Functionalized N‐Heterocyclic Carbene Ligands for Dual Enantioselective Control in the Cu‐Catalyzed Conjugate Addition of Dialkylzinc Compounds to Acyclic Enones

Abstract

A series of highly tunable, functionalized azolium compounds have been synthesized from chiral α‐amino acid derivatives such as β‐amino alcohols or α‐amino esters. The combination of a Cu salt and a chiral azolium efficiently facilitated the asymmetric conjugate addition (ACA) reactions of acyclic enones with dialkylzinc under ambient conditions without temperature control. Of the (hydroxy amide)‐functionalized azolium ligand precursors, which were derived from β‐amino alcohols, an azolium salt containing a tert‐butyl group as the stereodirecting group was found to be the best choice of ligand. Ligand screening revealed that the use of an azolium salt containing a sterically bulky alkyl substituent such as N‐CHRR′ on the azolium ring led to a marked increase in the enantioselectivity of the ACA reaction. Thus, a new efficient (hydroxy amide)‐functionalized azolium ligand precursor such as 26, which was prepared from 1‐(diphenylmethyl)benzimidazole and (S)‐tert‐leucinol, has been developed. The treatment of benzalacetone (30) with Et2Zn in the presence of catalytic amounts of [Cu(OTf)]2(C6H6) and 26 at room temperature gave the corresponding 1,4‐adduct 31 with excellent enantioselectivity (92 % ee). On the other hand, the enantioselectivity of the ACA reactions of acyclic enones with dialkylzinc was successfully reversed by the use of (ester amide)‐functionalized azolium salts, which were obtained from α‐amino esters. Several functionalized azolium ligand precursors from readily available serine esters have been designed and synthesized. Finally, it was found that 30 could react with Et2Zn under the influence of a bis(hexafluoroacetylacetonato)copper(II) salt and C2‐symmetric azolium salt 36 to afford ent‐31 in almost quantitative yield with 89 % ee. A plausible reaction mechanism for the switching of the stereoselectivity in the ACA reaction by these two functionalized azolium compounds is described.

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

“…Sakaguchi and co-workers [ 65 ] further extended this work and synthesized a series of highly tunable functionalized NHC-precursor azolium salts. The efficacy of the combination of these salts with Cu salts as catalyst was investigated for the asymmetric conjugate addition (ACA) of dialkylzinc to acyclic enones and it was found that the use of an azolium salt with a sterically bulky alkyl substituent such as N -CHRR (e.g., NCHPh 2 in 123 ) on the azolium ring results in a marked increase in the enantioselectivity of the ACA reaction.…”

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

“…In contrast to the conjugate addition reactions of organometallic compounds with cyclic enones, few highly enantioselective reactions of acyclic enones have been reported [71,[82][83][84][85][86][87][88][89][90][91][92][93]. We then focused on studying the Cu-catalyzed asymmetric 1,4-addition reaction of acyclic enone with Et 2 Zn using this promising class of bis(NHC) chiral ligand L1.…”

“…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]. Therefore, to the best of our knowledge, this is the first example of switchable enantioselectivity in a catalytic conjugate addition reaction of acyclic enone, with the same chiral ligand.…”

“…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].…”

Dealing at Arm's Length: Catalysis with N‐Heterocyclic Carbene Ligands Bearing Anionic Tethers

“…of 98.5:1.5. Alternatively, benzimidazolium‐based ligands such as 36 and 37 can assist conjugate additions to linear enones, albeit with slightly lower enantioselectivity . Owing to the fact that the benzimidazole backbone bears two alkyl substituents on the nitrogen atoms, these ligands can be prepared from amino acids in three steps.…”