The synthesis and SAR of novel diarylsulfone 11β-HSD1 inhibitors

Yan, Xuelei; Wang, Zhong Lin; Sudom, Athena; Cardozo, Mario; DeGraffenreid, Michael; Di, Yongmei; Fan, Pingchen; He, Xiao; Jaén, Juan C.; Labelle, Marc; Liu, Jinsong; Ma, Ji; McMinn, Dustin L.; Miao, Shichang; Sun, Daqing; Tang, Liang; Tu, Hua; Ursu, Stefania; Walker, Nigel; Ye, Qiuping; Powers, Jay P.

doi:10.1016/j.bmcl.2010.09.097

Cited by 17 publications

(12 citation statements)

References 19 publications

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“…Compared with reported methods, 14 our transformation involves milder conditions and requires less time. Moreover, we evaluated our method for late-stage functionalization applications.…”

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confidence: 96%

Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer

2017

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Disclosed is a mild, scalable, visible-light-promoted cross-coupling reaction between thiols and aryl halides for the construction of C–S bonds in the absence of both transition metal and photoredox catalysts. The scope of aryl halides and thiol partners includes over 60 examples and therefore provides an entry point into various aryl thioether building blocks of pharmaceutical interest. Furthermore, to demonstrate its utility, this C–S coupling protocol was applied in drug synthesis and late-stage modifications of active pharmaceutical ingredients. UV–vis spectroscopy and time-dependent density functional theory calculations suggest that visible-light-promoted intermolecular charge transfer within the thiolate–aryl halide electron donor–acceptor complex permits the reactivity in the absence of catalyst.

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“…Compared with reported methods, 14 our transformation involves milder conditions and requires less time. Moreover, we evaluated our method for late-stage functionalization applications.…”

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confidence: 96%

Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer

2017

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“…61)) in which sulfonyl group serves as a strong hydrogen bond acceptor (with A172 main chain amine group as a donor). In all remaining structures, the sulfonyl group occupies hydrophobic pockets, what stays in agreement with Bissantz, et al 29 …”

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confidence: 99%

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT₆receptor antagonists and beyond

et al. 2018

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The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C-H/O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.

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“…In addition, 4-fluoro- and 4-chloroanisole do also not show any S N Ar-chemistry under the conditions used. Such a reaction maybe achieved with thiolate nucleophiles, e.g., by coordination to an electron withdrawing metal fragment [ 43 ], substitution by EWGs [ 44 ], or elevated temperatures [ 45 ].…”

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confidence: 99%

Improved, Odorless Access to Benzo[1,2-d;4,5-d′]- bis[1,3]dithioles and Tert-butyl Arylsulfides via C-S Cross Coupling

2020

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Benzo[1,2-d;4,5-d′]bis[1,3]dithioles are important building blocks within a range of functional materials such as fluorescent dyes, conjugated polymers, and stable trityl radicals. Access to these is usually gained via tert-butyl aryl sulfides, the synthesis of which requires the use of highly malodorous tert-butyl thiol and relies on SNAr-chemistry requiring harsh reaction conditions, while giving low yields. In the present work, S-tert-butyl isothiouronium bromide is successfully applied as an odorless surrogate for tert-butyl thiol. The C-S bond formation is carried out under palladium catalysis with the thiolate formed in situ resulting in high yields of tert-butyl aryl sulfides. The subsequent formation of benzo[1,2-d;4,5-d′]bis[1,3]dithioles is here achieved with scandium(III)triflate, a less harmful reagent than the usually used Lewis acids, e.g., boron trifluoride or tetrafluoroboric acid. This enables a convenient and environmentally more compliant access to high yields of benzo[1,2-d;4,5-d′]bis[1,3]dithioles.

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The synthesis and SAR of novel diarylsulfone 11β-HSD1 inhibitors

Cited by 17 publications

References 19 publications

Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer

Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT₆receptor antagonists and beyond

Improved, Odorless Access to Benzo[1,2-d;4,5-d′]- bis[1,3]dithioles and Tert-butyl Arylsulfides via C-S Cross Coupling

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The synthesis and SAR of novel diarylsulfone 11β-HSD1 inhibitors

Cited by 17 publications

References 19 publications

Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer

Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6receptor antagonists and beyond

Improved, Odorless Access to Benzo[1,2-d;4,5-d′]- bis[1,3]dithioles and Tert-butyl Arylsulfides via C-S Cross Coupling

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The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT₆receptor antagonists and beyond