Lactone, 24. Mitt.: „γ-Lactonisierte”︁ Neuroleptika - Synthese,Stereochemie und Affinität am D2-Rezeptor

Lactones, XXIV: ?γ-Lactonized”? Neuroleptics - Synthesis, Stereochemistry and Affinity at the D₂ Receptor Addition of piperidines 15a-d to methylene lactones 8,14a gives the ?γ-lactonized”? diphenylbutylpiperidine-type neuroleptics 3a,b,d,4a-d. 8 can be produced by cyclization or - as well as 14 - from the corresponding α-carboxylactone. ¹H- and ¹³C-nmr data give evidence for the equatorial position of the aminomethyl group in all derivatives of 3 and 4 and bisequatorial-trans-configuration in 4a - d . ³H-spiroperidole displacement at the D₂ receptor in rat brain by 3,4 and the ?γ-lactonized”? butyrophenone neuroleptics 1,2a-c was investigated. Some compounds show moderate up to high ( 3b ) activity.     

Asymmetrische α-Amidoalkylierung: Synthesen enantiomerenreiner α-substituierter Piperidine mit 1-Camphanoyl-1,2,3,4-tetrahydropyridin

Asymmetric α-Amidoalkylation. Syntheses of Enantiomerically Pure α-Substituted Piperidines with 1-Camphanoyl-1,2,3,4-tetrahydropyridine In a novel asymmetric synthesis the homochiral enamide 1 is coupled with the silyl enol ethers 5a-c in a diastereoselective fashion to afford the amidoalkylation products 6/7a-c. These are employed in the synthesis of enantiomerically pure, in α-position R- and S-configurated piperidine alcohols 9 , the piperidine ketone 13 , (R)-homopipecolic acid 12R and the alkaloid (+)-sedamine 10RR .     

Massenspektrometrische Untersuchungen an isomeren α,β- und β, γ-ungesättigten Ketonen mit raumerfüllenden Substituenten

A Mass Spectrometric Study on Isomeric α,β- and β,γ-Unsaturated Ketones with Bulky Substituents The mass spectra of the α,β- and β,γ-unsaturated ketones 1-4 (scheme 1) are very different depending on the stereochemistry of the double bond. The E-configurated ketone 2 predominantly shows McLafferty fragmentation, whereas Z-configurated ketone 1 reveals ?-cleavage. In the β, γ-unsaturated ketones 3 and 4, mainly loss of the pertinent allyl radical by α-cleavage was observed.     

Zur Cyclisierung von α-(2-Mercapto- bzw. -2-Amino-benzoyl)-lactamen; Synthese von Benzothiopyrano [4,3-b]pyrrolinonen sowie von Pyrrolino- bzw. Tetrahydropyridino [3,2-c] chinolinonen1)

Cyclisation of α-(2-Mercaptobenzoyl)- and α-(2-Aminobenzoyl)lactames; Synthesis of Benzothiopyranopyrrolinones and Pyrrolinoquinolinones Compounds 8a, 8b, 8d, 8e and 8f are obtained by heating the mercaptobenzoyl- or methylaminobenzoyl-lactames 6a, 6b, 6d, 6e and 6f. With pyridine/HCI removal of the pyrroline N-methyl group takes place under formation of 8c and 8g. Cyclisation of the acyllactame 6i under the same conditions leads to the tetrahydropyridinoquinolinone 18. After hydrolysis of the acyllactames 6e, 6i or 6d the aminoalkyl(hydroxy)quinolinones or aminobenzoyl-γ-aminobutyric acid derivatives 11, 19 and 13 are isolated, which can be cyclized to 8e, 20 and 8d. The pyrroles 15a and 15b are formed by dehydrogenation of the pyrroline derivates 8b and 8e with DDQ.     

Chalkon-5′- und Flavanon-6-carbonsäuren

Chalcone-5′- and Flavanone-6-carboxylic Acids While 3-acetyl-4-hydroxybenzoic acid ( 1 ) reacts with the aldehydes 2a-c by Claisen-Schmidt reaction to the chalcone carboxylic acids 3a-c , the parent reaction with 2d is not successful. The chalcones 3a-b but not 3c can be transformed to the isomeric flavanone carboxylic acids 4a-b by common methods. 3c in MeOH/H₂SO₄ forms the methyl flavanone-carboxylate 4c which does not lead to the carboxylic acid of 4c by acid hydrolysis. Instead, 4c is split to chalcone carboxylic acid 3c quantitatively. 4′-nitroflavanone-6-carboxylic acid ( 4d ) can only be obtained by condensation of the diketones 5a-b with 4-nitrobenzaldehyd ( 2d ) as the methyl carboxylate, too. Here, instead of the expected α-aroylchalcone 6 or its tautomeric 3-aroylflavanone derivative, 4d is formed by hydrolytic removal of the arylcarboxylic acids 7a-b . The alkaline hydrolysis of compound 4d does not quantitatively afford the chalconecarboxylic acid 3d but results in destruction to a complex mixture of several compounds.     

Sulfonylsubstituierte Heterocyclen aus β-Oxo-β-sulfonyl-enolethern und Amidinen,Hydrazinen oder Hydroxylamin

Sulfonylsubstituted Heterocycles from β-Oxo-β-sulfonyl-enolethers and Amidines, Hydrazines, or Hydroxylamine Cyclocondensation of 3-ethoxy-2-sulfonyl-2-propen-1-ones 1 with benzamidine ( 2a ), guanidine ( 2b ), and S-benzyl-iso-thiourea ( 2c ) leads to the 2,4-disubstituted 5-sulfonyl-pyrimidines 3a-c.1 reacts with hydrazines 4a,b or hydroxylamine yielding the 4-sulfonyl-pyrazoles 5a – c and 4-sulfonyl-isoxazole 6 , respectively.     

Stereochemie der Reformatsky-Reaktion von 2-Alkylcyclohexanonen mit α-Brommethylacrylsäureethylester

Stereochemistry of the Reformatsky Reaction of 2-Alkylcyclohexanones with Ethyl α-(Bromomethyl)acrylate A relation between the chemical shifts of the ¹³C-NMR signals of the carbon atoms 4, 5 and 9 and the conformation of the lactone oxygen was found for spiro-α-methylene-γ-butyrolactones prepared by the Reformatsky reaction of 2-alkylcyclohexanones with ethyl α-(bromomethyl)acrylate. It was confirmed by CD measurements on the pyrazoline derivative of one of the lactones. From the structures of the reaction products it was deduced, that trans addition (relative to the substituent at position 2) of the organometallic reagent is prefered.     

Synthese von 3-methylenmonosubstituierten 2-Oxo-tetrahydrofuranen durch Umsetzung von α-Keto-γ-lactonen mit Wittig-Reagenzien

Synthesis of 3-Methylenetetrahydrofuran-2-ones from α-Keto-γ-lactones with Wittig Reagents The synthesis of the 3-methylenetetrahydrofuran-2-ones 3a--q from the α-keto-γ-lactones 1a,b and the Wittig compounds 2a--h is described.     

„Inverse”︁ Diels-Alder-Additionen, 7. Mitt. π-Elektronenreiche Heteroaromaten als „inverse”︁ Dienophile

?Inverse”? Diels-Alder Additions, VII: π-Electron Rich Heteroaromatic Compounds as “Inverse” Dienophiles. We describe [4 + 2] cycloadditions of substituted electron rich heteroaromatic compounds like furan, pyrrole, thiophene and N-methylimidazole with the s-cis-fixed azine system in 3,6-bis-(methoxycarbonyl)tetrazine and subsequent reactions.     

Zur Stereochemie der 3-Oxo-5-phenyl-1-cyclopentancarbonsäuren, 11. Mitt. Synthese der stereomeren 3-Oxo-5-(2,3,4-pyridyl)-cyclopentancarbonsäuren

Stereochemistry of 3-Oxo-5-phenylcyclopentanecarboxylic Acids, XI: Syntheses of Stereomeric 3-Oxo-5-pyridylcyclopentanecarboxylic Acids The stereoselective synthesis of the 3-oxo-cis-5-pyridylcyclopentanecarboxylic acids 4a?c by combined Michael and Dieckmann reaction from trimethyl ethanetricarboxylate and the methyl azacinnamates 1a?c is described. Acidic degradation of the trimethyl 3-oxo-5-pyridylcyclopentane-1,1,t-4-tricarboxylates 2a?c leads stereoselectively to the cis-acids 4a?c . By thermodynamically controlled epimerisation the corresponding trans-acids 3a and 3b are accessible in minor quantities by means of column chromatography.     

Zur Struktur der „Senföloxide”︁ und ihrer Bildung aus Nitronen

The Structures of “Isothiocyanate Oxides” and Their Synthesis from Nitrones The nitrones 2a and 2b react with benzyl isothiocyanate to yield the azomethines 4 and 2,4-dibenzyl-3-thioxo-1,2,4-thiadiazolidin-5-one (“benzyl isothiocyanate oxide” type ). The latter is also obtained from benzyl isothiocyanate by bromation and hydrolysis, followed by isomerisation of 4-benzyl-3-benzylimino-1,2,4-dithiazolidin-5-one (“benzyl isothiocyanate oxide” type ).     

An efficient and practical EPC synthesis of β-amino acids from L-asparagine

The synthesis of enantiomerically pure β-arnino acids (1a-c) via an O-activated equivalent of β-homoserine is discussed. The chiral synthon 2 was planned to be represented by (S)-3-N,N-dibenzylamino-4-mesyloxybutanoic acid methyl ester (3) or by (S)-3-N,N-dibenzylamino-4-mesyloxybutanenitrile (6). Both intermediates should be approached from L-aspartic acid 4 or L-asparagine 5 through selective reduction of the α-carboxyl group. It turned out that only nitrile 6 was suitable for the envisioned β-amino acid synthesis, since alcohol 14 - the synthetic precursor of 3 - was unstable towards intramolecular nucleophilic attack to accomplish the chiral building block 15. Reaction of mesylate 6 with different ‘Gilman cuprates’ afforded the 3-N,N-dibenzylamino nitrile derivatives 22a-c, which could be readily deprotected to give the target compounds 1a-c in 23-36% overall yield from asparagine. In contrast Me₂Cu(CN)Li₂ as an example for higher order ‘Lipshutz cuprates’ did not afford the desired substitution product 22a. The optical integrity of the synthesis was established by coupling of the methyl ester 24 with chiral 1-phenylethyl isocyanate followed by appropriate NMR studies of carbamate 25.     

Benzomorphan-Analoga mit Doxpicomin Partialstruktur: Synthese und psychopharmakologische Untersuchung von 5-Aminomethyl und 5-(α-Aminobenzyl) substituierten 2,6-Epoxy-3-benzoxocinen

Benzomorphan-Analoga mit Doxpicomin Partialstruktur: Synthese und psychopharmakologische Untersuchung von 5-Aminomethyl und 5-(α-Aminobenzyl) substituierten 2,6-Epoxy-3-benzoxocinen Addition of the β-alanine derivative 6 to the homophthalaldehyde monoacetal 5 and subsequent LiAlH₄-reduction led to the dihydroxy acetal 8 , which was cyclized with acid to give the 5-aminomethyl-2,6-epoxy-3-benzoxocines 2a and 2b . The reaction of 5 with the anion of the β-lactam 9 yielded two separable diastereomers: 10a with u,l-configuration and 10b with 1,1-configuration. Via the 2-benzopyran 11a ( 11b ), the aminoalcohol 12a ( 12b ), and the secondary amine 13a ( 13b ), the β-lactam adduct 10a ( 10b ) was transformed to give the 5-(α-dimethylaminobenzyl)-2,6-epoxy-3-benzoxocine 3d ( 3b ). The relative configurations of all these ?β-lactam route”? products ( 10-13, 3d , and 3b ) were established by their ¹H-NMR-spectra. Attempts failed to get the missing diastereomers 3a and 3c by epimerization of the β-lactams 11a and 11b or by reductive amination of the benzoyl derivatives 17a and 17b . Finally, 3a and 3c were obtained by phenylmagnesium bromide addition to the nitriles 21a and 21b , followed by LiAlH₄-reduction, formaldehyde/NaBH₃CN methylation and chromatographic separation. - In the Irwin-screen (mouse) only 2a · HCl, 3b , and 3d (100 mg/kg body weight) caused weak central effects.     

Über Pyridone,IV Die Struktur des „N-Methylnicotons”︁

The Structure of ?N-Methylnicoton”? ?N-Methylnicoton”? described by Karrer is found to be a mixture of 1-methyl-3-[1-methylpyrrolidyl-(2)]-pyridone-(2) and -pyridone-(6). The proof of the structures and the assignment is carried out spectroscopically and by independent synthesis.     

Search for New Anticonvulsant Compounds,Part 2. Structure-Activity Relationship Studies of New N-Substituted Amides of α-Piperazine-γ-Hydroxybutyric Acid as Active Anticonvulsants

In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of α-(4-phenylpiperazine)-γ-hydroxybutyric acid ( A and derivatives of N-benzylamides of α-(4-benzylpiperazine)-γ-hydroxybutyric acid ( B ), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100–300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B .     

Synthese des 3-Methyl-5,7,4′-trihydroxy-3′-methoxy-flavanons: Zur Frage des Vorkommens von „Olivin”︁ in Olivenblättern

Synthesis of 3-Methyl-5,7,4′-trihydroxy-3′-methoxy-flavanone Attempts to synthesize 2′,4,4′,6′-tetrahydroxy-3-methoxy-α-methyl-chalcone (= ?olivin”?), which is claimed to occur in Olea europaea leaves by Bocková et al., were unsuccessfull, obviously because of its low stability in solution; instead there was obtained the corresponding 3-methyl-5,7,4′-trihydroxy-3′-methoxyflavanone as a mixture of two diastereoisomers. The 2,3-trans-isomer which preponderates was crystallized, whereas the occurrence of the 2,3-cis-isomer in the reaction mixture was detected by NMR-spectroscopy. Neither transnor cis-”? olivine-flavanone”? could be found as constituents of the leaves of the olive tree applying TL-technique and co-chromatography. It is therefore concluded that the structure given by Bocková et al. for olivin must be revised.     

Functional activation of Gαq/11 protein via α1‐adrenoceptor in rat cerebral cortical membranes

Although it is recognized that α₁‐adrenoceptors are coupled to diverse intracellular signalling pathways, its primary transduction mechanisms are evoked by activating phospholipase C in the cell membrane through Gα_q/11, resulting in production of inositol 1,4,5‐trisphosphate and diacylglycerol. However, there have been few studies that indicate directly the involvement of Gα_q/11 proteins in this signalling pathway in the central nervous system. In the current study, we tried to pharmacologically characterize (?)‐adrenaline‐stimulated [³⁵S]GTPγS binding to Gα_q/11 in rat brain membranes. Functional activation of Gα_q/11 coupled to α₁‐adrenoceptor was investigated by using [³⁵S]GTPγS binding/immunoprecipitation assay in the membranes prepared from rat cerebral cortex, hippocampus, and striatum. The specific [³⁵S]GTPγS binding to Gα_q/11 was stimulated by (?)‐adrenaline in a concentration‐dependent and saturable manner in rat cerebral cortical membranes. In hippocampal or striatal membranes, the stimulatory effects of (?)‐adrenaline were scarce. The effect of (?)‐adrenaline was potently inhibited by prazosin, a potent and selective α₁‐adrenoceptor antagonist, but not by yohimbine, a selective α₂‐adrenoceptor antagonist. The response was mimicked by cirazoline, but not by R(?)‐phenylephrine. Although oxymetazoline also stimulated the specific [³⁵S]GTPγS binding to Gα_q/11 as an apparent “super‐agonist”, detailed pharmacological characterization revealed that its agonistic properties in this experimental system were derived from off‐target effects on 5‐HT_2A receptors, but not via α₁‐adrenoceptors. In conclusion, functional coupling of α₁‐adrenoceptors to Gα_q/11 proteins are detectable in rat brain membranes by means of [³⁵S]GTPγS binding/immunoprecipitation assay. It is necessary to interpret the experimental data with caution when oxymetazoline is included as an agonist at α₁‐adrenoceptors.     

Proline-containing β-turns

The conformations of the dipeptide t-Boc-Pro-d Ala-OH and the tripeptide tBoc-Pro-d Ala-Ala-OH have been determined in the crystalline state by X-ray diffraction and in solution by CD, n.m.r. and i.r. techniques. The unit cell of the dipeptide crystal contains two independent molecules connected by intermolecular hydrogen bonds. The urethane-proline peptide bond is in the cis orientation in both the molecular forms while the peptide bond between Pro and d Ala is in the trans orientation. The single dipeptide molecule exhibits a “bent” structure which approximates to a partial β-turn. The tripeptide adopts the 4 → 1 hydrogen-bonded type II β-turn with all trans peptide bonds. In solution, the CD and i.r. data on the dipeptide indicate an ordered conformation with an intramolecular hydrogen bond. N.m.r. data indicate a significant proportion of the conformer with a trans orientation at the urethane-proline peptide bond. The temperature coefficient of the amide proton of this conformer in DMSO-d₆ points to a 3 → 1 intramolecular hydrogen bond. Taken together, the data on the dipeptide in solution indicate the presence (in addition to the cis conformer) of a C₇ conformation which is absent in the crystalline state. The spectral data on the tripeptide indicate the presence of the type II β-turn in solution in addition to the nonhydrogen-bonded conformer with the cis peptide bond between the urethane and proline residues. The relevance of these data to studies on the substrate specificity of collagen prolylhydroxylase is pointed out.     

Nitroketenaminale, 9. Mitt.: Zur Umsetzung von α,β-ungesättigten Aldehyden mit Nitroketenaminalen

Nitroketeneaminals, IX: Reaction of α,β-Unsaturated Aldehydes with Nitroketeneaminals Reaction of α,β-unsaturated aldehydes 1a , b with nitroketeneaminal 2a in boiling acetic acid leads to 2-amino-3-nitropyridines 4 unsubstituted at C-6. By refluxing 1a and 2a in alcohol/acetic acid or in alcohols, respectively, 2-alkoxy-1,2,3,4-tetrahydropyridines 7a and 8a are obtained. The reaction of 1a and 2b yields 5-alkoxy-2,3,4,5,6,7-hexahydroimidazo[1,2-a]pyridines 7b and 8b . By ¹H-NMR spectroscopy the relative configuration of 7aC, 7aT, 7bC , and 7bT can be determined.