Efforts in Natural Product Total Synthesis via Dearomatization of Functionalized Arenes: I. Tetrodotoxin and II. Veratrum Alkaloids

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  • Robins, Jacob Gabriel
    • College of Arts and Sciences, Department of Chemistry
Abstract
  • I. Efforts Towards the Total Synthesis of (–)-TetrodotoxinA masked ortho-benzoquinone was used in a highly diastereoselective acylnitroso hetero-Diels-Alder [4+2] cycloaddition to forge the fully substituted syn 1,4-aminocyclohexanol motif embedded in the complex bioactive natural product tetrodotoxin. Multiple advanced intermediates en route to the target molecule were prepared but efforts to complete the total synthesis were thwarted by difficulties in a late-stage ketone homologation or in guanidinylation of a neopentylic amine. II. Hydroxyphosphonate-Enabled Tandem Phosphono-Adler-Becker Oxidations/Hetero-Diels-Alder Cycloadditions: Progress Towards the Total Synthesis of TetrodotoxinA heretofore unknown phosphono-Adler-Becker oxidation of dialkoxyphosphinylsalicyl alcohols was performed in tandem with an acylnitroso hetero-Diel-Alder [4+2] cycloaddition to construct complex oxazinanes. This synthetic strategy enables the use of “salicylaldehyde diene” equivalents following phosphite extrusion to reveal an aldehyde. Efforts to assemble a functionalized arene that would intercept this chemistry en route to tetrodotoxin are also reported. III. De Novo Synthesis of the DEF Stereotriad Core of the Veratrum AlkaloidsA convergent approach towards the synthesis of the Veratrum alkaloids is presented. The alkaloid-like tricyclic core common to jervine and cyclopamine was stereoselectively and efficiently prepared from cheap and readily available reagents. By analogy to the biosynthetic aromatization of cyclopamine to veratramine, a two-directional bicyclization was achieved wherein a functionalized phenol used to generate the D ring.
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  • In Copyright - Educational Use Permitted
Advisor
  • Johnson, Jeffrey S
  • Meek, Simon J
  • Aubé, Jeffrey
  • Wilkerson-Hill, Sidney M
  • Bowers, Albert A
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2021
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