Project Summary / Abstract The goal of research in the Leibfarth group is to develop platform synthetic methods that enhance the thermomechanical, adhesion, and degradation properties of polymers while also uncovering mechanistic insights that broadly inform synthetic method development. This goal informs our two complementary research areas that seek to 1) leverage chemo- and regioselective C–H functionalization to enhance the properties of commodity polymers and 2) develop stereoselective polymerization methods that uncover emergent polymer properties from simple chemical building blocks. We have identified a compelling opportunity to make progress on a grand challenge in biomedicine – the discovery of degradable biomaterials with concomitant control of thermomechanical properties, degradation profile, and metabolic fate – by leveraging our expertise at the interface of asymmetric catalysis, C–H functionalization, and polymer chemistry. In the five-year period of this MIRA grant, we propose to develop new catalytic approaches to control the stereochemistry of degradable polymers and establish a domain-selective approach to tune the material properties of polymers post-production. These methods will provide access to heretofore unknown semicrystalline biomaterials where critical parameters such as the chemical composition, polymer molar mass, and percent crystallinity can be systematically varied. The novel polymer structures accessed as a result of this work and the comprehensive evaluation of their degradation mechanism will enable the identification of design rules for the development of new classes surface eroding biomaterials. More specifically, we aim to develop new catalytic methods for the stereoselective polymerization of cyclic monomers through complementary kinetic resolution and enantioconvergent synthetic approaches. We envision that the discovery of previously unprecedented stereodefined polymers can be accomplished by developing a comprehensive understanding of structure–reactivity relationships that determine stereoselective addition of monomers to a reactive polymer chain-end. Further elaboration of this stereoselective polymerization philosophy will enable the pursuit of methods for stereoselective radical polymerization in a controlled manner through chiral Lewis acid catalysis, thus providing a strategy to create highly functional and stereodefined polymers from widely-available vinyl monomers. Complementary to the pursuit of stereoselective polymerization, we have identified late-stage functionalization as an underutilized approach to diversify the properties of existing polymers relevant to biomedicine without resorting to de novo synthesis. This philosophy can be used on current materials in medical devices as well as further expand the utility of the new, stereodefined polymers we discover in the course of our research program. By developing methods to conduct domain- selective C–H functionalization reactions, we propose to systematically tune the water transport into the amorphous phase of semicrystalline polymers and, therefore, influence their degradation mechanism.

Project Narrative The objective of this research program is to invent catalytic synthetic protocols for the creation of new, high-value materials for application in biomedicine. We will use the powerful tools of medicinal chemistry (e.g. asymmetric catalysis and late-stage functionalization) to generate stereochemically and functionally diverse polymeric substrates that can be exploited in the pursuit of next-generation degradable or functional medical devices.