Thiourea‐ and squaramide‐based bifunctional base catalysts represent nowadays a powerful tool in the field of asymmetric catalysis and have demonstrated very efficient for promoting a wide variety of transformations enantioselectively. New versions that incorporate one or various additional H‐bond donor site(s) in the catalyst structure have been developed recently which led to more active (reduced catalyst loadings) and selective catalysts. This review highlights the pioneering ideas and the most recent contributions to the area with the material organized according to the nature of the additional H‐bond donor functionality. The advantages, current limitations and perspectives of these new multifunctional catalysts are discussed.

The high tendency of α‐amino aldehydes to undergo 1,2‐additions and their relatively low stability under basic conditions have largely prevented their use as pronucleophiles in the realm of asymmetric catalysis, particularly for the production of quaternary α‐amino aldehydes. Herein, it is demonstrated that the chemistry of α‐amino aldehydes may be expanded beyond these limits by documenting the first direct α‐alkylation of α‐branched α‐amino aldehydes with nitroolefins. The reaction produces densely functionalized products bearing up to two, quaternary and tertiary, vicinal stereocenters with high diastereo‐ and enantioselectivity. DFT modeling leads to the proposal that intramolecular hydrogen bonding between the NH group and the carbonyl oxygen atom in the starting α‐amino aldehyde is key for reaction stereocontrol.

Here we describe a direct access to 2,2,3-trisubstituted syn γnitroaldehydes by addition of α-branched aryl acetaldehydes to nitroolefins promoted by a cinchona based squaric acid-derived amino acid peptide. Different α-methyl arylacetaldehydes react with β-aromatic and β-alkyl nitroolefins to afford the Michael adducts in high enantioselectivity and syn-selectivity. NMR experiments and DFT calculations predict the reaction to occur through the intermediacy of E-enolate. The interaction between the substrates and the catalyst follows Pápai's model, wherein an intramolecular H-bond interaction in the catalyst between the NH group of one of the tert-leucines and the squaramide oxygen seems to be key for discrimination of the corresponding reaction transition states.