Chiral Iodine‐Catalyzed Dearomatizative Spirocyclization for the Enantioselective Construction of an All‐Carbon Stereogenic Center

The first enantioselective dearomatizative spirocyclization of 1‐hydroxy‐N‐aryl‐2‐naphthamide derivatives has been accomplished by chiral organoiodine catalysis to stereoselectively create an all‐carbon stereogenic center, providing a straightforward approach to access spirooxindole derivatives in good yields and with high to excellent levels of enantioselectivity. Chiral hypervalent phenyl‐λ³‐iodanes generated in situ from the oxidation of the chiral phenyl iodine actually participate in the asymmetric oxidative dearomatizative spirocyclization reaction.     

Enantioselective Synthesis of Pyrrole‐Based Spiro‐ and Polycyclic Derivatives by Iridium‐Catalyzed Asymmetric Allylic Dearomatization and Controllable Migration Reactions

The first highly diastereo‐ and enantioselective synthesis of five‐membered spiro‐2H‐pyrroles was achieved using an Ir‐catalyzed asymmetric allylic dearomatization reaction. The spiro‐2H‐pyrrole derivatives readily undergo a controllable and stereospecific allylic migration under acid catalysis, providing polycyclic pyrrole derivatives in excellent yields and ee values. Additionally, the novel Ir‐complex K1 , derived from [Ir(cod)Cl]₂ (cod=1,5‐cyclooctadiene) and N‐benzhydryl‐N‐phenyldinaphthophosphoramidite (BHPphos), showed excellent control of both diastereo‐ and enantioselectivities.     

Asymmetric Fluorinative Dearomatization of Tryptophol Derivatives by Chiral Anion Phase‐Transfer Catalysis

An asymmetric fluorinative dearomatization reaction of tryptophol derivatives was developed via chiral anion phase‐transfer catalysis. Various fluorinated furoindolines were obtained in moderate to excellent yields and enantioselectivity in the presence of Selectfluor. The preliminary mechanistic studies suggested the existence of an in situ formed tryptophol boronic ester plays a critical role in determining the enantioselectivity. This method features the facile introduction of a fluorine atom in a highly enantioselective manner and construction of two contiguous quaternary stereogenic centers.     

Cooperative Activation with Chiral Nucleophilic Catalysts and N‐Haloimides: Enantioselective Iodolactonization of 4‐Arylmethyl‐4‐pentenoic Acids

Chiral triaryl phosphates promote the enantioselective iodolactonization of 4‐substituted 4‐pentenoic acids to give the corresponding iodolactones in high yields with high enantioselectivity. N‐Chlorophthalimide (NCP) is employed as a Lewis acidic activator and oxidant of I₂ for the present iodolactonization. In combination with 1.5 equivalents of NCP, only 0.5 equivalents of I₂ are sufficient to generate the iodinating reagent.     

Asymmetric Hydroxylative Phenol Dearomatization through In Situ Generation of Iodanes from Chiral Iodoarenes and m‐CPBA

′I′ is all the hype : A twofold excess of iodoarene in the title reaction leads to ortho‐quinols in good yields, whereas organocatalytic versions of this reaction enable subsequent epoxidation in a regio‐ and diastereoselective fashion. Chiral iodobiarenes led to enantioselectivities up to 50 % ee. m‐CPBA=meta‐chloroperoxybenzoic acid.

     

Asymmetric Dearomatization of β‐Naphthols through an Amination Reaction Catalyzed by a Chiral Phosphoric Acid

A highly efficient catalytic asymmetric dearomatization of naphthols by means of an electrophilic amination reaction catalyzed by chiral phosphoric acid is presented. This protocol provides a facile access to functionalized β‐naphthalenone compounds with a chiral quaternary carbon center in excellent yields and enantioselectivity (up to 99 % yield, up to 96 % ee).     

Direct Asymmetric Dearomatization of 2‐Naphthols by Scandium‐Catalyzed Electrophilic Amination

Catalytic asymmetric aminative dearomatization of 1‐substituted 2‐naphthols was successfully implemented with electrophilic azodicarboxylates under the catalysis of chiral Sc^III/pybox complexes. This intermolecular reaction represents a hitherto unknown enantioselective C? N bond‐forming process through direct dearomatization of phenolic compounds to generate chiral nitrogen‐containing quaternary carbon stereocenters.     

Helical Multi‐Coordination Anion‐Binding Catalysts for the Highly Enantioselective Dearomatization of Pyrylium Derivatives

A general and highly enantioselective synthesis of oxygen heterocycles from readily available in situ generated pyrylium derivatives has been realized by embracing a multi‐coordination approach with helical anion‐binding tetrakistriazole catalysts. The high activity of the tetrakistriazole (TetraTri) catalysts, with distinct confined anion‐binding pockets, allows for remarkably low catalyst loadings (down to 0.05 mol %), while providing a simple access to chiral chromanones and dihydropyrones in high enantioselectivities (up to 98:2 e.r.). Moreover, experimental and theoretical studies provide new insights into the hydrogen‐donor ability and key binding interactions of the TetraTri catalysts and its host:guest complexes, suggesting the formation of a 1:3 species.     

Catalytic Asymmetric Dearomatization by Visible‐Light‐Activated [2+2] Photocycloaddition

A novel method for the catalytic asymmetric dearomatization by visible‐light‐activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, thereby providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2‐position with a chelating N‐acylpyrazole moiety which permits the coordination of a visible‐light‐activatable chiral‐at‐rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol.     

Copper‐Catalyzed Intermolecular Asymmetric Propargylic Dearomatization of Indoles

The first copper‐catalyzed intermolecular dearomatization of indoles by an asymmetric propargylic substitution reaction was developed. This method provides a highly efficient synthesis of versatile furoindoline and pyrroloindoline derivatives containing a quaternary carbon stereogenic center and a terminal alkyne moiety with up to 86 % yield and 98 % ee.     

Highly Enantioselective Nucleophilic Dearomatization of Pyridines by Anion‐Binding Catalysis

The asymmetric dearomatization of N‐heterocycles is an important synthetic method to gain bioactive and synthetically valuable chiral heterocycles. However, the catalytic enantio‐ and regioselective dearomatization of the simplest six‐membered‐ring N‐heteroarenes, the pyridines, is still very challenging. The first anion‐binding‐catalyzed, highly enantioselective nucleophilic dearomatization of pyridines with triazole‐based H‐bond donor catalysts is presented. Contrary to other more common NH‐based H‐bond donors, this type of organocatalyst shows a prominent higher C2‐regioselectivity and is able to promote high enantioinductions via formation of a close chiral anion‐pair complex with a preformed N‐acyl pyridinium ionic intermediate. This method offers a straightforward and useful synthetic approach to chiral N‐heterocycles from abundant and readily available pyridines.     

Catalytic Enantioselective Flow Processes with Solid‐Supported Chiral Catalysts

Sustainability concerns are the wind in the sails for the development of novel, more selective catalytic processes. Hence, chiral catalysts play a crucial role in the green production of enantioenriched compounds. To further increase the green profile of this approach, the use of solid‐supported catalytic species is appealing due to the reduced generation of waste, as well as the possibility of reusing the precious catalyst. Even more attractive is the implementation of flow processes based on these immobilized catalysts, a flexible strategy that allows to generate from milli‐ to multi‐gram amounts of chiral product with a reduced footprint set‐up. Herein, we will present the efforts devoted in our laboratory towards the immobilization of chiral catalysts and their use in single‐pass, highly enantioselective, flow processes. Proline, diarylprolinols, other aminocatalysts, squaramides, thioureas, phosphoric acids and even chiral ligands and metal‐based catalysts constitute our current toolkit of supported species for enantioselective catalysis.     

Organocatalytic Asymmetric Arylative Dearomatization of 2,3‐Disubstituted Indoles Enabled by Tandem Reactions

The organocatalytic asymmetric arylative dearomatization of indoles was achieved through two tandem approaches involving 2,3‐disubstituted indoles and quinone imine ketals. One approach utilized the enantioselective cascade 1,4 addition/alcohol elimination reaction, the other employed the one‐pot tandem arylative dearomatization/transfer hydrogenation sequence. In both cases, enantiomerically pure indole derivatives that bear an all‐carbon quaternary stereogenic center were generated in high yields and excellent stereoselectivities (all d.r.>95:5, up to 99 % ee).     

Iridium‐Catalyzed Intermolecular Asymmetric Dearomatization of β‐Naphthols with Allyl Alcohols or Allyl Ethers

An Ir‐catalyzed intermolecular asymmetric dearomatization reaction of β‐naphthols with allyl alcohols or allyl ethers was developed. When an iridium catalyst generated from [Ir(COD)Cl]₂ (COD=cyclooctadiene) and a chiral P/olefin ligand is employed, highly functionalized β‐naphthalenone compounds bearing an all‐carbon‐substituted quaternary chiral center were obtained in up to 92 % yield and 98 % ee . The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of atom economy. Allyl ethers were found to undergo asymmetric allylic substitution reaction under Ir catalysis for the first time. The diverse transformations of the dearomatized product to various motifs render this method attractive.     

Enantioselective Synthesis of 3a‐Amino‐Pyrroloindolines by Copper‐Catalyzed Direct Asymmetric Dearomative Amination of Tryptamines

A direct asymmetric dearomative amination of tryptamines with O‐(2,4‐dinitrophenyl)hydroxylamine (DPH) was achieved using CuBr‐bisoxazoline complex as a catalyst, affording 3a‐amino‐pyrroloindolines in good to excellent enantioselectivity under mild reaction conditions. Furthermore, the synthetic value of this method was demonstrated in the total synthesis of (?)‐psychotriasine in a highly concise manner.     

Iridium‐Catalyzed Intramolecular Asymmetric Allylic Dearomatization Reaction of Benzoxazoles,Benzothiazoles, and Benzimidazoles

An iridium‐catalyzed intramolecular asymmetric allylic dearomatization reaction of benzoxazoles, benzothiazoles, and benzimidazoles was developed. The reaction was found to be compatible with a wide range of five‐membered‐ring electron‐deficient heteroaromatic compounds and furnished the corresponding dearomatized heterocycles in high yield with excellent enantioselectivity.     

Silver(I)‐ or Copper(II)‐Mediated Dearomatization of Aromatic Ynones: Direct Access to Spirocyclic Scaffolds

A high‐yielding silver(I)‐ or copper(II)‐catalyzed dearomatizing spirocyclization strategy allows the conversion of simple aromatic compounds that contain ynone substituents, including indole, anisole, pyrrole, and benzofuran derivatives, into functionalized spirocyclic scaffolds. A high‐yielding asymmetric variant furnishes spirocyclic indolenines in up to 89:11 e.r.