<i>C</i>₄-Symmetric Inherently Chiral Macrocycles from Organocatalytic Enantioselective Desymmetrization of Resorcin[4]arenes

Reported herein is the synthesis of C4-symmetric chiral resorcin[4]arene macrocycles by a catalytic enantioselective multicomponent reaction. Using (S)-piperidine-2-carboxamide-derived N,N′-dioxide as a chiral organocatalyst, the desymmetrization of resorcin[4]arenes via a 4-fold Mannich/cyclization reaction produced C4-symmetric (Pic)-resorcin[4]arene derivatives in 30%–47% yields with enantiomeric excess (ee) values up to 99%. This one-pot process generated 16 chemical bands in a single operation. The utility of the method was demonstrated by the conversion of the resulting products into functionalized chiral resorcin[4]arenes, which were able to catalyze the asymmetric addition of dialkylzinc to benzaldehydes.