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Enantioselective Carbon-Fluorine Bond Formation: A Molecular Editing Approach toward Drug Discovery

Periodic Reporting for period 1 - PHOTO-FLUOR (Enantioselective Carbon-Fluorine Bond Formation: A Molecular Editing Approach toward Drug Discovery)

Reporting period: 2018-05-09 to 2020-05-08

Light-driven reactions have become more and more popular in the organic chemistry community since light can trigger new reactivities. The main objective of the PHOTO-FLUOR project was the modification of bioactive molecules installing fluorine in their scaffold by activating the substrates with light. The resulting fluorinated products could have important applications as pharmaceutical or agrochemical compounds. Unluckily, our strategy did not work as expected, so we proposed a new methodology involving a photoinduced nickel-catalysed C-C bond formation reaction. In particular, this new methodology will pave a new greener synthetic path affording enantioenriched acyclic α,α-disubstituted carbonyl compounds. Going beyond the state of the art, the candidate has proposed a new synthetic strategy, which could be appealing for pharmaceutical companies to obtain new possible drugs, as acyclic α,α-disubstituted carbonyl compounds constitute a class of important synthetic intermediates, which can be easily further modified.
The candidate envisioned that the introduction of a fluorine within a double bond would be possible by the photoexcitation of iminium ions, generated upon condensation of a chiral amine catalyst with unsaturated aldehydes. Unfortunately, all the efforts were in vain.
The candidate worked also on the β–fluorination of saturated aldehyde through the enamine-mediated pathway. After screening different reaction conditions (solvents, temperature, Lewis acids, different light sources, and external photocatalysts), only decomposition of the starting aldehyde was observed in most of the cases.
As it was not possible to proceed with the initial idea (WP1), a new strategy has been set in motion. It merges the experience of the host (Prof. Melchiorre) in enantioselective photochemical C-C bond formation reactions and the one of Dr. Raha Roy in transition metal catalysis: the photoinduced nickel-catalyzed enantioselective C-C bond formation reaction to obtain enantioenriched carbonyl compounds. As demonstrated in the Periodic Technical Report the initial results are very promising.
Enantioenriched acyclic α,α-disubstituted carbonyl compounds are very handy synthetic intermediates for the synthesis of several natural products and APIs. Due to their efficacy, the development of new synthetic methods to prepare such molecules has been the subject of intense research. The vast majority of α-functionalization reactions were performed via the intermediacy of enolates or enolate equivalents. There is only one example where the nickel-catalyzed enantioselective reductive coupling has been used to synthesize this class of molecules. However, they employed a huge excess of manganese as a reductant. Therefore, we came up with this photoinduced nickel-catalyzed enantioselective carbon-carbon (C-C) bond formation reactions with no need to use the external metal reductant. The results generated within this project will likely find publication in top-tier international scientific journals (such as Angewandte Chemie or ACS Catalysis). In line with the dissemination, exploitation and communication strategy, we will make this publication “open access”.
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