A Doubly Axially Chiral Phosphoric Acid Catalyst for the Asymmetric Tandem Oxyfluorination of Enamides

摘要

The selective construction of carbon-fluorine bonds is of great interest to medicinal chemists because the replacement of a carbon-hydrogen bond with a carbon-fluorine bond continues to be an effective approach to the development of biologically active molecules with improved physical and metabolic profiles and biological activities. To this end, a number of impressive examples of catalytic enantioselective fluorination have been reported over the last decade. Our laboratory has recently introduced a novel strategy for asymmetric fluorination based on phase-transfer catalysis using chiral anionic catalysts based on BINOL-derived phosphates Eq. (1).) Motivated by the importance of the β-fluoroamine motif in medicinal chemistry we employed this strategy to develop a highly asymmetric fluorination of cyclic enamides, allowing us to isolate stable but highly versatile enantioenriched α-fluoro-N-acylimines. Given the proven ability of BINOL phosphoric acid catalysts to control addition to imines, we posited that aldehyde-derived enamides should be of particular interest as our protocol, upon enamide fluorination, would generate in the first instance a protonated N-acyliminium ion Eq. (2). This intermediate should exhibit hydrogen-bonding interactions with the chiral phosphate anion, allowing catalyst-controlled addition of an external oxygen nucleophile, constituting an oxyfluorination of enamides. The resulting stereodefined α-fluoro-N,O-aminal would be of particular interest as chiral N,O-aminals are prevalent in natural products and the effect of fluorine introduction on this motif remains, to the best of our knowledge, thus far unexplored. With regard to existing asymmetric N,O-aminal synthesis, Antilla and co-workers have reported the phosphoric acid-catalyzed addition of alcohols and hydroperoxides to N-acylimines, although examples delivering high enantioselectivity were restricted to aromatic imines and in no cases could simple water be used as nucleophile in order to obtain a hemiaminal.