Enantioselective Synthesis of a Highly Substituted Tetrahydrofluorene Derivative as a Potent and Selective Estrogen Receptor Beta Agonist

Maddess, Matthew L.; Scott, Jeremy P.; Alorati, Anthony; Baxter, Carl A.; Bremeyer, Nadine; Brewer, Sarah E.; Campos, Kevin R.; Cleator, Ed; Diéguez-Vázquez, Alejandro; Gibb, Andrew D.; Gibson, Andrew; Howard, Melissa E.; Keen, Stephen P.; Klapars, Artis; Lee, Jaemoon; Li, Jing; Lynch, Joseph E.; Mullens, Peter R.; Wallace, Debra J.; Wilson, Robert D.

doi:10.1021/op5000489

Cited by 16 publications

(8 citation statements)

References 37 publications

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“…2B). Electron-rich aryl ketones bearing hydroxyl, methoxy, or dioxole functionalities underwent the desired transformation in good to excellent yields (17,26,27,31,32,36, and 42, Fig. 2B).…”

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confidence: 99%

Interrupted carbonyl-olefin metathesis via oxygen atom transfer

Ludwig

Watson

Nasrallah

et al. 2018

Science

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Some of the simplest and most powerful carbon-carbon bond forming strategies take advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a fundamentally distinct mode of reactivity between carbonyls and olefins that differs from established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction paths. A range of epsilon, zeta-unsaturated ketones undergo Brønsted acid–catalyzed intramolecular cyclization to provide tetrahydrofluorene products via the formation of two new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies suggest that this carbocyclization reaction proceeds through the intermediacy of a transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks in this product class appear as common substructures in organic materials, bioactive natural products, and recently developed pharmaceuticals.

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confidence: 99%

Interrupted carbonyl-olefin metathesis via oxygen atom transfer

Ludwig

Watson

Nasrallah

et al. 2018

Science

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“…In the discovery phase of 63, the trifluoromethyl moiety was successfully incorporated by iodination of 61 and subsequent reaction with MFSDA and CuI in DMF to provide trifluoromethylated product 62 in 79 % yield. Further transformations provided the desired product 63 (Scheme ) . However, due to the long linear synthesis required to produce 63 , this route was deemed not to be viable for scale‐up and an alternative synthesis was used .…”

Section: Scope Of Trifluoromethylation Reaction Of Methyl Fluorosulfomentioning

confidence: 99%

“…Further transformations provided the desired product 63 (Scheme ) . However, due to the long linear synthesis required to produce 63 , this route was deemed not to be viable for scale‐up and an alternative synthesis was used . Here compound 64 was iodinated using NIS in acetic acid to provide the iodinated product in 92 % yield.…”

Section: Scope Of Trifluoromethylation Reaction Of Methyl Fluorosulfomentioning

confidence: 99%

Methyl fluorosulfonyldifluoroacetate (MFSDA): An Underutilised Reagent for Trifluoromethylation

Clarke

McGlacken

2016

Chemistry A European J

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The introduction of fluorine groups to pharmaceutical compounds can have a dramatic effect on the lipophilicity and metabolic stability of the molecule in vivo. Around 20 % of drugs contain at least one fluorine atom. The trifluoromethyl group is known to have beneficial effects and can dramatically affect the biological activity when substituted for a methyl group, for example. In any case, the direct and late-stage introduction of a trifluoromethyl group is a powerful transformation in the tool box of the medicinal chemist. The use of methyl fluorosulfonyldifluoroacetate (MFSDA) as a relatively inexpensive reagent for trifluoromethylation was first reported in 1989; however, in our opinion it has been somewhat underutilised. Herein, a comprehensive review of trifluoromethylation using MFSDA is reported, which we hope will further expose readers to this useful reagent.

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“…26 Since its introduction, MFSDA has been used as a convenient source of 'CuCF 3 ' and has proved useful in the trifluoromethylation of subpophyrins, 27 pyrazoles, 28 purine nucleosides, 29,30 oxazolyl intermediates, 31 pyrazolopyridines, 32 and others. 33,34 The accepted mechanism comprises an initial step involving the formation of a copper salt with the elimination of methyl halide. 26 The salt then decomposes to release difluorocarbene and a fluoride ion, which are in equilibrium with a DMF stabilised trifluoromethyl anion.…”

Section: A N U S C R I P Tmentioning

confidence: 99%