2-Fluoromalonate esters: fluoroaliphatic building blocks for the life sciences

Abstract

The majority of fluorinated pharmaceutical products bear structurally simple fluoro- and trifluoromethyl-aromatic subunits, in part because of the ready availability of a wide range of fluoro and trifluoromethyl aryl derivatives for both drug discovery and manufacturing campaigns. As life-science programmes are increasingly seeking more three-dimensional structures as hit-to-lead compounds, the requirement for complex organic molecules bearing fluorine attached to sp3 carbon in aliphatic systems and monofluorinated heterocycles is becoming more important. Consequently, the incorporation of new polyfunctional fluorinated building blocks into drug discovery projects is required, to drive the development of new generations of fluorinated pharmaceuticals in much the same way as the availability of fluorinated aromatic systems did in the past. Fluoromalonate esters are potentially very versatile fluorine containing building blocks that may be used for the introduction of fluorine atoms into aliphatic and heteroaromatic systems. The syntheses of fluoromalonate derivatives using commercially available fluorinating reagents on both research and manufacturing scales are described, and the use of fluoromalonates for appropriate alkylation, acylation, Michael addition, annelation, and biotransformation processes are presented, providing an indication of the synthetic possibilities available for accessing novel selectively fluorinated structures.