The β-blocker (S)-esmolol, has been synthesized in 97% enantiomeric excess and 26% total yield in a four-step synthesis, with a transesterification step of the racemic chlorohydrin methyl 3-(4-(3-chloro-2-hydroxypropoxy)phenyl)propanoate, catalysed by lipase B from Candida antarctica from Syncozymes, Shanghai, China. The β-blocker (S)-penbutolol, has been synthesized in 99% enantiomeric excess and in 22% total yield. The transesterification step of the racemic chlorohydrin 1-chloro-3-(2-cyclopentylphenoxy)propan-2-ol was catalyzed by the same lipase as used for the esmolol building block. We have used different bases for the deprotonation step of the starting phenols, and vinyl butanoate as the acyl donor in the transesterification reactions. The reaction times for the kinetic resolution steps catalysed by the lipase varied from 23 to 48 h, and were run at 30–38 °C. Specific rotation values confirmed the absolute configuration of the enantiopure drugs, however, an earlier report of the specific rotation value of (S)-esmolol is not consistent with our measured specific rotation values, and we here claim that our data are correct. Compared to the previously reported syntheses of these two enantiopure drugs, we have replaced toluene or dichloromethane with acetonitrile, and replaced the flammable acetyl chloride with lithium chloride. We have also reduced the amount of epichlorohydrin and bases, and identified dimeric byproducts in order to obtain higher yields.

The β-blocker (S)-bisoprolol hemifumarate has been synthesised in 96% enantiomeric excess with 19% total yield in a six-step synthesis. A transesterification reaction of the racemic chlorohydrin 1-chloro-3-(4-((2-isopropoxyethoxy)methyl)phenoxy)propan-2-ol catalysed by lipase B from Candida antarctica resulted in the R-chlorohydrin in high enantiomeric purity. Reaction of this building block with isopropylamine in methanol gave (S)-bisoprolol, and further reaction with fumaric acid gave (S)-bisoprolol fumarate in 96% ee. Specific rotation value confirmed the absolute configuration of the enantiopure drug.

(S)-Atenolol ((S)-2-(4-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) has been synthesized in >99% enantiomeric excess (ee) with the use of Candida antarctica lipase B from Syncozymes (Shanghai, China), in a kinetic resolution of the corresponding racemic chlorohydrin. A catalytic amount of base was used in deprotonation of the phenol building block. The enantiopurity of the chlorohydrin building block remained unchanged upon subsequent amination to yield the final drug. All four steps in the synthesis protocol have been optimized compared to previously reported methods, which makes this new protocol more sustainable and in accordance with green chemistry principles. The overall yield of (S)-atenolol was 9.9%, which will be further optimized.

(S)-Atenolol ((S)-2-(4-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) has been synthesized in >99% ee with use of Candida antarctica lipase B from Syncozymes (Shanghai, China), in a kinetic resolution of the corresponding racemic chlorohydrin. Deprotonation of the starting phenol building block was base catalyzed. The enantiopurity of the chlorohydrin building block remained unchanged upon subsequent amination. All four steps in the synthesis protocol have been optimized compared to previously reported methods, which makes this new protocol more sustainable and in accordance with green chemistry principles compared to previously reported protocols.