Current Research Projects
Current Research Projects
Identification and development of new natural anti-angiogenic molecules selected for their capacity to work in the hypoxic environment of tumours.
The stereoselective synthesis of optically active alcohols is a well studied topic in organic chemistry. In this area of research, the search for economical methods of enantioselective reduction of prochiral ketones is a rewarding goal. Polymethylhydrosiloxane (PMHS), a by-product of the silicone industry, is a safe and inexpensive hydrosilylating agent which can transfer its hydride to a variety of metal catalysts (Ti, Sn, Zn, …) thus participating in a wide range of reductions.
Our contribution to this area is focused on the discovery of new efficient catalytic systems for the asymmetric hydrosilylation of prochiral ketones. Two new systems have been found and have been thoroughly studied and optimized in our laboratory. The first system was inspired by the pioneer work of Mimoun on the use of chiral zinc complexes as catalysts for hydrosilylation. Extension of our studies on chiral ferrocenyl ligands prompted us to develop another low cost transition metal catalytic system focusing on N,S-zinc catalysts. The second system is based on the generation of chiral copper (I) hydrides from an easily available organometallic precursor. An unusual acceleration effect by oxygen was discovered and allowed the discovery of one of the fastest hydrosilylation catalyst reported so far. Enantioselectivies exceeding 95 % were obtained for the hydrosilylation of prochiral ketones after careful optimisation of the reaction conditions.
The development of new catalytic systems based on copper (I) hydrides opened the door for new applications in domino 1,4-reduction/aldolisation reactions. We have developed some modified NHC copper (I) complexes which proved extremely active for this type of reactions between various Michael acceptor and aldehydes (Collaboration with Professor Steven P. Nolan). These catalysts do not require activation and show high activity (TOF 15,000 h-1) as well as some anti diastereoselectivity.
This system was also optimized with diphosphine copper (I) catalysts and a careful optimisation of the reaction conditions and of the structure of the ligand, allowed us to reach high syn-diastereoselectivities as well as enantioselectivities for the coupling of methyl acrylate and various aldehydes(aromatic as well as aliphatic):
Using a copper (I) precursor and a proper diphosphine ligand, high reactivities can be reached, with TOF up to 40 000 h-1. Taniaphos-based ligands lead to enantioselectivities of up to 97% in the case of the major syn diastereoisomer.
An intramolecular version of the reductive aldol reaction was also optimized for the construction of enantiomerically enriched bicyclic adducts.
The cyclisation precursors are easily available on a large scale starting from commercially available 1,3-diketones and can be cyclized with a copper (I) diphosphine catalyst and a silane to give the bicyclic hydroxyl esters in excellent yield and diastereoselectivities. Careful selection of the chiral ligand showed again that Taniaphos ligands allowedus to reach enantioselectivities up to 95% for some adducts. This method allows a straightforward access to various size of bicycles on a multigram scale with low catalyst loading (down to 0.5 mol %) with fair to high enantioselectivities.
We were interested by applying the same methodology described above with borosilanes instead of silanes as pro-nucleophiles. Copper (I) catalysts have been shown to catalyze the conjugated addition of disilane and silylmetal nucleophiles on electrophilic double bonds. While the use of disilanes requires harsh conditions to proceed, the use of silyl metal species is also not suitable for silylative aldol reactions because the silyl group could add directly to the aldehyde. This problem of chemoselectivity is well known in copper hydride chemistry. In our initial experiments we tested the three component domino reaction in the presence of a Copper(I) catalyst and obtained the corresponding aldol adducts. Although no diastereoselectivities were observed with these substrates, we observed an excellent reactivity of our catalytic system as excellent yields were obtained in each case with low catalyst loading and short reaction time.
Our hypothesis was that the stereochemistry could be controlled by using chiral auxiliaries such as oxazolidinones on the Michael acceptors. After optimisation of the catalytic system and a the screening of various achiral diphosphine ligands, we managed to develop a highly reactive and stereoselective catalytic system. Diastereoselectivities up to 90% were obtained and the successful construction of quaternary centers was also achieved.
A library of catalysts was designed for asymmetric hydrogen transfer to acetophenone. At first, the whole library was submitted to evaluation using high throughput experiments (HTE). The catalysts were listed in ascending order, with respect to their performance, and best catalysts were identified. In the second step, various simulated evolution experiments, based on a genetic algorithm, were applied to this library. A small part of the library, called the mother generation (G0), thus evolved from generation to generation. The goal was to use our collection of HTE data to adjust the parameters of the genetic algorithm in order to obtain a maximum of the best catalysts within a minimal number of generations. It was namely found that simulated evolution’s results depended on the selection of G0 and that a random G0 should be preferred. We also demonstrated that it was possible to get 5 to 6 of the ten best catalysts while investigating only 10% of the library. Moreover, we developed a double algorithm making this result still achievable if the evolution started with one of the worst G0. This work was carried out in collaboration with the groups of Dr Claude de Bellefon (CPE, Lyon, France) and Prof. Bernadette Govaerts (UCL).
| contact : Olivier Riant | 8/07/2011 |