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

Yuuki Iwai,Shun Kamihigashi,Satoshi Sakaguchi,Azusa Ishibashi

doi:10.3390/catal9090780

Abstract

Bis(NHC) ligand precursors, L1, based on trans-1,2-diaminocyclohexane were designed and synthesized. To introduce chirality at the hydroxyamide side arm on the NHC of L1, a chiral β-amino alcohol, such as enantiopure leucinol, was used. Cu-catalyzed asymmetric conjugate addition reactions of cyclic and acyclic enones with Et2Zn were selected to evaluate the performance of L1 as a chiral ligand. For the reaction of cyclic enone, a combination of [bis(trimethylsilyl)acetylene]-(hexafluoroacetylacetonato)copper(I) (Cu(hfacac)(btmsa)) with a (±)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (rac; S,S)-L1, which was prepared from (S)-leucinol, was the most effective. Thus, treating 2-cyclohexen-1-one (3) with Et2Zn in the presence of catalytic amounts of Cu(hfacac)(btmsa) and (rac; S,S)-L1 afforded (R)-3-ethylcyclohexanone ((R)-4) with 97% ee. Similarly, use of (rac; R,R)-L1, which was prepared from (R)-leucinol, produced (S)-4 with 97% ee. Conversely, for the asymmetric 1,4-addition reaction of the acyclic enone, optically pure (−)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (R,R; S,S)-L1, worked efficiently. For example, 3-nonen-2-one (5) was reacted with Et2Zn using the CuOAc/(R,R; S,S)-L1 catalytic system to afford (R)-4-ethylnonan-2-one ((R)-6) with 90% ee. Furthermore, initially changing the counterion of the Cu precatalyst between an OAc and a ClO4 ligand on the metal reversed the facial selectivity of the approach of the substrates. Thus, the conjugate addition reaction of 5 with Et2Zn using the Cu(ClO4)2/(R,R; S,S)-L1 catalytic system, afforded (S)-6 with 75% ee.

Highlights

Synthesizing efficient chiral ligands for asymmetric catalysis is currently a major challenge in synthetic organic chemistry [1,2,3,4]
In the Cu-catalyzed conjugate addition reaction of acyclic enone using the bis(NHC) ligand, we described successful enantioselectivity reversal by changing of the counter anion of the
We previously reported successful enantioselectivity reversal of the Cu-catalyzed 1,4-addition reaction of 3 with Et2 Zn using the mono-N-heterocyclic carbenes (NHCs) azolium ligand, L4 (Figure 6), by changing the Cu precatalyst from Cu(OTf)2 to Cu(acac)2 [76]

Summary

Introduction

Synthesizing efficient chiral ligands for asymmetric catalysis is currently a major challenge in synthetic organic chemistry [1,2,3,4]. There have been several recent reports on chiral bis(NHC). They succeeded in creating a large variety of asymmetric transformations by using this versatile chiral ligand [34,35,36,37,38,39,40,41,42,43,44,45,46,47]. Iglesias and Sánchez et al reported the asymmetric hydrogenation of alkenes with bis(NHC) derived from tartaric acid [50,51]

Methods

Discussion

Conclusion