierten β,ε-, β,β-, β,γ- und γ,γ-Carotinen

Synthesis of Diastereo- and Enantioselectively Deuterated β,ε-, β,β-, β,γ- and γ,γ-Carotenes We describe the synthesis of (1′R, 6′S)-[16′, 16′, 16′-²H₃]-β, εcarotene, (1R, 1′R)-[16, 16, 16, 16′, 16′, 16′-²H₆]-β, β-carotene, (1′R, 6′S)-[16′, 16′, 16′-²H₃]-γ, γ-carotene and (1R, 1′R, 6S, 6′S)-[16, 16, 16, 16′, 16′, 16′-²H₆]-γ, γ-carotene by a multistep degradation of (4R, 5S, 10S)-[18, 18, 18-²H₃]-didehydroabietane to optically active deuterated β-, ε- and γ-C₁₁-endgroups and subsequent building up according to schemes \documentclass{article}\pagestyle{empty}\begin{document}${\rm C}_{11} \to {\rm C}_{14}^{C_{\mathop {26}\limits_ \to }} \to {\rm C}_{40} $\end{document} and C₁₁ → C₁₄; C₁₄+C₁₂+C₁₄→C₄₀. NMR.- and chiroptical data allow the identification of the geminal methyl groups in all these compounds. The optical activity of all-(E)-[²H₆]-β,β-carotene, which is solely due to the isotopically different substituent not directly attached to the chiral centres, is demonstrated by a significant CD.-effect at low temperature. Therefore, if an enzymatic cyclization of [17, 17, 17, 17′, 17′, 17′-²H₆]lycopine can be achieved, the steric course of the cyclization step would be derivable from NMR.- and CD.-spectra with very small samples of the isolated cyclic carotenes. A general scheme for the possible course of the cyclization steps is presented.     

Four N7‐alkoxybenzyl‐substituted 4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐diones: hydrogen‐bonded supramolecular structures in zero,one, two or three dimensions

3‐tert‐Butyl‐7‐(4‐methoxybenzyl)‐4′,4′‐dimethyl‐1‐phenyl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione, C₃₁H₃₇N₃O₃, (I), 3‐tert‐butyl‐7‐(2,3‐dimethoxybenzyl)‐4′,4′‐dimethyl‐1‐phenyl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione, C₃₂H₃₉N₃O₄, (II), 3‐tert‐butyl‐4′,4′‐dimethyl‐7‐(3,4‐methylenedioxybenzyl)‐1‐phenyl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione, C₃₁H₃₅N₃O₄, (III), and 3‐tert‐butyl‐4′,4′‐dimethyl‐1‐phenyl‐7‐(3,4,5‐trimethoxybenzyl)‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione ethanol 0.67‐solvate, C₃₃H₄₁N₃O₅·0.67C₂H₆O, (IV), all contain reduced pyridine rings having half‐chair conformations. The molecules of (I) and (II) are linked into centrosymmetric dimers and simple chains, respectively, by C—H...O hydrogen bonds, augmented only in (I) by a C—H...π hydrogen bond. The molecules of (III) are linked by a combination of C—H...O and C—H...π hydrogen bonds into a chain of edge‐fused centrosymmetric rings, further linked by weak hydrogen bonds into supramolecular arrays in two or three dimensions. The heterocyclic molecules in (IV) are linked by two independent C—H...O hydrogen bonds into sheets, from which the partial‐occupancy ethanol molecules are pendent. The significance of this study lies in its finding of a very wide range of supramolecular aggregation modes dependent on rather modest changes in the peripheral substituents remote from the main hydrogen‐bond acceptor sites.     

Aqueous-Mediated green synthesis of novel spiro[indole-quinazoline] derivatives using kit-6 mesoporous silica coated Fe3O4 nanoparticles as catalyst

In this work, a series of eight new spiro[3,4′]1,3-dihydro-2H-indol-2-one-2′-amino-4′,6′,7′,8′-tetrahydro-2′,5’(1’H,3’H)-quinazoline-diones were successfully synthesized through a three-component reaction of 1H-indole-2,3-diones (isatins), guanidine nitrate, and 1,3-cyclohexanediones, by use of Kit-6 mesoporous silica coated Fe₃O₄ nanoparticles (Fe₃O₄@SiO₂@KIT-6) as a highly efficient magnetically separable nanocatalyst in aqueous media at 60°C. Several notable features of thiseco-friendly protocol are high yields of products, short reaction times, operational simplicity, and the use of easily available and recyclable catalyst.     

Flip‐type disorder in 3‐substituted 2,2′:5′,2′′‐terthiophenes

In the crystal structures of four thiophene derivatives, (E)‐3′‐[2‐(anthracen‐9‐yl)ethenyl]‐2,2′:5′,2′′‐terthiophene, C₂₈H₁₈S₃, (E)‐3′‐[2‐(1‐pyrenyl)ethenyl]‐2,2′:5′,2′′‐terthiophene, C₃₀H₁₈S₃, (E)‐3′‐[2‐(3,4‐dimethoxyphenyl)ethenyl]‐2,2′:5′,2′′‐terthiophene, C₂₂H₁₈O₂S₃, and (E,E)‐1,4‐bis[2‐(2,2′:5′,2′′‐terthiophen‐3′‐yl)ethenyl]‐2,5‐dimethoxybenzene, C₃₆H₂₆O₂S₆, at least one of the terminal thiophene rings is disordered and the disorder is of the flip type. The terthiophene fragments are far from being coplanar, contrary to terthiophene itself. The central C—C=C—C fragments are almost planar but the bond lengths suggest slight delocalization within this fragment. The crystal packing is determined by van der Waals interactions and some weak, relatively short, C—H...S and C—H...π directional contacts.     

Three-Component Spiro Heterocyclization of Pyrrolediones with Malononitrile and Cyclic Enols

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates reacted with malononitrile and five-membered cyclic enols, indan-1,3-dione and cyclopentane-1,3-dione to give 1-substituted ethyl 2-amino-3- cyano-2′,5-dioxo-5′-phenyl-1′,2′-dihydro-5H-spiro[indeno[1,2-b]pyran-4,3′-pyrrole]-4′-carboxylates and ethyl 2-amino-3-cyano-2′,5-dioxo-5′-phenyl-1′,2′,6,7-tetrahydro-5H-spiro[cyclopenta[b]pyran-4,3′-pyrrole]-4′-carboxylates, respectively.     

Adenosine cyclic 3′,5′-(RP)- and (SP)-phosphoramidates,the first representatives of nucleoside cyclic 3′,5′-phosphoramidates derived from ammonia

Adenosine cyclic 3′,5′-phosphoramidate $\text{2}$ was synthesized by reacting adenosine cyclic 3′,5′-phosphate $\text{1}$ with POCl₃, in trimethyl phosphate for 1 h at O°C, followed by in situ treatment of the reaction mixture with a suspension of (NH₄)₂CO₃ in anhydrous DMF or pyridine or DMF/pyridine mixture for 30 min at 25° C. Diastereoisomers ($\text{R}$_P)-$\text{2}$ and ($\text{S}$_P)-$\text{2}$ the relative quantities of which depended on the solvent of (NH₄)₂CO₃ treatment, were separated by reversed phase partition chromatography. Hydrolysis of (R_P)-$\text{2}$ and (S_P)-$\text{2}$ proceeded with predominant (90% in 0.1 N HCl, 100% in 0.1 N NaOH) -P-O-C bond breaking.     

Synthesis and Conformational Studies of Unnatural Pyrimidine Nucleosides

ABSTRACT

Starting from 3,4-di-O-acetyl-L-rhamnal (6) and thymine (7) the unsaturated nucleosides 1-(2′,3′,6′-trideoxy-4′-O-acetyl-α- and β-L-erythro-hex-2′-enopyranosyl)-thymine (8a and 8b) were prepared in anomerically pure form. In solution 8a was shown to be present in the ⁵ H _o and ⁰ H ₅ conformations, whereas the predominant conformation of 8b was ⁵ H _o. Chemical transformation of 8a and 8b led to the saturated nucleosides 1-(2′,3′,6′-trideoxy-α- and β-L-erythro-hexopyranosyl)thymine (10a and 10b, respectively), which were converted into 1-(4′-azido-2′,3′,4′,6′-tetradeoxy-α- and β-L-threo-hexopyranosyl)thymine (12a and 12b). Preliminary biological studies showed that 9b was inactive against the HIV-1 and HIV-2 viruses.     

Methylene‐Bridged Metallocenes with 2,2′‐Methylenebis[1H‐inden‐1‐yl] Ligands: Synthesis,Characterization, and Polymerization Catalysis of a Synthetically Simple Class of C2‐ and C2v‐Symmetric ansa‐Metallocenes

The acid‐catalyzed reaction between formaldehyde and 1H‐indene, 3‐alkyl‐ and 3‐aryl‐1H‐indenes, and six‐membered‐ring substituted 1H‐indenes, with the 1H‐indene/CH₂O ratio of 2 : 1, at temperatures above 60° in hydrocarbon solvents, yields 2,2′‐methylenebis[1H‐indenes] 1 – 8 in 50–100% yield. These 2,2′‐methylenebis[1H‐indenes] are easily deprotonated by 2 equiv. of BuLi or MeLi to yield the corresponding dilithium salts, which are efficiently converted into ansa‐metallocenes of Zr and Hf. The unsubstituted dichloro{(1,1′,2,2′,3,3′,3a,3′a,7a,7′a‐η)‐2,2′‐methylenebis[1H‐inden‐1‐yl]}zirconium ([ZrCl₂( 1′ )]) is the least soluble in organic solvents. Substitution of the 1H‐indenyl moieties by hydrocarbyl substituents increases the hydrocarbon solubility of the complexes, and the presence of a substituent larger than a Me group at the 1,1′ positions of the ligand imparts a high diastereoselectivity to the metallation step, since only the racemic isomers are obtained. Methylene‐bridged ‘ansa‐zirconocenes’ show a noticeable open arrangement of the bis[1H‐inden‐1‐yl] moiety, as measured by the angle between the planes defined by the two π‐ligands (the ‘bite angle’). In particular, of the ‘zirconocenes’ structurally characterized so far, the dichloro{(1,1′,2,2′,3,3′,3a,3′a,7a,7′a‐η)‐2,2′‐methylenebis[4,7‐dimethyl‐1H‐inden‐1‐yl]}zirconium ([ZrCl₂( 5′ )] is the most open. The mixture [ZrCl₂( 1′ )]/methylalumoxane (MAO) is inactive in the polymerization of both ethylene and propylene, while the metallocenes with substituted indenyl ligands polymerize propylene to atactic polypropylene of a molecular mass that depends on the size of the alkyl or aryl groups at the 1,1′ positions of the ligand. Ethene is polymerized by rac‐dichloro{(1,1′,2,2′,3,3′,3a,3′a,7a,7′a‐η)‐2,2′‐methylenebis[1‐methyl‐1H‐inden‐1‐yl]}zirconium ([ZrCl₂( 2′ )])/MAO to polyethylene waxes (average degree of polymerization ca. 100), which are terminated almost exclusively by ethenyl end groups. Polyethylene with a high molecular mass could be obtained by increasing the size of the 1‐alkyl substituent.     

2′, 3′-Dideoxy-3′-fluorotubercidin and Related Dideoxyribonucleosides:. Synthesis via a 2′-deoxy-3′-oxoribofuranoside intermediate and conformation studies

An efficient synthesis of the unknown 2′-deoxy-D-threo-tubercidin ( 1b ) and 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) as well as of the related nucleosides 9a, b and 10b is described. Reaction of 4-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine ( 5 ) with (tert-butyl)diphenylsilyl chloride yielded 6 which gave the 3′-keto nucleoside 7 upon oxidation at C(3′). Stereoselective NaBH₄ reduction (→ 8 ) followed by deprotection with Bu₄NF(→ 9a )and nucleophilic displacement at C(6) afforded 1b as well as 7-deaza-2′-deoxy-D-threo-inosine ( 9b ). Mesylation of 4-chloro-7-{2-deoxy-5-O-[(tert-butyl)diphenylsilyl]-β-D-threo-pentofuranosyl}-7H-pyrrolo[2,3-d]-pyrimidine ( 8 ), treatment with Bu₄NF (→ 12a ) and 4-halogene displacement gave 2′, 3′-didehydro-2′, 3′-dideoxy-tubercidin ( 3 ) as well as 2′, 3′-didehydro-2′, 3′-dideoxy-7-deazainosne ( 12c ). On the other hand, 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) resulted from 8 by treatment with diethylamino sulfurtrifluoride (→ 10a ), subsequent 5′-de-protection with Bu₄NF (→ 10b ), and Cl/NH₂ displacement. ¹H-NOE difference spectroscopy in combination with force-field calculations on the sugar-modified tubercidin derivatives 1b , 2 , and 3 revealed a transition of the sugar puckering from the ^3′T_2′ conformation for 1b via a planar furanose ring for 3 to the usual ^2′T_3′ conformation for 2.