Copper-Catalyzed Enantioselective Research Articles

Copper-Catalyzed Enantioselective Radical Esterification of Propargylic C–H Bonds

AbstractThe copper-catalyzed enantioselective radical esterification of propargylic C–H bonds with tert-butyl peroxybenzoate (TBPB) as an oxidizing agent and an oxygenated nucleophile is reported. This variant of the Kharasch–Sosnovsky oxidation allows for the asymmetric esterification of open-chain carbon radicals without excessive amounts of alkyne substrates under mild reaction conditions, achieving a one-step conversion of simple alkynes into chiral propargylic esters.

Visible Light Induced Copper-Catalyzed Enantioselective Deaminative Arylation of Amino Acid Derivatives Assisted by Phenol.

The exploration of value-added conversions of naturally abundant amino acids has received considerable attention from the synthetic community. Compared with the well-established asymmetric decarboxylative transformation, the asymmetric deaminative transformation of amino acids still remains a formidable challenge, mainly due to the lack of effective strategies for the C-N bond activation and the potential incompatibility with chiral catalysts. Here, we disclose a photoinduced Cu-catalyzed asymmetric deaminative coupling reaction of amino acids with arylboronic acids. This new protocol provides a series of significant chiral phenylacetamides in generally good yields and excellent stereoselectivity under mild and green conditions (42-85 % yields, up to 97 % ee). Experimental investigations and theoretical calculations were performed to reveal the crucial role of additional phenols in improving catalytic efficiency and enantiocontrol.

Copper-Catalyzed Enantioselective Desymmetric Protosilylation of Prochiral Diynes: Access to Optically Functionalized Tertiary Alcohols.

In this protocol, a copper-catalyzed desymmetric protosilylation of prochiral diynes was developed. The corresponding products were obtained in moderate to high yields and enantiomeric ratios. This approach provides a simple method for synthesizing functionalized chiral tertiary alcohols in the presence of a chiral pyridine-bisimidazoline (Pybim) ligand.

W-Phos Ligand Enables Copper-Catalyzed Enantioselective Alkylation of N-Sulfonyl Ketimines with Grignard Reagents

Catalytic asymmetric addition of reactive Grignard reagents to ketimines poses a considerable challenge. Herein, a PNP-type W-Phos ligand developed recently by our group showed a unique effect toward this end, paving the way to a Cu(I)-catalyzed asymmetric alkylation reaction of N-sulfonyl ketimines, delivering optically active α-tertiary amines in high enantioselectivities. This catalytic protocol shows an unprecedented substrate scope with more than 80 examples, not only compatible with benzo five- and six-membered cyclic N-sulfonyl ketimines but also suitable for geometrically unstable (E or Z) acyclic N-sulfonyl ketimines. The application potential of the protocol is featured by the extensive presence of α-tertiary amines in natural products and pharmaceutical compounds and also demonstrated by downstream transformations with maintenance of the enantioselectivity.

Copper-Catalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation: Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives.

Alkene aminooxygenation and dioxygenation reactions that result in carbonyl products are uncommon, and protocols that control absolute stereochemistry are rare. We report herein catalytic enantioselective alkene aminooxygenation and dioxygenation that directly provide enantioenriched 2-formyl saturated heterocycles under aerobic conditions. Cyclization of substituted 4-pentenylsulfonamides, catalyzed by readily available chiral copper complexes and employing molecular oxygen as both oxygen source and stoichiometric oxidant, directly provides chiral 2-formyl pyrrolidines efficiently. Reductive or oxidative workup of these aldehydes provides their respective amino alcohols or amino acids (unnatural prolines). Enantioselective synthesis of an indoline and isoquinolines is also demonstrated. Concurrently, cyclization of various alkenols under similar conditions provides 2-formyl tetrahydrofurans, phthalans, isochromans, and morpholines. The nature of the copper ligands, the concentration of molecular oxygen, and the reaction temperature all impact the product distribution. Chiral nitrogen and oxygen heterocycles are common components of bioactive small molecules, and these enabling technologies provide access to saturated heterocycles functionalized with ready-to-use carbonyl electrophiles.

Copper-Catalyzed Enantioselective Decarboxylative Cyanation of Benzylic Acids Promoted by Hypervalent Iodine(III) Reagents.

Copper-catalyzed asymmetric radical cyanation reactions have emerged as a powerful strategy for rapid construction of α-chiral nitriles. However, the directly decarboxylative cyanation reactions of common alkyl carboxylic acids remain largely elusive. Herein, we report a protocol for copper-catalyzed direct and enantioselective decarboxylative cyanation of benzylic acids. The in situ activation of acid substrates by a commercially inexpensive hypervalent iodine(III) reagent promoted the yield of the alkyl radicals under mild reaction conditions without prefunctionalization. The structurally diverse chiral alkyl nitriles were produced in good yields with high enantioselectivities. In addition, the chiral products can be readily converted to other useful chiral compounds via further transformations.

Copper-Catalyzed Enantioselective Dienolate Additions to Aldehydes

Key words copper catalysis - enantioselectivity - enolate addition

Copper-Catalyzed Enantioselective Borylative Allyl-Allyl Coupling of Allenes and Allylic gem-Dichlorides.

A catalytic asymmetric reaction between allenes, bis(pinacolato)diboron, and allylic gem-dichlorides is reported. The method involves the coupling of a catalytically generated allyl copper species with the allylic gem-dichloride and provides chiral internal 1,5-dienes featuring (Z)-configured alkenyl boronate and alkenyl chloride units with high levels of chemo-, regio-, enantio-, and diastereoselectivity. The synthetic utility of the products is demonstrated with the synthesis of a range of optically active compounds. DFT calculations reveal key noncovalent substrate-ligand interactions that account for the enantioselectivity outcome and the diastereoselective formation of the (Z)-alkenyl chloride.

Copper-Catalyzed Enantioselective Radical Heteroatomic S—O Cross-Coupling

Copper-Catalyzed Enantioselective Radical Heteroatomic S—O Cross-Coupling

Copper-Catalyzed Enantioselective Radical Chlorination of Alkenes

Copper-Catalyzed Enantioselective Radical Chlorination of Alkenes

Copper-Catalyzed Enantioselective Reductive Aldol Reaction

Copper-Catalyzed Enantioselective Reductive Aldol Reaction

Copper-Catalyzed Enantioselective Decarboxylative Cyanation of β,γ-Unsaturated Carboxylic Acids to Access Chiral Allyl Nitriles

Copper-Catalyzed Enantioselective Decarboxylative Cyanation of β,γ-Unsaturated Carboxylic Acids to Access Chiral Allyl Nitriles

Copper-Catalyzed Enantioselective Borylation of Dialkyl Ketimines

Copper-Catalyzed Enantioselective Borylation of Dialkyl Ketimines

Copper-Catalyzed Enantioselective Vinylogous Aldol Reaction of Allylazaarenes

Copper-Catalyzed Enantioselective Vinylogous Aldol Reaction of Allylazaarenes

Copper-Catalyzed Enantioselective Radical 1,4-Difunctionalization of 1,3-Enynes.

Chiral allenes are important structural motifs frequently found in natural products, pharmaceuticals, and other organic compounds. Asymmetric 1,4-difunctionalization of 1,3-enynes is a promising strategy to construct axial chirality and produce substituted chiral allenes from achiral substrates. However, the previous state of the art in 1,4-difunctionalization of 1,3-enynes focused on the allenyl anion pathway. Because of this, only electrophiles can be introduced into the allene backbones in the second functionalization step, consequently limiting the reaction and allene product types. The development of asymmetric 1,4-difunctionalization of 1,3-enynes via a radical pathway would complement previous methods and support expansion of the toolbox for the synthesis of asymmetric allenes. Herein, we report the first radical enantioselective allene formation via a group transfer pathway in the context of copper-catalyzed radical 1,4-difunctionalization of 1,3-enynes. This method addresses a longstanding unsolved problem in asymmetric radical chemistry, provides an important strategy for stereocontrol with free allenyl radicals, and offers a novel approach to the valuable, but previously inaccessible, chiral allenes. This work should shed light on asymmetric radical reactions and may lead to other enantioselective group transfer reactions.

Copper-Catalyzed Enantioselective Reductive Cross-Coupling of Aldehydes and Imines.

A copper-catalyzed enantioselective reductive cross-coupling using aromatic aldehydes and imines, producing chiral β-amino alcohols, is described. The catalytic formation of enantioenriched chiral α-alkoxyalkylcopper(I) species from aromatic aldehydes and the subsequent reaction with imine electrophiles are attractive features of this protocol.

Copper-Catalyzed Enantioselective Allylation Using Allene

Copper-Catalyzed Enantioselective Allylation Using Allene

Synthesis of Phthalans Via Copper-Catalyzed Enantioselective Cyclization/Carboetherification of 2-Vinylbenzyl Alcohols.

Enantiomerically enriched phthalans were synthesized efficiently via an enantioselective copper-catalyzed alkene carboetherification reaction. In this reaction, 2-vinylbenzyl alcohols enantioselectively cyclize then couple with vinylarenes. The utility of the method was demonstrated by the enantioselective synthesis of ( R)-fluspidine, a σ1 receptor ligand.

Copper-Catalyzed Enantioselective Friedel–Crafts Alkylation

Copper-Catalyzed Enantioselective Friedel–Crafts Alkylation

Copper-Catalyzed Enantioselective Henry Reaction of β,γ-Unsaturated α-Ketoesters with Nitromethane in Water.

A highly enantioselective Henry reaction of β,γ-unsaturated α-ketoesters with nitromethane in water by virtue of chiral copper complexes has been developed. A series of unsaturated β-nitro-α-hydroxy esters bearing tetrasubstituted carbon stereocenters were obtained exclusively with high yields and excellent enantioselectivities. This method could avoid tedious anaerobic anhydrous manipulation and reduce the environmental pollution caused by organic solvents.