(6ab) Molecular Design Principles for Chemically Tunable Biomaterial Platform Technologies

Organic chemistry is a central science for the development of functional materials. My research program will specifically address the molecular design of biomaterials to elucidate structure-property relationships that can be utilized for unexplored applications and production methods. During my graduate training, I established new reaction methodologies and design principles for catalyst development. In my postdoctoral research, I am applying these fundamental concepts from organic chemistry to establish rational design strategies of polymeric materials with tunable properties for drug delivery and tissue engineering. The translation of such technologies to the clinic has the potential to alter poor patient prognoses and improve the quality of life of patients on a global scale. Because of this, I will continue a molecular approach to establish structure-property relationships for organic materials design in the next stage of my career, and am excited to mentor students and postdocs in a program dedicated to research at the intersection of organic chemistry, materials science, and chemical engineering with the goal of addressing longstanding challenges in medicine.

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

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.

Installation of Bioisosteres in Place of Carbon and Hydrogen. The replacement of specific functional groups of lead compounds 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 established as efficient, mild strategies 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.

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

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 from dynamic cross-linked networks without the need for electrospinning or extrusion. Like spider silks, these fibers can be formed by pultrusion and are drawn from a viscous liquid precursor. We have investigated the effects of the molecular structure, molecular weight, and degree of branching of the cross-linkers on the mechanical properties of the resulting materials. These studies allow for a deeper understanding of how organic chemistry can be used to rationally design fibrous materials with interesting properties.

Glucose-Responsive Materials 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 lectin mimic that is stable 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.

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 Organic Chemistry, Polymer Science, and Thermodynamics as well as advanced courses in Physical Organic Chemistry, Homogeneous Catalysis, and Soft Materials. Students I have mentored, as well as myself during my education, have found that research-focused courses are very informative and beneficial to developing their career goals. Because of this, I am excited to design hands-on laboratory and proposal-based seminar courses in the subjects of Reaction Development as well as Pharmaceutical Products and Medical Devices. 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.