Restricted Conformation of a Hydrogen Bond Mediated Catalyst Enables the Highly Efficient Enantioselective Construction of an All-Carbon Quaternary Stereocenter

Abstract

All reactions were carried out under an atmosphere of argon with magnetic stirring. Solvents were distilled under argon from calcium hydride (CH3CN and CH2Cl2) or sodium/benzophenone (Et2O, THF and toluene). Iridium catalyst Λ-Ir1, 1 pyridylpyrazole L1, 1 bispyrazole L2 2 and the β,β-disubstituted nitroalkene substrates 1,3,4 were prepared according to published procedures. All other reagents were purchased from commercial suppliers (TCI, Aldrich, Alfa and J&K) and used without further purification. Column chromatography was performed with silica gel from Huanghai Chemical Reagent (300-400 mesh). 1 H and 13 C NMR spectra were recorded on a Bruker AM ( 400MHz or 500 MHz) spectrometer at ambient temperature. NMR standards were used as follows: ( 1 H NMR) CDCl3 = 7.26 ppm, CD2Cl2 = 5.32 ppm; ( 13 C NMR) CDCl3 = 77.0 ppm, CD2Cl2 = 53.8 ppm.IR spectra were recorded on a Nicolet Avatar 330 FT-IR spectrophotometer. Chiral HPLC chromatograms were obtained from an Agilent 1260 Series HPLC system. CD spectra were recorded on a JASCO J-810 CD spectropolarimeter (600-200 nm, 1 nm band width, 50 nm/min scanning speed, accumulation of 3 scans). High-resolution mass spectra were recorded on a Bruker En Apex Ultra 7.0T FT-MS instrument using ESI technique. Enantiomeric excess (ee) values of the products were determined by HPLC on chiral phase. S3 Preparation of the Iridium Catalysts Synthesis of the Cyclometalating Ligands L3 and (R)-L4Scheme S1. Synthetic route to the cyclometalating ligand L3.A suspension of 9H-carbazole (7.26 g, 60.0 mmol) and K2CO3 (41.46 g, 300.0 mmol) in DMSO (150 mL) was stirred at room temperature for 1 h. 2-Fluorobenzonitrile (10.03 g, 60.0 mmol) was added and stirred at 150 °C overnight. After cooled to room temperature, the reaction mixture was poured into ice water (300 mL). Then the reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 200 mL) and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed by the mixture of n-hexane and ethyl acetate (v/v = 20/1, 3 x 50 mL) to afford the compound S1 as a white solid (14.71 g, 54.9 mmol, 91% yield).

Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate

“… 58 In 2016, the same authors reexamined the asymmetric 1,4-addition of indoles to β,β-disubstituted nitroalkenes and increased the efficiency of the catalyst by cyclizing the pendant carboxamide groups into lactams. 59 The resulting reduction in conformational freedom reduced the entropic penalty of hydrogen bonding, and further optimization replaced the pyridylpyrazole ligand with a bispyrazole, rendering the catalyst C 2 -symmetric, with two catalytic sites per iridium complex. Using these optimized ligands, 1,4-additions could be catalyzed with catalyst loadings as low as 0.05 mol % while maintaining high enantioselectivity.…”

Exploiting Octahedral Stereocenters: From Enzyme Inhibition to Asymmetric Photoredox Catalysis

“…We recently reported that the related catalyst L-Ir2 is highly effective in the addition of indoles to a-substituted-b-nitroacrylates at catalyst loadings down to 0.05 mol %, which is remarkable for the challenging construction of an all-carbon quaternary stereocenter (Figure 3 c). [23] Although these asymmetric transfer hydrogenation and asymmetric Friedel-Crafts reactions are not new, to the best of our knowledge, the developed metal-templated catalysts outperform all reported organocatalysts and transition-metal catalysts with respect to the combination of turnover number (catalyst loading) and enantioselectivity. However, it is also important to note that one pays a price for these exceptional catalytic properties, namely that the increased structural complexity of the designed catalysts requires tedious multistep syntheses.…”

“…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 …”

A copper-templated, bifunctional organocatalyst: a strongly cooperative dynamic system for the aldol reaction

“…Chiral ligands but also chirality at metal exclusively have been exploited to achieve highly stereoselective reactions. [5][6] Nevertheless several exciting examples that make use of octahedral geometries are known in the literature: cobalt [7][8][9][10][11][12] and iridium [13][14][15][16][17][18] have been successfully used to generate octahedral complexes able to perform asymmetric organocatalytic reactions through their coordination sphere. Remarkable examples include those of Gong, Meggers and coworkers, who have disclosed a series of iridium-templated catalysts with exclusive chirality at the metal center that were able to carry out Michael additions and conjugate reductions, aza-Henry reactions, α-amination and Friedel-Craft alkylations in high yields and stereoselectivities.…”

“…Remarkable examples include those of Gong, Meggers and coworkers, who have disclosed a series of iridium-templated catalysts with exclusive chirality at the metal center that were able to carry out Michael additions and conjugate reductions, aza-Henry reactions, α-amination and Friedel-Craft alkylations in high yields and stereoselectivities. [13][14][15][16][17][18] Catalysis took place through hydrogen bonding interactions from the ligands without any participation of the metal center. In turn, previous work by Belokon and co-workers had made use of Co(III) complexes comprising both chirality at metal and chiral hemisalen ligands to achieve high ee's in the alkylation of enolates under phase transfer conditions or the epoxidation of enones.…”