Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β‑Fluorinated Amides

The
last two decades have witnessed the emergence of direct enolization
protocols providing atom-economical and operationally simple methods
to use enolates for stereoselective C–C bond-forming reactions,
eliminating the inherent drawback of the preformation of enolates
using stoichiometric amounts of reagents. In its infancy, direct enolization
relied heavily on the intrinsic acidity of the latent enolates, and
the reaction scope was limited to readily enolizable ketones and aldehydes.
Recent advances in this field enabled the exploitation of carboxylic
acid derivatives for direct enolization, offering expeditious access
to synthetically versatile chiral building blocks. Despite the growing
demand for enantioenriched fluorine-containing small molecules, α-
and β-fluorinated carbonyl compounds have been neglected in
direct enolization chemistry because of the competing and dominating
defluorination pathway. Herein we present a comprehensive study on
direct and highly stereoselective Mannich-type reactions of α-
and β-fluorine-functionalized 7-azaindoline amides that rely
on a soft Lewis acid/hard Brønsted base cooperative catalytic
system to guarantee an efficient enolization while suppressing undesired
defluorination. This protocol contributes to provide a series of fluorinated
analogs of enantioenriched β-amino acids for medicinal chemistry.