CE07 - Chimie moléculaire, Chimie durable et procédés associés

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.

Scientific, technical and economic impact

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 by Umpolung of 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. Indeed, the conversion of achiral phosphines and sulfoxides into the corresponding strongly Lewis acidic phosphoniums and sulfoxoniums has been reported, and such species were then used as efficient Lewis superacid catalysts in several applications. However, this brilliant strategy had not been used with chiral P- or S(O)-based Lewis bases at the beginning of our project.

So far, we focused mainly on objective 2, namely the Umpolung of chiral Lewis bases into chiral strong Lewis acids.
We submitted a series of sulfoxides and phosphines to formal oxidative mono-fluorination conditions, leading to the corresponding fluoro-onium species. In several cases, the process was unclean, however, in some others, it was possible to isolate cleanly the desired potential catalysts. The latter were evaluated in potentially asymmetric reactions, either already known or not, showing good efficiency. However, so far, when employing the said chiral Lewis acids, only racemic reaction products were obtained. This questioned the structure of the employed chiral backbones, or the true role of the catalyst.
Consequently, the synthesis of chiral Lewis bases based on other backbones was undertaken.
Additionally, we developed an alternate method to carry out the Umpolung process on chiral Lewis bases, which showed good efficiency.
Furthermore, a combined NMR experimental and computational study was carried out to support the experimentally observed Lewis acidity trend in a series of acids obtained by Umpolung.

In objective 2, we will pursue our efforts in the understanding of the role of the catalysts, as well as in the identification of chiral backbones showing most potential. We will then identify best-suited reactions for the evaluation of the stereoinduction provided by the new chiral catalysts obtained.
In parallel, we will tackle objective 1, by developing new reactions catalyzed by achiral FLPs at first, then, after selecting the most promising ones, using chiral Lewis base-containing chiral FLPs.

None yet

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 coordinator

Monsieur 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.

Partner

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

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