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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - NOVOCAT (Tha novo catalytic synthesis of Î²-aminoacids from CO2)

Teaser

Summary

Given the non-toxicity and natural-abundance of CO2, it comes as no surprise that chemists have been challenged to design catalytic technologies that harness its potential as C1 synthon for synthetic applications. Among various scenarios, the conversion of CO2 into carboxylic acids constitutes an ideal target for CO2 sequestration since these compounds are fundamental units in organic syntheses as well as being privileged motifs in many pharmaceuticals. In recent years, the Martin group has pioneered the development of metal-catalyzed reductive carboxylation protocols using simple and commercially available organic halides or pseudohalides as coupling partners with CO2. Albeit significant advances have been achieved, the scope of these protocols is still rather narrow and rather substrate-dependent. Prompted by the utmost synthetic and societal relevance of amino acids, key structural units of proteins and compounds that display important biological activities (Figure 1), the means to convert ubiquitous CO2 into valuable amino acids in a catalytic endeavor would be particularly appreciated. as well as their unique role for our society. With such premise in hand, NOVOCAT aimed at the development of a catalytic platform for preparing Î²-amino acids via direct carboxylation of widely accessible aziridines with CO2. The objectives were the following:
- To prepare well-defined metal intermediates via C-N bond-cleavage of aziridines;
- To design a catalytic reductive carboxylation of aziridines via synergistic C-N bond
cleavage / CO2 insertion event, even in an asymmetric fashion;
- To apply the know-how for the synthesis of natural products
Despite extensive investigations, little success was achieved and the viability of obtaining amino acids from CO2 following the premises of NOVOCAT were not fully assessed. During our investigations with CO2, a serendipitous reaction was observed when using silylboranes as mediators for CO2 insertion in the presence of fluorine-containing molecules. Control experiments revealed that a Câ€“F silylation event occurs with great efficiency, an aspect that could be extended to a wide number of compounds analyzed, including within the context of late-stage functionalization.

Work performed

During the execution of NOVOCAT, considerable effort was devoted towards the synthesis of azanickelacycles and their reactivity with CO2 (objective 1). Although we managed to prepare some of these intermediates with a rather particular ligand backbone, CO2 insertion turned out not to be efficient enough to trigger the carboxylation event. This lack of reactivity is likely attributed to the non-innocent role of the ligand in this reaction, as the Martin group has observed that subtle differences on the ligand have a profound effect on reactivity. Unfortunately, the synthesis of other azanickelacycles possessing different ligand backbones was not possible. Similar discouraging results were observed when optimizing the catalytic reaction of aziridines with CO2 en route to Î²-amino acids. Although we made use of the HTE unit extensively, systematically analyzing the effect of the precatalyst, ligand, base, reductant, solvent and additives in a multidimensional manner, no reaction took place. Convinced about the relevance of a CO2 insertion into inert bonds, we switched our attention to the utilization of equally challenging scenario via C-F bond-cleavage. If successful, such pathway would potentially enable the possibility of promoting late-stage carboxylation techniques, thus changing fundamentally the properties of the drug, moving from a liphophilic environment (fluoride) to an hydrophilic motif (carboxylic acid). After extensive experimentation, it was serendipitously found that the presence of silylated reagents (initially perceived as vehicles towards the carboxylation event) triggered a previously unrecognized C-Si bond-forming event via C-F bond cleavage. (Scheme 1) Such a reaction can easily be extended to both aryl and alkyl series. Mechanistic experiments have been performed which demonstrate an abnormal nucleophilic substitution reaction over a rather strong C-F bond. We are currently finalizing the details of this reaction, and it is expected that the manuscript will be submitted to Angewandte Chemie within the next 1-2 months. It is worth noting that the group of Prof. Ruben Martin is still pursuing the carboxylation of aziridines according to the initial plan delineated in the Marie Curie proposal, and one postdoctoral student is currently actively working on the project. And the researcher didnâ€™t finish the derived C-F bond silylation project until he finished his contract, therefore, it was not possible to do the appropriate dissemination and communication of these new results.

Final results

It is certainly fair to mention that the challenges posed by NOVOCAT were not fully accomplished. We did considerable progress in Objective 1 (isolation of intermediate azanickelacycles), but we could not demonstrate the viability of a catalytic carboxylation event en route to -amino acids according to Objective 2. Therefore, it is probably not appropriate to highlight the potential impact of the proposal as initially planned. As mentioned above, however, we serendipitously found a Câ€“F silylation event when using silylborane reagents as mediators of the carboxylation reaction. It turned out that such reaction is rather general, enabling the viability of previously unrecognized C-Si bond-forming event via C-F bond-cleavage. It is worth noting that this reaction can even be performed in the absence of metal catalyst, and can easily be extended to both aryl and alkyl series. Mechanistic experiments have been performed which demonstrate an abnormal nucleophilic substitution reaction over a rather strong C-F bond. The manuscript is currently being written, and it is expected that it will be submitted for publication within the next 1-2 months. In view of the importance of this new finding, it is inevitable to predict that such a method will attract considerable interest at the Community, increasing the visibility of the host group. In particular, we expect that medicinal chemists will tremendously benefit from having such technique in hand, as it enables the conversion of an aryl fluoride (tremendous prevalent backbone in pharmaceuticals) into an aryl silane in the absence of a metal or ligand backbone. This is certainly remarkable as previous silylation events require rather sophisticated ligands or metal complexes that might hamper the reactivity and selectivity of the process. Given the synthetic utility of the corresponding aryl silanes, one can easily envision an integrated technique by which an aryl fluoride can be converted into an aryl silane, and without the need for isolation, further conversion into various products via known C-Si bond-functionalization. This would allow industrial chemists to derivative at late-stages fluoro-containing pharmaceuticals into new compounds of potential use as pharmacophores, thus having a significant economic impact at the pharmaceutical company.