G.K. SURYA PRAKASH*, FANG WANG
*Corresponding author
University of Southern California, Loker Hydrocarbon Research Institute, 837 Bloom Walk, Los Angeles, CA 90089, USA

Abstract

The benefit of introducing fluorine into pharmaceuticals has been widely recognized. This thus leads to an urgent demand of capable protocols that enable fluorination and fluoroalkylations with high efficacy and selectivity. Although challenges remain, significant progress has been made over the past three decades, thereby allowing efficient incorporation of fluorine into complex organic molecules. Covering a brief history of fluorine chemistry and its association with pharmaceutical chemistry, this article reviews what the authors consider the state of the art in the field of synthetic organofluorine chemistry.

INTRODUCTION

Although organofluorine compounds are very scarce in the biosphere, fluorine has become the kingpin of drug discovery (1). To date, 20-25 percent of drugs contain at least one fluorine atom. Due to its steric resemblance to hydrogen and extreme electronegativity (a small atom with a big ego), fluorine has been extensively employed to modulate the biological properties of drug molecules, such as acidity, basicity, protein binding affinity, and lipophilicity. The introduction of fluorine can enhance the metabolic stability (bioavailability) of organic molecules due to the unfavourable energetic cost of breaking a C-F bond to form a C-O bond. Owing to the large dipole moment of the C-F bond, fluorine substitution can also lead to substantial conformational changes through various stereoelectronic interactions, therefore altering the bioactivity of organic molecules (2). Moreover, the applications of 19F nuclear magnetic resonance imaging (MRI) and 18F radiolabeling (for Positron Emission Tomography, PET) have become the most promising strategies in in vivo and ex vivo ...