Despite the degradability and biocompatibility of poly(α-hydroxy acids), their utility remains limited because their thermal and mechanical properties are inferior to those of commodity polyolefins, which can be attributed to the lack of side-chain functionality on the polyester backbone. Attempts to synthesize high-molecular-weight functionalized poly(α-hydroxy acids) from O-carboxyanhydrides have been hampered by scalability problems arising from the need for an external energy source such as light or electricity. Herein, an operationally simple, scalable method for synthesizing stereoregular, high-molecular-weight (>200 kDa) functionalized polyesters have been developed by means of controlled ring-opening polymerization of O-carboxyanhydrides mediated by a highly redox reactive manganese complex and a zinc-alkoxide. Mechanistic studies indicated that the ring-opening process proceeded via the Mn-mediated decarboxylation with alkoxy radical formation (Chapter 2). In addition to the polymerization, a two-step facile chemical recycling strategy for poly(α-hydroxy acids) was developed to achieve closed-loop life cycles (Chapter 3). Moreover, this synthetic strategy is not limited to preparing homopolymers and block copolymers but also to producing stereoblock and gradient copolymers (Chapter 4). In particular, the gradient copolymers exhibited better ductility and toughness than their corresponding homopolymers and block copolymers, highlighting the potential feasibility of functionalized polyesters as strong and resilient polymeric materials (Chapter 5). Next, an atom-economical, scalable method for block copolymerization of O-carboxyanhydrides and epoxides to prepare functionalized poly(ester-b-carbonates) with high molecular weights (>200 kDa) was identified, that uses a single Lewis acidic zinc complex at room temperature in the absence of pressurized CO2 (Chapter 6). Kinetic studies showed that the first stage of the process, ring-opening polymerization of the O-carboxyanhydrides, exhibited zero-order kinetics, suggesting that the polymerization rate was independent of monomer concentration, thus allowing for a sharp switch in mechanism without a tapering effect (Chapter 7). The obtained poly(ester-b-carbonates) showed better toughness than their corresponding homopolymers and outperformed some commodity polyolefins (Chapter 8). Exploring this new chemical space of poly(ester-b-carbonates) via stereosequence-controlled synthetic methods would be a critical step toward improving this promising class of functionalized sustainable polymers (Chapter 9). / Doctor of Philosophy / Poly(α-hydroxy acids) is an environmentally friendly alternative to petrochemical polyolefins due to their excellent degradability and biocompatibility. However, it is difficult to synthesize high-molecular-weight functionalized polyesters on a large scale due to the inefficient catalysts and the need for external energy, such as light and electricity. Herein, a highly reactive Mn/Zn catalytic system for controllable O-carboxyanhydrides (OCAs) polymerization has been designed. Compared with the previously reported catalytic system, this method can be used to produce low-cost, large-scale preparation of high molecular weight (>200 kDa) polyesters without the need for external energy sources (Chapter 2). In addition, our synthesized polyesters can be completely degraded under mild conditions, thereby achieving a circular economy in the polyester industry (Chapter 3). More importantly, our operationally simple synthetic method could afford polyesters with different compositions, such as homopolymers, block copolymers, stereoblock copolymers, and gradient copolymers (Chapter 4). In particular, the obtained gradient copolymer is tough and ductile that could compete with commercial polyolefins in terms of mechanical and thermal properties, such as low-density polyethylene (LDPE) (Chapter 5). Next, we developed a single Lewis acidic zinc complex to achieve the copolymerization of OCA and epoxide to synthesize poly(ester-b-carbonates), which enriches the class of degradable polymers (Chapter 6). Moreover, this copolymerization showed unique reaction kinetics that enabled the perfectly clean switching of the polymerization mechanism during chain propagation (Chapter 7). The obtained poly(ester-b-carbonates) showed better toughness than their corresponding homopolymers and outperformed some non-degradable plastics (Chapter 8). The exploration of novel degradable polymers by sequence-controlled polymerization to replace non-degradable polyolefin on the market will continue in the near future (Chapter 9).

<p> </p><p>A chemoselective catalyst is preferred in a chemical reaction where protecting groups otherwise are needed. The two lipases <em>Candida antarctica </em>lipase B and <em>Rhizomucor miehei</em> lipase showed large chemoselectivity ratios, defined as (<em>k_cat</em>/<em>K</em>_M)_OH/ (<em>k_cat</em>/<em>K</em>_M)_SH, in a transacylation reaction with ethyl octanoate as acyl donor and hexanol or hexanethiol as acyl acceptor (<strong>paper I</strong>). The chemoselectivity ratio of the uncatalyzed reaction was 120 in favour of the alcohol. Compared to the uncatalyzed reaction, the chemoselectivity was 730 times higher for <em>Candida antarctica </em>lipase B and ten times higher for <em>Rhizomucor miehei</em> lipase. The <em>K</em>_M towards the thiol was more than two orders of magnitude higher than the <em>K</em>_M towards the corresponding alcohol. This was the dominating contribution to the high chemoselectivity displayed by the two lipases. In a novel approach, <em>Candida antarctica </em>lipase B was used as catalyst for enzymatic synthesis of thiol-functionalized polyesters in a one-pot reaction without using protecting groups (<strong>paper II</strong>). Poly(e-caprolactone) with a free thiol at one of the ends was synthesized in an enzymatic ring-opening polymerization initiated with mercaptoethanol or terminated with either 3-mercaptopropionic acid or g-thiobutyrolactone.</p><p> </p>

A chemoselective catalyst is preferred in a chemical reaction where protecting groups otherwise are needed. The two lipases Candida antarctica lipase B and Rhizomucor miehei lipase showed large chemoselectivity ratios, defined as (kcat/KM)OH / (kcat/KM)SH, in a transacylation reaction with ethyl octanoate as acyl donor and hexanol or hexanethiol as acyl acceptor (paper I). The chemoselectivity ratio of the uncatalyzed reaction was 120 in favour of the alcohol. Compared to the uncatalyzed reaction, the chemoselectivity was 730 times higher for Candida antarctica lipase B and ten times higher for Rhizomucor miehei lipase. The KM towards the thiol was more than two orders of magnitude higher than the KM towards the corresponding alcohol. This was the dominating contribution to the high chemoselectivity displayed by the two lipases. In a novel approach, Candida antarctica lipase B was used as catalyst for enzymatic synthesis of thiol-functionalized polyesters in a one-pot reaction without using protecting groups (paper II). Poly(e-caprolactone) with a free thiol at one of the ends was synthesized in an enzymatic ring-opening polymerization initiated with mercaptoethanol or terminated with either 3-mercaptopropionic acid or g-thiobutyrolactone.

Utilizing the diverse functionality of amino acids, a new class of amphiphilic graft copolymers has been synthesized, characterized, and explored for applications in biomaterials and nucleic acid delivery. This thesis research focused on the syntheses of oligopeptide-functionalized polyesters and polyolefins. Polyester functionalization was geared towards applications in biomaterials, tissue engineering, and drug delivery by incorporating sequences that promote cell-adhesion. These polyester- graft -oligopeptide materials were prepared by a 1,3-Huisgen cycloaddition reaction, "click" chemistry, of an azide-terminated oligopeptide (prepared by Fmoc-based solid phase peptide synthesis (SPPS)) and alkyne-containing polyester (synthesized by ring-opening polymerization). Following the syntheses of these materials, they were analyzed by nuclear magnetic resonance (NMR) and organic gel permeation chromatography (GPC). The oligopeptide-functionalized polyolefins were designed for nucleic acid complexation, and therefore the oligopeptide sequences were intended to incorporate positively-charged moieties ( e.g. , oligolysine) for DNA and short interfering RNA (siRNA) complexation. These graft copolymers, prepared by SPPS followed by ring-opening metathesis polymerization, have highly tunable structures that enable control over charge density and polymer backbone rigidity. Moreover, non-ionic hydrophilic grafts such as polyethylene glycol were integrated into these polyelectrolytes such that the charges along the polymer backbone are spaced accordingly while maintaining the hydrophilicity of the polymer. While numerous applications for such charged, "bio-tailored" materials can be envisioned, this work is geared towards positively-charged polyelectrolytes for their potential application in nucleic acid therapy, specifically the delivery of plasmid DNA and siRNA. These graft copolymers were characterized ( 1 H, 13 C NMR, organic and aqueous GPC), studied for their solution properties (static and dynamic light scattering), and investigated as polyplexes with plasmid DNA.