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Application of rhodium-catalyzed alkyne hydrothiolation to the syntheses of K777 and analogues : potential therapeutics for the treatment of Chagas' disease

University of British Columbia

Chagas’ disease is a neglected global disease that affects millions of people in Latin America and has started to spread to different areas around the world. This disease is the leading cause of heart failure in Latin America and has many other symptoms including digestive track problems and myocardial damage. The causative organism of this disease is T. Cruzi, which is spread though an insect vector as well as human methods such as blood transfusions, organ donation and food contamination. Current drug therapies are not sufficient; they suffer from lengthy dosage duration and have many dangerous side effects. In the last two decades the organism’s cysteine protease, cruzain has become a desired target for inhibition. Many cysteine protease inhibitors have been studied in the last two decades with one potential therapeutic - K777, an irreversible cysteine protease inhibitor, having the most promise. K777 contains a potent vinyl sulfone warhead, which acts as a Michael-acceptor to the cysteine residue in the catalytic triad of cruzain. K777 is currently entering phase 1 clinical trials. The potent warheard vinyl sulfone in K777 is of interest to the laboratory of Dr. Jennifer Love due to our methodology for synthesizing vinyl sulfides. We proposed that we could synthesize K777 and a variety of analogues using our rhodium-catalyzed alkyne hydrothiolation method as the first application of this method in total synthesis. Here we present the total synthesis of K777 and analogues highlighting the wide substrate scope of our methodology.

Text

2015-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42600

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/