Direct α‐Alkylation of Aldehydes by Brønsted‐Acid Catalysis

A Brønsted acid catalyzed direct alkylation reaction of aldehydes was described. The 3,5‐dinitrobenzoic acid promoted the reaction between aldehydes and diarylmethanols to afford the corresponding alkylation products with middle to high yields (up to 91% yield).     

Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α‐Keto Amides

The first enantioselective direct cross‐aldol reaction of α‐keto amides with aldehydes, mediated by a bifunctional ureidopeptide‐based Brønsted base catalyst, is described. The appropriate combination of a tertiary amine base and an aminal, and urea hydrogen‐bond donor groups in the catalyst structure promoted the exclusive generation of the α‐keto amide enolate which reacted with either non‐enolizable or enolizable aldehydes to produce highly enantioenriched polyoxygenated aldol adducts without side‐products resulting from dehydration, α‐keto amide self‐condensation, aldehyde enolization, and isotetronic acid formation.     

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

The formal [3+2] cycloaddition of epoxides and unsaturated compounds is a powerful methodology for the synthesis of densely functionalized five‐membered heterocyclic compounds containing oxygen. Described is a novel enantioselective formal [3+2] cycloaddition of epoxides under Brønsted base catalysis. The bis(guanidino)iminophosphorane as a chiral organosuperbase catalyst enabled the enantioselective reaction of β,γ‐epoxysulfones with imines, owing to its strong basicity and high stereocontrolling ability, to provide enantioenriched 1,3‐oxazolidines having two stereogenic centers, including a quaternary one, in a highly diastereo‐ and enantioselective manner.     

Asymmetric Catalysis on the Nanoscale: The Organocatalytic Approach to Helicenes

The first asymmetric organocatalytic synthesis of helicenes is reported. A novel SPINOL‐derived phosphoric acid, bearing extended π‐substituents, catalyzes the asymmetric synthesis of helicenes through an enantioselective Fischer indole reaction. A variety of azahelicenes and diazahelicenes could be obtained with good to excellent yields and enantioselectivities.     

Ruthenium(II)/Chiral Brønsted Acid Co‐Catalyzed Enantioselective Four‐Component Reaction/Cascade Aza‐Michael Addition for Efficient Construction of 1,3,4‐Tetrasubstituted Tetrahydroisoquinolines

An elegant synergistic catalytic system comprising a ruthenium complex with a chiral Brønsted acid was developed for a four‐component Mannich/cascade aza‐Michael reaction. The ruthenium‐associated ammonium ylides successfully trapped with in situ generated imines indicates a stepwise process of proton transfer in the ruthenium‐catalyzed carbenoid N?H insertion reaction. The different decomposition abilities of various ruthenium complexes towards diazo compounds were well explained by the calculated thermodynamic data. The transformation features a mild, rapid, and efficient method for the synthesis of enantiomerically pure 1,3,4‐tetrasubstituted tetrahydroquinolines bearing a quaternary stereogenic carbon center from simple starting precursors in moderate yields with high diastereo‐ and enantioselectivity.     

Disulfonimide‐Catalyzed Asymmetric Reduction of N‐Alkyl Imines

A chiral disulfonimide (DSI)‐catalyzed asymmetric reduction of N‐alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc‐protected N‐alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross‐coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)‐Rivastigmine, NPS R‐568 Hydrochloride, and (R)‐Fendiline.     

Direct Carbohydroxylation of Arylalkenes with Allylic Alcohols: Cooperative Catalysis of Copper,Silver, and a Brønsted Acid

The cooperative catalysis of copper, silver, and Brønsted acid is presented as a new strategy for olefin functionalization. The catalytic direct carbohydroxylation of arylalkenes with allylic alcohols provided a straightforward and efficient approach for preparing 4,5‐unsaturated alcohols. Synthetically useful functional groups, such as Cl, Br, carbonyl, and chloromethyl, remained intact during the functionalization reaction.     

Catalytic Enantioselective Synthesis of α‐Chiral Azaheteroaryl Ethylamines by Asymmetric Protonation

The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl‐substituted N‐heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza‐Michael addition to give a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of N‐heterocycles, nucleophiles, and substituents on the prochiral centre, generating the products in high enantioselectivity. DFT studies support a facile nucleophilic addition based on catalyst‐induced LUMO lowering, with site‐selective, rate‐limiting, intramolecular asymmetric proton transfer from the ion‐paired prochiral intermediate.     

Highly Acidic Conjugate‐Base‐Stabilized Carboxylic Acids Catalyze Enantioselective oxa‐Pictet–Spengler Reactions with Ketals

Acyclic ketone‐derived oxocarbenium ions are involved as intermediates in numerous reactions that provide valuable products, however, they have thus far eluded efforts aimed at asymmetric catalysis. We report that a readily accessible chiral carboxylic acid catalyst exerts control over asymmetric cyclizations of acyclic ketone‐derived trisubstituted oxocarbenium ions, thereby providing access to highly enantioenriched dihydropyran products containing a tetrasubstituted stereogenic center. The high acidity of the carboxylic acid catalyst, which exceeds that of the well‐known chiral phosphoric acid catalyst TRIP, is largely derived from stabilization of the carboxylate conjugate base through intramolecular anion‐binding to a thiourea site.     

Brønsted Acid‐Catalyzed,Highly Enantioselective Addition of Enamides to In Situ‐Generated ortho‐Quinone Methides: A Domino Approach to Complex Acetamidotetrahydroxanthenes

The highly enantioselective conjugate addition of enamides and enecarbamates to in situ‐generated ortho‐quinone methides, upon subsequent N,O‐acetalization, gives rise to acetamido‐substituted tetrahydroxanthenes with generally excellent enantio‐ and diastereoselectivities. A chiral BINOL‐based phosphoric acid catalyst controls the enantioselectivity of the carbon–carbon bond‐forming event. The products are readily converted into other xanthene‐based heterocycles.     

An Unexpected α‐Oxidation of Cyclic Ketones with 1,4‐Benzoquinone by Enol Catalysis

The first direct and asymmetric α‐aryloxylation of cyclic ketones via enol catalysis has been achieved using quinones as the reaction partners. Catalytic amounts of a phosphoric acid promote the exclusive formation of α,α‐disubstituted ketones from the corresponding α‐substituted ketones in good yields and enantioselectivities (up to 96.5:3.5 er). Preliminary mechanistic experiments suggest that this reaction proceeds via a proton‐coupled electron transfer (PCET) followed by radical recombination.     

IDPi Catalysis

High acidity and structural confinement are pivotal elements in asymmetric acid catalysis. The recently introduced imidodiphosphorimidate (IDPi) Brønsted acids have met with remarkable success in combining those features, acting as powerful Brønsted acid catalysts and “silylium” Lewis acid precatalysts in numerous thus far inaccessible transformations. Substrates as challenging to activate as simple olefins were readily transformed, ketones were employed as acceptors in aldolizations allowing sub‐ppm level catalysis, whereas enolates of the smallest donor aldehyde, acetaldehyde, did not polymerize but selectively added a single time to a variety of acceptor aldehydes.