Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

Aldol reaction chemoselectivity, racemic or enantioselective, has not been previously demonstrated in the presence of Knoevenagel active functional groups. Here, we show that unhindered β‐diketones remain unreacted while a ketone moiety undergoes a highly enantioselective aldol desymmetrization resulting in three new stereogenic centers using in water reaction conditions. A mechanistic hypothesis for the chemoselective formation of either aldol or Knoevenagel products is presented. It elucidates how these amino acid catalyzed reactions completely suppress formation of the expected Knoevenagel product under in water (heterogeneous) reaction conditions, but not when water is present as a dissolved cosolvent (homogeneous). Finally, the developed hypothesis reinforces and expands the role of water at an organic‐water interface.