Chiral Drug-Catalyzed Asymmetric alpha-Hydroxylation of beta-Keto Esters

Abstract

Using commercially available, basic nitrogen atom containing chiral drugs as the organocatalysts for asymmetric alpha-hydroxylation of beta-keto esters, it was found that the enantioselectivity reached 32% and 18% when using timolol and propranolol as the organocatalyst, respectively. The structures of timolol and propranolol were then modified and twelve analogs were synthesized to investigate the catalysis performance. It was found that under the optimized reaction conditions, using 30 mol% of (R)-1-(tert-butylamino)-3-(naphthalen-2-yloxy)propan-2-ol (7f) as the organocatalyst, 20 mol% of beta-cyclod-extrin as the cocatalyst, tert-butyl hydroperoxide as oxidant and n-hexane as solvent, the enantioselectivity reached up to 57% with the yield of 92%. The ee value of (S)-methyl-5-chloro-2-hydroxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2a) reached up to 99% with the yield of 68% after a single recrystallization from ethyl acetate.