Graduate Thesis Or Dissertation
 

A unified approach for the total synthesis of C₁₀-functionalyzed Lycopodium alkaloids

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  • Lycopodium alkaloids have shown widespread and noteworthy biological activity, consisting of over 250 known natural products. Moreover, their structural complexity and diversity have attracted considerable attention from numerous laboratories including our own. Recently, we have developed a unified approach that would provides access to numerous, previously unprepared C₁₀-functionalized lycopodium alkaloids. The first enantioselective total syntheses of all C₁₀-hydroxy lycopodium alkaloids have been accomplished. We have also made a significant progress towards himeradine A and other C₁₀-functionlyzed pentacyclic lycopodium alkaloids. Key steps in the synthetic sequence towards C₁₀-hydroxy lycopodium alkaloids include construction of six-membered ring using an organocatalyzed intramolecular Michael reaction, formation of tricyclic skeleton using a conformationally accelerated Mannich reaction and a tandem Oppenauer oxidation / aldol condensation cascade reaction to form the tetracyclic skeleton of the natural products. A proline sulfonamide catalyst has been explored and expanded for the intramolecular Michael reaction for the construction of common six-membered ring for all the C₁₀-functionalized lycopodium alkaloids. During our endeavor towards the sis- membered ring formation it was observed that rate of the Michael reaction and conversion to product increases dramatically in presence of the proline sulfonamide catalyst. The effect of C₁₀ stereochemistry (both R and S) was also explored in the Michael reaction and (R)-C₁₀-epimer proved to give better diastereoselectivity during the process. A conformationally accelerated, intramolecular Mannich reaction route was utilized to the tricyclic skeleton of all C₁₀-hydroxy lycopodium alkaloids to construct C₄- C₁₃. During the Mannich reaction the effect of C₁₀ stereochemistry was explored as well and it was found that C₄-C₁₃ bond could only be formed with (R)-C₁₀-epimer. In addition, protecting group on C₁₀ alcohol has significant effect on the intramolecular Mannich reaction. We have accomplished the first enantioselective total synthesis of 10-hydroxylycopodine, deacetylpaniculine and paniculine. During our endeavor towards these natural products we have utilized an Oppenauer oxidation/aldol condensation cascade reaction to form the tetracyclic skeleton from the tricyclic intermediate. We have reported the first fully characterized NMR data for 10-hydroxylycopodine and optical rotation data for all the C₁₀-hydroxy lycopodium alkaloids. Key aspects towards the C₁₀-functionalyzed lycopodium alkaloids are Mander’s reagent -mediated one carbon homologation, a tandem sulfone rearrangement / intramolecular Mannich cyclization to form the key tricyclic skeleton and synthesis of the advanced C₁₀-alcohol intermediate towards the western portion of himeradine A. Additionally, the western portion of himeradine A will serve as the common intermediate towards related pentacyclic C₁₀-functionalyzed lycopodium alkaloids. During the synthesis of the tricyclic C₁₀-alcohol, several routes have been explored to functionalize the C₄ center and finally the Mander’s reagent strategy successfully installed the C₃ ester. A significant tricyclic skeleton towards the pentacyclic C₁₀-functionalyzed lycopodium alkaloids was achieved through utilization of a tandem 1,3-sulfone rearrangement/intramolecular Mannich reaction as the key steps. Polymer supported PPh₃ was utilized to improve the yield of the Aza-Wittig / Mannich reaction sequence. We have discovered that the incorporation of the methyl-protecting group on C₅-enol and reduction of the C₃ ester to alcohol was necessary in order to successfully facilitate the C₁₄-desulfurization.
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