Synthesis of a malvidin-3-glucoside derivative with a difluoromethylene linkage

Robert A Hazlitt, Purdue University


Neurodegenerative diseases represent an enormous social and economic burden, with Alzheimer’s disease being at the top of the list, with a global cost of $604 billion per year. Substantial efforts in the understanding of neurodegenerative diseases have produced compelling evidence that oxidative stress is one of its primary causes. Of the antioxidants found in nature, anthocyanins are among the most potent. In particular, malvidin-3-glucoside has exhibited exceptional potential as a neuroprotective agent in vitro. However, upon entering the body, it is rapidly metabolized through cleavage of its weak glycosyl linkage and the resulting aglycone is unable to cross the blood-brain barrier in an appreciable level to elicit its antioxidative effects. Therefore, metabolically stable derivatives are needed in order to investigate the potential of the anthocyanin as a neuroprotective agent in vivo. We hypothesize that the oxygen of the labile glycosyl linkage could be replaced with a difluoromethylene bioisostere to furnish a hydrolytically stable derivative. Generally, the most straightforward method to install an internal difluoromethylene is through the nucleophilic addition of a difluoroenolate to an electrophile. A mild and effective method to generate difluoroenolates by the release of trifluoroacetate from α-keto pentafluoro gem-diols has been developed by our lab. We plan to use this methodology in the synthesis of a malvidin-3-glucoside derivative with a difluoromethylene linkage. The key intermediate in the synthesis, an α-keto pentafluoro gem -diol glucose derivative, has been accessed by two different synthetic routes, and a new, more efficient method to prepare pentafluoro gem -diols has been developed. In addition, the pentafluoro gem-diol intermediate has been used to demonstrate the utility of the trifluoroacetate release methodology by extending it to more complex molecules through the synthesis of the first CF2Br-glucopyranose and a difluoromethyl ketone derived from glucose. Recent work from our lab has shown that electron deficient α-aryl pentafluoro gem-diols undergo fragmentation to generate difluoroanions through the release of trifluoroacetate. In order to investigate the applicability of the method to more complex substrates, a pentafluoro gem-diol derived from flavene has been prepared and its fragmentation has been studied. In addition, the flavene derivative will be used to prepare a pentafluoro gem-diol flavone derivative, which will be used as the key intermediate in an alternative synthesis of a malvidin-3-glucoside derivative with a difluoromethylene linkage.




Wei, Purdue University.

Subject Area

Biochemistry|Organic chemistry

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