Catalytic enantioselective α-fluorination of carbonyl compounds using chiral transition metal complexes

Two catalytic systems were developed for efficient catalytic enantioselective alpha-fluorination reactions of carbonyl compounds. Cationic Pd complexes were found to be effective for fluorination of active methine and methylene compounds, and various substrates including beta-ketoesters, beta-ketophosphonates, and other related compounds were fluorinated in environmentally friendly alcoholic solvents (up to 99% ee). This system was also applicable to the reaction of 3-substituted oxindole derivatives. In addition, we succeeded in developing a novel trinary system NiCl2-binap/R3SiOTf/2,6-lutidine for the reaction of less acidic alpha-aryl acetic acid derivatives, and the desired reaction proceeded smoothly to give the corresponding monofluorinated compounds in a highly enantioselective manner (up to 88% ee). Our fluorination reactions are versatile, being applicable to stereoselective synthesis of chiral fluorinated analogues of fundamental building blocks and catalytic asymmetric synthesis of BMS204352, a promising agent for the treatment of stroke.