Access to Versatile β-Cyclodextrin Scaffolds through Guest-mediated Mono-acylation

Cyclodextrins (CDs) are naturally occurring macrocyclic oligosaccharides comprised of α-1,4 linked glucose units. CDs are non-toxic and bio-compatible scaffolds. They have a conical structure with a hydrophobic inner cavity, allowing them to form stable and soluble inclusion complexes with a variety of hydrophobic guest molecules. Furthermore, CDs can be derivatized at the primary or secondary alcohols with a variety of functional groups. Compared to native CDs, derivatized CDs feature a broader range of applications including molecular recognition of small molecules and biomacromolecules, catalysis, supramolecular polymers and targeted drug/DNA delivery. This thesis addresses the hypothesis that highly functionalized cyclodextrins can be accessed via guest-mediated acylation reactions. This thesis explored the development of two methodologies to functionalize heptakis-[6-deoxy-6-(2-aminoethylsulfanyl)]-β-CD, a versatile, amine-functionalized scaffold. The key reaction developed was a selective mono-functionalization of heptakis-[6-deoxy-6-(2-aminoethylsulfanyl)]-β-CD via an acyl transfer reaction proceeding through a covalent-capture mechanism. This approach permitted the installation of a 5-mercaptopentanamide at the primary rim in two steps in high yields. The amine-orthogonal thiol was amenable to functionalization with maleimides or through disulfide exchange. The free thiol also served as a handle for immobilization of the mono-functionalized CD onto solid support for supported synthesis. The functionalization of the primary rim amines of the solid-supported CD, is a rapid and highly modular means to introduce diversity to this scaffold. The combination of these two methodologies afforded access to a library of peptide functionalized CD scaffolds which were modified with environmentally sensitive fluorophores to generate fluorescent receptors. These receptors were applied for the differential sensing of various bile salts, and are currently being investigated for the detection of elevated bile salts in human serum.Ph.D