3-Fluoro- and trifluoromethylthio-piperidines
represent important
building blocks for discovery chemistry. We report a simple and efficient
method to access analogs of these compounds that are armed with rich
functionality allowing them to be chemoselectively derivatized with
high diastereocontrol.
The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-β-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 α-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.
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