Fluorous l-Carbidopa Precursors: Highly Enantioselective Synthesis and Computational Prediction of Bioactivity

New fluorous enantiopure (S)-α-aminated β-keto esters were prepared through a highly enantioselective electrophilic α-amination step in the presence of europium triflate and (R,R)-phenyl-pybox. These compounds are precursors of fluorinated analogues of l-carbidopa, which is known to inhibit DOPA decarboxylase (DDC), a key protein in Parkinson's disease. Fluorination provides better stability for biological applications, which could possibly lead to DDC inhibitors better than l-carbidopa itself. Induced fit docking computational simulations performed on the new structures interacting with DDC highlight that for an efficient binding at the DDC site, at least one hydroxyl substituent must be present at the aromatic ring of the l-carbidopa analogues and show that the presence of fluorine can further fix the position of the ligand in the active site.