Synthesis of Fluorinated N-Heterocycles: Analogues of Febrifugine

This thesis describes the synthesis and stereochemical investigation of fluorinated analogues of febrifugine and its synthetic derivative halofuginone. In particular, racemic cis- and trans-3-fluoro analogues of febrifugine were prepared using both piperidine and pyrrolidine ring systems as starting scaffolds. Febrifugine and halofuginone, provide structurally rich scaffolds for probing stereoelectronic effects of fluorine and in addition possess potentially very useful biological properties. The synthetic route was developed in a modular sequence, beginning with nitrogen protection using a Cbz group, followed by enamine formation. Electrophilic fluorination with Selectfluor® introduced fluorine at the β-position to nitrogen, affording cis/trans mixtures of fluorinated intermediates. Sakurai allylation then established new carbon–carbon bonds. Upon separation, the allyl group of each diastereomer underwent a Wacker oxidation followed by functionalization that enabled introduction of the required quinazolinone portion. Finally, removal of the N-Cbz protecting group lead to isolation of the 3-fluorofebrifugine analogues as their dihydrobromide salts. Use of 7-bromo-6-chloroquinazolinone, in an otherwise identical sequence, led to the preparation of cis- and trans-3-fluorohalofuginone. Parallel studies using pyrrolidine substrates demonstrated the generality of the approach, leading to analogous cis- and trans-fluorinated derivatives. In these later studies, fluorination of the enamine afforded cis/trans mixtures of 2-methoxy-3-fluoropyrrolidines, which were used for determining the stereochemistry. Finally, the interconversion between the cis- and trans-diastereomers was studied. In DMSO-d6 and as their free-bases, the isomerization of each separate diastereomer gave a common 35:65 ratio of cis- to trans- for the piperidine analogues while a 50:50 ratio of cis- to trans- was observed for the pyrrolidine analogues. Overall, this work establishes robust synthetic routes to fluorinated febrifugine and halofuginone analogues and provides new insight into stereochemical behaviour and isomerisation in β-amino ketone frameworks. The methodologies developed here extend to both piperidine and pyrrolidine scaffolds and lay the groundwork for future asymmetric synthesis and structural diversification of fluorinated heterocycles.