Skipped fluorination motifs : synthesis of building blocks and comparison of lipophilicity trends with vicinal and isolated fluorination motifs
- Author
- Robert Troup, Benjamin Jeffries, Raphael El-Bekri Saudain, Eleni Georgiou, Johanna Fish, James S. Scott, Elisabetta Chiarparin, Charlene Fallan and Bruno Linclau (UGent)
- Organization
- Abstract
- Given there is an optimal lipophilicity range for orally bioavailable drugs, structural modifications applied in the drug development process are not only focused on optimizing bioactivity but also on fine-tuning lipophilicity. Fluorine introduction can be used for both purposes. Insights into how fluorine introduction affects lipophilicity are thus of importance, and systematic series of fluorinated compounds with measured octanol-water partition coefficients are a powerful way to enhance our qualitative understanding in this regard and are essential as input for computational log P estimation programs. Here, we report a detailed comparison of all possible vicinal and skipped (1,3-substituted) fluorination motifs when embedded in structurally equivalent environments (X-CFnH2-n-CFmH2-m-X versus X-CFnH2-n-CH2-CFmH2-m-X, with n,m not equal 0 and X = CH2OH) to compounds with isolated fluorination (n not equal 0; m = 0, and including X-CH2-CFnH2-n-CH2-X, n = 0-2). It is shown that skipped fluorination is more powerful for log P reduction purposes compared to single or vicinal fluorination. Efficient stereoselective syntheses of the compounds with skipped fluorination motifs are reported, which where relevant can be made enantioselective using known chiral building blocks. These compounds, and some intermediates, will be of interest as advanced fluorinated building blocks.
- Keywords
- ETHYL BROMODIFLUOROACETATE, PHYSICOCHEMICAL PROPERTIES, VINYLIDENE, FLUORIDE, DRUG CANDIDATES, POLARITY, ALKYL, DISCOVERY, DESIGN
Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01GMMX6XE3Q895CPJKX3DAJHNA
- MLA
- Troup, Robert, et al. “Skipped Fluorination Motifs : Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs.” JOURNAL OF ORGANIC CHEMISTRY, vol. 86, no. 2, 2021, pp. 1882–900, doi:10.1021/acs.joc.0c02810.
- APA
- Troup, R., Jeffries, B., Saudain, R. E.-B., Georgiou, E., Fish, J., Scott, J. S., … Linclau, B. (2021). Skipped fluorination motifs : synthesis of building blocks and comparison of lipophilicity trends with vicinal and isolated fluorination motifs. JOURNAL OF ORGANIC CHEMISTRY, 86(2), 1882–1900. https://doi.org/10.1021/acs.joc.0c02810
- Chicago author-date
- Troup, Robert, Benjamin Jeffries, Raphael El-Bekri Saudain, Eleni Georgiou, Johanna Fish, James S. Scott, Elisabetta Chiarparin, Charlene Fallan, and Bruno Linclau. 2021. “Skipped Fluorination Motifs : Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs.” JOURNAL OF ORGANIC CHEMISTRY 86 (2): 1882–1900. https://doi.org/10.1021/acs.joc.0c02810.
- Chicago author-date (all authors)
- Troup, Robert, Benjamin Jeffries, Raphael El-Bekri Saudain, Eleni Georgiou, Johanna Fish, James S. Scott, Elisabetta Chiarparin, Charlene Fallan, and Bruno Linclau. 2021. “Skipped Fluorination Motifs : Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs.” JOURNAL OF ORGANIC CHEMISTRY 86 (2): 1882–1900. doi:10.1021/acs.joc.0c02810.
- Vancouver
- 1.Troup R, Jeffries B, Saudain RE-B, Georgiou E, Fish J, Scott JS, et al. Skipped fluorination motifs : synthesis of building blocks and comparison of lipophilicity trends with vicinal and isolated fluorination motifs. JOURNAL OF ORGANIC CHEMISTRY. 2021;86(2):1882–900.
- IEEE
- [1]R. Troup et al., “Skipped fluorination motifs : synthesis of building blocks and comparison of lipophilicity trends with vicinal and isolated fluorination motifs,” JOURNAL OF ORGANIC CHEMISTRY, vol. 86, no. 2, pp. 1882–1900, 2021.
@article{01GMMX6XE3Q895CPJKX3DAJHNA,
abstract = {{Given there is an optimal lipophilicity range for orally bioavailable drugs, structural modifications applied in the drug development process are not only focused on optimizing bioactivity but also on fine-tuning lipophilicity. Fluorine introduction can be used for both purposes. Insights into how fluorine introduction affects lipophilicity are thus of importance, and systematic series of fluorinated compounds with measured octanol-water partition coefficients are a powerful way to enhance our qualitative understanding in this regard and are essential as input for computational log P estimation programs. Here, we report a detailed comparison of all possible vicinal and skipped (1,3-substituted) fluorination motifs when embedded in structurally equivalent environments (X-CFnH2-n-CFmH2-m-X versus X-CFnH2-n-CH2-CFmH2-m-X, with n,m not equal 0 and X = CH2OH) to compounds with isolated fluorination (n not equal 0; m = 0, and including X-CH2-CFnH2-n-CH2-X, n = 0-2). It is shown that skipped fluorination is more powerful for log P reduction purposes compared to single or vicinal fluorination. Efficient stereoselective syntheses of the compounds with skipped fluorination motifs are reported, which where relevant can be made enantioselective using known chiral building blocks. These compounds, and some intermediates, will be of interest as advanced fluorinated building blocks.}},
author = {{Troup, Robert and Jeffries, Benjamin and Saudain, Raphael El-Bekri and Georgiou, Eleni and Fish, Johanna and Scott, James S. and Chiarparin, Elisabetta and Fallan, Charlene and Linclau, Bruno}},
issn = {{0022-3263}},
journal = {{JOURNAL OF ORGANIC CHEMISTRY}},
keywords = {{ETHYL BROMODIFLUOROACETATE,PHYSICOCHEMICAL PROPERTIES,VINYLIDENE,FLUORIDE,DRUG CANDIDATES,POLARITY,ALKYL,DISCOVERY,DESIGN}},
language = {{eng}},
number = {{2}},
pages = {{1882--1900}},
title = {{Skipped fluorination motifs : synthesis of building blocks and comparison of lipophilicity trends with vicinal and isolated fluorination motifs}},
url = {{http://doi.org/10.1021/acs.joc.0c02810}},
volume = {{86}},
year = {{2021}},
}
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