New Furano-sesquiterpenoids from Mediterranean Sponges

A mixture of sponges of the East Pyrenean Mediterranean is shown to contain the known sponge products longifolin ( 1 ), avarol ((+)- 3 ), and avarone ( 4 ) and the terrestrial-plant product sesquirosefuran ( 2 ), besides to the new furano-sesquiterpenoids tavacfuran (= 3-methyl-2-[(3′Z)-3′-methyl-4″-methyl-2″-furyl-3′-butenyl]furan; ( 5 ) and tavacpallescensin (= 5,10-dihydro-6,9-dimethyl-4H-benzo[5,6]cyclohepta[1,2-b]furan; 6 ) and the new furano-butenolide sesquiterpenoids tavacbutenolide-1 (= (±-4-ethoxy-2-methyl-4-)[(2′E)-2′-methyl-4′-(3″-methyl-2″-furyl)-2′-butenyl]-2-buten-4-olide; (±)- 7 ) and tavacbutenolide-2 (= (±)-4-ethoxy-3-methyl-4-[2′E)-3′-methyl-4′-(4″-methyl-2″-furyl)-2′-butenyl]-2-buten-4-olide; (±)- 8 ). Structural assignments are based on NMR data and on the synthesis of the (E)-isomer of 5 . The sponge Dysidea tupha of the same area is also shown to contain the two sesquiterpenoids ent-furodysinin ((?)- 14 ), which is enantiomeric to a product of a Dysidea sp. of Australian waters, and tuphabutenolide ((+)- 15 ).     

Synthesis of racemic and enantiomerically pure 2′-thia-2′,3′-dideoxycytidine as potential anti-hepatitis B virus agents

A novel class of nucleosides with the C₁, atom bonded to three hetero atoms was synthesized. 2′-Thia-2′,3′-dideoxycytidine was the pilot compound of this series. (±)-β-2′-Thia-1′,3′-dideoxycytidine ( 6 ) and (±)-α-2′-thia-2′,3′-dideoxycytidine ( 7 ) were synthesized from (±)-3-mercapto-1,2-propanediol. The synthesis of the enantiomerically pure 2′-thia-2′,3′-dideoxycytidines (α-D-form, β-D-form, α-1-form and β-L-form) from optically pure (S)-(2,2-dimethyl-1,3-dioxalan-yl)methyl p-toluenesulfonate ( 8 ) and its (R)-isomer 18 was also described. The preliminary biological results showed that (+)-β-D-2′-thia-2′,3′-dideoxycytidine ( 26 ) was the most active against human hepatitis B virus with an ED₅₀ of 3 μM.     

5a-Carba-β-D-, 5a-Carba-β-L- and 5-Thio-β-L-xylopyranosides as New Orally Active Venous Antithrombotic Agents

Mitsunobu displacement of (−)-(1S,4R,5S,6S)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-ol ((−)- 12 ; a (−)-conduritol-F derivative) with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one ( 16 ) provided a 5a-carba-β-D -pyranoside (+)- 17 that was converted into (+)-4-ethyl-7-[(1′R,4′R,5′S,6′R)-4′,5′,6′-trihydroxycyclohex-2′-en-1′-yloxy]-2H-1-benzopyran-2-one ((+)- 5 ) and (+)-4-ethyl-7-[(1′R,2′R,3′S,4′R)-2′,3′,4′-trihydroxycyclohexyloxy]-2H-1-benzopyran-2-one ((+)- 6 ). The 5a-carba-β-D -xyloside (+)- 6 was an orally active antithrombotic agent in the rat (venous Wessler's test), but less active than racemic carba-β-xylosides (±)- 5 and (±)- 6 . The 5a-carba-β-L -xyloside (−)- 6 was derived from the enantiomer (+)- 12 and found to be at least 4 times as active as (+)- 6 . (+)-4-Cyanophenyl 5-thio-β-L -xylopyranoside ((+)- 3 ) was synthesized from L -xylose and found to maintain ca. 50% of the antithrombotic activity of its D -enantiomer. Compounds (±)- 5 , (±)- 6 , and (−)- 6 are in vitro substrates for galactosyltransferase 1.     

Cyclophane-Type Fullerene-dibenzo[18]crown-6 Conjugates with trans-1, trans-2, and trans-3 Addition Patterns: Regioselective Templated Synthesis,X-Ray Crystal Structure,Ionophoric Properties,and Cation-Complexation-Dependent Redox Behavior

The fullerene-crown ether conjugates (±)- 1 to (±)- 3 with trans-1 ((±)- 1 ), trans-2 ((±)- 2 ), and trans-3 ((±)- 3 ) addition patterns on the C-sphere were prepared by Bingel macrocyclization. The trans-1 derivative (±)- 1 was obtained in 30% yield, together with a small amount of (±)- 2 by cyclization of the dibenzo[18]crown-6(DB18C6)-tethered bis-malonate 4 with C₆₀ (Scheme 1). When the crown-ether tether was further rigidified by K⁺-ion complexation, the yield and selectivity were greatly enhanced, and (±)- 1 was obtained as the only regioisomer in 50% yield. The macrocyclization, starting from a mixture of tethered bis-malonates with anti ( 4 ) and syn ( 10 ) bisfunctionalized DB18C6 moieties, afforded the trans-1 ((±)- 1 , 15%), trans-2 ((±)- 2 , 1.5%), and trans-3 ((±)- 3 , 20%) isomers (Scheme 2). Variable-temperature ¹H-NMR (VT-NMR) studies showed that the DB18C6 moiety in C₂-symmetrical (±)- 1 cannot rotate around the two arms fixing it to the C-sphere, even at 393 K. The planar chirality of (±)- 1 was confirmed in ¹H-NMR experiments using the potassium salts of (S)-1,1′-binaphthalene-2,2′-diyl phosphate ((+)-(S)- 19 ) or (+)-(1S)-camphor-10-sulfonic acid ((+)- 20 ) as chiral shift reagents (Fig. 1). The DB18C6 tether in (±)- 1 is a true covalent template: it is readily removed by hydrolysis or transesterification, which opens up new perspectives for molecular scaffolding using trans-1 fullerene derivatives. Characterization of the products 11 (Scheme 3) and 18 (Scheme 4) obtained by tether removal unambiguously confirmed the trans-1 addition pattern and the out-out geometry of (±)- 1 . VT-NMR Studies established that (±)- 2 is a C₂-symmetrical out-out trans-2 and (±)- 3 a C₁-symmetrical in-out trans-3 isomer. Upon changing from (±)- 1 to (±)- 3 , the distance between the DB18C6 moiety and the fullerene surface increases and, correspondingly, rotation of the ionophore becomes increasingly facile. The ionophoric properties of (±)- 1 were investigated with an ion-selective electrode membrane (Fig. 2 and Table 2), and K⁺ was found to form the most stable complex among the alkali-metal ions. The complex between (±)- 1 and KPF₆ was characterized by X-ray crystal-structure analysis (Figs. 3 and 4), which confirmed the close tangential orientation of the ionophore atop the fullerene surface. Addition of KPF₆ to a solution of (±)- 1 resulted in a large anodic shift (90 mV) of the first fullerene-centered reduction process, which is attributed to the electrostatic effect of the K⁺ ion bound in close proximity to the C-sphere (Fig. 5). Smaller anodic shifts were measured for the KPF₆ complexes of (±)- 2 (50 mV) and (±)- 3 (40 mV), in which the distance between ionophore and fullerene surface is increased (Table 3). The effects of different alkali- and alkaline-earth-metal ion salts on the redox properties of (±)- 1 were investigated (Table 4). These are the first-ever observed effects of cation complexation on the redox properties of the C-sphere in fullerene-crown ether conjugates.     

Total Synthesis of Racemic and Optically Active Compounds Related to Physostigmine and Ring-C Heteroanalogues from 3-[2′-(dimethylamino)ethyl]2,3-dihydro-5-methoxy-1,3-dimethyl-1H-indo l-2-ol

Oxindole 11 , obtained on 3-[2′-(dimethylamino)ethyl]alkylation of oxindole 12 , yielded, on stereoselective reduction with sodium dihydridobis(2-methoxyethoxy)aluminate, aminoalcohol 8 (Scheme 2). The quaternary methiodide 10 , obtained from 8 with MeI, gave, in nucleophilic displacements concurring with a Hofmann elimination, (±)-esermethole 6 , (±)-5-O-methylphysovenol ( 14 ), (±)-5-O-methyl-1-thiaphysovenol ( 15 ), and (±)-1-benzyl-1-demethylesermethole ( 16 ). Syntheses of (±)-1-benzyl-1-demethylphenserine ( 18 ), (±)-1-demethylphenserine ( 19 ), and (±)-phenserine ( 4 ) from 6 and 16 are described. Optically active 8a and 8b , obtained by chemical resolution, similarly gave the enantiomers 6a and 14a–16a of the (3aS)-series (prepared earlier from physostigmine ( 1a )) and their (3R)-enantiomers. The anticholinesterase activity of (±)- 4 , (±)- 18 , and (±)- 19 was compared with that of their optically active enantiomers.     

Mammalian Alkaloids: Configurations of Optically Active Salsoline- and 3′,4′-Dideoxynorlaudanosoline-1-carboxylic Acids

Synthesis of the optical isomers of (±)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate ((±)- 2 ) was accomplished by reaction of (±)- 2 with (+)-(R)-1-phenylethyl isocyanate, separation of the urea diastereoisomers (?)- 4A and (+)- 4B , and alcoholysis of the ureas in refluxing BuOH. Optically active isoquinoline-carboxylates 2A , B and hydantoins 8A , B isolated were characterized. The absolute configuration of the reaction products was established by X-ray analysis of the optically active hydantoin (+)- 8A . Hydrolysis of the methyl isoquinolinecarboxylates 2A , B with 48% HBr soln. at reflux afforded the desired optically active 3′,4′-dideoxynorlaudanosoline-1-carboxylic acids 1A , B required for enzyme-inhibition studies. Details of the X-ray diffraction analysis of (+)-methyl salsoline-1-carboxylate hydrobromide ((+)- 11A ·HBr) prepared earlier are included. CD spectra of (+)-(S)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate hydrobromide ((+)- 2A . HBr) and (?)-(R)-methyl salsoline-1-carboxylate hydrochloride ((?)- 11B ·HCl) confirmed the assignment of their (S)- and (R)-configurations, respectively.     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

Synthesis of 1,2,5-Thiadiazolidin-3-one 1,1-Dioxide Derivatives and Evaluation of Their Affinity for MHC Class-II Proteins

1,2,5-Thiadiazolidin-3-one 1,1-dioxide derivatives (±)- 1a – d and (±)- 2 were designed by molecular modeling as MHC (major histocompatibility complex) class-II inhibitors. They were prepared from the unsymmetrically N,N′-disubstituted acyclic sulfamides (±)- 4a – d (Scheme 1) and (±)- 11 (Scheme 2). These N-alkyl-N′-arylsulfamide precursors were synthesized by nucleophilic substitution of either a sulfamoyl-chloride or a N-sulfamoyloxazolidinone. Extension of base-induced cyclization methods from aliphatic to aromatic sulfamides gave access to the desired target molecules. The N-alkyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives (±)- 3a – c were also prepared by the oxazolidinone route (Scheme 4) for coupling to a tetrapeptide fragment. The X-ray crystal structure of 1,2,5-thiadiazolidin-3-one 1,1-dioxide (±)- 21a was solved, and the directionality of the H-bond donor (N−H) and acceptor (SO₂) groups of the cyclic scaffold determined (Figs. 1 and 2). The pK_a value of the N−H group in (±)- 21a was determined by ¹H-NMR titration as 11.9 (Fig. 3). Compounds (±)- 1a – d were shown to inhibit competition peptide binding to HLA-DR4 molecules in the single-digit millimolar concentration range.     

Die diasteromeren Aurochrome: Synthese,Analytik und Chiroptische Eigenschaften

The Diastereomeric Aurochromes: Their Synthesis, Analysis and Chiroptical Properties (all-E)-Aurochrome (5,8:5′,8′-diepoxy-5,8,5′,8′-tetrahydro-β,β-carotene; 1 ) has two pairs of constitutionally identical chiral centres and, therefore, is expected to exist in four pairs of enantiomers and two meso-forms. Using starting materials with well-defined configuration, we performed the syntheses of the following pure aurochromes: (5R,8R,5′R,8′R)-aurochrome ( 2 ) and its racemate, Meso-(5R,8R,5′S,8′S)-aurochrome ( 3 ), (5 R,8 S,5′ R,8′ S)-aurochrome ( 4 ) and its racemate, meso-(5R,8S,5′S,8′R)-aurochrome ( 5 ), (5R,8R,5′R,8′S)-aurochrome ( 6 ) and its racemate. The (5RS,8RS,5′SR,8′RS)-aurochrome ( 7 ) was detected chromatographically, using a HPLC system that allows clean separation of the four racemic- (or optically active) and the two meso-aurochromes. The optically active autochromes 2 and 4 exhibit non-conservative CD spectra with strong Cotton effects of opposite but not mirror-like tracings. Solutions of aurochromes in CHCl₃, in the presence of HCl, undergo epimerization at C(8). Those epimers with CH₃ trans to C(9) slightly predominate under equilibrium conditions. Deprotonation of the phosphonate (±)- 14 with strong base causes isomerization at the terminal oxirane into a dihydrofuran. This reaction allowed convenient syntheses of the diastereoisomeric aurochromes (±)- 2, 3 , (±)- 4, 5 , (±)- 6 , and (±)- 7 and of (5RS, 8RS)- and (5RS, 8SR)-12′-apo-aurochrome-12′-als ( 21 and 22 , respectively).     

Synthesis and transformations of (±)-trans-4aβ(H), saα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one

Hydrogenation of 4,7-dimethylcoumarin ( 1 ) in alkaline medium has been shown to furnish a mixture of (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one ( 2 ), (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 3 ) and (±)-cis-4aα(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 4 ) in 40:25:35:ratio, respectively. The stereochemistry of the major hydrogenation product 2 , has been established by transforming it to p-menthane derivatives e.g. (±)-2 (R)-[2′(R)hydroxy-4′(R) methylcyclohex-(1′S)-yl]propan-1-ol ( 20 ) and (±)-trans-3α,6β-dimethyl-3aβ(H),7aα(H)-octahydrobenzofuran ( 12 ). Starting from a mixture of lactones 2, 3 and 4 , lactone 3 has been obtained in pure state employing a sequence of reactions.     

New ylidene and spirocyclopropyl derivatives of cholestanone and dehydroepiandrosterone series and their ability to induce cholesteric mesophase in nematic solvent

New ylidene and spirocyclopropyl derivatives of cholestanone and dehydroepiandrosterone series were synthesized and their structure was determined by X-ray analysis. These compounds may be used as chiral dopants for cholesteric liquid crystal compositions which are applied in bistable displays with low power consumption. The ability of the synthesized substances to induce cholesteric mesophase in 4′-pentyl-1,1′-biphenyl-4-carbоnitrile nematic solvent was examined. The highest values of the helical twisting power |β| (190.0?±?2.3) and (165.5?±?1.9) µm^?1 mol pats^?1 were showed by (E)-2-{[3-(1,1′-biphenyl-4-yl)-1-phenyl-1H-pyrazol-4-yl]methyldene}-cholestanon and (1S,2S)-1-(1-phenyl-3-(4-methoxyphenyl)-1H-pyrazole-4-yl)-2,16′-spirocyclopropyldehydroepiandrosterone, correspondingly.     

Studies on Flavans. III. The Total Synthesis of (±)-7,4′-Dihydroxy-3′-methoxyflavan, (±)-7,3′-Dihydroxy-4′-methoxyflavan,and (±)-7,4′-Dihydroxyflavan

Abstract

The first total synthesis of (±)-7,3′-dihydroxy-4′-methoxyflavan (1) and (±)-7,4′-dihydroxy-3′-methoxyflavan (2), along with the synthesis of (±)-7,4′-dihydroxyflavan (3), three naturally occurring flavans, were described. The key step is the cyclization of 1,3-diaryl-1-propanol by BF₃·Et₂O.     

(±)-5′-Nor ribofuranoside carbocyclic guanosine

The synthesis of the guanine derivative (±)-2-amino-1,9-dihydro-9-[(1′α,2′β,3′β,4′α)-(2′,3′,4′-trihydroxy-1′-cyclopentyl]-6H-purin-6-one ( 2 ) is described. This compound is viewed as the carbocyclic ribofuranoside guanine nucleoside analogue lacking the 5′-methylene.     

Synthesis of 1′-substituted and 1′,3′-disubstituted (±)-2R*, 11bS*-9,10-Dimethoxy-1,3,4,6,7,11 b-Hexahydrospiro-[benzo[a]quinolizin-2,5′-imidazolidine]-2′,4′-diones

The results of the reaction between (±)-2R*,11bS*-2-alkyl(aryl)amino-1,3,4,6,7,11b-hexahydrobenzo[a]-quinolizine-2-carbonitriles 2 and isocyanates under a variety of experimental conditions are discussed. The ureides 3 and iminohydantoins 4 thus obtained were used to prepare N₃-monosubstituted and N₁,N₃-disubstituted derivatives of the (±)-2R*,11bS*-9,10-dimethoxy-1,3,4,6,7,11b-hexahydrospiro[benzo[a]quinolizin-2,5′-imidazolidine]-2′,4′-dione system 1 . The stereochemistry of these compounds is discussed, on the basis of spectroscopic evidence and study of their chemical reactivity.     

Analogs of Cinchona Alkaloids Incorporating a 9,9′-Spirobifluorene Moiety

The Cinchona alkaloid analogs (+)- and (?)- 5 with a quinuclidine-2-methanol residue attached to C(2) of a 9,9′-spirobifluorene moiety were prepared as a racemic mixture by reacting lithiated 2-bromo-9,9′-spirobifluorene 7 with (2-ethoxycarbonyl)quinuclidine (±)- 6 to give ketone (±)- 8 , followed by diastereoselective reduction with diisobutylaluminum hydride (DIBAL-H). The absolute configuration at C(9) and C(8), i.e., at the methanol bridge and the adjacent quinuclidine C-atom, in the two enantiomers of 5 is identical to the configuration at the corresponding centers in (?)-quinine ( 1 ) and (+)-quinidine ( 2 ), respectively. For the optical resolution of (±)- 5 , a chiral stationary phase for HPLC was prepared by covalently bonding quinine via a thiol spacer to a silica-gel surface. The enantiomer separation was accomplished at an α value of 1.61 with (±)- 5 being eluted last, in agreement with ¹H-NMR studies in CDCl₃ which showed that (+)- 5 underwent a more stable host-guest association with quinine than (?)- 5 . ¹H{¹H} Nuclear Overhauser effect (NOE) difference spectroscopical analysis of the host-guest associations with quinine in CDCl₃, combined with computer-model examinations, allowed the assignment of the absolute configurations as (+)-(8R,9S)- 5 and (?)-(8S,9R)- 5 . A detailed conformational analysis displayed excellent agreement between the results of computational methods (Monte Carlo multiple minimum simulations, analyses of the total energy as a function of the flexible dihedral angles in the molecule) and ¹H{¹H}-NOE difference spectroscopical data. It was found that (?)- 5 and (+)- 5 differ significantly in their conformational preference from their natural counterparts quinine ( 1 ) and quinidine ( 2 ). Whereas the natural alkaloids prefer the ‘open’ conformation, with the quinuclidine N-atom pointing away from the quinoline ring, analog (±)- 5 adopts preferentially (by ca. 4 kcal mol^?1) a ‘closed’ conformation, in which the quinuclidine N-atom points into the cleft of the 9,9′-spirobifluorene moiety. Since the basic quinuclidine N-atom in the ‘closed’ conformation is sterically shielded from forming strong H-bonds, the new Cinchona alkaloid analogs form less stable host-guest associations via H-bonding than quinine or quinidine.     

New Synthetic Routes to Biologically Interesting Geranylated Flavanones and Geranylated Chalcones: First Total Synthesis of (±)‐Prostratol F,Xanthoangelol, and (±)‐Lespeol

A new and efficient synthetic approach to biologically interesting geranylated flavanones and geranylated chalcones is described. Thus, the first total syntheses of the geranylated flavanones (±)‐prostratol F ( 1 ), (±)‐8‐geranyl‐3′,4′,7‐trihydroxyflavanone ( 2 ), and (±)‐6‐geranyl‐5,7‐dihydroxy‐3′,4′‐dimethoxyflavanone ( 3 ) were carried out starting from 2,4‐dihydroxyacetophenone ( 10 ) and 2,4,6‐trihydroxyacethophenone ( 17 ) in five to six steps (Schemes 2 and 3). The geranylated chalcones xanthoangelol ( 4 ), 3‐geranyl‐2,3′,4,4′‐tetrahydroxychalcone ( 5 ), (±)‐lespeol ( 6 ), and lespeol derivatives (±)‐ 7 – 9 were synthesized starting from 2,4‐dihydroxyacetophenone ( 10 ) in three to four steps (Schemes 2 and 6).     

Temperature dependence of the rate constants of the reactions of oxygen atoms with 1-pentene, 1-hexene,cis-2-pentene,and trans-2-pentene

The kinetics of the reactions of ground state oxygen atoms with 1-pentene, 1-hexene, cis-2-pentene, and trans-2-pentene was investigated in the temperature range 200 to 370 K. In this range the temperature dependences of the rate constants can be represented by k = A′ Tⁿ exp(− E′_a/RT) with A′ = (1.0 ± 0.6) · 10⁻¹⁴ cm³ s⁻¹, n = 1.13 ± 0.02, E′_a = 0.54 ± 0.05 kJ mol⁻¹ for 1-pentene: A′ = (1.3 ± 1.2) · 10⁻¹⁴ cm³ s⁻¹, n = 1.04 ± 0.08, E′_a = 0.2 ± 0.4 kJ mol⁻¹ for 1-hexene; A′ = (0.6 ± 0.6) · 10⁻¹⁴ cm³ s⁻¹, n = 1.12 ± 0.05, E′_a = − 3.8 ± 0.8 kJ mol⁻¹ for cis-2-pentene; and A′ = (0.6 ± 0.8) · 10⁻¹⁴ cm³ s⁻¹, n = 1.14 ± 0.06, E′_a = − 4.3 ± 0.5 kJ mol⁻¹ for trans-2-pentene. The atoms were generated by the H₂-laser photolysis of NO and detected by time resolved chemiluminescence in the presence of NO. The concentrations of the O(³P) atoms were kept so low that secondary reactions with products are unimportant. © 1997 John Wiley & Sons, Inc.     

Synthesis and investigation of antibacterial activities and carbonic anhydrase and acetyl cholinesterase inhibition profiles of novel 4,5-dihydropyrazol and pyrazolyl-thiazole derivatives containing methanoisoindol-1,3-dion unit

Novel 4,5-dihydropyrazole derivatives (3a–i), 3-(4-((3aR,4S,7R,7aS)-1,3-dioxo-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindol-2(3H)-yl)phenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothio amide, were obtained by the addition of thiosemicarbazide (2) to the chalcones (1a–i). The addition–cyclization of 2,4′-dibromoacetophenone (4) to pyrazole derivatives (3a–i) gave the new pyrazolyl-thiazole derivatives (5a–i), (3aR,4S,7R,7aS)-2-(4-(1-(4-(4-bromophenyl)thiazol-2-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione. Antibacterial and acetylcholinesterase (AChE) enzyme and human carbonic anhydrase (hCA) I, and II isoform inhibitory activities of the compounds 3a–i and 5a–i were investigated. Some of the compounds showed promising antibacterial activity. In addition, the hCA II and I were effectively inhibited by the lately synthesized derivatives, with K_i values in the range of 18.90?±?2.37 ?58.25?±?13.62?nM for hCA II and 5.72?±?0.98 ?37.67?±?5.54?nM for hCA I. Also, the K_i parameters of these compounds for AChE were obtained in the range of 25.47?±?11.11???255.74?±?82.20?nM. Also, acetazolamide, clinical molecule, was used as a CA standard inhibitor that showed K_i value of 70.55?±?12.30?nM against hCA II, and 67.17?±?9.1?nM against hCA I, and tacrine inhibited AChE showed K_i value of 263.67?±?91.95.     

Synthesis of Polypropionate Fragments Containing Tertiary-Alcohol Moieties. Cross-aldolisations with lithium enolates of 7-oxabicyclo[2.2.1]heptan-2-one derivatives

The Diels-Alder adduct of 2,4-dimethylfuran to 1-cyanovinyl (1′R)-camphanate ((+)-(1R,2S,4R)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′R)-camphanate ((+)- 1 )) was converted into (+)-2,7-dideoxy-2,4-di-C-methyl-L -glycero- ((+)- 6 ) and -D -glycero-L -altro-heptono-1,4-lactone ((+)- 7 ), into (?)-(3R,4R,5R,6S)-3,4:5,7-bis(isopropylidenedioxy)-4,6-dimethylheptan-2-one ((?)- 22 ), and into (+)-(2R,3R,4R,5S,6S)-3,4:5,6-bis(isopropylidenedioxy)-2,4-dimethylheptanal ((+)- 34 ). Condensation of ((+)- 34 with the lithium enolate of (?)-(1R,4R,5S,6R)-6-exo-[(tert-butyl)dimethylsilyloxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1] heptan-2-one ((?)- 38 ; derived from (+)- 1 ) gave a 3:2 mixture of aldols (+)- 39 and (+)- 40 (mismatched pairs of a α-methyl-substituted aldehyde and (E)-enolate) whereas the reaction of (±)- 34 with (±)- 38 gave a 10:1 mixture of aldols (±)- 41 and (±)- 39 . A single aldol, (?)- 44 , was obtained to condensing (+)- 34 with the lithium enolate of (+)-(1S,4S,5S,6S)-5-exo-(benzyloxy)-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptan-2-one ((+)- 43 ; derived from (?)-(1S,2R,4S)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′S)-camphanate ((?)- 3 )). All these cross-aldolisations are highly exo-face selective for the bicyclic ketones. The best stereochemical matching is obtained when the lithium enolates and α-methyl-substituted aldehydes can realize a ‘chelated transition state’ that obeys the Cram and Felkin-Anh models (steric effects). Polypropionate fragments containing eleven contiguous stereogenic centres and tertiary-alcohol moieties are thus prepared with high stereoselectivity in a convergent fashion. The chiral auxiliaries ((1R)- and (1S)-camphanic acid) are recovered at the beginning of the syntheses.     

(6′RS,8′RS,2E)- und (6′RS,8′SR,2E)-3-Methyl-3-(2y,2′,6′-trimethyl-7′-oxabicyclo[4.3.0]non-9′-en-8′-yl)-2-propenal ([(5RS,8RS)- und (5RS,8SR)-5,8-Epoxy-5,8-dihydro-ionyloinden]acetaldehyd): Synthese und Röntgenstrukturanalyse

Synthesis and X-Ray Structure of (6′RS,8′RS,2E)- and (6′RS,8′SR,2E)-3-Methyl-3-(2′,2′,6′-trimethyl-7′-oxabicyclo[4.3.0]non-9′-en-8′-yl)-2-propenal ([(5RS,8RS)- and (5RS,8SR)-5,8-Epoxy-5,8-dihydro-ionylidene]acetaldehyde) To check our previous spectroscopic assignments of the structures of trans- and cis-substituted furanoid end groups of carotenoid-5,8-epoxides, we now have synthesized the title compounds. An X-ray structure determination of a single crystal of the trans-isomer (±)- -10A is in agreement with the ¹ H-NMR spectroscopic arguments: isomers with Δδ (H? C(7), H? C(8)) = 0.15–0.22 ppm and J > 1.4 for H? C(7) belong to the cis-series; Δδ in trans-compounds is < 0.07 ppm, and H? C(7) appears as a broad singulett.