Synthesis of Axially Chiral Biaryls through Cobalt(II)-Catalyzed Atroposelective C-H Arylation.

Highly efficient synthesis of axially chiral biaryl amines through cobalt-catalyzed atroposelective C-H arylation using easily accessible cobalt(II) salt and salicyloxazoline ligand has been reported. This methodology provides a straightforward and sustainable access to a broad range of enantioenriched biaryl-2-amines in good yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee). The synthetic utility of the unprecedented method is highlighted by its scalability and diverse transformations.

Organocatalytic Atroposelective Cross-Coupling of 1-Azonaphthalenes and 2-Naphthols.

Atroposelective cross-coupling is one of the most appealing routes to construct axially chiral binaphthyl molecules due to the modular and succinct nature. Although transition-metal-catalyzed cross-couplings offer reliable synthetic means, alternative reaction modes that could be applied to broader substrate range without their pre-functionalization is highly desirable. Herein we show that the application of chiral Brønsted acid catalyst as organocatalyst could accomplish cross-coupling of 1-azonaphthalenes and 2-naphthols with high efficiency, exclusive C4-selectivity as well as excellent enantioselectivity and functional group compatibility. The identification of acylimidazolinone auxiliary for azo activating group, effective remote catalyst control and arene resonance effect synergistically play key roles in the development of this method. The utility is further demonstrated by transformations of the products into other binaphthyl compounds with perfectly retained axial chirality.

Construction of Non-Biaryl Atropisomeric Amide Scaffolds Bearing a C-N Axis via Enantioselective Catalysis.

The significant scaffold offered by atropisomeric amides with a C-N chiral axis has been extensively utilized for pharmaceuticals, agricultural science, and organic syntheses. As a result, the field of atropisomer synthesis has attracted considerable interest within chemistry communities. To date, a range of catalytic atroposelective approaches has been reported for the efficient construction of these challenging scaffolds. However, greatly concise and highly useful methodologies for the synthesis of these atropisomeric compounds, focusing on transition-metal, chiral amine, and phosphoric acid catalysis reactions, etc., are still desirable. Hence, it is indispensable to succinctly and systematically present all such reports by means of disclosing the mechanistic analysis and application, as well as the challenges and issues associated with the establishment of these atropisomers. In this review, we summarize the development of catalytic asymmetric synthetic strategies to access non-biaryl atropisomers rotating around a C-N chiral axis, including the reaction methods, mechanism, late-stage transformations, and applications.

Catalytic Atroposelective Electrophilic Amination of Indoles.

Reported here is the first catalytic atroposelective electrophilic amination of indoles, which delivers functionalized atropochiral N-sulfonyl-3-arylaminoindoles with excellent optical purity. This reaction was furnished by 1,6-nucleophilic addition to p-quinone diimines. Control experiments suggest an ionic mechanism that differs from the radical addition pathway commonly proposed for 1,6-addition to quinones. The origin of 1,6-addition selectivity was investigated through computational studies. Preliminary studies show that the obtained 3-aminoindoles atropisomers exhibit anticancer activities. This method is valuable with respect to enlarging the toolbox for atropochiral amine derivatives.

Rhodium-Catalyzed Atroposelective Click Cycloaddition of Azides and Alkynes.

The cycloaddition of azides and alkynes is the leading click chemistry technology and has been widely used in drug discovery, biology and material sciences. However, the development of a modular and scalable enantioselective click cycloaddition remains a long-standing challenge. Herein, we report a rhodium-catalyzed enantioselective click cycloaddition of azides and alkynes for rapid and modular access to atropisomeric triazoles in excellent yields and enantioselectivities. The process is mild, efficient and scalable, and features broad substrate scope.

Atroposelective Construction of Nine-Membered Carbonate-Bridged Biaryls.

We herein demonstrated an efficient method for the atroposelective construction of nine-membered carbonate-bridged biaryls through vinylidene ortho-quinone methide (VQM) intermediates. Diverse products with desirable pharmacological features were synthesized in satisfying yields and good to excellent enantioselectivities. In subsequent bioassays, several agents showed considerable antiproliferative activity via the mitochondrial-related apoptosis mechanism. Further transformations produced more structural diversity and may inspire new ideas for developing functional molecules.

Synthesis of Axially Chiral CF3 -Substituted 2-Arylpyrroles by Sequential Phosphine-Catalyzed Asymmetric [3+2] Annulation and Oxidative Central-to-Axial Chirality Transfer.

A sequential phosphine-catalyzed asymmetric [3+2] annulation of aldimines with allenoates and oxidative central-to-axial chirality transfer strategy has been developed. This approach is operationally simple, allowing for rapid access to a range of axially chiral CF3 -containing 2-arylpyrroles with high enantiomeric excess. Furthermore, an atroposelective synthesis of esaxerenone is presented, illustrating the practical potential of the reported method.

Single-Step Synthesis of Atropisomers with Vicinal C-C and C-N Diaxes by Cobalt-Catalyzed Atroposelective C-H Annulation.

The atroposelective synthesis of atropisomers with vicinal diaxes remains rare and challenging, due to the steric influence between the two axes and their unique topology. Herein, we disclose a single-step construction of atropisomers with vicinal C-C and C-N chiral diaxes by cyclopentadiene (Cp)-free cobalt-catalyzed intramolecular atroposelective C-H annulation, providing the desired diaxial atropisomers of unique structures with decent stereocontrols of both axes (up to >99 % ee and 70 : 1 dr). The optically pure products bearing fluorophores show circular polarized luminescence (CPL) properties, being candidate materials for potential CPL applications. Atropisomerization experiments and density function theory (DFT) calculations are conducted to study the rotational barriers and rotation pathways of the diaxes.

Atroposelective Synthesis of Triaryl α-Pyranones with 1,2-Diaxes by N-Heterocyclic Carbene Organocatalysis.

Atropisomers bearing multiple stereogenic axes are of increasing importance to the field of material science, pharmaceuticals, and catalysis. However, the atroposelective construction of multi-axis atropisomers remains rare and challenging, due to the intrinsical difficulties in the stereo-control of the multiple stereogenic axes. Herein, we demonstrate a single-step construction of a new class of 1,2-diaxially chiral triaryl α-pyranones by an N-heterocyclic carbene organocatalytic asymmetric [3+3] annulation of well-designed alkynyl acylazolium precursors and enolizable sterically hindered 2-aryl ketones. The protocol features broad substrate scope (>50 examples), excellent stereo-control (most cases >20 : 1 dr, up to 99.5 : 0.5 er), and potentially useful synthetic applications. The success of this reaction relies on the rational design of structurally matched reaction partners and the careful selection of the asymmetric catalytic system. DFT calculations have also been performed to discover and rationalize the origin of the high stereoselectivity of this reaction.

The Single-Component Flavin Reductase/Flavin-Dependent Halogenase AetF is a Versatile Catalyst for Selective Bromination and Iodination of Arenes and Olefins.

Flavin-dependent halogenases (FDHs) natively catalyze selective halogenation of electron rich aromatic and enolate groups. Nearly all FDHs reported to date require a separate flavin reductase to supply them with FADH2 , which complicates biocatalysis applications. In this study, we establish that the single component flavin reductase/flavin dependent halogenase AetF catalyzes halogenation of a diverse set of substrates using a commercially available glucose dehydrogenase to drive its halogenase activity. High site selectivity, activity on relatively unactivated substrates, and high enantioselectivity for atroposelective bromination and bromolactonization was demonstrated. Site-selective iodination and enantioselective cycloiodoetherification was also possible using AetF. The substrate and reaction scope of AetF suggest that it has the potential to greatly improve the utility of biocatalytic halogenation.

Experimental and Computational Studies on the Directing Ability of Chalcogenoethers in Palladium-Catalyzed Atroposelective C-H Olefination and Allylation.

We present herein our experimental and DFT computational studies on the directing ability of chalcogenoether motifs in Pd-catalyzed atroposelective C-H functionalization. The thioether motif was found to be a superior directing group compared to the corresponding ether and selenoether in terms of reactivity and enantiocontrol. Remarkably, DFT calculation provided a predictive model for the optimization of reaction conditions and the interpretation of the origin of enantioselectivity. Both Pd-catalyzed enantioselective C-H olefination and allylation reactions were successfully developed using chiral phosphoric acids as efficient ligands, providing a broad range of axially chiral biaryls in good yields with excellent enantioselectivities. The highly enantio- and diastereoselective construction of polyaryls bearing multiple stereogenic axes, gram-scale reaction and various chemical transformations make this protocol more attractive and significant.

Atroposelective Synthesis of 1,1'-Bipyrroles Bearing a Chiral N-N Axis: Chiral Phosphoric Acid Catalysis with Lewis Acid Induced Enantiodivergence.

We present herein a highly efficient atroposelective synthesis of axially chiral 1,1'-bipyrroles bearing an N-N linkage from simple hydrazine and 1,4-diones. Further product derivatizations led to axially chiral bifunctional compounds with high potential in asymmetric catalysis. For this chrial phosphoric acid (CPA)-catalyzed double Paal-Knorr reaction, an intriguing Fe(OTf)3 -induced enantiodivergence was also observed.

Organocatalytic Atroposelective Synthesis of N-N Axially Chiral Indoles and Pyrroles by De Novo Ring Formation.

The first highly atroposelective construction of N-N axially chiral indole scaffolds was established via a new strategy of de novo ring formation. This strategy makes use of the organocatalytic asymmetric Paal-Knorr reaction of well-designed N-aminoindoles with 1,4-diketones, thus affording N-pyrrolylindoles in high yields and with excellent atroposelectivities (up to 98 % yield, 96 % ee). In addition, this strategy is applicable for the atroposelective synthesis of N-N axially chiral bispyrroles (up to 98 % yield, 97 % ee). More importantly, such N-N axially chiral heterocycles can be converted into chiral organocatalysts with applications in asymmetric catalysis, and some molecules display potent anticancer activity. This work not only provides a new strategy for the atroposelective synthesis of N-N axially chiral molecules but also offers new members of the N-N atropisomer family with promising applications in synthetic and medicinal chemistry.

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C-H Olefination Enabled by an Amino Amide Transient Directing Group.

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through PdII -catalyzed atroposelective C-H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in CoIII -catalyzed enantioselective C(sp3 )-H amidation of thioamide. Mechanistic studies suggest that C-H cleavage is the enantioselectivity-determining step.

Design and Atroposelective Construction of IAN analogues by Organocatalytic Asymmetric Heteroannulation of Alkynes.

An organocatalytic atroposelective strategy for accessing enantioenriched axially chiral IAN analogues was developed for the first time. A class of novel atropisomeric C2-arylquinoline skeletons were synthesized with high enantiocontrol via chiral phosphoric-acid-catalyzed heteroannulation of in situ generated vinylidene ortho-quinone methide (VQM) intermediates with ortho-aminophenones. The strategy tolerated a broad substrate scope, providing a facile organocatalytic approach to IAN analogues in good yields and excellent enantioselectivities under mild reaction conditions. Moreover, the synthetic utility of this methodology was illustrated through further transformations into IAN-type ligand and axially chiral thiourea.

Synthesis of Axially Chiral Biaryl-2-amines by PdII -Catalyzed Free-Amine-Directed Atroposelective C-H Olefination.

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by PdII -catalyzed atroposelective C-H olefination. A broad range of axially chiral biaryl-2-amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram-scale synthesis. The resulting axially chiral biaryl-2-amines also provide a platform for the synthesis of a set of chiral ligands.

Organocatalytic Asymmetric Annulation of ortho-Alkynylanilines: Synthesis of Axially Chiral Naphthyl-C2-indoles.

A chiral Brønsted base catalyzed asymmetric annulation of ortho-alkynylanilines has been developed to access axially chiral naphthyl-C2-indoles via vinylidene ortho-quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl-C2-indole skeletons with excellent enantioselectivity and functional-group tolerance. This transformation was applicable to decagram-scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl-C2-indoles for a series of carbon-heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl-C2-indoles were applied as a chiral skeleton for organocatalytic aza-Baylis-Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.

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.

Enantioselective Synthesis of Biaryl Atropisomers by Pd-Catalyzed C-H Olefination using Chiral Spiro Phosphoric Acid Ligands.

The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C-H activation. Herein, we reported the synthesis of axially chiral biaryls by Pd-catalyzed atroposelective C-H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.

Scalable, Stereocontrolled Formal Syntheses of (+)-Isoschizandrin and (+)-Steganone: Development and Applications of Palladium(II)-Catalyzed Atroposelective C-H Alkynylation.

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium-catalyzed atroposelective C-H alkynylation and its application in gram-scale, stereocontrolled formal syntheses of (+)-isoschizandrin and (+)-steganone. tert-Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).