Atropisomers have emerged as important structural scaffolds in natural products, drug design, and asymmetric synthesis. Recently, N−N biaryl atropisomers have drawn increasing interest due to their ...unique structure and relatively stable axes. However, its asymmetric synthesis remains scarce compared to its well‐developed C−C biaryl analogs. In this concept, we summarize the asymmetric synthesis of N−N biaryl atropisomers including N−N pyrrole−pyrrole, N−N pyrrole−indole, N−N indole−indole, and N−N indole−carbazole, during which a series synthetic strategies are highlighted. Also, a synthetic evolution is briefly reviewed and an outlook of N−N biaryl atropisomers synthesis is offered.
Although N−N Biaryl atropisomers has emerged into valuable scaffolds in natural products, drug design and asymmetric synthesis, its asymmetric synthesis is scare until recently. This concept will focus on the asymmetric synthesis of the divergent N−N biaryl atropisomers scaffolds including N−N bipyrroles atropisomers, N−N pyrrole−indole atropisomers, N−N bisindoles atropisomers, N−N indole−carbazole atropisomers.
N−N Atropisomers are a common motif in natural products and represent a significant dimension for exploration in modern pharmaceutical and medicinal chemistry. However, the catalytic atroposelective ...synthesis of such molecules remains challenging, hampering meaningful development. In particular, an enantioselective synthesis of N−N bisindole atropisomers is unprecedented. Herein, the first enantioselective synthesis of N−N bisindole atropisomers via the palladium‐catalyzed de novo construction of one indole skeleton is presented. A wide variety of N−N axially chiral bisindoles were generated in good yields with excellent enantioselectivities via a cascade condensation/N‐arylation reaction. Structurally diverse indole‐pyrrole, indole‐carbazole, and non‐biaryl‐indole atropisomers possessing a chiral N−N axis were accessed using this protocol. Moreover, investigations using density functional theory (DFT) calculations provided insight into the reaction mechanism and enantiocontrol.
An enantioselective synthesis of N−N bisindole atropisomers based on the de novo construction of one indole skeleton is presented. A wide variety of N−N axially chiral bisindoles were obtained in good yields with excellent enantioselectivities. Structurally diverse indole‐pyrrole, indole‐carbazole and non‐biaryl‐indole atropisomers possessing a chiral N−N axis were accessed using this protocol.
Palladium‐catalyzed enantioselective dearomative arylalkynylation of N‐substituted indoles, through a Heck/Sonogashira sequence, was established using a new BINOL‐based phosphoramidite as the chiral ...ligand. A wide range of 2,3‐disubstituted indolines, bearing vicinal quaternary and tertiary stereocenters, were efficiently constructed in one step with excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (>20:1).
Double the function: A highly enantioselective dearomative arylalkynylation of N‐substituted indoles with alkynes has been established by using palladium and a BINOL‐based phosphoramidite as the chiral ligand. A wide range of 2,3‐disubstituted indolines, bearing vicinal tertiary and quaternary stereocenters, were constructed in one step with excellent enantio‐ and diastereoselectivities.
N−C Biaryl atropisomers are prevalent in natural products and bioactive drug molecules. However, the enantioselective synthesis of such molecules has not developed significantly. Particularly, the ...enantioselective synthesis of N−C biaryl atropisomers by stereoselective metal‐catalyzed aryl amination remains unprecedented. Herein, a Pd‐catalyzed cross‐coupling strategy is presented for the synthesis of N−C axially chiral biaryl molecules. A broad spectrum of N−C axially chiral compounds was obtained with excellent enantioselectivities (up to 99 % ee) and good yields (up to 98 %). The practicality of this reaction was validated in the synthesis of useful biological molecules.
A Pd‐catalyzed enantioselective amination of amidines has been developed for the synthesis of N−C biaryl atropisomers. A wide range of benzimidazole derivatives containing N−C axial chirality can be conveniently constructed in excellent yields and enantioselectivities by intramolecular amination.
Over the past few decades, the Buchwald–Hartwig reaction has emerged as a powerful tool for forging C−N bonds, and has been vital to the pharmaceuticals, materials, and catalysis fields. However, ...asymmetric Buchwald–Hartwig amination reactions for constructing centered chirality, planar chirality, and axial chirality remain in their infancy owing to limited substrate scope and laggard ligand design. The recent surge in interest in the synthesis of C−N/N−N atropisomers, has witnessed a renaissance in asymmetric Buchwald–Hartwig amination chemistry as the first practical protocol for the preparation of C−N atropisomers. This review highlights reported asymmetric Buchwald–Hartwig amination protocols and provides a brief overview of their chemical practicality.
The asymmetric version of the Buchwald–Hartwig reaction has been developed as a powerful asymmetric‐catalysis tool bolstered by the great success of its achiral version in the pharmaceuticals, materials, and catalysis fields. This review showcases research into the use of the asymmetric Buchwald–Hartwig reaction for constructing centered, axial, and planar chiralities. A brief overview of the chemistry is also provided based on this research.
The catalytic asymmetric construction of N−N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon‐carbon biaryl atropisomers, ...hampering meaningful development. Herein, the first palladium‐catalyzed enantioselective C−H activation of pyrroles for the synthesis of N−N atropisomers is presented. Structurally diverse indole‐pyrrole atropisomers possessing a chiral N−N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N−N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C−H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N−N atropisomers.
Enantioselective synthesis of N−N indole‐pyrrole and bisindole atropisomers was achieved by a palladium‐catalyzed TDG‐enabled C−H functionalization. A wide variety of the N−N atropisomers were produced in good yields with excellent enantioselectivities by C−H alkenylation, alkynylation, allylation or arylation reactions.
A palladium-catalyzed dearomative arylborylation of indoles is reported, which provides straightforward access to structurally diverse indolines bearing vicinal tetrasubstituted and borylated ...trisubstituted stereocenters in moderate to good yields with excellent diastereoselectivities. By using a BINOL-based chiral phosphoramidite ligand and an sp
2
–sp
3
mixed-boron reagent, an enantioselective dearomative arylborylation was achieved and chiral boron-containing products were accessed in up to 94% ee. Synthetic tranformations of the resulting organoborons were conducted to afford a number of unique indoline derivatives.
Abstract
Transition‐metal‐catalyzed hydroarylation of unsymmetrical internal alkynes remains challenging because of the difficulty in controlling regioselectivity and stereoselectivity. Moreover, the ...enantioselective hydroarylation of alkynes using organoboron reagents has not been reported. Herein, we report for the first time that palladium compounds can catalyze the hydroarylation of 1‐alkynylindoles with organoborons for the synthesis of chiral C−N atropisomers. A series of rarely reported vinylindole atropisomers was synthesized with excellent regio‐, stereo‐ (Z‐selectivity), and enantioselectivity under mild reaction conditions. The ready availability of organoborons and alkynes and the simplicity, high stereoselectivity, and good functional group tolerance of this catalytic system make it highly attractive.
A highly enantioselective intramolecular arylative dearomatization of indoles via palladium-catalyzed reductive Heck reactions was developed. The new strategy led to a series of optically active ...indolines bearing C2-quaternary stereocenters in modest to good yields with excellent enantioselectivities (up to 99% ee).
Diarylamines and related scaffolds are ubiquitous atropisomeric chemotypes in biologically active natural products. However, the catalytic asymmetric synthesis of these axially chiral compounds ...remains largely unexplored. Herein, we report that a BINOL‐derived chiral phosphoric acid (CPA) successfully catalyzed the atroposelective coupling of quinone esters and anilines through direct C−N bond formation to afford N‐aryl quinone atropisomers with an unprecedented intramolecular N−H−O hydrogen bond within a six‐membered ring in good yields and enantioselectivities with the quinone ester as both the electrophile and the oxidant. A gram‐scale experiment demonstrated the utility of this synthetic protocol. Moreover, this methodology provides a platform for the synthesis of structurally diverse secondary amine atropisomers by nucleophilic addition.
A chiral‐phosphoric‐acid‐catalyzed process was developed for the asymmetric synthesis of N‐aryl quinoid atropisomers through direct C−N bond formation. In this way, a broad range of functionalized N‐aryl quinone atropisomers containing an unprecedented intramolecular N−H−O hydrogen bond within a six‐membered ring were constructed in high yields with excellent enantioselectivity.
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