Organocatalytic asymmetric syn-aldol reactions of aldehydes with long-chain aliphatic ketones on water and with dihydroxyacetone in organic solvents

An on-water, asymmetric, and direct synaldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by a primary amino acid-based organocatalyst afforded the syn-aldol adducts in high yields with excellent diastereo- and enantioselectivities (up to > 20/1 dr, > 99% ee), and a highly enantioselective syn-aldol reaction of dihydroxyacetone with a variety of aldehydes in THF proceeded with 14/1 to > 20/1 dr and 92 to > 99% ee. Water not only accelerated the reaction, but also enhanced the enantioselectivity. This positive water effect might arise from the hydrogen bond formed between a pendant hydroxy group of surface water molecules at the hydrophobic interface with the amide oxygen of the organocatalyst, which increases the acidity of the amide NH and thereby strengthens the related hydrogen bond formed with the aldehyde.