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The phytochemical investigation of the n-hexane, the EtOAc, and the n-BuOH soluble fractions of the methanolic extract of the arial parts of Perovskia abrotanoides Karelin furnished ten compounds including the two new tetracyclic diterpenes abrotandiol (7) and abrotanone (8) besides the known cirsimaritin (9), hespiridin (10), rosmarinic acid (11), stigmast-5-en-3beta-ol (12), stigmast-5,22-dien-3beta-ol (13), stigmast-5-en-3beta,7alpha-diol (14), ursolic acid (15) and betulinic acid (16). Compounds 7 and 8 both show a 6,5,6,6 ring skeleton with a trans-1,1-dimethylcyclohexano[e,b]tetrahydrofuran element perpendicular to a benzodihydropyran system. The complete structure elucidation of these compounds has been achieved with NMR techniques.

P2 membrane receptors for nucleotides represent significant targets for experimental pharmacology and drug research. In earlier publications, we have shown that Reactive Blue 2 (RB 2), one of the most widely used P2-receptor antagonists, displays only moderate affinity and does not discriminate between native P2X- and P2Y-receptor subtypes. In the present study we have pharmacologically evaluated a series of 15 synthesized and re-evaluated four commercially obtained and chromatographically purified RB 2 type anthraquinone derivatives on contractions of the rat vas deferens (RVD) elicited by alpha,beta-methylene ATP (alpha,beta-meATP), mediated by P2X1-receptors, and relaxations of the carbachol-precontracted guinea-pig taenia coli (GPTC) elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS), mediated by P2Y1-like receptors. Based on the structure-activity relationships (SAR) it is concluded that hydrophobic interactions of aromatic pi-electron systems, hydrogen bonds with nitrogen as donor and acceptor atoms, and, particularly, position, conformational distance and number of anionic sulfonate groups are of great importance for the blockade of the two native P2-receptor subtypes. We have also identified novel, for the most part reversible antagonists that bind with higher affinity and improved subtype selectivity in comparison to RB 2. In particular, 1-amino-4-{4-[4-chloro-6-(2-sulfonatophenylamino)-[1,3,5]triazine-2-ylamino]-2-sulfonatophenylamino}-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid trisodium salt (MG 50-3-1) is the most potent antagonist at the P2Y1-like-receptors of the GPTC reported so far (IC50=4.6 nM). It is significantly less potent as reversible antagonist at the P2X1-receptors of the RVD (IC50=2.8 microM). Thus, MG 50-3-1 represents a selective pharmacological tool and may be a lead compound for future investigations.

The second-generation asymmetric synthesis of the trans-tris(homoglutamic) acids reported herein proceeds via Strecker reaction of chiral ketimines, obtained from condensation of racemic 2-ethoxycarbonylmethylcyclopentanone and commercially available (S)- and (R)-1-phenylethylamine, respectively. In the key stereodifferentiating step, the cyanide addition leads to mixtures of diastereomeric alpha-amino nitrile-esters, the composition of which is independent of the reaction temperature and the type of the solvent, respectively. Hydrolysis of the alpha-amino nitrile-esters with concentrated H(2)SO(4) yielded diastereomeric mixtures of secondary alpha-amino amido-esters, which after separation were hydrogenolyzed and hydrolyzed each to the enantiomeric trans-1-amino-2-carboxymethylcyclopentanecarboxylic acids. Their configuration was completely established by NMR methods, CD spectra, and X-ray analysis of the trans-1S,2R-configured secondary alpha-amino amido-ester. In receptor binding assays and functional tests, trans-1S,2R-1-amino-2-carboxymethylcyclopentanecarboxylic acid hydrochloride was found to behave as a selective mGluR(2)-antagonist without relevant binding properties at iGluRs.

Asymmetric synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-diones has been achieved. The underlying second generation asymmetric synthesis proceeds via a Strecker reaction with commercially available (R)-1-phenylethylamine (1-PEA) as chiral auxiliary, TMSCN as cyanide source and racemic ethyl 2-(2-oxocyclohex-1-yl)ethanoate. A ring closure addition–elimination reaction between an amide nitrogen and the ester functionality leads to the 1-amino-3-azabicyclo[4.4.0]decan-2,4-diones. The absolute configurations of the title compounds have been assigned based on detailed NMR-spectroscopic analysis and X-ray data.

The second generation asymmetric synthesis reported herein proceeds via a Strecker reaction of chiral ketimines, obtained from the condensation of racemic 2-methoxycyclopentanone and (S)- and (R)-1-phenylethylamine. In the key stereodifferentiating step, the cyanide addition leads to mixtures of diastereomeric nitriles, the composition of which dramatically changes under the influence of protic and aprotic solvents. Hydrolysis of the nitriles to carboxamides with concd H2SO4 yielded diastereomeric mixtures of carboxamides each of which was hydrogenolysed and hydrolysed after separation to the four stereoisomers of the 1-amino-2-methoxy- and 1-amino-2-hydroxy-cyclopentanecarboxylic acid. Their stereochemistry was established by NMR methods and by X-ray analyses of the trans as well as the cis configured compounds.

Three compounds, namely the interesting biflavanonol GB-2(naringenin 1-3, 11-8-dihydroquercetin, 1), 1-4',1-5,11-5,1-7,11-7-pentahydroxyflavanone(l-3,11-8)chromone [naringenin-(3 -8) 5,7-dihydroxychromone, 21 and stigmasterol, have been isolated from the leaves of Cratoxylum neriifolium Kurz. Compounds 1 and 2 show rotameric behavior due to the presence of a single bond between the highly substituted flavanone and flavanonol part and the flavanone and chromone part, respectively. Complete NMR spectral assignments of 1 and 2 have been done at 27 C and 90 C for the first time followed by a study of conformational behavior at room temperature by ROESY.

We previously reported a structure-activity study which identified Acid blue 129 (1-amino-4-(2,4,6-trimethylphenylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid) as a highly selective antagonist at the P2Y-receptor of the guinea pig taenia coli. In contrast to the less selective P2Y-receptor antagonist Acid blue 25 (1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid) with its unsubstituted phenyl ring, Acid blue 129 does not show any effect at the P2X-receptor of the rat vas deferens. It was hypothesized that the nonplanar orientation of the substituted phenyl ring vs. the anthraquinone core, caused by the buttressing methyl groups in 2',6'-position, prevents binding of Acid blue 129 to the P2X-receptor. To prove this assumption we synthesized new compounds structurally related to Acid blue 129. The effects of all compounds were studied on contractions of the rat vas deferens elicited by α,β-methylene ATP (α,β-MeATP; mediated by P2X-receptors) and relaxations of the carbachol-precontracted guinea pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPβS; mediated by P2Y-receptors). All compounds were more or less P2Y- vs. P2X-selective. In contrast to our assumption, it is the 4'-methyl group of Acid blue 129 and of its new analog MG 32 (1-amino-4-(4-methylphenylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid) which completely prevents binding to the P2X-receptor up to 100 μM antagonist concentration, whereas the P2X-receptor is blocked by related compounds lacking the 4'-methyl group. Acid blue 129 and MG 32 were the most interesting compounds. Both turned out to be potent P2Y-receptor antagonists with IC 50 -values of approximately 3 pM. They are highly selective vs. both P2X-receptor and non-P2-receptor effects. Drug Dev. Res. 59:64-71, 2003.

The anthraquinone derivative Reactive Blue 2 (RB 2) is one of the most widely used P2-receptor antagonists, still claimed to be P2Y-selective. RB 2 is defined as a mixture of two constitutional isomers and commercially available in different identity and purity. A sample of RB 2, offered for sale by RBI, purchased from Biotrend, Köln, Germany, was chromatographically purified and identified by 1H- and 13C-NMR studies as a 35:65 mixture of the terminal ring F meta and para constitutional isomers. The two constitutional isomers of RB 2 were synthesised and tested alongside with the ortho isomer Cibacron Blue 3GA (CB 3GA) on contractions of the rat vas deferens (RVD) elicited by alpha,beta-methylene ATP (alpha,beta-MeATP), mediated by P2X(1)-receptors, and relaxations of the carbachol-precontracted guinea pig taenia coli elicited by adenosine 5'-O-(2-thiophosphate) (ADPbetaS), mediated by P2Y(1)-like-receptors. All compounds inhibited the alpha,beta-MeATP induced contraction of the RVD and the ADPbetaS induced relaxation of the carbachol precontracted guinea-pig taenia coli. The IC(50)-values at P2X(1)-R were 9.1 microM for CB 3GA, 28.4 microM for RB 2, 19.7 microM for RB 2 meta, and 35.5 microM for RB 2 para. The IC(50)-values at P2Y(1)-like-R were 17.4 microM for CB 3GA, 7.7 microM for RB 2, 12.0 microM for RB 2 meta, and 2.6 microM for RB 2 para. The results clearly show that neither RB 2 as a mixture nor the pure ortho and meta isomer are P2Y(1)-like- versus P2X(1)-selective antagonists. In contrast the pure para-isomer of RB 2 is a moderately P2Y(1)-like- versus P2X(1)-selective antagonist.

Synthesis of enantiopure 2,4-methanovalines has been achieved by means of asymmetric Strecker synthesis starting from racemic 2-methylcyclobutanone. The trans-configured α-amino acids were obtained from cyanide additions carried out in methanol, whereas the cis-configured 2,4-methanovalines were accessible via reactions in hexane. Relative stereochemistry was elucidated from NOESY experiments, while absolute configurations were assigned from X-ray crystallographic analysis.

Asymmetric syntheses of trans- ( R , R )- and ( S , S )-1,2-diaminocyclohexanecarboxylic acids have been achieved with ee >99% while the respective cis -( R , S )- and ( S , R )-stereoisomers were obtained as 1-amino-2-benzoylaminocyclohexanecarboxylic acids. The underlying second generation asymmetric synthesis proceeds via Strecker reaction with commercially available ( R )- and ( S )-1-phenylethylamine (1-PEA) as chiral auxiliaries, TMSCN as cyanide source and racemic 2-benzoylaminocyclohexanone. The key stereodifferentiating step of the cyanide addition to the chiral ketimine intermediates has been studied under the influence of protic and aprotic solvents. Hydrolysis of the nitriles to the carboxamides with conc. H 2 SO 4 yielded dramatic changes in the product composition as a function of temperature and time. Hydrolysis of both the attendant amido groups are concomitant processes in case of the trans -configured carboxamides while the cis -stereoisomers undergo selective carboxamide hydrolysis, with the benzoyl protecting group remaining intact, leading to orthogonally protected α,β-diamino acids. The absolute configurations of the amino acids and their intermediates have been assigned based on detailed NMR spectroscopic analysis and X-ray data.

The non-ionic emulsifier Cremophor® EL can be quantified using a special potentiometric titration technique with barium chloride activation and precipitation with sodium tetraphenylborate. The end point of the titration is indicated by an ionsensitive coated wire electrode which responds to an excess of tetraphenylborate ions. Sample preparation is necessary to quantify the excipient in plasma of patients receiving ciclosporin formulations with Cremophor® EL (Sandimmun®), since plasma proteins cause disturbances of the titration. Solid phase extraction was tested with various sorbent materials. Although some of the sorbents yielded good extraction rates of Cremophor® EL from aqueous solutions, the extraction rates from plasma were significantly lower. Therefore, plasma protein precipitation with acetonitrile has been examined as an alternative to SPE and has been proved the superior method. Using the precipitation technique, a recovery rate of above 90% was achieved. Furthermore, the limit of detection from plasma was found to be 30 μg, in analogy to the determination from aqueous solutions. The combination of the plasma protein precipitation with the potentiometric titration allows quantitation and thus pharmakokinetic investigations of Cremophor® EL in patients treated with Sandimmun® after kidney-transplantation.

A series of 12 carbocyclic α-amino acids has been prepared from four different racemic 2-alkylated cyclopentanones and ( R )-1-phenylethylamine as the chiral auxiliary by means of an asymmetric Strecker synthesis. The stereoselectivity was influenced by solvent, temperature and size of the substituent at the 2-position of the cyclopentanones. For the methyl and ethyl substituted amino acids all four possible stereoisomers could be obtained, whereas for the isopropyl and tertiary butyl compounds an unexpected side reaction prohibited the isolation of the cis configured amino acids. The 1,3-induction mechanism observed for the kinetically controlled α-amino nitrile formation in the 2-methyl and 2-ethyl series was overlayed by a 1,2-induction in the respective 2-isopropyl and 2-tertiary butyl series.

The phytochemical investigation of a methanolic leaf extract of Aglaia rubiginosa furnished 15 isoprenoid constituents, eight of which represented new natural entities. Two androstane derivatives (1 and 2), previously synthesized, and also obtained by microbiological transformations; an extraordinary 17-octanor-cycloartane-ring-A-seco acid (3); four cycloartane-type triterpenes (4-7); and three unusual cholesterol derivatives (8-10) were isolated, along with two known dammaranes (11 and 12), a stigmastandiol (13), and beta-sitosterol and its beta-D-glucoside. Spectroscopic structure elucidation of the new natural products (1-3, 6, 7, 8-10) is described.

The effect of temperature on the resolution of (RS)-sotalol by immobilized cellobiohydrolase I (CBH I) was studied between 5 and 40 degrees C and Van 't Hoff plots of ln k versus 1/T were acquired at different pH values of the aqueous mobile phase and in the presence of varying organic cosolvents. The elution order of the enantiomers reverses in the range between 17 and 28 degrees C. Beyond this range, enantioseparations with comparatively high resolution factors are achieved either by decreasing or by increasing the temperature. The composition of the mobile phase influences the "crossover" temperature as well as the character of the global adsorption process of the (R)-(-)-enantiomer. Under certain conditions, (R)-(-)-sotalol exhibits an unusual endothermic adsorption behavior. Its retention time increases with increasing temperature. At room temperature (23 degrees C) the enantiomeric elution order can also be regulated by the solvent additive.

The title compound, (1-carboxamido-2-methoxycyclohexyl)ammonium chloride 0.25-hydrate, C 8 H 17 N 2 O + 2 .Cl - .0.25H 2 O, (I), was obtained in the course of our research efforts towards 2,4-propano analogues of the naturally occurring α-amino acid L s -threonine. In order to elucidate the absolute stereochemistry of (I), the absolute configuration was determined by exploiting anomalous dispersion effects. The crystal structure contains four independent molecules within the asymmetric unit, which are linked by a network of hydrogen bonds and include the Cl - ions. The absolute configuration of all four molecules is the same; however, differences in the conformation of some groups are present.

Quantitative Structure Activity-Relationships between the antituberculous activity of a series of 61 substituted xanthones and their 13C NMR chemical shifts, lipophilicity, and molar refractivities of the substituents were investigated. In addition to these structural parameters, the test concentrations of the compounds were considered because of the varying solubility. While the multiple linear regression-based Adaptive Least Squares analysis revealed only weak correlations between the antituberculous activity classes of the compounds and their physicochemical parameters, significantly better results were obtained by the Artificial Neural Network technique, which describes nonlinear relationships between the activity as dependent and the physicochemical parameters as independent variables.

Starting from racemic 2-methoxycyclohexanone and ( S )- or ( R )-1-phenylethylamine, respectively, the four stereoisomers of 1-amino-2-hydroxycyclohexanecarboxylic acid are obtained via an asymmetric Strecker synthesis with ee values ranging from 87 to 98%. Their stereochemistry is established by NMR methods and by X-ray analyses. Hydrogenolysis of a benzylic C–N bond by conc. sulphuric acid as well as cleavage of a methoxy ether by conc. HCl are two intriguing reactions which are observed within the five-step procedure described herein.

Separation buffers for the determination of the corticosteroids cortisone, hydrocortisone, prednisone and prednisolone with micellar electrokinetic chromatography were developed with respect to separation efficacy and the migration times, depending on the type and the concentration of the organic modifier acetonitrile as well as on the addition of gamma-cyclodextrin. The buffer containing 50 mM SDS and 16% (v/v) acetonitrile enables the rapid profiling of prednisolone together with cortisone and prednisone. Addition of gamma-cyclodextrin alters the elution sequence, but does not further enhance resolution of the corticosteroids. Baseline separation at long migration times for cortisone, hydrocortisone, prednisone and prednisolone is achieved with a buffer containing 50 mM each of SDS, dehydrocholic acid sodium salt and glycodeoxycholic acid sodium salt.

A series of substituted xanthones was tested for their activity against four mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. lufu, M. smegmatis) by determination of the minimum inhibitory concentrations (MIC values). For the most active compounds, supplementary characterisation was performed by bacterial growth kinetics, which allows a more precise interpretation of their antimycobacterial effects. From the test set, 1-methyl-2,4,7-trinitroxanthone (8a) showed the highest antimycobacterial activity with a MIC value of 3 micrograms/mL against M. tuberculosis, which is comparable to the effect of well known drugs used in the treatment of tuberculosis. For all other compounds, the MIC values could not be determined, due to the comparatively low activity and to the poor solubility of the compounds, respectively. The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.

The hitherto unknown (+)- and (−)-cis-2-aminocyclobutanols 6a,b and 7a,b, as well as the corresponding benzyloxycyclobutanamines 8a,b, have been synthesized by means of asymmetric reductive amination, with de values of 100% and ee values ranging from 96.9 to 99.8%. The relative cis configuration has been established by NO experiments, whereas the absolute stereochemistry has been deduced from the CD spectra of the corresponding salicylidene derivatives and confirms the like induction at C-1.

A new spirocyclic nortriterpene, 22-acetoxy-15-deoxo-eucosterol, was isolated together with a corresponding pentaglycoside from the bulbs of Veltheimia viridifolia . The structures of the isolated compounds were elucidated by spectroscopic methods including 1D- and 2D- 1 H NMR, 13 C NMR, 1D-INEPT, ID- and 2D-TOCSY, HSQC, HMBC, ROESY experiments, FAB- and HRESI-mass spectrometry.

A series of homochiral 7-substituted 1-aminoindams was prepared by means of asymmetric reductive amination from racemic 7-substituted 1 -indanones via E-imines and E-imine/ enamine mixtures, respectively, and subjected to 5-hydroxytryptamine (5-HT) receptor subtype binding studies. The ee's of the title compounds were determined by HPLC of the corresponding Mosher's amides and range from 96 to 99.9%. The absolute configuration was elucidated by means of correlation CD spectroscopy. On the basis of the pK I values obtained from various test systems, structure activity relationships have been established with respect to the absolute configuration, degree of N-alkylation, and the type of 7-substituents. The tested 1-aminoindans show the highest affinity to the 5-HT 1A receptor, with decreasing magnitude for the 5-HT 2A , 5-HT 1D , and 5-HT 2C receptors. The highest affinities for the 5-HT 1A receptor were observed for the R-(-)-7-propoxy-1-(di-n-propylamino)indan hydrochloride (R-(-)-30), S,S'-(+)-7-benzylamido-1-(1phenylethylamino)indan hydrochloride [S,S'-(+)-19] and R-(-)-7-methoxy-1-(di-n-propylamino)indan hydrogenembonate (R-(-)-29) with pK I = 7.07 ± 0.19, 6.40 ± 0.09, and 6.22 ± 0,10, respectively, in comparison to 8-OH-DPAT with pK I = 8.70±0.30. Nearly all other compounds showed low affinity at all 5-HT receptors tested. The three above mentioned ligands were tested on HeLa cells (cell line HA6) expressing recombinant human 5-HT 1A receptors for their effects on forskolin-stimulated cAMP accumulation in intact cells. Both the di-n-propylamino substituent bearing R-(-)-30 and R-(-)-29 acted as efficacious agonists with a pEC 50 value of 5.89 ± 0.20 for R-(-)-30 compared to 5-HT with a pEC 50 value of 8.06 ± 0.14, S,S'-(+)-19 with the 1-phenylethylamino substituent was devoid of intrinsic activity up to the highest tested concentration (10 μM).

A series of homochiral cis -2-alkoxy- and 2-aryloxycyclohexanamines 5b-5e has been synthesised by means of asymmetric reductive amination of the corresponding racemic 2-oxygenated cyclohexanones 2 with ee -values ranging from 95 to >99%. The respective 2-hydroxy and 2-cyclohexyl derivatives 5g-5h have been prepared from the 2-phenoxycyclohexanamine 4e . Relative and absolute stereochemistry has been elucidated.

The stereoisomers of amidinomycin 7 and their intermediates 1-6, which are produced from homochiral 3-oxocyclopentanecarboxylic acids by asymmetric synthesis, are tested for their antimicrobial effects by agar diffusion test and by Bouillon serial dilution assay. Their antibiotic activities against Bacillus subtilis, Staphylococcus aureus, and Micrococcus Iuteus, respectively, are reported. Structure-activity relationships depend on the type and combination of functional groups, on only the relative stereochemistry as well as on the grade of lipophilia of the tested compounds.

The ethanol extract ofGynura procumbensshowed virucidal and antireplicative actions against herpes simplex virus HSV-1 and HSV-2. It was further chromatographed on MCI gel CHP20P column giving the extract fractions F1 (water), F2 (water-methanol) F3 (methanol), and F4 (ethyl acetate). All but F1 had virucidal action against both viral types. We reported here the active compounds from F2 and F3. The antiherpetic compounds of F2 was a mixture of dicaffeoylquinic acids with virucidal and antireplicative actions against HSV-2 (IC5096.0 and 61.0 μg/mL, resp.) Virucidal compounds of F3 were a mixture ofβ-sitosterol and stigmasterol (IC50250.0 μg/mL against HSV-1), a mixture ofβ-sitosteryl and stigmasteryl glucosides (IC5050.0 μg/mL against HSV-2) and 1, 2-bis-dodecanoyl-3-α-D-glucopyranosyl-sn-glycerol (IC50of 40.0 μg/mL against HSV-2). Herbal products containing 1 and 2% of standardized ethanol extract were prepared. Double-blind randomized controlled clinical trial of the products was performed in patients with recurrent herpes labialis. Results showed that the number of patients, whose lesions healed within 7 days and the average healing time of both groups differed insignificantly. Viral culture on D7 indicated a decrease of infected patients from 48.7% to 7.69% in treated group whereas in placebo group the infected patients decreased from 31.25% to 20.00%. The viral reduction in treated group indicated the benefit of the product. Insignificant result might arise from a low number of participated patients and insufficient concentration of plant extract in herbal product.

1H and 13C NMR chemical shifts and the homo- and heteronuclear coupling constants of 14 nitroxanthones are presented. Specific nitro increments for xanthones depending on substituent position and on the respective ring carbon position and shift additivity rules were developed by means of multiple linear regression analysis.

A multidimensionally coupled screening system based on reversed-phase high performance liquid chromatography/normal-phase automated multiple development with ultra violet and mass spectral detection has been further improved regarding the achievable peak capacity. This optimized method was used to reinvestigate the phytochemistry of Amaryllis belladonna and led to the identification of nine additional alkaloids, namely anhydrolycorin-7-one, 6-OH-buphanisine, 6-OH-crinine, crinine, galanthine, hippadine, ismine, pratorimine and pratosine which are described for the first time in the title plant.

The CD spectra of eight guaianolides from the aerial parts of Centaurea scoparia have been investigated. Most of these compounds contain a C-7, C-6 trans-fused α-methylene γ-lactone moiety and display negative cotton effects in the range of 252–271 nm for the nπ∗ transition of the α-methylene γ-lactone chromophore and a positive Cotton effect between 216–225 nm in case of a second chromophore in 8S-position for 4′-hydroxymethacrylates and between 241–246 nm for 4′-hydroxytiglates, which may be used for the determination of the absolute configuration of such guaianolides on the basis of spectral correlations with chlorojanerin, the absolute configuration of which was established by X-ray analysis.

The natural amidinomycin ((1R, 3S)-14) and its three stereoisomers are synthesized from homochiral 3-oxocyclopentanecarboxylic acids (1a) by asymmetric methods, which are based on an asymmetric reductive amination to produce methyl cis-N-(1-phenylethyl)-3-aminocyclo-pentanecarboxylates (3b) via optically active methyl N-(1-phenylethyl)-3-iminocyclopentane-carboxylates (2b) for the cis-isomers of 14. Optically pure trans-3-aminocyclopentane-carboxylic acids (4a) are obtained from the homochiral keto acids 1a via asymmetric reductive amination of 3-hydroxy-iminocyclopentanecarboxylic acids (5a) and lead to the trans-isomers of 14.

A new chlorine-containing guaianolide, chloroscoparin, was isolated from the ethanol extract of the aerial parts of CENTAUREA SCOPARIA Sieb. together with three known chlorine-containing guaianolides. The structures of the isolated compounds were elucidated by spectroscopic methods including (1)H-NMR-, 2D (1)H- (1)H COSY-, (13)C-NMR-, APT-, DEPT-, HETCOR-, long-range-HETCOR-, 2D INADEQUATE-, and mass spectra. The relative configuration was determined by 2D-NOESY studies. New NMR data for the known compounds are reported.

C 21 H 25 NO.HCl, M r =343.90, orthorhombic, P2 1 2 1 2 1 , a=8.588 (1), b=11.700 (1), c=18.130 (2) A, V=1821.7 (4) A 3 , Z=4, D x =1.254 Mg m -3 , λ(Mo Kα)=0.71069 A, μ=2.139 mm -1 , F(000)=736, T=293 K, final R=0.037 for 3192 observed reflections. Condensation of 2-(benzyloxy)cyclohexanone with (R)-1-phenylethylamine yields, by rearrangement, an unexpected reaction product mixture of (αR,2S)- and (αR,2R)-2-benzyl-2-[N-(α-phenylethyl)amino]cyclohexanone hydrochlorides. The absolute configuration of one the epimers (the title compound) is elucidated as (αR, 2S), showing the cyclohexanone ring in the chair conformation

The natural amidinomycin ((1R, 3S)-14) and its three stereoisomers are synthesized from homochiral 3-oxocyclopentanecarboxylic acids (1a) by asymmetric methods, which are based on an asymmetric reductive amination to produce methyl cis-N-(1-phenylethyl)-3-aminocyclo-pentanecarboxylates (3b) via optically active methyl N-(1-phenylethyl)-3-iminocyclopentane-carboxylates (2b) for the cis-isomers of 14. Optically pure trans-3-aminocyclopentane-carboxylic acids (4a) are obtained from the homochiral keto acids 1a via asymmetric reductive amination of 3-hydroxy-iminocyclopentanecarboxylic acids (5a) and lead to the trans-isomers of 14.

The synthesis of the four 1-amino-2-methylcyclohexanecarboxylic acids 13, 14, 15, and 16 from diastereomeric mixtures of the α-amino nitriles 1–4 by successive application of conc. H2SO4, Pd/C H2, and conc. HCl is described. The amino nitriles 1–4 were prepared by asymmetric Strecker synthesis under various reactions, The formation of 1–4 is thermodynamically controlled in protic solvents (e.g. MeOH), whereas the reaction is under kinetic control in non-protic solvents (e.g. hexane), The separation of the α-amino amides 5–8, which were obtained by partial hydrolysis of 1–4, was achieved by CC, LPLC, and HPLC. The absolute configuration of all synthesized compounds was determined by means of only two X-ray analyses with consecutive correlations. The steric control of the asymmetric Strecker synthesis is discussed.

A series of homochiral 7-substituted 1-aminoindams was prepared by means of asymmetric reductive amination from racemic 7-substituted 1 -indanones via E-imines and E-imine/ enamine mixtures, respectively, and subjected to 5-hydroxytryptamine (5-HT) receptor subtype binding studies. The ee's of the title compounds were determined by HPLC of the corresponding Mosher's amides and range from 96 to 99.9%. The absolute configuration was elucidated by means of correlation CD spectroscopy. On the basis of the pK I values obtained from various test systems, structure activity relationships have been established with respect to the absolute configuration, degree of N-alkylation, and the type of 7-substituents. The tested 1-aminoindans show the highest affinity to the 5-HT 1A receptor, with decreasing magnitude for the 5-HT 2A , 5-HT 1D , and 5-HT 2C receptors. The highest affinities for the 5-HT 1A receptor were observed for the R-(-)-7-propoxy-1-(di-n-propylamino)indan hydrochloride (R-(-)-30), S,S'-(+)-7-benzylamido-1-(1phenylethylamino)indan hydrochloride [S,S'-(+)-19] and R-(-)-7-methoxy-1-(di-n-propylamino)indan hydrogenembonate (R-(-)-29) with pK I = 7.07 ± 0.19, 6.40 ± 0.09, and 6.22 ± 0,10, respectively, in comparison to 8-OH-DPAT with pK I = 8.70±0.30. Nearly all other compounds showed low affinity at all 5-HT receptors tested. The three above mentioned ligands were tested on HeLa cells (cell line HA6) expressing recombinant human 5-HT 1A receptors for their effects on forskolin-stimulated cAMP accumulation in intact cells. Both the di-n-propylamino substituent bearing R-(-)-30 and R-(-)-29 acted as efficacious agonists with a pEC 50 value of 5.89 ± 0.20 for R-(-)-30 compared to 5-HT with a pEC 50 value of 8.06 ± 0.14, S,S'-(+)-19 with the 1-phenylethylamino substituent was devoid of intrinsic activity up to the highest tested concentration (10 μM).

The hitherto unknown (+)- and (−)-cis-2-aminocyclobutanols 6a,b and 7a,b, as well as the corresponding benzyloxycyclobutanamines 8a,b, have been synthesized by means of asymmetric reductive amination, with de values of 100% and ee values ranging from 96.9 to 99.8%. The relative cis configuration has been established by NO experiments, whereas the absolute stereochemistry has been deduced from the CD spectra of the corresponding salicylidene derivatives and confirms the like induction at C-1.

A series of substituted xanthones was tested for their activity against four mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. lufu, M. smegmatis) by determination of the minimum inhibitory concentrations (MIC values). For the most active compounds, supplementary characterisation was performed by bacterial growth kinetics, which allows a more precise interpretation of their antimycobacterial effects. From the test set, 1-methyl-2,4,7-trinitroxanthone (8a) showed the highest antimycobacterial activity with a MIC value of 3 micrograms/mL against M. tuberculosis, which is comparable to the effect of well known drugs used in the treatment of tuberculosis. For all other compounds, the MIC values could not be determined, due to the comparatively low activity and to the poor solubility of the compounds, respectively. The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.

The rare 4- and 5-alkylindan-2-ols have been synthesized in 62–72% yields by formal 1,6- and 1,4-nucleophilic ring opening of the 2-hydroxyindan 3a,7a-oxide, respectively.