Development of an enantioselective allylic alkylation of acyclic α-fluoro-β-ketoesters for the asymmetric synthesis of 3-fluoropiperidines

The first usefully-enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-β-ketoesters has been achieved using the Trost family of chiral ligands providing products in up to 92% ee. This work provides new insights that can address the typically modest selectivities associated with acyclic α-fluoroenolates, and provides experimental evidence that the typically poor levels of enantiocontrol associated with these systems is not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows useful 3-fluoropiperidine intermediates to be easily prepared, and we demonstrate that these systems are amenable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.