Steroide. XLVIII. 16α-Heterosubstituierte Östradiol-3-methyläther

Steroids. XLVIII. 16 α-Heterosubstituted 3-Methoxy-estra-1,3,5(10)-triene-17β-ols The synthesis of 16α-heterosubstituted 3-methoxy-estra-1,3,5(10)-triene-17β-ols 2a—2e from 16β-bromo-3-methoxy-estra-1,3,5(10)-triene-17β-ol 1 by substitution with nucleophiles is described. Additional compounds of this class 2f—2h are obtained by transformation of the new 16α-substituents. Jones oxidation of 2b and 2c yields the 17-keto compounds 3b and 3c . The configuration of the new compounds is confirmed by i.r. and ¹H n.m.r. spectra.     

Steroide. 66. 1H-NMR-Untersuchungen. Konfigurationszuordnung 15, 16, 17-trisubstituierter Steroide

Steroids. 66. ¹H-N.M.R.-Investigations. Configurational Assignment of 15, 16, 17-Trisubstituted Steroids The ¹H-n.m.r.-spectra of 15, 16, 17-trisubstituted estra-1,3,5(10)-trienes are discussed in view of the configurational assignment of the substituents. A reliable elucidation of their stereo-chemistry is possible on the basis of the coupling constants J_16H,17H, J_15H,16H and J_14αH,15H. Additional parameters are the chemical shifts of the 15-, 16-, 17- and 18-protons (13β-methyl group) and the downfield shift of carbinol proton signals, caused by the reaction of hydroxyl groups with trichloroacetyl isocyanate. The chemical shifts of the 13β-methyl group can be calculated for compounds with trans configuration from substituent increments and for the other compounds by comparison with the chemical shifts of 16, 17-disubstituted compounds. The influence of different 16α-substituents on the chemical shifts of 15α- and 17α-protons is investigated. The downfield shifts of 15- and 17-proton signals due to the addition of trichloroacetyl isocyanate to 15, 17-diols depend on the configuration of the 16-substituents.     

Steroide. LIII. 1H-NMR-Untersuchungen. Konfigurationszuordnung von 16-substituierten 17-Hydroxy-Steroiden

Steroids. LIII. ¹H N.M.R.-Investigations. Configurational Assignment of 16-Substituted 17-Hydroxy Steroids The ¹H n.m.r. spectra of epimeric 16-substituted 17β-hydroxy-3-methoxy-estra-1,3,5(10)-trienes can be used for configurational assignment. The values of the coupling constants J_16,17 allow the elucidation of the configuration, when all of the four epimeric compounds with the same 16-substituent are available. When only one compound is available, a reliable configurational assignment by J_16,17 is only possible, when J ≤ 2 cps (16β,17α-configuration of the substituents) or when J > 8 cps (16β,17β-configuration). Further parameters for configurational assignment are the chemical shifts of the 13β-methyl protons and the 17-proton, the downfield shifts of the 17-proton signals, caused by acetylation or by “in situ” reaction with trichloroacetyl isocyanate, and the chemical shift as well as the sum of the coupling constants of the 16-protons. The contributions of the 16-substituents to the chemical shift of the 17-proton are compared with similar values, obtained from 1-substituted acenaphthenes. Equations for the calculation of these contributions are presented for the trans compounds.     

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.     

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.     

Synthesen von β-Fur-2-yl-α-halogenacrylonitrilen

Syntheses of β-Fur-2-yl-α-halogenacrylonitriles Syntheses of β-fur-2-yl-α-halogenacrylonitriles 2a–f by Wittig-olefination of furfurales, Hunsdiecker-reaction of β-(5-nitro-fur-2-yl)-α-cyanoacrylic acid 3 , halogenation of β-fur-2-yl acrylonitriles and reaction of furfurales with β-azido-α-halogen-γ-methoxy-Δ^α,β-crotonolactones 9 are described.     

Die Reaktion von α,β-Dihalogen-propionitrilen mit monosubstituierten Hydrazinen - einfache Synthese 1-substituierter 3- bzw. 5-Amino-pyrazole

The Reaction of α,β-Dihalogeno-propionitriles with Monosubstituted Hydrazines — A Simple Synthesis of 1-Substituted 3- or 5-Amino-pyrazoles In methanol hydrazines 3 , and α,β-dihalogeno-propionitriles 1, 2 even at 0°C irreversibly yield 3 · HX, and α-halogenoacrylonitriles 4, 5 (A₁). Fast addition of alkyl- and aralkyl- hydrazines 3 to 4, 5 (C) gives 1-substituted 1-(2′-halogeno-2′-cyan-ethyl)-hydrazines 6 , the addition of arylhydrazines 3 to 4, 5 (D) 1-aryl-2-(2′-halogeno-2′-cyan-ethyl)-hydrazines 8 . In methanol 6 spontaneously cyclise (E) to hydrogen halides 7 · HX of 1-alkyl- and 1-aralkyl-3-amino-pyrazoles, 8 with 2 moles of acids (F) to salts 10 · 2HY of 1-aryl-4-halogeno-5-imino-pyrazolidines, and the free 10 spontaneously (G) to hydrogen halides 9 · HX of 1-aryl-5-amino-pyrazoles. Mechanisms (A₁), (C), (D), (E), (F), and (G) are proved by t.l.c., ¹H-n.m.r., and isolation of intermediates, the structures of 7 resp. 9 , using the significant ¹H-n.m.r.-parameter Δ. Simple general syntheses are described for 3-amino-pyrazoles 7 (R = H, alkyl, aralkyl) or 5-amino-pyrazoles 9 (R = aryl) starting with α,β-dihalogeno-propionitriles 1, 2 , and for α-bromo-acrylonitrile 5 .     

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.     

Steroide. 67. 16,17-Aziridine des Östra-1,3,5(10)-trien-3-methylethers

Steroids. 67. 16,17-Aziridines of 3-Methoxy-estra-1,3,5(10)-triene Reduction of the 16β-azido-17-α-mesyloxy- and 16α-azido-17β-mesyloxy-estra-1,3,5(10)-triene-3-methylether ( 2 and 10 ) with hydrazine hydrate and Raney nickel gives the 16,17-trans-aminoalcohol-O-mesylates 3 and 11 . Treatment of 3 with basic reagents affords products of Wagner-Meerwein rearrangement, 11 gives under analogous conditions the 16α-amino-17β-hydroxy compound and the 16α, 17α-aziridine. Smooth ring closure to the 16,17-N-mesylaziridines 6 and 13 can be achieved by reaction of the 16,17-trans-mesylamido-mesyloxy compounds 8 and 12 with bases in DMSO. The torsional angles of the reactive groups are discussed.     

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.     

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.     

α-Substituierte Phosphonate. XXXIV. Zur Veresterung und N-Formylierung von α-Aminomethan-bisphosphonsäuren mit Orthoameisensäuretriethylester

α-Substituted Phosphonates. XXXIV. Esterification and N-Formylation of α-Aminomethane-bisphosphonic Acids with Triethylorthoformate In contrast to simple mono- and bisphosphonic acids esterification of dialkylaminomethanebisphosphonic acids with orthoformate (OAE) proceeds very slowly. Monoalkyl and monoarylaminomethanebisphosphonic acids, respectively react with OAE in constrast to analogous hydroxy compounds more readily primarily by formylating the N-atom and then esterification to formyl aminomethane bisphosphonictetraesters 10 . Acetaminomethanephosphonic acid ( 12 ) reacts without N-formylation, while the aminomethanebisphosphonic acid ( 14 ) reacted to give a mixture of mono- and bis-formylated products 15 and 16 . By acidic hydrolysis of 10 the ester- and formylgroups are splitt off, while the ester group can selectively be removed by reaction with Me₃SiBr/H₂O. – As shown by ¹H-, ¹³C- and ³¹P-n.m.r. spectroscopy the phosphorylated formamides 10 exists in two rotameres, the ratio depending on the solvent. The n.m.r. signals could be correlated to E-resp. Z-form undoubtedly by using shift-agents or the benzene-diluting technique. A rotational barrier of 22,8 kcal for 10c could be calculated.     

Untersuchungen zur Bromierung/Dehydrobromierung von 17α-Cyanmethyl-17β-hydroxy-östr-5(10)-en-3-on

Investigations on the Bromination/Dehydrobromination of 17α-Cyanomethyl-17β-hydroxy-estr-5(10)-en-3-one Bromination/dehydrobromination of 17α-Cyanomethyl-17β-hydroxy-estr-5(10)-en-3-one 1a in the presence of pyridine leads to 17α-cyanomethyl-17β-hydroxy-estra-4, 9-dien-3-one 2a . The reaction was studied in various solvents with several bromination agents. Intermediates and byproducts of the reaction were isolated and their structures elucidated.     

Partial Synthesis of [1β,2α,17,17-D4] Gibberellin A1

An efficient route for an alternative synthesis of gibberllin A₁ from gibberellin A₃ is described. Based on iodolactonisation the method provides access to gibberellin A₁ labeled by deuterium with both high incorporation of the isotope and high stereoselectity at the positions 1β and 2α. The additional deuterium labeling at C-17 was introduced via the corresponding 16-norketone resulting in [1β,2α,17,17-D₄] gibberellin A₁.     

Partialsynthesen von Cardenoliden und Cardenolid-Analogen. VII. Synthese A/B-cis- und C/D-cis-verknüpfter Steroidmono- und -bis(α-methylen-γ-butyrolactone)

Partial Syntheses of Cardenolides and Cardenolide Analogues. VII. Synthesis of A/B-cis- and C/D-cis-linked Steroidal Mono- and Bis (α-methylene-γ-butyrolactones) The synthesis of A/B-cis- and C/D-cis-linked steroidal mono- and bis(α-methylene-γ-butyrolactones) 10–13 , 18 and 24 by Reformatsky-type reaction of 3β-acetoxy-14-hydroxy-5β, 14β-androstan-17-one( 6 ), 14-hydroxy-5β, 14β-androstane-3,17-dione ( 8 ), 3β-acetoxy-14-hydroxy-5β,14β-pregnan-20-one ( 17 ) and 14-hydroxy-5β,14β-pregnane-3,20-dione ( 23 ), respectively, with ethyl α-(bromomethyl)acrylate is described. All steroidal lactones exhibit strong inhibitory activity on the proliferation of Ehrlich ascites carcinoma cells in suspension culture. For inhibitory activity the lactone moiety at C-17 of the steroid molecule is more important than the lactone moiety at C–3 and C–20, respectively.     

r-5-(α-Halogenbenzyl)-3, t-4-diaryl-c-4-hydroxy-oxazolidin-2-one als Ringtautomere von α-(Arylaminocarbonyloxy)-β-halogen-dihydrochalkonen

r-5-(α-Halogenobenzyl)-3, t-4-diaryl-c-4-hydroxy-oxazolidin-2-ones as Ring Tautomers of α-(N-Arylaminocarbonyloxy)-β-halogeno-dihydrochalcones The reaction of chalcone halogenohydrins ( 1–3 ) with arylisocyanates does not stop at the stage of the α-arylaminocarbonyloxy-β-halogeno-dihydrochalcones ( 7 ), but the cyclic urethanes 4–6 are formed. Compound 7h was synthesized independently. The structure and stereochemistry of 4–6 and 7h were determined by ¹³C n.m.r. spectroscopy.     

Synthese und Strukturaufklärung von 19-Nor-pregnanderivaten mit stickstoffhaltigen Vierringen in 14,15-Stellung

Synthesis and Structural Elucidation of 19-Nor-pregnane Derivatives with Nitrogen-Containing Four-Membered Rings in 14,15-Position The introduction of a C₂ side chain in the 17-position of 3-methoxy-14β, 15β-(3′,4′-azetidine)-estra-1,3,5(10)-trien-17β-ol ( 1 ) is described. Hydroboration of the 17-ethylidene compound 4 gives a mixture of the 17αH and 17α-pregnane derivatives 6 and 6a in 70% and 10% yields, respectively. Birch reaction of 6 , followed by oxidation yields the 14β,15β-(3′,4′-azetidine)-19-nor-pregn-4-ene-3,20-dione ( 12 ). The new compounds were characterized by ¹H-n.m.r. The structure of product 13 was determined by X-ray crystallography.     

Umsetzung von Bromderivaten des 6β-Bromcholest-4-en-3-ons mit NaBH4 und 13C-NMR-spektroskopische Charakterisierung der Reduktionsprodukte

Reaction of Bromo Derivatives of 6β-Bromocholest-4-en-3-one with NaBH₄ and ¹³C-NMR Spectroscopic Characterization of the Reduction Products Bromo derivatives of 6β-bromcholest-4-en-3-one ( 1a–f ) were reduced with sodium borohydride. The main product of the reduction of 2α,6β-dibromcholest-4-en-3-one ( 1b ) was 2α-bromocholesterol ( 2b ). In other cases the corresponding derivatives of 6β-bromocholest-4-en-3β-ol ( 3a ) were formed. The chemical shifts of all new products were determined. They confirmed the structure of these new compounds.     

Allgemeine Synthesen und rationelle Strukturparameter isomerer Derivate von [3,4]-kondensierten Pyrazolen

General Syntheses and Rational Parameters for Structural Assignment of Isomeric Derivatives of [3,4]-fused Pyrazoles 4 isomeric 1- or 2-methyl-, and 1- or 2-benzyl-pyrazolo[3,4-b]pyridones, i.e. the 4-oxo-types 17a, b or 11a, b and the 6-oxo-types 16a, b or 10a, b , are synthesized unambiguously. Cyclisation of 1-substituted 3- or 5-(1-methyl-2-ethoxycarbonyl-vinylamino)-pyrazoles 9a, b or. 15a, b , which were synthesized from 1-substituted 3- or 5-amino-pyrazoles and ethyl acetoacetate yields 11a, b or 17a, b in downtherm, but 10a, b or 16a, b in presence of acidic catalysts. The acidic cyclisation is preceded by a new rearrangement of 9 or 15 into 1- substituted 3- 27 or 5-amino-4-(1-methyl-2-ethoxycarbonyl-vinyl)-pyrazoles 30 ; mechanism and concurring reactions are explained. Because of their higher electron densities at C-4 it is easier to cyclise derivatives of 5-amino-pyrazoles compared to 3-amino-pyrazoles. All isomeric 1- or 2-substituted 4(6)-chloro-6(4)-methyl-pyrazolo-[3,4-b]pyridines are formed with POCl₃ from the corresponding oxo-compounds. The position of a substituent at N-1 or N-2 of [3,4]-fused pyrazoles can be assigned using the significant ¹H-n.m.r.-parameter Δ = δ — − δ_HMPT (conc. HC—3). If solvent influences are considered, δ(C  O) is a useful ¹³C-n.m.r.-parameter to distinguish the 4-oxo-types ( 11a, b; 17a, b ) from the 6-oxo-types ( 10a, b; 16a, b ) of pyrazolo[3,4-b]pyridones. Further own and lit. dates conc. structural assignment (n.m.r., i.r., u.v.) are discussed critically.     

Synthese,Reaktivität und 1H-NMR-Daten von 14,15-Methylenderivaten der Androstan- und Östratrienreihe

Synthesis, Reactivity and ¹H-NMR-Spectroscopy of 14,15-Methylene Derivatives of the Androstane and Estratriene Series Under the activating and syn-directing effect of the 17-hydroxy group the Simmons Smith cyclopropanation of 14,15-unsaturated 17-hydroxy steroids of the androstane and estratriene series 1a, 5 and 9 affords the 14,15-methylene steroids 2a, 6 and 10 with cis position of the 14,15-methylene and 17-hydroxy groups in a stereospecific reaction. Oxidation of these compounds yields the 17-keto derivatives 3, 7 and 11 , which were reduced to the compounds 4a, 8 and 12 with trans position of the 14,15-methylene and 17-hydroxy groups by complex hydrides or diborane. In a phase transfer catalyzed reaction dichloro- or dibromocarbene was added to 3β, 17β-diacetoxy-5α-androst-14-ene 1b forming the 14β, 15β-dihalogenmethylene steroids 13 and 14 . The 17-keto steroids 7 and 11 were transformed into 17-methyl and 17-ethynyl derivatives 15–20 . Cleavage of the cyclopropane ring of 2a, 2b and 3 by catalytic hydrogenation affords the 14β-methyl derivatives 21–23 , the acid catalyzed ring opening with hydrogen chloride yields the 14β-chloro, 15β-methyl derivatives 24–29 . Structure elucidation has been established by ¹H n.m.r. and mass spectroscopy. The configuration at C17, C14 and C15 was also determined by means of ¹H n.m.r. spectroscopy, using the chemical shifts of the 18-protons, the coupling constants and the chemical shifts of the 17-protons. The configuration of the 17-disubstituted steroids was established with the aid of an europium shift reagent.