Reversal of Enantioselectivity in the Conjugate Addition Reaction of Cyclic Enones with the CuOTf/Azolium Catalytic System

Satoshi Sakaguchi,Chihiro Takeda,Satoki Shimizu,Yuki Nakano

doi:10.3390/molecules26113404

Satoshi Sakaguchi, Chihiro Takeda + Show 2 more

Open Access

https://doi.org/10.3390/molecules26113404

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Journal: Molecules	Publication Date: Jun 4, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: Kansai University

Abstract

Hydroxyamide-functionalized azolium salt (NHC•HI 4) was evaluated for dual enantioselective control in a Cu-catalyzed asymmetric conjugate addition (ACA) reaction. This investigation was based on our previously reported ACA reaction catalyzed using CuOTf combined with NHC•AgI complex 1. It was revealed that the stereocontrol of the catalytic ACA reaction depended on the order of the addition of the substrates. Additionally, the chiral NHC ligand precursors, substrates, the relationship between the catalyst ee (eecat) and product ee (eepro), and halogen counter anion were completely evaluated. These results suggested that the catalytic performance of the CuOTf/4 system was comparable with that of the CuOTf/1 system. Furthermore, to gain knowledge of the Cu species generated using CuOTf and NHC ligand precursor, the reaction of CuOTf with 1 was investigated. Although obtaining the corresponding NHC•CuX species failed, the corresponding NHC•AuCl complex 11 could be synthesized by allowing 1 to react with AuCl•SMe2.

Highlights

The asymmetric conjugate addition (ACA) reaction is a powerful synthetic tool for the stereoselective formation of carbon–carbon bonds [1–4]
We showed that the hydroxyamide-functionalized NHCAgI (NHC = N-heterocyclic carbene) complex 1b, derived from leucine, was a versatile chiral ligand precursor for dual enantioselective control in the CuOTf-catalyzed ACA reaction of a cyclic enone with Et2Zn [15,16]
The CuOTf/10b/NaBr (4/5/5 mol%) system was effective (Entry 4). These results might suggest that the success of the ACA reaction by Method B requires a Cu/azolium/halide catalytic ratio of 1/1/2

Summary

Introduction

The asymmetric conjugate addition (ACA) reaction is a powerful synthetic tool for the stereoselective formation of carbon–carbon bonds [1–4]. When 2 was added as the last component to the mixture of CuOTf (4 mol%), 4b (10 mol%), and Et2Zn in THF (Method B), the conjugate adduct ((S)-3) with the opposite configuration was obtained in 91% yield with 80% ee (Entry 2). These results in the ACA reactions with the CuOTf/4 system were comparable with those obtained in the reactions with the CuOTf/1 system. As expected, when Et2Zn was added to a THF solution of CuOTf, ent-4b, and 2 (Method A), the corresponding 1,4-adduct, (S)-3, was preferentially obtained in 79% yield with 69% ee (Entry 2). The ACA reaction of 2-cyclohepten-1-one with Me2Zn by Method B afforded (S)-3-methylcycloheptanone ((S)-9) in 90% yield and with 93% ee (Entry 6)

Influence of Counter Anion on Azolium Salt

● Method A

● Method B

General Procedures

General Procedure for Method A

General Procedure for Method B

Findings

Conclusions