Conspectus Axially chiral compounds have received much attention from chemists because of their widespread appearance in natural products, biologically active compounds, and useful chiral ligands in ...asymmetric catalysis. Because of the importance of this structural motif, the catalytic enantioselective construction of axially chiral scaffolds has been intensively investigated, and great progress has been accomplished. However, the majority of methodologies in this field focus on the use of metal catalysis, whereas approaches involving organocatalysis have started to emerge only recently. This Account describes certain advances in the organocatalytic asymmetric synthesis of axially chiral compounds involving the following strategies: kinetic resolution, desymmetrization, cyclization/addition, direct arylation, and so on. We began our investigation by developing a highly efficient strategy for the kinetic resolution of axially chiral BINAM derivatives involving a chiral Brønsted acid-catalyzed imine formation and transfer hydrogenation cascade process, thereby providing a convenient route to generate chiral BINAM derivatives in high yields with excellent enantioselectivities. The desymmetrization of 1-aryltriazodiones (ATADs) through an organocatalyzed tyrosine clicklike reaction wherein a nucleophile was added to the ATAD afforded an interesting type of axially chiral N-arylurazole in an excellent remote enantiocontrolled manner. We then focused on a direct construction strategy involving cyclization and the addition strategy given the inherent limitations of the kinetic resolution in terms of the chemical yield and the desymmetrization in terms of the substrate scope. By utilizing the catalytic enantioselective Paal–Knorr reaction, we disclosed a general and efficient cyclization method to access enantiomerically pure arylpyrroles. The direct heterocycle formation and the stepwise method, which was executed in a one-pot fashion containing enantioselective cyclization and subsequent aromatization, were successfully applied for the construction of diverse axially chiral arylquinazolinones catalyzed by chiral Brønsted acids. We discovered the asymmetric organocatalytic approach to construct axially chiral styrenes through the 1,4-addition of arylalkynals in good chemical yields and enantioselectivities. Such structural motifs are important precursors for further transformations into biologically active compounds and useful synthetic intermediates and may have potential applications in asymmetric syntheses as olefin ligands or organocatalysts. To further tackle this challenge, we accomplished the phosphoric acid-catalyzed enantioselective direct arylative reactions of 2-naphthol and 2-naphthamine with quinone derivatives to deliver efficient access to a class of axially chiral BINOL and NOBIN derivatives in good yields with excellent enantioselectivities under mild reaction conditions. Most importantly, we discovered that the azo group can effectively perform as a directing and activating group for organocatalytic formal aryl C–H functionalization via formal nucleophilic aromatic substitution of azobenzene derivatives. Thus, a wide range of axially chiral arylindoles were synthesized in good yields with excellent enantioselectivities. We anticipate that this strategy will foster the development of many other transformations and motivate a new enthusiasm for organocatalytic enantioselective aryl functionalization. Moreover, SPINOLs are fundamental synthetic precursors in the construction of other chiral organocatalysts and ligands. We have successfully developed a phosphoric acid-catalyzed enantioselective approach for SPINOLs. This approach is highly convergent and functional-group-tolerant for the efficient generation of SPINOLs with good results, thus delivering practical access to this privileged structure.
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.
An organocatalytic strategy for accessing enantioenriched axially chiral IAN analogues has been developed. A class of novel atropisomeric C2‐arylquinoline skeletons were synthesized with high enantiocontrol via chiral phosphoric acid catalyzed heteroannulation of alkynes. The synthetic utility was shown by further transformations into IAN‐type ligand and axially chiral thiourea.
N‐arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C−H amination of arenes has been widely recognized as the most efficient ...approach to access these structures. Conventional strategies involving transition‐metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C–N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N‐arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N‐arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal‐catalyzed C–N cross‐coupling, but also brings about opportunities for the exploitation of structurally diverse N‐aryl atropisomers and OLED materials.
In the frame: Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N‐arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N‐arylcarbazoles in good yields with excellent enantiocontrol. This approach offers opportunities for the exploitation of structurally diverse N‐aryl atropisomers and OLED materials. CPA=chiral phosphoric acid.
A Cu/CPA co‐catalytic system has been developed for achieving the direct hydrophosphinylation of alkynes with phosphine oxides in delivering novel axially chiral phosphorus‐containing alkenes in high ...yields and excellent enantioselectivities (up to 99 % yield and 99 % ee). DFT calculations were performed to elucidate the reaction pathway and the origin of enantiocontrol. This streamlined and modular methodology establishes a new platform for the design and application of new axially chiral styrene‐phosphine ligands.
Through a newly developed Cu/CPA co‐catalytic system, the direct hydrophosphinylation of alkynes with nucleophilic phosphine oxides was achieved to access novel axially chiral phosphorus‐containing alkenes in high yields and excellent enantioselectivities (up to 99 % yield and 99 % ee). DFT calculations were performed to elucidate the reaction pathway and the enantiocontrol model.
Atropisomeric biaryl motifs are ubiquitous in chiral catalysts and ligands. Numerous efficient strategies have been developed for the synthesis of axially chiral biaryls. In contrast, the asymmetric ...construction of o-quinone-aryl atropisomers has yet to be realized. Inspired by the rapid progress of the chemistry of biaryls, here we present our initial investigations about the atroposelective construction of axially chiral arylquinones by a bifunctional chiral phosphoric acid-catalyzed asymmetric conjugate addition and central-to-axial chirality conversion. With o-naphthoquinone as both the electrophile and the oxidant, three types of arylation counterparts, namely 2-naphthylamines, 2-naphthols and indoles, are utilized to assemble a series of atropisomeric scaffolds in good yields and excellent enantioselectivities. This approach not only expands the axially chiral library but also offers a route to a class of potential, chiral biomimetic catalysts.
Axially chiral 2‐arylpyrrole frameworks are efficiently accessed through a direct chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes, which are generated by ...organocatalytic asymmetric N‐alkylation reactions. This approach accommodates a broad scope of substrates with remarkably high chirality transfer efficiency, affording novel atropisomers with a fully substituted pyrrole moiety and high enantiopurities. Given the enantioenriched atropisomeric alkenes, novel heterocyclic 2‐arylazepine atropisomers were realized through a rationally designed ene reaction.
Axially chiral 2‐arylpyrrole frameworks are efficiently accessed through a direct chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes, generated by organocatalytic asymmetric N‐alkylation reactions. This approach accommodates a broad scope of substrates with remarkably high chirality transfer efficiency. Given the enantioenriched atropisomeric alkenes, novel heterocyclic 2‐arylazepine atropisomers were realized through a rationally designed ene reaction.
Described herein is an imidazole ring formation strategy for the synthesis of axially chiral N‐arylbenzimidazoles by means of chiral phosphoric acid catalysis. Two sets of conditions were developed ...to transform two classes of 2‐naphthylamine derivatives into structurally diverse N‐arylbenzimidazole atropisomers with excellent chemo‐ and regioselectivity as well as high levels of enantiocontrol. It is worth reflecting on the unique roles played by the nitroso group in this domino reaction. It functions as a linchpin by first offering an electrophilic site (N) for the initial C−N bond formation while the resulting amine performs the nucleophilic addition to form the second C−N bond. Additionally, it could facilitate the final oxidative aromatization as an oxidant. The atropisomeric products could be conveniently elaborated to a series of axially chiral derivatives, enabling the exploitation of N‐arylbenzimidazoles for their potential utilities in asymmetric catalysis.
A benzimidazole ring formation strategy for the synthesis of axially chiral N‐arylbenzimidazoles by means of chiral phosphoric acid catalysis is presented. Two sets of conditions were developed to transform two classes of 2‐naphthylamine derivatives into structurally diverse N‐arylbenzimidazole atropisomers with excellent chemo‐ and regioselectivity as well as high levels of enantiocontrol.
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.
By judicious development of acylimidazolinone as activating group and the use of a chiral Brønsted acid (CBA) catalyst, the cross‐coupling of 1‐azonaphthalenes with 2‐naphthols was realized with high efficiency, exclusive C4‐selectivity and excellent enantioselectivity. The reaction tolerates various functional groups and stereoretentive conversions of products to other binaphthyl compounds were found viable.
The axially chiral arylquinazolinone acts as a privileged structural scaffold, which is present in a large number of natural products and biologically active compounds as well as in chiral ligands. ...However, a direct catalytic enantioselective approach to access optically pure arylquinazolinones has been underexplored. Here we show a general and efficient approach to access enantiomerically pure arylquinazolinones in one-pot fashion catalysed by chiral phosphoric acids. A variety of axially chiral arylquinazolinones were obtained in high yields with good to excellent enantioselectivities under mild condition. Furthermore, we disclosed a method for atroposelective synthesis of alkyl-substituted arylquinazolinones involving Brønsted acid-catalysed carbon-carbon bond cleavage strategy. Finally, the asymmetric total synthesis of eupolyphagin bearing a cyclic arylquinazolinone skeleton was accomplished with an overall yield of 32% in six steps by utilizing the aforementioned methodology.
The application of Suzuki–Miyaura coupling reaction to forge the atropisomeric biaryls has seen remarkable progress but exploration of this chemistry to directly forge chiral C(aryl)‐C(alkene) axis ...is underdeveloped. The replacement of arene substrates by alkenes intensifies the challenges in terms of reactivity, configurational atropostability of product and selectivity control. By meticulous ligand design and fine‐tuning of reaction parameters, we identified a highly active 3,3′‐triphenylsilyl‐substituted phosphite ligand to realize arene‐alkene Suzuki–Miyaura coupling of hindered aryl halides and vinyl boronates under very mild conditions. The axially chiral acyclic aryl‐alkenes were generated in commendable efficiency, enantioselectivity and E/Z selectivity.
The construction of axially chiral acyclic aryl‐alkene skeletons via classic Suzuki–Miyaura reaction has been challenging compared to the biaryls. Rational optimization established an enabling 3,3′‐triphenylsilyl‐substituted phosphite ligand for asymmetric coupling of hindered aryl halides and vinyl boronates under mild conditions, affording the acyclic aryl‐alkenes in good yield, atroposelectivity and E/Z selectivity.
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