Doctor of Philosophy (PhD)



Document Type



The theonellamides are a family of compounds distinguished by their crosslinking ô-histidinoalanine (ô-HAL) residue. Part one of this dissertation details the synthesis of an orthogonally protected ô-HAL building block that will be incorporated into a total synthesis of theonellamide C. Selective deprotection of each amine and acid of this orthogonally protected building block is also demonstrated. Various reaction partners for the assembly of ô-histidinoalanine were explored. One approach involved the coupling of N-Fmoc-â-iodoalanine benzyl ester and (Nðim)-blocked histidine nucleophiles including a fused bicyclic urea and a Boc-His(Nð-Pac)-OMe. While the imidazolium salts were identified by mass spectrometry, elimination of the iodide group was a major side reaction. Successful nucleophilic opening of a five-membered ring sulfamidate (derived from Fmoc-D-Ser-OH) by Boc-L-His-OTCE led to preparation of a regiochemically and stereochemically pure ô-HAL derivative. Thus, a new set of orthogonal protecting groups have been identified: Fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethylester (TCE), tert-butyl carbamate (Boc), and benzyl (Bn) ester. Part two of this dissertation outlines the synthesis of a trimethyl lock-based prodrug model system, wherein photothermal activation of a salt containing a cationic near-IR dye and an anionic prodrug, releases a paclitaxel side-chain fragment via a tandem aryl Claisen rearrangement and lactonization. The prodrug model system was prepared via coupling of the paclitaxel sidechain alcohol to an acid with a pendant substrate for the rearrangement-lactonization. Claisen rearrangement studies in various solvent systems on the release of the paclitaxel fragment demonstrated that aqueous alcoholic solutions of allyl aryl ethers accelerated the rearrangement relative to hydrocarbon solvents, temperatures achieved were still too high to be feasible in biological systems. The 1,1-dimethylallyl group was identified for its rate-accelerating properties. Studies of the Claisen rearrangement in aqueous methanol demonstrated that the aryl dimethylallyl ether derivatives rearranged significantly faster than the unsubstituted allyl ethers. Moreover, electron donating groups facilitated the reaction. A salt was formed from a cationic near-IR laser dye (IR-780) and 1-(1,1-dimethylallyl ether)-4-benzoic acid, then suspended as nanoparticles in water. Photothermal studies of these aggregated species are underway.



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Committee Chair

Taylor, Carol

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Chemistry Commons