Biocatalytic Asymmetric Synthesis of (S)- and (R)-Timolol

A new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure.