Chiral Amino Alcohols via Catalytic Enantioselective Petasis Borono–Mannich Reactions

Chiral amino alcohols are valuable building blocks in the synthesis of drugs, natural products, and chiral ligands used in enantioselective catalysis. The Petasis borono-Mannich reaction is a multicomponent condensation reaction of aldehydes, amines, and boronic acids to afford chiral amines. This report describes a practical, easily scaled, enantioselective Petasis borono-Mannich reaction of glycolaldehyde with primary or secondary amines and boronates catalyzed by BINOL-derived catalysts to afford chiral 1,2-amino alcohols in high yields and enantioselectivities. The reactions are executed at room temperature in ethanol or trifluorotoluene using commercially available reagents and leverage an inherently attractive feature of the multicomponent reaction: the ability to use amines and boronates that possess a wide range of structural and electronic properties. Computational modeling of the diastereomeric transition states using DFT calculations identified a nonconventional CH···O interaction and CH-π as key features that selectively stabilize the transition state, leading to the major enantiomer. The enantioselective catalytic reaction exemplifies a truly practical multicomponent condensation to afford 1,2-amino alcohols in a highly enantioenriched form.