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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Asymmetric Synthesis of Homotropinone and Tropane Alkaloids using Enantiopure Sulfinimines and the Synthesis and Applications of MethanoprolinesDavis, Franklin A.; Krow, Grant; Andrade, Rodrigo B.; Zdilla, Michael J., 1978-; Cannon, Kevin C. (Temple University. Libraries, 2011)The development of new methodologies for the asymmetric synthesis of homotropinone and tropane alkaloids using enantiopure sulfinimines [RS(O)N=CR1R²] is the primary objective of this thesis. In one study a four-step intramolecular Mannich cyclization cascade reaction was devised for the asymmetric synthesis of substituted homotropinone alkaloids from enantiopure sulfinimine-derived N-sulfinyl ß-amino ketone ketals. These amino ketone ketal chiral building blocks were prepared in 67-71% yields and high dr (25-14:1) by addition of the Weinreb amide enolate of N-methoxy-Nmethylacetamide to masked oxo sulfinimines (N-sulfinyl imines). Treatment of these Weinreb amides with Grignard reagents gave the N-sulfinyl ß-amino ketone ketals in 93- 95% yields without epimerization. Heating the acyclic ß-amino ketone ketals with the buffer solution NH4OAc:HOAc resulted in a one-pot 4 step intramolecular Mannich cyclization cascade reaction to give substituted homotropinones including (–)- euphococcinine and (–)-adaline in 82-90% yields. In another study a sulfinimine-derived α,ß-unsaturated pyrrolidine nitrone was utilized in the development of a Lewis acid catalyzed [3+2] nitrone cycloaddition reaction for the asymmetric synthesis of the tropane alkaloid (+)-cocaine. The masked oxo sulfinimine was treated with an excess of the sodium enolate of methyl acetate to give N-sulfinyl ß-amino ester in 87% yield and high dr (97:3). Reduction of the ester to aldehyde followed by a Horner-Wadsworth-Emmons olefination reaction afforded the α,ß-unsaturated N-sulfinyl amino acetal. Hydrolysis of the unsaturated amino acetal gave a pyrrolidine, which was selectively oxidized to the pyrrolidine nitrone. The nitrone on heating with the Lewis acid Al(O-t-Bu)3 for 96 h underwent an intramolecular [3+2] cycloaddition to give a tricyclic isoxazolidine, which was transformed into (+)-cocaine in three steps 25% overall yield. This 9 step, 25% overall yield synthesis of (S)-(+)-cocaine from the masked oxo sulfinimine is the most efficient enantioselective route to cocaine from acyclic starting materials. This new methodology is adaptable to the preparation of various cocaine analogs including the first cocaine C-1 analogs. In other studies conformationally constrained novel pyrrolidine analogs (methanopyrrolidines) were synthesized stereoselectively to study the substituent (H, OH, or F) effect on amide conformational preferences. A nucleophilic displacement synthetic route was devised to prepare highly functionalized 5(6)-anti-substituted-methanopyrrolidines from N-benzyl-2-azabicyclo[2.1.1]hexylbromide(s) intermediates with the aid of neighboring group participation. These methanopyrrolidines were then transformed to constrained proline analogs (methanoprolines) to evaluate the impact of proline ring pucker on amide conformations. An α-methoxycarbonyl group was introduced in methanopyrrolidines by treating tert-butoxycarbonyl protected methanopyrrolidines with s-BuLi and quenching with various electrophiles such as CO2, DMF or ClCO2Me. Amide trans-cis conformational preferences (Ktrans/cis) of N-acetyl-methanopyrrolidines and N-acetyl-methanoprolines were determined in various solvents such as CDCl3 and D2O using NMR techniques, including NOE. The small trans amide preference for substituted fluoro- and hydroxy-methanopyrrolidines shows that it is the interaction of the !-methyl ester group and the amide moiety of the methanoprolines that plays a major role in determining amide conformational preferences. The gamma-substituent effect is primarily related to ring pucker and a resultant enhancement of the interaction between the amide carbonyl oxygen and ester carbonyl carbon. The results are relevant to the conformational stability of collagen and protein engineering.
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.
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.