Der Zugang zum Antitumor-Antibiotikum CC-1065 mittels Hetero-Cope-Umlagerung von Vinyl-N-phenylhydroxamaten

The Access to the Three Subunits of the Antitumor Antibiotic CC-1065 by Hetero-Cope Rearrangement of Vinyl N-Phenylhydroxamates . The use of the hetero-Cope rearrangement of vinyl N phenylhydroxamates to indoles for the preparation of the 1,2-dihydro-3H, 6H-benzo[1,2-b:4,3-b′]dipyrrole skeleton, the structural subunits characteristic of the antitu-mor antibiotic CC-1065 as well as the phosphodiesterase inhibitors PDE-I and PDE-II is described.     

Synthese von 2,3-unsubstituierten,N-acylierten Indolen durch sigmatrope[3,3]-Umlagerung von O-Vinyl-N-phenylhydroxylaminderivaten

Synthesis of 2,3-Unsubstituted N-Acylindoles by [3,3]-Rearrangement of the N-Phenyl-O-vinylhydroxylamine Derivatives Summary, Treatment of N-phenylhydroxamic acids with vinylacetate in the presence of Li₂PdCl₄ affords 2,3-unsubstituted N-acylindoles via hetero-Cope-rearrangement of the intermediate N-O-vinylhydroxylamine derivatives.     

Hetero-Cope-Umlagerungen. 4. Mitteilung. Regiokontrollierte Indolsynthesen

Hetero-Cope-Rearrangements, Regio-Controlled Synthesis of Indoles The reaction of O-deprotonated N-phenylhydroxylamines 1 with various electron-deficient allenes 2 , 14 , 16 gives, via Michael addition and Cope-rearrangement, substituted anilines 5 , which are easily convertible into indoles 6 . In this manner, sulfoxides 17 , serve as equivalents of 2-vinylindoles. Diels-Alder reaction with this 2-vinylindole equivalent followed by indolisation affords isoquinuclidine derivative 21 which may be a useful precursor for the preparation of Iboga alkaloids.     

A Stereospecific `2‐Aza‐divinylcyclopropane' Rearrangement

The stereochemical course of the thermal 2‐aza‐Cope rearrangement of the optically pure acyl azide (−)‐(1S)‐ 5 was investigated by determination of the absolute configuration of the rearrangement product (1R,8S)‐ 9 . The reaction proceeds by a sequence of stereospecific steps from 5 to an equilibrating mixture of exo‐ and endo‐isocyanates 6 and 7 . The endo‐isomer 7 undergoes Cope rearrangement to the putative intermediate 8 , which is trapped and characterized as the adduct 9b of butan‐1‐ol. The absolute configuration of 9b was determined by its reduction to the amide 20 , and determination of the X‐ray structure of the N‐camphanoylamide 21 derived from camphanic acid of known absolute configuration.     

Domino Reactions with Fluorinated Five-membered Heterocycles – Syntheses of Trifluoromethyl Substituted Butenolides and γ-Ketoacids

Summary. A new approach to trifluoromethyl substituted butenolides and their thioanalogues is described starting from 2-fluoro-3-trifluoromethylfurans and -thiophenes, respectively. The reaction sequence includes three steps – nucleophilic displacement reaction, Claisen, and finally Cope rearrangement – which can be run as domino reaction. A modification of the domino reaction (transesterification instead of Cope rearrangement) provides a concise access to α-trifluoromethyl-γ-ketoacids.     

Domino Reactions with Fluorinated Five-membered Heterocycles – Syntheses of Trifluoromethyl Substituted Butenolides and γ-Ketoacids

A new approach to trifluoromethyl substituted butenolides and their thioanalogues is described starting from 2-fluoro-3-trifluoromethylfurans and -thiophenes, respectively. The reaction sequence includes three steps – nucleophilic displacement reaction, Claisen, and finally Cope rearrangement – which can be run as domino reaction. A modification of the domino reaction (transesterification instead of Cope rearrangement) provides a concise access to α-trifluoromethyl-γ-ketoacids.     

Density Functional Study of the Oxy‐Cope Rearrangement

With the goal of explaining the very large rate acceleration in the anion‐assisted Cope rearrangement, the behavior of the prototypes of the Cope rearrangements, namely hexa‐1,5‐diene ( 4 ), hexa‐1,5‐dien‐3‐ol ( 5 ), and the oxy anion 6 of the latter were compared. For this purpose, two‐dimensional DFT (hybrid B3LYP functionals with 6‐31G* basis set) potential‐energy surfaces (PESs) were computed, based on two interatomic distances. As the reliability of DFT/B3LYP‐computed energies can not be taken for granted, we first performed model computations on the experimentally well‐studied bridged homotropylidenes 1 – 3 . Then, the transition states of the Cope rearrangements of 3‐methylhexa‐1,5‐dien‐3‐ol ( 7 ), (2Z,4Z,7Z)‐cyclonona‐2,4,7‐trien‐1‐ol ( 9 ), 1‐methoxy‐2‐endo‐vinylbicyclo[2.2.2]oct‐5‐en‐2‐exo‐ol ( 11 ), and (1S,2R)‐2‐hydroxy‐1‐methyl‐2‐vinylbicyclo[4.4.0]dec‐6‐en‐8‐one (arbitrary numbering; 13 ) and of their oxy anions 8 , 10 , 12 , and 14 , respectively, were computed by the same method. These examples were chosen because kinetic data have been measured for most of them (except for 13 and 14 ) and/or because they furnished already important contributions to the discussion of the character of the Cope rearrangement. The computation of ΔG^≠ for a given temperature allowed to calculate the rate constants at that temperature for the different rearrangements and to compare them with the experimental data. In the cases of the neutral and anionic oxy‐Cope rearrangements, the equation ΔΔG^≠=2.3026⋅RT⋅ΔpK_a suggested a correlation between the difference in the pK_a values of the pair of reactants and the pair of transition states and the change of the two free energies of activation.     

Über den Mechanismus der Cope-Umlagerung

On the Mechanism of the Cope Rearrangement The rates of the Cope rearrangement of 2,5-dicyano-3-methyl-hexa-1, 5-diene ( 12 ), (E)- and (Z)-2, 5-dicyano-hepta-1,5-diene ((E)- and (Z)- 14 ) as well as of 2, 5-dimethoxycarbonyl-3-methyl-hexa-1,5-diene ( 13 ) and (E)- and (Z)-2,5-dimethoxycarbonyl-hepta-1,5-diene ((E)- and (Z)- 15 ) were measured in decane solution in the temperature range of 50 to 150° (see Tables 5 and 8 to 12). A detailed English summary of this work is given in [1 b].     

Photocyclisierungen von 1, 1'-Polymethylen-di-2-pyridonen. 46. Mitteilung über Photoreaktionen

Photocyclization of 1, 1′-Polymethylene-di-2-pyridones . Benzophenone sensitized irradiation of the four dipyridones 1-4 gave the internal photocyclization products 6 (64%, Scheme 4), 7 (60%, Scheme 5), 8 (Scheme 6), and 11 (26%, Scheme 7), respectively. The decamethylene compound 5 yielded only polymeric material. The primary [2+2] photoproduct 8 from dipyridone 3 (Scheme 6) is relatively unstable. Further irradiation or heating to 65° induced a Cope rearrangement to give compound 9 which, on heating to 137°, was converted into the isomeric compound 10 . This product, as well as the other photoproducts mentioned, are rearranged back to their respective starting materials upon direct irradiation with 254 nm light or by heating to higher temperatures. The various possibilities for cycloadditions of pyridones are discussed as well as the possible factors which are responsible for the highly regioselective photoreactions of the dipyridones 1–4 .     

A Fused Benzocyclooctene Ring System via an Aromatic Cope Rearrangement: Thermal Reactions of trans‐1‐Aryl‐2‐ethenylcyclobutanecarbonitriles

The results of an aromatic Cope rearrangement of a trans‐1‐aryl‐2‐ethenylcyclobutanecarbonitrile are reported (Scheme). The use of this rearrangement for the construction of the fused benzocyclooctene ring system and a preliminary study of the electronic requirements to favor such a transformation are also described.     

A Model Study towards a Conceptually New Synthetic Entry into the Seco‐ and Heteroyohimbine Alkaloid Families

A model study is presented that paves the way to a new and flexible synthetic approach towards the seco‐ and heteroyohimbine alkaloid class. The key step involves a highly diastereoselective Cope rearrangement of an (E,E)‐azacyclodeca‐3,7‐diene grafted onto a 3‐ethylindole moiety to furnish a trans‐3,4‐divinylpiperidine derivative in 83% yield.     

Comparison of 13C- and 1H-Magnetic Resonance Spectroscopy as Techniques for the Quantitative Investigation of Dynamic Processes. The cope rearrangement in bullvalene

The potential advantages of ¹³C-(¹H-noise decoupled) spectroscopy (in the Fourier transform mode) over ¹H-spectroscopy for the quantitative investigation of molecular dynamic process is discussed. The Cope rearrangement in bullvalene, an example of complex exchange of spins over different magnetic sites, has been studied by both kinds of spectroscopy as a test.     

Synthese von N-Methyl- und N,N-Dimethylmerucathin sowie von N-Methyl- und N,N-Dimethylpseudomerucathin aus L-Alanin

Synthesis of N-Methyl- and N,N-Dimethylmerucathine and of N-Methyl- and N,N--Dimethylpseudomerucathine Starting from L -Alanine Starting form L -alanine, N-methylmerucathine (= (3R,4S)-4-(methylamino)1-phenyl-1-penten-3-ol; (3R,4S,)- 6 ), N,N-dimethylmerucathine (= (3R,4S)-4-(dimethylamino)-1-phenyl-1-penten-3-ol; (3R,4S)- 9 ), N-methylpseudomerucathine (= (3S,4S)-4-(methylamino)-1-phenyl-1-penten-3-01; (3S,4S)-6), and N,N-dimethylpseudomerucathine (= (3S,4S)-4-(dimethylamino)-1-phenyl-1-penten-3-ol; (3S,4S)- 9 ) were synthesized. The four compounds were analyzed by HPLC and compared with a natural khat extract.     

Conformationally Biased Mimics of Mannopyranosylamines: Inhibitors of β‐Mannosidases?

The enol ether 7 was prepared by cleavage of the N−O bond of the known isoxazolidine 3 , followed by N‐alkylation to 4 , silylation and oxidation to the N‐oxide 6 , and Cope elimination. Cu‐Catalysed cyclopropanation of 7 led to the diastereoisomeric cyclopropanes 8 and 9 , which were subjected to a Curtius degradation. The resulting carbamates 12 and 16 were deprotected to the ammonium salts 14 and 18 , respectively. Both salts adopt a B_1,4 conformation, similarly as the ester 8 , while the isomeric ester 9 exists in a ca. 6 : 4 equilibrium of the ⁴C₁ and B_1,4 conformers. The β‐mannoside mimic 14 does not inhibit snail β‐mannosidase at 10 mM , but the α‐mannoside mimic 18 inhibits Jack bean α‐mannosidase (IC₅₀=80 μM ). These results are in keeping with the postulate that glycoside cleavage of β‐D ‐glycopyranosides requires a conformational change in agreement with the principle of stereoelectronic control.     

Cycloaddition Reaction of 1,4‐Dihydronaphthalene 1,4‐Epoxide with Cyclooctatetraene: Cope Rearrangement in an Adduct

The reaction of 1,4‐dihydro‐1,4‐epoxynaphthalene with cyclooctatetraene at 130±5° for 14 days gave the four products 2a,3,3a,4,9,9a,10,10a‐octahydro‐4,9‐epoxy‐3,10‐ethenocyclobuta[b]anthracene ( 13 ), 25‐oxanonacyclo[10.10.2.2^5,9.1^14,21.0^2,11.0^3,10.0^4,6.0^13,22.0^15,20]heptacosa‐7,15,17,19,23,26‐hexaene ( 14 ), 5,5a,6,6a,6b,6c,12a,12b,12c,13,13a,14‐dodecahydro‐5,14‐epoxy‐6,13‐ethenocycloocta[3′,4′]cyclobuta[1′,2′:3,4]cyclobuta[1,2‐b]anthracene ( 15 ) and bis‐adduct 16 . The structures of the products were determined by spectroscopic methods. It was observed that adduct 14 undergoes a Cope rearrangement. The Cope rearrangement of this adduct was investigated in the temperature range of ?85° to 100° by NMR spectroscopy.     

Umlagerung von Vinyl-Cyclopropan-Carbaminalen

Rearrangement of Vinyl-Cyclopropane-Carbaminals Both (c-2, t-3-diphenyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 4 ) and its (t-2, t-3)-isomer 10 underwent a thermal rearrangement to (E)-N-2-benzylidene-1-indanyl-pyrrolidine ( 5 ). Under the conditions of the rearrangement, 5 was partially converted into 2-benzyl-1-indanone ( 6 ) in a base catalysed reaction. The structures of 5 and 6 were derived from spectroscopic data and from degradation reactions.- N,N′-(t-2-Vinyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 11 ) rearranged thermally to N-(2-methylidene-3-cyclopenten-1-yl)pyrrolidine ( 12 ), the structure of which was established from spectroscopic evidence and from a hydrogenation to N-(2-methylcyclopentyl)pyrrolidine ( 13 , cis/trans mixture 3:2). The aminal 4 was reduced with formic acid to give N-(c-2, t-3-diphenyl-r-1-cyclopropyl)methyl-pyrrolidine ( 14 ). If perdeuterio formic acid was used, the mixture product 14-d/14-d ₂ was obtained which contained exactly one deuterium atom in its methylene group and about half a deuterium atom on C(1). This labeling pattern is mechanistically explained with the existence of a fast equilibrium between the iminium ion 19 and the enamine 18 , so that 18 and 19 are considered to be plausible reactive intermediates in the above mentioned thermal rearrangement. - Based on this, several mechanisms for the rearrangements 4 → 5, 10 → 5 and 11 → 12 were considered: A Pictet-Spengler- or Mannich-type reaction, which starts from the iminium ion 23 and is followed by a cyclopropylmethyl-homoallylic rearrangement and by deprotonation (path a, Scheme 5), was judged to be improbable because the postulated intermediates could lead more easily to other stable products than the observed ones. If the reaction is formulated as a [3,3]-sigmatropic shift occurring on exclusively the (E)-isomer 5 suggests a concerted process whose steric course is predominantly controlled by strain factors. Alternatively, the reaction could be formulated via a dipolar ( 27 ) or a diradical ( 26 ) species derived from the enamine 22 (paths c and d, Scheme 5); attempts to trap such species by a number of agents were unsuccessful. - The previously unknown aminals 10 and 11 were synthesized by standard methods.     

Regioselektive Metallierung von Aromaten,II. Zweitmetallierung von 1-Lithionaphthalin und 9-Lithioanthracen

Regioselective Metallation of Aromatic Compounds, II. Second Metallation of 1-Lithionaphthalene and 9-Lithioanthracene Both 1-lithionaphthalene ( 2 ) and 9-lithioanthracene ( 12 ) undergo specific metallations whereby a second lithium is introduced at the adjacent peri-positions ( 5, 18 ) (in the presence of n-butyllithium/N,N,N′,N′-tetramethylethylenediamine (TMEDA)). Explanations for such directed second metallations, for which other examples are known, are provided by MNDO calculations. Not only are the dilithiated products stabilized by symmetrically double bridging (implying a thermodynamic driving force) but also the activated hydrogens in the monolithio precursors are indicated clearly. The LUMO-coefficients on these hydrogens are largest and the C H bond lengths longest. Dimers, more realistic models for the solution species, show these characteristics as well.     

Über Pterinchemie. 58. Mitteilung [1]. Sterische Eigenschaften von acylierten 5,6,7,8-Tetrahydropterinen. Rotameren von 5-Trifluoracetyl-tetrahydropterin-Derivaten

Sterochemical Properties of the Acylated 5,6,7,8-Tetrahydropterines. Rotameres of the 5-Trifluoroacetyl-tetrahydropterine Derivatives 6-Methyl- and 6,7-dimethyl-5,6,7,8-tetrahydropterine are acylated with the anhydrides of acetic acid and trifluoroacetic acid. It is shown that the reactivity of the nitrogen otoms increases in the following order: N(3), N(8), N(2′) and N(5). Two rotameres are present in the ¹H-NMR. spectra of the N(5)-trifluoroacetates, but not in those of the N(5)-acetates.     

Konstitution von Palustridin

Palustridine (I, C₁₈H₃₁N₃O₃), which co-occurs with palustrine in Equisetum palustre L., has been shown to be N_b-formyl-palustrine. Hydrolysis with dilute mineral acid yields palustrine, and formylation of the latter gives palustridine. The mass spectral fragmentation pattern differs from that of palustrine, and is very similar to that of N_b-acetylpalustrine. The earlier proposed skeleton of palustrine is independently confirmed.     

Trennung von spaltprodukten durch Extraktionschromatographie

The separation of fission products which form anionic species in mineral acids and of uranium and neptunium from samples of neutron-irradiated uranium is described. The method used is extraction chromatography with tri-n-butylphosphate (TBP) and di-(2-ethylhexyl)-orthophosphoric acid (HDEHP) as extractants and polytrifluoromonochloroethylene powder as the solid support. In the first column Zr, U and Np are extracted with TBP from 8N HNO₃/NaClO₃. In the second column, HDEHP is applied as extractant and 9N HCl/NaClO₃ as the mobile phase for the isolation of Nb, Sb, and I, and in the third column (HDEHP), the rare earths and Mo are extracted from 0.1N HCl. Finally with the fourth column (TBP), Te and Tc are isolated from 6N HCl. These four groups of elements are further separated by elution from the columns. From the final effluent containing Ru, Rh, Cs, Sr, and Ba, Ru is distilled from HClO₄, and Rh is precipitated with NH₄OH. The determination of chemical yields with X-ray fluorescence techniques is described for Zr, Mo, Te, Cs, Ce and U.

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Aus einer Dissertation, Mainz 1967.