Alexandre Alexakis

Enantioselective copper-catalyzed conjugate addition and allylic substitution reactions

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-Catalysed Conjugate Addition

The review covers the efforts made over the last decade towards designing efficient copper-catalysed systems for the asymmetric conjugate addition reaction.

Metal-catalyzed asymmetric conjugate addition reaction: formation of quaternary stereocenters

All-carbon quaternary stereocenters are ubiquitous motifs in biological products and pharmaceutical agents. However, due to sterical reasons, these centers are not always easily accessible. The metal-catalyzed conjugate addition reaction to trisubstituted conjugated substrates presents a viable methodology to create quaternary centers. In this article, different ways of activating the conjugate system towards nucleophilic addition will be described. An overview will be given on the different types of quaternary centers that are accessible through the conjugate addition reaction.

Organocopper conjugate addition reaction in the presence of trimethylchlorosilane

Abstract In the presence of TMSCl, the conjugate addition of organocuprates to various α, β-unsaturated esters, amides, ketones and nitriles is greatly improved. The reaction is faster, the yields are very high and the reaction is very clean.

Enantioselective Organocatalytic Conjugate Addition of Aldehydes to Vinyl Sulfones and Vinyl Phosphonates as Challenging Michael Acceptors

Chiral framework: Chiral amines with pyrrolidine frameworks catalyze the enantioselective conjugate addition of a wide range of aldehydes to various vinyl sulfones and vinyl phosphonates in high yields and with enantioselectivities up to >99 % ee (see scheme). The high versatility of the Michael adducts is exemplified by various functionalizations with conservation of the optical purity.Chiral amines with a pyrrolidine framework catalyze the enantioselective conjugate addition of a broad range of aldehydes to various vinyl sulfones and vinyl phosphonates in high yields and with enantioselectivities up to >99 % ee. This novel process provides synthetically useful chiral gamma-gem-sulfonyl or phosphonyl aldehydes which can be widely functionalized with retention of the enantiomeric excess. Mechanistic insights including DFT calculations are explored in detail.

Chiral phosphorus ligands for the asymmetric conjugate addition of organocopper reagents

The asymmetric conjugate addition of medium order alkyl cuprate reagents. R5Cu3Li2, to 2-cyclohexen-1-one. 2-cyclopenten-1-one and 2-cyctohepten-1-one, with the help of phosphorus ligand B*, is described. 3-Alkyl substituted cyclohexanones are obtained in essentially optically pure form. The same chiral ligand, associated with CuI, in catalylic amount (10%), allows the asymmetric conjugate addition of Et2Zn to 2-cyclohexen-1-one.

Enantioselective One‐Pot Organocatalytic Michael Addition/Gold‐Catalyzed Tandem Acetalization/Cyclization

A one-pot process consisting of a Michael addition to a nitroenyne and a subsequent acetalization/cyclization is reported (see scheme; TMS=trimethylsilyl), which results in the formation of nitro-substituted tetrahydrofuranyl ethers with high diastereo- and enantioselectivities. Organocatalysis and gold catalysis are compatible and complementary in a one-pot process.

Enantioselective copper-catalyzed conjugate addition using chiral diaminocarbene ligands

Chiral diaminocarbene ligands, generated by in-situ deprotonation of the corresponding chiral imidazolinium salts, are shown to be efficient ligands in the asymmetric copper-catalyzed 1,4-conjugate addition of diethylzinc to enones, allowing enantiomeric excesses of up to 51% to be achieved.

Enantioselective Organocatalytic Fluorination-Induced Wagner–Meerwein Rearrangement†

Cracked under strain: Strained allylic cyclobutanols and cyclopropanols readily undergo a ring expansion described by the title rearrangement. This reaction is promoted by catalytic amounts of 1 and displays high tolerance with respect to the substrate scope. The corresponding β-fluoro spiroketone products are isolated in high yields and with excellent stereoselectivities. EDG=electron-donating group, EWG=electron-withdrawing group.

Chiral amines as organocatalysts for asymmetric conjugate addition to nitroolefins and vinyl sulfones via enamine activation.

Over the last decade the potential of organocatalysis has successfully been demonstrated. In particular, chiral amines such as pyrrolidine analogues have emerged as a broadly applicable class of organocatalyst for asymmetric conjugate addition via enamine activation. This Feature Article documents the development of these catalysts, emphasizing the design and mechanistic features that supply high selectivity in asymmetric Michael reactions.