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Homogeneous and heterogeneous enantioselective Single Electron Transfer (SET) catalysis in cross-coupling reactions

Periodic Reporting for period 2 - EnanSET (Homogeneous and heterogeneous enantioselective Single Electron Transfer (SET) catalysis in cross-coupling reactions)

Reporting period: 2020-02-01 to 2021-01-31

Chirality of organic molecules plays a paramount role in our society as a consequence of the direct relation between the absolute molecular configuration and many properties and applications of molecular compounds and materials. The demand of enantiomerically pure compounds has increased considerably driven by the request of the pharmaceutical industry, as well as applications such as flavours, fragrances, and materials. In this context, the development of new methodologies to obtain enantiomerically pure compounds has become a challenge for the scientific community.
The overall objective of EnanSET project is to developing novel enantioselective SET cross-coupling reactions of redox active esters (RAEs) by environmental friendly metal-complex due to this kind of compounds do not need previous activation. Additionally, inspired by demand of the industrial processes, the need to develop clean and green chemical processes in order to avoid environmental concerns and the advantages that heterogeneous catalysis provides, we will develop the first SET heterogeneous catalysis with MOFs through the postsynthetic incorporation of chiral Ni or Ti-residues on the pore structure.
The scientific objectives described of this project are the following:
A) Outgoing phase (Scripps Research Institute, La Jolla, California, USA)
- Asymmetric Ni-complex synthesis and evaluation of its capacity to catalyze enantioselective cross-coupling reaction of redox-active ester (RAEs).
- Development of Ti-catalysed cross-coupling of RAEs.
- Enantioselective version of Ti-catalysed cross-coupling reactions.
B) Incoming phase (University of Granada, Spain)
-Chiral MOFs Synthesis and Asymmetric heterogeneous catalysis
The main aim of EnanSET during the secondment at The Scripps Research Institute (TSRI) in USA was to develop novel enantioselective single electron transfer cross-coupling reactions of redox active esters (RAEs) with Ni-complexes using enantiopure ligands (WP1). Unfortunately, all our attempts did not give the expected results in terms of enantiomeric excess. However, during the screening of the multiple conditions tested we observed a very interesting reactivity of one of the Ni complexes tested which led to a collaboration with the pharmaceutical Pfizer Inc. After the low enantiomeric excess obtained in using Ni-complex, we decided move to non-toxic SET complex as titanium complexes to develop the first Ti-catalysis of RAEs (WP2) also well fitted to environmentally friendly processes.
In this context, Ti-catalysis gave good results in term of coupling efficiency in Negishi reaction. As the main aim of EnanSET was to develop the first enantioselective cross coupling reactions using RAEs, we decided to move on with the enantioselective version of Negishi reaction catalysed by Ti-complex (WP3). Unfortunately, the enantiomeric excess (ee) of the reaction was again very low.
The changes to the original plan and subsequent adaptation of the WP3 imposed time restrictions that pushed the project researcher to request an amendment of 3 months in the fellowship.

Regarding incoming phase at University of Granada, due to the measures taken by Spanish institutions (beneficiary) as result of the COVID-19 pandemic, we underwent a complete lockdown for 2.5 months without any access to the laboratory. This situation also affected me for the rest of the period covered in this report, access to the laboratory was restricted to rotatory shifts and the usage of central facilities needed for chemical characterization also suffered from limited access. In Addition, the MSCA fellowship has been finalized 4 months in advance due to incompatibility with one of the best and more competitive fellowship in Spain. The fellow was awarded with a “La Caixa Junior Leader Retaining fellowship”, that will allow her to settle back in Europe and start her independent academic career.

The main goal of EnanSET during the incoming phase was to develop a novel enantioselective SET reaction RAEs catalyzed by MOFs. Our goal in WP4 was to incorporate the active center in the organic ligand by coordination with a functional group. However, our attempts did not give the expected results in terms of the incorporation of the active center. As alternative, we finalized the study and characterization of a new heterometallic titanium MOF that the fellow developed in her previous post-doctorate and that had not yet been published. Unfortunately, this material was unable to catalyse the formation of new C-C bonds, but we demonstrated the possibility of using highly stable titanium MOFs to degrade chemical warfare agents (CWAs) in water without the need for additional additives. This porous solid makes use of a synergistic catalysis mechanism in which two metals cooperate and make it possible to avoid the addition of base to the medium.

The focus of WP5 was the development of asymmetric heterogeneous catalysis using MOFs. Unfortunately, due to the pandemic situation and the early ending of the MSCA fellowship, this WP could not be implemented completely. We were only able to prepare the necessary RAEs and attempt a proof of concept in homogeneous phase: radical formation of new C-C bond between RAEs and Michael acceptor (Geise reaction) catalyzed by Titanium complex.

A general overview of the results and exploitation and dissemination of EnanSET project are:
- Publication: 2 directly related with the project and 5 from collaborations in peer-reviewed top-tier international journals in Chemistry.
- Conference/Congresses: 2 (MOFs 2018 and American Chemical Society Fall Conference 2019)
- Training and courses: 8
- Outreach: European researchers´ night and Network for Women in Science
- Teaching to undergraduate students
Heeding the need that exists in our society to develop new efficient methods for synthesizing enantiopure compounds as medicaments and, considering that among the numerous cross-coupling reactions catalyzed by SET complexes reported so far, reproducibility issues are discussed, and we developed new material as potential heterogeneous catalyst. In addition, we decided to try environmentally friendly alternatives by using less toxic metals as iron or cobalt. In homogeneous phase Iron complexed did not yield good enantiomeric excess but when we tried cobalt complexes in presence of enantio phosphine ligands we observed a very promising result. A proof of concept is shown using heterometallic chemical robustness of some MOFs (titanium, iron and cobalt MOFs).
Therefore, this project will allow to obtain a powerful tool for the synthesis of organic compounds of interest to the pharmaceutical industry using a more environmentally friendly methodology, which would have a great impact on society. Despite the fact that the expected results have not been obtained and there is still work to be done, the advances in the area have been very significant as seen in the collaborations with the pharmaceutical industry. However, it should be noted that the EnanSET project deals with fundamental research and that there are no short term potential impacts envisioned for the moment. With the results obtained during EnanSET, the researcher will now continue investigating the radical formation of new C-C bond catalysed by MOFs as an independent “La Caixa Junior Leader” at the Instituto de Ciencia Molecular-Universidad de València.