Optically pure 3-substituted glutarates can be prepared from the alcoholic ringopening 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 CALBcatalyzed 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.

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