Atroposelective Synthesis of Axially Chiral N‐Arylpyrroles by Chiral‐at‐Rhodium Catalysis

Ye, Chen‐Xi; Chen, Shuming; Han, Feng; Xie, Xiulan; Ivlev, Sergei I.; Houk, K. N.; Meggers, Eric

doi:10.1002/ange.202004799

“…The past decade has witnessed significant advancements in the construction of C−N axial chirality, owing to the prevalence of this atropisomeric unit in natural products, pharmaceuticals, and chiral ligands [1–6] . Several powerful strategies have been established, such as metal‐ or organocatalyzed enantioselective C−N coupling, [7–11] de novo synthesis of arenes or heteroarenes, [12–20] desymmetrization process [21–26] and dynamic kinetic resolution ( DKR ) [27–41] . However, there still remains a pressing need to develop new approaches to enhance the diversity of C−N atropisomers, especially the biologically active motifs.…”

Section: Figurementioning

confidence: 99%

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

Deng,

Dong,

Ge

et al. 2024

Angewandte Chemie

2

0

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The development of new methods for regio‐ and stereoselective activation of C‐O bonds in ethers holds significant promise for synthetic chemistry, offering advantages in terms of environmental sustainability and economic efficiency. Moreover, the C–N atropisomers represent a fascinating and crucial chiral system, extensively found in natural products, pharmaceutical leads, and the frameworks of advanced materials. In this work, we have introduced a nickel‐catalyzed regio‐ and enantioselective carbon‐oxygen arylation reaction for atroposelective synthesis of N‐arylisoquinoline‐1,3(2H,4H)‐diones. The high regioselectivity of C–O cleavage benefits from the high stability of the in‐situ formed (amido)ethenolate via oxidative addition. Additionally, the self‐activation of the aryl C–O bond facilitates the reaction under mild conditions, leading to outstanding enantioselectivities. The diverse post‐functionalizations of the axially chiral isoquinoline‐1,3(2H,4H)‐diones further highlighted the utility of this protocol in preparing valuable C–N atropisomers, including the chiral phosphine ligands.

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“…The past decade has witnessed significant advancements in the construction of C−N axial chirality, owing to the prevalence of this atropisomeric unit in natural products, pharmaceuticals, and chiral ligands [1–6] . Several powerful strategies have been established, such as metal‐ or organocatalyzed enantioselective C−N coupling, [7–11] de novo synthesis of arenes or heteroarenes, [12–20] desymmetrization process [21–26] and dynamic kinetic resolution ( DKR ) [27–41] . However, there still remains a pressing need to develop new approaches to enhance the diversity of C−N atropisomers, especially the biologically active motifs.…”

Section: Figurementioning

confidence: 99%

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

Deng,

Dong,

Ge

et al. 2024

Angew Chem Int Ed

4

0

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The development of new methods for regio‐ and stereoselective activation of C‐O bonds in ethers holds significant promise for synthetic chemistry, offering advantages in terms of environmental sustainability and economic efficiency. Moreover, the C–N atropisomers represent a fascinating and crucial chiral system, extensively found in natural products, pharmaceutical leads, and the frameworks of advanced materials. In this work, we have introduced a nickel‐catalyzed regio‐ and enantioselective carbon‐oxygen arylation reaction for atroposelective synthesis of N‐arylisoquinoline‐1,3(2H,4H)‐diones. The high regioselectivity of C–O cleavage benefits from the high stability of the in‐situ formed (amido)ethenolate via oxidative addition. Additionally, the self‐activation of the aryl C–O bond facilitates the reaction under mild conditions, leading to outstanding enantioselectivities. The diverse post‐functionalizations of the axially chiral isoquinoline‐1,3(2H,4H)‐diones further highlighted the utility of this protocol in preparing valuable C–N atropisomers, including the chiral phosphine ligands.

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“…In one category, functionalization of the peripheral groups in existing (hetero)aryl rings allows restriction of the C-N rotation by size-increasing effect. [15][16][17][18][19][20][21][22] Alternatively, de novo construction of a new (hetero)aryl ring with incorporatation of the C or N atom into it may also restrict the conformation of the C-N axis. The latter strategy is particularly important because new chiral platforms are constructed with modularity, which allows exploitation of diverse chiral structures.…”

Section: Chiral Ligands Have Also Been Demonstratedmentioning

confidence: 99%

Enantioselective Access to C-N Axially Chiral Isoquinolones via Dynamic Kinetic Transformation of Carbene Reagents: Unique Chiral Induction Enabled by Dual Role of the Catalyst

Wang

¹

,

Wu

²

,

Zhang

³

et al. 2022

Preprint

0

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Isoquinolones are important structural motifs in synthetic and medicinal chemistry. Reported herein is highly atroposelective access to C-N axially chiral isoqionolones via rhodium-catalyzed C-H activation of N-alkoxy benzamides and [3+3] annulation with imidoyl sulfoxonium ylides. The coupling system proceeded efficiently under mild and redox-neutral conditions with excellent functional group tolerance as a result of dynamic kinetic transformation of the ylidic coupling reagent (carbene precursor). Experimental and computational studies revealed a pathway of C-H activation, carbene insertion, and formal nucleophilic substitution-cyclization for this coupling system. In particular, the C-N cyclization is enantio-determining and occurs via an unusual rhodium-catalyzed -bond metathesis mechanism. The benzamide, the imidoyl sulfoxonium ylide, and the chiral catalyst each played a dual role. The amide functionality acts as a directing group as well as an electrophilic acylating group, and the imidoyl sulfoxonium ylide participated as a nucleophile-functionalized carbene reagent. Applications of representative products as potentially useful chiral ligands have also been demonstrated.

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Atroposelective Synthesis of Axially Chiral N‐Arylpyrroles by Chiral‐at‐Rhodium Catalysis

Cited by 30 publications

References 30 publications

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

Enantioselective Access to C-N Axially Chiral Isoquinolones via Dynamic Kinetic Transformation of Carbene Reagents: Unique Chiral Induction Enabled by Dual Role of the Catalyst

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