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.
Highlights
The introduction of small alkyl groups onto bioactive compounds as space filling groups is a common strategy in the drug optimization process
We describe a systematic study on the lipophilicity modulations of the isopropyl, cyclopropyl and 3-oxetanyl groups and their various possible analogues, featuring fluorination at a single carbon atom (Figure 4), using the directly comparable isobutanol, cyclopropylmethanol and 3-oxetanylmethanol scaffolds
While D2 is a β-fluorohydrin, its fluorine is substituted at a tertiary position, with the C–F bond able to polarize the six C–H bonds of the methyl groups, which has a lipophilicity lowering effect
Summary
The introduction of small alkyl groups onto bioactive compounds as space filling groups is a common strategy in the drug optimization process. The modification of a geminal dimethyl moiety to an oxetanyl group has proven to be a useful biomimetic replacement leading to a significant logP decrease (compare 3 with 4) [1618]. We describe a systematic study on the lipophilicity modulations of the isopropyl, cyclopropyl and 3-oxetanyl groups and their various possible analogues, featuring fluorination at a single carbon atom (Figure 4), using the directly comparable isobutanol, cyclopropylmethanol and 3-oxetanylmethanol scaffolds.
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