Polybrominated diphenyl ethers from Dysidea herbacea,Dysidea chlorea and Phyllospongia foliascens

The marine sponges Dysidea herbacea, D. chlorea and Phyllospongia foliascens were differentiated with difficulty in the field. D. herbacea contained 2-(2',4'-dibromophenoxy)-3,4,5-tribromophenol (1), 2-(2',4'-dibromophenoxy)-4,5,6-tribromophenol (2) and 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (6). D. chlorea contained only 2-(2',4'-dibromophenoxy)-4,6-dibromophenol(3), a compound previously reported as a metabolite of D. herbacea. Phyllospongia foliascens contained 2-(3',5'-dibromo-2'-methoxy-phenoxy)-3,5-dibromoanisole (7) and a 1:2 mixture of 2-(3',5'-dibromo-2'-hydroxyphenoxy)-3,5,6-tribromophenol (8) and 2-(3',5'-dibromo-2'-hydroxyphenoxy)-3,4,5,6-tetrabromophenol (9).     

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.     

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).     

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.     

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.     

Enantioselektive synthese von isobutenyl-cyclobutancarbons?uren als vierring—analoga zur chrysanthemums?ure—II1

The enantiomers of 2,2-dimethyl-3-cis-(2'-methylpropenyl)-cyclobutane-1-carboxylic acids (4 and 4') and 2,2-dimethyl-3-trans-(2'-methylpropenyl)-cyclobutane-1-carboxylic acids (10 and 10') were synthesized m optically pure state. Starting from (?)-α-pinene (14) resp. (+)-α-pinene (14') 2,2-dimethyl-3-cis-formyl-cyclobutane-1-car-boxylic acid methylester (21 and 21') was received in an enantioselective pathway and isomerised by acid-catalysisto 2,2-dimethyl-3-trans-formyl-cyclobutane-1-carboxylic acid methylester (23 and 23'). In a following Wittig-reaction the 4 aldehyde-esters 21, 21', 23 and 23' were converted to the enantiomers of isobutenyl-cyclobutane-carboxylic acid methylesters and esterified by m-phenoxibencylic alcohol resp. hydrolysed to isobutenyl-cyclo-butane-carboxylic acids.     

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.     

Six new metabolites from the brown alga halidrys siliquosa (phaeophyta,fucales)

Six monomethyl hydroquinols with oxygenated diterpene side chains have been isolated from the brown alga Halidrys siliquosa. We have isolated 5',12'-dioxohalidrol (1), 5',12'-dioxoisohalidrol (2), 12'α-hydroxy-5',13'- dioxohalidrol (3), 12'α-hydroxy-5',13'-dioxoisohalidrol (4), 12'β-hydroxy-5',13'-dioxoisohalidrol (5) and 5'-hydroxy-12-oxohalidrol (6).     

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     

Insertion of isoprene units into indole and 3-substituted indoles in aqueous systems

Indole (1) and 3- methylbut - 2 - enyl bromide (2) were reacted in aqueous solution over a wide range of pH, in absence of Lewis catalysts, leading to 3-(3'-methylbut-2'-enyl) indole (3), 2,3-di-(3'-methylbut-2-enyl) indole (4) and to 2 - (3 - indolyl) - 3,3 - di - (3' - methylbut - 2' - enyl) - 2,3 - dihydroindote (6) in acidic buffer, whereas compound 6 was not formed at basic pH. Both the reactivity and the selectivity of the reaction appear to be influenced by the acidity of the medium. The reaction extended to biologically significant 3-substituted indoles gave a series of new products. 3-Substituted indoles bearing a basic group at their β-position (7, 11, 12 and 13) in acetic buffer (pH = 3) gave mainly cyclization to dihydrofurano or dihydropyrrolo [2.3-b] indoles (15,16, 20, 21 and 23), whereas those with the basic group at the γ-position (9,10) gave the 2 - (3 - methylbut - 2 - enyl) indole derivatives (18,19) only.     

Preparation,crystal structure and reactions of a new spin-labelling reagent,cis-3,5-dibromo-4-oxo-2,2,6,6- tetramethylpiperidin-1-yloxy : Crystal structure of a derived bis-nitroxide

Methods for the preparation of cis - 3,5 - dibromo - 4 - oxo - 2,2,6,6 - tetramethylpiperidin -1 - yloxy (2b) and its use as a convenient, selective spin-labelling reagent for amino functions, are described. The crystal and molecular structures of 2b and the bis-nitroxide 4 - [(2',2',5',5' - tetramethylpyrrolin -1 - yloxy) - 3' - carbonyloxy] - 2, 2,6,6 - tetramethyl - 3,5 - dibromo - 3,4 - dehydropiperidin - 1 - yloxy (3) [obtained on treatment of 2b with triethylamine] have been determined by conventional heavy-atom techniques. In 2b the individual molecules have mirror symmetry with the bromine atoms equatorial. The N-O bond length is 1.278(5) Å, CN?C is 125.1(3)° and the N-O bond makes an angle of 24.2° with the CN?C plane. In 3 there are two different nitroxide groups. The pyrrolinyloxy ring is virtually planar with a N-O bond length of 1.252(13) Å and CN?C of 113.1(10)°. The 6 -membered ring exists in a sofa conformation with a pseudoaxial Br atom. Its nitroxide group is tetrahedrally distorted. The N-O bond length is 1.268(15) Å, CN?C is 121.7(10)° and the N-O bond makes an angle of 16.0° with the CN?C plane. The packing of 3 is dictated by a short Br... .O secondary bond of 3.09(1) Å, 0.28 Å less than the sum of the van der Waal's radii resulting in dimeric units related by a centre of symmetry.     

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.     

Synthesis of some analogues of nucleoside 5′-triphosphates

Reaction of propane -1,3- disulphonyl chloride with the appropriate 5' - amino - 5'.- deoxyribonucleoside gave 5' - deoxy -5′-(3- sulphopropanesulpho5' - Deoxy - 5' - p- sulphaminobenzenesulphonylaminothymidine (8) was obtained by treatment of 5' - p- aminobenzenesulphonylamino - 5' -deoxythymidine (10) with SO₃,-triethylamine. This reaction gave also some 5'-p- aminobenzenesulphonylamino - 5' - deoxy - 3' - O - sulphothymidine (12). Compounds 2 and 3 were inactive when tested for inhibitory activity against E.coli RNA polymerase holoenzyme. Compounds 1 and 8 inhibited E.coli DNA polymerase I non-competitively at relatively high concentrations. Compound 4 was without significant inhibitory activity against HSV-1 DNA polymerase.     

Total synthesis of ganglioside GQ1b and the related polysialogangliosides

The first total synthesis of ganglio-series gangliosides GQ1b, GT1b and GD1b, which contain α-sialyl-(2→8)-α-sialic acid residue in the structure, will be described. Glycosylation of 2-(trimethylsilyl)ethyl O-(2-acetamido-6-O-benzyl-2-deoxy-3,4-O-iso-propylidene-β- -galactopyranosyl)-(1→4)-O-(2,6-di-O-benzyl-β- -galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside (7) with methyl [phenyl 5-acetamido-8-O-(5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy- -glycero-α- -galacto-2-nonulopyranosylono-1′,9-lactone)-4,7-di-O-acetyl-3,5-dideoxy-2-thio- -glycero- -galacto-2-nonulopyranosid]onate (8) using N-iodosuccinimide (NIS)-trifluoromethanesulfonic acid (TfOH) in acetonitrile gave the protected GD2 pentasaccharide 9, which was converted into the pentasaccharide acceptor 10 by de-O-isopropylidenation. Glycosylation of 10 with methyl thioglycoside derivatives 18, 26, 34 by use of dimethyl(methylthio)sulfonium triflate (DMTST) gave the protected ganglioside oligosaccharides 19, 27 and 35, respectively. Compounds 9, 19, 27 and 35 were transformed into the corresponding α-trichloroacetimidates 13, 22, 30 and 38, via reductive removal of benzyl groups, O-acetylation, selective removal of 2-(trimethylsilyl)ethyl group, and treatment of trichloroacetonitrile. Condensation of the imidates 13, 22, 30 and 38 with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (14) gave the corresponding β-glycosides 15, 23, 31 and 39, which were converted, via selective reduction of azido group, coupling with octadecanoic acid, de-O-acylation, and saponification of methyl esters and lactone groups, into the corresponding gangliosides GD2 (17), GD1b (25), GT1b (33) and GQ1b (41).     

Chiroptical properties and enantioselectivity in hydrogenation with rhodium(I) complexes of chiral bis-diphenylphosphines derived from -glucose and -galactose

(2R,3S)-2-Diphenylphosphinomethyl-3-diphenylphosphinotetrahydropyran (3) has been prepared in 64% yield from the dimesylate 5, derived from -galactose. The surprisingly different reactivities of dimesylates 2 and 5 towards diphenylphosphide anion are considered and the conformational properties of 1–6 discussed in terms of their CD spectra. The rhodium(I) complexes 9 and 10 exhibit low to relatively high enantioselectivities in hydrogenation of Z-α-acetylaminocinnamic acid and α-acetylaminoacrylic acid. The chiroptical and conformational properties of the bidentate ligands (3, 6), and their rhodium(I) complexes (9, 10) are correlated with the observed enantioselectivities.     

Studies of nucleosides and nucleotides—LXXIV: Purine cyclonucleosides—34 a new method for the synthesis of 2'-substituted 2'-deoxyadenosines

8,2'-O-Cycloadenosine was protected at 3' and 5'-OHs with acetyl groups and cleaved using liq. H₂S. Subsequent dethiolation and mesylation gave 2'-O-mesyl-3',5'-di-O-acetyl-arabinosyladenine (6). When 6 or its deacetylated parent compound (7) was heated with sodium azide in DMF, 3'-azido-3'-deoxyxylofuranosyladenine (9) was the only product. The cyclonucleoside was then protected with tetrahydropyranyl groups and subjected to a similar series of reactions as above to give 2'-O-mesyl-3',5'-di-O-tetrahydropyranylarabinosyladenine (14). The compound 14 was heated with sodium azide after which acidic deprotection afforded 2'-azido-2'-deoxyadenosine (16). Hydrogenation of 16 gave 2'-amino-2'-deoxyadenosine (18). 2'-Chloro-2'-deoxyadenosine (19) was also obtained by treatment of 14 with lithium chloride and subsequent deprotection. UV, IR and NMR spectral data of these compounds are described.     

Studies on the syntheses of heterocyclic compounds—DCCLXII : Alternative synthesis of trans-3-(1'R*-hydroxyethyl)-4-(2',2'-dimethoxyethyl)-2-azetidinone,a synthetic intermediate of thienamycin

Synthesis of trans-3-(1'R^*-hydroxyethyl)-4-(2',2'-dimethoxyethyl)-2-azetidinone (5), an important intermediate for the synthesis of thienamycin (1), was investigated starting from the isoxazoline derivatives 3 and 9. The most effective method was catalytic hydrogenation of trans-4-t-butoxycarbonyl-3-(2,2'-dimethoxyethyl)-5-methyl-isoxazoline (9) with Adams catalyst in acetic acid, followed by trimethylsilylation of the resulting epimeric aminoesters 11A and B, cyclization with EtMgBr, and deblocking. Novel reductions of the isoxazolines with sodium borohydride and nickel chloride or with diborane followed by catalytic hydrogenation were also reported.     

Electronic control of stereoselectivity-21 : Stereochemical parallelism between dienophilic capture and singlet oxygenation of isodicyclopentadiene derivatives

The stereochemistry and product distribution resulting from reaction of 4',5',6',7'- tetrahydrospirol[cyclopropane-1,2']-[4,7]methano[2$\text{H}$]indene(5), endo-2-methyl(6a) and 2,2-dunethyl-4,7-dihydro-4,7-methano-2$\text{H}$-indene (6b), as well as 4',5',6',7'-tetrahydrospiro[cyclopentane-1,2']-[4,7]methano-[2$\text{H}$]indene (7) with singlet oxygen have been determined. Stereochemical assignments to the diepoxide products were readily deduced by ¹³C-NMR comparison with the spectra of the parent isomcrs of established structure (X-ray). To unravel the stereochemistry of the epoxy aldehydes, recourse was made to 2D NOE experiments The observed stereosclectivity and reaction profile of each substrate are analyzed and placed in proper mechanistic and energetic perspective.     

Photochemistry of 5-aryl-2(3H)-furanones. : A new route to the synthesis of chromones

The photochemistry of 5-phenyl-, 5-(2',5'-dimethoxyphenyl)-, 5-(2'-acetoxy-5'-methoxyphenyl)- and 5- (2',5'-diacetoxyphenyl)- 2(3H)-furanone (1a-d) has been investigated. Compound 1a yields phenyl vinyl ketone as expected. Similarly, 1b affords the corresponding aryl vinyl ketone but, in this case, photodimerization also occurs. Irradiation of the two o-acetoxyaryl furanones 1c and 1d gives rise to the formation of chromones as the main products. This interesting result can be accounted for in terms of a photochemical opening of the lactonic ring followed by radical addition to the acetoxy group.     

Search for a simpler synthetic model system for intramolecular 1,3-dipolar cycloaddition to the 5,6-double bond of a pyrimidine nucleoside

In search for a simpler model system for the study of intramolecular thermal reactions between the base and 5'-functionalized sugar moiety in nucleosides, 1-(3-azidopropyl)uracil (2), 1-(4-azidobutyl) pyrimidines (12 and 13) and 1-(5-azidopentyl)-uracil (14) was synthesized through the corresponding ω-benzoyloxy-(6,7 and 8) and ω-hydroxyalkyl-pyrimidines (9,10 and 11). Heating 2 gave 1,N⁶-trimethylene-6-aminouracil (4), while heating 12 and 13 gave N¹-C₆ cleaved addition products. 15 and 16, respectively. 15 was regiospecifically transformed to 1,2,3-triazole derivatives, 17,18 and 19. Heating 1-(4-azidobutyl)-5-bromouracil (20) yielded 3,9-tetramethylene-8-azaxanthine (22). 9 with NBA gave 1,0⁶-tetramethylene-5-bromo-6-hydroxy-5,6-dihydrouracil (24) and the 5-brominated analog of 9 (25). The 4-functionalized butyl side chain proved to serve as a substitute for the 5'-functionalized sugar moiety in pyrimidine ribonucleosides.