Mayotlide: synthetic approaches and structural elucidation

• Autores: Jesús Herraiz Cobo
• Directores de la Tesis: Fernando Albericio Palomera (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2017
• Idioma: español
• Tribunal Calificador de la Tesis: Amadeu Llebaria Soldevila (presid.), Marta Planas Grabuleda (secret.), Rogelio Fernández Rodríguez (voc.)
• Programa de doctorado: Programa de Doctorado en Química Orgánica por la Universidad de Barcelona
• Materias:
  • Química
    • Química analítica
      • Espectroscopia de resonancia magnética
      • Espectroscopia de masas
    • Bioquímica
      • Péptidos
    • Química orgánica
      • Compuestos heterocíclicos
• Enlaces
  • Tesis en acceso abierto en:  Dipòsit Digital de la UB  TDX 
• Resumen

  • Mayotlide is a marine peptide isolated by PharmaMar S.A. from Spongia sp.. The sequence of the aminoacids were achieved by MS-MS spectrometry, where two of them were tryptophans. The NMR spectroscopy revealed the presence of N1-C3a bond between the tryptophans, which means that one of them was cyclized. On the first structure proposal, the aminoacids were forming two macrocyclic rings: on the ring B, all the aminoacids of molecule were tied by amide bond, remarking the presence of the cyclized tryptophan as a hexahydropyrroloindole unit (HPI). The ring A was established by three aminoacids of the ring B: one tryptophan, one isoleucine and the HPI, which became closed by the N1-C3a bond between the two tryptophans. The aminoacid analysis demonstrated the L configuration of all of them, just remaining the HPI with unknown stereochemistry.

    Due to the configuration of the HPI system, there can be four diasteromers. To the best of our knowledge, there were not empirical evidences about which one could be more favorable. Hence, a computational study of the ring A through the MOE program was performed, evidencing that the rings A with the exo HPI adducts (L and D) were more stable than the endo ones. Among the exo ones, another computational study with the whole molecule revealed that the mayotlide with the exo-L adduct of the HPI was more stable.

    Once that there was established a starting point with the HPI, it was necessary to find out a synthetic strategy that could fulfill the necessary requirements. A methodology developed by Baran and coworkers for the synthesis of the Trp-HPI fragment on molecules related to mayotlide was adapted to our proposal. On the first step of this strategy, under reaction conditions, the starting tryptophan cyclizes, providing exclusively the HPI with the exo configuration, at the same time that the N1-C3a bond between the HPI and 2-iodoaniline is formed. The 2-iodoaniline, along with a disubstituted alkyne, condense together yielding the upper tryptophan without loss of the former stereochemistry, reaching the Trp-HPI framework in two steps with high yields.

    Taking advantage of this methodology and an appropriate use of the protecting groups in order to perform the corresponding cyclizations of the two macrocyclic rings, the mayotlide with the exo-L HPI was accomplished. Nevertheless, nor the NMR neither the MS-MS pattern of the final compound coincided with the natural product ones. Thus, the next alternative would consist on repeating the synthesis but with the exo-D adduct of the HPI instead.

    During the last synthesis, the bibliography and the analytical data of the natural product were extensively revised. There were no documented precedents of natural peptides with the Trp-HPI motif, and the initial structure did not justify the most important data extracted from the MS-MS. the main fragmentation concerned to the isoleucine, and on the first proposal such aminoacid was not forming part of a conflictive scaffold. Likewise, among the eight proposed linear sequences for the ring B, the isoleucine just appear in one as C-terminus of the b-ions, when it is one of the aminoacids that forms part of both macrocycles.

    The most related family of peptides to mayotlide are the kapakahines. Kapakahines, instead of having a Trp-HPI moiety as the central part of the molecule, exhibit a Trp-α carboline, with an aminoacid establishing the bridge for a very tensioned tetracyclic system. Such structure may justify the isoleucine fragmentation pattern, but on the other hand the sequence of the aminoacids did not fix. It was necessary to invert the central sequence of the aminoacids to reach out a final structure proposal which justifies all the requirements, relabeled as “kapakahine H”.