Development of Enantioselective Fluorination Reaction and Its Application to the Synthesis of Biologically Active Compounds

The selective construction of carbon-fluorine bonds is of great interest to medicinal chemists because the replacement of hydrogen and oxygen atoms with fluorine atom in biologically active molecules can confer molecules with improved physicochemical properties and biological activities. Since the first discovery of enantioselective fluorination using N-fluorocamphorsultam, our synthetic interests have been focused on the development of chiral N-fluorosulfonamide derivatives capable of enantioselective fluorination. However, these initial efforts revealed several limitations in both chemical yields and enantioselectivities of the fluorinated products. We present here the background of our recent development of the enantioselective fluorination reaction and some successful applications of the methods to the design and synthesis of fluoroisosteres of biologically active natural products. Two novel approaches using the cinchona alkaloids/Selectfluor® combination and bis (oxazoline) -metal complex have been pursued, respectively. Cinchona alkaloid/ Selectfluor® combination, i.e., N-fluoroammonium salts of cinchona alkaloids, was found to be an effective enantioselective fluorinating reagent for a wide range of substrates such as silyl enol ethers, β-keto esters, arylcyano esters, and oxindoles without any additives. The bis (oxazoline) s were found to be efficient and unique catalysts for enantioselective fluorination in the presence of a catalytic amount of metal salts. An interesting phenomenon, “elective” enantioselectivity, has been observed in the fluorination of β-keto esters. Switching the metal center from copper to nickel in the presence of the same bis (oxazoline) ligands gave a complete reversal of enantioselectivity.