A novel synthesis of 2'-hydroxy-1',3'-xylyl crown ethers

Six novel 2' - hydroxy - 1',3' - xylyl crown ethers (8a–e and 13)¹ have been synthesized utilizing the allyl group to protect the OH function during the cyclization reaction. The macrocycles 6a-e were formed in yields of 26 to 52%, by intermolecular reaction of 4 - chloro - 2,6 - bis(bromomethyl) - 1 - (2 - propenyloxy)benzene (5) with polyethylene glycols; 6a was also obtained by an intramolecular cyclization reaction of monotosylate 14.A 30-membered ring with a 2' - hydroxy - 1',3' - xylyl sub-unit was obtained in 87% yield by reaction of ditosylate 9 with bis [2 - (o - hydroxyphenoxy)ethyl]ether (11) in the presence of cesium fluoride. The synthesis of crown ethers with a 2' - hydroxy - 1',3' - xylyl sub-unit (1c–e, H for CH₃) by demethylation of the corresponding 2'-methoxy crown ethers 1c–e with lithium iodide were unsuccessful; it would appear that the demethylation reaction is restricted to 15- and 18-membered rings. One of the 2' - hydroxy - 1',3' - xylyl crown ethers 8d forms a crystalline 1:1-complex with water.     

5'-Substituted 2,2'-anhydrouridines

3',5'-Di-O-acetyl-2'-halogenouridines (1a, 1c and 1d) can be partially deacetylated at C-5' by transesterification with methanol-HCl, providing the 3'-O-acetyl derivatives 2a–2c. These can be converted into the 5'-O-mesyl derivatives 3a–3c, and latter into the 5'-chloro compounds 3d-3f. All 5'-substituted 2'-halogeno compounds give the corresponding 2,2'-anhydrouridine derivatives 4a–4c on treatment with NaOMe. Structures were proved by IR and ¹H-NMR.     

The synthesis and crystal structure of 5-acetyl-2'-deoxyuridine

5- Acetyl - 2' - deoxyuridine (1) has been synthesised by treating 2' - deoxy - 5 - ethynyluridine with dilute sulphuric acid. Condensation of the trimethylsilyl derivative of 5-acetyluracil with 2-deox-3, 5-di-O-p-toluoyl-α-d-erythropen chloride gave a mixture of α- and β-anomeric blocked nucleosides from which the α-anomer was isolated and the p-toluoyl groups removed to give 5 - acetyl -1 - (α - d - 2- deoxyerythropentofuranosyl) uracil. Only a poor yield of the β-anomer (1) was obtained by this procedure. The UV spectra and m.p. obtained for 1 differed from the values quoted in the literature. The crystals of 1 are monoclinic, space group P2₁, with a = 9.525, b = 12.16, c = 5.22 Å, β = 92.03° and two molecules in the unit cell. The structure was refined by least-squares calculations to R 3.4% for 1426 observed counter amplitudes. The pyrimidine ring is essentially planar with the acetyl group inclined at 6° to it. The sugar ring has the highly unusual C(4')-exo conformation and the arrangement about C(4')-C(5') is such that O(5') is oriented gauche with respect to both O(1') and C(3'). The glycosidic torsion angle O(1')-C(1')-N(1)-C(6) is 56° (anti conformation).     

2'-Desoxytubercidin: synthese des o-3'-phosphoramidites und kondensation zu 2'-desoxytubercidylyl(3' → 5')-2'-desoxytubercidin

The phosphoramidite of 2'-deoxytubercidin (2) has been prepared by phosphitylation of compound 3b with chlorodiisopropylaminomethoxyphosphane. The intermediate 3b was obtained from 2'-deoxytubercidin (1) by N⁴-benzoylation and subsequent O-5'-dimethoxytritylation. Condensation of compound 2 with O-3'-silylated 3e gave the fully protected dimer 4b, which was converted into 2'-deoxytubercidylyl (3' → 5')-2'-deoxytubercidin(4a). Compound 4a isoster with 2'-deoxyadenosylyl(3' → 5')-2'-deoxyadenosine (d(ApA)) exhibits a hypochromicity of 11% (270 nm) due to strong stacking interactions. Cleavage of the dinucleoside monophosphate 4a with nuclease S₁ occurs five times faster than that of d(ApA). This shows that the single strand specific enzyme recognises the geometry of the stacked nucleobases.     

11H-Pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinoléines (aza-7 ellipticines) substituées sur leur position 6

6-Dialkylaminoalkylamino substituted 11H-pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinolines (7-aza ellipti-cines) were obtained by a six step synthesis starting from 2-chloro-3-nitro pyridine and 6-amino-5-methyl (and 5,8-dimethyl) isoquinoline-1-2H-ones already described. A brief survey of biological results shows that derivatives of this new heterocyclic ring system are less interesting than their 5H-pyrido(3',4':4,5]pyrrolo[2,3-g]isoquinolines (9-aza ellipticines) and pyrido[4,3-b]carbazoles (ellipticines) analogues.     

Microbiological transformations—XII: Microbiological reduction of racemic 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)propan-2-one and 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)butan-2-one by rhodotorula mucilaginosa

The microbiological reduction of (±)-l-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-one (4) and (±)-1-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-one (5) by Rhodotorula mucilaginosa was investigated. Both enantiomers of 4 are reduced stereospecifically to corresponding alcohols; (+)-(2S, l'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (6) and (-)-(2S,l'S)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (7). p ]The substrate selectivity in the reduction of 5 was observed: R enantiomer of 5 yields stereospecifically (+)-(2S,1'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-ol (8) while S(-)5 remains unchanged.     

Lithiation of 3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-2'-deoxyuridine: synthesis of 6-substituted 2'-deoxyuridines

Synthesis of 6-substituted 2'-deoxyuridines can be effected by lithiation of 3',5'-$\text{O}$-(tetraisopropyldisiloxane-1,3-diyl)-2'-deoxyuridine with LDA followed by the reaction of its lithio derivative with electrophiles. This method provides a general, regiospecific and simple route to various types of 6-substituted 2'-deoxyuridines which have, so far, been known to be difficult to prepare.     

Synthese de la cyclo-5'-8 desoxy-5' adenosine: stereochimie et mecanisme de la cyclisation d'un derive de l'iodo-5' adenosine par le zinc

N,N'-Dibenzoyl 2', 3'-O-isopropylidene 5'-deoxy 5'-iodo adenosine can efficiently transformed into the corresponding 5',8-cyclo-7,8-dihydronucleoside by zinc in pyridine. Only one diastereoisomer is obtained. By spin decoupling and NOE techniques at 250 MHz, the R-configuration at C-8 was established. This compound showed typical dihedral angles of about 90° for the vicinal protons H-1', H-2' and H-3', H-4'. Using adenosine derivatives stereospecifically labelled at C-5', it was demonstrated that the cyclisation occurs with racemisation at that position.     

Photochemistry of β,γ-enones-VIII: On the remarkable photostability of some β,γ.β',γ'-dienones and the 1,3-acyl shift photoreactivity of two β,γ.γ',δ'-dienones

The direct irradiation of the β,γ.β',γ'-dienones 1–5 and the β,γ.γ',δ'-dienones (E)-6a, (E)-7a and 8a at λ 300 nm has been studied. The β,γ.β,γ'-dienones 1–5 are remarkable photostable for λ ? 300 nm, even upon prolonged irradiation, in contrast to simple β,γ-enones which upon irradiation exhibit α-cleavage, γ-hydrogen abstraction, (E)-(Z) isomerization and oxetane formation. The observed photostability of the β,γ.β',γ'-dienones is rationalized in terms of a rapid radiationless decay of the excited singlet state, enhanced by CT-interaction between the carbonyl ¹(n-π*) state and the homoconjugated 1,4-diene moiety, which precludes fluorescence, photochemical reactions and intersystem crossing (ISC).The β,γ.γ',δ'-dienones (E)-(6a), (E)-7a and 8a exhibit only a 1,3-acyl shift (1,3-AS) without (E)-(Z) isomerization of the alkenyl moiety, to yield (E)-6b, (E)-7b and 8b. It is concluded that the 1,3-AS proceeds from the ¹(n-π*) state with a rate which is very large relative to the rate of ISC to the ³(n-π*) state, thus precluding any internal triplet energy transfer (1TET) from the ³(n-π*) to the ³(π-π*) state which would manifest itself by (E)-(Z) isomerization.     

Observations relevant to the mechanism of the reductive aminations of ketones with sodium cyanoborohydride and ammonium acetate

Fortimicin B (2) has been converted to 6'-epi-fortimicin B 5 and 6'-epi-fortimicin A 4 both of which have the same diaminosugar moiety as that present in gentamicin C₂3. The syntheses of the 6'-epi-fortimicins and their antibacterial activities are reported.Although reductive amination of 1,2'-di-N-benzyloxycarbonyl-6'-oxo-fortimicin B-4,5-carbamate 17 with sodium cyanoborohydride and ammonium acetate in methanol gave a mixture of 1,2'-di-N-benzyloxycarbonyl-6'-epi-fortimicin B-4,5-carbamate 18 and 1,2'-di-N-benzyloxycarbonylfortimicin B-4,5-carbamate 14, attempted reduction of 1,2'-di-N-benzyloxycarbonyl-6'-iminofortimicin B-4,5-carbamate 16, under identical conditions gave only recovered imine. The significance of these results relative to the mechanism of the reductive amination of carbonyl compounds with sodium cyanoborohydride and amine salts is discussed.     

Preparation of 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes by Vilsmeier-Haack reaction and its use in the synthesis of heterocyclic chalcones and dipyrazolopyridines

Novel 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes 5 have been synthesized from the 4,5-dihydropyrazolo[3,4-b]pyridine-6-ones 4 via Vilsmeier-Haack reaction. Further treatment of carbaldehydes 5 with acetophenones 6 and hydrazine hydrate afforded chalcone analogues 7 and dipyrazolo[3,4-b:4′,3′-e]pyridines 8, respectively.     

Synthesis of a series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides

A series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides 1a-d, analogues of 3TC that has high biological activities against HIV and HBV, have been synthesized from the gem-difluorohomoallyl amine 7 in a straightforward fashion. Our synthesis featured the construction of thiofuranose skeleton through ring closure of key intermediates and installation of pyrimidine ring with amino group in compounds 13a,b.     

The addition of benzocyclobutenylidene to benzene : The facile rearrangement of spiro[benzocyclobutene-1,7'-cyclohepta-1',3',5'-triene] to 9a,10-dihydrobenz[α]azulene

Thermal decomposition of the sodium salts of benzocyclobutenone tosylhydrazone and 2-methylbenzocyclobutenone tosylhydrazone in benzene affords 9a,10-dihydrobenz[α]azulene 4 and trans-10-methyl-9a, 10-dihydrobenz[α]azulene 3, respectively. A mechanism involving initially the addition of the carbene benzocyclobutenylidene, or its 2-Me derivative, to the benzene ring is postulated. A proposed intermediate in the reaction, spiro [benzocyclobutene 1,7' cyclohepta-1',3',5'-triene] 12 has been synthesised, and shown to give rise to 4 under the reaction conditions. The rate of rearrangement of 12 → 4 has been measured, and the activation energy determined: E_a = 125.9 ± O.8 KJmol^?1 and A = 1.38 × lO¹⁴sec^?1. The mechanism for the rearrangement must involve ring opening of the benzocyclobutene moiety of 12 to give an o- xylylene intermediate which is postulated to possess considerable diradical character. At 71.8 °, this ring opening is 2.7 × 10⁶ times faster than the ring opening of the parent benzocyclobutene molecule. The decomposition of the sodium salt of 2-(7' -cyclohepta-1',3',5' trienyl)benzaldehyde tosylhydrazone has also been investigated and is shown to yield 4a,10-dihydrobenz[α]azulene, 9,10-dihydrobenz[α]azulene and 8,9-benzotricyclo [5.3.0.0^2.10]deca-3,5,8-triene. A mechanism involving intramolecular 1,3-dipolar addition of a diazo grouping to a cycloheptatriene Π-bond, followed by decomposition of the resulting pyrazoline intermediate, is proposed.     

Biphenylenes-xxxi: Condensation of benzocyclobutene-1,2-dione with aliphatic and heterocyclic 1,2-diamines and the synthesis of cis-2-cyano-3-(2'-cyanovinyl)-1,4-diaz

As possible routes to 1,4-diazabiphenylene and its 2,3-disubstituted derivatives we have studied the condensation of benzocyclobutene-1,2-dione (BBD) with various 1,2-diamines. Instead of giving the 1,4-diazabiphenylene ring system, BBD reacted with ethylenediamine, diaminomaleonitrile, 4,5-diaminopyrimidine, 2-aminopyridine, also 2,3- and 3,4-diaminopyridine to give, respectively, 2-o-carboxyphenylimidazolidinium acetate 4, 3,4-dicyano-2,5-dihydro[2,5]benzodiazocine-1,6-dione 10, 4-amino-5a,9b-dihydro-5-,9b-dihydroxybenzo [3',4']cyclobuta[1',2'-4,5]imidazo[1,2-c]pyrimidine 14, 5a,9b-dihydro-5a,9b-dihydroxybenzo[3',4']cyclobuta[1',2'-4,5] imidazo[1,2-a]pyridine 17, the 4-amino derivative 16 of the latter, and the zwitter ion 18 of 4-amino-3(2-carboxy-benzylideneamino) However, BBD reacted with 4,5-diaminobenzotriazole to give the expected 1,2,3,6,11-penta-aza-1-H-indeno [4,5-b]biphenylene 20, which, on amination followed by oxidation, gave a very low yield of cis-2-cyano-3-(2'-cyanovinyl)-1,4-diazabiphenylene 3. In model experiments, 7,8-diphenylfurazano [3,4-f]quinox-aline 28 was reduced to 2,3-diamino-5,6-diphenyl quinoxaline 29, which on oxidation, gave a mixture of cis- and trans-2-cyano-3-(2'-cyanovinyl)5,6-diphenylpyrazine, 30 and 31. The pentacyclic compounds, 1,3,6,II-tetra-aza-2-oxa-2H-indeno [4,5-b]biphenylene 23 and 1,3,5,10-tetra-aza-1-H-indeno[5,6-b] biphenylene 25, were formed from BBD and the appropriate 1,2-diamines but the 5-membered heterocyclic rings could not be cleaved by reduction and hydrolysis respectively) to give tetracyclic diamines which might have undergone oxidation to give derivatives of 1,4-diazabiphenylene. Compounds 14, 16, 20, 23, 25 and 28 are derivatives of new heterocyclic systems.     

Flavonoids—38: Reaction of 2'-hydroxychalcone dibromides and -α-bromochalcones with azide ion

The reaction of 2'-hydroxychalcone dibromides 1 or α-bromo-2'-hydroxychalcones 15 with sodium azide resulted in a mixture of α-azido-2'-hydroxychalcones 2, 3-aryl-5-(2-hydroxy-pheny)isoxazoles 3, flavones 4, aurones 5 and 4-aryl-5-(2-hydroxybenzoyl)-1,2,3-triazoles 6. The product ratio was strongly influenced by the character of the substituent at position C-4. Similar results were obtained with 2'-benzyloxy-4-nitrochalcone dibromide (10) and 2'-benzyloxy-α-bromo-4-mtrochalcone (17). The mechanism of the transformation of chalcone dibromides into the products via an α-bromochalcone intermediate is discussed.     

Approaches to wired terpyridine: Bithienyl alkynyl derivatives of 2,2′:6′,2″-terpyridine and their ruthenium(II) complexes

Two approaches to the formation of ruthenium(II) complexes containing ligands with conjugated 2,2′:6′,2″-terpyridine (tpy), alkynyl and bithienyl units have been investigated. Bromination of 4′-(2,2′-bithien-5′-yl)-2,2′:6′,2″-terpyridine leads to 4′-(5-bromo-2,2’-bithien-5′-yl)-2,2′:6′,2″-terpyridine (1), the single crystal structure of which has been determined. The complexes [Ru(1)₂][PF₆]₂ and [Ru(tpy)(1)][PF₆]₂ have been prepared and characterized. Sonogashira coupling of the bromo-substituent with (TIPS)CCH did not prove to be an efficient method of preparing the corresponding complexes with pendant alkynyl units. The reaction of 4′-ethynyl-2,2′:6’,2″-terpyridine with 5-bromo-2,2′-bithiophene under Sonogashira conditions yielded ligand 2, and the heteroleptic ruthenium(II) complex [Ru(2)(tpy)][PF₆]₂ has been prepared and characterized.     

Synthesis of oligoribonucleotides by use of S,S-diphenyl n-monomethoxytrityl ribonucleoside 3'-phosphorodithioates

The fully protected ribonucleotide units (6a–d) have been synthesized in 42–62% overall yields by the 5- or 6-step reactions. The dimethoxtrityl, monomethoxytrityl, tetrahydropyran-2-yl, and phenylthio groups were introduced onto the 5'-OH, exo-amino, 2'-OH, and 3'-phosphoryl functions, respectively. The units were converted to the OH or phosphodiester components by treatment with trifluoroacetic acid or with phosphinic acid-triethylamine. Both the components were appropriately coupled by means of mesitylenedisulphonyl chloride 3-nitro-1,2,4-triazole to give dimers in high yields. This method was successfully applied to the synthesis of GpUpApUpUpApApUpAp, i.e. the 5'-terminal base sequence of brome mosaic virus m RNA No. 4 filament.     

New series of platinum group metal complexes bearing η- and η-cyclichydrocarbons and Schiff base derived from 2-acetylthiazole: Syntheses and structural studies

The mononuclear complexes [(η⁶-arene)Ru(ata)Cl]PF₆ {ata = 2-acetylthiazole azine; arene = C₆H₆ [(1)PF₆]; p-ⁱPrC₆H₄Me [(2)PF₆]; C₆Me₆ [(3)PF₆]}, [(η⁵-C₅Me₅)M(ata)]PF₆ {M = Rh [(4)PF₆]; Ir [(5)PF₆]} and [(η⁵-Cp)Ru(PPh₃)₂Cl] {η⁵-Cp = η⁵-C₅H₅ [(6)PF₆]; η⁵-C₅Me₅ (Cp^*) [(7)PF₆]; η⁵-C₉H₇ (indenyl); [(8)PF₆]} have been synthesised from the reaction of 2-acetylthiazole azine (ata) and the corresponding dimers [(η⁶-arene)Ru(μ-Cl)Cl]₂, [(η⁵-C₅Me₅)M(μ-Cl)Cl]₂, and [(η⁵-Cp)Ru(PPh₃)₂Cl], respectively. In addition to these complexes a hydrolysed product (9)PF₆, was isolated from complex (4)PF₆ in the process of crystallization. All these complexes are isolated as hexafluorophosphate salts and characterized by IR, NMR, mass spectrometry and UV–Vis spectroscopy. The molecular structures of [2]PF₆ and [9]PF₆ have been established by single-crystal X-ray structure analyses.     

Palladium acetate complexes bearing chelating N-heterocyclic carbene (NHC) ligands: Synthesis and catalytic oxidative homocoupling of terminal alkynes

The imidazolium salts 1,1′-dibenzyl-3,3′-propylenediimidazolium dichloride and 1,1′-bis(1-naphthalenemethyl)-3,3′-propylenediimidazolium dichloride have been synthesized and transformed into the corresponding bis(NHC) ligands 1,1′-dibenzyl-3,3′-propylenediimidazol-2-ylidene (L₁) and 1,1′-bis(1-naphthalenemethyl)-3,3′-propylenediimidazol-2-ylidene (L₂) that have been employed to stabilize the Pd^II complexes PdCl₂(κ²-C,C-L₁) (2a) and PdCl₂(κ²-C,C-L₂) (2b). Both latter complexes together with their known homologous counterparts PdCl₂(κ²-C,C-L₃) (1a) (L₃ = 1,1′-dibenzyl-3,3′-ethylenediimidazol-2-ylidene) and PdCl₂(κ²-C,C-L₄) (1b) (L₄ = 1,1′-bis(1-naphthalenemethyl)-3,3′-ethylenediimidazol-2-ylidene) have been straightforwardly converted into the corresponding palladium acetate compounds Pd(κ¹-O-OAc)₂(κ²-C,C-L₃) (3a) (OAc = acetate), Pd(κ¹-O-OAc)₂(κ²-C,C-L₄) (3b), Pd(κ¹-O-OAc)₂(κ²-C,C-L₁) (4a), and Pd(κ¹-O-OAc)₂(κ²-C,C-L₂) (4b). In addition, the phosphanyl-NHC-modified palladium acetate complex Pd(κ¹-O-OAc)₂ (κ²-P,C-L₅) (6) (L₅ = 1-((2-diphenylphosphanyl)methylphenyl)-3-methyl-imidazol-2-ylidene) has been synthesized from corresponding palladium iodide complex PdI₂(κ²-P,C-L₅) (5). The reaction of the former complex with p-toluenesulfonic acid (p-TsOH) gave the corresponding bis-tosylate complex Pd(OTs)₂(κ²-P,C-L₅) (7). All new complexes have been characterized by multinuclear NMR spectroscopy and elemental analyses. In addition the solid-state structures of 1b·DMF, 2b·2DMF, 3a, 3b·DMF, 4a, 4b, and 6·CHCl₃·2H₂O have been determined by single crystal X-ray structure analyses. The palladium acetate complexes 3a/b, 4a/b, and 6 have been employed to catalyze the oxidative homocoupling reaction of terminal alkynes in acetonitrile chemoselectively yielding the corresponding 1,4-di-substituted 1,3-diyne in the presence of p-benzoquinone (BQ). The highest catalytic activity in the presence of BQ has been obtained with 6, while within the series of palladium-bis(NHC) complexes, 4b, featured with a n-propylene-bridge and the bulky N-1-naphthalenemethyl substituents, revealed as the most active compound. Hence, this latter precursor has been employed for analogous coupling reaction carried out in the presence of air pressure instead of BQ, yielding lower substrate conversion when compared to reaction performed in the presence of BQ. The important role of the ancillary ligand acetate in the course of the catalytic coupling reaction has been proved by variable-temperature NMR studies carried out with 6 and 7′ under catalytic reaction conditions.     

Total syntheses of cross-conjugated carotenals

Total syntheses of the cross-conjugated carotenals renierapurpurin-20-al (χ,χ-caroten-20-al, 2), (2R,2' R)-tetradesoxybacterioruberin-20- al ((2R,2'R)-2,2'- bis-(3-methylbutyl)-3,4,3',4'-tetrahydro-ψ,ψ -caroten-20-al, 3) and (2R,6R,2'R, 6' R)-2,2'dimethyl-decapreno -?,? -caroten -25-al (4) from the common intermediate 8,8'-diapo-20-acetoxycarotene 8,8' dial (5) are described. The cross conjugated 20-(2,3 4-trimethylbenzal)renierapurpurin (16) has also been synthesized