Synthesis of Novel Chiral Phosphoric Acid‐Bearing Two Acidic Phenolic Hydroxyl Groups and its Catalytic Evaluation for Enantioselective Friedel‐Crafts Alkylation of Indoles and Enones

A novel chiral phosphoric acid catalyst bearing two acidic phenolic hydroxyl groups was synthesized. Its catalytic activity as a chiral Brøsted acid has been examined in the enantioselective Friedel‐Crafts alkylation of indoles and enones as a model reaction. In comparison with the other chiral phosphoric acid catalysts, the reaction catalyzed by the novel chiral catalyst afforded the desired 3‐substituted indoles in a higher enantioselectivity (up to 69% ee).     

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.     

Enantioselective Palladium‐Catalyzed Carbonylative Carbocyclization of Enallenes via Cross‐Dehydrogenative Coupling with Terminal Alkynes: Efficient Construction of α‐Chirality of Ketones

An enantioselective Pd^II/Brønsted acid‐catalyzed carbonylative carbocyclization of enallenes ending with a cross‐dehydrogenative coupling (CDC) with a terminal alkyne was developed. VAPOL phosphoric acid was found as the best co‐catalyst among the examined 28 chiral acids, for inducing the enantioselectivity of α‐chiral ketones. As a result, a number of chiral cyclopentenones were easily synthesized in good to excellent enantiomeric ratio with good yields.     

Chiral Metal–Organic Frameworks Bearing Free Carboxylic Acids for Organocatalyst Encapsulation

Two chiral carboxylic acid functionalized micro‐ and mesoporous metal–organic frameworks (MOFs) are constructed by the stepwise assembly of triple‐stranded heptametallic helicates with six carboxylic acid groups. The mesoporous MOF with permanent porosity functions as a host for encapsulation of an enantiopure organic amine catalyst by combining carboxylic acids and chiral amines in situ through acid–base interactions. The organocatalyst‐loaded framework is shown to be an efficient and recyclable heterogeneous catalyst for the asymmetric direct aldol reactions with significantly enhanced stereoselectivity in relative to the homogeneous organocatalyst.     

The Organocatalytic Asymmetric Prins Cyclization

We describe here the design and development of an organocatalytic Prins cyclization. In the presence of a confined chiral imidodiphosphoric acid catalyst, salicylaldehydes react with 3‐methyl‐3‐buten‐1‐ol to afford highly functionalized 4‐methylenetetrahydropyrans in excellent regio‐ and enantioselectivity. The extreme steric demand of the acid catalyst is key for the success of this transformation.     

Chiral Phosphoric Acid Dual‐Function Catalysis: Asymmetric Allylation with α‐Vinyl Allylboron Reagents

We report a dual function asymmetric catalysis by a chiral phosphoric acid catalyst that controls both enantioselective addition of an achiral α‐vinyl allylboronate to aldehydes and pseudo‐axial orientation of the α‐vinyl group in the transition state. The reaction produces dienyl homoallylic alcohols with high Z‐selectivities and enantioselectivities. Computational studies revealed that minimization of steric interactions between the alkyl groups of the diol on boron and the chiral phosphoric acid catalyst influence the orientation of α‐vinyl substituent of the allylboronate reagent to occupy a pseudo‐axial position in the transition state.     

Atroposelective Phosphoric Acid Catalyzed Three‐Component Cascade Reaction: Enantioselective Synthesis of Axially Chiral N‐Arylindoles

An efficient organocatalytic atroposelective three‐component cascade reaction of 2,3‐diketoesters, aromatic amines, and 1,3‐cyclohexanediones has been developed for the highly enantioselective synthesis of axially chiral N‐arylindoles. The success of this method derives from the use of a newly developed second‐generation chiral spirocyclic phosphoric acid as the catalyst. In addition, this protocol was extended to the synthesis of an axially chiral monophosphorus ligand.     

Nickel‐Catalyzed Asymmetric Hydrogenation of 2‐Amidoacrylates

Earth‐abundant nickel, coordinated with a suitable chiral bisphosphine ligand, was found to be an efficient catalyst for the asymmetric hydrogenation of 2‐amidoacrylates, affording the chiral α‐amino acid esters in quantitative yields and excellent enantioselectivity (up to 96 % ee). The active catalyst component was studied by NMR and HRMS, which helped us to realize high catalytic efficiency on a gram scale with a low catalyst loading (S/C=2000). The hydrogenated products could be simply converted into chiral α‐amino acids, β‐amino alcohols, and their bioactive derivatives. Furthermore, the catalytic mechanism was investigated using deuterium‐labeling experiments and computational calculations.     

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.     

BINOL Phosphoric Acid‐Catalyzed Asymmetric Mannich Reaction of Cyclic N‐Acyl Ketimines with Cyclic Enones

A highly enantio‐ and diastereoselective Mannich reaction of cyclic N‐acyl ketimines generated in situ from 3‐hydroxyisoindolin‐1‐ones with cyclic enones has been accomplished using a chiral phosphoric acid catalyst to afford the chiral isoindalinone derivatives in high yields with excellent enantioselectivities (upto 97 % ee). This is the first report on the synthesis of chiral isoindolin‐1‐ones bearing adjacent quaternary and tertiary stereogenic centers.     

Catalytic Enantioselective 1,3‐Alkyl Shift in Alkyl Aryl Ethers: Efficient Synthesis of Optically Active 3,3′‐Diaryloxindoles

Reported is the first organocatalytic asymmetric 1,3‐alkyl shift in alkyl aryl ethers for the synthesis of chiral 3,3′‐diaryloxindoles using a chiral Brønsted acid catalyst. Preliminary results showed that each enantiomer of the 3,3′‐diaryloxindole, and a racemic mixture, showed different antiproliferative activities against HeLa cell lines by using an MTT assay.     

Organocatalytic Enantioselective Protonation for Photoreduction of Activated Ketones and Ketimines Induced by Visible Light

The first catalytic asymmetric photoreduction of 1,2‐diketones and α‐keto ketimines under visible light irradiation is reported. A transition‐metal‐free synergistic catalysis platform harnessing dicyanopyrazine‐derived chromophore (DPZ) as the photoredox catalyst and a non‐covalent chiral organocatalyst is effective for these transformations. With the flexible use of a chiral Brønsted acid or base in H⁺ transfer interchange to control the elusive enantioselective protonation, a variety of chiral α‐hydroxy ketones and α‐amino ketones were obtained with high yields and enantioselectivities.     

Chiral Brønsted Acid from Chiral Phosphoric Acid Boron Complex and Water: Asymmetric Reduction of Indoles

A new chiral Brønsted acid, generated in situ from a chiral phosphoric acid boron (CPAB) complex and water, was successfully applied to asymmetric indole reduction. This “designer acid catalyst”, which is more acidic than TsOH as suggested by DFT calculations, allows the unprecedented direct asymmetric reduction of C2‐aryl‐substituted N‐unprotected indoles and features good to excellent enantioselectivities with broad functional group tolerance. DFT calculations and mechanistic experiments indicates that this reaction undergoes C3‐protonation and hydride‐transfer processes. Besides, bulky C2‐alkyl‐substituted N‐unprotected indoles are also suitable for this system.     

Chiral Jacobsen's catalyst immobilized on zinc poly(styrene‐phenylvinylphosphonate)‐phosphate functionalized by diamine as highly efficient and reusable catalyst for alkene epoxidation

Chiral Jacobsen's catalyst anchored on zinc poly(styrene‐phenylvinylphosphonate)‐phosphate (ZnPS‐PVPA) functionalized by diamines shows superior catalytic activities (conversion up to 99%; enantiomeric excess up to 99%) in the enantioselective epoxidations of unfunctional olefins with m ‐chloroperoxybenzoic acid and NaIO₄ as oxidants. The whole chiral salen Mn(III) catalyst, including the ZnPS‐PVPA support and the linker as well as chiral salen Mn ligand together contribute to the chirality of products. The heterogeneous catalyst has the potential for use in industry owing to superior stability (recycling nine times) and activity in large‐scale reactions (such as 200 times).     

Facile Synthesis of Chiral Spirooxindole‐Based Isotetronic Acids and 5‐1H‐Pyrrol‐2‐ones through Cascade Reactions with Bifunctional Organocatalysts

Unprecedented organocatalyzed asymmetric cascade reactions have been developed for the facile synthesis of chiral spirooxindole‐based isotetronic acids and 5‐1H‐pyrrol‐2‐ones.The asymmetric 1,2‐addition reactions of α‐ketoesters to isatins and imines by using an acid–base bifunctional 6′‐OH cinchona alkaloid catalyst, followed by cyclization and enolization of the resulting adducts, gave chiral spiroisotetronic acids and 5‐1H‐pyrrol‐2‐ones, respectively, in excellent optical purities (up to 98 % ee). FT‐IR analysis supported the existence of hydrogen‐bonding interaction between the 6′‐OH group of the cinchona catalyst and an isatin carbonyl group, an interaction that might be crucial for catalyst activity and stereocontrol.     

Catalytic Regio‐ and Enantioselective Alkylation of Conjugated Dienyl Amides

A method for catalytic asymmetric alkylation of conjugated dienyl amides has been developed and it allows efficient and high‐yielding transformations of a wide range of polyconjugated amides into the corresponding chiral products. Smooth addition of organomagnesium reagents to relatively unreactive dienyl amides with excellent 1,6‐ and 1,4‐selectivities, as well as enantioselectivites above 90 %, is achieved owing to the complementary action of the Lewis acid and a chiral copper‐based catalyst.     

Aerobic Asymmetric Dehydrogenative Cross‐Coupling between Two CH Groups Catalyzed by a Chiral‐at‐Metal Rhodium Complex

A sustainable C? C bond formation is merged with the catalytic asymmetric generation of one or two stereocenters. The introduced catalytic asymmetric cross‐coupling of two C? H groups with molecular oxygen as the oxidant profits from the oxidative robustness of a chiral‐at‐metal rhodium(III) catalyst and exploits an autoxidation mechanism or visible‐light photosensitized oxidation. In the latter case, the catalyst serves a dual function, namely as a chiral Lewis acid for catalyzing enantioselective enolate chemistry and at the same time as a visible‐light‐driven photoredox catalyst.     

Enantioselective Dearomatization of Naphthol Derivatives with Allylic Alcohols by Cooperative Iridium and Brønsted Acid Catalysis

The combination of a transition‐metal catalyst and organocatalyst was designed to achieve a highly enantioselective system for the allylic dearomatization reaction of naphthols with racemic secondary allylic alcohols. The desired β‐naphthalenones, bearing an all‐carbon quaternary center, were obtained in good yields with high chemo‐ and enantioselectivities. The cooperative catalytic system, involving a chiral iridium complex and phosphoric acid, provided measurable improvements in yields, and chemo‐ and enantioselectivities relative to single‐catalyst systems. Control experiments indicated that the chiral iridium complex functions as a key species in the control of the absolute configuration, thus enabling the formation of both β‐naphthalenone enantiomers by simply employing opposite enantiomeric ligands.     

Lewis Acid Catalyzed Asymmetric Three‐Component Coupling Reaction: Facile Synthesis of α‐Fluoromethylated Tertiary Alcohols

A chiral dicationic palladium complex is found to be an efficient Lewis acid catalyst for the synthesis of α‐fluoromethyl‐substituted tertiary alcohols using a three‐component coupling reaction. The reaction transforms three simple and readily available components (terminal alkyne, arene, and fluoromethylpyruvate) to valuable chiral organofluorine compounds. This strategy is completely atom‐economical and results in perfect regioselectivities and high enantioselectivities of the corresponding tertiary allylic alcohols in good to excellent yields.     

Enantioselective Aza Michael‐Type Addition to Alkenyl Benzimidazoles Catalyzed by a Chiral Phosphoric Acid

Highly enantioselective Michael‐type addition (MTA) reactions between N‐protected alkenyl benzimidazoles and either pyrazoles or indazoles as nitrogen nucleophiles are accomplished for the first time using chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcomes, where the catalyst substituent and the N‐protecting group of benzimidazole contributed to the resulting high enantioselectivity.