Asymmetric Organocatalytic Direct Aldol Reactions of Ketones with α-Keto Acids and Their Application to the Synthesis of 2-Hydroxy-γ-butyrolactones

A variety of organocatalysts for the asymmetric direct aldol reactions of ketones with α-keto acids were
designed on the basis of molecular recognition and prepared from proline and aminopyridines. The organic
molecule 8e, derived from proline and 6-methyl-2-amino pyridine, was the best catalyst, affording excellent
enantioselectivities (up to 98% ee) for the direct aldol reactions of acetone or 2-butanone with a wide
range of α-keto acids and for the reactions of various acyclic aliphatic ketones with 3-(2-nitrophenyl)-2-oxopropanoic acid. The aldol adducts could be converted to 2-hydroxy-γ-butyrolactones by reaction
sequences of diastereoselective reduction and lactonization. Experimental and theoretical studies on the
transition states revealed that the amide N−H and the pyridine N of the organocatalyst selectively form
hydrogen bonds with the keto oxygen and the carboxylic acid hydroxy of the α-keto acid, respectively.
These two hydrogen-bonding interactions are important for the reactivity and enantioselectivity of the
direct asymmetric aldol condensation.