Periodic Reporting for period 1 - ORGANO-GOLD CAT (Merging organo- and gold-catalysis to design cascade reactions: a shortcut toward molecular complexity)
Reporting period: 2015-06-01 to 2017-05-31
comprising optimal chiral molecules that increase the probability of success in identifying drug-candidate structures. The proposed research aims to develop conceptually innovative catalytic methods to rapidly generate, in one single step,
architecturally complex chiral natural-like compounds. Natural products have been selected in evolution and their underlying structural scaffolds define biologically relevant fractions of chemical space. Consequently, compound libraries inspired by
natural structures deliver lead candidates with a higher hit-rate than conventional lead generation strategies.
More specifically, the goal of the research project is to combine the potential of asymmetric organocatalysis and gold catalysis, powerful fields of molecule activation, to find cost-effective synthetic
methods for reproducing the rich structural diversity of natural molecules. The resulting synthetic library constitutes an ideal starting point for biological screening carried out in collaboration with a world-wide
recognized pharma-company (Lundbeck A/S), will increase the probability of success in identifying drug-candidat estructures.
The development of the proposed research encoutered a very moderate succes, and the combination of two distinct catalytic cycles proved much more challenging than expected. As a consequence, it has been impossible to access the targeted library of complex molecules in an enantiopure
form, as requiered for biological screening, menaing the impossibility of conducing test and lead optimisations as initially planned with Lundbeck A/S, our industrial partner.
Among the different transformations proposed in the project, none could be succesfully implemented due to inherent problems of reactivity, and apparent incompatibility of the
two catalytic systems. In ths context, it has been envisionned to modify the catalytic system, by changing from gold to other metals able to play a similar role, such as silver, platinum, copper or palladium.
However, only traces of the desired complex molecules could be isolated with low enantiomeric excess when other metals were used, showing the challenging nature of the project.
A second approach has then been studied, relying on the use of covalent organocatalysis (primary and secondary amine catalysis) instead of its non-covalent version.
Disapointingly, this new approach did not prove more successful, and in this case, none of the targeted transformations could be achieved. Deeper studies highlighted the
lack of reactivity of aminocatalitically generated enamines and poly-enamines with 2-alkynyl-enones in the presence of either gold or other metal complexes.
The targeted library of complex chiral furan-based molecules could not be prepared, meaning that it could not be exploited in collaboration with the industrial partner.
During this period, in order to secure some publications, the study of a new concept in organocatalysis has been decided in agreement with all the partners, based on the use of visible light to activate organocatalytically generated
chiral iminium ions, allowing for the enantioselective catalytic beta-alkylation of enals, a very challenging transformation never achieved through classical polar chemistry.
This study constitutes a proof of concept that iminium ions could be synthetically used in their excited state, and opens new opportunities for developping unprecedented transformations.
The high quality of the research developped allowed its publication in one of the very best journal dedicated to chemical research (Nature Chemistry, 2017, DOI: 10.1038/nchem.2748).
Furthermore, this article was highlighted in Chemistry World (https://www.chemistryworld.com/news/new-organic-catalysts-mimic-vertebrate-vision/3007066.article) and Chem (Chem, 2017, 2, 616-618), providing an additional worlwide visibility to the research carried out thanks to the horizon 2020 program. Finally, thanks to the MSCA funding, the results obtained have been disseminated through communications in several national and international symposium, as two posters and three oral communications: ESOC 2015 in Lisbon, XXVI reunión Bienal de Quimica Organica 2016 in Huelva, JCO 2016 in Paris, ISGC 2017 in La Rochelle.
- The synthetic challenge adressed by this finding offers a new way to create carbon-carbon bonds in an enantioselective and sustainable fashion, a central topic for the preparation of complex chiral molecules.
- As any new concept, it offers many opportunities for developping new chemical transformations difficult or impossible to achieve through conventional approaches, therefore broadening the whole toolbox of synthetic organic chemistry ans deeply impacting the worlwide scientific community.
- The very high level of publication of this finding (nature chemistry, impact factor 25.87) ensuring a worldwide visibility to the work supported by the horizon 2020 program, accounts for the excellence of the european scientific research.
- The new mode of activation of enals developped is expected to find applications for the rapid preparation of chiral bio-active molecules of interest for the society such as drugs.