Download Synthesis of fluorinated molecules as Agonists of the γ

Synthesis of fluorinated molecules as Agonists of the γ-Aminobutyric Acid Type B
(GABAB)Receptor
Munia Sowaileh,a Amy Salyer,b Gregory Hockerman,b and David Colbya
a
Department of BioMolecular Sciences, University of Mississippi, University, Mississippi,
USA b Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University,
West Lafayette, Indiana, USA.
Background and Objective
GABAB receptors are linked to CNS diseases such as epilepsy, drug addiction, and
neurodegenerative disorders. Of the few pharmaceuticals that target GABAB receptors,
baclofen is the only one approved by the FDA. A novel series of α,α-difluoromethyl
secondary alcohols have been recently reported as GABAB agonists by our group. The aim
of this project is to explore the activity of the α,α-difluoromethyl tertiary alcohol analogues as
GABAB agonists.
Methods
Previously, our lab reported a method to generate difluoroenolates from α-keto pentafluoro
gem-diols and subsequently add them to aldehydes to obtain α,α-difluoromethyl secondary
alcohols. The scope of the method was expanded to include additions to ketones in order to
produce α,α-difluoromethyl tertiary alcohols. Biological evaluation of the resultingα,αdifluoromethyl tertiary alcohols at GABABwas measured using the inhibition of forskolinstimulated accumulation of cAMP.
Results
The ketones did not react well with the difluoroenolates, so α-halo ketones were employed to
achieve good yields. Although several analogues suffered from poor solubility, the
analogues that were successfully tested displayed activities between 40–90% at 100 μmol.
Discussion and Conclusions
The halogen atom activated the ketone and facilitated the aldol reaction improving the yields
significantly. Preliminary studies have indicated that tertiary alcohols display activity as
GABAB agonists.