Development of an Enantioselective Allylic Alkylation of Acyclic α-Fluoro-β-ketoesters for Asymmetric Synthesis of 3-Fluoropiperidines

The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of alpha-fluoro-beta-ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic alpha-fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3-fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.

Automated summary

The first enantioselective Pd-catalyzed asymmetric allylic alkylation of alpha-fluoro-beta-ketoesters has been achieved with up to 92% ee using Trost family chiral ligands. This work provides new insights into the modest selectivities associated with acyclic alpha-fluoroenolates and experimental evidence that poor levels of enantiocontrol in these systems are not necessarily due to E/Z enolate mixtures. Additionally, this methodology enables the easy preparation of useful 3-fluoropiperidine intermediates, demonstrating applicability to a variety of functionalization reactions for the discovery of bioactive products.