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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.

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.

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.

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 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 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.

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 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 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.

The reaction of himachalol with m-chloroperoxybenzoic acid afforded a rearrangement product, the structure of which was deduced by 2D NMR analysis to be 3α,4α-epoxyhimachalane-2α,7α-diol. The recently proposed 1 H NMR assignments for himachalol have been revised, based on the analysis of 2D COSY, DEPT, HETCOR and NOE experiments

Die asymmetrische Synthese der 2-substituierten Cycloheptanamine 4 aus racemischen Cycloheptanonen durch reduktive Aminierung wird in einem Dreistufenverfahren beschrieben. Aus den Ketonen 1 werden durch Umsetzung mit den chiralen Hilfsaminen R-(+)- bzw. S-(-)-1-Phenylethylamin Imin-Isomerengemische 2 erhalten, die nach Hydrierung uber Raney-Nickel ein einziges cis-konfiguriertes sekundares Amin 3 liefern. Hydrogenolyse uber Pd/C fuhrt zu den optisch aktiven primaren cis-2-substituierten Cycloheptanaminen 4. Asymmetric Reductive Amination of Cycloalkanones, XI1,2): Synthesis of Optically Active 2-Substituted Cycloheptanamines Asymmetric synthesis of 2-substituted cycloheptanamines from racemic cycloheptanones by means of reductive amination in a three-step procedure is described. Condensation of the ketones 1 with the optically active auxiliary R-(+)- or S-(-)-1-phenylethylamine leads to the imine mixtures 2 which are hydrogenated over Raney nickel to give the optically active, diastereomerically pure secondary amines 3. Hydrogenolysis with Pd/C yields the optically active cis-2-substituted cycloheptanamines 4.

Es wird die EPC-Synthese (Enantiomerically Pure Compounds) der optisch aktiven cis-bicyclischen Lactame 5 mit annellierten 5.5-, 5.6-, 6.5- und 6.6- gliedrigen Ringen sowie der korrespondierenden optisch aktiven cis-bicyclischen Amin-Hydrochloride 6 (Cyclopentanopyrrolidin, Octahydroperindin, Perhydroindol und Dekahydrochinolin) aus den kongeneren cycloaliphatischen Aminosaureestern 4 durch intramolekulare Aminolyse und nachfolgende Lithiumalanat-Reduktion beschrieben. Die erforderlichen Ausgangsverbindungen 4 werden aus den racemischen Cycloalkanon-2-essig- bzw. 2-propionsaureestern 1 und den chiralen Hilfsaminen R-(+)- bzw. S-(−)-1-Phenylethylamin durch dreistufige asymmetrische Synthesen gewonnen1). Die relative Konfiguration der Verbindungen 5 und 6 wurde durch 1H-NMR-Spektroskopie, die optische Reinheit der optisch aktiven cis-bicyclischen Amin-Hydrochloride 6 durch HPLC der entspr. Mosher-Amide 7 bestimmt. Asymmetric Reductive Amination of Cycloalkanones, X: EPC-Synthesis of cis-Bicyclic Lactames and Amines We report the EPC-synthesis (Enantiomerically Pure Compounds) of optically active cis-bicyclic lactames 5 with annellated 5.5-, 5.6-, 6.5- and 6.6- membered rings, as well as their corresponding optically active cis-bicyclic amine hydrochlorides 6: cyclopentanopyrrolidine, octa-hydropyrindine, perhydroindole and decahydroquinoline by intramolecular aminolysis of the corresponding primary 1-aminocycloalkane-2-acetic and 2-propionic acid ester hydrochlorides 4 and subsequent lithiumalanate-reduction. The starting compounds 4 are synthesised in an asymmetric three-step-procedure from the cycloalkanone-2-acetic and 2-propionic acid ethyl esters 1 and the chiral auxiliary R-(+)- and S-(−)-1-phenylethylamine. The relative configurations of compounds 5 and 6 were derived from 1H-NMR-spectroscopy. The optical purity of the optically active cis-bicyclic amine hydrochlorides 6 is determined by HPLC-analysis of the corresponding Mosher-amides 7.

Es wird die Synthese der 2-Hydroxyxanthone 8 uber die entsprechenden Polymethoxyxanthone 7 beschrieben, die in Ring C mehrfach hydroxyliert sind. Die Darstellung verlauft entweder uber die 2-Phenoxybenzosauren 5 oder die polymethoxylierten 2-Hydroxybenzophenone 6. Quantitative Structure-Activity Relations of Polyhydroxyxanthones, II1): Synthesis of Polyoxygenated 2-Hydroxyxanthones 2-Hydroxyxanthones 8, which are additionally hydroxylated in ring C, have been synthesized via the polymethoxyxanthones 7. 2-Phenoxybenzoic acids 5 and the polymethoxylated 2-hydroxybenzophenones 6, respectively function as intermediates.

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.

A series of homochiral sterically hindered mono- and bicyclic amidines was prepared as hypoglycaemic agents by lethargic reaction of O-methylcaprolactim and 3-ethoxy-2-azabicyclo[2.2.2]oct-2-ene, respectively, with homochiral cis -2-substituted cyclopentane amines provided by asymmetrical reductive amination of racemic 2-substituted cyclopentanones. All compounds, except the cyclohexylmethyl-isoquinuclidone derivative which inhibited secretion at 100 μM, significantly stimulated insulin secretion 2–8-fold at 10 μM and 100 μM in INS-1 cells. The most potent activator was the 2-cyclopentyl-substituted caprolactam derivative 5e . The stimulatory effects on secretion increased with rising steric hindrance of both the amidine α-carbon and the bicyclic amidine moiety itself. Enantiomeric discrimination was observed for the 2-[( cis -2-bulkysubstituted cyclopentyl)imino]hexahydroazepine halides 5e and 5f and for the 3-[( cis -2-substituted cyclopentyl)imino]-2-azabicyclo[2.2.2]octane halides 6a and 6c . The amidines depolarized INS-1 cells and generated action potentials, accompanied by a decrease of membrane conductance. Simultaneously [Ca 2+ ] i increased, probably due to Ca 2+ -entry through voltage-dependent Ca 2+ -channels. At high concentrations, where inhibition of secretion was observed, [Ca 2+ ] i still rose upon application of the amidines, indicating an additional inhibitory pathway downstream to the elevation of [Ca 2+ ] i . Even at high concentrations (100 μM), the amidines had no toxic effects on insulin secreting INS-1 cells.

Long-range CH correlation and long-range selective proton decoupling (LRSPD), together with other standard NMR techniques, led to the complete 13C and 1H NMR spectral assignments of 2-acetyl-1-tetralone and demonstrated its existence in the endo-enolic form.

Es wurde die Abhangigkeit der Diastereo- und Enantioselektivitat bei der asymmetrischen reduktiven Aminierung racemischen 2-Methylcyclohexanons (1) von der Art der verwendeten Katalysatoren und Reduktionsmittel untersucht. Die Diastereo- und Enantioselektivitat wurden 13C-NMR-spektroskopisch bestimmt. Dabei erweist sich Raney Ni als Katalysator der Wahl. Dagegen lassen sich die entsprechenden Campherazomethine 5 nur mit Pd/C hydrieren und gleichzeitig zu 2-exo-Aminobornanen 6 hydrogenolysieren. Asymmetric Reductive Amination of Cycloalkanones, III: Influence of Catalyst and Reducing Agent on the Diastereo- and Enantioselectivity The dependence of diastereo- and enantioselectivity in the asymmetric reductive amination of racemic 2-methylcyclohexanone (1) on the type of catalyst and reducing agent has been investigated. Diastereo- and enantioselectivity were determined by 13C-NMR spectroscopy. Raney nickel proved to be the catalyst of choice. With Pd/C the campherazomethines 5 are hydrogenated and simultaneously hydrogenolized to yield the 2-exo-aminobornanes 6.

Es wird die stereoselektive Synthese der 3-Oxo-5-pyridyl-cyclopentancarbonsauren 4a–c durch kombinierte Michael- und Dieckmannreaktion aus Ethantricarbonsauretrimethylester und den Azazimtsauremethylestern 1a-c beschrieben. Der saure Abbau der 3-Oxo-5-pyridyl-cyclopentan-1.1.t-4-tricarbonsauretrimethylester 2a−c fuhrt stereoselektiv zu den cis-Sauren 4a−c. Nach thermo-dynamisch gesteuerter Epimerisierung gelingt es, die entsprechenden trans-Sauren 3a und 3b in kleinen Mengen durch saulenchromatographische Trennverfahren zu isolieren.

Es wird die stereoselektive Synthese der (±)erythro- und (±)threo-3-(4-Fluorphenyl)-2-methylglutarsauren (9), (10) durch Michaeladdition von Malonsauredimethylester (2) an E-2-Methyl-4′-fluorzimtsauremethylester (1) uber die substituierten Butantricarbonsaureester 3,4 und die substituierten Butantricarbonsauren 7,8 beschrieben. 3 und 4 werden mit Bromessigsauremethylester zu substituierten Pentantetracarbonsaureestern 5 bzw. 6 alkyliert. Uber Verseifungsversuche von 5 und 6 wird berichtet. Stereochemistry of Substituted Glutaric Acids, II: Syntheses of Substituted 3-(4-Fluorophenyl)-glutaric Acids The stereoselective syntheses of (±)erythro- and (±) threo-3-(4-fluorophenyl)-2-methyl-glutaric acids (9), (10) by Michael addition of dimethyl malonate (2) to methyl E-2-methyl-4′-fluorocinnamate (1)via the subst. trimethylbutanetricarboxylates 3,4 and the subst. butanetricarboxylic acids 7,8 are described. 3 and 4 have been alkylated with methyl bromoacetate to the subst. tetramethylpentanetetracarboxylates 5 and 6. Attempts towards saponification of 5 and 6 are reported.

Beim Versuch, die trans-Cyclopentanon-carbonsaure 1 durch sauren Abbau des Triesters 6 zu erhalten, entsteht das 4-Methyl-1-(4-fluorphenyl)-cyclopenten-1-on-3 (5) in geringer Menge. Synthetisch wird 5 aus der trans-Cyclopentanoncarbonsaure 2 durch dehydratisierende Decarbonylierung gewonnen. 1 kann nicht nachgewiesen werden. Stereochemistry of 3-Oxo-5-phenylcyclopentanecarboxylic Acids, X: Attempted Synthesis of t-2-Methyl-3-oxo-r-5-(4-fluorophenyl)-t-1-cyclopentanecarboxylic Acid It is shown, that the trans-cyclopentanonecarboxylic acid 1 is not acessible by acidic degradation of the triester 6. Instead, 4-methyl-1-(4-fluorophenyl)cyclopentene-1-one-3 (5) is obtained in low yield. By dehydrating decarbonylation, 5 can be prepared from the trans-cyclopentanonecarboxylic acid 2.

Es wird die Chemo-, Regio- und Stereoselektivitat der Methylierung von r-5-(4-Fluorphenyl)-c-2-methyl-3-oxo-1.1.t-4-cyclopentantricarbonsaure-trimethylester (1) und r-5-(4-Fluorphenyl)-t-2-methyl-3-oxo-1.1.t-4-cyclopentantricarbonsaure-trimethylester (2) beschrieben. Aus 1 entstehen r-5-(4-Fluorphenyl)-3-methoxy-c-2-methyl-3-cyclopenten-1.1.4-tricarbonsaure-trimethylester (3) und r-5-(4-Fluorphenyl)-c-2-methyl-t-4-methyl-3-oxo-1.1.c-4-cyclopentantricarbonsaure -trimethylester (4). Aus 2 wird zusatzlich zu 3 und 4 2.2-Dimethyl-r-5-(4-fluorphenyl)-3-oxo-1.1.t-4-cyclopentantricarbonsaure-trimethylester (7) gebildet. Stereochemistry of 3-Oxo-5-phenyl-1-cyclopentanecarboxylic Acids, VI: Chemo-, Regio- and Stereoselectivity of the Methylation of Substituted 2-Cyclopentanonecarboxylates The methylation, as well as its chemo-, regio- and stereoselectivity, of trimethyl r-5-(4-fluorophenyl)-c-2-methyl-3-oxo-1,1,t-4-cyclopentanetricarboxylate (1) and trimethyl r-5-(4-fluoro-phenyl)-t-2-methyl-3-oxo-1,1,t-4-cyclopentanetricarboxylate (2) is described. The reaction with 1 yields trimethyl r-5-(4-fluorophenyl)-3-methoxy-c-2-methyl-3-cyclopentene-1,1,4-tricarboxylate (3) and trimethyl r-5-(4-fluorophenyl)-c-2-methyl-t-4-methyl-3-oxo-1,1,c-4-cyclopentanetricarboxylate (4). Starting from 2, a third product, trimethyl 2,2-dimethyl-r-5-(4-fluorophenyl)-3-oxo-1,1,t-4-cyclopentanetricarboxylate (7) is obtained.

Es wird die EPC-Synthese der Octahydrophenanthridin-hydrochloride 4 aus den optisch aktiven 2-Arylcyclohexanaminen 1 a) unter Pictet-Spengler-Bedingungen und b) uber die entspr. Formamide 2 und die Hexahydrophenanthridine 3 beschrieben. Asymmetric Reductive Amination of Cycloalkanones, VII: EPC-Synthesis of Arylsubstituted cis-4aR,10b- and cis-4aS,10bS-Octahydrophenanthridines We report the EPC synthesis of octahydrophenanthridine-hydrochlorides 4 from optically active 2-arylcyclohexanamines 1 a) using Pictet-Spengler reaction conditions and b) via the corresponding formamides 2 and hexahydrophenanthridines 3.

Es wird die Reindarstellung und Konfigurationszuordnung der (±)-threo- und erythro-2-Methyl-3-phenyl-glutarsauren (5, 6) uber die (±)-threo- und erythro-2-Phenylbutan-1.1.3-tricarbonsauren (3, 4) beschrieben. Stereochemistry of Substituted Glutaric Acids, I: (±)-threo- and erythro-2-methyl-3-phenylglutaric Acids Syntheses of (±)-threo-and erythro-2-methyl-3-phenylglutaric acids (5,6) via the (±)-threo- and erythro-2-phenylbutane-1,1,3-tricarboxylic acids (3, 4) is described. The configurations of the products were determined.

Die asymmetrische Synthese von 2-substituierten Cyclohexanaminen aus racemischen Cyclohexanonen durch reduktive Aminierung in einem Dreistufenverfahren wird beschrieben. Die aus den Ketonen 5 durch Umsetzung mit den optisch aktiven Hilfsaminen 6 leicht zuganglichen Imine 7 werden mit Raney-Nickel zu den sekundaren Aminen 8 hydriert. Hydrogenolyse uber Palladium-Katalysator fuhrt zu den primaren Aminen 9. Mit Raney-Nickel gelingt in sehr guten chemischen Ausbeuten die Synthese der diastereomer reinen und hochgradig enantiomer reinen Amine 8 bzw. 9. Die Enantiomerenreinheit der Amine 9 wird uber die diastereomeren Acylamine 10 durch HPLC bestimmt. Die Stereochemie einschlieslich der absoluten Konfiguration der Verbindungen 8 und 9 wird durch 1H-, 13C-NMR, durch CD der Salicylidene 11 und das Rontgenbeugungsspektrum von Amin 9c ermittelt. – Als Reaktionsmechanismus wird eine kinetisch gesteuerte asymmetrische Hydrierung mit vorgelagerter thermodynamischer Transformation uber die partiell deuterierte Verbindung 13 nachgewiesen. Asymmetric Reductive Amination of Cycloalkanones, 2. Synthesis and Absolute Configuration of 2-Substituted Cyclohexanamines Asymmetric synthesis of 2-substituted cyclohexanamines from racemic cyclohexanones by means of reductive amination in a three-step procedure is described. Condensation of the ketones 5 with the optically active auxiliary amines 6 leads to the imines 7, which are hydrogenated to the secondary amines 8 with Raney nickel. Hydrogenolysis with palladium-on-charcoal yields the primary amines 9. With Raney nickel as catalyst the synthesis of the amines 8 and 9 runs with high chemical yield under complete diastereomeric and high grade enantiomeric control, respectively. Enantiomeric excess is determined via the diastereomeric acylamines 10 by means of HPLC. Stereochemical analysis including the absolute configuration of 8 and 9 is performed with 1H, 13C NMR spectroscopy, via the CD of the salicylidenes 11 and the X-ray spectrum of the amine 9c. – Reaction mechanism is investigated via the partially deuterated amine 13 to come up as a kinetically controlled asymmetric hydrogenation combined with a thermodynamically controlled transformation.

Die stereoselektiven Synthesen und stereochemischen Zuordnungen der 5-Phenyldihydro-isosarkomycinpaare, t-4-Methyl-3-oxo-c-5-phenyl-r-l-cyclopentancarbonsaure (5) und c-4-Methyl-3-oxo-t-5-phenyl-r-1 -cyclopentancarbonsaure (7) werden beschrieben. Der schrittweise Aufbau des Cyclopentanongerustes verlauft uber Michael-Addition, C-Alkylierung der entstandenen threo- sowie erythro-2-Phenyl-111,3-butantricarbonsaureester 12 und 13 und den stereospezifischen Dieckmann-Ringschlus zu ∼-4-Methyl-3-oxo-t-5-phenyl- 1,l,r-2-cyclo-pentantricarbonsaure-trimethylester (14) bzw. t-4-Methyl-3-oxo-t-5-phenyl-l,I,r-2-cyclopen-tantricarbonsaure-trimethylester (15). Beim partiellen Abbau der polysubstituierten Verbindungen 14 und 15 zu den Verbindungen 5 und 7 werden alle Zwischenprodukte gefast und eindeutig zugeordnet. Stereochemistry of 3-0x0-5-phenyl-1-cyclopentanecarboxylic Acids, III). — The Stereomeric 5-Phenyldihydroisosarcomycins Stereoselective syntheses and stereochemical correlations of the 5-phenyldihydroisosarcomycin pairs t-4-methyl-3-0x0-c-5-phenyl-r-1 -cyclopentdnecarboxylic acid (5) and c-4-methyl-3-0x0-t-5-phenyl-r-1-cyclopentanecarboxylic acid (7) are reported. Stepwise synthesis of the cyclo-pentanone skeleton proceeds via Michael addition, C-alkylation of threo- and erythro-2-phenyl-1,I,3-butanetricarboxylates 12 and 13 respectively, and stereospecific Dieckmann condensation to trimethyl c-4-methyl-3-oxo-t-5-phenyl-1,1,r-2-cyclopentanetricarboxylate (14) as well as trimethyl t-4-methyl-3-oxo-t-5-phenyl-1,1,r-2-cyclopentanetricarboxylate (15). The polysubstituted compounds 14 and 15 are separately degraded to the compounds 5 and 7. All intermediates have been isolated and stereochemically identified.