Attempts towards the enantioselective total synthesis of (-)-cycleanine and anthrax lethal factor inhibitors

Dakhil, Otman. (2009) Attempts towards the enantioselective total synthesis of (-)-cycleanine and anthrax lethal factor inhibitors. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

(-)-Cycleanine is a bisbenzyltetrahydroisoquinoline (BBIQ) member of the large family of tetrahydroisoquinoline (IQ) alkaloids. The aim of the present work is the total synthesis of (-)-cycleanine via a strategy of using differential and selectively protected of gallic acid as the starting material. Subsequent homologation of the carboxyl group of the protected gallic acid intermediate to produce the secondary amine, followed by a Schotten-Baumann reaction and the Bischler-Napieralski cyclization to produce the desired intermediate. The presence of the chosen chiral auxiliary assisted the formation of the desired distereoisomers. Crystals of the key intermediates to the diaryl ether coupling step were collected and the absolute configurations were confirmed based on the X-ray data. Strategies involving the use of a SNAr reaction and Ullmann reactions on this intermediate were used to form the diaryl ether linkage to produce cycleanine. -- Anthrax is an acute transferable disease caused by Bacillus anthracis, and the disease is highly lethal in some forms. The design of appropriate anti-toxins to assist in the treatment of the infection in the advanced stages is desirable. A recent study that showed 5-hydroxydopamine derivatives were non-competitive inhibitors of anthrax lethal factor (LF) encouraged our interest in discovering more potent LF inhibitors that posse a similar polyphenolic design. These studies led us to consider the use of some of the intermediates obtained in the course of the attempts towards the enantioselective synthesis of (-)-cycleanine and of other BBIQs of interest, for the enantioselective synthesis of some analogues of those LF inhibitors. Precursors for the final targets were prepared and these endeavors are reported in this thesis.

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