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Crafting Organofluorine

MARTIN SCHÜLER1*, PATRICIA ARGIBAY2

1. Orgafluor SL, Carrer Baldiri Reixac 4, 08028 Barcelona, Spain

2. Unidad de Química Combinatoria, Carrer Baldiri Reixac 10, 08028 Barcelona, Spain

Abstract

This communication covers contemporary methodologies to access organofluorine materials which are of growing interest for the materials sciences and life science industries. The orthogonal strategies currently employed in chemical manufacturing are reviewed and challenges faced by the synthetic chemist to introduce fluorine in a regio- and stereospecific manner are examined. Industrial applications involve fluorinating agents that are compatible with a high degree of molecular functionality, affording structurally complex organofluorine compounds in a convenient and economic manner.


INTRODUCTION

Fluorination has long become a standard tool to increase bioavailability and metabolic stability of biologically active lead structures.  The fact that nature has rarely evolved effective mechanisms to incorporate fluorine in biological pathways makes organofluorine compounds generally inert towards enzymatic degradation and only in a few rare cases has the release of fluoride by enzymatic action led to the withdrawal of a new molecular entity from its clinical use (1).

Fluorine is closest to hydrogen in terms of atomic size and while its introduction has only limited impact on the steric properties of an organic molecule, it can strongly affect its electronic properties to modulate the acidity and basicity of neighboring groups, thermal and oxidative stability, its lipophilicity, and molecular conformation (2). As a consequence the pharmacokinetic profile of the biologically active compound can be dramatically altered, a methodology which is increasingly harvested in pharmaceutical development (Figure 1). This trend is clearly evidenced by the almost 30 percent of New Molecular Entities (NME) approved by the FDA in 2014 containing fluorine a ...




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