Brønsted-Acid Catalyzed Diastereo- and Enantioselective Synthesis of Spiroisoindolinones from Enamides

A highly stereoselective Brønsted-acid catalyzed synthesis of densely substituted spiroisoindolinones from enamides and 3-hydroxy-isoindolinones is described. With simple Brønsted-acids, such as para-toluene sulfonic acid, spiroisoindolinones with three contiguous stereogenic centers are formed in high yields (up to 97 %) and diastereoselectivities (up to >98 : <2 : 0 : 0 dr) under mild reaction conditions. With the use of a chiral phosphoric acid catalyst, a diastereo- and enantioselective synthesis of the corresponding spiroisoindolinones was achieved. Mechanistic investigations indicate a step-wise mechanism via an initial addition of the enamide to an electrophilic N-acylimine species followed by an intramolecular aza-Friedel-Crafts reaction. Addition of a strong Lewis acid can be used to facilitate the second step for less reactive substrates.