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

Abstract

Asymmetric catalysts, whether metal complexes with chiral ligands, chiral organometallics, or chiral organic compounds (organocatalysts), achieve asymmetric induction by transferring chiral information from the catalyst to the substrate(s). [1] The source of the catalysts chirality therefore plays a crucial role for its mode of action, and is typically derived from one or more tetrahedral stereogenic centers (mostly carbon atoms, but also heteroatoms, such as sulfur or phosphorus), axial chirality, planar chirality, or a combination thereof (Scheme 1). In contrast, only few reports exist of asymmetric catalysts that derive their chirality exclusively from an octahedral stereocenter. [2][3][4] This seems surprising, considering the prevalence of the octahedral coordination geometry in chemistry and its ability to support the generation of structures with high complexity and, as a result of ligand crowding and chelate effects, often low conformational flexibility. [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. [6] However, excellent metal-, bio-, and organo-catalysts already exist for this transformation, [7] and we were therefore wondering whether an octahedral chiral-at-metal catalyst could be developed for a more challenging asymmetric conversion. 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 t...

Metal-templated chiral Brønsted base organocatalysis

“…When applied to the sulfaMichael addition 46-53 , we were pleased to find that the reaction of N-pyrazolylcrotonate (1a) with p-methylbenzenethiol (2a) provided after 12 h at À 78°C the addition product (R)-3a in 96% yield and 97% ee just using 0.05 mol% L-IrBB1 (Table 1, entry 1), whereas, as expected, the previously designed H-bonding iridium catalysts 36,37 did not catalyse this reaction (Supplementary Table 1). Even with a catalyst loading of merely 0.02 mol% L-IrBB1, (R)-3a was obtained in unchanged high yield (96%) and with high enantioselectivity (96%) (entry 2), reflecting a turnover number of 4,800.…”

“…Recently, we reported iridiumcoordinated pyrazole complexes as asymmetric H-bonding catalysts 36,37 . We hypothesized that the corresponding deprotonated pyrazolato complexes might serve as chiral Brønsted bases with an amino group in the 3-position of the coordinated pyrazolato ligand [42][43][44] (A in Fig.…”

“…We decided to next investigate the asymmetric formation of a C-C bond and selected the azaHenry (nitro-Mannich) reaction 54 . Encouragingly, the reaction between (nitromethyl)benzene (4a) and N-Boc-Schiff base 5a (refs 55-57), a reaction that cannot be catalysed by our previously developed H-bonding iridium complexes (Supplementary Table 2) 36,37 , afforded in the presence of L-IrBB1 the C-C bond formation product (1R,2S)-6a under the implementation of two stereocenters with 92% ee and 122:1 dr, albeit requiring a high catalyst loading of 10 mol% (Table 2, entry 1). Reducing the catalyst loading to 1 mol% diminished the enantiomeric excess to just 71% (entry 2).…”

“…We recently introduced octahedral chiral-at-metal [22][23][24][25][26][27][28][29][30][31][32][33][34][35] iridium(III) complexes as inert templates for the design of lowloading asymmetric hydrogen bonding catalysts 36,37 . Octahedral stereocenter [38][39][40] permit the straightforward generation of compounds with high shape and stereochemical complexity and should therefore be highly suitable as structural templates for multifunctional catalysts.…”

Exploiting Octahedral Stereocenters: From Enzyme Inhibition to Asymmetric Photoredox Catalysis

“…We developed chiral catalysts for transfer hydrogenations, Friedel-Crafts reactions, sulfa-Michael additions, azaHenry reactions, and the a-amination of aldehydes. [19][20][21][22][23] All of these catalysts are based on bis-cyclometalated iridium(III) (Figure 3 b). [22] In this design, the nitroalkene substrate is activated through the formation of two hydrogen bonds to a coordinated amidopyrazole moiety while the Hantzsch ester [24] is activated towards hydride transfer and placed in a suitable position through the formation of a hydrogen bond …”