Fluorination of Medicinal Compounds

Conformation Effect

GABA


(R)-3F-GABA


Substitution of the hydrogen attached to the carbon by fluorine can have a significant influence on the properties of a molecule due to the way it can alter the molecules conformation.

The conformation of the fluorinated molecule changes due to the gauche effect between fluorine and the substituents on the adjacent carbon. This ‘gauche effect’ is illustrated in the examples of 3-F GABA (the (R)-3F-GABA and (S)-3F-GABA enantiomers) compared to GABA.

The design principle behind this fluorination is that the gauche interaction between fluorine and the ammonium substituent to favour a specific conformation which allows for further stereocontrol to probe receptors, and in the case of GABA, recognition by the transaminase.

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N. Meanwell, Journal of Medicinal Chemistry, 2018.