Reversal of Stereoselectivity in the Cu-Catalyzed Conjugate Addition Reaction of Dialkylzinc to Cyclic Enone in the Presence of a Chiral Azolium Compound

Abstract

Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-one (30) with Et(2)Zn catalyzed by Cu(OTf)(2) in the presence of an azolium salt derived from a chiral beta-amino alcohol gave (S)-3-ethylcyclohexanone (31) in good enantioselectivity. Among a series of chiral azolium compounds examined, the benzimidazolium salt (10) having both a tert-butyl group at the stereogenic center and a benzyl substituent at the azolium ring was found to be the best choice of ligand in the Cu(OTf)(2)-catalyzed reaction. Good enantioselectivity was observed when the reaction was conducted by employing a benzimidazolium derivative rather than an imidazolium derivative. The influence of the substituent at the azolium ring on the stereoselectivity of the reaction was also examined. In addition, from the results of the reaction catalyzed by Cu(OTf)(2) combined with an azolium compound derived from (S)-leucine methyl ester, it was found that the hydroxy side chain in the chiral ligand is probably crucial for the enantiocontrol of the conjugate addition reaction. On the other hand, it was discovered from a screening test of copper species that the reversal of enantioselectivity was realized by allowing 30 to react with Et(2)Zn in the presence of Cu(acac)(2) combined with the same ligand precursor to afford (R)-31 as a major product. The influence of the stereodirecting group at the chiral ligand on the stereoselectivity in the Cu(acac)(2)-catalyzed reaction differed completely from that observed in the Cu(OTf)(2)-catalyzed reaction. Reaction with a cyclic enone consisting of a seven-membered ring such as 2-cyclohepten-1-one (40) resulted in increasing the enantioselectivity of the reaction. Thus, treatment of 40 with Et(2)Zn catalyzed by Cu(OTf)(2) combined with a benzimidazolium salt produced the corresponding (S)-conjugate adduct in a 92:8 enantiomer ratio (er), while the Cu(acac)(2)-catalyzed reaction with the same ligand afforded (R)-product in a 9:91 er.

(±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction

“…Previously, we showed that the reversal of enantioselectivity was achieved in the Cu-catalyzed conjugate addition reaction of cyclic enone using a mono-NHC azolium ligand L4 with a chiral hydroxyamide side-arm ( Figure 6) [76]. For example, 3 was reacted with Et 2 Zn catalyzed by Cu(OTf) 2 /L4 to afford (S)-4, whereas (R)-4 was obtained in the same reaction with the Cu(acac) 2 /L4 catalytic system [74]. However, no reversal of enantioselectivity was observed in the Cu-catalyzed 1,4-addition reaction of acyclic enone when changing the Cu precatalyst in the presence of L4 [71].…”

“…Introducing an appropriate hemilabile chiral donor group at the NHC side arm provides a chelating NHC-based ligand [60][61][62][63][64][65][66][67]. As part of our research program on developing chiral NHC ligand precursors, we have reported a Cu-catalyzed enantioselective conjugate addition reaction of enone with Et 2 Zn, using a chiral hydroxyamide-functionalized azolium ligand precursor [68][69][70][71][72][73][74][75][76]. Much attention has been given to the 1,4-addition reaction [77][78][79][80].…”

Novel chiral thiazoline‐containing N―O ligands in the asymmetric addition of diethylzinc to aldehydes: substituent effect on the enantioselectivity

“…[11][12][13][14][15][16][17] Among various chiral ligands, the chiral b-amino alcohols have been widely developed as a typical class of catalysts. [18][19][20][21][22] It was found that b-amino tertiary alcohol ligands possessed high catalytic activity to obtain high enantiomeric excess (ee) values in the asymmetric addition of diethylzinc to aldehydes. However, under the same condition, chiral primary alcohols always resulted in corresponding products with lower ee values.…”

“…Among various chiral ligands, the chiral β‐amino alcohols have been widely developed as a typical class of catalysts . It was found that β‐amino tertiary alcohol ligands possessed high catalytic activity to obtain high enantiomeric excess (ee) values in the asymmetric addition of diethylzinc to aldehydes.…”

Synthesis of Novel Imidazolium and Benzimidazolium Salts from Halomethyl Derivatives of 4-Pyrones

“…Imidazolium and benzimidazolium salts are an important class of quaternary ammonium compounds (QACs) which have extensively achieved considerable attention in different chemical, biochemical and industrial areas [1][2][3][4][5][6][7]. Deprotonation of N,N -disubstituted derivatives of these salts, generates N-heterocyclic carbenes (NHCs) species.…”