Callophycolide A is a meroditerpene isolated from Callophycus serratus, a Fijian red macroalgae. Callophycolide A has been shown to inhibit bacterial growth, and it exhibits moderate cytotoxicity against multiple human cancer cell lines. Most importantly, it exhibits moderate activity against Plasmodium falciparum, the dead- liest malaria-causing parasite to humans. Due to its antimalarial action and the need for antimalarial drugs on the pharmaceutical market, efforts toward a modular approach to the total synthesis of callophycolide A are presented that incorporate inexpensive, commercially available starting materials, offer gram-level scalability, and utilize known chemistry, including copper-mediated aryl allylation, hydrolytic kinetic resolution, base-promoted epoxide ring-opening, and the Steglich esterification. Once completed, this synthetic pathway can be used as a template for the total synthesis of other related marine natural products, such as the callophycols, callophycoic acids, and the bromophycolides.
Callophycoic acids, also isolated from C. serratus, are the first examples of diterpene- benzoic acids observed in macroalgae. In addition, these acids, particularly callophycoic acids G and H, exhibit modest antibacterial activity. Although they are not strongly potent against malaria, they share a trans-decalin core identical to callophycols A and B, which are halogenated diterpene-phenols isolated from C. serratus that do exhibit modest antimalarial activity. Due to their identical core and their simpler structure (i.e., trisubstituted olefin tail), if a divergent total synthesis of callophycoic acids G and H can be established, it can serve as a template for synthesizing natural products that have been identified to be more potent against malaria, such as the callophycols, which are more complex in structure. Herein, a total synthesis of callophycoic acids G and H is investigated, which consists of a Wittig reaction, nucleophilic addition, and a bromonium-induced cation-pi cascade cyclization, and the progress toward the target molecules in the current study will be disclosed.
To access chiral intermediates for the aforementioned metabolites, catalytic methods were sought. Hydrolytic kinetic resolution (HKR) resolves racemic epoxides using water as the nucleophile and is most often catalyzed by chiral Co(III)-salens. Previous studies have shown that the counter-ion of the Co(III)-salen has a direct effect on the rate of the HKR; when catalyzed by a 50:50 mix of (R,R)-Co(III)-salen-OH and (R,R)-Co(III)-salen-SbF6, the fastest HKR rates occurred. It has further been shown that the enantioselectivity is primarily associated with the reaction of (R,R)-Co(III)-salen-OH on the activated epoxide. Based on the aforementioned origin of selectivity, a catalyst containing a 50:50 mix of (R,R)-Co(III)-salen-OH and (±)-trans-Co(III)-salen-SbF6 could, in principle, give high activities and enantioselectivities for HKR comparable to a mixed counter-ion system containing both (R,R)-Co(III)-salens. In this dissertation, a series of experiments are described that demonstrate that highly selective catalysis is only achieved using 100% enantiopure ligand and that mixtures of (R,R)-Co(III)-salen and (±)-trans-Co(III)-salen yield lower activity and selectivity. Control experiments demonstrate that this is due to rapid counter-ion scrambling under the reaction conditions, precluding the possibility of effectively co-utilizing enantiopure (expensive) and racemic (inexpensive) catalysts with differing counter-ions. The mechanistic investigations resolving the counter-ion scrambling are consistent with the currently accepted mechanism for catalysis, involving cooperative activity of the two Co(III)-salen species that activate the epoxide and water in the reaction. Moreover, the application of HKR in the progress toward the total synthesis of callo- phycolide A will be highlighted and discussed.
| Identifer | oai:union.ndltd.org:GATECH/oai:smartech.gatech.edu:1853/53976 |
| Date | 21 September 2015 |
| Creators | Key, Rebecca E. |
| Contributors | France, Stefan A. |
| Publisher | Georgia Institute of Technology |
| Source Sets | Georgia Tech Electronic Thesis and Dissertation Archive |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
| Format | application/pdf |
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