Organocatalyzed Kinetic Resolution and Desymmetrization of (di)Amines – ORKIDEA

Chiral amines are attractive targets in organic synthesis as useful building blocks to access complex scaffolds, but also due to their ubiquitous presence in numerous biologically relevant molecules. An extensive array of enantioselective methods has been developed to access these chiral amines using organic, organometallic or enzymatic catalysis. One alternative relies on the kinetic resolution of racemic mixture of amines, allowing to selectively convert one enantiomer while the other one ideally remains untouched. Organocatalyzed approaches were developed in this field, but they remain limited in terms of selectivities and applicability. The latter are mostly based on enantioselective N-acylations, where a chiral nucleophilic organocatalyst activates an electrophile to selectively transfer a functional group to one enantiomer. However, this strategy is greatly hampered by the strong and competitive nucleophilic character of the amine moiety, leading to background reactions resulting in poor selectivities. The ORKIDEA project aims at tackling this challenge through the development of new organocatalyzed processes for the acylative kinetic resolution of amines, with the ambition of reaching high selectivities regardless the nucleophilicity of the amine derivatives employed. We also aim at exploiting even more challenging diamine derivatives through unusual activation modes, for their kinetic resolution (anti diamines) as well as their desymmetrization (meso diamines). The first strategy relies on modular chiral pyridine N-oxides (PNOs) as highly nucleophilic organocatalysts, while the second strategy targets the use of chiral bifunctional aldehyde organocatalysts, which, to the best of our knowledge, were never used for the catalytic mono selective N-acylation of diamines.