CORDIS - EU research results

Exploring Chemical Reactivity with Organocatalysis

Final Report Summary - ORGA-NAUT (Exploring Chemical Reactivity with Organocatalysis)

The ORGA-NAUT project aimed at devising strategies to address a fundamentally important issue in enantioselective reaction design: the control of remote stereochemistry. Today, synthetic chemists can address even the most daunting of challenges connected with the asymmetric catalytic functionalisation of carbonyl compounds at their α and β positions. In contrast, there are no known general strategies for the corresponding direct, catalytic and enantioselective transformation to a carbonyl group at more remote positions. In the initial phase of our investigations, we have demonstrated how the fruitful combination of asymmetric aminocatalysis (a versatile chemical strategy whose potential has not yet been fully explored) with the principle of vinylogy (the transmission of electronic effects trough π-conjugated systems) could address this synthetic issue, expanding the chemists’ ability to functionalise a carbonyl compound at the γ-, δ-, and ε-carbon atoms with high stereoselectivity.
In addition, we have combined asymmetric aminocatalysis with photoredox catalysis driven by visible light. The recent emergence of photoredox catalysis has demonstrated that inorganic photoredox catalysts, opportunely excited with visible light, allow access to open-shell radical species that participate in bond constructions that are unavailable using amine organocatalysis alone. In this way, even α-functionalisations of aldehydes, which have been considered impossible, become a reality. Inspired by these studies, I sought to apply this activation concept to the asymmetric γ-functionalisation of unsaturated carbonyl compounds. In the course of these investigations, the ORGA-NAUT team has found a very simple method for accessing open-shell radical species without the need for expensive photoredox catalysts. To achieve this, we exploited the ability of chiral enamines to actively participate in the photo-excitation of substrates by inducing the transient formation of photon-absorbing ground-state chiral electron donor-acceptor (EDA) complexes with alkyl halides of high electron affinity. This offered the possibility of addressing a sought-after problem in the realm of enantioselective photochemistry, providing an unprecedented yet simple strategy to control the stereochemical outcome of catalytic photochemical reactions driven by visible light (Nature Chem. 2013, 5, 750-756).
To corroborate the idea that the photochemistry of enamine-induced EDA complexes may provide a general reactivity framework for conceiving other enantioselective catalytic photoreactions, we translated this strategy to develop the first asymmetric catalytic perfluoroalkylation of unmodified enolates (J. Am. Chem. Soc. 2015, 137, 5678–5681). Recently, we have further expanded our approach to the chemistry of iminium ions in order to forge quaternary carbon stereocentres, an achievement that has found publication in Nature 2016, 532, 218–222.
Overall, during the ORGA-NAUT we have found a bridge (the donor-acceptor interactions) to connect two powerful fields of molecule activation: asymmetric organocatalysis and photochemistry, challenging the current perception that photochemistry is too unselective to parallel the impressive levels of efficiency reached by the asymmetric catalysis of thermal reactions. Our strategy differs from but complements the approach of photoredox catalysis, a fast developing area of modern chemical research. On this basis, our findings have the potential to immediately impact the organic chemistry community, particularly when considering the universal need for more sustainable and environmentally responsible chemical processes.