Part I: Polyrotaxanes as MRI Contrast Agents and NPC Therapeutics. Part II: Development of an Analytic-directed Synthesis System

The work described in this dissertation is separated into two parts. Part I describes the development of cyclodextrin-based polyrotaxanes (PRs) as both MRI contrast agents and as potential therapeutics for Niemann-Pick Type C (NPC) disease. Polyrotaxanes are a class of supramolecular materials which are constructed through the non-covalent threading of macrocyclic molecules onto a polymer core that are retained by the covalent attachment of bulky molecules to the ends of the polymer as end-caps. This unique architecture provides a rigid and rod-like morphology that imparts attractive biological and mechanical properties compared to other nanomaterials used in biological applications. In our case, we have developed PRs constructed from cyclodextrin derivatives threaded onto Pluronic triblock copolymer cores. Their utility as MRI contrast agents as well as NPC therapeutics is reported in Chapter 2. The development of a greener and more scalable synthesis of PRs using a solid-state approach is described in Chapter 3. Part II of this thesis describes the development of a multi-scale automated synthesis system guided by mass spectrometry. Continuous-flow and high throughput experimentation are two technologies which are rapidly changing the way modern synthesis is conducted. Continuous-flow reactors allow for a level of control over reaction parameters that is unparalleled relative to batch systems, thus providing the capability to execute reactions faster, greener, and safer than ever before. Chapter 4 describes the development of a continuous-flow platform for the synthesis of diphenhydramine which includes a continuous-flow reactor, on-line mass spectrometric monitoring, and continuous-flow crystallization. Also integrated in this effort is the use of accelerated reactions in microdroplets to guide continuous-flow synthesis. High throughput experimentation technologies have already transformed the way in which biological assays are conducted and are rapidly making their way into the organic synthetic process. The development of a high throughput reaction screening approach based on desorption electrospray ionization mass spectrometry (DESI-MS) is described in Chapters 5 and 6. This system, capable of executing and analyzing thousands of reactions per hour, has the potential to dramatically accelerate the process of reaction optimization and discovery