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Skipped fluorination motifs: synthesis of building blocks, and comparison of lipophilicity trends with vicinal and isolated fluorination motifs

Skipped fluorination motifs: synthesis of building blocks, and comparison of lipophilicity trends with vicinal and isolated fluorination motifs
Skipped fluorination motifs: synthesis of building blocks, and comparison of lipophilicity trends with vicinal and isolated fluorination motifs
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 ≠ 0 and X = CH2OH) to compounds with isolated fluorination (n ≠ 0; m = 0, and including X–CH2CFnH2–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.
0022-3263
1882–1900
Troup, Robert Ian
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Jeffries, Benjamin Francis Joseph
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El Bekri-Saudain, Raphael Bilal Theo
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Georgiou, Eleni
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Fish, Johanna
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Scott, James S.
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Chiarparin, Elisabetta
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Fallan, Charlene
2753821a-35b7-4cbf-851d-9a3a8929af2b
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Troup, Robert Ian
4e5eae00-ac0a-44a4-8c32-1042d6261c46
Jeffries, Benjamin Francis Joseph
5dd25e94-d698-4270-9c65-800495794388
El Bekri-Saudain, Raphael Bilal Theo
101cd813-4d9a-463a-b3d0-e7d1cf9185a8
Georgiou, Eleni
e91f8a7f-6ee4-49d1-a77b-612471269c9f
Fish, Johanna
9de5c823-c554-415a-b4d5-431c31fb3679
Scott, James S.
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Chiarparin, Elisabetta
5051f89a-b801-4746-8f20-457fdcbed396
Fallan, Charlene
2753821a-35b7-4cbf-851d-9a3a8929af2b
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

Troup, Robert Ian, Jeffries, Benjamin Francis Joseph, El Bekri-Saudain, Raphael Bilal Theo, Georgiou, Eleni, Fish, Johanna, Scott, James S., Chiarparin, Elisabetta, Fallan, Charlene and Linclau, Bruno (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).

Record type: Article

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 ≠ 0 and X = CH2OH) to compounds with isolated fluorination (n ≠ 0; m = 0, and including X–CH2CFnH2–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.

Text
Linclau vicinal-skipped logP manuscript_revised BL 4acc - Accepted Manuscript
Restricted to Repository staff only until 5 January 2022.
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More information

Accepted/In Press date: 24 December 2020
e-pub ahead of print date: 5 January 2021

Identifiers

Local EPrints ID: 446484
URI: http://eprints.soton.ac.uk/id/eprint/446484
ISSN: 0022-3263
PURE UUID: 0db74a73-4a84-4cfa-9450-809072929ff7
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

Catalogue record

Date deposited: 11 Feb 2021 17:32
Last modified: 26 Nov 2021 02:43

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Contributors

Author: Robert Ian Troup
Author: Benjamin Francis Joseph Jeffries
Author: Raphael Bilal Theo El Bekri-Saudain
Author: Eleni Georgiou
Author: Johanna Fish
Author: James S. Scott
Author: Elisabetta Chiarparin
Author: Charlene Fallan
Author: Bruno Linclau ORCID iD

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