Synthesis of again natural products and synthetic rocaglate derivatives

• Main Author: Lajkiewicz, Neil Jason
• Language: en_US
• Published: 2016
• Subjects: Organic chemistry
• Online Access: https://hdl.handle.net/2144/15438

The enantioselective total syntheses and absolute configuration assignments of (+)-ponapensin and (+)-elliptifoline have been achieved via enantioselective [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate. The resulting cyclopenta[b,c]benzopyran was reduced through a reagent-controlled, diastereoselective reduction. Amidation was accomplished through direct ester-amide exchange mediated by trimethylaluminum, and diastereoselective N-acyliminium cyclization was observed likely due to stereoelectronic stabilization of one face of the N-acyliminium. The total syntheses revealed the absolute configuration to be opposite of what was hypothesized. These observations led to an interesting biosynthetic hypothesis in which a kinetic resolution/parallel kinetic resolution may be taking place. Through testing this conjecture, an asymmetric transfer hydrogenation kinetic resolution methodology was developed and applied to the first enantioselective total syntheses of (+)-aglaiastatin and (-)-aglaroxin C. The total syntheses confirmed the absolute configuration of these metabolites, and the natural enantiomers were found to be the most biologically active. Chiral urea, thiourea, trifluoroethanols, and TADDOLs have been evaluated as catalysts in the asymmetric [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate. Chiral trifluoroethanols such as Pirkle's alcohol promoted [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate with enantioselectivities up to 40% ee with 20 mol% loading. These additives may be interacting with 3-hydroxyflavone through an excited state double proton transfer mechanism. The synthesis, unexpected light-driven di-epimerization, and biological evaluation of a novel rocaglate-derived β-lactone and β-lactone analogs have been achieved. In addition to in vitro inhibition of the serine hydrolases ABHD10 and ACOT1/2, the most potent β-lactone enantiomer was found to inhibit ABHD10 in PC3 cells, suggesting that derivatives of this β-lactone may serve as valuable chemical probes. The mechanism of the photochemical di-epimerization was investigated and may be occurring through photochemical electron transfer. Biotinylated rocaglate derivatives have been synthesized and evaluated in a streptavidin pull down assay to determine the molecular target of rocaglates. eIF4G was pulled down as the molecular target for one of the biotinylated analogs, but eIF4A was not pulled down by any of the biotinylated analogs.