AdvisorAndrade, Rodrigo B.
Committee memberAndrade, Rodrigo B.
Davis, Franklin A.
Sieburth, Scott McNeill
Cannon, Kevin C.
Aspidosperma Alkaloids and Bis-aspidosperma Alkaloids
Strychnos Alkaloids and Bis-strychnos Alkaloids
Total Synthesis of Natural Products
Permanent link to this recordhttp://hdl.handle.net/20.500.12613/4093
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AbstractAll Strychnos and Aspidosperma alkaloids possess a core pyrrolo[2,3-d]carbazole ABCE tetracycle. In order to develop an efficient and divergent methodology for the synthesis of Strychnos alkaloids, a streamlined synthetic sequence to the ABCE tetracycle has been developed. It features a Mitsunobu activation of an N-hydroxyethyl gramine intermediate and subsequent intramolecular aza-Baylis-Hillman reaction. This method was first applied in the total synthesis of (±)-alstolucine B. Additional key steps in the synthesis included (1) chemoselective intermolecular and intramolecular Michael additions and (2) a Swern indoline oxidation. The second application of this method was in the first total synthesis of (-)-melotenine A, a novel rearranged Aspidosperma alkaloid with potent biological activity. Additional key steps in the synthesis included (1) a Piers annulation of a vinyl iodide and a methyl ketone to prepare the D ring and (2) a site-selective intermolecular vinylogous aldol reaction
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Concise Syntheses of bis‐Strychnos Alkaloids (−)‐Sungucine, (−)‐Isosungucine, and (−)‐Strychnogucine B from (−)‐StrychnineZhao, Senzhi; Chen, Heng; Sirasani, Gopal; Dobereiner, Graham; Andrade, Rodrigo B.; Teijaro, Christiana; Vaddypally, Shivaiah; Zdilla, Michael; 0000-0001-5375-0241; 0000-0001-6203-9689; 0000-0003-0212-2557; 0000-0001-6885-2021 (2016-06-15)The first chemical syntheses of complex, bis‐Strychnos alkaloids (−)‐sungucine (1), (−)‐isosungucine (2), and (−)‐strychnogucine B (3) from (−)‐strychnine (4) is reported. Key steps included (1) the Polonovski–Potier activation of strychnine N‐oxide; (2) a biomimetic Mannich coupling to forge the signature C23−C5′ bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH3CN‐mediated reduction to fashion the ethylidene moieties in 1–3. DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-StrychnineZhao, Senzhi; Teijaro, Christiana; Chen, Heng; Sirasani, Gopal; Vaddypally, Shivaiah; O'Sullivan, Owen; Zdilla, Michael; Dobereiner, Graham; Andrade, Rodrigo B.; 0000-0001-5375-0241; 0000-0001-6203-9689; 0000-0003-0212-2557; 0000-0001-6885-2021 (2019-03)It was developed a concise synthetic route resulting in the first syntheses of bis-Strychnos alkaloids (-)-sungucine, (-)-isosungucine, and (-)-strychnogucine B from commercially available (-)-strychnine. Employing a highly convergent synthetic strategy, it was demonstrated that both Strychnos monomers could be efficiently prepared from commercially available (-)-strychnine. The venerable Mannich reaction was enlisted to join the two Strychnos monomers in a biomimetic fashion. Subsequent epimerization and olefin isomerization yielded (-)-strychnogucine B. Functional group manipulation transformed (-)-strychnogucine B into (-)-sungucine and (-)-isosungucine. Computational chemistry was employed to rationalize the regiochemical course of key steps en route to the bis-Strychnos targets.
Synthetic Approaches to Strychnos and Bis-aspidosperma AlkaloidsAndrade, Rodrigo B.; Wuest, William M.; Wengryniuk, Sarah E.; Cannon, Kevin C. (Temple University. Libraries, 2017)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.