CALB-catalyzed kinetic resolution of (RS)-3-benzoylthio-2-methylpropyl azolides: kinetic and thermodynamic analysis

Abstract

Zofenopril as an ACE inhibitor expired recently was found to have a favourable safety profile in comparison with other ACE inhibitors in treating high blood pressure, congestive heart failure, and acute myocardial infarction. It can be synthesised from the key building blocks of (S)-3-benzoylthio-2-methylpropanoic acid and (4S)-phenylthio-L-proline. In this report, an efficient hydrolytic resolution via Candida antarctic lipase B (CALB) for preparing the former block in isopropyl ether (IPE) containing (RS)-3-benzoylthio-2-methylpropyl pyrazolide (1) and water was developed. Quantitative improvements of the enzyme activity and enantioselectivity in terms of k_2SK_mS⁻¹ = 5.726 L h⁻¹ g⁻¹ and E = 217 at 45 °C were found from the kinetic analysis. Insights into the CALB performance via thermodynamic analysis were then addressed and compared with those by using (RS)-3-benzoylthio-2-methylpropyl 1,2,4-triazolide (2) as the substrate. A putative thermodynamic model was moreover hypothesised for elucidating the more enthalpy reduction of 68.92-70.86 kJ mol⁻¹ from the acyl part of (S)-1 and (S)-2 as well as that of 23.69-25.63 kJ mol⁻¹ from the triad imidazolium to Ser105 and leaving 1,2,4-triazole moiety of (R)-2 and (S)-2 on stabilising the corresponding transition states.

Keywords:

• CALB
• hydrolytic resolution
• (S)-3-benzoylthio-2-methylpropanoic acid
• azolide
• Zofenopril

Disclosure statement

There is no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

This work was financially supported [Project No. MOST 108-2221-E-182-03] by Ministry of Science and Technology (MOST), Taiwan, R.O.C.