I. Total Synthesis of (+)-Spongiolactone and Derivatives Enabling Initial Structure-Activity Relationship Studies: Discovery of a More Potent Derivative II. Studies Toward Recyclable Isothiourea Catalysts
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β-lactone containing natural products are attractive targets for total synthesis and subsequent biological studies. Given the remarkable ability of this moiety to covalently inhibit specific proteins, we were drawn to spongiolactone as a synthetic target. Through our studies, the first total synthesis of this compound was achieved along with the synthesis of several derivatives. This synthesis enabled cytotoxicity studies to be carried out against a variety of cancer cell lines, with good activity observed in the human chronic myelogenous leukemia (K562) cell line. Particularly intriguing was the discovery of a more potent derivative than the natural product itself which was then modified and taken on to activity based protein profiling (ABPP) studies. The first magnetite-supported benzotetramisole (BTM) catalyst was prepared and utilized in the kinetic resolution of secondary alcohols. Overall, the selectivity factor was lower than the parent (+)-BTM (s = 48 versus s = 148, respectively), however the resulting ester was achieved in excellent enantiomeric excess, albeit with low reaction conversion. Further studies suggest an unfavorable inactivation of the catalyst taking place in the presence of uncapped magnetite. The first soluble, polymer-supported BTM catalyst was also synthesized using polyisobutylene as the support. Behavior of this catalyst system was superior to the magnetite-BTM adduct in the kinetic resolution of secondary alcohols and the conversion was efficient, providing the resolved alcohol and ester both in 90% ee which corresponds to a selectivity factor of 79. Preliminary studies show problems of recyclability as indicated by the drop in selectivity factor (s = 51) and increase in reaction time to 16 hours. Further studies are necessary toward recoverability and recyclability of this system.
Harvey, Natalie Laura (2015). I. Total Synthesis of (+)-Spongiolactone and Derivatives Enabling Initial Structure-Activity Relationship Studies: Discovery of a More Potent Derivative II. Studies Toward Recyclable Isothiourea Catalysts. Doctoral dissertation, Texas A&M University. Available electronically from