β-Fur-2-yl-α-halogenacrylonitrile. IV. Reaktionen von β-Fur-2-yl-α-halogenacrylonitrilen mit Alkoholen und Phenolen

β-Fur-2-yl-α-halogenacrylonitriles. IV. Reactions of β-Fur-2-yl-α-halogenacrylonitriles with Alcohols and Phenols β-Fur-2-yl-α-halogenacrylonitriles 1a – c react with alcohols and phenols to yield β-fur-2-yl-β-alkoxyacrylonitriles and β-fur-2-yl-β-aroxyacrylonitriles 2a – k respectively. With ethylene glycol α-[2-(fur-2-yl)-1, 3-dioxolan-2-yl]acetonitriles 3a, b are formed.     

β-Fur-2-yl-α-halogenacrylonitrile. I. Darstellung von β-Fur-2-yl-ß-aminoacrylonitrilen und β-Fur-2-yl-α-aminoacrylonitrilen

β-Fur-2-yl-α-halogenacrylonitriles. I. Preparation of β-Fur-2-yl-ß-aminoacrylonitriles and β-Fur-2-yl-α-aminoacrylonitriles β-Fur-2-yl-α-halogenacrylonitriles 1 react with secondary amines to yield β-fur-2-yl-ß-aminonitriles 2 and β-fur-2-yl-α-aminoacrylonitriles 3 . The ¹ H-n.m.r. spectra of the E/Z isomers are discussed.     

β-Fur-2-yl-α-halogenacrylonitrile. VIII. Konformationsuntersuchungen an substituierten β-Fur-2-yl-acrylonitrilen

β-Fur-2-yl-β-halogenacrylonitriles. VIII. Investigations of the Conformation of Substituted β-Fur-2-yl-acrylonitriles X-ray analysis, n.m.r.-investigations in the presence of Eu(FOD)₃ and NOE-measurement indicate, that the E-isomer of β-substituted β-fur-2-yl-acrylonitriles exist in the s-cis conformation, whereas the E-isomer of the α-substituted β-fur-2-yl-acrylonitriles prefer the s-trans-conformation. The influence of the configuration and conformation on the chemical shift of the H-3-furan protons is discussed.     

β-Fur-2-yl-α-halogenacrylonitrile. VII. Reaktionen von β-(5-Brom-fur-2-yl)-α-bromacrylonitril mit Mercaptan,Thioharnstoff und Thioharnstoffderivaten

β-Fur-2-yl-α-halogenacrylonitriles. VII. Reactions of β-(5-Bromo-fur-2-yl)-α-bromoacrylonitriles with Mercaptans, Thiourea and Thiourea Derivatives β-(5-Bromo-fur-2-yl)-α-bromoacrylonitrile 1 reacts with ethylmercaptan to yield β-(5-bromo-fur-2-yl) β-ethylthioacrylonitrile 3 . With thiourea β,β′-thio-bis[β-(5-bromo-fur-2-yl)]-acrylonitrile 2 is formed. The pyrimidines 4 and 5 have been prepared by the reaction of 1 with s-methylthiourea and 2-aminothiazole, respectively. The structure of the new compounds were determined by means of x-ray analysis, ¹H-n.m.r., ¹³C-n.m.r. and mass-spectroscopy.     

Furylvinylhalogenide. IX. Reaktionen von β-Fur-2-yl-β-chlor-α-cyanacrylsäureestern mit Aminen

Furylvinylhalides. IX. Reactions of β-fur-2-yl-β-chloro-α-cyanoacrylates with amines β-Fur-2-yl-β-chloro-α-cyanoacrylates 4 react with amines to yield β-Fur-2-yl-β-amino-α-cyanoacrylates 5 . The ¹H-n.m.r. spectra of 5 are discussed.     

Furylvinylhalogenide. X [1]. Reaktionen von β-Fur-2-yl-β-chlor-α-cyanacrylsäurederivaten mit Hydrazinen

Furylvinylhalides. X. Reactions of β-Fur-2-yl-β-chloro-α-cyanoacrylic Acid Derivatives with Hydrazines β-Fur-2-yl-β-chloro-α-cyanoacrylic acid derivatives 3 react with hydrazines yielding 3-fur-2-yl-5-aminopyrazoles 5 or 3-fur-2-yl-4-cyanpyrazolin-5-ones 6 . In some cases the β-hydrazino-α-cyanoacrylic acid derivatives 4 , could be isolated.     

β-Fur-2-yl-α-halogenacrylonitrile. V [1] Darstellung von β-(5-Nitro-fur-2-yl)-α-azidoacrylonitril und β-(5-Nitro-fur-2-yl)-α-aminoacrylonitril

β-Fur-2-yl-α-halogenacrylonitriles. V. Preparation of β-(5-Nitro-fur-2-yl)-α-azidoacrylonitrile and β-(5-Nitro-fur-2-yl)-α-aminoacrylonitrile β-(5-Nitro-fur-2-yl)-α-chloroacrylonitrile ( 1 ) reacts with sodium azide to yield β-(5-nitro-fur-2-yl)-α-azidoacrylonitrile ( 2 ). By Staudinger-reaction β-(5-nitro-fur-2-yl)-α-aminoacrylonitrile ( 5 ) is formed. The ¹H- and ¹³C-n.m.r. spectra of E/Z isomers are discussed.     

Reaktionen von β-Chlorvinylaldehyden. IV [1]. Synthesen von 2-Formylmethylen-2H-1-benzopyranen und Benzopyrylocyaninfarbstoffen aus β-Chlorvinylaldehyden

Reactions of β-Chlorovinylaldehydes. IV. Syntheses of 2-Formylmethylene-2H-1-benzopyranes and Benzopyrylocyaninedyes from β-Chlorovinylaldehydes α-Alkyl-β-chlorocrotonaldehydes react with salicylaldehyde in methanolic solution of potassium hydroxide forming 2-formyl-methylene-2H-1-benzopyranes 1 . The corresponding benzopyryliumsalts 2 which are easily available from 1 and strong acids, exist in the enolic form. They react at room temperature in alcoholic solution with elimination of ethyl formiate, yielding dark blue compounds which were identified as 2,2′-benzopyrylotrimethincyanindyes 3 . The structure of 3 has been elucidated by means of ¹H-n.m.r.-spectra.     

β‐Aminopeptidase‐Catalyzed Biotransformations of β2‐Dipeptides: Kinetic Resolution and Enzymatic Coupling

We have previously shown that the β‐aminopeptidases BapA from Sphingosinicella xenopeptidilytica and DmpA from Ochrobactrum anthropi can catalyze reactions with non‐natural β³‐peptides and β³‐amino acid amides. Here we report that these exceptional enzymes are also able to utilize synthetic dipeptides with N‐terminal β²‐amino acid residues as substrates under aqueous conditions. The suitability of a β²‐peptide as a substrate for BapA or DmpA was strongly dependent on the size of the C_α substituent of the N‐terminal β²‐amino acid. BapA was shown to convert a diastereomeric mixture of the β²‐peptide H‐β²hPhe‐β²hAla‐OH, but did not act on diastereomerically pure β²,β³‐dipeptides containing an N‐terminal β²‐homoalanine. In contrast, DmpA was only active with the latter dipeptides as substrates. BapA‐catalyzed transformation of the diastereomeric mixture of H‐β²hPhe‐β²hAla‐OH proceeded along two highly S‐enantioselective reaction routes, one leading to substrate hydrolysis and the other to the synthesis of coupling products. The synthetic route predominated even at neutral pH. A rise in pH of three log units shifted the synthesis‐to‐hydrolysis ratio (v_S/v_H) further towards peptide formation. Because the equilibrium of the reaction lies on the side of hydrolysis, prolonged incubation resulted in the cleavage of all peptides that carried an N‐terminal β‐amino acid of S configuration. After completion of the enzymatic reaction, only the S enantiomer of β²‐homophenylalanine was detected (ee>99 % for H‐(S)‐β²‐hPhe‐OH, E>500); this confirmed the high enantioselectivity of the reaction. Our findings suggest interesting new applications of the enzymes BapA and DmpA for the production of enantiopure β²‐amino acids and the enantioselective coupling of N‐terminal β²‐amino acids to peptides.     

Partialsynthesen von Cardenoliden und Cardenolid-Analogen. I. α,β- und β,γ-ungesättigte Lactonring-methylierte Cardenolide

Partial Syntheses of Cardenolides and Cardenolide Analogues. I. α,β- and β,γ-Unsaturated Lactone Ring-Methylated Cardenolides Base-catalyzed methylation of digitoxigenin 1a with methyl iodide and sodium hydride in DMF leads to the α,β-unsaturated cardenolides 2–5 and, after rearrangement of the CC-double bond, to the β,γ-unsaturated cardenolides 6 and 7 . Opening of the lactone ring results in the formation of 8 . Allylic oxidation of 4b affords the 14,21-epoxide 10 . Only the 22-methyl derivative 4a and its 3-O-tridigitoxoside 4d show strong biological effectivity, whereas methylation at 21R- or 21S-position results in considerable loss in activity.     

Reaktionen von β-Chlorvinylaldehyden. V [1]. Zur Bildung von 2,2′-Thiopyrylotrimethinfarbsalzen aus 2-(α-Formylalkyliden)-2H-thiopyranen

Reactions of β-Chlorovinylaldehydes. V. The Formation of 2,2′-Thiopyrylocyanine Dyes from 2-(α-Formylalkylidene)-2H-thipyranes Substituted β-chlorocrotonaldehydes react with Na₂S · 9H₂O to form 2-(α-formyl-alkylidene)-2H-thiopyranes 1 . The corresponding thiopyrylium salts 2 which are easily available from 1 and strong acids exist in the enolic form (2-β-hydroxyvinyl-thiopyrylium salts). They are converted at room temperature in methanol solution to dark green compounds, which are identified as 2,2′-thiopyrylotrimethincyanine dyes 3 . The mechanism of formation of compounds 3 is discussed.     

Approach to the Controlled Synthesis of Nucleopeptides I. Nε-(6-Purinoyl-L-Lysine and β-(5-Uracilyl)-Dl-Alanine

N^ε-(6-purinoyl)-L-lysine has been prepared by acylation of L-lysine copper complex or N^α-carbobenzoxy-L-lysine with 6-trichloromethylpurine followed by the removal of the protecting group. β-(5-uracilyl)-DL-alanine has been prepared by condensation of 5-chloro-methyluracil with diethyl acetamidomalonate, followed by acid hydrolysis.     

Vinyloge Acylverbindungen. XX. Reaktivität und Toxizität arylsubstituierter β-Chlorvinylketone, β-Chlorvinylaldehyde und β-Chlorvinylmethyleniminiumsalze

Vinylogous Acyl Compounds. XX. Reactivity and Toxicity of Aryl-substituted β-Chlorovinyl Ketones, β-Chlorovinyl Aldehydes, and β-Chlorovinyl Methyleniminium Salts Based on kinetic measurements, the nucleophilic replaceability of the chlorine in aromatic β-chlorovinyl ketones ArCO-CH  CH-Cl ( 1 ), isomeric β-chlorovinyl aldehydes OCH CHC(Cl)Ar( 2 ), and corresponding β-chlorovinyl methyleniminium salts Me₂N^⊕;CH CHC(Cl)Ar X^⊖ ( 3 ) is compared and related to toxicological findings. The chemical reactivity of these important synthetic building blocks increases in the order 2 < 1 < 3 , the acute toxicity (24 h LD₅₀ i. p. in the mouse) shows the graduation 2 < 3 < 1 . Compounds of type 1 prove to be relatively toxic (LD₅₀ 24–42 mg/kg) and display a marked necrotic action after percutaneous absorption, whereas the aldehydes 2 have not only a minor acute toxicity (LD₅₀ 158–298 mg/kg) but also a somewhat less marked skin damaging activity. In addition, the LD₅₀ values of selected β-chlorovinyl carbonyl compounds are compared with those of corresponding halogen-free compounds as well as of vinylogous carbonamidium salts ArCO CHCH N^⊕R₃X^⊖. The latter, which can be used as synthetic equivalents of 1 , differ in both the reduced acute toxicity and missing skin damaging properties.     

Partialsynthesen von Cardenoliden und Cardenolid-Analogen. XIII. Synthese substituierter 14,21-Epoxy-5β,14β-card-20(22)-enolide

Partial Syntheses of Cardenolides and Cardenolide Analogues. XIII. Synthesis of Substituted 14,21-Epoxy-5β,14β-card-20(22)-enolide The 12-substituted 14,21-epoxy-5β,14β-card-20(22)-enolides 3 and 5 were synthesized by oxidation of the appropriate 17β-(3-furyl) derivatives 2b and 2c , respectively, with chromic acid. 5 was converted to the conjugated Δ⁹⁽¹¹⁾-12-ketone 6 by dehydrogenation with selenium dioxide. The biological activities of the new compounds were investigated and are discussed.     

β-Thiocyanatovinylcarbonylverbindungen. III. 1H-NMR-Untersuchungen an β-Thiocyanato-vinylaldehyden

β-Thiocyanato-vinyl-carbonyl Compounds. III ¹H-NMR Investigations of β-Thiocyanato-vinylaldehydes The ¹H-NMR spectra of some alkyl- and phenylsubstituted Z/E-isomeric β-thiocyanato-vinylaldehydes are represented. The assignment for Z/E-isomers is made using the chemical shifts of the CHO-protons and paramagnetic shift experiments. The discussion of the ΔEu-values allows to determine the conformation of the CHO-group. The main products in the case of the alkyl-substituted β-thiocyanato-vinylaldehydes are the Z-isomeric compounds which fact is attributed to mechanistic and electronic effects.     

Intermediates of Prostanoid Synthesis. Stereospecific conversion of (+)-5β-hydroxycyclopenten-2-yl-1β-acetic acid γ-lactone into (+)-1β-methoxycarbonylmethyl-2β,3β-(p-nitrobenzylidene)-dioxycyclopentan-5-one

Starting from (+)-5β-hydroxycyclopenten-2-yl-1β-acetic acid γ-lactone ( 1 ), (+)-1β-methoxycarbonylmethyl-2β, 3β-(p-nitrobenzylidene)-dioxycyclopentan-5-one ( 7 ) was prepared within 4 steps. Subsequent cleavage of the latter gives (−)-3β-hydroxy-1-methoxy-carbonylmethylcyclopent-1-en-5-one ( 8a ). Hydroxylation of the lactone ( 1 ) was found to give (+)-2β,3β,5β-trihydroxycyclopentyl-1β-acetic acid γ-lactone ( 2a ) with cis-oriented hydroxy groups in respect to the lactone ring. No formation of the trans-isomer, as has been reported earlier [4], was observed.     

Herstellung und Charakterisierung der Sulfamate von Estra-3,17ξ-diolen. Schnelle Umsetzung von 16α-Fluorestradiol zum 16α-Fluorestradiol-3,17β-disulfamat

Estradiols are able to form two monosulphamates and one disulphamate. In the present work all the sulphamates of 17α-estradiol, 17β-estradiol and 16α-fluoroestradiol were synthesized and characterized. For characterization NMR spectroscopy was used first of all. Because of its high sulphatase inhibitory efficiency 16α-fluoroestradiol-3,17β-disulphamate found a special interest among the new sulphamates. Just the binding between sulphamate and sulphatase favoured 16α-[^18F]fluorestradiol-3,17β-disulphamate to a new radio-pharmaceutical which should be appropriate to image the active sites of sulphatase by positron emission tomography. The preparation of 16α-[¹⁸F]fluoro-estradiol-3,17β-disulphamate requires a simple and rapid procedure. The conditions for such a procedure were also elaborated using non-radioactive substances.     

Partialsynthesen von Cardenoliden und Cardenolid-Analogen. II. Synthese von Cardenolid-analogen γ-Steroidyl-butenoliden

Partial Syntheses of Cardenolides and Cardenolide Analogues. II. Synthesis of Cardenolide-Analogous γ-Steroidyl-Butenolides The synthesis of the cardenolide-analogous stereoisomeric γ-steroidyl-butenolides 5 and 6 and of the γ-steroidyl-α-methyl-butenolide 13 , starting from β-ketosulfoxide 3 by alkylation with methyl bromoacetate and methyl α-bromopropionate, respectively, followed by the sodium borohydride reduction of the alkylated intermediates is described. 1,3-dipolar addition of diazomethane to 5 followed by pyrolysis of butyrolactone-pyrazoline-adduct 11 yields γ-steroidyl-β-methyl-butenolide 10 , the structural isomer of 13 .     

Cell‐Permeable β‐Peptide Inhibitors of p53/hDM2 Complexation

Look at what the cat(ionic motif) dragged in! We report a general strategy to increase the cell permeability of β³‐peptides. Introduction of a minimal cationic motif within the folded structure of a high‐affinity β³‐peptide ligand for hDM2 led to molecules with high 3₁₄‐helical structure, high hDM2 affinity and sufficient cell permeability to upregulate p53‐dependent genes in live mammalian cells. Minimally cationic β³‐peptides represent the critical first step towards a class of protease‐resistant peptidomimetics that might modulate intracellular biological pathways.

     

HPLC and 13C-NMR study of carboxymethyl-β-(1 → 6)-D-gluco-β-(1 → 3)-D-glucan derived from saccharomyces cerevisiae

Sodium salt of carboxymethyl-β-(1 → 6)-D-gluco-β-(1 → 3)-D-glucan (CMG-Na) was prepared from β-D-glucan isolated from baker's yeast (Saccharomyces cerevisiae). Three samples, Fractions I, II, and III, were further separated from the crude CMG-Na derivative. For the physicochemical characterization of the separated fractions, the methods of high-performance liquid chromatography (HPLC) in the size-exclusion mode and carbon?13 nuclear magnetic resonance (¹³C-NMR) spectroscopy were applied. The HPLC method revealed that the molecular weights, M_n, M_w, and M_z averages, of Fraction II were 9.71 × 10⁴, 2.27 × 10⁵, and 3.59 × 10⁵ Da, respectively, whereas those of Fraction III were 1.52 × 10⁴, 2.13 × 10⁴, and 3.57 × 10⁴ Da, respectively. The ¹³C-NMR spectra of Fraction II showed a ratio of 3 : 1 for β?(1 → 3) / β?(1 → 6), whereas for Fraction III, the content of β-(1 → 3) units was smaller. © 1993 John Wiley & Sons, Inc.