16 research outputs found
Eisen-katalysierte Kreuzkupplungen und Synthese biologisch aktiver Naturstoffe
No full textNaturstoffe spielen in der menschlichen Gesellschaft seit Jahrtausenden eine wichtige Rolle. Neben der Verwendung natürlicher Gifte oder Halluzinogene ist der Einsatz pflanzlicher Extrakte in der traditionellen Medizin zu nennen.[1] Während man früher auf die Isolierung dieser Substanzen aus den natürlichen Quellen angewiesen war, ist man heute Dank der modernen Chemie dazu in der Lage, viele Substanzen auch synthetisch herstellen zu können.[2] Hierdurch werden die natürlichen Ressourcen geschont und ein Zugang zu den im Organismus oft nur in geringen Mengen vorhandenen Sekundärmetaboliten geschaffen. Aufgrund der Komplexität vieler Naturstoffe ist man bestrebt neben den bereits verfügbaren Synthesemethoden neue und effizientere zur Darstellung polyfunktioneller Strukturen zu entwickeln. Besonders ökonomisch ist es dabei, die einzelnen Transformationen katalytisch durchzuführen. Ein wichtiger Meilenstein der modernen Chemie war die Entwicklung Übergangsmetall-katalysierter Kreuzkupplungen zur C-C- und C-Heteroatom-Bindungsbildung. Die Grundlagen dazu wurden in den 1970er und 1980er Jahren gelegt.[3] Obwohl die meisten Katalysatorsysteme eine hohe Effizienz bei milden Reaktionsbedingungen aufweisen, wird dieser Vorteil durch die Verwendung teurer oder toxischer Metallkatalysatoren teilweise kompensiert.In der vorliegenden Arbeit stand daher sowohl die Entwicklung und Verwendung umweltfreundlicher Katalysatorsysteme im Mittelpunkt als auch die Anwendung neuartiger Synthesemethoden in der Naturstoffchemie. Im ersten Teil der Dissertation wird eine neue, Eisen-katalysierte Kreuzkupplung zwischen Enoltriflaten sowie Enolphosphaten und Grignardreagenzien vorgestellt.[4] Der zweite Teil befasst sich mit der ersten asymmetrischen Totalsynthese des Alkaloids (–)-Isooncinotin.[5] In dieser Synthese sind alle Schlüsselschritte katalytischer Natur. Im dritten Teil wird eine Route für die erste Totalsynthese der Dictyodendrine vorgestellt. Dabei wurde vor allem auf moderne Synthesemethoden zum Aufbau des heterozyklischen Gerüstes zurückgegriffen. Weiterhin wurden verschiedene Derivate der Dictyodendrine hergestellt, welche eine Ermittlung des Pharmakophors und eine Optimierung der biologischen Eigenschaften ermöglichen sollen
Total synthesis of dictyodendrin B
No full textA concise total synthesis of dictyodendrin B (1) is reported, a scarce marine alkaloid endowed with promising telomerase inhibitory activity. Key steps of the chosen route are a reductive cyclization of ketoamide 11 to indole 12 mediated by low-valent titanium (from TiCl3 and KC8) followed by a photochemical 6π-electrocyclization, which was performed in the presence of Pd/C and nitrobenzene to effect concomitant dehydrogenation/aromatization of the product initially formed. Regioselective bromination of the resulting pyrrolocarbazole 13 followed by lithium/bromine exchange and quenching of the resulting organolithium species with p-methoxybenzaldehyde installed the side chain at C2. Oxidation of the benzylic alcohol 15 thus obtained to ketone 17 was best achieved with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) in dilute CH2Cl2 solution to avoid the formation of undue amounts of the unsymmetrical dimer 16. Ketone 17 was elaborated into the natural product by selective cleavage of the isopropyl ether with BCl3, introduction of the sulfate moiety with the aid of trichloroethyl chlorosulfuric acid ester, deprotection of all lateral methyl ether groups, and final reductive cleavage of the trichloroethyl ester moiety. The spectroscopic data of synthetic dictyodendrin B thus formed matched those of an authentic sample in all regards. Moreover, it was shown that global deprotection of the peripheral −OH groups in pyrrolo[2,3-c]carbazole 13 is accompanied by spontaneous air-oxidation to form the quinone core of dictyodendrin C
Total Synthesis of Dictyodendrin B
No full textA concise total synthesis of dictyodendrin B (1) is reported, a scarce marine alkaloid endowed with promising telomerase inhibitory activity. Key steps of the chosen route are a reductive cyclization of ketoamide 11 to indole 12 mediated by low-valent titanium (from TiCl3 and KC8) followed by a photochemical 6π-electrocyclization, which was performed in the presence of Pd/C and nitrobenzene to effect concomitant dehydrogenation/aromatization of the product initially formed. Regioselective bromination of the resulting pyrrolocarbazole 13 followed by lithium/bromine exchange and quenching of the resulting organolithium species with p-methoxybenzaldehyde installed the side chain at C2. Oxidation of the benzylic alcohol 15 thus obtained to ketone 17 was best achieved with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) in dilute CH2Cl2 solution to avoid the formation of undue amounts of the unsymmetrical dimer 16. Ketone 17 was elaborated into the natural product by selective cleavage of the isopropyl ether with BCl3, introduction of the sulfate moiety with the aid of trichloroethyl chlorosulfuric acid ester, deprotection of all lateral methyl ether groups, and final reductive cleavage of the trichloroethyl ester moiety. The spectroscopic data of synthetic dictyodendrin B thus formed matched those of an authentic sample in all regards. Moreover, it was shown that global deprotection of the peripheral −OH groups in pyrrolo[2,3-c]carbazole 13 is accompanied by spontaneous air-oxidation to form the quinone core of dictyodendrin C
Total Syntheses of the Telomerase Inhibitors Dictyodendrin B, C, and E
No full textConcise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2),
C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the
common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC
cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction
to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem
to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations
of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone
core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the
first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination
of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal−halogen exchange or
cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very
labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction
followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be
achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride
and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or
-stannanes met with failure
Selective Iron‐Catalyzed Cross‐Coupling Reactions of Grignard Reagents with Enol Triflates, Acid Chlorides, and Dichloroarenes.
No full textTotal Syntheses of the Telomerase Inhibitors Dictyodendrin B, C, and E
No full textConcise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2),
C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the
common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC
cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction
to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem
to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations
of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone
core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the
first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination
of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal−halogen exchange or
cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very
labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction
followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be
achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride
and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or
-stannanes met with failure
Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors
No full textChemInform Abstract: Discovery and Optimization of a New Class of Potent and Non-Chiral Indole-3-carboxamide-Based Renin Inhibitors.
No full textDiscovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors
No full textSelective Iron-Catalyzed Cross-Coupling Reactions of Grignard Reagents with Enol Triflates, Acid Chlorides, and Dichloroarenes
No full textCheap, readily available, air stable, nontoxic, and environmentally benign iron salts such as
Fe(acac)3 are excellent precatalysts for the cross-coupling of Grignard reagents with alkenyl triflates
and acid chlorides. Moreover, it is shown that dichloroarene and -heteroarene derivatives as the
substrates can be selectively monoalkylated by this method. All cross-coupling reactions proceed
very rapidly under notably mild conditions and turned out to be compatible with a variety of
functional groups in both reaction partners. A detailed analysis of the preparative results suggests
that iron-catalyzed C−C bond formations can occur via different pathways. Thus, it is likely that
reactions of methylmagnesium halides involve iron−ate complexes as the active components,
whereas reactions of Grignard reagents with two or more carbon atoms are effected by highly
reduced iron-clusters of the formal composition [Fe(MgX)2]n generated in situ. Control experiments
using the ate-complex [Me4Fe]Li2 corroborate this interpretation
