Die Struktur des Harpagosids. 2. Mitteilung über Iridoide

The structure and configuration of harpagoside, a bitter principle from the roots of Harpagophytum procumbens DC, have been elucidated by degradation reactions and NMR. spectra. The hitherto uncertain position of a secondary hydroxyl group could be assigned to C-6 of the aglycone moiety. As earlier postulated, harpagoside ( 1 ) as well as its saponification product, harpagide ( 12 ), belong to a series of natural enol ethers known as iridoids.     

Die Chemie des Wieland-Gumlich-Aldehyds und seiner Derivate [1] 136. Mitteilung über Alkaloide [2]

The course of the reactions involved in the process of degradation of strychnine ( 1 ) to Wieland-Gumlich aldehyde (WGA) ( 2 ), first performed by Wieland, Kaziro & Gumlich , has been elucidated. 23-Isonitrosostrychnine hydrochloride ( 9a ) upon treatment with thionyl chloride undergoes a fragmentation (2nd order Beckmann rearrangement), thus furnishing N(a)-cyanoformyl-WGA hydrochloride ( 14a ). On heating in an acidic medium, the latter compound is transformed — at least partially via the cyclic urethane 15 — into WGA ( 2 ), which is an important keyintermediate in the syntheses of strychnine and curare alkaloids. The compound 2 can now be obtained in high purity and good yield. A corresponding degradation has been realized with quaternary analogues ( 27 → 3 ) as well as with 10-chlorostrychnine ( 58 → 62 ). 10-Chlorostrychnine ( 58 ) was prepared by chlorination of strychnine with chlorine in conc. hydrochloric acid according to Leuchs & Steinborn. As by-products of the reaction, 10, 15-dichlorostrychnine ( 59 ) and 10, 15, 19-trichlorostrychnine ( 60 ) could be identified. Starting from WGA a series of derivatives have been prepared. Special mention is made of the two epimeric methyl ethers 18 and 19 . The absolute configuration at the centre 17 of WGA and of these two substances has been established by optical comparisons of 3 epimeric pairs. The methyl ether 18 , by-product « B », is obtained if methanol is used in working up the Beckmann rearrangement products of 23-isonitrosostrychnine hydrochloride ( 9a ). A second by-product, « A », results by working up under alkaline conditions. This compound has the structure 44 with inverted configuration at centre 16. Degradation of 44 under controlled conditions leads either to WG-diol ( 42 ) or to 16-epi-WG-diol ( 51 ). Besides « A z.rdang; and « B » a series of by-products and intermediates ( 16, 17, 11a, 22. 23, 24 and 25 ) could be detected in the course of the process of strychnine degradation.     

Über die Struktur eines neuartigen Indolalkaloids,des Talbotins. 141. Mitteilung über Alkaloide [1]

From the leaves of the African Apocynacea Pleiocarpa talbotii Wernham a novel indole alkaloid, talbotine, C₂₁H₂₄N₂O₄, has been isolated. Talbotine ( 1 ) contains a secondary N_(b)-atom and a cyclic hemiacetal group. Catalytic hydrogenation leads to 19, 20-dihydrotalbotine ( 6 ), hydrogenation in the presence of formaldehyde gives N_(b)-methyl-19, 20-dihydrotalbotine ( 8 ). In the presence of sodium methoxide and methanol, 1 is converted into the lactone 12 and the methyl ester 13 . In these reactions carbon 17 is lost as formic acid. These data, together with the analyses of the NMR. spectra of talbotine and its derivatives as well as the interpretation of the various types of the mass spectral fragmentation, lead to formula 1 for the alkaloid. Dehydrogenation of talbotine methyl ether ( 3 ) with palladium and maleic acid gives the ß-carboline derivative 26 . The N_(b)-methiodide of the latter is converted into N_(b)-methyl-talbotine methyl ether on reduction with sodium borohydride. From these data as well as from the analyses of NMR. and IR. spectra the complete relative stereochemistry of talbotine could be derived. Application of the Horeau method to the nitrogen atom b of the methyl ether 3 on the one hand and to the hydroxyl group on C17 in N_(b)-methyl-19, 20-dihydrotalbotine ( 8 ) on the other hand gives consistent results and establishes S configuration of centre 15.     

Säurekatalysierte Umlagerungen von 1,5-Dimethyl-6-methyliden-tricyclo[3.2.1.02,7]oct-3-en-8endo-olen

Acid Catalysed Rearrangement of 1,5-Dimethyl-6-methyliden-tricyclo[3.2.1.0^2,7]oct-3-en-8endo-ols The tricyclic alcohols 2,3,4 and 6 (Scheme 1) are synthesized by the reaction of the tricyclic ketone 1 with sodiumborohydrid or metalloorganic reagents. Their configuration at C(8) is determined by NMR. in the presence of Eu(fod)₃. The exo-attack of 1 by the nucleophil forming the endo-alcohol is favored, the π-electrons of C(3) = C(4) hindering the endo-attack. On treatment with sulfuric acid in dioxane/water at 25° the tertiary alcohols yield aryl-substituted ketones. 3 gives in 78.5% yield a mixture of the 3-(dimethylphenyl)-2-butanones 12 and 13 , in addition to 16.5% of (2,3,4-trimethylphenyl)-2-propanon ( 14 ) (Scheme 2). The alcohols 4 and 6 yield mixtures of the 2-(dimethylphenyl)-3-pentanones 19 and 20 (72%), and 2-(dimethylphenyl)-propiophenones 21 and 22 (68%), respectively (Scheme 2). In the case of the secondary alcohol 2 mainly products derived from hydration at the C(6), C(9) double bond are formed, namely the mixture of diols 23 and 24 (21%), and the mixture of the isomeric 2-(dimethylphenyl)propanals 25, 26 and 27 (3%) (Scheme 3). - The structures of 12–14, 19/20, 21/22, 23/24 and 25/26/27 were established by spectroscopic data. In the case of 12 and 13 the degradation of their mixture to the known 1-(dimethylphenyl)ethanols 17/18 confirmed the assignment. - The most probable mechanism for the rearrangement of 3 is shown in Schemes 4 and 5. The reaction proceeds from 3 through a, b and g to 12 and 13; 14 is formed via e, f and i . In the case of 4 and 6 only the reaction analogue to 3 → a → b → g ?12/13 takes place. The isomeric aldehyds 25–27 formed from 2 could have the structures s, t , and v . The former two could be generated in a similar way as 12/13 from 3 , the latter one as shown in Scheme 8.     

Magnetische Kernresonanz-Untersuchungen über die Struktur der Komplexe aus Nitroaromaten mit aromatischen aminen 10. Mitteilung über nucleophile aromatische Substitutionsreaktionen [1]

1. NMR. and visible spectra of the addition products of N,2,4,6-tetranitro-N-methyl-aniline, 2,4,6-trinitrochlorobenzene, and 2,4-dinitro-6-cyano-chlorobenzene with aromatic amines (1-naphthylamine, N-mono- and -di-methyl-1-naphthylamine, 5-aminotetralin, N-methylaniline) demonstrate that electron donator-acceptor complexes (π-complexes) are formed.     

Die Struktur des Spermin-Alkaloides Aphelandrin aus Aphelandra squarrosa NEES. 170. Mitteilung über organische Naturstoffe

The structure of the spermine alkaloid aphelandrine from Aphelandra squarrosa NEES The new spermine alkaloid aphelandrine ( 2 ) has been isolated from Aphelandra squarrosa NEES . By oxidation of 2 with KMnO₄ followed by methylation (CH₂N₂) 12 and 14 could be prepared (Scheme 2). Fusion of 2 with KOH yielded spermine ( 1 ) whereas hydrolysis of 2 in hot hydrochloric acid results in lacton 17 , the structure of which could be elucidated by comparison with a synthetically prepared model compound (Scheme 3). The benzylic bonds N (10), C(11) as well as O(16), C(17) of 2 could be cleaved by hydrogenolysis (compare 23 and 26 ; Scheme 4). The elucidation of the correct linkage of the spermine moiety with the aromatic dicarboxylic acid is based mainly on chemical and spectroscopic evidence of the tetrahydro derivative 26 , the Hofmann-degradation products 28 , 30 and 31 (Scheme 6) as well as the ester 35 , prepared by partial hydrolysis of 2 (Scheme 7).     

Die Aminoalkylierung von Chinoxalinen und Chinoxalonen 6. Mitteilung über grignard-reaktionen mit halogenalkylaminen [1]

Quinoxaline and 2(1H)-quinoxalones react with organomagnesium salts differently from the corresponding phthalazines and quinazolines. 3-Dimethylaminopropyl-magnesiumchloride alkylates quinoxaline easily by addition to the 2 and 3 position forming a tetrahydroquinoxaline 2 , which can be dehydrogenated to the corresponding dialkylated quinoxaline 3 . The monosubstituted dihydroquinoxaline 5 is obtained only with difficulty. It can equally be dehydrogenated, yielding 6 . Quinoxalones react with CH₃MgI, C₆H₅MgBr, (CH₃)₂N? (CH₂)₃? MgCl by addition to the 3,4-C?N bond (not at the CO-group), yielding 11–13 . These dihydroquinoxalones are dehydrogenated to the 3-substituted 2(1H)-quinoxalones 14–16 . Only 3-phenyl-quinoxalone adds a Grignard reagent at the CO group, forming a 2-substituted 3-phenylquinoxaline ( 26 ). 3-Methyl-quinoxalone exhibits an abnormal behaviour: It is deprotonated by the mentioned reagents at the CH3 group, and the 3-methylenequinoxalone-anion so formed attacks another molecule of methylquinoxalone, finally yielding 32 and 33 .     

Über die Umsetzung von 1-Phenylpyrazol mit Äthylmagnesiumbromid. 8. Mitteilung über Grignard-Reaktionen [1]

In contrast to butyllithium, ethylmagnesium-bromide reacts with 1-phenyl-pyrazole exclusively by deprotonation, at the ortho position of the phenyl-ring. With nitriles the intermediate 2-(1-pyrazolyl)-phenylmagnesiumbromide gave good to excellent yields of 1-(2-aroyl or 2-hetaroyl-phenyl)-pyrazoles (Table 1, compounds 5a – 5i ); with ketones the corresponding methanol derivatives (Table 2, compounds 6a – 6c ) were found, whilst CO₂ yielded the corresponding 1-(2-carboxyphenyl)-pyrazole ( 3 ). Surprisingly enough, 1-(o-bromo-phenyl)-pyrazole and magnesium did not yield a single product, but a mixture of 3 compounds, which on reaction with 4-benzoylpyridine gave the three alcohols 19 , 20 and 21 .     

Die molekulare und kristalline Struktur von 9,10-Dihydro-4-(3-dimethylamino-propyliden)-4H-benzo[4,5] cyclohepta[1,2-b]thiophen-hydrochlorid. Untersuchungen über synthetishe Arzneimittel, 19. Mitteilung [1]

The α-isomer of 9,10-dihydro-4-(3-dimethylamino-propylidene)-4 H-benzo[4,5] cyclohepta [1, 2-b] thiophen is shown to have the trans configuration by means of an X-ray analysis of its hydrochloride.     

Die Aminoalkylierung von Phtalazinen und Phtalazonen mit Hilfe der GRIGNARD-Reaktion. 4. Mitteilung über GRIGNARD-Reaktionen mit Halogenalkylaminen [1]

Phtalazines and 4(3H)-phthalazones are aminoalkylated in high yield by 3-dimethylaminopropyl-magnesiumchloride. Phthalazines add only one molecule of the GRIGNARD reagent at the C?N-double bond, giving mono-aminoalkylated 1,2-dihydrophthalazines which undergo no further reaction without previous oxydation. Phthalazones react with the carbonyl and the C?N-group yielding in one step di-aminoalkylated dihydrophthalazines. The dihydrophthalazines are easily oxydized with K₃Fe(CN)₆ to the corresponding phthalazines.     

Beiträge zur Chemie der 4-Hydroxyindol-Verbindungen 10. Mitteilung über synthetische indolverbindungen [1]

Catalytic hydrogenation of 4-benzyloxyindoles does not stop at the hydroxyindole stage, but slowly leads to the 4,5,6,7-tetrahydro-4-ox-indoles 3 . Some procedures for the selective preparation of 4-hydroxyindoles 2 are described. When 4-benzyloxy-3-(1-hydroxyimino-ethyl)-indole ( 4c ) is warmed with trifluoroacetic acid, cleavage of the ether results as well as partial benzylation of the free hydroxyindole in the position 5 ( 5a, 5b ); no Beckmann rearrangement is observed. Esters of 4-benzyloxy-indole-2-carboxylic acid are formylated with POCl₃/dimethylformamide in the 7-position to give 7a ; in the corresponding dimethylamide, on the other hand, the formyl group enters the 3-position to give 8 . Both 4- and 7-hydroxyindole are oxidized with Frémy's salt to the 4, 7-quinone 13 ; on reduction this yields 4, 7-dihydroxyindole 14 , which is tautomerized by base-catalysis to 5, 6-dihydro-4, 7-dioxo-indole 15 . The course of the etherification of 4-hydroxyindoles with epichlorohydrin and related compounds is described, and the resulting side-chains are characterized by their NMR. spectra.     

Herzwirksame Glykoside aus der weissen Meerzwiebel. Konstitution des Scilliphäosids und des Glucoscilliphäosids. 55. Mitteilung über Herzglykoside [1]

Scilliphaeoside (I), C₃₀H₄₂O₉, and glucoscilliphaeoside (III), C₃₆H₅₂O₁₄, represent two minor glycosides which occur in the bulbs of the white sea onion or squill [Scilla (= Urginea) maritima (Baker) L.]. Glucoscilliphaeoside is easily converted into scilliphaeoside and D-glucose by selective enzymatic cleavage with β-glucosidases (e. g. strophanthobiase). Acid hydrolysis splits glucoscilliphaeoside into anhydroscilliphaeosidin (IV) and L-scillabiose (= β-D -glucosyl-L -rhamnose), scilliphaeoside yields the same anhydro-aglycone IV and L-rhamnose. The true genin scilliphaeosidin (VI), C₂₄H₃₂O₅, has now been gained by a combined oxidative and hydrolytic cleavage of the rhamnose residue of scilliphaeoside. By chemical evidence and spectroscopical data scilliphaeosidin is characterized as a trihydroxy-Δ⁴-steroid of the bufadienolide type. The assumed locations of the three hydroxylic functions at C-3, C-12 and C-14 are established by permanganate degradation of the lactone ring of di-O-acetyl-scilliphaeosidin (VII) to the etianic acid derivatives XIII and XIV, which are also available from digoxigenin. These correlations prove the structure of scilliphaeoside (I) as 12β-hydroxy-proscillaridin A, glucoscilliphaeos de (III) representing 12β-hydroxy-scillaren A.     

Indolalkaloide aus Conopharyngia durissima STAPF. 134. Mitteilung über Alkaloide [1]

The alkaloids akuammiline ( 1 ) and anhydrovobasindiol ( 6 ) were isolated from the trunk bark of the Apocynacea Conopharyngia durissima STAPF . The structure of the unknown base anhydrovobasindiol was elucidated and this base was partially synthetised from the alkaloid vobasine. The well-known akuammiline could be correlated by LiAlH₄ reduction to picralinol ( 4 ).     

Präparative Verwendung von Mannich-Basen von Hydroxy-indolen als Alkylierungsmittel. 4. Mitteilung über synthetische Indol-Verbindungen [1]

The MANNICH bases 4-dimethylaminomethyl-5-hydroxy-indole and 7-dimethylaminomethyl-6-hydroxy-indole are suitable agents for alkylating C-acidic compounds such as nitroalkanes and ethyl formamido-malonate. The products obtained have been transformed into (substit.) aminoethyl derivatives or amino-acids containing the basic side-chain in the benzene nucleus and which are, therefore, isomeric to tryptamines and tryptophans.