(3f) Synthetically Tunable Materials across Multiple Length Scales

Molecular design principles are crucial for the development of tunable functional materials. In my graduate work, I used mechanistic approaches to design catalytic systems for small molecule and polymer synthesis, leading to a deeper understanding of reaction methods for challenging bond formations as well as ligand effects in olefin metathesis catalysts. In my postdoctoral research, I have used related chemistry and chemical engineering approaches for the molecular design of biomaterials on longer length scales, including glucose-responsive hydrogels and biomacromolecule-based fibers. My program will establish structure-property relationships to develop a molecular approach to biomaterials engineering. This program will lie at the intersection of chemical engineering, chemistry, and materials science with the goal of addressing longstanding challenges in medicine.

Designing a biomaterial for a specific medical function requires overcoming both synthetic and biological hurdles. Application in living systems involves important consideration of a variety of challenges, including biocompatibility, immune response, stability, and degradation. Structural requirements to optimize these properties are most often empirically determined. Instead, rational and predictive strategies based on molecular control over material properties and biological response would better facilitate their development. My research program will design modular and bioinspired syntheses of polymeric fibrous biomaterials designed to have roles in mitigating inflammation, fibrosis, and infection as well as promoting wound healing. In addition to addressing specific challenges in translational medicine, successful development of these research areas will result in the emergence of platform technologies in which fiber-based materials with established physical properties can be tailored for a specific chemical and biological function.

Graduate Research at the California Institute of Technology, Division of Chemistry and Chemical Engineering. Advisors: Professors Robert H. Grubbs and Gregory C. Fu

Installation of Bioisosteres in Place of Carbon and Hydrogen. The replacement of specific functional groups of small molecule targets with bioisosteres has become a common strategy in medicinal chemistry. This is exemplified by the incorporation of fluorine in place of hydrogen to tune metabolic stability, lipophilicity, and bioactivity. Following identification of lead compounds, site-selective fluorination remains a synthetic challenge. My graduate research addressed a major challenge in fluorination chemistry – the selective formation of beta-fluorinated carbonyl compounds. Previously discovered methods largely suffer from poor regioselectivity, difficult substrate synthesis, or harsh reaction conditions. The strategy I employed involves the reaction of readily accessible allylic fluorides using a robust Wacker oxidation exhibiting reversed regioselectivity to produce aldehydes. These aldehydes can then be easily derivatized to a variety of compounds, providing a mild route to diverse fluorinated building blocks that can be utilized by medicinal chemists toward drug targets.

In similar fashion to fluorination chemistry, silicon bioisosteres have been incorporated in place of carbon atoms to study the effect on bioactivity of target compounds. Hydrosilylation is sensitive to steric interactions, and many compounds that would be derived from tri- and tetrasubstituted olefins cannot be accessed in this way. Over the last decade, nickel-catalyzed cross-coupling reactions have been developed as an efficient, mild strategy toward the production of C–C bonds. I developed a nickel-catalyzed cross-coupling reaction to form C–Si bonds tolerant of sterically hindered alkyl electrophiles. We demonstrated broad functional group tolerance of the reaction, and accessed organosilanes that cannot be produced from hydrosilylation. These reaction methodologies provide efficient alternative strategies for the incorporation of hydrogen and carbon bioisosteres in drug discovery.

Development of New Catalysts and Materials Applications of Olefin Metathesis. Olefin metathesis has proven to be a highly versatile reaction for the synthesis of both small molecules and polymers, and is utilized by organic, polymer, and materials chemists. Despite this, the production of ultra high molecular weight polymers with low dispersities remains challenging. We synthesized series of new ruthenium catalysts with aminophosphine ligands and performed systematic studies to determine design principles to better relate the effect of ligand structure on catalyst activity. Specifically, we incorporated P–N bonds in the phosphine ligand structure to investigate incongruent substituents on the phosphine architecture. Kinetic and computational studies disentangled contributions from ligand electronic, steric, conformational, and distortion effects on catalyst activity. We have also been able to utilize Grubbs catalysts to form brush block copolymers that rapidly self assemble into ordered nanostructures studied by small angle X-ray scattering. The resulting polymer films have been explored in applications such as pressure-responsive materials and photonic crystals.

Postdoctoral Research at the Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research. Advisors: Professors Robert S. Langer and Daniel G. Anderson

Glucose-Responsive Hydrogels for Insulin and Glucagon Delivery. Patients with type 1 diabetes regularly experience hyper- and hypoglycemic episodes. Glucose-responsive insulin delivery has been the focus of significant research efforts, but a major challenge in translating effective systems to clinic is glucose recognition. Common approaches to glucose recognition include the use of enzymes or lectins, which can be immunogenic and unstable, and synthetic phenylboronic acids, which suffer from poor selectivity. The focus of my research towards glucose-responsive insulin is to design and synthesize a synthetic lectin mimic that is stable, nontoxic, and glucose-selective to be conjugated to insulin-loaded materials. In order to achieve tight glycemic control, I have developed and performed release studies on related materials to release glucagon, a hormone secreted by the pancreas of healthy individuals in response to hypoglycemia. The effects of systematic changes to molecular structure on bulk properties of the hydrogels has been of particular interest.

Biomimetic Production of Polymer Fibers. Polymer fibers, ubiquitous in functional materials toward biomedical applications, are typically produced using protocols requiring organic solvents and high energy processes. I have recently discovered a new method for forming polysaccharide fibers, reaching over 10 meters in length, from dynamic crosslinked networks without the need for organic solvents or extrusion. Like spider silks, these fibers are formed by pultrusion and are drawn from a viscous fluid precursor. We have investigated the effects of chemical modifications near the site of crosslinking and crosslink density on the mechanical properties of the fluid precursors and the resulting fibers. A central goal of deciphering structure-property relationships for this system is to establish molecular design rules for the development of a platform technology, opening doors to applications of bioinspired polymer fibers.

Teaching Interests:

From a diverse laboratory background requiring a broad skill set, I am excited to teach laboratory courses in addition to lecture courses. I am interested in designing undergraduate courses in Introduction to Chemical Engineering, Organic and Polymer Chemistry, Thermodynamics, and Kinetics, as well as graduate coursework covering the Principles of Biomolecular Engineering. Students I have mentored, as well as myself during my education, have found that graduate courses that are heavily influenced by current research problems are informative and beneficial to developing their career goals. I believe that exposure to research-based problem solving can also be very helpful for undergraduate students considering applying to graduate programs. Because of this, I am excited to design hands-on laboratory and proposal-based seminar courses in the subjects areas of Biomaterials and Reaction Development. These topics will extend to my research program, and multidisciplinary training in a collaborative environment will provide the foundation for students and postdocs to conduct impactful research and excel in their career aspirations.