Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Benjamin Jeffries; Zhong Wang; Robert I Troup; Anaïs Goupille; Jean-Yves Le Questel; Charlene Fallan; James S Scott; Elisabetta Chiarparin; Jérôme Graton; Bruno Linclau

doi:10.3762/bjoc.16.182

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Beilstein J Org Chem. 2020 Sep 2:16:2141-2150. doi: 10.3762/bjoc.16.182. eCollection 2020.

Affiliations

¹ School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.
² Université de Nantes, CNRS, CEISAM UMR 6230, F-44000 Nantes, France.
³ Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK.

Abstract

A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable, and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent.

Keywords: aliphatic fluorination; cyclopropane; isopropyl; isostere; lipophilicity; oxetane.

Grants and funding

We are grateful to AstraZeneca for a CASE award, and to the EPSRC for a CASE Conversion grant (EP/M508147/1), a standard grant (EP/P019943/1), and a core capability grant (EP/K039466/1). The CCIPL (Centre de Calcul Intensif des Pays de Loire) is acknowledged for provision of computer time.