A variety of highly functionalized polycyclic isoxazoles are prepared by a two-step protocol: (1) 1,3-dipolar cycloaddition of o,o′-disubstituted benzonitrile oxides to para-quinone mono-acetals, then (2) dehydrogenation. The cycloaddition proceeds in a regioselective manner, favouring the formation of the 4-acyl cycloadducts, which are suitable intermediates for the synthesis of semi-aromatized polycyclic targets derived from polyketide type-II biosynthesis.