Synthesis of R–GABA Derivatives via Pd(II) Catalyzed Enantioselective C(sp3)−H Arylation and Virtual Validation with GABAB1 Receptor for Potential leads

Abstract GABA (γ–amino butyric acid) analogues like baclofen, tolibut, phenibut, etc., are well–known GABA B1 inhibitors and pharmaceutically important drugs. However, there is a huge demand for more chiral GABA aryl analogues with promising pharmacological actions. Here, we demonstrate the chiral ligand acetyl–protected amino quinoline (APAQ) mediated enantioselective synthesis of GABA B1 inhibitor drug scaffolds from easily accessible GABA via Pd–catalyzed C(sp 3 )−H activation. The synthetic methodology shows moderate to good yields, up to 74% of ee . We have successfully demonstrated the deprotection and removal of the directing group to synthesize R –tolibut in 86% yield. Further, we employed computation to probe the binding of R –GABA analogues to the extracellular domain of the human GABA B1 receptor. Our Rosetta–based molecular docking calculations show better binding for four R –enantiomers of GABA analogues than R –baclofen and R –phenibut. In addition, we employed GROMACS MD simulations and MMPB(GB)SA calculations to identify per–residue contribution to binding free energy. Our computational results suggest analogues (3 R )‐4‐amino‐3‐(3,4‐dimethylphenyl) butanoic acid, (3 R )‐4‐amino‐3‐(3‐fluorophenyl) butanoic acid, (3 R )‐3‐(4‐acetylphenyl)‐4‐aminobutanoic acid, (3 R )‐4‐amino‐3‐(4‐methoxyphenyl) butanoic acid, and (3 R )‐4‐amino‐3‐phenylbutanoic acid are potential leads which could be synthesized from our methodology reported here.