Date of Award

December 2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

M. Mahmun Hossain

Committee Members

Alexander Arnold, James Cook, Mark Dietz, Arsenio Pacheco

Abstract

PART I: A CONCISE SYNTHESIS OF MICROTUBULE INHIBITOR TRYPROSTATIN A AND B AND ITS ANALOGSMicrotubules are promising targets for treating cancer by stopping the cell division in mitosis(M). Tryprostatins A and B (TPS A and B) are one of the important alkaloids for treating cancer, via microtubule inhibition. Studied found that Tryprostatins A and B act as an antimitotic agent by inhibiting cell cycle progression of tsFT210 cells in the G2/M phase at a final concentration of 50 µg/ml of TPS A and 12.5 µg/ml of TPS B, respectively. Usually, Tryprostatins A and B are isolated from natural source Aspergillus fumigatus in trace amounts. Their interesting biological activity and simple structure have drawn attention from the synthetic community, and several total syntheses have been reported. But most of the synthetic procedures are lengthy and overall yield of the product is very low. This feature makes these compounds very expensive. The cost of Tryprostatin A is $208 for 500µg, and Tryprostatin B is $900 for 5mg. Here, we report a concise and efficient total synthesis of Tryprostatin A and B in only four steps with overall yield 40% and 57% respectively. The key step of our reaction was the alkylation of diprenylated gramine salt with diketopiperazine core in the presence of quinine. Also, in our synthesis, we modify the Krapcho decarboxylation reaction by using Dimethylacetamide (DMA) as a solvent in place of DMSO/DMF. Additionally, to make Tryprostatin analogs, we synthesized a series of C2, N-dialkylated gramine salt by direct lithialtion of N-protected gramine with alkyl halide and studied the reaction mechanism and synthetic scope of the reaction. We hope that one of these derivatives will be selective against cancer cells, with therapeutic concentrations in the nanomolar region.

PART II: BRØNSTED ACID CATALYZED REACTIONS OF AROMATIC KETONES WITH ETHYL DIAZOACETATE AND ITS SYNTHETIC SCOPE

3-hydroxy acrylates and related 3-oxo-esters are interesting precursors not only for biomedical and pharmaceutical products such as contact lenses, dental materials, carriers for controlled drug delivery, and hydrogels but also for the monomeric building block for polymers. Again, chemical modifications of 3-oxo esters and 3-hydroxy acrylates help us to synthesize novel drugs such as BRL-37959 (an analgesic), naproxen (painkiller), horsfiline (painkiller), coerulescine (an analgesic) as well as indole moiety and molecules bearing all-carbon quaternary stereocenters. In 1998 and later in 2004, our group reported the formation of 3-hydroxy-2-aryl acrylates by 1,2-aryl migration from the reactions of aromatic aldehydes with ethyl diazoacetate (EDA) in the presence of the iron Lewis acid catalyst and the Brønsted acid type catalyst, respectively. In this project, we extended our method for the formation of 3-hydroxy acrylates and related 3-oxo-esters by using less reactive aromatic and aliphatic ketones with EDA in the presence of Brønsted acid catalyst. Depending on the migratory aptitude of alkyl and aryl groups, a wide range of 3-hydroxy acrylates and related 3-oxo-esters are formed which can be effectively used to form a broad range of products extending from medicinal compounds to synthetic materials.

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