A Deep Cavitand Templates Lactam Formation in Water

Abstract

Cyclization reactions are common processes in organic chemistry and show familiar patterns of reaction rates vs ring size. While the details vary with the nature of bond being made and the number of unsaturated atoms, small rings typically form quickly despite angle strain, medium size rings form very slowly due to internal strains, and large rings form slowly (when they form at all) because fewer and less probable conformations bring the ends of the substrate together. High dilution is commonly used to slow the competing bi- and higher molecular processes. Here we apply cavitands to the formation of medium size lactams from ω-amino acids in aqueous (D2O) solution. The cavitands bind the amino acids in folded conformations that favor cyclization by bringing the ends closer together. Yields of a 12-membered lactam are improved 4.1-fold and 13-membered lactam 2.8-fold by the cavitand template. The results open possibilities for moving organic reactions into water even when the processes involve dehydration.