Novel and efficient syntheses of 3′,5′-diamino derivatives of 2′,3′,5′-trideoxycytidine and 2′,3′,5′-trideoxyadenosine. Protonation behavior of 3′,5′-diaminonucleosides

High yielding synthetic routes to 3′,5′-diamino-2′,3′,5′-trideoxycytidine and 3′,5′-diamino-2′,3′,5′-trideoxyadenosine are described. In addition, the protonation behavior of 3′,5′-diamino-2′,3′,5′-trideoxycytidine, 3′,5′-diamino-2′,3′,5′-trideoxyadenosine, 3′,5′-diamino-3′,5′-dideoxythymidine, and 3′,5′-diamino-2′,3′,5′-trideoxyuridine has been studied by means of pH-metric measurements and NMR spectroscopy. The ionization constants and the sequence of protonation sites have been determined.     

An efficient synthesis of new 1-H-4′-methyl-3′,4′-dihydrospiro[piperidine-4,2′(1′H)quinoline] scaffolds

Efficient synthesis of new 3′,4′-dihydrospiro[piperidine-4,2′(1′H)quinolines] by a four step synthetic route based on 1-benzyl-4-piperidone reactivity is reported.     

Difluorocarbene chemistry: synthesis of gem-difluorocyclopropenylalkynes and 3,3,3′,3′-tetrafluorobicyclopropyl-1,1′-dienes

A series of gem-difluorocyclopropenylalkynes are easily obtained in good yields by the Sonogashira reaction of 3,3-difluoro-1-iodocyclopropenes with terminal alkynes. Onto these new alkynes addition of difluorocarbene, generated from the decomposition of FSO₂CF₂COOTMS in diglme in the presence of 10 mol% anhydrous NaF at 120 °C, gives 3,3,3′,3′-tetrafluorobicyclopropyl-1,1′-dienes. Acid hydrolysis of gem-difluorocyclopropenylalkynes in refluxing CH₃OH affords the corresponding methoxycarbonylenynes.     

Synthesis, crystal structures, and photochromic properties of 6,6′ or 7,7′ or 6,7′-dimethyl-[2,2′-bi-1H-indene]-3,3′-diethyl-3,3′-dihydroxy-1,1′-diones

New photochromic title compounds 1, 2, and 3 have been prepared starting from 4-methylphthalic anhydride. Compounds 3a and 3b are a pair of enantiomers and were obtained as a racemic mixture (numbered as 3). Compounds 1, 2, and 3 were successfully separated from the isomeric mixture product through fractional crystallization, and their structures are confirmed by X-ray crystallographic analysis. UV-vis absorption and photochromic properties of 1, 2, and 3 have also been investigated. Results reveal that the substituents, even like the simple methyl, on the benzene rings of biindenylidenedione could considerably affect the photochromic property, as well as other properties of this kind of compounds.     

5′-Noraristeromycin derivatives isomeric to aristeromycin and 2′-deoxyaristeromycin

A straightforward synthesis of (1S,2R,3R,4R)-4-(6-aminopurin-9-yl)-2-hydroxymethylcyclopentane-1,3-diol (2), an isomer of aristeromycin, and its 2′-deoxy derivative 3 from readily available disubstituted cyclopentenes is presented. An antiviral analysis of 2 showed it to have significant activity versus Epstein-Barr virus (IC₅₀ 0.62 μg/mL in the Elisa assay) and to be free of cytotoxicity effects against the host cells. In a much less comprehensive antiviral analysis, 3 also was active towards Epstein-Barr (IC₅₀ 7.58 μg/mL in the Elisa assay) but this was accompanied by cellular toxicity.     

A simple route for the synthesis of 3,3,3′,3′-tetramethyl-2,3,3′,4′-tetrahydro-1H,1′H-[4,9′-bixanthene]-1,1′(2′H,9′H)-dione and its derivatives catalyzed by Mn and other transition metal cations

A simple and efficient unusual coupling reaction of 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one and its derivatives was accomplished in the presence of Mn²⁺, Cu²⁺, Cd²⁺, Hg²⁺, Fe³, or La³⁺. The structure elucidation was accomplished by IR, ¹H NMR, ¹³C NMR, X-ray crystallography, UV-Visible and elemental analysis. A reaction mechanism is proposed.     

Synthesis and crystal structure of 2′-deoxy-2′-fluoro-4′-thioribonucleosides: substrates for the synthesis of novel modified RNAs

We report herein the synthesis of appropriately protected 2′-deoxy-2′-fluoro-4′-thiouridine (5), -thiocytidine (7), and -thioadenosine (35) derivatives, substrates for the synthesis of novel modified RNAs. The synthesis of 5 and 7 was achieved via the reaction of 2,2′-O-anhydro-4′-thiouridine (3) with HF/pyridine in a manner similar to that of its 4′-O-congener whereas the synthesis of 35 from 4′-thioadenosine derivatives was unsuccessful. Accordingly, 35 was synthesized via the glycosylation of the fluorinated 4-thiosugar 25 with 6-chloropurine. The X-ray crystal structural analysis revealed that 2′-deoxy-2′-fluoro-4′-thiocytidine (8) adopted predominately the same C3′-endo conformation as 2′-deoxy-2′-fluorocytidine.     

New and efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides

A short, efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides 1 has been developed through the diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide.     

Crystallization-based optical resolution of 1,1′-binaphthalene-2,2′-dicarboxylic acid via 1-phenylethylamides: control by the molecular structure and dielectric property of solvent

In the recrystallization of a diastereomeric mixture of amides (RS_a,S)-1 formed from racemic 1,1′-binaphthalene-2,2′-dicarboxylic acid and (S)-1-phenylethylamine, either of the diastereomers crystallizes out as a diastereomerically pure form, depending on the solvent employed; sterically undemanding solvents, acetone, dichloromethane, and acetonitrile, afford crystals formulated as (S_a,S)-1·solvent with an exception of ethanol, which affords (R_a,S)-1·EtOH, while sterically bulkier solvents afford (R_a,S)-1 including no solvent. The stereoselectivity can be rationalized by the crystal structures. A dielectrically controlled resolution (DCR) can also be carried out by using mixed solvents, which contain, for example, 25 vol % of acetone and varying ratios of hexane and 1-propanol in total 75 vol %; (S_a,S)-1·acetone is deposited as crystals from the solvents with a dielectric constant (ε) range 8.9 ? ε ? 10.2, while (R_a,S)-1 is deposited from the solvents with 14.8 ? ε ? 20.3.     

Regioselective monobromination of (E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-aryl-2-propen-1-ones using bromodimethylsulfonium bromide and synthesis of 8-bromoflavones and 7-bromoaurones

A wide variety of monobrominated compounds 2a-l have been prepared in good yields from (E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-aryl-2-propen-1-ones (1a-l) through regioselective ring bromination using 1.5 equiv of bromodimethylsulfonium bromide (BDMS) at room temperature. Similarly, some of the 2′-hydroxychalcones can be converted directly into tribromides 3 or dibromides 4 by employing 4.0 equiv of BDMS under different reaction conditions which in turn can be transformed into 8-bromoflavones and 7-bromoaurones on treatment with 0.2 M ethanolic KOH solution. Mild reaction conditions, good yields and no chromatographic separation are some of the salient features of the present protocol.     

Diastereoselective synthesis of 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinolines)

Knoevenagel products formed by the condensation of N-monoalkyl barbituric acids with o-tert-amino benzaldehydes undergo tert-amino effect reactions (T-reactions) yielding 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinoline) derivatives as a mixture of (S^∗,S^∗)- and (S^∗,R^∗)-diastereomers. Mostly, the major diastereomer has the S^∗,S^∗-configuration. According to X-ray diffraction data in the solid form and NOE data in solution, diastereoselectivity of the T-reactions can be associated with the structure of the Knoevenagel products whose conformation is fixed by the strong intramolecular C-H?π interaction.     

Facile acid-catalyzed condensation of 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone with phenols, methoxyaromatic systems and enols

Various phenols, methoxy aromatic compounds, 3- and 4-hydroxycoumarins and enols smoothly condense with 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone 1 in an acid medium producing 2-aryl/alkyl-2,2′-biindan-1,1′,3,3′-tetrones in high yields. The adducts of resorcinol, 1,3,5-trihydroxybenzene and α- and β-naphthols of 1 preferably remain in the intramolecular hemi-ketal form, confirmed by X-ray diffraction studies. On the other hand para and meta substituted phenols condense with 1 in an acid medium to produce 6 or 7 substituted 2′,4-spiro(1′,3′-indanedion)-indeno[3,2-b]chromenes in good yields.     

Chiral syntheses of 6′-β-fluoroaristeromycin, 6′-β-fluoro-5′-noraristeromycin and aristeromycin

Carbocyclic nucleosides substituted at the C-6′ position are receiving increasing attention. Chiral synthetic accessibility to the biologically promising 6′-β-fluoroaristeromycin is lacking. Its preparation and that of the 5′-nor analogue are described. Along the way, a new method to aristeromycin arose as an outgrowth of a requisite structure proof.     

One-pot synthesis of 5,5′-dibromo-2,2′-dipyridylacetylene and its boronic acid derivative

5,5′-Dibromo-2,2′-dipyridylacetylene was prepared from 2,5-dibromopyridine and (trimethylsilyl)acetylene via the new one-pot synthesis approach using a regioselective palladium-catalyzed coupling reaction with a 60% yield. Several protocols of lithium-halogen exchange were then attempted to synthesize 6,6′-(1,2-ethynediyl)bis[3-pyridylboronic acid] from 5,5′-dibromo-2,2′-dipyridylacetylene. The former was successfully obtained with a 54% yield by a reverse addition method using toluene and THF and it showed potential as a useful building block for cross-coupling reactions in the formation of carbon-carbon bonds.     

A pyrazolyl-terminated 2,2′:6′,2″-terpyridine ligand: Iron(II), ruthenium(II) and palladium(II) complexes of 4′-(3,5-dimethylpyrazol-1-yl)-2,2′:6′,2″-terpyridine

The preparation of 4′-(3,5-dimethylpyrazol-1-yl)-2,2′:6′,2″-terpyridine (2) under acidic conditions results in the formation of the salts [H₂2][MeOSO₃]₂ and [H₂2][EtOSO₃]₂, treatment of which with base leads to neutral 2. The structure of [H₂2][EtOSO₃]₂ · H₂O has been established by single crystal X-ray diffraction. The complexes [Fe(2)₂][PF₆]₂ and [Ru(2)₂][PF₆]₂ have been prepared and characterized, and the single crystal structure determination of [Ru(2)₂][PF₆]₂ is reported; [Fe(2)₂][PF₆]₂ is isostructural with [Ru(2)₂][PF₆]₂. Treatment of [Fe(2)₂]²⁺ with PdCl₂ produces [Pd(2)Cl]⁺, isolated and structurally characterized as the hexafluoridophosphate salt, illustrating that metal exchange within the tpy-binding domain occurs in preference to palladium(II) coordination by the N-donor atom of the pendant 3,5-dimethylpyrazol-1-yl unit in 2. [Pd(2)Cl]²⁺ can also be prepared from PdCl₂ and [H₂2][MeOSO₃]₂ in refluxing methanol.     

Highly diastereoselective chemoenzymatic synthesis of (2′R)- and (2′S)-2′-deoxy[2′-H]guanosines

In an effort to develop an efficient synthetic method of highly diastereoselective (2′R)- and (2′S)-2′-deoxy[2′-²H]guanosines, chemoenzymatic conversion was investigated. The synthesis of (2′R > 98% de)-2′-deoxy[2′-²H]guanosine was achieved by biological transdeoxyribosylation using (2′R > 98% de)-2′-deoxy[2′-²H]uridine, 2,6-diaminopurine, and Enterobacter aerogenes AJ-11125, followed by treatment with adenosine deaminase. (2′S > 98% de)-2′-Deoxy[2′-²H]guanosine was synthesized from (2′S > 98% de)-2′-deoxy[2′-²H]uridine and 2,6-diaminopurine using thymidine phosphorylase and purine nucleoside phosphorylase instead of E. aerogenes AJ-11125.     

Synthesis and anion recognition properties of 8,8′-dithioureido-2,2′-binaphthalene

A novel artificial receptor based on 2,2′-binaphthalene skeleton bearing two thiourea groups was prepared via nickel(II)-catalyzed homocoupling of the corresponding bromide. The receptor showed high binding ability for F⁻ and AcO⁻ in acetonitrile.     

Hydrothermal syntheses, structures and characterizations of three one-dimensional polyoxomolybdates with 4,4′-dimethylenebiphenyl diphosphonic acid as bridge

Three heterometallic 1-D polymers, [{Ni(1,10-phen)₂(H₂O)}₂ {(Mo₅O₁₅)(4,4′-dbp)}·(5.75H₂O)] (4,4′-dbp=O₃PCH₂C₆H₄C₆H₄CH₂PO₃) (1), [{Co(1,10-phen)₂(H₂O)}₂ {(Mo₅O₁₅)(4,4′-dbp)}·(5.5H₂O)] (2) and [{Ni(2,2′-bpy)₃}{Ni(2,2′-bpy)₂(H₂O)} {(Mo₅O₁₅)(4,4′-dbp)}·(4.75H₂O)] (3), have been synthesized under hydrothermal conditions. Their structures were determined by single crystal X-ray diffraction. The 1-D chains is constructed of [Mo₅O₁₅(4,4′-dbp)]⁴⁻ units, which are further decorated and charge compensated by [M(1,10-phen)₂] (M=Ni, Co) or [Ni(2,2′-bpy)₂] subunits. The thermogravimetric analyses and magnetic properties of 1 and 2 were studied.     

The highly regiospecific synthesis and crystal structure determination of 1,1′-2,5′ substituted ring-locked ferrocenes

1,1′-Ferrocene biscarboxaldehyde (1) has been prepared and the aldehyde groups were subsequently protected with acetal groups to produce 1,1′-bisacetalferrocene (2). A ring-locked ferrocene was synthesised by further derivatisation of the cyclopentadiene rings at the 2,2′ positions with phosphine substituents to produce 2,2′-bis-(acetal)-1,1′-diphenylphosphinoferrocene (3), which was subsequently coordinated to either a nickel chloride (5) or nickel bromide (6) metal centre. The ring-locked ferrocene complexes produced 2,5′-bis-(acetal)-1,1′-diphenylphosphinoferrocene substitution patterns. The acetal protecting groups of 2,2′-bis-(acetal)-1,1′-diphenylphosphinoferrocene were removed to produce 1,1′-bis-carboxaldehyde-2,2′-diphenylphosphinoferrocene (4). The Cp rings of 1,1′-bisacetalferrocene were also further derivatised at the 2,2′ positions with a silane to produce the ring-locked 1,1′-siloxane-2,5′-bisacetalferrocenophane (7). The acetal protecting groups were removed from this to produce 1,1′-siloxane-2,5′-ferrocenophanecarboxaldehyde (8). For both the phosphine and siloxane electrophiles, the substitution on the Cp rings gives chiral products (obtained as racemic mixtures). Due to the highly regioselective nature of the reaction and diastereoselectivity in the products only C₂-symmetric compounds were observed without the presence of meso diastereoisomers. Subsequent ring-locking forced the Cp rings to rotate, leading to 1,1′-ring-locked ferrocenes with 2,5′-arrangement of the acetal groups (i.e. on opposite faces of the ferrocene unit).