Copper-Catalyzed Asymmetric Conjugate Addition Research Articles

Catalytic Asymmetric Vinylogous Conjugate Addition of Butenolide to 2-Ester-Substituted Chromones: Access to Chiral Chromanone Lactones via Trapping of a Copper(I) Enolate by Trimethyl Borate.

A copper-catalyzed asymmetric vinylogous conjugate addition of butenolide to 2-ester-substituted chromones is described, and it delivers syn- or anti-chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe)3 as an additive, resulting in enhanced stereoselectivities, as revealed by density functional theory calculations, which also provided theoretical insight into the origin of the ligand-dependent diastereodivergence.

Stereodivergent Construction of 1,3-Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction.

Herein, we report a synthesis of cyclohexanones bearing multi-continuous stereocenters by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium-catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2-position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3-position) by a proper combination of two chiral catalysts with different enantiomers.

Copper-Catalyzed Asymmetric Conjugate Addition of Alkene-Derived Nucleophiles to Alkenyl-Substituted Heteroarenes

We herein report the copper-catalyzed asymmetric conjugate addition of β-substituted alkenyl heteroarenes, the one of most challenging Michael acceptors, with alkenes as the latent nucleophiles. Diverse chiral heteroarenes bearing two vicinal stereocenters were obtained in good to excellent yields, generally excellent enantioselectivity, and a good level of diastereoselectivity. The products of the Michael addition can be readily transformed into other valuable acyclic enantioenriched structures bearing three contiguous stereocenters via chiral amine catalysis. Mechanistic studies, including an isotope labeling experiment, a nonlinear effect study, kinetic isotope effect experiments, and initial-rate kinetics studies, were implemented, and the experimental results indicated that the hydrocupration step might be the turnover-limiting step. Moreover, the origin of preferential alkene hydrocupration in the presence of β-substituted alkenyl heteroarenes and the Ph-BPE-ligated CuH catalyst was also elucidated via some control experiments.

Synthesis of the Taxol Core via Catalytic Asymmetric 1,4-Addition of an Alkylzirconium Nucleophile.

The Taxol core was prepared in five steps via a key copper-catalyzed asymmetric conjugate addition trapping sequence. The use of a bromodiene-derived alkylzirconium nucleophile followed by trapping with POCl3/DMF gave a highly functionalized intermediate featuring a quaternary center in 69% yield with 92% ee. After 1,2-addition, Suzuki-Miyaura cross-coupling, allylic oxidation, and a type II intramolecular Diels-Alder reaction, the taxol core was obtained in 11% overall yield with 92% ee.

Phosphoramidite-based photoresponsive ligands displaying multifold transfer of chirality in dynamic enantioselective metal catalysis

The transfer and amplification of chirality in biological and artificial systems is a fundamental process that allows for a dynamic control of structure and function. Only a few responsive systems harness the dynamic transfer of chirality and can act as photoswitchable chiral inductors. Here we demonstrate that photoresponsive phosphoramidite ligands based on a chiral biaryl-substituted molecular switch can be used to alter the activity and invert the stereoselectivity of a copper-catalysed asymmetric conjugate addition. The phosphoramidites were obtained as pairs of diastereoisomers, each displaying a distinct catalytic activity and stereoselectivity as a result of the light-controlled matched–mismatched interaction between the fixed chirality at the phosphorus atom and the dynamic chirality of the switch. The result is an elegant balance of two competing catalysts, of which the complementary catalytic performance is tunable via light, which takes advantage of the internal dynamic transfer of chirality on reversible alkene photoisomerization. This discovery paves the way for the future development of more complex chirality-dependent photoresponsive and multitasking catalysts. [Figure not available: see fulltext.].

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 Conjugate Additions of Bis(pinacolato)diboron and Dimethylzinc to Acyl- N-methylimidazole Michael Acceptors: A Highly Stereoselective Unified Strategy for 1,3,5,... n (OH, Me) Motif Synthesis.

A unified strategy for the construction of prevalent 1,3,5,... n (OH, Me) motifs based on consecutive copper-catalyzed asymmetric conjugate borylation (ACB) and methylation (ACA) reactions involving α,β-unsaturated 2-acyl- N-methylimidazoles is described. Good yields and high diastereoselectivities have been obtained in ACA and ACB reactions for both matched and mismatched pairs as illustrated in the synthesis of syn/ anti and anti/ anti (Me, OTBS, Me) and (OH, OTBS, Me) motifs.

β-Chloroaldehydes from Trapping Zirconium Enolates Produced in Asymmetric 1,4-Additions.

Zirconium enolates, derived from copper-catalyzed asymmetric conjugate additions, are trapped with the Vilsmeier-Haack reagent. Asymmetric additions generate quaternary carbon centers with high enantioselectivity (generally ∼90% ee), and the enolates are converted to unsaturated β-chloroaldehydes (41-57% yields). The reaction tolerates changes to the nucleophile, can be used to form five-, six-, or seven-membered ring products, and is scalable to 5 mmol, and the products are readily elaborated by condensation, cross coupling, and addition reactions.

Copper-Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

Copper-Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

Enantioselective synthesis of chiral acylsilanes by copper/HZNU-Phos-catalyzed asymmetric conjugate addition of diethyzinc to α,β-unsaturated acylsilanes

The catalytic asymmetric copper-catalyzed conjugate addition of diethylzinc reagent to α,β-unsaturated acylsilanes was found to proceed smoothly in moderate to good yields and enantioselectivities (up to 85% ee) in the presence of the multifunctional HZNU-Phos.

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 Asymmetric Conjugate Addition of α,β-Unsaturated Carbonyls

Key words copper catalysis - enantioselectivity - diastereoselectivity - conjugate addition - enones - borylation

Ligand-Controlled Stereodivergent, Enantioselective Conjugate Addition of 2-Oxazoline- and 2-Thiazoline-4-carboxylate to Nitroalkene Catalyzed by Chiral Copper Complexes.

The copper-catalyzed asymmetric conjugate addition of 2-oxazoline- and 2-thiazoline-4-carboxylate to a nitroalkene proceeded to give either the syn or anti adduct selectively in high enantiomeric excess when an appropriate chiral ligand was used. Subsequent reduction of the nitro group followed by hydrolysis of the oxazoline ring yielded an optically active γ-lactam of protected α-quaternary serine derivative.

Copper-Catalyzed Asymmetric Conjugate Addition

Copper-Catalyzed Asymmetric Conjugate Addition

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

The copper-catalyzed asymmetric conjugate addition (ACA) of nucleophiles onto polyenic Michael acceptors represents an attractive and powerful methodology for the synthesis of relevant chiral molecules, as it enables in a straightforward manner the sequential generation of two or more stereogenic centers. In the last decade, various chiral copper-based catalysts were evaluated in combination with different nucleophiles and Michael acceptors, and have unambiguously demonstrated their usefulness in the control of the regio- and enantioselectivity of the addition. The aim of this review is to report recent breakthroughs achieved in this challenging field.

Efficiency of Industrially Relevant Atropisomeric Diphosphines in Copper-Catalyzed 1,4-Asymmetric Conjugate Addition of Dialkylzincs to Cyclic or Acyclic Enones or Dienones

Industrially relevant atropisomeric diphosphines such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 6,6′-bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-5,5′-bi-1,4-benzodioxin (SYNPHOS), and 5,5′-bis(diphenylphosphino)-2,2,2′,2′-tetrafluoro-4,4′-bi-1,3-benzodioxole (DIFLUORPHOS) have demonstrated their efficiency in the copper-catalyzed asymmetric conjugate addition of various dialkylzincs to α-aryl enones, α-aryl dienones, and cyclic dienones. Excellent 1,4- or 1,6-regioselectivities and enantioselectivities (up to 97% ee) were attained, even with challenging sterically hindered Michael acceptors.

Asymmetric Conjugate Addition of Alkylzirconocenes to Cyclopent-4-ene-1,3-dione Monoacetals

Copper-catalyzed asymmetric conjugate additions are powerful reactions that allow the formation of single-enantiomer building blocks in a few steps. However, highly enantioselective conjugate addition to five-membered-ring substrates is more challenging and is often neglected. Here, we report catalytic asymmetric 1,4-addition of alkylzirconocenes, formed in situ from readily available alkenes, to cyclopent-4-ene-1,3-dione monoacetals. Good to high enantioselectivities are observed and the procedure tolerates various functional groups.

2.2]Paracyclophane-derived monodentate phosphoramidite ligands for copper-catalyzed asymmetric conjugate addition of diethylzinc to substituted chalcones.

Copper-catalyzed asymmetric conjugate addition of diethylzinc to chalcones could be realized by using [2.2]paracyclophane-derived monodentate phosphoramidite ligands. The excellent yield and enantioselectivity (up to 98% yield and 95% enantiomeric excess) could be realized with low catalyst loading of 1.0 mol % and low ligand loading of 1.2%.

Copper-Catalyzed Asymmetric Conjugate Addition to α-Alkylidene Cycloalkanones

The asymmetric copper-catalyzed conjugate addition to α-alkylidene cycloalkanones, substituted at their terminal position with aromatic and aliphatic groups, is reported. While high enantioselectivity is reached using chiral phosphoramidite ligands, with R₃Al reagents, moderate diastereoselectivity was observed upon hydrolysis of the aluminium enolates. A Grignard reagent also react with high diastereo­selectivity.

Recent Advances in Copper-Catalyzed Asymmetric Conjugate Addition of Grignard Reagents

Recent Advances in Copper-Catalyzed Asymmetric Conjugate Addition of Grignard Reagents