Stereoselective synthesis of caffeic acid amides via enzyme-catalyzed asymmetric aminolysis reaction

In this study, a new method was developed to prepare enantiopure caffeic acid amides by enzyme-catalyzed asymmetric aminolysis reaction. Methoxymethyl chloride (MOMCl) was first introduced as a protective and esterified reagent to obtain the MOM-protected caffeic acid MOM ester Id. Aminolysis reaction occurred between Id and (R, S)-alpha-phenylethylamine in the presence of an immobilized lipase (Novozym 435) from Candida antarctica. Compared with the methyl-protected caffeic acid methyl ester 1c, Id as substrate improved the lipase-catalyzed reaction rate by 5.5-fold. After Novozym 435-catalyzed aminolysis reaction was established, we evaluated the effects of synthesis parameters on the catalytic activity and enantioselectivity of Novozym 435. A reaction conversion rate of 25.5% and an E value of >100 were achieved under the following optimum conditions: reaction solvent, anhydrous isooctane; reaction temperature, 70 degrees C; reaction time, 24 h; ester-to-amine substrate molar ratio, 1:40; and enzyme additive amount, 40 mg. Kinetic and thermodynamic analyses were conducted to determine the main factors affecting enantiomeric discrimination. Novozym 435 still showed 80% of its initial activity after recycling five times. Highly optically pure caffeic acid amides with an enantiomeric excess of 98.5% were finally obtained by HCl deprotection. The established enzyme-catalyzed asymmetric aminolysis method in this study might be used to prepare other caffeic acid amides. (C) 2013 Elsevier B.V. All rights reserved.