Abstract

Project I Celogentin C, isolated by Kobayashi from the seeds of Celosia argentea in 2001 exhibits strong inhibitory behavior towards polymerization of tubulin – globular protein, which plays crucial role during the cell division cycle. We have attempted synthesis of the left-hand ring of celogentin C via the intramolecular alkylation and the Knoevenagel condensation strategies. Utilizing synthetic methodologies in the field of nitroacetyl chemistry, developed by Kornblum and Rajappa we have successfully prepared the intermolecular Knoevenagel condensation product – the late-stage precursor to the left-hand ring of celogentin C. Synthesis of this key intermediate subsequently led to the preparation of the left-hand ring and the total synthesis of celogentin C by other members of Castle's group.

Project II Thioviridamide is the potent apoptosis inducer isolated by Hayakawa from the bacterial broth of Streptomyces olivoviridis. Unusual structural features of the thioviridamide macrocycle contain two novel amino acids, never before encountered in a natural product - S-(2-aminovinyl)cysteine (avCys) and β-hydroxy-N1,N3-dimethylhistidinium (hdmHis). No stereochemical information except for the Z-configuration of the β-thioenamide linkage was reported in the literature. We have performed a computational study to predict the thioviridamide stereochemistry. Initial populations of conformers for the likely candidate structures were produced using OPLS-AA force field. Prediction of the NMR properties was accomplished at the mPW1PW91/6-311+G(2d,p) level of theory with the polarizable continuum model of salvation. Utilizing Boltzmann averaging and statistical analysis we have determined that the only possible cases of stereochemical inversion occur at the sites of the two novel amino acids.

Project III Model studies towards the synthesis of the β-thioenamide subunit of thioviridamide were performed. The radical addition reaction of thiyl radicals to ynamides produces Z- (kinetic products) or E- β-thioenamides (thermodynamic products) depending on the reaction conditions. Two distinct sets of reaction conditions allowing kinetic or thermodynamic control of β-thioenamide formation were developed. Synthesis of the model β-thioenamide subunit of thioviridamide was attempted.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2010-06-07

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd3617

Keywords

Celogentin C, Thioviridamide, Knoevenagel, avCys, hdmHys, OPLS-AA, NMR prediction, thyil radical, radical addition, ynamide, thioenamide, triazone

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