Diastereoselective synthesis of polyfluoroalkylated α-aminophosphonic acid derivatives

Abstract

The asymmetric synthesis of biorelevant aminophosphonates and aminophosphonic acids bearing trifluoromethyl, tetrafluoroethyl, perfluoropropyl or chlorodifluoromethyl group in the α-position to phosphonyl group is developed. Diastereoselective reduction of α-(poly)fluoroalkylated iminophosphonates, bearing stereodirecting α-phenylethyl group at the nitrogen atom, with sodium borohydride produces diastereomeric N-(α-phenylethyl) polyfluoroalkylphosphonates, readily separated by column chromatography. The highly stereoselective reaction of (R)-N-tert-butylsulfinylimine of tetrafluoropropanal with generated in situ diethyltrimethysilylphosphite leads to (R,R)-N-(tert-butylsulfinyl)tetrafluopropylphosphonate. Sequential N- and O-deprotection affords enantiomerically pure polyfluoroalkylphosphonate and aminophosphonic acids. The presence of α-phenylethyl group at the nitrogen atom allows easy determination of absolute configuration of the newly formed stereogenic center by the 31P,19F NMR method.