Gold(I)-catalyzed enantioselective addition and cycloaddition reactions

  1. Jaime Fernández Casado
Dirixida por:
  1. José Luis Mascareñas Cid Director
  2. Fernando José López García Director

Universidade de defensa: Universidade de Santiago de Compostela

Ano de defensa: 2018

  1. Diego A. Alonso Velasco Presidente/a
  2. Susana López Estévez Secretaria
  3. Pedro Miguel Pimenta Góis Vogal
  1. Departamento de Química Orgánica

Tipo: Tese


This Doctoral Thesis has been focused on the development of new gold(I)-catalyzed enantioselective addition and cycloaddition reactions. In particular, in the first chapter, dedicated to the development of enantioselective addition reactions, we describe the discovery of the first intermolecular reaction involving the synergistic combination of an enamine-mediated organocatalysis and a gold (I) catalyst. The process, which involves the alkylation of an aldehyde with an allenamide, affords aldehydes incorporating tertiary and even all-carbon quaternary α-stereocenters. While the reaction outcome is influenced by several parameters, we have found conditions that provide the products with moderate to good levels of enantioselectivity. In particular, we describe the development of an enantioselective variant of this reaction using a chiral organocatalyst derived from the commonly employed Hayashi-Jørgensen organocatalysts. Thus, the use of this chiral organocatalyst allowed the corresponding products to be obtained from moderate to quantitative yields and with enantioselectivities of up to 82% ee. The process has been applied to α-mono- and α-disubstituted aldehydes, bearing at least one aromatic ring. On the other hand, different carbonyl- or sulfonyl-allenamides were also suitable partners. From a mechanistic point of view, the gold(I) catalyst is proposed to activate the allenamide, leading to a zwitterionic intermediate that is trapped by the transient enamine, generated in situ from an aldehyde and the secondary amine organocatalyst. Moreover, we have studied by NMR and mass spectroscopy the role of certain additives, avoiding the deactivation of the gold(I) catalyst by coordination with the organocatalyst. In the second chapter, we describe the successful development of an enantioselective gold(I)-catalyzed (2+2+2) cascade cycloaddition between N-allenamides and alkenyl-oximes, a reaction that provides aza-bridged medium-sized bicyclic systems, such as tropanes and related azabicycles. For the development of the enantioselective variant, we performed a systematic study of different chiral gold complexes and reaction conditions. Moreover, we found that the structure of the allenamide and the type of oxime employed (alkyl vs acyloxy oxime) is key to achieve high levels of enantioinduction. Thus, selecting the appropriate chiral ligand, allenamide and oxime partner, enantioselectivities of up to 90% could be achieved. To sum up, this method constitutes one of the very first examples of the use of an oxime moiety in gold catalysis and one of the very few catalytic and enantioselective methods that allowed to build aza-bridged bicyclic systems from readily available acyclic starting materials.