Pairing-Enhanced Regioselectivity: Synthesis of Alternating Poly(lactic-<i>co</i>-glycolic acid) from Racemic Methyl-Glycolide

Poly­(lactic-co-glycolic acid) (PLGA) is used in vivo for various biomedical applications. Due to its biodegradability and biocompatibility, PLGA is uniquely suited for controlled drug delivery with parenteral administration. Previously, we established the synthesis of isotactic, alternating PLGA from enantiopure starting materials. Here, to fill in the gap of the current field, we have developed the synthesis of syndioenriched, alternating PLGA from racemic methyl-glycolide (rac-MeG). The synthesis of alternating PLGA is accomplished by a highly regioselective ring-opening polymerization of rac-MeG with an optimized racemic aluminum catalyst. Mechanistic studies are carried out to elucidate the pairing-enhanced catalyst regio- and stereocontrol. Polymer sequence fidelity has been established by NMR investigations, confirming a high degree of alternation of the comonomer sequence and moderate syndiotacticity within the backbone stereoconfiguration. The resulting syndioenriched material is amorphous, which will facilitate the drug complexation behavior

Stereocomplexation of Stereoregular Aliphatic Polyesters: Change from Amorphous to Semicrystalline Polymers with Single Stereocenter Inversion

Stereocomplexation is a useful strategy for the enhancement of polymer properties by the co-crystallization of polymer strands with opposed chirality. Yet, with the exception of PLA, stereocomplexes of biodegradable polyesters are relatively underexplored and the relationship between polymer microstructure and stereocomplexation remains to be delineated, especially for copolymers comprising two different chiral monomers. In this work, we resolved the two enantiomers of a non-symmetric chiral anhydride (CPCA) and prepared a series of polyesters from different combinations of racemic and enantiopure epoxides and anhydrides, via metal-catalyzed ring-opening copolymerization (ROCOP). Intriguingly, we found that only specific chiral combinations between the epoxide and anhydride building blocks result in the formation of semicrystalline polymers, with a single stereocenter inversion inducing a change from amorphous to semicrystalline copolymers. Stereocomplexes of the latter were prepared by mixing an equimolar amount of the two enantiomeric copolymers, yielding materials with increased melting temperatures (ca. 20 °C higher) compared to their enantiopure constituents. Following polymer structure optimization, the stereocomplex of one specific copolymer combination exhibits a particularly high melting temperature (Tm = 238 °C)

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

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

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

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