Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Document Type

Dissertation

Abstract

Despite advances in medicine, antibiotic resistance threatens to return once preventable diseases to the human population. The microbisporicins are 24-amino acid antibiotic peptides belonging to the lantibiotic class, which pathogens have been slow to develop resistance. The uncommon post-translational modification S-[(Z)-2-aminovinyl]-D-cysteine (AviCys) is likely crucial to their activity, and appears in a small number of other peptides with compelling biological activities. Total synthesis of an AviCys-containing peptide has eluded the chemical community.

The primary challenge of AviCys synthesis is the construction of a thioenamide functional group. We demonstrate that acid-promoted reactions between an amide and acetal produce the desired Z-thioenamide. We use mechanistic calculations to highlight the stereoelectronic control of this transformation, while careful examination of reaction byproducts helped us to optimize the yield and selectivity. To this end, we developed a stereoselective method for Z-thioenamide generation in a model system.

While progressing to peptidyl thioenamide formation, we encountered an issue with the stereochemistry of our cysteine building block. Examination of the diastereomeric products of reactions with our cysteine building bloack led us to conclude that it was racemic. We used chiral HPLC and Mosher’s derivatization to determine the steps responsible for racemization. We redesigned the synthesis of the cysteine building block to produce enantiomerically enriched material.

Early attempts at thioenamide formation between amino acid derived coupling partners showed us that double protection of the α-amino amide amine was required. The optimal amine protection was as a tetrachlorophthalimide (Tcp). We protected valinamide with Tcp and formed a thioenamide en route to the C-terminal ring of cypemycin, an AviCys-containing peptide with antileukemia activity. Deprotection of the Tcp amine was achieved, under carefully controlled conditions, followed by coupling with Boc-leucine to form a tripeptide. Liberation of the terminal acid and amine was achieved, though classic conditions for deprotection had to be tweaked for compatibility of the thioenamide functional group. Macrocyclization was accomplished to form a Pht-capped cypemycin C-terminal ring.

Date

10-23-2019

Committee Chair

Taylor, Carol

Available for download on Tuesday, October 20, 2020

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