Chiral Counteranion Strategy for Asymmetric Oxidative C(sp3)H/C(sp3)H Coupling: Enantioselective α‐Allylation of Aldehydes with Terminal Alkenes

The first enantioselective α‐allylation of aldehydes with terminal alkenes has been realized by combining asymmetric counteranion catalysis and palladium‐catalyzed allylic C? H activation. This method can tolerate a wide scope of α‐branched aromatic aldehydes and terminal alkenes, thus affording allylation products in high yields and with good to excellent levels of enantioselectivity. Importantly, the findings suggest a new strategy for the future creation of enantioselective C? H/C? H coupling reactions.     

Manganese‐Catalyzed Synthesis of cis‐β‐Amino Acid Esters through Organometallic CH Activation of Ketimines

Manganese‐catalyzed C? H functionalization reactions of ketimines set the stage for the expedient synthesis of cis‐β‐amino acid esters through site‐ and regioselective alkene annulations. The organometallic C? H activation occurred efficiently with high functional group tolerance, delivering densely functionalized β‐amino acid derivatives with ample scope.     

Nickel(0)‐Catalyzed Enantioselective [3+2] Annulation of Cyclopropenones and α,β‐Unsaturated Ketones/Imines

Ni⁰‐catalyzed chemo‐ and enantioselective [3+2] cycloaddition of cyclopropenones and α,β‐unsaturated ketones/imines is described. This reaction integrates C?C bond cleavage of cyclopropenones and enantioselective functionalization by carbonyl/imine group, offering a mild approach to γ‐alkenyl butenolides and lactams in excellent enantioselectivity (88–98 % ee) through intermolecular C?C activation.     

Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

The first example of enantioselective S?H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S?H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.     

Enantioselective NH Insertion Reaction of α‐Aryl α‐Diazoketones: An Efficient Route to Chiral α‐Aminoketones

A highly enantioselective N? H insertion reaction of α‐diazoketones was developed by using cooperative catalysis by dirhodium(II) carboxylates and chiral spiro phosphoric acids. The insertion reaction provides a new access route to diverse chiral α‐aminoketones, which are versatile building blocks in organic synthesis, with fast reaction rates, good yields and high enantioselectivity under mild and neutral conditions.     

Enantioselective Palladium‐Catalyzed Insertion of α‐Aryl‐α‐diazoacetates into the OH Bonds of Phenols

A palladium‐catalyzed asymmetric O? H insertion reaction was developed. Palladium complexes with chiral spiro bisoxazoline ligands promoted the insertion of α‐aryl‐α‐diazoacetates into the O? H bond of phenols with high yield and excellent enantioselectivity under mild reaction conditions. This palladium‐catalyzed asymmetric O? H insertion reaction provided an efficient and highly enantioselective method for the preparation of synthetically useful optically active α‐aryl‐α‐aryloxyacetates.     

Kinetic Resolution of α‐Hydroxy‐Substituted Oxime Ethers by Enantioselective Cu−H‐Catalyzed Si−O Coupling

A catalyst‐controlled enantioselective alcohol silylation by Cu?H‐catalyzed dehydrogenative Si?O coupling of hydroxy groups α to an oxime ether and simple hydrosilanes is reported. The selectivity factors reached in this kinetic resolution are generally high (s≈50), and these reactions thereby provide reliable access to highly enantioenriched α‐hydroxy‐substituted oxime ethers. The synthetic usefulness of these compounds is also demonstrated.     

Pd(II)‐Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza‐Wacker Cyclization to Access β‐Stereogenic γ‐Lactams

Herein, we describe an unprecedented cascade reaction to β‐stereogenic γ‐lactams involving Pd(II)‐catalyzed enantioselective aliphatic methylene C(sp³)?H alkenylation–aza‐Wacker cyclization through syn‐aminopalladation. Readily available 3,3′‐substituted BINOLs are used as chiral ligands, providing the corresponding γ‐lactams with broad scope and high enantioselectivities (up to 98 % ee).     

Organocatalytic Enantioselective Oxidative CH Alkenylation and Arylation of N‐Carbamoyl Tetrahydropyridines and Tetrahydro‐β‐carbolines

The first organocatalytic enantioselective C? H alkenylation and arylation reactions of N‐carbamoyl tetrahydropyridines and tetrahydro‐β‐carbolines (THCs) are described. The metal‐free processes represent an efficient and straightforward approach to a variety of structurally and electronically diverse α‐substituted tetrahydropyridines and THCs in good yields with excellent regio‐ and enantioselectivities. Preliminary control experiments provide important insights into the reaction mechanism.     

α‐Aminoxy‐Acid‐Auxiliary‐Enabled Intermolecular Radical γ‐C(sp3)−H Functionalization of Ketones

A method for site‐specific intermolecular γ‐C(sp³)?H functionalization of ketones has been developed using an α‐aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C?H bond is achieved by 1,5‐hydrogen atom abstraction by an oxidatively generated iminyl radical. Tertiary and secondary C‐radicals thus formed at the γ‐position of the imine functionality undergo radical conjugate addition to various Michael acceptors to provide, after reduction and imine hydrolysis, the corresponding γ‐functionalized ketones.     

Catalytic Asymmetric Synthesis of α‐Arylpyrrolidines and Benzo‐fused Nitrogen Heterocycles

Herein, we report a practical two‐step synthetic route to α‐arylpyrrolidines through Suzuki–Miyaura cross‐coupling and enantioselective copper‐catalyzed intramolecular hydroamination reactions. The excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium‐ring dibenzo‐fused nitrogen heterocycles.     

Nucleophilic β‐Carbon Activation of Propionic Acid as a 3‐Carbon Synthon by Carbene Organocatalysis

Direct β‐carbon activation of propionic acid (C₂H₅CO₂H) by carbene organocatalysis has been developed. This activation affords the smallest azolium homoenolate intermediate (without any substituent) as a 3‐carbon nucleophile for enantioselective reactions. Propionic acid is an excellent raw material because it is cheap, stable, and safe. This approach provides a much better solution to azolium homoenolate synthesis than the previously established use of acrolein (enal without any substituent), which is expensive, unstable, and toxic.     

B(C6F5)3/Chiral Phosphoric Acid Catalyzed Ketimine–Ene Reaction of 2‐Aryl‐3H‐indol‐3‐ones and α‐Methylstyrenes

The enantioselective ketimine–ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine–ene reactions of 2‐aryl‐3H‐indol‐3‐ones with α‐methylstyrenes were achieved by utilizing a B(C₆F₅)₃/chiral phosphoric acid (CPA) catalyst. These ketimine–ene reactions proceed well with low catalyst loading (B(C₆F₅)₃/CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2‐allyl‐indolin‐3‐ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C₆F₅)₃ significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen‐bonding interactions, especially the enhanced N?H???O hydrogen‐bonding interaction, differentiates the free energy of the transition states of CPA and B(C₆F₅)₃/CPA, thereby inducing the improvement of stereoselectivity.     

Axially Chiral Dibenzazepinones by a Palladium(0)‐Catalyzed Atropo‐enantioselective C−H Arylation

Atropo‐enantioselective C?H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo‐enantioselective palladium(0)‐catalyzed methodology that forges the axis of chirality during the C?H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C?H functionalization proceeds by an enantio‐determining CMD to yield configurationally stable eight‐membered palladacycles.     

PdII‐Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II‐catalyzed enantioselective C(sp³)?H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C?H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II‐catalyzed enantioselective β‐C(sp³)?H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C?H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.     

Chiral γ‐Lactams by Enantioselective Palladium(0)‐Catalyzed Cyclopropane Functionalizations

Cyclopropanes fused to pyrrolidines are important structural features found in a number of marketed drugs and development candidates. Typically, their synthesis involves the cyclopropanation of a dihydropyrrole precursor. Reported herein is a complementary approach which employs a palladium(0)‐catalyzed C? H functionalization of an achiral cyclopropane to close the pyrrolidine ring in an enantioselective manner. In contrast to aryl–aryl couplings, palladium(0)‐catalyzed C? H functionalizations involving the formation of C(sp³)? C(sp³) bonds of saturated heterocycles are very scarce. The presented strategy yields cyclopropane‐fused γ‐lactams from chloroacetamide substrates. A bulky Taddol phosphonite ligand in combination with adamantane‐1‐carboxylic acid as a cocatalyst provides the γ‐lactams in excellent yields and enantioselectivities.     

Synthesis and Structural Analysis of Aspergillus fumigatus Galactosaminogalactans Featuring α‐Galactose, α‐Galactosamine and α‐N‐Acetyl Galactosamine Linkages

Galactosaminogalactan (GAG) is a prominent cell wall component of the opportunistic fungal pathogen Aspergillus fumigatus. GAG is a heteropolysaccharide composed of α‐1,4‐linked galactose, galactosamine and N‐acetylgalactosamine residues. To enable biochemical studies, a library of GAG‐fragments was constructed featuring specimens containing α‐galactose‐, α‐galactosamine and α‐N‐acetyl galactosamine linkages. Key features of the synthetic strategy include the use of di‐tert‐butylsilylidene directed α‐galactosylation methodology and regioselective benzoylation reactions using benzoyl‐hydroxybenzotriazole (Bz‐OBt). Structural analysis of the Gal, GalN and GalNAc oligomers by a combination of NMR and MD approaches revealed that the oligomers adopt an elongated, almost straight, structure, stabilized by inter‐residue H‐bonds, one of which is a non‐conventional C?H???O hydrogen bond between H5 of the residue (i+1) and O3 of the residue (i). The structures position the C‐2 substituents almost perpendicular to the oligosaccharide main chain axis, pointing to the bulk solvent and available for interactions with antibodies or other binding partners.     

Reductive C−C Coupling from α,β‐Unsaturated Nitriles by Intercepting Keteniminates

We present an atom‐economic strategy to catalytically generate and intercept nitrile anion equivalents using hydrogen transfer catalysis. Addition of α,β‐unsaturated nitriles to a pincer‐based Ru?H complex affords structurally characterized κ‐N‐coordinated keteniminates by selective 1,4‐hydride transfer. When generated in situ under catalytic hydrogenation conditions, electrophilic addition to the keteniminate was achieved using anhydrides to provide α‐cyanoacetates in high yields. This work represents a new application of hydrogen transfer catalysis using α,β‐unsaturated nitriles for reductive C?C coupling reactions.     

(3R,4S)‐3‐Phenyl‐1‐[(R)‐1‐phenyl­ethyl]‐4‐[(R)‐1‐phenylethyliminomethyl]azetidin‐2‐one

The configuration of the chiral ring atoms of the title compound, C₂₆H₂₆N₂O, obtained in an enantioselective synthesis, has been established relative to the known R configuration of the α‐methyl­benzyl moieties. The crystal packing involves a two‐dimensional network of C—H?π interactions between the aromatic rings.     

Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with α‐Carbonyl Alkyl Bromides and Indoles

A new iron‐facilitated silver‐mediated radical 1,2‐alkylarylation of styrenes with α‐carbonyl alkyl bromides and indoles is described, and two new C?C bonds were generated in a single step through a sequence of intermolecular C(sp³)?Br functionalization and C(sp²)?H functionalization across the alkenes. This method provides an efficient access to alkylated indoles with broad substrate scope and excellent selectivity.