A Unified Approach for the Total Synthesis of C10-functionalyzed Lycopodium Alkaloids PDF Download

Author: Mrinmoy Saha
Publisher:
ISBN:
Category : Alkaloids
Languages : en
Pages : 451

Get Book Here

Book Description
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.