Fluorination and Fluoroalkylation Strategies for Synthetic and Medicinal Chemistry

SUMMARY
Fluorination of an organic compound affects physicochemical properties, which in medicinal settings perturbs
pharmacodynamic, pharmacokinetic, distribution, and/or metabolic profiles both in vitro and in vivo. Thus, the
ability to selectively install fluorinated groups under mild conditions is essential for accessing new therapeutics
and biological probes. However, the unique physical properties of fluorinated substrates and/or reagents typically
perturb fundamental organic reactivities, which can complicate synthetic sequences to access fluorinated
compounds. Thus, many routine organic reactions simply do not work in the presence of fluorinated reagents or
with fluorinated substrates. Additionally, the unique properties of fluorinated substrates enable new reactivities
that cannot be achieved by the respective non-fluorinated counterparts, which provides opportunities to develop
innovative reactions and strategies for accessing medicinally relevant substructures
With this R35 program, the Altman group has a long-term goal of developing innovative catalyst systems,
reagents, and/or synthetic strategies for accessing medicinally relevant fluorinated substructures. In this area,
we develop fluorination and fluoroalkylation methodologies using innovative strategies (e.g. electrochemistry, C–
H functionalization, deoxyfluoroalkylation, transition metal catalyzed reactions) that enable synthetic chemists to
convert simple and readily available functional groups (e.g. alcohols, carbonyls, fluorinated alkenes) into a broad
spectrum of highly valuable fluorinated analogs. Additionally, we explore synthetic transformations in which
fluorinated substructures react through distinct mechanisms and/or deliver products with distinct selectivities
relative to analogous reactions of nonfluorinated substrates. Development of the proposed strategies will enable
medicinal chemists to access new and unique biological probes and therapeutics. A second long-term goal is to
explore physicochemical perturbations imparted by fluorinated substructures that might influence drug stability,
distribution, metabolism, and/or ligand-protein interactions, and to apply such principles in the design of next-
generation fluorinated therapeutic candidates with improved drug-like properties. In the next phase of our work,
we will apply modern innovative synthetic reactions to deliver next-generation fluorinated analogs of natural
products that will retain the therapeutically valuable pharmacodynamic action and also improve stability and
distribution relative to the parent compounds.

Grant Number: 5R35GM124661-10
NIH Institute/Center: NIH
Principal Investigator: Ryan Altman