Enantioselective Copper-Catalyzed Conjugate Addition Research Articles

Direct Catalytic Enantioselective Conjugate Addition of α-Substituted Benzyl Nitriles to Alkyl Acrylates.

The first enantioselective copper-catalyzed conjugate addition of α-substituted benzyl nitriles to alkyl acrylates is described. This protocol allows the direct and 100% atom-economic generation of a nitrile-containing quaternary stereogenic center in a highly enantioselective manner. The practical application of our methodology was demonstrated through the concise formal synthesis of (-)-aphanorphine.

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors.

The copper-catalyzed enantioselective conjugate addition (ECA) of organometallic nucleophiles to electron-deficient alkenes (Michael acceptors) represents an efficient and attractive methodology for providing a wide range of relevant chiral molecules. In order to increase the attractiveness of this useful catalytic transformation, some Michael acceptors bearing challenging electron-deficient functions (i.e., aldehydes, thioesters, acylimidazoles, N-acyloxazolidinones, N-acylpyrrolidinones, amides, N-acylpyrroles) were recently investigated. Remarkably, only a few chiral copper-based catalytic systems have successfully achieved the conjugate addition of different organometallic reagents to these challenging Michael acceptors, with excellent regio- and enantioselectivity. Furthermore, thanks to their easy derivatization, the resulting chiral conjugated products could be converted into various natural products. The aim of this tutorial review is to summarize recent advances accomplished in this stimulating field.

Enantioselective synthesis of 3-amino-hydrobenzofuran-2,5-dionesviaCu(i)-catalyzed intramolecular conjugate addition of imino esters

The copper-catalyzed enantioselective intramolecular conjugate addition of imino esters for desymmetrization of cyclohexadienones was described, providing access to enantioenriched 3-amino-hydrobenzofuran-2,5-diones.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: Scope, Limitations and Iterative Reactions.

AbstractThe copper catalyzed enantioselective addition of dimethylzinc to α,β‐unsaturated ketones having a heterocyclic moiety on the other side is investigated in the presence of a chiral bidentate hydroxyalkyl‐NHC ligand.

Copper-Catalyzed Enantioselective Conjugate Addition to α,β-Unsaturated Aldehydes with Various Organometallic Reagents

β-Substituted aldehydes constitute a very important class of compounds found in nature. Synthesis of this motif can be envisioned by C–C bond formation on enals. For this purpose, we report herein the development of enantioselective copper-catalyzed conjugate addition of various organometallic reagents to α,β-unsaturated aldehydes with (R)-H8BINAP, (R)-TolBINAP, and (R)-SEGPHOS as chiral ligands. Three sets of conditions were successfully developed and several enals were used. Reactivity and regio- and enantioselectivities were strongly dependent on reaction conditions and substrates. Good to excellent regio- and enantioselectivities were obtained with zinc reagents R2Zn and aluminum reagents R3Al. However, the asymmetric conjugate addition of Grignard reagents afforded only moderate to good regio- and enantioselectivities.

Copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones with chiral sulfoxide–phosphine ligands

The copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones was achieved with chiral sulfoxide–phosphine (SOP) ligands. This process showed good functional group tolerance and gave the 1, 4-adducts with excellent enantioselectivities (up to 96% ee).

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

An efficient copper-catalyzed enantioselective conjugate addition of dimethylzinc to α,β- and α,β,γ,δ-unsaturated 2-acyl-N-methylimidazoles has been achieved using a chiral bidentate hydroxyalkyl-NHC ligand. The reactions proceeded with both excellent regio- and enantioselectivity (14 examples, 87-95 % ee) to afford the desired 1,4-adducts, which were easily transformed to the corresponding aldehydes, esters, and ketones. Subsequently, this powerful methodology was therefore successfully applied in the synthesis of natural products. Furthermore, an iterative process was also disclosed leading to highly desirable 1,3-desoxypropionate skeletons (up to 94 % d.e.).

Stereoselective Synthesis of Densely Functionalized Pyrrolidin-2-ones by a Conjugate Addition/Nitro-Mannich/Lactamization Reaction

Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones (5). The versatility of the reaction is shown for a wide range of N-p-(methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield). An enantioselective copper-catalyzed conjugate addition of diethylzinc led to highly crystalline products that could be recrystallized to enantiopurity in high yield. A range of successful chemoselective transformations were investigated, which widens the applicability of the pyrrolidn-2-ones as stereochemically pure building blocks for further organic synthesis.

ChemInform Abstract: Enantioselective Copper‐Catalyzed Conjugate Addition of Trimethylaluminum to β,γ‐Unsaturated α‐Ketoesters.

ChemInformVolume 43, Issue 23 Preparative Organic Chemistry ChemInform Abstract: Enantioselective Copper-Catalyzed Conjugate Addition of Trimethylaluminum to β,γ-Unsaturated α-Ketoesters. Ludovic Gremaud, Ludovic Gremaud Dep. Org. Chem., Univ. Geneva, CH-1211 Geneva 4, Switz.Search for more papers by this authorAlexandre Alexakis, Alexandre Alexakis Dep. Org. Chem., Univ. Geneva, CH-1211 Geneva 4, Switz.Search for more papers by this author Ludovic Gremaud, Ludovic Gremaud Dep. Org. Chem., Univ. Geneva, CH-1211 Geneva 4, Switz.Search for more papers by this authorAlexandre Alexakis, Alexandre Alexakis Dep. Org. Chem., Univ. Geneva, CH-1211 Geneva 4, Switz.Search for more papers by this author First published: 10 May 2012 https://doi.org/10.1002/chin.201223055Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume43, Issue23June 5, 2012 RelatedInformation

The effects of solvent on switchable stereoselectivity: copper-catalyzed asymmetric conjugate additions using D2-symmetric biphenyl phosphoramidite ligands

A highly enantioselective copper-catalyzed conjugate addition of diethylzinc to acyclic aromatic enones was developed with phosphoramidite ligands bearing a D(2)-symmetric biphenyl backbone. This type of reaction demonstrated that toluene and THF solvents can completely reverse the absolute configuration of the products, thus simplifying the process of accessing either enantiomer (S: 92% ee, 94% yield; R: 99% ee, 96% yield).

ChemInform Abstract: Copper‐Catalyzed Enantioselective Conjugate Addition

AbstractReview: 87 refs.

NHC Copper Catalyzed Enantioselective Conjugate Addition

The direct boronate conjugate addition to unsaturated carboxylic esters, ketones, and thioesters is realized by a NHC copper(I) complex, derived from an easily prepared C 1-symmetric imidazolinium salt, to prepare β-boryl carbonyl type products in excellent yields and enantio­selectivities.

ChemInform Abstract: Chiral Boronate Derivatives via Catalytic Enantioselective Conjugate Addition of Grignard Reagents on 3‐Boronyl Unsaturated Esters and Thioesters.

There is a growing interest in the development of new methods to prepare chiral organoboronate derivatives in optically pure form. An efficient copper-catalyzed enantioselective conjugate addition methodology using Grignard reagents and 3-boronyl acrylate derivatives was optimized for the preparation of chiral alkylboronate products in high yields and up to 98% ee. The resulting 1,8-diaminonaphthalene adducts can be transformed into the corresponding boronic acid, pinacol boronate, and trifluoroborate salt. This method extends the realm of chemical reactions compatible with useful boron-containing substrates.

Chiral Boronate Derivatives via Catalytic Enantioselective Conjugate Addition of Grignard Reagents on 3-Boronyl Unsaturated Esters and Thioesters

There is a growing interest in the development of new methods to prepare chiral organoboronate derivatives in optically pure form. An efficient copper-catalyzed enantioselective conjugate addition methodology using Grignard reagents and 3-boronyl acrylate derivatives was optimized for the preparation of chiral alkylboronate products in high yields and up to 98% ee. The resulting 1,8-diaminonaphthalene adducts can be transformed into the corresponding boronic acid, pinacol boronate, and trifluoroborate salt. This method extends the realm of chemical reactions compatible with useful boron-containing substrates.

Catalytic asymmetric conjugate addition of dialkylzinc reagents to α,β-unsaturated sulfones

An efficient method is reported for the highly enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to alpha,beta-unsaturated sulfones using a monodentate phosphoramidite ligand.

Design and synthesis of new chiral pyridine–phosphite ligands for the copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones

A series of new chiral pyridine–phosphite ligands have been prepared from ( R)-pyridyl alcohols and BINOL-derived chlorophosphite, and successfully employed in the copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones. Using the simple and inexpensive CuBr 2 as a precursor, the enantioselective additions to various substituted acyclic enones afforded products in high yields and good enantioselectivities (up to 92% ee).

Enantioselective Copper-Catalyzed Conjugate Addition of Dimethylzinc to 5-(1-Arylalkylidene) Meldrum’s Acids

The asymmetric formation of all-carbon quaternary benzylic stereocenters containing a methyl substituent was realized by the enantioselective copper-catalyzed 1,4-addition of dimethylzinc to alkylidene Meldrum’s acids in the presence of a chiral phosphoramidite. Copper source and ligand optimization studies are presented, as well as the scope and limitations of dimethylzinc addition to various alkylidene Meldrum’s acids. Good to excellent yields and enantioselectivities were obtained.

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

Asymmetric conjugate additions of dialkylzinc reagents to enones promoted by new purely atropisomeric phosphoramidite ligands

Enantiopure 1,1’-binaphthylazepine was employed in the preparation of two new phosphoramidites by reaction of the corresponding dichlorophosphoramidite with (R)- or (S)BINOL. In such compounds the chirality of both diol and amine moieties is only due to atropisomerism. Their catalytic efficiency was tested in the enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to acyclic, cyclic and macrocyclic α,β-unsaturated ketones. Interestingly, the diastereoisomeric ligands provided the same enantioselectivity in the addition to chalcone, but worked differently with cyclic and macrocyclic enones. The best result, as far as enantiomeric excess is concerned, was observed in the conjugate addition of Me2Zn to 2-cyclopentadecenone, affording the valuable fragrance (-) muscone in 84%ee.

Synthesis of Amidoalkyl Imidazol-2-ylidene Ligands and Their Application to Enantioselective Copper-Catalysed Conjugate Addition

A small library of precursors to chiral amidoalkyl imidazol-2-ylidene ligand was synthesised via a two-step procedure starting from commercially available amino alcohols. Preliminary screening of these bidentate ligands for the enantioselective copper-catalysed conjugate addition of diethyl zinc to cyclohexenone revealed some moderate ee values. Related chiral iminoalkyl imidazole-2-ylidene ligands demonstrated much poorer enantioselectivity. The results indicate that chelation involving a covalent copper-nitrogen bond gives better selectivity than that arising from a dative copper-nitrogen co-ordination.