A New Reagent for Direct Difluoromethylation

Fujiwara, Yuta; Dixon, Janice A.; Rodriguez, Rodrigo; Baxter, Ryan D.; Dixon, Darryl D.; Collins, Michael R.; Blackmond, Donna G.; Baran, Phil S.

doi:10.1021/ja211422g

Cited by 589 publications

(300 citation statements)

References 17 publications

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“…Difluorination of benzylic C-H bonds that was promoted by visible light or silver catalyst generated difluoromethylarenes efficiently, yet selectivity is problematic for multi-alkylated arenes [13][14][15] . Baran and coworkers 16,17 reported a radical difluoromethylation of heteroarenes with zinc difluoromethanesulfinate, but reactions with arenes have not been reported. Several transition metal-catalysed difluoromethylation involved the using of difluoromethyl surrogates such as a-silyldifluoroacetate 18 and difluoromethylphenylketone 19 have emerged recently.…”

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confidence: 99%

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

2014

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Difluoromethylated arenes are one of the privileged structural motifs that are important for fine tuning the biological properties of drug molecules. No general catalytic method exists for the formation of difluoromethylarenes. Previous methods for the preparation of difluoromethylarenes typically required harsh conditions, multiple steps or stoichiometric amount of catalysts. Here we report a cooperative dual palladium/silver catalyst system for direct difluoromethylation of aryl bromides and iodides under mild conditions. We develop the system by initial preparation of the putative intermediates in the dual-catalytic cycles, followed by studying the elemental steps to demonstrate the viability of the proposed cooperative catalytic cycle. The reaction is compatible with a variety of functional groups such as ester, amide, protected phenoxide, protected ketone, cyclopropyl, bromide and heteroaryl subunits such as pyrrole, benzothiazole, carbazole or pyridine.

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confidence: 99%

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

2014

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“…16 Routes to access the difluoromethyl motif involve reaction of an aldehyde with sulfur tetrafluoride, 17 reaction of nucleophilic "RCF 2 -" species with electrophiles, [18][19][20][21] reaction of a nucleophilic C, S, N, or O nucleophiles with difluorocarbene, [22][23][24][25][26] or transfer of a difluoromethyl radical to an appropriate substrate. [27][28][29] To explore the enzymatic synthesis of a difluoromethyl group, an appropriate substrate was required. To investigate the putative transformation in the forward direction, an S-adeonosylmethionine analogue bearing a fluorine atom at the 5'-position would be required, however such 5'-modified SAM derivatives have not been reported.…”

Section: Methodsmentioning

confidence: 99%

Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme

Thompson

McMahon

Naismith

et al. 2016

Bioorganic Chemistry

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Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme, Bioorganic Chemistry (2015), doi: http:// dx.doi.org/10.1016/j.bioorg. 2015.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5',5'-Difluoro-5'-deoxyadenosine 7 (F 2 DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5'-fluoro-5'-deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F 2 DA 7 was found, however, not to undergo the enzyme catalysed reaction with L-selenomethionine, unlike FDA 2, which undergoes reaction with L-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F 2 DA 7 and tartrate was solved to 1.8 Å, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of fluoride for reaction. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed.

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“…Compounds 15a-j were prepared using a cross-coupling reaction between 14 and the corresponding boronic acids/esters, along with reduction of the methyl ester group with LiAlH4 or DIBAL-H Compounds 15a-j were prepared using a cross-coupling reaction between 14 and the corresponding boronic acids/esters, along with reduction of the methyl ester group with LiAlH 4 or DIBAL-H (Scheme 2). We also synthesized 16 and 17 by direct trifluoromethylation and isopropylation of 13a (Scheme 3) [14]. …”

Section: Candidate Synthesismentioning

confidence: 99%

Identification of Selective ERRγ Inverse Agonists

Kim

Yoo

et al. 2016

Molecules

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GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC 50 = 0.44, >10, >10, and 10 µM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 µM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

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A New Reagent for Direct Difluoromethylation

Cited by 589 publications

References 17 publications

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme

Identification of Selective ERRγ Inverse Agonists

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