Catalytic Asymmetric Synthesis of Mixed 3,3′‐Bisindoles and Their Evaluation as Wnt Signaling Inhibitors

Abstract

Indol an Indol: Die erste effiziente katalytische asymmetrische Kupplung von Indolen mit Isatin‐Nitroalkenen gelang durch Einsatz eines Komplexes aus dem chiralen Imidazolin‐Aminophenol‐Ligand 1 (siehe Schema) und Cu(OTf)2. Die biologische Aktivität der so erhaltenen chiralen 3,3′‐Bisindole wurde in einem Inhibitionsassay des Wnt‐Signalwegs bestätigt.

Chiral‐at‐Metal Octahedral Iridium Catalyst for the Asymmetric Construction of an All‐Carbon Quaternary Stereocenter

“…Only a handful of studies are available dealing with this particular reaction, thereby presumably reflecting the involved challenge of overcoming a significant steric repulsion between the incoming carbon nucleophile and the carbon substituents of the nitroalkene electrophile. Nevertheless, Hoveyda and co‐workers introduced a Cu‐catalyzed dialkylzinc conjugate addition,9 Arai and co‐workers reported a Cu‐catalyzed addition of indoles to isatin‐derived nitroalkenes,10 Jia and co‐workers disclosed a Ni‐catalyzed addition of indoles to β‐CF 3 ‐β‐disubstituted nitroalkenes,11 Ricci and co‐workers reported a phase‐transfer asymmetric organocatalytic conjugate addition of cyanide to β,β‐disubstituted nitroalkenes, albeit with only modest enantioselectivities,12 Melchiorre and co‐workers introduced the asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes catalyzed by natural cinchona alkaloids, including one reaction using a β,β‐disubstituted nitroalkene,13 and finally Kastl and Wennemers introduced a proline‐peptide‐catalyzed asymmetric addition of aldehydes to β,β‐disubstituted nitroalkenes under formation of γ‐nitroaldehydes 14. The restricted scope of dialkylzinc reagents and the high catalyst loadings of 10 mol % or more required for the remaining methods confirm the significant difficulty of this conversion.…”

Chiral‐at‐Metal Octahedral Iridium Catalyst for the Asymmetric Construction of an All‐Carbon Quaternary Stereocenter

“…[5] We recently demonstrated the use of chiral-atmetal octahedral complexes for the tailored design of a highly efficient asymmetric noncovalent catalyst that requires low catalyst loading by reporting an inert iridium(III)-based catalyst for the conjugate asymmetric transfer hydrogenation of b,b-disubstituted nitroalkenes. Nevertheless, Hoveyda and co-workers introduced a Cu-catalyzed dialkylzinc conjugate addition, [9] Arai and co-workers reported a Cu-catalyzed addition of indoles to isatin-derived nitroalkenes, [10] Jia and co-workers disclosed a Ni-catalyzed addition of indoles to b-CF 3 -b-disubstituted nitroalkenes, [11] Ricci and co-workers reported a phase-transfer asymmetric organocatalytic conjugate addition of cyanide to b,b-disubstituted nitroalkenes, albeit with only modest enantioselectivities, [12] Melchiorre and co-workers introduced the asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes catalyzed by natural cinchona alkaloids, including one reaction using a b,b-disubstituted nitroalkene, [13] and finally Kastl and Wennemers introduced a proline-peptide-catalyzed asymmetric addition of aldehydes to b,b-disubstituted nitroalkenes under formation of g-nitroaldehydes. In this respect, the asymmetric conjugate addition of carbon nucleophiles to b,b-disubstituted nitroalkenes constitutes a highly attractive reaction as it permits the construction of a stereogenic carbon atom bound to four other carbon substituents (all-carbon quaternary stereocenter).…”

“…[8] Only a handful of studies are available dealing with this particular reaction, thereby presumably reflecting the involved challenge of overcoming a significant steric repulsion between the incoming carbon nucleophile and the carbon substituents of the nitroalkene electrophile. Nevertheless, Hoveyda and co-workers introduced a Cu-catalyzed dialkylzinc conjugate addition, [9] Arai and co-workers reported a Cu-catalyzed addition of indoles to isatin-derived nitroalkenes, [10] Jia and co-workers disclosed a Ni-catalyzed addition of indoles to b-CF 3 -b-disubstituted nitroalkenes, [11] Ricci and co-workers reported a phase-transfer asymmetric organocatalytic conjugate addition of cyanide to b,b-disubstituted nitroalkenes, albeit with only modest enantioselectivities, [12] Melchiorre and co-workers introduced the asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes catalyzed by natural cinchona alkaloids, including one reaction using a b,b-disubstituted nitroalkene, [13] and finally Kastl and Wennemers introduced a proline-peptide-catalyzed asymmetric addition of aldehydes to b,b-disubstituted nitroalkenes under formation of g-nitroaldehydes. [14] The restricted scope of dialkylzinc reagents and the high catalyst loadings of 10 mol % or more required for the remaining methods confirm the significant difficulty of this conversion.…”

Enantioselective synthesis of mixed 3,3′-bisindoles via a phosphine-catalyzed umpolung γ-addition of 3′-indolyl-3-oxindoles to allenoates

“…From a synthetic viewpoint, preparation of optically enriched mixed 3,3 0 -bisindole structures is a long-standing and challenging task, especially in view of the presence of an all-carbon quaternary stereogenic center at the indole C 3 -position [15][16][17][18][19][20]. In recent years, various synthetic strategies have been developed for their asymmetric synthesis, including: 1,4-conjugate additions or epoxide-opening via Friedel-Crafts reactions of indoles [21][22][23][24], Rh-or Ru-mediated multicomponent tandem reactions [25][26][27], as well as nucleophilic substitutions of various 3-indolylmethanols and their structural analogues [28][29][30][31][32][33][34][35][36]. Undoubtedly, given the extreme synthetic value of the mixed 3,3 0 -bisindole motifs, there still exists an urgent need to devise efficient approaches for their enantioselective synthesis, especially those methods amenable for the preparation of a broad spectrum of natural products.…”