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

• Main Authors: Azusa Ishibashi, Shun Kamihigashi, Yuuki Iwai, Satoshi Sakaguchi
• Format: Article
• Language: English
• Published: MDPI AG 2019-09-01
• Series: Catalysts
• Subjects: asymmetric catalysis; conjugate addition; reversal of enantioselectivity; <i>N</i>-heterocyclic carbene; ligand design
• Online Access: https://www.mdpi.com/2073-4344/9/9/780

Bis(NHC) ligand precursors, <b>L1</b>, based on <i>trans</i>-1,2-diaminocyclohexane were designed and synthesized. To introduce chirality at the hydroxyamide side arm on the NHC of <b>L1</b>, a chiral <i>&#946;</i>-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 <b>L1</b> as a chiral ligand. For the reaction of cyclic enone, a combination of [bis(trimethylsilyl)acetylene]-(hexafluoroacetylacetonato)copper(I) (Cu(hfacac)(btmsa)) with a (&#177;)-<i>trans</i>-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (<i>rac</i>; <i>S</i>,<i>S</i>)-<b>L1</b>, which was prepared from (<i>S</i>)-leucinol, was the most effective. Thus, treating 2-cyclohexen-1-one (<b>3</b>) with Et₂Zn in the presence of catalytic amounts of Cu(hfacac)(btmsa) and (<i>rac</i>; <i>S</i>,<i>S</i>)-<b>L1</b> afforded (<i>R</i>)-3-ethylcyclohexanone ((<i>R</i>)-<b>4</b>) with 97% <i>ee</i>. Similarly, use of (<i>rac</i>; <i>R</i>,<i>R</i>)-<b>L1</b>, which was prepared from (<i>R</i>)-leucinol, produced (<i>S</i>)-<b>4</b> with 97% <i>ee</i>. Conversely, for the asymmetric 1,4-addition reaction of the acyclic enone, optically pure (&#8722;)-<i>trans</i>-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (<i>R</i>,<i>R</i>; <i>S</i>,<i>S</i>)-<b>L1</b>, worked efficiently. For example, 3-nonen-2-one (<b>5</b>) was reacted with Et₂Zn using the CuOAc/(<i>R</i>,<i>R</i>; <i>S</i>,<i>S</i>)-<b>L1</b> catalytic system to afford (<i>R</i>)-4-ethylnonan-2-one ((<i>R</i>)-<b>6</b>) with 90% <i>ee</i>. 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 <b>5</b> with Et₂Zn using the Cu(ClO₄)₂/(<i>R</i>,<i>R</i>; <i>S</i>,<i>S</i>)-<b>L1</b> catalytic system, afforded (<i>S</i>)-<b>6</b> with 75% <i>ee</i>.