Norbornane as the novel pseudoglycone moiety in nucleosides

Novel nucleoside analogues based on bicyclo[2.2.1]heptene/heptane were prepared by linear synthesis starting from commercially available 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene 1. The crucial step of the synthesis was insertion of the amino group to the position 7 of the substituted bicyclo[2.2.1]heptene with anti-configuration by a Ritter reaction (H₂SO₄, AcOH, CH₃CN). All nucleobases were constructed at this amino function. The prepared family of the target nucleosides was tested for cytostatic and antiviral activity.     

Novel thermolytic transformations of n-benzoyl 2-aza 3-oxa bicyclo(2.2.1)hept-5-ene and n-benzoyl 2-aza 3-oxa bicyclo(2.2.1)heptane

Novel thermolytic pathways were encountered in careful studies with N-benzoyl 2-aza 3-oxa bicyclo (2.2.1)heptene (1) and N-benzoyl 2-aza 3-oxa bicyclo(2.2.1)heptane (2). Compound 1 thermally fragments by four major pathways, namely, (3,3)-sigmatropic shift, (4 + 2) cycloreversion, N-O rupture and C-N homolysis. The (3,3)-sigmatropic shift provides a novel route to unusual, bicyclic heterocycles. Electron withdrawing aryl groupings tend to promote the (3,3)-sigmatropic shift pathway over others. The (4 + 2)-cycloreversion of 1 leads to nitroso carbonyl benzene and cyclopentadiene. The weak σ bonds of PhCONO undergo ready homolysis. The intermediate arising from N-O rupture leads to a cyclopentenone radical similar to that involved in the PG endoperoxide → PGE change. This radical either combines with benzoyl radical leading to 4-dibenzoylamino cyclopentenone or is transformed to an enamide by loss of hydrogen, which, in turn, undergoes (4 + 2)-cycloaddition with cyclopentadiene leading to a novel spiro adduct. The C-N rupture leads to the formation of benzanilide.Nitrosocarbonyl benzene is a powerful electrophile. With cyclohexene it forms a hydroximic ester, initiated by nucleophile acceptance at the CO oxygen. In contrast, it reacts with P(OMe)₃ leading to diphenylurea via nucleophile acceptance at NO oxygen. Thermolysis of 2 proceeds largely by N-O rupture, similar to that normally observed in the PG endoperoxide → PGE change.     

Anionic ring opening of norbornenes fused to heterocycles

The 2-hydroxy and 2-oxo derivatives of 1,2,3,4-tetrahydro-1,4-methanophenazine were prepared and found to evolve in basic media through the opening of their bicyclo[2.2.1]heptene moiety, affording 2,3-dihydro-1H-cyclopenta[b]quinoxaline derivatives with two-carbon 1-substituents that depend on the starting compound. In the case of 2-hydroxy starting compounds, ring-opening occurs regardless of the orientation of the hydroxyl group, and in methanolic solution is spontaneous, though slow, even in the absence of added base (at least in the case of the endo derivative). It is presumably favoured by the steric strain of the heteroaryl-fused bicyclo[2.2.1]heptene moiety, and is hypothesized to involve the base-promoted formation of anionic intermediates that are stabilized by the π-deficient nature of the quinoxaline system.     

Wagner-Meerwein rearrangement in the course of the ozonolysis of a bornene derivative

The ozonolysis of the bicyclo[2.2.1]heptene derivative 1 or 2 gave the octaline derivative 6 (the structure was confirmed by X-ray crystallographic analysis) or 7. The exo-addition of ozone to the double bond of 1 or 2 was followed by the fragmentation in carbonyl oxide and aldehyde. Then, the strong electrophilic character of the carbonyl oxide induces an unexpected Wagner-Meerwein rearrangement to give zwitterion 4. Finally, a fragmentation reaction with elimination of dioxygen gave the tetrasubstituted C-C double bonds of 6 or 7.     

Neighbouring effect in the course of the ozonolysis of a hindered bornene derivative

In the course of the ozonolysis of the bicyclo[2.2.1]heptene anhydride 1, the three bis-lactones 3-5 have been obtained (the structures were confirmed by X-ray crystallographic analysis).     

On the synthesis of β-bromohydrine ethers via intermolecular alkoxyl radical addition to bicyclo[2.2.1]heptene

Primary, secondary, and tertiary alkoxyl radicals add exo-selectively to the olefinic π-bond in bicyclo[2.2.1]heptene to afford exo-2-alkoxybicyclo[2.2.1]hept-3-yl radicals, which are trapped with BrCCl₃ preferentially from the endo face to furnish β-bromohydrine ethers in 23-67% yield.     

Furannes et pyrroles disubstitues en 2,3—XVIII : Synthese et rearrangement de 4H-dihydro-9,10 benzo[4,5]cyclohepta[1,2-b]furannones-4

Cyclisation of 2-arylethyl 3-furancarboxylic acid chlorides gives 4H-9,10-dihydro benzo[4,5]cyclohepta[1,2-b]furan-4-ones 8 only when the aryl moiety is activated by a m-methoxy group or when the 5-position of furyl acid chlorides is blocked by a substituent. If the Friedel-Crafts reaction is performed with an excess of aluminium chloride, 4H-5,6-dihydro benzo[3,4]cyclohepta[2,1-b]furan-4-ones 13 appear in lower yields probably through isomerisation of 8. The rearrangement 8 → 13 also occurs by treatment of 8 in boiling hydrated pyridine hydrochloride.     

Etude des petits cycles—XXXVI. Photo-oxygenation d'alkylidenecyclopropanes. Syntheses specifiques d'alkenylcyclopropanols,de β′-hydroxy α-enones et d'α,α′-dienones

The dye-sensitized photo-oxygenation of alkylidenecyclopropanes 1a–4a at –50°C gives the hydroperoxydes 1b–4b, which were reduced in situ by PPh₃ into 1-alkenylcyclopropanols 1c–4c in high yield. At higher temperatures, 1b–4b rearranged exclusively into β′-hydroxy α-enones 1d–4d if pyridine was added (α,α′-dienones 1e–4e are also formed competitively in absence of pyridine). At 3°C the photosensitised oxygenation of alkylidenecyclopropanes 1a–4a gives ketones 1k–4k, cyclobutanones 1i–4i and β′-hydroxy α-enones 1d–4d. The origin of products is discussed.     

Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes in dichloromethane-methanol

Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes 3a-d at −78 °C in dichloromethane-methanol gave the hydroperoxides 6a-d in 70-80% yields. Ozonolysis of bis-endo-diacetylbicyclo[2.2.2]octene 15 and bis-endo-diacetyl-7-oxabicyclo-[2.2.1]heptene 16 under the same reaction conditions gave the hydroperoxides 17 and 18, respectively. The intramolecular sequential nucleophilic addition of the carbonyl groups to the carbonyl oxide group was observed for the first time and was found to be faster than the intermolecular nucleophilic addition of a methanol molecule to the carbonyl oxide group. Ozonolysis of compound 23 in CH₂Cl₂-MeOH at −78 °C followed by reduction with Me₂S gave compounds 24 and 25, in which the stereochemistry of the methoxyl groups was determined by X-ray analysis.     

Synthesis,some properties,and crystalline modifications of <Emphasis Type="Italic">fac</Emphasis>-[Ru(NO)(Py)<Subscript>2</Subscript>Cl<Subscript>3</Subscript>]

According to the data of ¹H NMR spectroscopy, trans-hydroxochloro complexes containing from two to four pyridine molecules in the internal sphere are formed on the heating of a dilute aqueous solution of K₂[Ru(NO)Cl₅] with pyridine. The evaporation of the reaction solution with concentrated hydrochloric acid gives fac-[Ru(NO)(Py)₂Cl₃] (I) in a yield of ~90%. The structures of two crystalline modifications of this complex are determined by X-ray diffraction analysis (CIF files ССDС nos. 1452208 (Ia) and 1452207 (Ib)). IR spectroscopy shows that the irradiation of complex I (λ ~ 450 nm, T = 80 K) results in photoisomerization with the formation of the metastable state MS1 in which the nitroso group is coordinated by the oxygen atom. The activation parameters of the photoisomerization are determined from the data of differential scanning calorimetry (DSC). Compound trans-[Ru(NO)Py₄(OH)]Cl₂ ? H₂O is isolated in a yield of ~70% on reflux of complex I with a pyridine excess in an aqueous solution, and the presence of molecules of water of crystallization in this compound is confirmed by thermal gravimetry (TG) and IR spectroscopy.     

Cyclopropanation of nitroso Diels-Alder cycloadducts and application to the synthesis of a 2′,3′-methano carbocyclic nucleoside

Treatment of nitroso Diels-Alder cycloadducts 1 with diazomethane in the presence of palladium acetate gives synthetically useful exo-6-oxa-7-azatricyclo[3.2.1.0^2,4]octane derivatives 7 in good to excellent yield. Using this methodology, a conformationally restricted 2′,3′-methano carbocyclic nucleoside was efficiently synthesized from nitroso cycloadduct 1a in seven steps.     

PCl3- and organometallic-free synthesis of tris(2-picolyl)phosphine oxide from elemental phosphorus and 2-(chloromethyl)pyridine hydrochloride

In the superbase KOH/H₂O/toluene/phase-transfer catalyst system, 2-picolyl chloride, generated in situ from 2-(chloromethyl)pyridine hydrochloride, reacts with elemental phosphorus at 65–95?°C for 3?h to afford tris(2-picolyl)phosphine oxide in 50% yield. Single crystal X-ray analysis of the latter revealed one polymorph form of this tertiary phosphine oxide.     

A diastereoselective synthesis of functionalized bis-spirorhodanine-linked cyclopentanes via C(sp3)–H activation

A diastereoselective synthesis of bis-spirorhodanine-linked cyclopentane derivatives via the [2 + 2+1] cycloaddition reaction between alkyl (Z)-2-(3-alkyl-4-oxo-2-thioxothiazolidin-5-ylidene)acetates (alkylidenerhodanines) and azomethine ylides, prepared in situ from iodine mediated reaction of 2-methylquinoline and pyridine in the presence of base, has been developed. The structure of a typical product was confirmed by X-ray crystallography.     

Selective reduction of tertiary alkyl,benzyl, and allyl halides to hydrocarbons using lithium 9,9-di-n-butyl-9-borabicyclo[3.3.1]nonanate

The title 9-borabicyclo[3.3.1]nonane(9-BBN) ate complex (1) brings about selective removal of tertiary alkyl, benzyl and allyl halides to give the corresponding hydrocarbons in excellent yields without concomitant attack on secondary, primary and aryl derivatives. The reduction of cis- and trans - 4 - t - butyl - 1 - methylcyclohexyl chlorides (2) with 1 gives 4 - t - butyl - 1 - methylcyclohexanes (3) with partial inversion of configuration in cyclohexane, while that in benzene gives thermodynamically stable trans-3 predominantly. The reactions of 1,1 - dimethyl - 5 - hexenyl chloride (4) and 1,7,7 - trimethylbicyclo[2.2.1]hept - 2 - yl chloride (8) with 1 proceed with the rearrangements characteristic to a carbonium ion intermediate. The reduction of 1 - ethyl - 1 - methylpentyl chloride with 1 follows a second-order rate equation.     

Inorganic base-catalyzed formation of antivirally active N-substituted benzamides from α-amido sulfones and N-nucleophile

Background

Heteronucleophiles as well as carbanionic reagents can be used to react with α-amido sulfones, thus giving the opportunity to prepare a large array of amino derivatives. Since, novel 1,3,4-oxadiazole-2-thiol derivatives can serve as potent nucleophiles, we employed 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the nucleophilic source of nitrogen in the reaction with α-amido sulfones.

Results

A series of N-substituted benzamides bearing 1,3,4-oxadiazol unit were prepared for the first time by the reaction of in situ generated protected imine from α-amido sulfones with 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophile. Some of the synthesized products displayed favourable antiviral activity against cucumber mosaic virus (CMV) in preliminary antiviral activity tests. The title compounds 5c, 5o and 5r revealed curative activity of 42.2%, 48.7% and 40.5%, respectively against CMV (inhibitory rate) compared to the commercial standard Ningnanmycin (53.4%) at 500 μg/mL.

Conclusion

A practical synthetic route to N-benzoyl-α-amido sulfones by the reaction of 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophiles with in situ generated protected imine from N-benzoyl-α-amido sulfones is presented. The reaction catalyzed by an inorganic base has considerable significance to exploit the potential of α-amido sulfones in organic synthesis.     

Protecting-group-free catalytic asymmetric total synthesis of (−)-rosmarinecine

The protecting-group-free asymmetric total synthesis of (?)-rosmarinecine was achieved in only four steps from the commercially available (±)-3-hydroxypyrrolidine hydrochloride (2a). The key steps include the direct oxidation of (±)-2a to (±)-3-hydroxy-1-pyrroline N-oxide (1a) using the Davis reagent and the domino reaction; viz., the lipase-catalyzed dynamic kinetic resolution of (±)-1a with 1-ethoxyvinyl ethyl maleate followed by the intramolecular [3+2] dipolar cycloaddition reaction of the generated optically active ester. Some insights into the mechanism of the racemization of the optically active 1a, observed during the enzymatic process, were also obtained.     

Application of intramolecular cycloaddition/retro cycloaddition reactions for the synthesis of unsymmetrical 2,2′-bipyridine and 2-benzofuropyrazin-2-ylpyridine analogues

1,2,4-Triazines bearing cycloalkeno[c]pyridine substituents at the 5-position, 2a-d, prepared by an intermolecular Diels-Alder reaction of bi-5,5-triazines with cyclic enamines, were provided with an alkynyloxy or a 2-cyanophenoxy group at the 3-position of the triazinyl unit. A subsequent intramolecular Diels-Alder reaction of the former, followed by loss of N₂ leads to two new classes of 2,2′-bipyridine analogues containing different heterocyclic units, namely cycloalkeno[c]pyridine and 2,3-dihydrofuro- or 2,3-dihydropyrano[2,3-b]pyridine 8a-h; the intramolecular reaction of the 2-cyanophenoxy compound gives benzo[4,5]furo[2,3-b]pyrazine 10a-c.     

2-azatricyclo[2.2.1.01,6]heptane: Synthesis and conversion to 2-azabicyclo[2.2.1]heptanes

A facile route to 6-substituted 2-azabicyclo[2.2.1]heptanes via the novel tricyclic system, 2-azatricyclo[2.2.1.0^1,6]heptane (2), is described. The key intermediate (2) was prepared by oxidation of 4-aminomethylcyclopentene with lead tetra-acetate, and the bicyclic system was obtained by reaction of acetate with 2.MeI. Equilibration of exo- and endo-6-hydroxy-1-methyl-2-azabicyclo[2.2.1]heptane afforded an exo-endo isomeric ratio close to that of norborneol, and on this basis it is suggested that the steric requirements of the nitrogen lone pair are similar to that of CH.     

Stereochemistry of cyclobutanone resulted from cycloadditions of t-butylcyanoketene to bicyclo[2.2.1]heptene derivatives, as evidence for a π2s+π2a reaction mode

The stereochemistry of the cyclobutanones 1-7, resulted from the reaction of t-butylcyanoketene with bicyclo[2.2.1]heptene, bicyclo[2.2.1]heptadiene, 1,4 - dihydro - 1,4 - methanonaphthalene, 1,4 - dihydro - 9 - (1 - methylethylidene) - 1,4 - methanonaphthalene, 1,4 - dihydro - 1,4 - epoxynaphthalene, l,4,4a,8b - tetrahydro - 1,4 - methanobiphenylene (l,4,4a,8b) and 1,4,4a,8b - tetrahydro - 1,4 - methanobiphenylene(1,4,4aβ,8bβ) was established as having the cyclobutanone ring exo and the t-Bu group in the configuration. These findings represent a stereochemical argument in favour of a _π2_s + _π2_a reaction mode of t-butylcyanoketene to the above mentioned bicyclo[2.2.1]heptene derivatives. Observations regarding preservation of the original configurations of alkenes as well as the geometrical distorsion of the cyclobutanones are shortly discussed.     

The reaction of (Sp)-2-(diphenylphosphino)ferrocenecarboxylic acid with carbodiimide reagents: Characterisation of the acid anhydride and urea products

Interaction of (S_p)-2-(diphenylphosphino)ferrocenecarboxylic acid [(S_p)-1] with N,N′-dicyclohexylcarbodiimide (DCC) and N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide (EDC) have been investigated in order to study the reacting system itself and to characterise side-products typically arising during the diimide-promoted condensation of acid (S_p)-1 with nucleophiles. The reaction between (S_p)-1 and DCC was found to give preferentially the respective urea derivative in the absence of a base, and (S_p)-2-(diphenylphosphino)ferrocenecarboxylic anhydride [(S_p,S_p)-3] when the same reaction was performed in the presence of 4-(dimethylamino)pyridine (DMAP). With EDC, the preference for a reaction pathway was less pronounced: whereas the reaction without the base afforded exclusively the corresponding urea, that in the presence of DMAP yielded a mixture of the urea and anhydride (S_p,S_p)-3.