from gold to silver: streamlining metal-catalysed cross-coupling reactions

Informations projet

silvercatpharma

N° de convention de subvention: 658256

DOI

10.3030/658256

Projet clôturé

Date de signature de la CE 23 Mars 2015

Date de début 1 Avril 2015

Date de fin 31 Mars 2017

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 158 121,60

Contribution de l’UE

€ 158 121,60

Coordonné par

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 1 - silvercatpharma (from gold to silver: streamlining metal-catalysed cross-coupling reactions)

Période du rapport: 2015-04-01 au 2017-03-31

Résumé du contexte et des objectifs généraux du projet

SILVERCATPHARMA project aims at developing reactions for the formation of new carbon-carbon bonds catalyzed by d11-blocks metals and their application to pharmaceuticals in Novartis. The importance of the project lies on the fact that this reaction is pivotal for the construction of new molecules of different entities and great efforts should be put in order to find methodologies that allow the construction of new carbon-carbon bonds in a cheap and environment friendly manner.

The development of reactions within the context of SILVERCATPHARMA represents the basis for the synthesis of bioactive molecules in Novartis; in the future these compounds can be potential candidates for the treatment of important diseases and so be the foundation for treatments that will reach thousands of people. In so doing we desire to show how basic research, such as the use of d-11 blocks metals in synthesis, plays a pivotal role for the disclosure of new molecules that can have a future effect on the population.

SILVERCATPHARMA takes into account the important of the formation of new carbon-carbon bonds at an industrial level. For this reason it aims at the design of new metal-catalysed C-C reactions under mild conditions through the exploitation of small nanoclusters. The use of gold in this sense will help in to understand of the basic reactivity principles. Then, the attention will move onto gol-silver clusters as potential catalysts for the above mentioned reactions. Gold nanoclusters are a promising class of model catalysts. They will provide new opportunities for the comprehension of metal nanocatalysis and for the new design of highly selective catalysts for specific chemical processes. The possibility of a rational design of gold and silver clusters for the synthesis of fine chemicals represents a way to optimize the outcome of reactions.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Gold nanoclusters are a promising class of model catalysts. They can provide new opportunities for the comprehension of metal nanocatalysis and for the new design of highly selective catalysts for specific chemical processes. Silvercatpharma goal was a rational design of gold and silver clusters for the synthesis of fine chemicals. We succeeded in the synthesis and characterization of one gold cluster: its reactivity was tested in the rearrangement of an enyne in order to verify its reactivity in the formation of new carbon-carbon bond. The test was successful so we moved to the [2+2] cycloaddition reaction. Of particular interest is its use for the synthesis of cyclobutane and cyclobutene rings. Because of the tremendous interest in the fields of medicinal chemistry and material science, a scantiness of methods for the construction of cyclobutanes has been revealed, particularly in comparison to its larger homologues. Moreover the cyclobutane moiety recurs in nature, such as in alkaloids, terpene-derived compounds and marine natural products like dictazoles. Unfortunately the Ag-Au cluster previously synthesized failed to give the desired product which was instead efficiently obtained using only gold as catalyst. The implemented methodology was finally applied to the synthesis of two natural products, rumphellaone and hushinone.
In conclusion, we were still able to promote a [2+2] cycloaddition reaction promoted by gold and we demonstrated its usefulness in the total synthesis of two natural compounds, rumphellanone and hushinone. These results were made visible by:

High impact publications (the last one just submitted).

- Synthesis of Rumphellaone A and Hushinone by a Gold-Catalyzed [2+2] Cycloaddition
Org. Lett. 2016, 18, 1614-1617.
- Enantioselective Synthesis of Cyclobutenes by Intermolecular [2+2] Cycloaddition with Non-C2 Symmetric Digold Catalysts (submitted)

A review article was also published:

- Anatomy of gold catalysts: facts and myths
Org. Biomol. Chem. 2015, 13, 7103-7118.

Oral and written presentation in international congresses:

1. OMCOS, June 28th- July 2nd 2015, Sitges- Barcelona, Spain (poster).
2. 24th International Symposium: Synthesis in Organic Chemistry, July 20th-23rd 2015, Cambridge, UK (poster).
3. IKCOC-13, November 9th-13th 2015, Kyoto, Japan (oral presentation).
4. Gordon Research Conference on Natural Products & Bioactive Compounds, July 31st-August 5th 2016, Proctor Academy in Andover (NH), United States (poster).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

"With the work done within SILVERCATPHARMA, we were finally able to introduce a new methodology for the efficient construction of new carbon-carbon bond via [2+2] cycloaddition reaction. This methodology paves the way for a more ""atom economic"" and so ""environment-friend"" type of chemistry. As a proof of these concepts, we provided a short and efficient synthesis of two natural compounds, namely rumphellaone A and hushinone: they represent a remarkable advance considering the improvement of efficiency with respect to the previous reported synthesis (number of steps for synthesising the molecules and reactions yield). Moreover, we are currently reporting a unprecedented asymmetric reaction promoted by gold for the construction of the above mentioned natural products (manuscript accepted and currently under revision).

The interest on this catalysis does not belong only to academic settings but industrial as well, as witnessed by the work carried out in Novartis (ongoing projects, still not completed): two molecules have been synthesised and they are currently subjected to in vivo and in vitro studies. Moreover, this industrial interest can result in the application of the chemistry for the synthesis of biologically active compounds. This industrial interest and application is still at is infancy and beneficial and broad effects will be seen in the due course."

visual abstract of the publication