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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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.
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.
TOTAL SYNTHESIS OF STRYCHNOS AND ASPIDOSPERMATAN ALKALOIDSAndrade, Rodrigo B.; Sieburth, Scott McNeill; Wengryniuk, Sarah E.; Cannon, Kevin C. (Temple University. Libraries, 2017)The Strychnos class of indole alkaloids contain a pyrrolo[2,3-d]carbazole ABCE tetracyclic framework. The second-generation ABCE tetracycle approach was employed in the total synthesis of (±)-20-epi-lochneridine and progress toward total synthesis of (±)-alstolucine B. The second-generation approach featured Mitsunobu activation of the hydroxyethyl group in a gramine intermediate followed by intramolecular aza-Baylis-Hillman reaction. The substrate for hydroboration was redesigned to (±)-18-desmethyl akuammicine (1,1-disubstituted double bond), since the hydroboration of trisubstituted alkenes afforded tertiary alcohol via Markovnikov addition. The key steps were n-Bu3SnH mediated cyclization reaction to accomplish D-ring, tert-butyl hypochlorite indoline oxidation, and anti-Markovnikov hydroboration to introduce a primary alcohol. The total syntheses of Strychnos-Strychnos type bis-indole alkaloids (−)-leucoridine A and C were accomplished from the biomimetic dimerization of (−)-dihydrovalparicine. En route to (−)-dihydrovialparicine, known alkaloids (+)-geissoschizoline and (−)-dehydrogeissoschizoline were also prepared from commercially available N-tosyl indole 3-carboxaldehyde. Key steps consisted of an in situ dimerization of (−)-dihydrovalparicine from (−)-1, 2-dehydrogeissoschizoline with trifluoroacetic acid in the presence of 4 Å molecular sieves. Acid mediated ring-opening of the indolenine in (−)-leucoridine A to afford (−)-leucoridine C. DFT calculations were employed to elucidate the mechanism of dimerization, which suggested that a stepwise aza-Michael/spirocyclization sequence was preferred over the alternate hetero Diels-Alder cycloaddition reaction. A novel domino Michael/Mannich [4+2] annulation method was applied for concise total synthesis of Aspidospermatan alkaloids (+)-20-epi-condyfoline and progress toward the total synthesis of (+)-condyfoline. The additional key steps consisted of a LiHMDS mediated cyclization to form D-ring, dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) mediated spirocyclization to form pentacyclic thioether and indoline oxidation with MnO2.