Construction of dibenzo-fused seven- to nine-membered carbocycles via Brønsted acid-promoted intramolecular Friedel–Crafts-type alkenylation

Otani, Takashi; Ueki, Kanako; Cho, Kinryo; Kanai, Kaname; Tateno, Kotaro; Saito, Takao

doi:10.1039/c5cc01257k

Cited by 24 publications

(10 citation statements)

References 35 publications

(7 reference statements)

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“…In addition, the presence of a reactive exocyclic double bond could render many late-stage chemistries inapplicable. We sought to employ a recently reported elegant approach to Amitriptyline’s skeleton [ 41 ], which could provide a straightforward path to aryl-substituted Amitriptylines. Indeed, this approach delivered four amine-reactive carboxy-modified Amitriptylines in a fast and expedient manner ( Figure S7 ).…”

Section: Resultsmentioning

confidence: 99%

An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement

et al. 2021

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Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a robust and sensitive method to quantify ligand engagement with specific GPCRs genetically fused to NanoLuc luciferase or the luminogenic HiBiT peptide. However, development of fluorescent tracers is often challenging and remains the principal bottleneck for this approach. One way to alleviate the burden of developing a specific tracer for each receptor is using promiscuous tracers, which is made possible by the intrinsic specificity of BRET. Here, we devised an integrated tracer discovery workflow that couples machine learning-guided in silico screening for scaffolds displaying promiscuous binding to GPCRs with a blend of synthetic strategies to rapidly generate multiple tracer candidates. Subsequently, these candidates were evaluated for binding in a NanoBRET ligand-engagement screen across a library of HiBiT-tagged GPCRs. Employing this workflow, we generated several promiscuous fluorescent tracers that can effectively engage multiple GPCRs, demonstrating the efficiency of this approach. We believe that this workflow has the potential to accelerate discovery of NanoBRET fluorescent tracers for GPCRs and other target classes.

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Section: Resultsmentioning

confidence: 99%

An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement

et al. 2021

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“…On the basis of our own experimental observations and existing literature precedence, [4,22] the plausible reaction mechanism was depicted as shown in scheme 3. We assume that the reaction might be initiated by the Pd/C‐catalyzed reaction of 1 a coupling with a terminal acetylene to afford the intermediate 3 aa , followed by the sequential activation of alkyne by acid species to form the complex E‐2 .…”

Section: Figurementioning

confidence: 96%

“…The reaction of 1 a and 2 a was completed within 11 h under standard conditions, generating the desired product (4 aa) in 85% (0.789 g) yield (Scheme 2a). As discussed above, the formation of 7-phenyl-6H-benzo [6,7]oxepino [3,2-c] On the basis of our own experimental observations and existing literature precedence, [4,22] the plausible reaction mechanism was depicted as shown in scheme 3. We assume that the reaction might be initiated by the Pd/C-catalyzed reaction of 1 a coupling with a terminal acetylene to afford the intermediate 3 aa, followed by the sequential activation of alkyne by acid species to form the complex E-2.…”

Section: Full Papermentioning

confidence: 99%

Pd/C and TFA‐promoted One‐pot, Two‐step Cascade Reaction: An Effective Synthesis of Oxepines

et al. 2021

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A Pd/C and TFA-promoted effective one-pot synthesis of oxepines starting from iodoheteroaryl/aryl ethers and terminal alkyne has been developed under mild conditions. This transformation involves intermolecular CÀ C bond formation between the aryl iodide and terminal alkynes followed by intramolecular hydroarylation of alkyne, affording the desired oxepines in good yields. A possible mechanism was proposed.

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“…Based on the previous reports and our experimental observations, a plausible mechanism is outlined in Scheme 4. [21] The reaction could involve initial complexation of azomethine nitrogen [À C(Cl)=NÀ ] of 1 a with TFA to give E-1, then nucleophilic attack at the adjacent chlorine bearing carbon by the C-3 center of the indole 2 c to give E-2, which on release of HCl and TFA to afford desired product 3 ac.…”

Section: Table 4 Tfa Prompted Synthesis Of Oxepine Fused N-heterocycl...mentioning

confidence: 99%

Metal‐Free TFA‐Promoted Regioselective (Hetero)Arylation: Synthesis of (Hetero)Aryl Substituted and Carbazole/Oxepine Fused N‐Heterocycles

et al. 2022

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Metal-free TFA promoted arylation/heteroarylation was achieved under mild conditions via the reaction of chloro-derivatives of nitrogen heterocycles [e. g., =CÀ C(Cl)=NÀ ] with electron rich arenes/ heteroarenes. It was also observed that apart from participating in the heteroarylation step, TFA was able to facilitate the hydroarylation/o-arylation process in the same pot affording the carbazole/oxepine fused Nheterocycles. The reaction proceeded with similar efficiency on gram scale.

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Construction of dibenzo-fused seven- to nine-membered carbocycles via Brønsted acid-promoted intramolecular Friedel–Crafts-type alkenylation

Cited by 24 publications

References 35 publications

An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement

An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement

Pd/C and TFA‐promoted One‐pot, Two‐step Cascade Reaction: An Effective Synthesis of Oxepines

Metal‐Free TFA‐Promoted Regioselective (Hetero)Arylation: Synthesis of (Hetero)Aryl Substituted and Carbazole/Oxepine Fused N‐Heterocycles

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