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

Project Information

PHOTO-FLUOR

Grant agreement ID: 796460

DOI

10.3030/796460

Project terminated on 6 November 2018

EC signature date 19 March 2018

Start date 9 May 2018

End date 8 May 2020

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 170 121,60

EU contribution

€ 170 121,60

Coordinated by

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

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

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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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