Copper-Catalyzed Asymmetric Conjugate Addition of Grignard Reagents to Trisubstituted Enones. Construction of All-Carbon Quaternary Chiral Centers

Abstract

The copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted cyclic enones affords enantioenriched all-carbon quaternary centers with up to 96% ee. The chiral ligand is a diaminocarbene, directly generated in situ. The combination of Grignard reagent and diaminocarbene is unprecedented in conjugate addition, and the additon of the phenyl group, on such enones, cannot be done by other conjugate addition methods.

Design of Chiral Hydroxyalkyl‐ and Hydroxyarylazolinium Salts as New Chelating Diaminocarbene Ligand Precursors Devoted to Asymmetric Copper‐Catalyzed Conjugate Addition

“…1 H (400 MHz), 13 C (100 MHz), 31 P (162 MHz) and 19 F (376.5 MHz) NMR spectra were recorded on a Bruker ARX400 spectrometer with complete proton decoupling for nuclei other www.eurjic.orgthan 1 H. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl 3 , 1 H: δ = 7.27 ppm, 13 C: δ = 77.0 ppm and (CD 3 ) 2 CO: 1 H: δ = 2.05 ppm, 13 C: δ = 205.1 ppm). Data are reported as follows: chemical shift (δ in ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, sept = septuplet, m = multiplet), coupling constants [Hz], integration and attribution.…”

“…[12] Whereas the Arnold's imidazolium salt 3 gives a moderate selectivity in the copper-catalyzed conjugate ad-dition of diethylzinc to 2-cyclohexenone (51 %ee), our hydroxyalkyl salt 4, containing the stereogenic centre in the α-position, afforded higher selectivities (89 % ee). Moreover, 4 is extremely suitable for the formation of all-chiral quaternary centres using Grignard reagents toward various 3-substituted-2-cyclohexenones (up to 96 % ee) [13] or 3-allyl-substituted 2-cyclohexenones where a remarkable regiodivergent addition (1,4 vs. 1,6) occurred (up to 98 % ee). [14] To improve the potential of this promising class of chelating NHCs, we have kept on making efforts to improve the scaffold's design, and we have attempted to compare two different types of NHC precursors: on one hand, the imidazolinium salts 5 and 8 exhibit a stereogenic centre within the N-heterocycle, and on the other hand, the azolium salts 6-7 and 9 bear a stereogenic centre within the chelating side chain (Figure 2).…”

Enantioselective Cu‐Catalyzed 1,4‐Addition of Grignard Reagents to Cyclohexenone Using Taddol‐Derived Phosphine–Phosphite Ligands and 2‐Methyl‐THF as a Solvent

“…[15] In conclusion, we have identified phosphine-phosphite ligands of type 7 as a novel (second) class of chiral P,P ligands suitable for the Cu-catalyzed asymmetric 1,4-addition of Grignard reagents to cyclohexenone. [16,17] These readily accessible ligands proved to be compatible with an unsurpassed range of Grignard reagents, and owing to their modular nature it should be possible to achieve further (individual) ligand tuning for specific reaction systems. [9b, 10] Furthermore, we came across a very interesting solvent effect with (racemic) 2-methyl-THF, which has only recently been recognized as an environmentally benign solvent because of its low water miscibility and its origin from renewable resources.…”

New C2-symmetric six-membered carbene ligands for asymmetric diethylzinc addition of arylaldehydes

“…Almost at the same time, another type of hydroxy-bearing NHC salt 2 derived from (L)-valine was prepared by Mauduit's group and this compound showed high efficiency in chiral molecular recognition. 20 Furthermore, the same group designed and synthesized a series of new bidentate NHC precursors 3 based on commercial available amino alcohols, [21][22][23] which were successfully applied in Cu II -catalyzed asymmetric addition of diethylzinc to cyclohexanone, as well as asymmetric allylic substitution of allyl phosphates with Grignard reagents. Moreover, the same ligand 3 was proved to be an excellent ligand in multicomponent catalytic enantioselective transformations.…”