Apratoxin D – A Formal Total Synthesis; Asymmetric Synthesis of all Four Stereoisomers of Mefloquine Hydrochloride; α-Alkylation and α-Arylation of N-alkoxyenamines and α-Epoxy-N-sulfonyl Hydrazones



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Apratoxin D, a potent inhibitor of cancer cell growth, particularly against H-460 human lung cancer cells, was synthesized for the first time by our lab in 2012. We endeavored to improve upon that synthetic route proposing an alternative strategy for a more flexible pathway to the polyketide fragment. Specifically, this allowed a modular process that could result in variable substituents at the C-37 carbon, which has been shown to be critical in the inhibitory activity of the apratoxins. In the first chapter, we present an effective strategy based off of an organocopper asymmetric allylation of α,ß-unsaturated-N-acyloxazolidinones, demonstrating good diastereoselectivity (9:1) and yield. Second, we present an asymmetric (er > 99:1) total synthesis of all four stereoisomers of mefloquine hydrochloride which are subsequently used for biological assays to evaluate its use as a TP53 readthrough enhancer. Mefloquine has shown effectiveness at enhancing TP53 readthrough alongside aminoglycoside G418, marking its potential in cancer treatment in cases of TP53 nonsense mutations. Finally, we present a new strategy for umpolung based functionalization of ketones and aldehydes through a copper catalyzed nucleophilic addition of Grignard reagents to N-alkoxyenamines. Classic enolate based α-functionalization of carbonyls is inherently limited due to the SN2 pathway of the transition state. Umpolung strategies allow access to a greater range of α-functionalized products. This was accomplished with as little as 30 mol % loading of CuBr•DMS with 77% yield, and in-situ removal of the 3,5-isoxazolidinone to reveal the ketone directly. Additionally, we expand upon our previously published umpolung strategy for α-arylation and α-alkylation of α-epoxy-N¬-sulfonyl hydrazones to aliphatic systems, demonstrating its effectiveness across a range of sp, sp2, sp3 hybridized Grignard nucleophiles with excellent diasteroselectivity (>25:1 syn:anti) and yield (64-89%). Classic enolate chemistry cannot produce the difficult to form α-substituted ß-hydroxy carbonyl compounds with α-quarternary centers. Our strategy can access these products with good diastereoselectivity (up to 9:1 syn:anti) and yield (36-80%). Additionally, we propose a mechanism for this reaction and support this with computational data accounting for the observed selectivity in both the unsubstituted and α-methyl substituted substrates.



Mefloquine, Apratoxin, Hydrazone, Umpolung, Α-alkylation, Α-arylation, Copper catalysis


Portions of this document appear in: Ferguson, Michael W., Chloe AN Gerak, Christalle CT Chow, Ettore J. Rastelli, Kyle E. Elmore, Florian Stahl, Sara Hosseini-Farahabadi, Alireza Baradaran-Heravi, Don M. Coltart, and Michel Roberge. "The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418." PloS one 14, no. 5 (2019): e0216423.