CALB-Catalyzed Two-Step Alcoholytic Desymmetrization of 3-Methylglutaric Diazolides in MTBE

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Abstract

Optically pure 3-substituted glutarates can be prepared from the alcoholic ring-opening of cyclic anhydride derivatives, esterification of 3-substituted glutaric acid, and hydrolysis, alcoholysis, aminolysis, and ammonolysis of the diester derivatives via hydrolases or organocatalysts. Unfortunately, most of them mainly focus on the first-step desymmetrization, leading to the difficulty on producing optically pure enantiomers. As a general trend in lipase-catalyzed desymmetrization of 3-methylglutarates, poorer enantiomeric excesses with lower chemical yields were found, as the methyl substituent is relatively small to induce a high enzyme stereodiscrimination. The two-step desymmetrization for CALB-catalyzed alcoholysis of 3-methylglutaric di-1,2,4-triazolide 1a in anhydrous MTBE is first developed to increase the enzyme activity in each reaction step. The enantioselectivity for the second-step kinetic resolution is furthermore improved by using 3-methylglutaric dipyrazolide 1b as the substrate. The kinetic and thermodynamic analysis is, moreover, addressed for shedding insights into the desymmetrization process.

Keywords

Two-step desymmetrization Kinetic and thermodynamic analysis CALB 3-Methylglutaric diazolide 

Nomenclature

(Et)

enzyme concentration (mg mL−1)

E1

selectivity defined as k10k20−1

E2, E3

dimensionless parameters defined as k30(k10 + k20)−1and k40(k10 + k20)−1, respectively

ee

enantiomeric excess defined as (X2S − X2R)(X2S + X2R)−1

Km1, Km2, Km3, Km4

Michaelis-Menten constant for each reaction step in Scheme 1 (mM)

KI

inhibition constant from alcohol (mM)

k1, k2, k3, k4

kinetic constants in Scheme 1 (h−1)

(M)0

initial alcohol concentration (mM)

(S)0, (S)

diazolide concentration initially and at a specific time (mM)

T

absolute temperature (K)

t

time (h)

t*

dimensionless time defined as (k1 + k2)t

Vmax,1, Vmax,2, Vmax,3, Vmax,4

maximum velocity for each reaction step in Scheme 1 (mM h−1)

X1, X2R,X2S, X3

molar fractions based on (S)0 for 1, (R)-2, (S)-2, and 3, respectively

ΔΔG

free energy difference for two transition states (kJ mol−1)

ΔΔH

enthalpy difference for two transition states (kJ mol−1)

ΔΔS

entropy differences for two transition states (J mol−1 K−1)

Superscript

*

for dimensionless group

Subscript

0

initial state

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12010_2017_2675_MOESM1_ESM.doc (3 mb)
ESM 1 (DOC 3086 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication January/2018

Authors and Affiliations

  1. 1.Department of Chemical and Materials EngineeringChang Gung UniversityTaoyuan CityTaiwan
  2. 2.Graduate Institute of Biochemical and Biomedical EngineeringChang Gung UniversityTaoyuan CityTaiwan

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