Phosphoric Acid-Catalyzed Enantioselective Synthesis of Axially Chiral Cyclobutanamides

Chiral cyclobutanamide is a privileged scaffold in drug discovery. Here, we describe, for the first time, the synthesis of axially chiral cyclobutanamides via phosphoric acid-catalyzed enantioselective condensation between N-arylcarbamyl cyclobutanones and hydroxylamines. Rational substrate design, incorporating an amide moiety (CONHR) into the cyclobutanone backbone and the formation of a multi-hydrogen bonding network involving the N-H of this amide portion, is responsible for the excellent enantioselectivity achieved in the stereodetermining dehydration process, which is supported by a detailed mechanistic study.