Copper-Catalyzed Asymmetric Addition Research Articles

Synthesis of Chiral Substituted meta‐Bromoanilines as Ligands for Copper-Catalyzed Asymmetric Aldol Addition Reactions

Synthesis of Chiral Substituted meta‐Bromoanilines as Ligands for Copper-Catalyzed Asymmetric Aldol Addition Reactions

Synthesis of W-Phos Ligand and Its Application in the Copper-Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones.

The asymmetric catalytic addition of linear Grignard reagents to ketones has been a long-standing challenge in organic synthesis. Herein, a novel family of PNP ligands (W-Phos) was designed and applied in copper-catalyzed asymmetric addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcohols in good to high yields with excellent enantioselectivities (up to 94 % yield, 96 % ee). The process can also be used to synthesize chiral allylic tertiary alcohols from more challenging α,β-unsaturated ketones. Notably, the potential utility of this method is demonstrated in the gram-scale synthesis and modification of various densely functionalized medicinally relevant molecules.

Inside Back Cover: Concise and Stereodivergent Approach to Chromanone Lactones through Copper‐Catalyzed Asymmetric Vinylogous Addition of Siloxyfurans to 2‐Ester‐Substituted Chromones (Angew. Chem. Int. Ed. 26/2022)

Enantioenriched chromanone lactones were prepared by copper-catalyzed asymmetric vinylogous addition of siloxyfurans to 2-ester-substituted chromones, as reported by Jin Cui, Masakatsu Shibasaki, and co-workers in their Communication (e202203128). The catalytic system features the use of chiral ligands to control the diastereo- and enantioselective addition of copper vinylogous enolates to chromones. The cover illustrates superimposed product structures, dropping a hint about the ligand-controlled diastereodivergence.

Enantioenriched N,O-Ketals via Copper-Catalyzed Asymmetric Addition of Alcohols to Ketimines

Key words copper catalysis - N,O-ketals - enantioselectivity

Enantioselective Addition of Diethylzinc to Aromatic Aldehydes Using Chiral Oxazoline-Based Ligands

Chiral oxazoline ligands containing an aromatic ring were prepared from norephedrine and pyrrole-2-carbonitrile or 2-hydroxybenzoyl chloride. The synthesized ligands were used in the copper-catalyzed asymmetric addition of diethylzinc to aromatic aldehydes to provide optically active 1-arylpropan-1-ols with high conversion (92%) and enantioselectivity (up to 99% ee).

Copper-catalyzed asymmetric silyl addition to alkenyl-substituted N-heteroarenes.

Asymmetric conjugate addition of PhMe2SiBPin to a wide range of N-heteroaryl alkenes proceeded in the presence of a copper catalyst coordinated with an easily accessible chiral phosphoramidite ligand to afford useful β-silyl N-heteroarenes in high yields (up to 96%) and excellent enantioselectivities (up to 97% ee).

Retooling Asymmetric Conjugate Additions for Sterically Demanding Substrates with an Iterative Data-Driven Approach.

The development of catalytic enantioselective methods is routinely carried out using easily accessible and prototypical substrates. This approach to reaction development often yields asymmetric methods that perform poorly using substrates that are sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include more challenging substrates is decidedly nontrivial. Here, we address this challenge through the development of a systematic workflow to broaden the applicability and reliability of asymmetric conjugate additions to substrates conventionally regarded as sterically and electronically demanding. The copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles to form tertiary centers, although successful for linear alkyl chains, fails for more sterically demanding linear α,β-unsaturated ketones. Key to adapting this method to obtain high enantioselectivity was the synthesis of modified phosphoramidite ligands, designed using quantitative structure–selectivity relationships (QSSRs). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of 20 chiral ligands. The copper-catalyzed asymmetric addition is now more broadly applicable, even tolerating linear enones bearing tert-butyl β-substituents. The presence of common functional groups is tolerated in both nucleophiles and electrophiles, giving up to 99% yield and 95% ee across 20 examples.

Copper-Catalyzed Asymmetric Addition of Tertiary Carbon Nucleophiles to 2 H-Azirines: Access to Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters.

A catalytic asymmetric nucleophilic addition of tertiary carbon nucleophiles to 2 H-azirines was established in the presence of the chiral N,N'-dioxide/CuII complex. Various chiral aziridines with vicinal tetrasubstituted stereocenters were obtained in high yields with excellent diastereoselectivities and enantioselectivities. Moreover, on the basis of the control experiments, X-ray structures of the products, and catalyst, a possible transition state was proposed to explain the stereoselectivity.

ChemInform Abstract: Enantioselective Synthesis of 3‐Alkynyl‐3‐hydroxyindolin‐2‐ones by Copper‐Catalyzed Asymmetric Addition of Terminal Alkynes to Isatins.

A highly efficient copper-catalyzed asymmetric addition of terminal alkynes to isatins has been developed. In the presence of a catalytic amount of copper iodide and a chiral phosphine ligand, the reaction gave the corresponding chiral 3-alkynyl-3-hydroxyindolin-2-ones in high yields with high enantioselectivity. This methodology has a broad substrate scope, and the synthetic utility of the present protocol was further demonstrated by the transformation of chiral alkynylation products.

Copper-Catalyzed Asymmetric Nucleophilic Addition to Ketones

Copper-Catalyzed Asymmetric Nucleophilic Addition to Ketones

Copper-catalyzed asymmetric addition of olefin-derived nucleophiles to ketones.

Enantioenriched alcohols found in an array of bioactive natural products and pharmaceutical agents are often synthesized by asymmetric nucleophilic addition to carbonyls. However, this approach generally shows limited functional-group compatibility, requiring the use of preformed organometallic reagents in conjunction with a stoichiometric or substoichiometric amount of chiral controller to deliver optically active alcohols. Herein we report a copper-catalyzed strategy for the stereoselective nucleophilic addition of propargylic and other alkyl groups to ketones, using easily accessible (poly)unsaturated hydrocarbons as latent carbanion equivalents. Our method features the catalytic generation of highly enantioenriched organocopper intermediates and their subsequent diastereoselective addition to ketones, allowing for the effective construction of highly substituted stereochemical dyads with excellent stereocontrol. Moreover, this process is general, scalable, and occurs at ambient temperature.

Enantioselective Synthesis of 3-Alkynyl-3-hydroxyindolin-2-ones by Copper-Catalyzed Asymmetric Addition of Terminal Alkynes to Isatins.

A highly efficient copper-catalyzed asymmetric addition of terminal alkynes to isatins has been developed. In the presence of a catalytic amount of copper iodide and a chiral phosphine ligand, the reaction gave the corresponding chiral 3-alkynyl-3-hydroxyindolin-2-ones in high yields with high enantioselectivity. This methodology has a broad substrate scope, and the synthetic utility of the present protocol was further demonstrated by the transformation of chiral alkynylation products.

Copper-Catalyzed Asymmetric Pinacolboryl Addition of Imines

Copper-Catalyzed Asymmetric Pinacolboryl Addition of Imines

Catalytic Enantioselective Vinylogous Mukaiyama–Michael Addition of 2-Silyloxyfurans to Cyclic Unsaturated Oxo Esters

The copper-catalyzed asymmetric addition of 2-silyloxyfurans to cyclic unsaturated oxo esters is reported. The reaction proceeds with excellent diastereocontrol (usually dr 99:1) and modest to high enantioselectivity, depending on the nature of the ester group and the substitution of the cyclic oxo ester. We have shown that these substrates can be transformed into a variety of building blocks bearing a γ-butenolide or γ-lactone connected to a cycloalkane or cycoalkene moiety.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Conjugate Addition of Diethylzinc to Substituted Chalcones Using a Chiral Phosphine Ligand.

Abstract A series of chiral phosphine PFAM and phosphine oxide POFAM ligands were studied for the copper-catalyzed asymmetric diethylzinc addition to enones. One of these ligands, PFAM2 , was an efficient catalyst with a variety of enones to give conjugate addition products in up to 96% yield and 92% ee.

Copper-catalyzed asymmetric conjugate addition of diethylzinc to substituted chalcones using a chiral phosphine ligand

A series of chiral phosphine PFAM and phosphine oxide POFAM ligands were studied for the copper-catalyzed asymmetric diethylzinc addition to enones. One of these ligands, PFAM2, was an efficient catalyst with a variety of enones to give conjugate addition products in up to 96% yield and 92% ee.

Copper-catalyzed asymmetric addition of arylboronates to isatins: a catalytic cycle involving alkoxocopper intermediates

A copper-catalyzed addition of arylboronates to isatins has been developed to give 3-aryl-3-hydroxy-2-oxindoles under mild conditions. The catalytic cycle of this process has been examined through a series of stoichiometric reactions and an effective asymmetric variant has also been described by the use of a chiral N-heterocyclic carbene ligand.

Copper-catalyzed asymmetric addition of Et 2Zn to 2-cyclohexen-1-one and 2-carbamoyloxy-2-cyclohexen-1-one with phosphoramidite, phosphite, and bidentate phosphite–oxazoline ligands

New biphenol-backboned phosphite–oxazoline bidentate ligands were synthesized and applied in the copper-catalyzed asymmetric conjugate additions on 2-cyclohexen-1-one with Et 2Zn. In these reactions, the non-chiral oxazoline unit has demonstrated significant impact on the enantioselectivity. 2-Carbamoyloxy-2-cyclohexen-1-one is a new α-oxygenated cyclic enone substrate and was synthesized and applied to the aforementioned addition with certain phosphoramidite, phosphite, and the new bidentate ligands. Good ee has been obtained on this substrate.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Addition of Diethylzinc to Boc‐Protected Imines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Dimethylzinc-Initiated Radical Reactions

Developments in modern organic synthesis owe much to the field of radical chemistry. Mild reaction conditions, high selectivity, good functional group tolerance and high product yield are features that have made reactions involving radical species indispensable tools for synthetic chemists. In part, the discovery of new radical initiators has led to the efficiency that now characterizes most radical reactions. This Account describes our investigations of radical reactions initiated by dimethylzinc. In 2001, we unexpectedly observed this reaction while investigating the amidophosphane-copper-catalyzed asymmetric addition of dimethylzinc to N-sulfonyl imines with tetrahydrofuran (THF) as reaction solvent. However, instead of adding the desired methyl group to the N-sulfonyl imine, we produced the THF adduct in excellent yield. This result laid the foundation for our discovery of novel modes of reactivity. Further investigations of the unexpected addition reaction revealed that a trace amount of air was needed for reaction progress, indicating that radical intermediates were involved. Indeed, controlled injection of air into the reaction flask by a syringe pump through a sodium hydroxide tube afforded the products in good to excellent yield. In addition, the reaction proved to be chemoselective for a C=N bond over a C=O bond, as well as for 1,4-addition over 1,2-addition. We developed asymmetric variants of the radical addition reaction of ethers to imines using chiral N-sulfinyl imines to produce the adducts in reasonably high stereoselectivity (up to 11:1). A 93:7 diastereomeric ratio of the adduct was obtained when bis(8-phenylmenthyl) benzylidenemalonate was used in the radical addition of ethers to C=C bonds. Interestingly, in the presence of dimethylzinc and air, arylamines, alkoxyamines, and dialkylhydrazines react with THF to give amino alcohols, oximes, and hydrazones, respectively, in moderate to high yields. We performed a tin-free intermolecular addition of functionalized primary alkyl groups, generated from their corresponding iodides, to N-sulfonyl imines using dimethylzinc, air, boron trifluoride diethyl etherate, and a catalytic amount of copper(II) triflate. Direct C-H bond cleavage from cycloalkanes was also feasible in the presence of dimethylzinc, air, and boron trifluoride diethyl etherate to give the corresponding cycloalkyl radicals, which were suitable nucleophiles for N-sulfonyl imines. In all of the above reactions, dimethylzinc was a superior radical initiator than other conventional initiators such as dibenzoyl peroxide, diethylzinc, and triethylborane. We hope the coming decades will witness the report of other novel radical initiators that would complement the reactivity modes of existing ones.