Cu-catalyzed Conjugate Addition Research Articles

Enantioselective copper-catalyzed conjugate additions of in situ generated organozirconium reagents to N-heterocyclic Michael acceptors

Stereoselective conjugate additions of organometallic reagents provide access to many useful chiral compounds. In this work, we have studied the enantioselective Cu-catalyzed conjugate addition of organozirconium reagents, which were generated in situ by hydrozirconation of alkenes. We show that N-heterocyclic Michael acceptors, represented by unsaturated lactams and 2,3-dihydropyridin-4(1H)-ones can be useful substrates for Cu-catalyzed conjugate additions of organozirconium reagents. Phosphorus ligands screening identified Feringa's phosphoramidite as the most active and enantioselective ligand for this transformation, which afforded corresponding conjugate addition products with an enantiomeric purity of up to 92:8 e.r. The absolute configuration of one of the conjugate addition products was established by comparison of DFT calculated and experimental electronic CD spectra. The study also showed that mildly reactive organozirconium reagents combined with relatively unreactive Michael acceptors afford typically conjugate addition products in medium yields. DFT calculations of LUMO maps also supported non-reactivity of heterocyclic Michael acceptors. LUMO maps showed decreasing electrophilicity at the β-carbon due to donor substituents present near unsaturated carbonyl scaffold.

The Cu-catalyzed asymmetric conjugate addition with chiral diphosphite ligands derived from D-(-)-tartaric acid

ABSTRACTA series of diphosphite ligands, which were derived from D-(-)-tartaric acid, have been synthesized and successfully applied in the Cu-catalyzed asymmetric conjugate addition of organozincs to enones. There was a synergic effect between the stereogenic centers of the D-(-)-tartaric acid skeleton and the axially H8-binaphthyl moieties of ligand 2c. And ligand 2c shows a comparative catalytic performance to ligand 1-N-benzylpyrrolidine-3,4-bis[(S)-1,1′-H8-binaphthyl-2,2′-diyl]phosphite-L-tartaric acid1d derived from L-(+)-tartaric acid. Therefore, for cyclic enones, both enantiomers of the addition products can be obtained in high enantioselectivity (ees up to 96%) by simply selecting ligands 1d or 2c derived from D-(-)-tartaric acid or L-(+)-tartaric acid. Moreover, the sense of enantiodiscrimination of the products was mainly determined by the configuration of the binaphthyl phosphite moieties.

ChemInform Abstract: Copper‐Catalyzed Aza‐Michael Addition of Aromatic Amines or Aromatic Aza‐Heterocycles to α,β‐Unsaturated Olefins.

AbstractThe reactions are carried out in the presence of a Cu complex, formed from CuCl/KOtBu and a specified ligand.

ChemInform Abstract: Chiral Phosphine‐Phosphoramidite Ligands in Asymmetric Catalysis

AbstractReview: 53 refs.

Copper-Catalyzed Aza-Michael Addition of Aromatic Amines or Aromatic Aza-Heterocycles to α,β-Unsaturated Olefins.

A highly efficient and mild Cu-catalyzed conjugate addition reaction of aromatic amines and aromatic aza-heterocycles to α,β-unsaturated olefins is described. The transformation is promoted by 3-7 mol % of a Cu complex generated in situ from a mixture of inexpensive CuCl, a readily available phosphine or imidazolium salt, and KOt-Bu at ambient temperature. A wide range of β-amino sulfone, β-amino nitrile, and β-amino carbonyl compounds is efficiently and selectively synthesized in high yields (62-99%).

Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones

Abstract A series of novel chiral diphosphite ligands have been synthesized from (1 R ,2 R )- trans -1,2-cyclohexanediol, (1 S ,2 S )- trans -1,2-cyclohexanediol, racemic trans -1,2-cyclohexanediol and chlorophosphoric acid diary ester, and were successfully employed in the Cu-catalyzed asymmetric 1,4-conjugate addition of diethylzinc to cyclohexenone with up to 99% ee . It was found that ligand 1,2-bis[( R )-1,1′-binaphthyl-2,2′-diyl]phosphitecyclohexanediol 6a derived from racemic diol skeleton can show similar catalytic performance compared with ligand (1 R ,2 R )-bis[( R )-1,1′-binaphthyl-2,2′-diyl]phosphitecyclohexanediol 6a′ derived from enantiopure starting material. A significant dependence of stereoselectivity on the type of enone and the ring size of the cyclic enone was observed. Moreover, the configuration of the products was mainly determined by the configuration of the binaphthyl moieties of diphosphite ligands in the 1,4-addition of cyclic enones.

Synthesis of novel tartaric acid-derived chiral phosphite ligands and their application in the Cu-catalyzed conjugate addition of diethylzinc to cyclic enones

Five novel tropos (3R,4R)- and/or (3S,4S)-N-benzyltartarimide-derived biphenylphosphite ligands were synthesized and applied in the Cu-catalyzed asymmetric conjugate addition of diethylzinc to cyclic enones with up to 75% e.e. Compared with the reported ligand 1-N-benzylpyrrolidine-3,4-bis[(R)-1,1’-binaphthyl-2,2’-diyl]phosphite-L-tartaric acid, the issue that L-(+)-tartaric acid backbone and (R)-binaphthyl showed strong matched/mismatched character was solved with these tropos ligands. It was found that the enantioselectivity was mainly controlled by the absolute configuration of N-benzyltartarimide backbone, and both enantiomers of the addition products can be obtained by simply changing the configuration of N-benzyltartarimide substituent.

NOBIN-based chiral phosphite-type ligands and their application in asymmetric catalysis

P∗-Monodentate diamidophosphite and diastereomeric P,N-containing phosphite ligands have been synthesized from enantiomerically pure N-Bn-NOBIN and used as asymmetric inductors in Pd-catalyzed allylic substitution and Cu-catalyzed conjugate addition reactions. The best results (up to 93% ee) were obtained for the Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl acetate with 1-cyclohexenylpyrrolidine. The reactions of P,N-containing ligands with Pd(COD)Cl2 at molar ratios of L/M=1 and 2 were studied using 1H, 13C, and 31P NMR spectroscopy as well as HRESI mass spectrometry, showing the trans-PdCl2L2 complex was the only product.

ChemInform Abstract: Creation of Highly Congested Quaternary Centers via Cu‐Catalyzed Conjugate Addition of Alkenyl Alanates to β‐Substituted Cyclic Enones.

ChemInformVolume 44, Issue 33 Isocyclic Compounds ChemInform Abstract: Creation of Highly Congested Quaternary Centers via Cu-Catalyzed Conjugate Addition of Alkenyl Alanates to β-Substituted Cyclic Enones. Daniel Mueller, Daniel Mueller 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 Daniel Mueller, Daniel Mueller 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: 25 July 2013 https://doi.org/10.1002/chin.201333046Read 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. Volume44, Issue33August 13, 2013 RelatedInformation

Application of pyranoside phosphite-pyridine ligands to enantioselective metal-catalyzed allylic substitutions and conjugate 1,4-additions

A series of glucopyranoside phosphite–pyridine ligands have been applied in the metal-catalyzed allylic substitution and conjugate 1,4-addition reactions of several substrate types. We have been able to identify ligands that provided promising enantioselectivities in the Pd-catalyzed intermolecular allylic substitution of cyclic substrates (ee’s up to 86%) and desymmetrization (ee’s up to 94%) and in the Cu-catalyzed conjugate addition of challenging aliphatic enones (ee’s up to 90%).

Cu-Catalyzed Conjugate Addition of Alkenyl Alanates to Cyclic Enones

Cu-Catalyzed Conjugate Addition of Alkenyl Alanates to Cyclic Enones

Creation of Highly Congested Quaternary Centers via Cu-catalyzed Conjugate Addition of Alkenyl Alanates to β-Substituted Cyclic Enones

Creation of Highly Congested Quaternary Centers via Cu-catalyzed Conjugate Addition of Alkenyl Alanates to β-Substituted Cyclic Enones

Creation of Highly Congested Quaternary Centers via Cu-catalyzed Conjugate Addition of Alkenyl Alanates to β-Substituted Cyclic Enones

Easily prepared alkenylalanates proved to be excellent nucleophiles for the creation of highly congested quaternary centers via copper-catalyzed conjugate addition. In addition, functionalized cis-decaline systems can now be prepared in a simple two-step sequence involving Cu-catalyzed conjugate addition with functionalized alkenylalanates.

Cu-Catalyzed Conjugate Addition of Grignard Reagents to Pyranones

Cu-Catalyzed Conjugate Addition of Grignard Reagents to Pyranones

Sugar-based monodentate phosphoramidite ligands for Cu-catalyzed enantioselective conjugate addition to enones

In this paper we present new, monodentate phosphoramidite ligands based on amines derived from the easy available monosaccharide d-xylose and BINOLs. Ligands were used for copper-catalyzed conjugate addition to acyclic and cyclic enones. The highest enantioselectivity achieved in this study was 77% ee for the conjugate addition to trans-chalcone, which is comparable to the best results published to date for phosphoramidite ligands based on carbohydrate-derived amines.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Conjugate Addition to Challenging Michael Acceptors and Synthesis of Relevant Target Molecules

AbstractReview: 56 refs.

Multinuclear Cu-Catalyzed Asymmetric Conjugate Addition

Multinuclear Cu-Catalyzed Asymmetric Conjugate Addition

Copper-catalyzed Asymmetric Conjugate Addition to Challenging Michael Acceptors and Synthesis of Relevant Target Molecules

We report herein the enantioselective Cu-catalyzed conjugate addition of organometallic reagents to sensitive Michael acceptors and their application to the synthesis of relevant target molecules. This is one of the most important methodologies to form a C-C bond in an enantioselective manner. A wide range of α,β-unsaturated aldehydes and β,γ-unsaturated-α-ketoesters has been successfully used. Reactivity, regio- and enantioselectivities were strongly dependent on the reaction conditions, therefore moderate to very good results were obtained. Furthermore, γ-substituted-α-ketoesters were used as chiral building blocks for further derivatization with complete retention of the chiral information to obtain key compounds.

Asymmetric Cu-Catalyzed Conjugate Addition Followed by Amidomethylation

Asymmetric Cu-Catalyzed Conjugate Addition Followed by Amidomethylation

Synthesis of novel chiral bidentatephosphite ligands derived from the pyranoside backbone of monosaccharides and their application in the Cu-catalyzed conjugate addition of dialkylzinc to enones

A series of novel bidentatephosphite ligands, derived from methyl 3,6-anhydro-α- d-glucopyranoside and chlorophosphoric acid diaryl ester, were easily synthesized. These ligands were successfully employed in the Cu-catalyzed asymmetric conjugate 1,4-addition of the organozinc reagents diethylzinc and/or dimethylzinc to enones. The stereochemically matched combination of glucopyranoside and ( R)-H 8-binaphthyl in ligand 2,4-bis{[( R)-1,1′-H 8-binaphthyl-2,2′-diyl] phosphite}-methyl 3,6-anhydro-α- d-glucopyranoside was essential to afford 85% ee for 3-ethylcyclohexanone with an ( S)-configuration in THF, using Cu(OTf) 2 as a catalytic precursor. When the reaction was carried out at lower temperatures, changing from −10 to −80 °C, a marginal influence of the temperature on the enantioselectivity of the reaction was observed. The presence of the methyl substituent at the 1-position of the glucopyranoside skeleton had a negative effect on the enantioselectivity in the 1,4-addition of ZnEt 2 to acyclic enones.