DKRHet4

Kinetic resolution is a widely developed process that has been used for industrial and academic applications to allows the effective preparation of enantiomerically pure compounds. Despite its widespread use, a recognised inherent drawback is that the theoretical maximum yield of a single enantiomer from a racemate is 50%. This limitation can be overcome by a using a dynamic kinetic resolution (DKR) approach, that necessitates the individual enantiomers of the racemic starting material to interconvert (enantiomerization) at a timescale compatible with a subsequent enantioselective derivatization event (such as acylation that is the subject of this proposal). Current state-of-the art DKRs commonly use secondary alcohols and tri-substituted lactols (that contain a H- substituent at the carbinol), with enantiomerization often allowed through reversible dehydrogenation/hydrogenation or intramolecular ring closure/ring opening. The focus of this proposal and a widely recognized remaining challenge in this area that has not been realized to date is to extend the DKR approach to fully-substituted/tertiary alcohols or tetra-substituted lactols (where zero substituents at the carbinol centre = H). This project will demonstrate the challenging DKR of tetra-substituted morpholinone derived lactols (WP1) and fully substituted heterocyclic alcohols (WP2). We will use reversible intramolecular ring-opening/ring closing, or reversible intermolecular nucleophilic addition as an enantiomerization strategy, combined with isothiourea- promoted enantioselective acylation, to generate medicinally relevant N-heterocycles in enantiomerically pure form.