Atroposelective Synthesis of 3-Aryl-Indoles Through a One-Pot 2,3-Difunctionalization of Simple Indoles

Indole and its derivatives represent the most important heterocycles that are widely present in bioactive molecules,natural products and advanced materials,and thus functionalization of simple indoles to construct complex indole derivatives is a research area of great current interest.2,3-Difunctionalization of indoles has been extensively studied,but the reported examples are limited to the synthesis of 2,3-disubstituted indole derivatives or dearomatized products containing central chirality.Until now,atroposelective 2,3-difunctionalization of simple indoles for the synthesis of axially chiral molecules is unknown.In this article,we report a straightforward and general strategy for atroposelective 2,3-difunctionalization of simple indoles,forming indole-containing axially chiral products in good yields and excellent enantioselectivities.The strategy we introduce herein may lead to the discovery of new approaches for multifunctionalization of indoles and other heterocyclic scaffolds,thus accessing novel axially chiral heteroarene-containing scaffolds that may find applications in medicinal chemistry and asymmetric catalysis.

Atroposelective Synthesis of 2-Arylindoles via Chiral Phosphoric Acid-Catalyzed Direct Amination of Indoles

Indole-based atropisomers are a very important class of axially chiral compounds.However,the atroposelective synthesis of axially chiral 2-arylindole remains largely unexplored.In this study,we report the successful synthesis of atropisomeric 2-arylindoles using direct amination of indoles with p-quinonediimines in the presence of chiral phosphoric acid as a catalyst.Quinonediimine acts as an aminating reagent through formal polarity inversion of imine.The malonate group on the 2-aryl of 2-indoles was found to be essen-tial for high enantioselectivity of the products.This could be due to the additional interaction between the ester group and the cata-lyst,as well as the intramolecular hydrogen bonding.Our findings provide a new strategy for the asymmetric construction of 2-arylindole atropisomers.

Design and synthesis of axially chiral aryl-pyrroloindoles via the strategy of organocatalytic asymmetric(2+3)cyclization

The catalytic asymmetric construction of axially chiral indole-based frameworks is an important area of research due to the unique characteristics of such frameworks.Nevertheless,research in this area is still in its infancy and has some challenges,such as designing and constructing new classes of axially chiral indole-based scaffolds and developing their applications in chiral catalysts,ligands,etc.To overcome these challenges,we present herein the design and atroposelective synthesis of aryl-pyrroloindoles as a new class of axially chiral indole-based scaffolds via the strategy of organocatalytic asymmetric(2+3)cyclization between 3-arylindoles and propargylic alcohols.More importantly,this new class of axially chiral scaffolds was derived into phosphines,which served as efficient chiral ligands in palladium-catalyzed asymmetric reactions.Moreover,theoretical calculations provided an in-depth understanding of the reaction mechanism.This work offers a new strategy for constructing axially chiral indole-based scaffolds,which are promising for finding more applications in asymmetric catalysis.

Catalytic Asymmetric Synthesis of Axially Chiral 3,3'-Bisindoles by Direct Coupling of Indole Rings

Comprehensive Summary A new strategy for the enantioselective synthesis of axially chiral 3,3'-bisindoles was devised by the direct coupling of two indole rings.This strategy makes use of the C3-umpolung reactivity of 2-indolylmethanols,which enables the catalytic asymmetric addition reaction of 2-indolylmethanols with rationally designed 2-substituted indoles,thus constructing axially chiral 3,3'-bisindole scaffolds in overall excellent yields(up to 98%)with high enantioselectivities(up to 96:4 er).This approach not only has overcome the challenges in constructing axially chiral five-five-membered heterobiaryls,but also represents a new application of the C3-umpolung reactivity of 2-indolylmethanols in asymmetric catalysis.More importantly,this class of axially chiral 3,3'-bisindoles can undergo a variety of post-functionalizations to give axially chiral 3,3'-bisindole-based organocatalysts,which have found their preliminary applications in asymmetric catalysis.

Design and catalytic atroposelective synthesis of axially chiral isochromenone-indoles

The catalytic atroposelective synthesis of axially chiral isochromenone-indoles has been established by the strategy of designing homophthalic anhydride-based indole derivatives as a new type of indole-based platform molecules for dynamic kinetic resolution.By this strategy,a wide range of axially chiral isochromenone-indoles were synthesized in high yields with excellent enantioselectivities(up to 98% yield,97% ee) via the catalytic asymmetric sulfonylation reaction of homophthalic anhydridebased indole derivatives with aryl sulfonyl chlorides under the catalysis of chiral quaternary ammonium salt as a phase-transfer catalyst.

Catalytic Atroposelective Catellani Reaction Enables Construction of Axially Chiral Biaryl Monophosphine Oxides

An unprecedented atroposelective Catellani reaction between phosphine oxide-containing aryl bromides,aryliodides,and nucleophiles for the construction of phosphine-containing biaryl atropisomers was established using an enantiopure norbornene derivative as the chiral mediator.A broad range of atropisomeric biaryl-based monophosphine oxides were obtained in good efficiency with excellent enantioselectivity.

Atropoenantioselective synthesis of heterobiaryl N-oxides via dynamic kinetic resolution

A highly efficient enantioselective construction of heterobiaryl N-oxides was developed.A series of axially chiral heterobiaryl N-oxides were generated via the cascade reaction of aminobenzamides with heterobiaryl aldehydes in the presence of chiral phosphoric acids.A number of atropisomers were afforded in moderate to good yields with excellent enantioselectivities and diastereoselectivities.Preliminary results demonstrate that the heterobiaryl N-oxides can be utilized as efficient chiral ligands in asymmetric catalysis.

Diversity-Oriented Enantioselective Construction of Atropisomeric Heterobiaryls and N-Aryl Indoles via Vinylidene Ortho-Quinone Methides

An atroposelectively diversity-oriented synthetic strategy was developed for the divergent synthesis of axially chiral heterocycles through organocatalytic asymmetric intramolecular annulation of alkyne via vinylidene ortho-quinone methides(VQMs).The methodology reported herein was characterized by rapid reactions(most completed in seconds),high stereocontrol(up to 98%ee),and broad substrate scope(60 examples of different skeletal types,stereogenicelements,andring sizes).

Merging C–H and C–C Activation in Pd(Ⅱ)-Catalyzed Enantioselective Synthesis of Axially Chiral Biaryls

The merging of C-H and C-C bond cleavage into one single chemical process remains a daunting challenge,especially in an asymmetric manner.Herein,a Pd(Ⅱ)-catalyzed enantioselective tandem C-H/C-C activation for the synthesis of axially chiral biaryls is described.Two types of simple cyclopropanes,such as vinylcyclopropanes and cyclopropanols,were used as efficient and readily available coupling partners.

N-heterocyclic carbene-catalyzed atroposelective synthesis of axially chiral 5-aryl 2-pyrones from enals

Axially chiral molecules have been widely used in inorganic,material and medicinal chemistry.Compared with well-established N-heterocyclic carbene(NHC)-catalyzed asymmetric construction of centrally chiral molecules,NHC-catalyzed atroposelective synthesis of axially chiral molecules remains largely underdeveloped.Notably,alkynyl acyl azolium intermediates were commonly used in constructing a heteroaryl ring to furnish axially enantioenriched heteroaryl-aryls.The inherent character of the intermediates often led to react with sterically hindered substrates difficultly.Herein,we have successfully disclosed the atroposelective synthesis of axially chiral heteroaryl-aryls from sterically hindered enols through the use of chiral NHCs as catalysts for highly enantioselective Coates-Claisen rearrangements via catalytically generatedα,β-unsaturated acyl azoliums.This approach will enable the concise synthesis of valuable tetra-ortho-substituted 2-pyrones in one step with good yield and chirality control.

A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

(Z)-7-Aryl-5-acyldibenzo[e,g][1,4]diazocin-6(5H)-one,a unique saddle-shaped bridged biaryl containing synchronized aryl–aryl and N-aryl stereogenic axes,was constructed for the first time in good yields with up to 96%enantiomeric excess(ee).The threecomponent coupling reaction,involving aryl iodide,2,2′-diisocyano-1,1′-biphenyl,and carboxylate,constructs the eight-membered ring in an atroposelective manner through palladium-catalyzed double isocyanide insertion followed by C–Obond formation during reductive elimination and amide formation after acyl transfer.