Green Chemo-Enzymatic Protocols for the Synthesis of Enantiopure β-Blockers (S)-Esmolol and (S)-Penbutolol

Abstract

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.

Synthesis of Enantiopure (S)-Atenolol by Utilization of Lipase-Catalyzed Kinetic Resolution of a Key Intermediate

“…We have previously predicted the mechanism of the formation of this dimeric ether compound in syntheses of similar beta-blockers. Here, we also present full characterization of the corresponding by-product in the synthesis of enantiopure ( S )-esmolol [ 19 ].…”

“…We have previously predicted the mechanism of the formation of this dimeric ether compound in syntheses of similar beta-blockers. Here, we also present full characterization of the corresponding by-product in the synthesis of enantiopure (S)-esmolol [19]. When two equivalents of epichlorohydrin were added to a solution containing phenol 1 and catalytical amounts of sodium hydroxide, the by-product 2c was not observed after 4 hours of reaction.…”

Chemo-Enzymatic Synthesis of Enantiopure β-Antagonist (S)-Betaxolol

“…We here present a green and sustainable method for (S)-betaxolol using a similar synthesis protocol as previously reported with CALB as the catalyst [16][17][18]. Figure 2 shows a suggested model of the faster-reacting enantiomer, the R-form, of the general substrate 1-O-alkyl-2-alkanol, as the tetrahedral intermediate of the butanoates of 1-O-alkyl-2-alkanols from a kinetic resolution of the racemic substrate in the active site of CALB.…”

“…We have previously reported protocols for obtaining high enantiomeric excess of similar β-blockers as (S)-betaxolol with lipase B from Candida antarctica (CALB) as catalyst in the kinetic resolution of the secondary halohydrin building blocks [16][17][18]. Several studies of the active site in CALB based on modelling and experimental data of similar substrates has been published, mostly with an unsubstituted benzene ring coupled to the oxygen moiety in 1-O-alkyl-2-alkanols.…”

“…The large group (-CH2OR2) connected to the stereocenter is p out of the active site, the acyl group is bound to Ser105, and the small group/hal CH2R1) is located in the stereospecificity pocket, which has a tryptophane residue (T at the bottom. This cavity limits the size of the small group of the substrate [19][20][21] We here present a green and sustainable method for (S)-betaxolol using a synthesis protocol as previously reported with CALB as the catalyst [16][17][18].…”