Departament of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneve 4, Switzerland, Department of Organic Chemistry, Stockholm University, Arrhenius Laboratoriet, 106 91 Stockholm, Sweden, Organic Chemistry II, Dormund University of Technology, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany, and Departament de Quimica Fisica i Inorganica, Universitat Rovira i Virgili, C/ Marcel · li Domingo s/n, 43007 Tarragona, Spain

Enantioselective Copper-Catalyzed Conjugate Addition and Allylic Substitution Reactions

Enantioselective Conjugate Additions

Arylated products are found in various fields of chemistry and represent essential entities for many applications. Therefore, the formation of this structural feature represents a central issue of contemporary organic synthesis. By the action of electricity the necessity of leaving groups, metal catalysts, stoichiometric oxidizers, or reducing agents can be omitted in part or even completely. The replacement of conventional reagents by sustainable electricity not only will be environmentally benign but also allows significant short cuts in electrochemical synthesis. In addition, this methodology can be considered as inherently safe. The current survey is organized in cathodic and anodic conversions as well as by the number of leaving groups being involved. In some electroconversions the reagents used are regenerated at the electrode, whereas in other electrotransformations free radical sequences are exploited to afford a highly sustainable process. The electrochemical formation of the aryl–substrate bond ...

Electrochemical Arylation Reaction.

The development of efficient methods to access complex molecules with multistereogenic centers has been a substantial challenge in both academic research and industrial applications. One approach to this challenge is catalytic asymmetric tandem transformations, which allow a rapid increase in molecular complexity from readily available starting materials to produce enantiopure compounds. In recent years, considerable efforts have been directed towards the development of asymmetric tandem transformations. This Minireview highlights recent developments and the applications of metal-catalyzed and organocatalytic asymmetric tandem transformations triggered by conjugate additions.

Catalytic asymmetric tandem transformations triggered by conjugate additions.

Asymmetric catalysis with transition-metal complexes is the basis for a vast array of stereoselective transformations and has changed the face of modern synthetic chemistry. Key to this success has been the design of chiral ligands to control the regio-, diastereo-, and enantioselectivity. Phosphoramidites have emerged as a highly versatile and readily accessible class of chiral ligands. Their modular structure enables the formation of ligand libraries and easy fine-tuning for a specific catalytic reaction. Phosphoramidites frequently show exceptional levels of stereocontrol, and their monodentate nature is essential in combinatorial catalysis, where a ligand-mixture approach is used. In this Review, recent developments in asymmetric catalysis with phosphoramidites used as ligands are discussed, with a focus on the formation of carbon-carbon and carbon-heteroatom bonds.

Phosphoramidites: Privileged Ligands in Asymmetric Catalysis

Phosphoramidite ligands, based on a chiral amine and atropoisomerically flexible biphenols, induce high enantioselectivities (ee's up to 98%) in the copper-catalyzed conjugate addition of dialkyl zinc reagents to a variety of Michael acceptors.

Novel Biphenol Phosphoramidite Ligands for the Enantioselective Copper-Catalyzed Conjugate Addition of Dialkyl zincs

Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins.

Biphenol-based phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of diethylzinc.

The copper-catalyzed asymmetric conjugate addition of dialkyl zinc leads to homochiral zinc enolates. These intermediates were trapped in situ with activated allylic electrophiles, without the need of additional palladium catalysis. High trans selectivity (85/15 to 100/0) and excellent enantioselectivities (up to 99%) could be attained. The functionalized nature of the electrophiles makes the new synthons potential candidates for further elaboration.

One-pot asymmetric conjugate addition-trapping of zinc enolates by activated electrophiles.

The asymmetric conjugate addition of diethyl zinc to acyclic enones is described. With 1% Cu(OTf)2 and 2% of a chiral phosphite ligand, the catalyst allowed ee's up to 92'% to be obtained. The addition of dimethyl zinc to a macrocyclic 15-membered ring enone lead to optically active R-(-)-muscone, in 53% yield and 79% enantiomeric excess.

Catalytic Asymmetric Conjugate Addition on Macrocyclic and Acyclic Enones. Synthesis of R-(-)-Muscone

A tandem asymmetric conjugate addition-cyclopropanation was developed, in which a cyclic or linear enone was converted to a TMS-protected 3-substituted-cyclopropanol in an efficient one-pot reaction. These compounds were then selectively cleaved to yield alpha-methyl-beta-alkyl ketones, alpha-methylene-enones, or chain extended gamma-alkyl-enones. This methodology was applied to the formal total synthesis of (-)-(S,S)-clavukerin A and (+)-(R,S)-isoclavukerin.

Sebastien March

Papers

Novel Biphenol Phosphoramidite Ligands for the Enantioselective Copper-Catalyzed Conjugate Addition of Dialkyl zincs

Biphenol-based phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of diethylzinc.

One-pot asymmetric conjugate addition-trapping of zinc enolates by activated electrophiles.

Catalytic Asymmetric Conjugate Addition on Macrocyclic and Acyclic Enones. Synthesis of R-(-)-Muscone

Tandem Enantioselective Conjugate Addition−Cyclopropanation. Application to Natural Products Synthesis