Cyclization reactions play an important role in synthesizing a significant number of small molecule scaffolds for various purposes, including drug discovery. However, the application of cyclization reactions in the modifications of biomolecules in a single step is still limited. This dissertation reports a stereoselective thiomorpholine ring formation reaction to site-selectively modify N-terminal cysteines of unprotected peptides or proteins in a single step. We showed that α-fluoroketone molecules afford the cyclization reaction with the beta amino thiol group of N-terminal cysteine. Both chemo and stereo-selectivity of this reaction have been studied using 2D NMR analyses. Cysteine located at the Nterminal of a short protein (VHP protein) has been modified site-selectively with a fluorescein isothiocyanate (FITC) containing an α-fluoroketone linker to demonstrate the applicability of this reaction in modifying biomolecules. This chemistry has the potential to generate homogeneous and stable antibody-drug conjugates (ADCs) for the treatment of cancer. This dissertation also demonstrates a fluorine-thiol displacement reaction (FTDR) to synthesize various macrocyclic and stapled peptides, which renders medicinally privileged peptides with improved biological properties such as binding affinities and cell membrane permeability. The cyclization of fluoroacetamide containing peptides with benzenedimethane thiol linkers enhances peptides' alpha helicity. These FTDR stapled peptides exhibit better cellular uptake compared to the classic ring-closing metathesis (RCM) stapled peptides. Compared to the proteoglycan-aided cell penetration by peptides stapled with RCM, the preliminary mechanistic studies of our FTDR-stapled peptides revealed that our thiolated linkers allowed peptides to enter cells in multiple pathways. Taken together, our FTDR-based stapling approach may provide a novel class of cell-permeable peptides that might open a new window to probe intracellular targets. This dissertation reports another cyclization reaction between hydrazine and carbamate, synthesized from 7-hdyroxy coumarin derivatives. We demonstrate that the secondary nitrogen of hydrazine is much more reactive than the primary nitrogen for intramolecular cyclization reactions. Hydrazine affords urea bonds upon the substitution of a coumarin moiety of carbamates to generate 6 or 7 membered cyclic scaffolds. The exocyclic free amine might allow facile generation of a library of compounds. In addition, further optimization of this reaction might allow using these hydrazine containing molecules in monitoring the real-time activity of histone deacetylases (HDACs). / Chemistry

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