Revisiting the Cleavage of Evans Oxazolidinones with LiOH/H2O2

Abstract

The use of LiOH/H2O2 for cleavage of Evans oxazolidinones is an essential but often overlooked part of using these ubiquitous chiral auxiliaries in synthetic routes. These conditions were disclosed in the literature more than 30 years ago and have found widespread use with little change. During studies focused on the synthesis of a drug candidate, we discovered the evolution of oxygen under the LiOH/H2O2 conditions for cleavage of an Evans auxiliary. We find this phenomenon to be general and tied to the fact that the initially formed peracid is not stable under the reaction conditions. The peracid is rapidly reduced by the excess H2O2 present in the reaction mixture, leading to the release of a stoichiometric amount of oxygen. This can present a significant risk for maintaining proper inertion in the presence of the flammable organic solvent, and we propose options for safely executing this chemistry at multikilogram scale.