Enantioselective [2 + 2] photocycloaddition of quinolone using a<i>C</i><sub>1</sub>-symmetric chiral phosphoric acid as a visible-light photocatalyst

Takagi, Ryukichi; Tanimoto, Takaaki

doi:10.1039/d2ob00607c

“…Hence, we developed several new BINOL-derived organophotocatalysts bearing thioxanthone photosensitizers, the best being C 1 -symmetric photocatalyst 38a . In parallel, independent reports by Bach et al demonstrated that a thioxanthone-functionalized C 2 -symmetric chiral phosphoric acid was competent in (2 + 2)-cycloadditions …”

Section: Chiral Phosphoric Acid-catalyzed Asymmetric Three-component ...mentioning

confidence: 99%

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,β-Substituted Amines

Bouchet

¹

,

Varlet

²

,

Masson

³

2022

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Metrics & MoreArticle Recommendations CONSPECTUS: Enamide and enecarbamate derivatives containing a nucleophilic center at the β-position from their nitrogen atom as well as a latent electrophilic site at their α-position are interesting motifs in organic chemistry. This dual reactivity� analogous that of the enamines�enables difunctionalization and increased structural complexity. Furthermore, an electron-withdrawing group on nitrogen drastically increases their stability. In that respect, enamides and enecarbamates are excellent partners for multicomponent transformations, and our research primarily focuses on these compounds in particular. Difunctionalization generally occurs through the nucleophilic addition of the enecarbamate on an electrophile to form iminium, which can subsequently react with a nucleophilic species. Although potent, such an approach is highly challenging due to the low stability of the intermediate iminium, leading to undesired hydrolysis or oligomerization. Epimerization, competitivity, and compatibility issues between the reaction partners are additional hindrances to developing these methodologies. To overcome these limitations, we described many complementary strategies.To control the enantioselectivity of these transformations, chiral phosphoric acids were found to be particularly well-suited to activate multiple reactants due to the formation of a hydrogen bonds network, allowing for an organized transition state in a chiral pocket. Interestingly, when deprotonated as phosphates, they can also play the role of ligands for Lewis acidic metals.To avoid iminium oligomerization, we successfully used stabilized α-arylated enamides. However, this approach was restricted to a simple nucleophilic addition at the β-position. To achieve the difunctionalizations of α-unsubstituted derivatives, we explored reversibly linked nucleophile and electrophile to address their compatibility problem. Alternatively, we devised a sequential methodology for resolving the stability issue of the N-acyl iminium based on its intermediate trapping using a temporary nucleophile (alcohol or thiol). Interestingly, the trapping agent could further be displaced by the desired final α-substituent under Lewis acidic or photocatalytic activation. This led us to design new chiral and bifunctional phosphoric acid catalysts bearing chromophores to merge asymmetric organocatalysis and photochemistry. These photocatalysis studies incited us to focus on radical processes to manage original functionalizations that would not be feasible otherwise. β-Alkylation and β-trifluoromethylation of enecarbamates via visible-light-promoted atom transfer radical additions were successfully performed. As β-allylations remained unattainable with the precedent methods, we eventually turned our attention to cerium(IV)-mediated oxidative single electron transfers. It allowed for singly occupied molecular orbital activation of these substrates to elicit their umpolung reactivity. Thus, the functionalization of enecarbamate derivatives appears ...

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Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate‐Mediated Photocycloaddition

Shimose,

Ishigaki,

Sato

et al. 2024

Angewandte Chemie

0

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Dearomative construction of multiply‐fused 2D/3D frameworks, composed of aromatic two‐dimensional (2D) rings and saturated three‐dimensional (3D) rings, from readily available quinolines has greatly contributed to drug discovery. However, dearomative cycloadditions of quinolines in the presence of photocatalysts usually afford 5,6,7,8‐tetrahydroquinoline (THQ)‐based polycycles, and dearomative access to 1,2,3,4‐THQ‐based structures remains limited. Herein, we present a chemo‐, regio‐, diastereo‐, and enantioselective dearomative transformation of quinolines into 1,2,3,4‐THQ‐based 6‐6‐4‐membered rings without any catalyst, through a combination of nucleophilic addition and borate‐mediated [2+2] photocycloaddition. Detailed mechanistic studies revealed that the photoexcited borate complex, generated from quinoline, organolithium, and HB(pin), accelerates the cycloaddition and suppresses the rearomatization that usually occurs in conventional photocycloaddition. Based on our mechanistic analysis, we also developed further photoinduced cycloadditions affording other types of 2D/3D frameworks from isoquinoline and phenanthrene.

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Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate‐Mediated Photocycloaddition

Shimose,

Ishigaki,

Sato

et al. 2024

Angew Chem Int Ed

0

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Dearomative construction of multiply‐fused 2D/3D frameworks, composed of aromatic two‐dimensional (2D) rings and saturated three‐dimensional (3D) rings, from readily available quinolines has greatly contributed to drug discovery. However, dearomative cycloadditions of quinolines in the presence of photocatalysts usually afford 5,6,7,8‐tetrahydroquinoline (THQ)‐based polycycles, and dearomative access to 1,2,3,4‐THQ‐based structures remains limited. Herein, we present a chemo‐, regio‐, diastereo‐, and enantioselective dearomative transformation of quinolines into 1,2,3,4‐THQ‐based 6‐6‐4‐membered rings without any catalyst, through a combination of nucleophilic addition and borate‐mediated [2+2] photocycloaddition. Detailed mechanistic studies revealed that the photoexcited borate complex, generated from quinoline, organolithium, and HB(pin), accelerates the cycloaddition and suppresses the rearomatization that usually occurs in conventional photocycloaddition. Based on our mechanistic analysis, we also developed further photoinduced cycloadditions affording other types of 2D/3D frameworks from isoquinoline and phenanthrene.

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Enantioselective [2 + 2] photocycloaddition of quinolone using aC₁-symmetric chiral phosphoric acid as a visible-light photocatalyst

Abstract: The enantioselective intra- and intermolecular [2+2] photocycloaddition of quinolone using a C1-symmetric chiral phosphoric acid as a visible-light photocatalyst is developed. The thioxanthone chromophore on phosphoric acid plays an important...

Cited by 7 publications

References 70 publications

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,β-Substituted Amines

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,β-Substituted Amines

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate‐Mediated Photocycloaddition

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate‐Mediated Photocycloaddition

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Enantioselective [2 + 2] photocycloaddition of quinolone using aC1-symmetric chiral phosphoric acid as a visible-light photocatalyst

Abstract: The enantioselective intra- and intermolecular [2+2] photocycloaddition of quinolone using a C1-symmetric chiral phosphoric acid as a visible-light photocatalyst is developed. The thioxanthone chromophore on phosphoric acid plays an important...

Cited by 7 publications

References 70 publications

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,β-Substituted Amines

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,β-Substituted Amines

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate‐Mediated Photocycloaddition

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate‐Mediated Photocycloaddition

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Product

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Enantioselective [2 + 2] photocycloaddition of quinolone using aC₁-symmetric chiral phosphoric acid as a visible-light photocatalyst