Enantioselective total synthesis of tetrahydroisoquinoline alkaloids and anthrax lethal factor inhibitiors

Zein, A. L. (2012) Enantioselective total synthesis of tetrahydroisoquinoline alkaloids and anthrax lethal factor inhibitiors. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Tetrahydroisoquinolines ('THIQ') which contain a B ring that is reduced at the C1-C2 and C3-C4 positions are known to be key biosynthetic precursors to many naturally occurring alkaloids. The enantioselective synthesis of each of the enantiomers of N -norlaudanidine, a minor Papaver somniferum opium benzyltetrahydoisoquinoline alkaloid has been achieved using a (S )- or (R )-α-methylbenzylamine chiral auxiliary-mediated strategy. The use of this chiral auxiliary has proven to be convenient and effective in a Bischler-Napieralski cyclization-reduction to enantioselectively form each of the enantiomers of N-norlaudanidine as confirmed by X-ray crystallography. Structures of each of these secondary amines are reported as well as the tetrahydroprotoberberine alkaloids (-)-( S )-tetrahydropalmatrubine and (-)-(S)corytenchine. The thesis will also report on our findings to date toward the total synthesis of (1R ,1'S )-temuconine using this strategy. Temuconine was isolated from Aristolochia elegans by Shamma and coworkers who stated it to be the enantiomer of a compound previously obtained by others, from Chilean Berberis valdiviana . (-)-Temuconine has been reported to have potent antiplasmodial activities, but its structure is different to that reported earlier by Shamma. -- A second set of synthetic targets reported herein are potential anthrax lethal factor inhibitors. Anthrax is an acute infectious disease that normally affects animals and is caused by the Bacillus anthracis bacterium. Some tetrahydroisoquinoline unit-containing compounds, which were racemic, were recently found by Wong to be anthrax lethal factor inhibitors. This finding prompted us to investigate the enantioselective synthesis of these compounds using our chiral auxiliary-mediated strategy.

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