Modular enantioselective access to β-amino amides by Bronsted acid-catalysed multicomponent reactions

beta-Amino acids are structural motifs widely found in therapeutic natural products, novel biomimetic polymers and peptidomimetics. As a convergent method, the synthesis of stereoenriched beta-amino amides through the asymmetric Mannich reaction requires specialized amide substrates or a metal catalyst for enolate formation. By a redesign of the Ugi reaction, a conceptually different solution to prepare chiral beta-amino amides was established using ambiphilic ynamides as two-carbon synthons. The modulation of ynamides or oxygen nucleophiles concisely furnished three classes of beta-amino amides with generally good efficiency as well as excellent chemo- and stereo-control. The utility is verified in the preparation of over 100 desired products that bear one or two contiguous carbon stereocentres, including those that directly incorporate drug molecules. This advance also provides a synthetic shortcut to other valuable structures. The amino amides could be elaborated into beta-amino acids, anti-vicinal diamines, gamma-amino alcohols and beta-lactams or undergo transamidation with amino acids and amine-containing pharmaceuticals.