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The ubiquity of nitrogen in life and material sciences makes the search for new C-N bond forming reactions a topic of utmost interest in modern organic chemistry. The use of nitrenes, in this context, provides unique opportunities for the development of new synthetic methods. However, despite recent significant achievements, the scope of catalytic nitrene transfers remains limited to C-H amination and alkene aziridination reactions. This research proposal, thus, was aimed at improving the knowledge in the chemistry of nitrenes through the design of new catalytic reactions for the synthesis of nitrogen-containing bioactive molecules.

1. Catalytic alkene oxyamination
We began by developing an efficient and selective catalytic oxyamination of simple alkenes. The reaction was carried out in the presence of acetic acid as the nucleophile, with a variety of aromatic and aliphatic alkenes to afford 1,2-vicinal amino alcohols in good yields (52-95%) and complete regioselectivity (see scheme 1, attached document). With respect to the styrene derived substrates, various electron-donating and electron-withdrawing were tolerated. Substituted alkenes also furnished the desired products in good yields. In the case of aliphatic alkenes, the yields were lower (20-58%), when compared to those of the styrene derived products (scheme 2).
We, then, extended the reaction to other nucleophiles. Various carboxylic acids such as pivalic acid, benzoic acid, and phenylacetic acid generated the corresponding 1,2-aminoalcohol in good yields (scheme 3). We found that is was necessary to prepare the corresponding hypervalent iodine reagents in order to ensure the presence of a single carboxylic acid in the reaction. The reaction can also take place in an intramolecular manner whereas it was also tolerant to alcohols, and amino acids, thus, providing complex products from simple starting materials.

2. Catalytic alkene diamination
Next, with these conditions in hand, we started to develop conditions for the diamination. We began with the intramolecular reaction as this would provide an efficient method to synthesize functionalized pyrrolidine type products. A careful screening of the parameters led us to optimize the reaction conditions (table 1). Thus, application of these conditions allowed us to explore the scope and limitations of the diamination reaction. The cyclization generated a wide variety of highly functionalized pyrrolidine products in 34-77% yields, and, in some cases, as a single diastereomer (scheme 4).
Next, we turned our attention to the more challenging intermolecular diamination with the aim to produce 1,2-diamines with two differentially substituted nitrogen functions. We began by screening reaction conditions (table 2). With the optimal conditions in hand we began to explore the scope of the reaction (table 3). In general, the reaction selectively produced a variety of diaminated products (47-60% yields). Styrenes with both electron withdrawing and electron donation groups were tolerated, however, aliphatic alkenes did not produce even traces quantities of the desired product.

3. Catalytic alkene carboamination
The next step was to develop an unprecedented intermolecular alkene carboamination. However, we are still searching for a suitable carbon nucleophile to perform this reaction. It should be mentioned that, in the course of our investigations, the first example of intermolecular alkene carbomination has been published in Nature (T. Piuo, T. Rovis, Nature, 2015, 527, 86-90). The very first example of this reaction highlights that it is a highly challenging transformation for which solutions remain to be found. To this end, the use of nitrenes may provide such an opportunity.

4. Catalytic asymmetric alkene difunctionalization
In parallel, we have investigated the use of commercially available chiral dirhodium(II) complexes in the asymmetric intramolecular alkene oxyamidation but the enantiomeric excesses remain moderate (<40%). To improve these results, we have started to explore the synthesis of chiral Rh2(esp)2 complexes, though with limited success in the framework of the MSCA fellowship. But because the catalytic asymmetric intermolecular nitrene addition remains a challenge to address, the development of chiral Rh(II) complexes is still under investigations in the group.

5. Mechanistic studies
Test experiments (not shown) have revealed that the difunctionalization reaction is catalyzed by an unprecedented rhodium bound nitrene. Based on the experimental results we have proposed a hypothetical mechanism for the alkene difunctionalization (Scheme 5). The mechanism was further investigated by a series of DFT computations in collaboration with Prof. Vincent Gandon (ICSN). These calculations revealed that the rhodium-bound nitrene (Rh2)=NTces is a relevant Lewis acid for the activation of aziridines, and the mechanism proceed via
1. coordination of the rhodium-bound nitrene to the nitrogen of the aziridine which activates the aziridine towards the nucleophilic attack (see scheme 4). The activation may proceed either by N-Rh, or N-N coordination;
2. Nucleophilic attack. (Scheme 6)

6. Synthetic application
We have envisaged the application of the intramolecular diamination to the synthesis of Pestalazine B according to the retrosynthetic scheme (scheme 7). The key diketopiperazine precursor was prepared in two steps with a yield of 50% from a commercially available tryptophan derivative and methyl N-benzyl-leucinate. However, the key indole diamination reaction was found to proceed with moderate efficiency and selectivity 'scheme 8), thereby hampering the completion of the synthesis.

In conclusion, the catalytic oxidative nitrene addition to olefins provides a solution to address the issue of regioselectivity in intermolecular alkene difunctionalization. Application of the reaction conditions allows isolating the corresponding 1,2-amino alcohols or 1,2-diamines with complete regioselectivity.
Given the ubiquity of amino alcohols in nature and drugs, this reaction enhances the synthetic value of nitrenes as reagents in organic synthesis. Thus, if we are able to construct complex molecules from simple starting materials, the application of catalytic alkene difunctionalization with nitrenes can afford a broad range of potentially biologically potent or medicinally relevant compounds. As such, the use of nitrenes for the preparation of drugs could have a large socio-economic impact.
The study of the mechanism has revealed an unexpected role for the rhodium-bound nitrene species that can behave as a Lewis acid. This newly uncovered feature of the nitrene may afford new opportunities in organic synthesis with the discovery on new transformations. Accordingly, this MSCA fellowship has reached its main goal, that is improving the knowledge in the synthetic chemistry of nitrenes. This result has allowed the Dauban's group at the ICSN to firmly maintain as one of the acknowledged leaders in the field of nitrene chemistry in Europe.

Informations connexes


Véronique DEBISSCHOP, (Déléguée régionale)
Tél.: +33 1 69823264
Fax: +33 1 69823333
Numéro d'enregistrement: 184415 / Dernière mise à jour le: 2016-06-24