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  • March 19, 2019
  • Bender, Trandon
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Selective modification of complex molecular scaffolds in the form of carbohydrates and natural products in a controllable way is a long-standing challenge. In carbohydrates, this problem results from the difficulty of activating carbon oxygen (C–O) bonds that are similar in reactivity making it difficult to differentiate between which bonds are activated. Natural products present a completely unique challenge in that they often contain disparate functional groups that present cross reactivity issues making activation of a natural product in a controllable way challenging. Each presents its own challenge, but the ability to perform selective modification of carbohydrates and natural products offers new routes to valuable chiral synthons from a renewable source and the opportunity to create new chemical space in molecular scaffolds that are often mined for biologically active drug candidates, respectively. Fluoroarylborane-based catalysts (such as B(C6F5)3) are uniquely capable in this regard as they heterolytically activate Si–H bonds to generate an oxophilic silylium (R3Si+) equivalent along with a reducing borohydride (H–BR3–). Although silylium ions are notoriously oxophilic and aggressive electrophiles that would seemingly be a poor choice for carrying out selective chemistry on a complex molecule, much less one with diverse (often oxygenated) functionality, together these components enable the selective activation and reduction C–O bonds in carbohydrates and complex natural products. Imperative to the selective deoxygenation of carbohydrates was the realization that selective neighboring group participation results in chemoselective formation of cyclic intermediates which are reduced with high diastereoselectivity to generate chiral synthons. With the observation that cyclic intermediates guide selective activation in polyoxygenated substrates, we expanded this application to include selective allylic C–O bond reduction in linear styryl-carbohydrates which also relied on cyclic intermediates to achieve high levels of selectivity. Ultimately, neighboring group participation in styryl-carbohyrates was harnessed to realize carbon-carbon bond formation to generate carbocycles in a highly diastereoselective fashion where cyclic intermediates are again implicated in the highly selective transformations. Investigating fluroarylborane-based catalyst activation of natural products required that addition of an exogenous phosphine Lewis base to modify the catalyst speciation and enable aggressive silylium ions to be harnessed for the selective modification of natural product scaffolds. Importantly, manipulation of the catalyst, the silane reagent, and the reaction conditions provide good control over which (and how) the functional groups are modified. The application of this methodology on complex bioactive compounds (natural products or drugs) thus provides a powerful tool for assessing how structural diversifications of these bioactive compounds correlates with bioactivity.
Date of publication
Resource type
Rights statement
  • In Copyright
  • Miller, Alexander
  • Brookhart, Maurice
  • Gagne, Michel
  • Templeton, Joseph
  • Brustad, Eric
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017

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