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FP7

REMOTECAT Report Summary

Project reference: 622413
Funded under: FP7-PEOPLE

Final Report Summary - REMOTECAT (Asymmetric organocatalysts for remote functionalization strategies)

Many chemical processes would not occur — at least, not at a rate that has any practical application — without catalysts. Catalysts have thus become indispensable in a wide range of industrial reactions. However, the study of these systems can offer much more: it can change our understanding of fundamental chemical concepts and challenge us to rethink the “rules” of the chemical world. Research in the area of aminocatalysis moves at breathtaking speed: many catalytic reactions now considered “standard issue” by organic chemists were almost unthinkable just 10 years ago. The ability to synthesize and selectively modify small organic molecules is crucial for many applications, including drug discovery and the search for new materials. The development of new catalysts often makes it possible to generate previously unattainable compounds, which could have unique physical, chemical or biological properties.
The project entitled "Asymmetric organocatalysts for remote functionalization strategies" (REMOTEcat) consisted of an innovative proposal in the area of asymmetric organocatalysis tutorized by Prof. K. A. Jørgensen at the Department of Chemistry, Aarhus University, Denmark with the aim of covering the above challenges. The project has been scientifically based on aminocatalysis and merging transition-metal and aminocatalysis in a double-activation fashion for the discovery of new reactivity patterns. Research conducted during the execution of the REMOTEcat project led to positive results developing new remote functionalization strategies.
The first enantioselective formal [4+2] cycloaddition to 3-nitroindoles was reported applying organocatalysis. By the combination of 3-nitroindoles and 2,4-dienals with an hydrogen-bonding aminocatalyst, chiral dihydrocarbazole scaffolds were formed in moderate to good yields (up to 87%) and enantioselectivities (up to 97% ee) under mild reaction conditions. The novel reaction concept was demonstrated to also include enantioselective cycloaddition reactions for 3-nitrobenzothiophene providing the cycloaddition products in up to 98% ee. Synthetic manipulation of the chiral cycloadducts by a diastereoselective reduction of the olefin in the product was also presented. Mechanistic studies based on experimental observations and computational studies pointed towards an asynchronous/stepwise addition followed by an elimination step in which the hydrogen-bonding catalyst plays a pivotal role. The present development provides an alternative reaction concept for the cycloaddition reaction to 2,3-indolyne and 2,3-benzothiophyne, as the generation of these hetarynes have not yet been possible.
The first asymmetric γ-allylation of α,β-unsaturated aldehydes based on combined organo- and transition metal catalysis was reported. Whereas the employment of an iridium catalyst allows for selective access to both diastereomers of branched products in excellent regio- and stereoselectivities, the linear products can be accessed in good yields and excellent regio- and enantioselectivity by the application of a palladium catalyst. The developed method thus provides selective access to all six isomers of γ-allylated product in a divergent fashion by the application of the appropriate combination of aminocatalyst, transition metal catalyst and ligands.
A novel asymmetric [3+2] cycloaddition of vinyl cyclopropanes and α,β-unsaturated aldehydes was also disclosed. The reaction is promoted by synergistic palladium and organocatalysis and allowed for asymmetric formation of highly substituted cyclopentanes with up to four stereocenters in high yields and stereoselectivities. Notably, products containing a quaternary stereocenter could be formed. In addition, the reaction was shown to perform well on gram scale and the synthetic potential of the obtained products was evaluated.
The successful examples described above constitute innovative strategies in the field of aminocatalysis and synergistic catalysis to achieve remote functionalizations. Synergistic catalysis (e.g. aminocatalysis combined with transition metal catalysis) will continue to grow and be recognized as a powerful catalysis strategy. As the results of the REMOTEcat project exemplify, the synergistic interaction of two catalytic cycles brings several benefits, (a) introducing novel reactivity not attainable with a single catalyst; (b) improving existing reactions, often by suppressing side reactions; (iii) creating or improving stereocontrol through highly organized transition states.
The REMOTEcat project addressed fundamental questions for our understanding of organocatalytic processes and their application to the synthesis of key building blocks for the chemical and pharmaceutical areas. The outcomes of the project contributed to the European competitiveness in the competitive area of organocatalysis. Dissemination of project results was carried out in high impact peer-review chemistry journals. In addition, there is a favorable outlook that the synthetic methods developed could be transferred to the EU chemical industry (after further development, out of the scope of this project).
A deep understanding of the catalytic processes is crucial to increase the chances of designing new catalysts to control stereoselectivity. In addition, it also contributes to the development of a modern chemistry where toxicity issues are often minimized and the environmentally friendly, “green” aspect of organocatalysis coupled with the sustainability of these catalysts is considered widely for replacing standard chemical processes at industry level. Accordingly, transferable academic research to the private sector will contribute to generate and absorb new knowledge and boost innovation.
Project website: remotecat.blogspot.dk
Contact details: Prof. Dr. Karl Anker Jørgensen, e-mail: kaj@chem.au.dk; Dr. Fernando Tur, e-mail: espinosa@chem.au.dk

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Blach, Ulla (Project economist)
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Record Number: 187580 / Last updated on: 2016-08-12