Mechanism of Alternating Poly(lactic-co-glycolic acid) Formation by Polymerization of (S)- and (R)-3-Methyl Glycolide Using an Enantiopure Aluminum Complex

Abstract

The mechanism(s) of alternating PLGA synthesis by ring-opening polymerization of (S)-and (R)-3-methyl glycolide promoted by enantiopure aluminum complexes have been rationalized by density functional theory (DFT) calculations. The high regioselectivity of the (S)-MeG polymerization is obtained by repetitive ring opening at the glycolyl site by the (R)-catalyst whereas a lower regioselectivity is predicted by the ROP of (R)-MeG. The behavior of the two monomers is rationalized by unveiling the active site fluxionality of the enantiopure catalyst, identifying the rate-limiting steps that encode a preference at the glycolyl site versus the lactyl site, and revealing selection of the opposite monomer enantioface. The microstructure of the PLGA copolymers is predicted by considering the influence of the configuration of the last inserted unit. The identification of the preferred mechanistic paths may allow for a targeted catalyst design to enhance control of the polymer microstructures.

Ring Opening Polymerization of Six- and Eight-Membered Racemic Cyclic Esters for Biodegradable Materials

“…Organocatalytic systems, such as phosphazene base/alcohol systems, have been proposed for this reaction, solving the toxicity issue associated with tin [52]. Recently, Lu et al proposed a methodology for the synthesis of alternating PLGA using chiral aluminum complexes already tested in the isoselective and syndioselective ROP of rac-LA and meso-LA [53][54][55].…”

“…Regarding the ROP of rac-LA, actually, the first reported stereoselective Salen catalyst was the Spassky system (Figure 15) [83], which showed a high isoselectivity, represented by the optical purity (OP = α /156) in Table 1. Computational DFT studies were executed to investigate the reaction mechanism and the origin of stereo-and regioselectivity of rac-LA [84], meso-LA [9] and MeG [55] ROP catalyzed by Spassky's system focusing on the two transition states (TSs) and two intermediates as shown in Figure 16. In general, Salen catalysts offer several advantages in controlling the stereoselectivity during lactides and diolides ROP, leading to the formation of polymers with specific stereoisomeric configurations.…”