Multifunctional heterocyclic scaffolds for hybrid Lewis acid/Lewis base catalysis of carbon–carbon bond formation

Several new classes of hybrid catalysts have been synthesized by tethering heterocyclic metal (Lewis acid) chelating scaffolds to several different amines capable of facilitating enamine catalysis. Oxazole, thiazole, and imidazole-based chiral precatalysts were prepared in several steps from amino acid starting materials, and these were combined with a variety of metal Lewis acids for potential use as catalysts for various carbon–carbon bond formations. Air- and moisture-tolerant catalysts for enantioselective direct aldol reactions with activated benzaldehyde acceptors were identified, with optimal results obtained with proline-derived oxazole–carboxamide precatalysts combined with Zn(OTf)2 or lanthanide (III) salts. Control studies support the hypothesis that these act as unimolecular hybrid catalysts for the aldol reaction of propionaldehyde and 4-nitrobenzaldehyde. [Display omitted]