Flexible approach to stemona alkaloids: Total syntheses of (-)-stemospironine and three new diastereoisomeric analogs

• Autores: Núria Bardají Valls
• Directores de la Tesis: Félix Busqué Sánchez (dir. tes.), Marta Figueredo Galimany (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2013
• Idioma: inglés
• Materias:
  • Química
    • Bioquímica
      • Alcaloides
• Enlaces
  • Tesis en acceso abierto en:  TESEO  TDX  DDD 
• Resumen

  • FLEXIBLE APPROACH TO STEMONA ALKALOIDS: TOTAL SYNTHESES OF (-)-STEMOSPIRONINE AND THREE NEW DIASTEREOISOMERIC ANALOGS The extracts of several plants of the Stemonaceae family have long been used in Asian countries against different diseases and for their antiparasitic properties. Significant constituents of these extracts are a series of structurally related secondary metabolites named as Stemona alkaloids. All the Stemona alkaloids are polycyclic and most of them present a central pyrrolo[1,2-a]azepine system as a characteristic structural feature. The majority also incorporate at least one substructure of alpha-methyl-gamma-butyrolactone. Our research group designed a strategy in which the pyrroloazepine system is generated at an early stage of the sequence and the other specific fragments are then incorporated, with the aim of developing a flexible approach, with some intermediates being common precursors for various alkaloids. The typical pyrroloazepine core is synthesized through a 1,3-dipolar cycloaddition reaction between a chiral nitrone and an electrondeficient olefin.

    In this thesis, the syntheses of stemospironine and three new diastereoisomeric analogs, 116, 119 and 120 have been achieved. Thus, spirolactonization in the key intermediate 62 was accomplished by esterification of the tertiary alcohol followed by basic treatment of the phosphonate 86, yielding lactone 63. After removal of the silyl protection, the alcohol was oxidized, and the corresponding aldehyde was treated with ethyl bromomethylacrylate and zinc furnishing a 1:1 mixture of bislactones. Once the hydrogenation of C-C double bonds was accomplished, each bislactone was converted to amines 116 and 120, respectively. On the other hand, spirolactonization of 125 furnished an unsaturated lactone, which was hydrogenated to yield 127. A stereoselective ¿-methylation rendered the stemospironine-like configuration at C11. Then, the remaining transformations were performed as before, affording stemospironine and its analog 119. The analytical data of the synthetic stemospironine are in total agreement with those described for the natural alkaloid.

    References:

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