Discovery of the trifluoroacetate release process and its strategic application toward the synthesis of biologically active molecules

Changho Han, Purdue University

Abstract

The natural product parthenolide is a sesquiterpene lactone isolated from the anti-inflammatory medicinal herb, Ferverfew (Tanacetum parthenium). Although parthenolide shows selective cytotoxicity toward drug-resistant multiple myeloma cancer stem cells, its low potency and poor aqueous solubility limited its potential in clinical trials. We have taken a number of approaches to improve its potency and water solubility. The incorporation of fluorine into biologically active molecules is a known strategy that can be used to enhance bioavailability. Therefore, one of our approaches was to introduce fluorine into parthenolide. However, due to its structural complexity, exceedingly mild, efficient, and high-yielding reaction conditions were needed. Our efforts to incorporate fluorine atoms on parthenolide lead us to design a novel synthetic methodology to generate α,α-difluoroenolates via releasing trifluoroacetate by mimicking nature's hydrolytic C-C bond cleavage strategy. We have shown the synthetic utilities of our novel methodology by reacting generated α,α-difluoroenolates with various electrophiles. We further expanded the synthetic versatility of trifluoroacetate release process by generating other reactive intermediates, such as gem-difluoro carbanions. With the aryl pentafluoro gem-diol system, the competitive path has been extensively investigated. The results of this study led us to apply our methodology toward the synthesis of metabolically stable anthocyanin derivatives. Among the many anthocyanins, we aimed to synthesize metabolically stable analogues of malvidin 3-glucoside because it has shown a relatively strong neuroprotective effect compared to other anthocyanins.

Degree

Ph.D.

Advisors

Colby, Purdue University.

Subject Area

Chemistry|Biochemistry

COinS