Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

Abstract

SummaryIn a previous study it was shown that the enantioselective α-fluorination of racemic α-chloroaldehydes with a chiral organocatalyst yielded the corresponding α-chloro-α-fluoroaldehydes with high enantioselectivity. It was also revealed that kinetic resolution of the starting aldehydes was involved in this asymmetric fluorination. This paper describes the determination of the absolute stereochemistry of a resulting α-chloro-α-fluoroaldehyde. Some information about the substrate scope and a possible reaction mechanism are also described which shed more light on the nature of this asymmetric fluorination reaction.

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

“…Subsequently, Shibatomi and co-workers insisted on the kinetic resolution process in the asymmetric fluorination mechanism. 144 Thus, the asymmetric induction in this transformation required not only the enantiofacial distinction of enamine intermediates for electrophilic fluorination but also a kinetic resolution for the corresponding ( S )- α -chloroaldehydes. Moreover, they reported the determination of the absolute configuration of desired α -chloro- α -fluoroaldehydes via X-ray crystallographic analysis of its corresponding α -chloro- α -fluoro- β -keto ester derivatives.…”

Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation Reactions

“…Subsequent mechanistic studies suggest that the reaction mechanism involves a kinetic resolution of the starting α-chloro-aldehyde. 60 …”

Asymmetric Methods for Carbon‐Fluorine Bond Formation

“…All used enamine catalysis (secondary amine organocatalysts), and two of them (procedures by Beeson and MacMillan [61c] and Jørgensen et al [61d] ) are still the most commonly used methods for asymmetric α-fluorinations of aldehydes, due to their efficiency and excellent enantioselectivity. [63][64][65][66][67][68][69][70][71] Both the MacMillan and the Jørgensen catalysts (see Scheme 29 and Scheme 30) differentiate the nonfluorinated aldehyde substrates and the α-fluoroaldehyde products efficiently, despite the enhanced acidity of the product, which should promote enamine formation and racemization. [61d] The Jørgensen catalyst is also highly efficient in various other direct α-functionalizations of aldehydes.…”