Synthesis of α-acetoxy and its hydroxy indole derivative with high enantiomeric excess using chemoenzymatic reactions

Chiral tetrahydroindoles serve as a privileged structures in drug discovery; however, efficient synthetic routes to their functionalized derivatives remain limited. This study reports, for the first time, an efficient two-step chemoenzymatic route for the synthesis of enantioenriched 4-oxo-4,5,6,7-tetrahydro-1H-indol-5-yl acetate (2) and its hydroxy derivative 5-hydroxy-6,7-dihydro-1H-indol-4(5H)-one (3). In the first step, a regioselective α-acetoxylation of 6,7-dihydro-1H-indol-4(5H)-one (1) was performed using potassium permanganate and acetic acid to yield a racemic indole rac-2. The subsequent kinetic resolution was systematically evaluated using four different lipases-namely Rhizopus arrhizus lipase (RAL), Pseudomonas fluorecens lipase (PFL), Hog pancreatic lipase (HPL), and Penisillium roqueferti lipase (PPL) across four organic solvents. The results showed that enantioselectivity varied significantly depending on the medium, with PPL in THF proving to be the most effective biocatalytic system. This reaction afforded hydroxy enone (+)-5-hydroxy-6,7-dihydro-1H-indol-4(5H)-one (3) with 94% enantiomeric excess (ee) and the acetoxy enone (-)-1,5,6,7-tetrahydro-4H-indol-5-yl acetate (2) with 58% ee, achieving an excellent enantiomeric ratio (E = 52.2) at a conversion rate of 38.2%. Overall, this research offers a robust and sustainable method for acquiring chiral indole building blocks with high optical purity for pharmaceutical applications.