Graduate Thesis Or Dissertation

 

Part I: Synthetic Studies toward C10-functionalized Lycopodium Alkaloids. Part II: Exploration of the Pummerer Cyclization and Its Application to the Total Syntheses of the Abietane Diterpenoids Public Deposited

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/zk51vn87w

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  • This dissertation is separated into two parts according to the two major distinct research projects. In Part I, the full account of synthetic studies toward C10-functionalized lycopodium alkaloids is described. In Part II, the detailed discussion on the exploration of the Pummerer cyclization methodology and its application to the total synthesis of the abietane diterpenoids is presented. In the first part of this dissertation, total synthesis of lycopodium alkaloids containing the challenging C4-C10 bond with C4 all-carbon quaternary center was explored. In close collaboration with Dr. Mrinmoy Saha, multiple steps in the existing route have been further optimized such as the sulfone-ester coupling reaction and the ketal hydrolysis reaction. Selective desilylation was achieved under neutral conditions. Next, the Zn(OTf)2 promoted Mannich cyclization constructed the key tricyclic core with C3 unit. The critical C4-C10 bond formation through radical cyclization was explored as well. In the 2nd generation approach, the substrate-controlled Michael cyclization was systematically investigated to afford high yield and diastereoselectivity. A comprehensive explanation on the conformationally accelerated intramolecular Mannich cyclization was also performed. At last, the 2nd generation total synthesis of C10-oxygenated lycopodium alkaloids was accomplished with improved yield and efficiency. In the second part of this dissertation, different aspects of Pummerer cyclization were studied which led to expanded scope for viable substrates, especially for substrates with β-hydrogens (relative to the sulfoxide). Two sets of the divergent reaction conditions (TFAA, 1,2-DCE, 4 h; then add BF3•Et2O, 36 h versus TFAA, 1,2-DCE, 30 min; then add BF3•Et2O, TfOH, 7 h) were discovered and led to cyclized sulfides and eliminated tricycles correspondingly. Furthermore, the in-depth mechanism study (e.g., controlled experiments, quenching experiment and NMR monitoring) unearthed the two unique pathways, vinyl sulfide and acyl oxonium ion pathways, which provide a better understanding of Pummerer mechanism. The application of this Pummerer methodology to the aromatic abietane diterpenoids is described. The newly developed Pummerer cyclization enabled rapid access to the polyfunctionalized tricyclic skeleton. In addition, a non-oxidative Pummerer rearrangement was unearthed that directly converted a benzylic sulfoxide to benzylic alcohol. The hybridization-controlled stereoselective alkylation correctly set the C4 stereochemistry. At last, the enantioselective total syntheses of multiple abietane diterpenoids (ent-triptobenzene T, vitexifolin C, hinokiol, 4-epi-triptobenzene L, triptobenzene L, and nepetaefolin F) was accomplished using a unified, common intermediate approach strategy.
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  • Milton Harris Fellowship
  • National Science Foundation
  • David P. Shoemaker Fellowship
  • Tarter Fellowship
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  • Ongoing Research
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  • 2019-02-08 to 2020-03-08

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