Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - CATA-LUX (Light-Driven Asymmetric Organocatalysis)

Teaser

Visible light photocatalysis and metal-free organocatalytic processes are powerful strategies of modern chemical research with extraordinary potential for the sustainable preparation of organic molecules. However, these environmentally respectful approaches have to date...

Summary

Visible light photocatalysis and metal-free organocatalytic processes are powerful strategies of modern chemical research with extraordinary potential for the sustainable preparation of organic molecules. However, these environmentally respectful approaches have to date remained largely unrelated. The CATA-LUX project seeks to merge these fields of molecule activation to redefine their synthetic potential.
Light-driven processes considerably enrich the modern synthetic repertoire, offering a potent way to build complex organic frameworks. In contrast, it is extremely challenging to develop asymmetric catalytic photoreactions that can create chiral molecules with a well-defined three-dimensional arrangement. By developing innovative methodologies to effectively address this issue, CATA-LUX will provide a novel reactivity framework for conceiving light-driven enantioselective organocatalytic processes.
The project aims to translate the effective tools governing the success of ground-state asymmetric organocatalysis into the realm of photochemical reactivity, exploiting the potential of key organocatalytic intermediates to directly participate in the photoexcitation of substrates. At the same time, the chiral organocatalyst can ensure effective stereochemical control. This single catalyst system, where stereoinduction and photoactivation merge in a sole organocatalyst, serves for developing novel enantioselective photoreactions. In a complementary dual catalytic approach, the synergistic activities of an organocatalyst and a metal-free photosensitiser are combined to realise asymmetric variants of venerable photochemical processes, which have never before succumbed to a stereocontrolled approach.

The CATA-LUX proposal challenges the current perception that photochemistry is too unselective to parallel the impressive levels of efficiency reached by the asymmetric catalysis of thermal reactions, expanding the way chemists think about making chiral molecules. On this basis, our findings have the potential to immediately impact the organic chemistry community, particularly when considering the universal need for environmentally respectful chemical processes.

Work performed

The CATA-LUX project is developing in a very positive way. We have addressed all the milestones and the objectives originally planned for the first 30 months of activities, including the more challenging ones. CATA-LUX is divided into two Incubator Projects and aims to deliver conceptually novel strategies for efficiently making chiral molecules using light.
The main target of the Incubator Plan 1 (Tasks 1-4) was to establish the potential of key organocatalytic intermediates to directly participate in the photoexcitation of substrates without needing an external photosensitiser. At the same time, the chiral organocatalyst ensures effective stereochemical control. The resulting single catalyst system, where stereoinduction and photoactivation conjugate in a sole organocatalyst, serves to develop novel stereoselective photochemical transformations that cannot be achieved using thermal pathways. In this context, we have successfully demonstrated that chiral enamines, which are primarily understood as nucleophiles in their ground state, can become potent single-electron reductants upon light excitation and trigger the generation of radicals through the SET reduction of electron-poor organic halides, thus promoting enantioselective α-alkylation of aldehydes (Task 4 of the project). This study has been published in Angew. Chem. Int. Ed. 2017, 56, 4447-4451. The knowledge accumulated with this study will be extremely useful to achieve further synthetic goals in the future phases of CATA-LUX. For example, the notion that organic molecules in their excite state can turn on unconventional reactivities, which are not available in their ground-state, served to develop another process, which was very recently published in J. Am. Chem. Soc. 2018, 140, 8439–8443. In this study, we have discovered that chiral iminium ions can directly reach an electronically excited state upon light absorption to become strong chiral oxidants that can activate reagents via single-electron transfer manifolds. This study shows that feedstock chemicals generally used as solvents, such as toluene and xylene derivatives, can be used as substrates for making chiral molecules with high enantioselectivity.

In addition, this part of the project intrinsically required a mechanistically-driven approach, since an intimate understanding of the photochemical and photophysical processes was required (Task 3). Important mechanistic clues were obtained by determining the quantum yield of the photochemical reactions. These approaches were combined with the classical experimental techniques most relevant to photophysical investigations.

Final results

\"CATA-LUX is developing in a very positive way. Some results have surpassed in novelty our expectations. What I consider a unique feature of the ERC programme is that it allows to pursue high-risk, high-gain research lines and explore beyond the frontiers of knowledge. This condition creates a stimulating research environment that is often conducive to serendipitous discoveries. This happened also in the initial phase of CATA-LUX (from month 1 till month 30).
One of the main targets of the project is to exploit the potential of chiral organocatalytic intermediates, such as enamines, to directly reach an excited state upon visible-light absorption. The chemical reactivity of electronically excited molecules differs fundamentally from that in the ground state, which is the underlying concept of photochemistry. This explains why the light excitation of organocatalytic intermediates can turn on novel catalytic functions unavailable to conventional ground-state organocatalysis. We are successfully exploiting the excited-state reactivity of chiral enamines (see previous section), a target which was originally identified as Task 4 of the ERC project. But recently we have found that also iminium ions, other general chiral intermediates in organocatalysis, can unveil a rich photochemistry upon light excitation. We could not anticipate this reactivity behaviour when planning the research activities of CATA-LUX. Specifically, excitation of chiral iminium ions turns them into strong chiral oxidants, enabling enantioselective photochemical β-alkylations of enals that are unachievable via conventional ground-state pathways. This new activation mode can provide fresh opportunities to design novel photochemical enantioselective processes. We have used this strategy to develop novel asymmetric transformations (Nature Chem. 2017, 9, 868–873, Angew. Chem. Int. Ed. 2019, 58, 1213–1217, Angew. Chem. Int. Ed. 2019, 58, 16878-16883). This fundamentally new photochemical approach will be extremely useful also in the future phases of CATA-LUX.

As a recognition of these achievements, which are very much related to the ERC project, I recently wrote a review to outline the historical context and the scientific motivations for combining photocatalysis and organocatalysis. This review charted the essential ideas, challenges, serendipitous observations, and milestone reactions that were essential for progress in the field. The manuscript has been published in a topical interdisciplinary journal (\"\"Expanding the potential of enantioselective organocatalysis with light”, Nature 2018, 554, 41-49).\"