Synthesis and analysis of (γ,γ', γ'', - Trifluoro)neopentyl (TFNP) aryl ethers as a polar fluoroaliphatic motif

Atsushi Tarui; Bruno A. Piscelli; Nawaf Al-Maharik; Josephine Mary Stewart; Patricie Niemcová; David Bradford Cordes; Aidan McKay; Cormac D. Murphy; Rodrigo A. Cormanich; David O'Hagan

doi:10.1002/chem.202402532

Synthesis and analysis of (γ,γ', γ'', - Trifluoro)neopentyl (TFNP) aryl ethers as a polar fluoroaliphatic motif

Atsushi Tarui
, Bruno A. Piscelli
, Nawaf Al-Maharik
, Josephine Mary Stewart
, Patricie Niemcová
, David Bradford Cordes
, Aidan McKay
, Cormac D. Murphy
, Rodrigo A. Cormanich
, David O'Hagan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

A route is developed to (γ,γ’,γ’’’-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C−F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis. The LogPs of TFNP ethers are lower (more hydrophilic) than their neopentyl analogues. The metabolism of selected TFNP ethers was explored in the fungus Cunninghamella elegans.

Original language	English
Article number	e202402532
Number of pages	5
Journal	Chemistry - A European Journal
Volume	30
Issue number	57
Early online date	24 Sept 2024
DOIs	https://doi.org/10.1002/chem.202402532
Publication status	Published - 11 Oct 2024

Keywords

(y,y',y''-trifluoro)neopentyl (TFNP) aryl ethers
Organofluorine chemistry
Polar-aliphatic motifs
Tert-butyl group
Metabolism

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Tarui_2024_CEJ_Synthesis-analysis-(y,y',y''-trifluoro)neopentyl_CC
Copyright © 2024 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Final published version, 2.21 MBLicence: CC BY

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Janus faced fluorocyclohexanes: Properties and applications of Janus faced fluorocyclohexanes
O'Hagan, D. (PI)
1/12/19 → 14/03/23
Project: Standard

CCDC 2324025 - 2324028: Experimental Crystal Structure Determination
Tarui, A. (Creator), Piscelli, B. A. (Creator), Al‐Maharik, N. (Creator), Stewart, J. M. (Creator), Niemcová, P. (Creator), Cordes, D. B. (Creator), McKay, A. P. (Creator), Murphy, C. D. (Creator), Cormanich, R. A. (Creator) & O'Hagan, D. (Creator), Cambridge Crystallographic Data Centre, 2024
DOI: 10.5517/ccdc.csd.cc2j0bkg, https://dx.doi.org/10.5517/ccdc.csd.cc2j0blh and 2 more links, https://dx.doi.org/10.5517/ccdc.csd.cc2j0bmj, https://dx.doi.org/10.5517/ccdc.csd.cc2j0bnk (show fewer)
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Tarui, A., Piscelli, B. A., Al-Maharik, N., Stewart, J. M., Niemcová, P., Cordes, D. B., McKay, A., Murphy, C. D., Cormanich, R. A., & O'Hagan, D. (2024). Synthesis and analysis of (γ,γ', γ'', - Trifluoro)neopentyl (TFNP) aryl ethers as a polar fluoroaliphatic motif. Chemistry - A European Journal, 30(57), Article e202402532. https://doi.org/10.1002/chem.202402532

@article{41851b19601d4aac9df6469a5f585832,

title = "Synthesis and analysis of (γ,γ', γ'', - Trifluoro)neopentyl (TFNP) aryl ethers as a polar fluoroaliphatic motif",

abstract = "A route is developed to (γ,γ{\textquoteright},γ{\textquoteright}{\textquoteright}{\textquoteright}-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C−F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis. The LogPs of TFNP ethers are lower (more hydrophilic) than their neopentyl analogues. The metabolism of selected TFNP ethers was explored in the fungus Cunninghamella elegans.",

keywords = "(y,y',y''-trifluoro)neopentyl (TFNP) aryl ethers, Organofluorine chemistry, Polar-aliphatic motifs, Tert-butyl group, Metabolism",

author = "Atsushi Tarui and Piscelli, \{Bruno A.\} and Nawaf Al-Maharik and Stewart, \{Josephine Mary\} and Patricie Niemcov{\'a} and Cordes, \{David Bradford\} and Aidan McKay and Murphy, \{Cormac D.\} and Cormanich, \{Rodrigo A.\} and David O'Hagan",

note = "Funding: The authors thank EPSRC for a grant (EP/S030506/1) and BBSRC for an EastBio Studentship (JMS), and one of us (AT) thanks Setsunan University for supporting research leave in the UK. PN and CDM acknowledge the BiOrbic Centre, funded by Science Foundation Ireland, for financial support (grants 18/EPSRC-CDT/3582 and 16/RC/3889). FAPESP are thanked for a Young Researcher Award to RAC (\#2018/03910-1) and a scholarships to BAP (\#2023/14064-2 and \#2022/10156-7). CNPq is acknowledged for a fellowship to RAC (\#306912/2023-6) and FAEPEX for research funding.",

year = "2024",

month = oct,

day = "11",

doi = "10.1002/chem.202402532",

language = "English",

volume = "30",

journal = "Chemistry - A European Journal",

issn = "0947-6539",

publisher = "John Wiley \& Sons, Ltd",

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T1 - Synthesis and analysis of (γ,γ', γ'', - Trifluoro)neopentyl (TFNP) aryl ethers as a polar fluoroaliphatic motif

AU - Tarui, Atsushi

AU - Piscelli, Bruno A.

AU - Al-Maharik, Nawaf

AU - Stewart, Josephine Mary

AU - Niemcová, Patricie

AU - Cordes, David Bradford

AU - McKay, Aidan

AU - Murphy, Cormac D.

AU - Cormanich, Rodrigo A.

AU - O'Hagan, David

N1 - Funding: The authors thank EPSRC for a grant (EP/S030506/1) and BBSRC for an EastBio Studentship (JMS), and one of us (AT) thanks Setsunan University for supporting research leave in the UK. PN and CDM acknowledge the BiOrbic Centre, funded by Science Foundation Ireland, for financial support (grants 18/EPSRC-CDT/3582 and 16/RC/3889). FAPESP are thanked for a Young Researcher Award to RAC (#2018/03910-1) and a scholarships to BAP (#2023/14064-2 and #2022/10156-7). CNPq is acknowledged for a fellowship to RAC (#306912/2023-6) and FAEPEX for research funding.

PY - 2024/10/11

Y1 - 2024/10/11

N2 - A route is developed to (γ,γ’,γ’’’-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C−F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis. The LogPs of TFNP ethers are lower (more hydrophilic) than their neopentyl analogues. The metabolism of selected TFNP ethers was explored in the fungus Cunninghamella elegans.

AB - A route is developed to (γ,γ’,γ’’’-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C−F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis. The LogPs of TFNP ethers are lower (more hydrophilic) than their neopentyl analogues. The metabolism of selected TFNP ethers was explored in the fungus Cunninghamella elegans.

KW - (y,y',y''-trifluoro)neopentyl (TFNP) aryl ethers

KW - Organofluorine chemistry

KW - Polar-aliphatic motifs

KW - Tert-butyl group

KW - Metabolism

U2 - 10.1002/chem.202402532

DO - 10.1002/chem.202402532

M3 - Article

SN - 0947-6539

VL - 30

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 57

M1 - e202402532

ER -

Synthesis and analysis of (γ,γ', γ'', - Trifluoro)neopentyl (TFNP) aryl ethers as a polar fluoroaliphatic motif

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Keywords

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Projects

Janus faced fluorocyclohexanes: Properties and applications of Janus faced fluorocyclohexanes

Datasets

CCDC 2324025 - 2324028: Experimental Crystal Structure Determination

Cite this