Solvent Dependency in Stereoselective δ‐Lactam Formation of Chiral α‐Fluoromalonate Derivatives: Stereodivergent Synthesis of Heterocycles with Fluorine Containing Stereocenters Adjacent to Tertiary Stereocenters

The discovery and investigation of solvent dependency in stereoselective intramolecular amidation of chiral 5‐aminofunctionalized‐2‐fluoromalonate ester derivatives, which gives access to highly functionalized δ‐lactams with a quaternary fluorine‐containing stereocenter, is disclosed. Experimental work together with density functional theory calculations led to understanding of how to direct and switch the stereochemical outcome of the stereoselective δ‐lactam formation. The merging of this solvent‐dependent stereoselective switch with asymmetric catalysis and cascade reactions gives access to an unprecedented strategy for stereodivergent synthesis of all possible stereoisomers of fluorine‐containing stereocenters adjacent to tertiary stereocenters of a wide range of heterocyclic compounds with 95‐>99% ee in one‐pot. It is also useful for application in total synthesis of fluorine‐containing pharmaceuticals.