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Synthetic Approaches to Strychnos and Bis-aspidosperma Alkaloids
Teijaro, Christiana Nicole
Teijaro, Christiana Nicole
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Thesis/Dissertation
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2017
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Chemistry
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http://dx.doi.org/10.34944/dspace/2496
Abstract
Alkaloids from the Strychnos and Aspidosperma families all contain a pyrrolo[2,3- d]carbazole ABCE tetracyclic core. In regards to the Strychnos alkaloids, methodology developed within the Andrade laboratory featuring a key biscyclization strategy utilizing a Mitsunobu activation of a gramine intermediate and successive intramolecular vinylogous Mannich reaction affords the pyrrolo[2,3-d]carbazole ABCE tetracyclic core. The biscyclization methodology was applied to the first asymmetric synthesis of (‒)-alstolucine A, (‒)-alstolucine B, and (‒)-alstolucine F as well as (‒)-echitamidine and (‒)-Ndemethylalstogucine. Another key step in the synthesis of these natural products includes a SmI2 reduction of an α-hydroxyketone. These natural products inhibit ATP-Binding Cassette (ABC) protein C10 selectively over P-glycoprotein (PGP). Photoaffinity analogs of (‒)-alstolucine B, and (‒)-alstolucine F were synthesized and used in preliminary studies to determine the binding site of the natural products to ABCC10. Bis-Strychnos alkaloids represent structurally complex and diverse molecules with a wide range of biological activities. The first biomimetic, semi-synthesis of (‒)- strychnogucine B, (‒)-isosungucine, and (‒)-sungucine were accomplished. Two key steps within the syntheses comprised (1) a Polonovski-Potier reaction using strychnine N-oxide to afford an activatable coupling fragment and (2) a BF3·OEt2 mediated biomimetic Mannich coupling to yield the bis-Strychnos alkaloids. (‒)-Strychnogucine B has been shown to have anti-malarial activity while (‒)-sungucine has been shown to have novel anti-cancer activity, via its ability to kill cancer cells resistant to apoptosis. iv In respect to Aspidosperma alkaloids, methodology developed within the Andrade laboratory featuring an asymmetric domino Michael/Mannich/N-alkylation strategy allows for rapid, easy access to the ABE ring system of the pyrrolo[2,3-d]carbazole ABCE tetracyclic core. This methodology was used to synthesize the monomeric Aspidosperma alkaloids (‒)-tabersonine and (‒)-16-methoxytabersonine to be applied in the synthesis of (‒)-melodinine K, (‒)-conophylline, and (‒)-conophyllidine. These bis-Aspidosperma alkaloids have remarkable biological activities. They have been shown to be cytotoxic to cancer cells. More noteworthy, (‒)-conophylline is able to induce β-cell differentiation of a wide range of stem cells into β-cells. β-cells are responsible for the production of insulin within the pancreas giving rise to a potential therapeutic use for type I diabetes.
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