Tandem dynamic kinetic resolution and enzymatic polycondensation to synthesize mPEG-functionalized poly(amine-co-ester)-type chiral prodrugs

Abstract

Amphiphilic poly(amine-co-ester)s, which contain a single effective enantiomer of an asymmetric drug and thus can avoid potentially serious side effects, are difficult to prepare through nonselective chemical routes not only in the process of introducing chiral drugs to the polymer, but also in the synthesis of the polymer's backbone by metal catalysts. A model of racemic mexiletine, an important antiarrhythmic agent, was used to demonstrate the tandem combination of Candida antarctica lipase B (CAL-B)- and Pd/C-catalyzed dynamic kinetic resolution (DKR) and subsequent CAL-B-catalyzed polycondensation, as an efficient protocol to prepare poly(ethylene glycol)-functionalized poly(amine-co-ester)s containing (R)-mexiletine with 99% ee value. Chemoenzymatic DKR and enzymatic polymerization conditions were optimized, and the optical purity of incorporated (R)-mexiletine was confirmed through its hydrolysis from polyester. The copolymers can readily self-assemble into nanometer-scale-sized micelles with well-dispersed spheres, which have a size distribution that can be efficiently adjusted by changing the polymer concentration. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013