Chiral Lewis Bases – Pivotal Species for Asymmetric FLP- and Lewis Acid-Catalysis – CLABcat
Chiral Lewis Bases – Pivotal Species for Asymmetric FLPs- and Lewis Acid-Catalysis
As a possible alternative to transition metals as catalysts, chiral frustrated Lewis pairs and chiral strong Lewis acids, both non-metallic, are struggling to develop their full potential due to the hitherto crucial need for chiral boron-based strong Lewis acids, which are difficult to access and handle. CLABcat proposes 2 approaches to overcome this hurdle.
Bypassing strong borated chiral Lewis acids
Despite the long-standing and still spectacular achievements of transition metals as catalysts, they exhibit some drawbacks whose importance could grow in the next decades: 1) transition metals are expensive materials; 2) They are an issue in the pharmaceutical industry because of their toxicity —with very low authorized levels in active pharmaceutical ingredients—, which hampers their use in late-stage synthesis and imposes either their very costly removal (waste-producing supplementary purification steps) or the use of alternative, non-catalytic or non-stereoselective methods (again producing waste); 3) Their difficult elimination and their multi-faceted reactivity can lead to false positive results in the development of new reactions or in biologic tests; 4) The increasing demand for transition metals, especially the «Platinum group metals« (PGMs), due to their use in emerging technologies and to the rapid development of some largely populated countries, associated to a limited stock and a production localized in non-European countries, makes them a geostrategic concern and critical raw materials for the European Union.<br />Recently, Frustrated Lewis Pairs (FLPs), especially non-metallic ones, emerged as a potential alternative to transition metal catalysts, even in hydrogenation, a key industrial (and academic) process, which was almost exclusively catalyzed by metals. However, the number of reports on asymmetric catalysis by chiral FLPs is still very limited, since such catalytic systems so far rely usually on chiral boron-based strong Lewis acids, whose synthesis and handling are difficult.<br />The objective of CLABcat is to overcome these issues.
In CLABcat we wish to avoid the difficult multistep synthesis and handling of chiral strong Lewis acids required for enantioselective Lewis acid- and FLPs-catalysis, and to switch the paradigm towards chiral Lewis bases, which are much more broadly available. Accordingly, we will follow 2 objectives.
In Objective 1, we intend to develop unprecedented FLPs-catalyzed reactions, with potential for enantioselection and whose enantio-discriminating step depends on chirality on the Lewis base, not on the Lewis acid as in existing FLPs-catalyzed asymmetric reactions. In particular, we plan to investigate on the activation of yet unexplored substrates in FLPs chemistry.
In Objective 2, we intend to develop chiral Lewis acid catalysts formed in situ from chiral Lewis bases, thus avoiding the usual tedious synthesis and use of chiral boranes and relying on broadly available or more easily accessible chiral Lewis bases.
We have studied a type of substrate still untapped in FLP catalysis, although briefly studied in stoichiometric version. However, replicating the literature results proved impossible, and developing new conditions, by varying the Lewis acid and base as well as a nucleophilic partner or the solvent, was unfortunately unsuccessful.
On the other hand, we were able to access new, very strong Lewis acids from Lewis bases by improving a procedure from the literature that was tedious and unable to afford the strongest acids in our series. Some of these Lewis acids were then evaluated as catalysts in annulations between strained cycloalkanes and carbonyl derivatives. They showed very good activities and selectivities, better than in the case of triflic acid as Bronsted acid catalyst. Nevertheless, it appeared that our Lewis acids behaved rather like hidden Bronsted acids in these reactions.
In both objectives, we will continue our efforts to identify reactions suitable for FLPs that would comprise chiral Lewis bases, or for Lewis acids obtained by in situ conversion of Lewis bases. Once these reactions are identified, we will test chiral catalysts to obtain stereoenriched products.
One-step Oxidative Monofluorination of Electron-deficient Sulfoxides to Access Highly Lewis Acidic Sulfur(VI) Cations; Berreur, J.; Diez-Varga, A.; Manel, A.; Leroux, F. L.; Panossian, A.* Chem. Eur. J. 2022, 28, e202202564.
DOI: 10.1002/chem.202202564
hal.archives-ouvertes.fr/hal-03795951
doi.org/10.1002/chem.202202564
Electrophilic fluorosulfoxonium cations as hidden Brønsted acid catalysts in (n + 2) annulations of strained cycloalkanes; Manel, A.; Berreur, J.; Leroux, F. R.; Panossian, A.* Org. Chem. Front. 2021, 8, 5289-5295.
DOI: 10.1039/D1QO00840D
hal.archives-ouvertes.fr/hal-03325336v1
pubs.rsc.org/en/content/articlelanding/2021/qo/d1qo00840d/
Enantioselective catalysis by non-metal frustrated Lewis pairs; Panossian, A.*; Leroux, F. R.; Bortoluzzi, J. in: Topics in Enantioselective Catalysis – Recent Achievements and Future Challenges (Ed. A. Marinetti), World Scientific 2022, chapter 5, pp. 123–159.
ISBN: 978-981-124-842-9
DOI: 10.1142/9789811248436_0005
doi.org/10.1142/9789811248436_0005
Frustrated Lewis Pairs (FLPs) were discovered a decade ago as potential complements or alternatives to transition metal (TM) catalysts as they are able to activate H2 and other small molecules. However, the young field of catalysis by chiral FLPs is almost limited to the reduction of unsaturated substrates, whose enantio-discriminating step relies on difficultly accessible chiral strong Lewis acids, so far precluding industrial application. CLABcat aims at discovering new reactions in asymmetric catalysis by FLPs and new chiral catalysts, which will rely instead on much more broadly available chiral Lewis bases. Considering some constraints related to TMs (cost, supply, toxicity, removal, etc.), CLABcat will thus lead to greener and more cost-effective processes for the industrial renewal of the country, and have economical, industrial, medico-social and geostrategic impact.
Project coordination
Armen Panossian (Laboratoire d'Innovation Moléculaire et Applications (LIMA))
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
UMR 7042 Laboratoire d'Innovation Moléculaire et Applications (LIMA)
Help of the ANR 207,583 euros
Beginning and duration of the scientific project:
September 2018
- 48 Months
