Formation of Quaternary Stereogenic Centers by NHC–Cu‐Catalyzed Asymmetric Conjugate Addition Reactions with Grignard Reagents on Polyconjugated Cyclic Enones

Abstract

The copper-catalyzed conjugate addition of various Grignard reagents to polyconjugated enones (dienone and enynone derivatives) is reported. The catalyst system, composed of copper triflate and an NHC ligand, led to the unusual selective formation of the 1,4-addition products. This reaction allows for the creation of all-carbon chiral quaternary centers with enantiomeric excesses up to 99%. The remaining unsaturation on the 1,4 adducts give access to valuable synthetic transformations.

Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: a Powerful Synthetic Platform

“…Furthermore,aniterative process was also disclosed leading to highly desirable 1,3-desoxypropionate skeletons (up to 94 % d.e. ).Inthe last two decades,t ransition-metal-catalyzed enantioselective conjugate additions (ECA) of organometallic reagents to electron-deficient unsaturated systems have emerged as av ersatile and efficient methodology for the asymmetric formation of C À Cbonds.[1] Among the myriad of transition metals studied, tremendous attention has been given to copper catalysis,which resulted in significant breakthroughs, [2] such as perfect regiocontrol in 1,6-or 1,4-addition with extended Michael acceptors [3] as well as the subsequent sequential 1,6/1,4 processes.[4] These recent achievements with alarge variety of Michael acceptors and organometallic reagents allowed for the efficient preparation of numerous valuable enantioenriched building blocks [1] with remarkable applications in total synthesis.[5] Nevertheless,t he enantioselective transfer of amethyl group to form all-carbon methylsubstituted chiral scaffolds,w hich are present in numerous natural products, [5] remains achallenge. [6] On the other hand, the electron-withdrawing group (EWG) of Michael acceptors has to be considered not only as aplatform for postfunctionalization but should also be compatible with the methylated organometallic reagents and allow its enantioselective addition.…”

Effect of Multinuclear Copper/Aluminum Complexes in Highly Asymmetric Conjugate Addition of Trimethylaluminum to Acyclic Enones

“…[1] Although there have been various reports on the asymmetric conjugate addition of organometallic reagents to cyclic enones for the creation of an all-carbon substituted chiral quaternary stereogenic center, [2] the use of acyclic enones still presents a formidable challenge. [1] Although there have been various reports on the asymmetric conjugate addition of organometallic reagents to cyclic enones for the creation of an all-carbon substituted chiral quaternary stereogenic center, [2] the use of acyclic enones still presents a formidable challenge.…”

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Over the past few decades, the asymmetric conjugate addition of organometallic reagents to activated olefins has become one of the most powerful approaches to chiral molecules, especially for installation of a small alkyl group on a chiral carbon atom. [1] Although there have been various reports on the asymmetric conjugate addition of organometallic reagents to cyclic enones for the creation of an all-carbon substituted chiral quaternary stereogenic center, [2] the use of acyclic enones still presents a formidable challenge. The steric congestion around a b,b-disubstituted olefin prevents 1,4addition, but favors 1,2-addition, and the chiral catalyst hardly recognizes the enantioface because of the similarity of substituents on an olefinic carbon atom ( Figure 1).

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Catalytically Active Species in Copper/DiPPAM‐Catalyzed 1,6‐Asymmetric Conjugate Addition of Dialkylzinc to Dienones: A Computational Overview

“…However, 1,6-ACA has been described with a range of electrophiles, nucleophiles, metal-based catalysts, and chiral ligands families. [3][4][5][6][7][8][9] Mauduit et al have developed an efficient chiral tridentate P,N,O ligand, named diphenylphosphinoazomethinylate salt (DiPPAM, L), [10] which has proved its efficiency for copper-catalyzed 1,6-ACA of dialkylzinc reagents to cyclic [5,7] and more recently to acyclic [11][12][13] dienones (Scheme 1). While good to excellent regioselectivity and enantioselectivity could be achieved with this catalytic system, attempts to characterize intermediates were unsuccessful and the active catalytic species has remained unidentified.…”