Efficient Chemoenzymatic Synthesis of (RS)-, (R)-, and (S)-Bunitrolol

Abstract

A new chemical and the first chemoenzymatic synthesis of β-adrenergic receptor blocking agent bunitrolol is reported in racemic (RS) and enantioenriched forms (R and S). The intermediates (R)-and (S)-1-chloro-3-(2-cyanophenoxy)propan-2-ol intermediates were synthesized from the corresponding racemic alcohol through enzymatic kinetic resolution. The commercial available lipases PS-C and CCL exhibited complementary enantioselectivity during transesterification of the racemic alcohol with vinyl acetate affording the (R)-alcohol along with (S)-acetate and the (S)-alcohol along with (R)-acetate, respectively, and represent an example of enzymatic switch for reversal of enantioselectivity. The effects of various reaction parameters, such as temperature, time, substrate and enzyme concentration, and reaction medium, on the activity and enantioselectivity were optimized. The (R)-and (S)-alcohols were converted into (S)-and and (R)-bunitrolol, respectively, by treatment with tert-butylamine. The (R)-and (S)-acetates, obtained enzymatically were deacetylated to the corresponding alcohol by chemical hydrolysis and further converted into (S)-and and (R)-bunitrolol by chemical means. This is the first chemoenzymatic synthesis of both of the enantiomers of the drug. (RS)-, (R)-, and (S)-Bunitrolol were also synthesized following the 'all chemical' routes from (RS)-, (R)-, and (S)-epichlorohydrin via the corresponding (RS)-, (S)-, and (R)-2-cyanoglycidyl ether and the (RS)-, (R)-, and (S)-1-chloro-3-(2-cyanophenoxy)propan-2-ol intermediates with improved overall yields and better enantiomeric excesses compared to the reported processes.in greener chemistry. 16 In this context, the enzymatic kinetic resolution of a racemic secondary alcohol provides the desired scope 17 and encouraged us to design a new chemoenzymatic route for (R)-and (S)-bunitrolols (Scheme 2).The starting racemic epoxide (RS)-2 was prepared in 80% yield by the reaction of 3 with (RS)-4 in the presence of potassium carbonate in acetonitrile under reflux following the reported procedure. 10b The treatment of (RS)-2 with lithium chloride in tetrahydrofuran and acetic acid afforded the desired substrate (RS)-9 required for enzymatic kinetic resolution 18 (Scheme 3).

Streamlined Chemo-Enzymatic Synthesis of Molnupiravir via Lipase Catalyst

“…It was found that, with the increase in the enzyme amount, the conversion rate increased and reached a peak with a conversion efficiency of uridinetouridine monoester observed to be 96.06% at 40 mg/mL and then gradually started forming diester with 80,120 mg/mL lipase ( Figure S4 ). 12 a–d…”

“…Consequently, our main focus has been on developing an efficient pathway to obtain Molnupiravir (route D) by employing a two-step process that involves the production of a regioselective monoacylated intermediate. Lipase, a highly versatile biocatalyst, has been extensively used for the kinetic resolution of racemic alcohols for the synthesis of enantiopure drugs and drug intermediates . Due to its high chemo-, regio-, and stereoselectivity, which encouraged us toward the synthesis of Molnupiravir, lipase was selected for the biocatalytic regioselective acylation of uridine in this study.…”

“…Lipase, a highly versatile biocatalyst, has been extensively used for the kinetic resolution of racemic alcohols for the synthesis of enantiopure drugs and drug intermediates. 12 Due to its high chemo-, regio-, and stereoselectivity, which encouraged us toward the synthesis of Molnupiravir, lipase was selected for the biocatalytic regioselective acylation of uridine in this study. The retrosynthetic approach toward the production of Molnupiravir was outlined in ( Scheme 2 ).…”

Lipase mediated new chemo‐enzymatic synthesis of (RS)‐, (R)‐, and (S)‐bunolol

“…Lipase was one of the first enzymes to be utilized as a biocatalyst in the 1980s, and it has since been developed for a variety of chemo enzymatic reactions, [30][31][32][33][34][35][36] owing to its stability in terms of pH, organic solvent, temperature, and other physical parameters. [37][38][39] 3.1 | Optimization of reaction condition with lipases, acyl donor, course of time interval, temperature, and so forth…”

“…Lipase was one of the first enzymes to be utilized as a biocatalyst in the 1980s, and it has since been developed for a variety of chemo enzymatic reactions, 30‐36 owing to its stability in terms of pH, organic solvent, temperature, and other physical parameters 37‐39 …”