Synthesis and Structural Features of
α-Fluorocarbonyl Systems

Abstract

Molecules that bear carbon-fluorine bonds, especially on chiral centres, are becoming of interest to the pharmaceutical industry due to the effects on the bioactivity of a drug molecule. This thesis adds to the pool of chiral α-fluorocarbonyl systems and the discussion of the grey area surrounding their conformational preference. First, dimethyl 2-fluoromalonate was investigated as a nucleophile and as an electrophile. The fluorodiester was successfully reacted with a short series of electrophilic alkylating agents and, separately, a nucleophilic amine. Consequently, in collaboration with GlaxoSmithKline, these two strategies were combined to use dimethyl 2-fluoromalonate as a fluorinated ‘building block’ in the synthesis of a 6-membered fluorolactam.

This fluorolactam subsequently underwent an enzymatic chiral resolution to yield an enantiomerically enriched analogue as an intermediate in the synthesis of a pre-clinical candidate spleen tyrosine kinase (Syk) inhibitor being developed by GSK. The process was optimised and quantitatively analysed by a ‘green metrics’ package developed by the EU IMI Chem21 consortium and found to be significantly less wasteful than the literature alternative synthetic route. Work on analogous 5- and 7-membered fluorolactams was carried out following the success of the 6-membered system.

In collaboration with Almac Group, another α-fluorodicarbonyl species, ethyl 2-fluoroacetoacetate, was chosen as a substrate for carbonyl reductase (CRED) screening. Enzymatic routes to all four possible diastereomeric fluoroalcohol derivatives were found and work to determine the absolute stereochemistries of the products is ongoing.

Following analysis of the structural preferences of the X-ray crystal structures of products developed in this thesis, the final chapter investigates the conformational preference of α-fluorocarbonyl moieties in the Cambridge Structural Database. This research was coupled with NMR experiments and computational calculations, from the literature and our own work, of these species in the solution state to determine that there is a greater syn F-C-C=O preference in more polar environments and that any inherent preference may potentially be overridden by a number of competing factors. The assumption that anti is the preferred conformation of α-fluorocarbonyl species must, therefore, be treated with caution.