The Organocatalytic α‐Fluorination of Chiral γ‐Nitroaldehydes: the Challenge of Facing the Construction of a Quaternary Fluorinated Stereocenter

Abstract

Chiral γ‐nitroaldehydes 1 are easily accessible by the organocatalytic Michael addition of aldehydes to nitroalkenes. In this paper, we report the organocatalytic fluorination of 1 with N‐fluorobenzenesulfonimide (NFSI) leading to the highly stereoselective construction of a challenging quaternary fluorinated stereocenter at the α position of α,α‐dialkyl aldehydes. The reaction takes place via a chiral trisubstituted enamine, so far rather unexplored in the field of organocatalysis. Fluorinated products 3 are direct precursors of chiral monofluorinated 3,4‐polysubstituted pyrrolidines. Mechanistic details are discussed with the aid of computational results.

De Novo Synthesis of Orthogonally-Protected C2-Fluoro Digitoxoses and Cymaroses: Development and Application for the Synthesis of Fluorinated Digoxin

“…The failure above (Scheme ) promoted us to design a de novo synthesis of C2 fluorinated sugars on the basis of one of the authors’ experiences in organocatalytic α-fluorination of chiral aldehydes . As chiral catalysts can be used in the fluorination process, it can be expected that the stereoselectivity is unlikely to be a big problem . However, one great challenge is whether proper conditions could be identified for the deprotection to yield the pyranoses, as α-fluoroaldehydes are reported to be highly unstable, which are often reduced in situ to the corresponding fluorohydrins. , Isolation of different isomers is another hurdle to the success of this strategy.…”

“…As chiral catalysts can be used in the fluorination process, it can be expected that the stereoselectivity is unlikely to be a big problem . However, one great challenge is whether proper conditions could be identified for the deprotection to yield the pyranoses, as α-fluoroaldehydes are reported to be highly unstable, which are often reduced in situ to the corresponding fluorohydrins. , Isolation of different isomers is another hurdle to the success of this strategy. Nevertheless, we embarked on the project.…”

Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

“…In 2016, the Quintavalla group reported a protocol for enantioselective construction of a fluorinated quaternary stereogenic center at α position of α , α -dialkyl aldehydes 115 bearing an enantiomerically pure chiral center in the C β -position catalyzed by chiral secondary amine catalysts (Scheme 28). 149 During the catalyst screening, organocatalysts bearing acidic protons were found to clearly improve the reactivity of the electrophilic fluorination process. Thus, the combination of J0rgensen’s diarylprolinols C11 or ent -C11 and trifluoroacetic acid as co-catalyst had been shown to enhance the reaction rate and diastereocontrol.…”

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

“…Lombardo-Quintavalla and coworkers studied the catalytic enantioselective α-fluorination reaction of α-branched γ-nitroaldehydes as specific substrates, which are accessed as essentially enantiopure compounds from the amine-catalyzed addition of the corresponding aldehyde to nitroolefins ( Scheme 3 ) [ 50 ]. This α-fluorination was not trivial because previous α-fluorinations of aldehydes involving the α,α-dialkyl substituted congeners led to diminished enantioselectivities.…”