Reacciones de metátesis e hidrotiolación como herramientas sintéticas para la obtención de compuestos con interés biológico

  1. Víctor Rojas Ocáriz
Supervised by:
  1. Alberto Avenoza Aznar Director
  2. Jesús Héctor Busto Sancirián Director

Defence university: Universidad de La Rioja

Year of defence: 2016

Committee:
  1. Francisco Javier Cañada Vicinay Chair
  2. Javier Carreras Pérez-Aradros Secretary
  3. Rosa M. López Álvarez Committee member
Department:
  1. Chemistry
Doctoral Programme:
  1. Programa Oficial de Doctorado en Química

Type: Thesis

Abstract

This thesis is focused on the study of reactivity of unsaturated systems, both alkenes and alkynes, to provide other more complex systems with a biological interest. For this purpose, metathesis and hydrothiolation reactions have been used as key steps. In the first part of this report, we performed a thorough study of the metathesis reaction on 7-azanorbornene systems. Ring rearrangement metathesis (RRM) in N-acyl-1-substituted-7-azanorbornene derivatives was carried out in different reaction conditions to achieve bicyclic lactams and a novel spirocyclic system with pyrrolizidine, indolizidine and pyrrole[1,2a]azepine substructures. In the second part, we applied the cross metathesis reaction (CM) to obtain a family of neoglycoaminoacid derivatives with a linker, which is generated in the CM process, and used to separate the sugar moiety of the amino acid residue. The conformational analysis of these new neoglycoconjugates showed the high flexibility of the carbohydrate moiety in comparison to the more restricted spatial arrangement of these carbohydrates in natural glycoaminoacids. Having in mind we were unable to make use of CM reaction employing N-acetyl-D-galactosamine (GalNAc), we decided to create the linker from hydrothiolation reaction, applied to alkenes (TEC) and alkynes (TYC). Depending on starting materials, the final compound can present one or two sugars on the side chain of the amino acid. Afterwards, these neoglycoaminoacids have been incorporated into an epitope of recognition of a mucin-like glycoprotein (MUC1) with the APDTRP sequence. Sugar moieties linked to backbone were not able to fix a specific conformation, as it was deduced from conformational analysis. Additionally, affinity studies between lectins and the neoglycoconjugates with a sole carbohydrate were carried out, showing that the new elongated compounds had a similar behavior than the observed in the natural epitope of serine. Finally, we were able to elucidate the X-ray structure of one of our neoglycopeptides associated with the scFV fragment of SM3 antibody.