Stereodivergent synthesis of hydroxyethylamine isosters via chiral sulfoxide chemistry

Hydroxyethylamine transition-state isosteres of amide linkages, very important structural modules in a wide range of potent protease inhibitors, in particular aspartic proteases such as HIV-protease (Saquinavir, Amprenavir, Nelfinavir) and Plasmepsins.In this communication we will describe a conceptually new, stereocontrolled approach to hydroxyethylamine transition-state isosteres, based on a stereoselective sulfoxide chemistry developed entirely in our laboratories. Condensation of chiral, enantiomerically pure -amino-sulfoxides with the imine precursors, affords with reasonable stereocontrol and excellent yields the intermediate adducts. Treatment of the latters under "Non-oxidative" Pummerer Reaction (NOPR) conditions produces the target isosteres with very good yields, and highly stereoselective and stereodivergent pathways dependinig on the solvent employed (acetonitrile and dichloromethane, rispectively). The different mechanisms of the stereoselective displacement of the sulfinyl group by hydroxyl, will be discussed. Scope and limitations of this novel synthetic methodology will be also presented.