[2.2]Paracyclophane-Based Isothiourea-Catalyzed Highly Enantioselective α-Fluorination of Carboxylic Acids

Abstract

Planar chiral [2.2]paracyclophane-based isothiourea catalysts have been prepared over a few simple steps in high yields.In the presence of these catalysts, highly efficient catalytic enantioselective fluorination of carboxylic acids has been accomplished, providing a broad range of optically active αfluoroesters in high yield and excellent enantioselectivity.

Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions

“…Unfortunately, the α-alkylated ester 1n and the homologous phenylpropionic acid ester 1o were not found to be reactive, which is in accordance with previous observations for other C1 ammonium enolate applications. 5 − 7 , 9 , 19 …”

“…Unfortunately, the α-alkylated ester 1n and the homologous phenylpropionic acid ester 1o were not found to be reactive, which is in accordance with previous observations for other C1 ammonium enolate applications. [5][6][7]9,19 Finally, we also carried out quenches with a few other aliphatic alcohols and amines. The use of ethanol and i-PrOH (products 3a OEt and 3a OiPr ) resulted in slightly lower enantioselectivities compared with the use of MeOH, which can be rationalized by a slightly slower esterification with these alcohols, thus allowing for some epimerization of intermediates II.…”

“…Furthermore, it should be possible to carry out the reaction either totally in the absence of an external base, or at least using only catalytic amounts of base, considering the fact that the released succinimide should be capable of serving as the base required for enolate formation. Encouragingly, during the finalization of this manuscript, Zheng and coworkers reported an elegant complementary approach for the α-fluorination of free carboxylic acids (which are activated in situ upon the addition of TsCl) in the presence of a newly designed [2.2]­paracyclophane-based isothiourea catalyst (Scheme B), thus underscoring the potential of this catalysis concept.…”

Advances in Chemical Crystallography: A Themed Issue Honoring Professor Alexandra M. Z. Slawin on the Occasion of Her 60th Birthday

“…We have expanded the scope of electrophiles applicable within this catalyst turnover strategy to include iminium ions generated under either photoredox conditions or Brønsted acid catalysis, as well as bis-sulfone Michael acceptors, and pyridinium salts (Scheme 1e) [76][77][78][79]. Recently, Waser also reported an elegant example of this turnover strategy for the enantioselective α-chlorination of pentafluorophenyl esters [80], while Zheng and co-workers reported a related approach using diphenyl methanol as an external turnover reagent for the fluorination of carboxylic acids [81,82]. A significant challenge within this area is the identification of electrophilic reaction partners that react with the catalytically-generated C(1)-ammonium enolate, but are compatible with the nucleophilic tertiary amine catalyst and aryloxide, which is essential for catalyst turnover.…”

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides

“…We have expanded the scope of electrophiles applicable within this catalyst turnover strategy to include iminium ions generated under either photoredox conditions or Brønsted acid catalysis, as well as bis-sulfone Michael acceptors, and pyridinium salts (Scheme 1e) [76][77][78][79]. Recently, Waser also reported an elegant example of this turnover strategy for the enantioselective α-chlorination of pentafluorophenyl esters [80], while Zheng and co-workers reported a related approach using diphenyl methanol as an external turnover reagent for the fluorination of carboxylic acids [81,82]. A significant challenge within this area is the identification of electrophilic reaction partners that react with the catalytically-generated C(1)-ammonium enolate, but are compatible with the nucleophilic tertiary amine catalyst and aryloxide, which is essential for catalyst turnover.…”