Cu(I)-Catalyzed Asymmetric Arylation of Pyrroles with Diaryliodonium Salts toward the Synthesis of N–N Atropisomers

Xu, Qi; Zhang, Huan; Ge, Fang-Bei; Wang, Xiaomei; Zhang, Peng; Lu, Chuan‐Jun; Liu, Renrong

doi:10.1021/acs.orglett.2c00812

Cited by 51 publications

(21 citation statements)

References 73 publications

(26 reference statements)

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“…To advance the divergent synthesis of N−N atropisomers, a copper(I)-catalyzed asymmetric arylation of pyrroles protocol was developed by our group. 12 Diaryliodonium salts are excellent arylation reagents that are commonly used in copper-mediated reactions. 28 With the assistance of a copper catalyst, enantioselective arylative cyclizations and arylative semipinacol rearrangement were reported (Scheme 14a left).…”

Section: Desymmetrization Strategymentioning

confidence: 99%

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Feng,

Lu,

Liu

2023

Acc. Chem. Res.

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Metrics & More Article Recommendations CONSPECTUS: Atropisomers bearing a rotation-restricted axis are common structural units in natural products, chiral ligands, and drugs; thus, the prevalence of asymmetric synthesis has increased in recent decades. Research into atropisomers featuring an N-containing axis (N−X atropisomers) remains in its infancy compared with the well-developed C−C atropisomer analogue. Notably, N−X atropisomers could offer divergent scaffolds, which are extremely important in bioactive molecules. The asymmetric synthesis of N−X atropisomers is recognized as both appealing and challenging. Recently, we devoted our efforts to the catalytic asymmetric synthesis of N−X atropisomers, benzimidazole−aryl N−C atropisomers, indole−aryl N−C atropisomers, hydrogen-bond-assisted N−C atropisomers, pyrrole−pyrrole N−N atropisomers, pyrrole−indole N−N atropisomers, and indole−indole N−N atropisomers. To obtain the N−C atropisomers, an asymmetric Buchwald−Hartwig reaction of amidines or enamines was employed. Using a Pd(OAc) 2 /(S)-BINAP or Pd(OAc) 2 /(S)-Xyl-BINAP catalyst system, benzimidazole−aryl N−C atropisomers and indole−aryl N−C atropisomers were readily obtained. To address the issue of the reduced stability of the diarylamine axis, a six-membered intramolecular N−H−O hydrogen bond was introduced into the N−C atropisomer scaffold. A tandem N-arylation/oxidation process was used for the chiral phosphoric acid (CPA)-catalyzed asymmetric synthesis of N-aryl quinone atropisomers. For N−N atropisomers, a copper-mediated asymmetric Friedel−Crafts alkylation/arylation reaction was developed. The desymmetrization process was completed successfully via a Cu(OTf) 2 /chiral bisoxazoline or (CuOTf)•Tol/bis(phosphine) dioxide system, thereby achieving the first catalytic asymmetric synthesis of N/N bipyrrole atropisomers. Asymmetric Buchwald−Hartwig amination of enamines was utilized to provide N−N bisindole atropisomers with excellent stereogenic control. This was the first asymmetric synthesis of N−N atropisomers featuring a bisindole structural scaffold using the de novo indole construction strategy. The asymmetric N−N heterobiaryl atropisomer synthesis was substantially facilitated using palladium-catalyzed transient directing group (TDG)-mediated C−H functionalization. Atropisomeric alkenylation, allylation, or alkynylation was accomplished using the Pd(OAc) 2 /L-tert-leucine system. Herein, we summarize our work on the palladium-, copper-, and CPA-catalyzed asymmetric syntheses of N−C and N−N atropisomers. Furthermore, the application of our work in the synthesis of bioactive molecule analogues and axially chiral ligands is demonstrated. Subsequently, the stability of the chiral N-containing axis is briefly discussed in terms of single crystals and obtained rotational barriers. Finally, an outlook on the asymmetric N−X atropisomer synthesis is provided.

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Section: Desymmetrization Strategymentioning

confidence: 99%

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Feng,

Lu,

Liu

2023

Acc. Chem. Res.

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“…One year later the same group realized the asymmetric arylation of pyrroles using diaryliodonium salts [21] . In this case the atroposelective transformation was promoted by a (CuOTf) 2 ⋅ Tol in combination with a Xyl‐BINAPO 12 as chiral bis(phosphine) dioxide ligand proceeding through a desymmetrization of prochiral bipyrroles.…”

Section: Desymmetrization Strategymentioning

confidence: 99%

“…One year later the same group realized the asymmetric arylation of pyrroles using diaryliodonium salts. [21] In this case the atroposelective transformation was promoted by a (CuOTf) 2 • Tol in combination with a Xyl-BINAPO 12 as chiral bis(phosphine) dioxide ligand proceeding through a desymmetrization of prochiral bipyrroles. The impressive number of NÀ N atropisomers produced accounts for the goodness of the protocol which furnished elevated yields and enantioselectivity employing a diversified typology of substituted pyrroles (11 a-11 i) (Scheme 3a).…”

Section: Copper(i)-catalyzed Arylation Of Prochiral Pyrroles With Dia...mentioning

confidence: 99%

Enantioselective Strategies for The Synthesis of N−N Atropisomers

et al. 2023

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Axially chiral compounds have been always considered a laboratory curiosity with rare prospects of being applied in asymmetric synthesis. Things have changed very quickly in the last twenty years when it was understood the important role and the enormous impact that these compounds have in medicinal, biological and material chemistry. The asymmetric synthesis of atropisomers became a rapidly expanding field and recent reports on the development of N−N atropisomers strongly prove how this research field is a hot topic open to new challenges and frontiers of asymmetric synthesis. This review focuses on the recent advances in the enantioselective synthesis of N−N atropisomers highlighting the strategies and breakthroughs to obtain this novel and stimulating atropisomeric framework.

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“…Liu and Lu et al synthesized atropisomeric pyrroles through FC alkylation using a Cu-bisoxazoline catalyst and arylation of pyrroles using diaryliodonium salt promoted by a Cu-bis(phosphine) dioxide catalyst. 48 Li et al realized the N -acylation and N -alkylation reactions of quinazolinone type benzamide, 49 and Zhang and Shi et al performed the chiral phosphoric acid catalyzed synthesis of N–N axially chiral indoles ( 83a – d ) and pyrroles ( 84a – d ) ( Scheme 28 ). 50 …”

Section: Enantio- and Diastereoselective Synthesis Of N–n Atropisomersmentioning

confidence: 99%

Role of Cinchona Alkaloids in the Enantio- and Diastereoselective Synthesis of Axially Chiral Compounds

et al. 2022

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Conspectus Asymmetric synthesis using organic catalysts has evolved since it was first realized and defined. Nowadays, it can be considered a valid alternative to transition metal catalysis for synthesizing chiral molecules. According to the literature, the number of asymmetric organocatalytic processes associated with atropisomer synthesis has rapidly increased over the past 10 years because organocatalysis addresses the challenges posed by the most widespread strategies used for preparing axially chiral molecules with satisfactory results. These strategies, useful to prepare a wide range of C–C, C–heteroatom, and N–N atropisomers, vary from kinetic resolution to direct arylation, desymmetrization, and central-to-axial chirality conversion. In this field, our contribution focuses on determining novel methods for synthesizing atropisomers, during which, in most cases, the construction of one or more stereogenic centers other than the stereogenic axis occurred. To efficiently address this challenge, we exploited the ability of catalysts based on a cinchona alkaloid scaffold to realize enantioselective organic transformations. Desymmetrization of N-(2-tert-butylphenyl) maleimides was one of the first strategies that we pursued for preparing C–N atropisomers. The main principle is based on the presence of a rotationally hindered C–N single bond owing to the presence of a large tert-butyl group. Following the peculiar reactivity of this type of substrate as a powerful electrophile and dienophile, we realized several transformations. First, we investigated the vinylogous Michael addition of 3-substituted cyclohexenones, where a stereogenic axis and two contiguous stereocenters were concomitantly and remotely formed and stereocontrolled using a primary amine catalyst. Subsequently, we realized desymmetrization via an organocatalytic Diels–Alder reaction of activated unsaturated ketones that enabled highly atropselective transformation with efficient diastereoselectivity, thereby simultaneously controlling four stereogenic elements. Employing chiral organic bases allowed us to realize efficient desymmetrizations using carbon nucleophiles, such as 1,3-dicarbonyl compounds, cyanoacetates, and oxindoles. These reactions, performed with different types of catalysts, highlighted the versatility of organocatalysis as a powerful strategy for atropselective desymmetrization of pro-axially chiral maleimides. Hereafter, we studied the Friedel–Crafts alkylation of naphthols with indenones, a powerful method for enantioselective synthesis of conformationally restricted diastereoisomeric indanones. We realized the first axially chiral selective Knoevenagel condensation using cinchona alkaloid primary amine as the catalyst. This reaction provided a powerful method to access enantioenriched olefins containing the oxindole core. Subsequently, we initiated an intense program for the computational investigation of the reaction mechanism of our atropselective processes. An understanding of the catalytic activity for vinylogous atropselect...

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Cu(I)-Catalyzed Asymmetric Arylation of Pyrroles with Diaryliodonium Salts toward the Synthesis of N–N Atropisomers

Cited by 51 publications

References 73 publications

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Enantioselective Strategies for The Synthesis of N−N Atropisomers

Role of Cinchona Alkaloids in the Enantio- and Diastereoselective Synthesis of Axially Chiral Compounds

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