Organic reactions in frozen water: Michael addition of amines and thiols to the dehydroalanine side chain of nocathiacins

Nocathiacins are densely functionalized cyclic thiazolyl peptide natural products with potent in vitro and in vivo antibacterial activity against a variety of gram-positive bacteria, including a number of multiple drug-resistant strains. Attempts to prepare Michael adducts using known conditions resulted in the formation of complex mixture of products. In order to overcome this problem, we developed unique conditions in which Michael addition of amine and thiol nucleophiles to the dehydroalanine moiety of nocathiacins was successfully achieved in frozen water. Under these conditions, the Michael addition was highly chemoselective, very efficient and provided good isolated yields of the desired products.