Date of Degree
PhD (Doctor of Philosophy)
F. Christopher Pigge
Part A. Bifunctional cyclooctynes in copper-free click chemistry for applications in radionuclide chemistry: A new monofluorinated cyclooctyne (MFCO) with a reasonable kinetic profile was synthesized in three steps. We have demonstrated that MFCO can be used as a lynchpin to conjugate biomolecules to radionuclide chelators using copper-free 1,3-dipolar cycloaddition reactions with azides. Many bifunctional biomolecule-chelators were synthesized, and then radiolabelled with very high radiochemical purity and specific activity. MFCO-amine analogues were also synthesized and used in construction of chelator-biomolecule conjugates (particularly, NDP-α-MSH analogues) for applications in radioimaging. Bis-MFCO based bivalent ligands with various linker lengths were also synthesized as precursors to multivalent ligands for use in cancer diagnosis and therapy.
Part B. 4-Alkylpyridine derivatives in intramolecular dearomatization and heterocycle synthesis: 4-Alkylpyridine derivatives substituted with different carbon nucleophiles were synthesized and subjected to intramolecular spirocyclization under various conditions to afford synthetically useful diazaspiro[4.5]decanes as well as diazaspiro[5.5]undecanes in good yields. The same 4-alkyl substrates were used to synthesize anhydrobase intermediates which, then participated in aldol-like condensation in the presence of Lewis acid to yield highly conjugated dihydropyridines. Acid hydrolysis produced substituted pyridines tethered with functionalized butyro- and valero lactams. The synthesis of related azaspiro[4.5]decanes and azaspiro[5.5]undecanes from reaction of
hypervalent iodine reagents with 4-methoxy-substituted benzyl and phenethyl substrates linked to β-keto amide nucleophiles was also briefly investigated.
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