ON THE MERITS OF STEREOSELECTIVE DESYMMETRIZATION REACTIONS IN THE ASSEMBLY OF COMPLEX NATURAL MOLECULES: THE TOTAL SYNTHESIS OF PACTAMYCIN AND PASPALINE Public Deposited

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  • March 19, 2019
Creator
  • Sharpe, Robert
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • I. Asymmetric Synthesis of the Aminocyclitol Pactamycin, a Universal Translocation Inhibitor A concise, enantioselective synthesis of the aminocyclopentitol natural product pactamycin is presented. The critical feature of this approach was the execution of an asymmetric Mannich reaction and symmetry-breaking diketone monoreduction to assemble the C1, C2, and C7 relative stereochemistries early in the route, enabling facile construction of the remaining core functionalities. A remarkable series of serendipitous stereochemical outcomes ensued in the sequence that followed, ultimately providing the title compound in fifteen steps from the commercially available 2,4-pentanedione, constituting the shortest reported synthesis to date. The development and evolution of this synthetic strategy is thoroughly detailed, and an analysis of observed outcomes is presented. This synthesis was designed to immediately enable the facile preparation of structural analogs for the purposes of structure-activity relationship investigations. II. Preparation and Biological Evaluation of Synthetic and Polymer-Encapsulated Congeners of the Antitumor Agent Pactamycin: Insight into Functional Group Effects and Biological Activity Using the previously described total synthesis of pactamycin as a platform for synthetic diversity, twenty-five unique synthetic congeners of the natural product have been prepared to provide greater understanding into the source of pactamycin’s biological profile. Specific attention was given to the production of synthetic derivatives at the branch points of pactamycin’s unique functional groups (i.e. aniline, salicylate, and dimethylurea). In addition, the encapsulation of pactamycin and its derivatives into the PRINT© technology was demonstrated. This work has provided unprecedented access to a large number of pactamycin synthetic congeners, and subsequent in vitro analysis of the prepared compounds revealed a number of insights into the source of pactamycin’s activity. III. Inception and Development of a Global and Local Desymmetrization Approach to the Synthesis of Steroidal Alkaloids: Stereocontrolled Total Synthesis of Paspaline. An enantioselective synthesis of the indole diterpene alkaloid paspaline is described. Key features of this synthesis included the execution of both “global” and “local” desymmetrization reactions to enable expedient assembly of challenging quaternary centers in the core structure. A complete account of the conception and development of this approach is described, and an analysis of desired (and undesired) outcomes is provided. The described route affords a new conceptual blueprint for installing challenging stereocenters in this family of molecules, and the steps contained therein provide the synthetic community with complimentary disconnections in the arena of steroid natural product synthesis.
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  • In Copyright
Advisor
  • Johnson, Jeffrey
  • Brookhart, Maurice
  • Meek, Simon
  • Crimmins, Michael T.
  • Gagne, Michel
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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