Can we have too many fluorines?

The incorporation of fluorine atoms in drug like molecules has become increasingly prevalent over the last few decades. A publication from Merck in 2008 reported on how the total number of fluorine-containing drugs had significantly increased since the late 50s (Figure 1).


The strategy of incorporating fluorine atoms impart on a wide range of properties, from increasing potency, impacting on lipophilicity and permeability across cells. A more prevalent strategy for the medicinal chemist relies on the incorporation of fluorines for the modulation of drug metabolism and improvements on the physicokinetic properties. Fluorines are frequently used as bioisoteres of carbonyl-containing moieties and can reduce metabolism by directly replacing a proton prone to oxidation. Gillis et al. recently reviewed some instances where the incorporation of fluorine atoms had a key impact on metabolism and pharmacokinetic properties but also played a unique role in influencing molecular conformational. However, an interesting aspect of fluorine atoms comes from their use of labelled ligands in Positron Emission Tomography (PET) imaging. PET imaging is used as a non-invasive technique to demonstrated target exposure in clinical studies and as a clinical tool for cancer diagnosis. In such cases, short lived radionucleotides such as [18F]-fluorines are incorporated at a late-stage in tracer molecules, hence the need for clean and efficient late-stage fluorination methodologies.

There has been tremendous progress in organo-fluorine chemistry over the last decades where fluorines are introduced efficiently and some recent reviews can be found here and here. The methods are too numerous to describe or list. For example nucleophilic fluorination reactions, and in particular [18F]-fluorination, do still remain widely used but yields can be low (Figure 2).


Metal-Free Oxidative Fluorination of Phenols with [18F]Fluoride; Gouverneur et al.; Angew. Chem. 2012, 124, 6837

However, electrophilic fluorination have become more widely popular due to their reactivity toward a wide range of functional group but are largely limited to a very small selection of reagents, namely SelectFluor, NFSI and N-F-pyridinium (Figure 3).


From a drug discovery perspective, could these late-stage fluorination methodologies be applied to rapidly explore the fluorination of a scaffold that could otherwise be lengthy to prepare? Could improved potency be gained by a late stage fluorination? What about improving metabolism by a simple last step fluorination? The synthetic methodology is available and a recent article from the Ritter group ‘Late-stage fluorination: Fancy Novelty or useful tool?’ seems to suggest that recent advances have enabled such strategies.


The Many Roles for Fluorine in Medicinal Chemistry; William K. Hagmann; J. Med. Chem., 2008, 51 (15), pp 4359–4369; DOI: 10.1021/jm800219f

ADMET rules of thumb II: A comparison of the effects of common substituents on a range of ADMET parameters; Paul Gleeson, Gianpaolo Bravi, Sandeep Modi, Daniel Lowe; Bioorganic & Medicinal Chemistry, 2009, 17(16), pp 5906-5919; DOI: 10.1016/j.bmc.2009.07.002

Applications of Fluorine in Medicinal Chemistry; Eric P. Gillis, Kyle J. Eastman, Matthew D. Hill, David J. Donnelly, and Nicholas A. Meanwell; J. Med. Chem., 2015, 58 (21), pp 8315–8359; DOI: 10.1021/acs.jmedchem.5b00258.

Metal-Free Oxidative Fluorination of Phenols with [18F]Fluoride; Gao, Z.; Lim, Y. H.; Tredwell, M.; Li, L.; Verhoog, S.; Hopkinson, M.; Kaluza, W.; Collier, T. L.; Passchier, J.; Huiban, M.; Gouverneur, V. Angew. Chem. 2012, 124, 6837

Introduction of Fluorine and Fluorine-Containing Functional Groups; Theresa Liang, Constanze N. Neumann, Tobias Ritter; Angewandte Chemie International Edition 2013, 52 (32), pp 8214–8264; DOI: 10.1002/anie.201206566

Modern Carbon–Fluorine Bond Forming Reactions for Aryl Fluoride Synthesis; Michael G. Campbell, Tobias Ritter; Chem. Rev., 2015, 115 (2), pp 612–633; DOI: 10.1021/cr500366b

Late-Stage Fluorination: Fancy Novelty or Useful Tool?; Constanze N. Neumann and Tobias Ritter; Angewandte Chemie International Edition, Special Issue: 150 Years of BASF, 2015, 54 (11), pp 3216-3221; DOI: 10.1002/anie.201410288

Blog written by Michael Paradowski



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