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

Abstract

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.

Stereodivergent Conjugate Addition between Iminium and α-Azaaryl α-Fluoroenolate Intermediates by Synergistic Amine and Lewis Acid Catalysis

“…The catalytic asymmetric synthesis of fluorine-containing stereogenic centers has been extensively studied in recent years due to their remarkable significance in medicinal chemistry. , The biological properties of chiral fluorinated molecules have been closely associated with their absolute and relative configurations of the stereocenters . Along this line, stereodivergent dual catalysis can offer a valuable opportunity for exploring structure–activity relationships in drug discovery applications by allowing the selective generation of all possible stereoisomers of multistereogenic molecules containing fluorinated stereocenters. − …”