Short description
(English)
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The asymmetric conjugate addition has made tremendous progress during the last years, either with Cu or Rh catalysts. Although the scope seems quite large, there is one particular category of important substrates that are still underdeveloped. The addition to - substituted Michael acceptors is difficult or impossible with the current methodologies. Though, this reaction would afford valuable synthons having an all-carbon chiral quaternary center. There are thousands of natural products having this particularity and a good solution to this problem is welcome. There is currently no such example in Rh catalyzed conjugate additions, and in Cu catalyzed ones there are only 5 articles on this topic, two of them from our group. Our goal is to find improved ligands for these transformations and to explore the scope of the substrates amenable to be used.
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Partners and International Organizations
(English)
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AT, BE, CH, DE, DK, ES, FI, FR, GR, HU, IE, IT, LT, MT, NL, PL, PT, RO, SE, SI, SK, TR, UK
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Abstract
(English)
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The aim of this COST network is to find new processes and selectivities in transition-metal catalyzed reactions. The range of studies go from hydrogenations (WG 1), to oxidations (WG 2) and C-C bond formation (WG 3). Most of these reactions focus on the asymmetric aspects, the one requiring the highest stereochemical selectivities. Our group (in WG 3) has concentrated its efforts on the formation of chiral all-carbon quaternary centers, through an asymmetric conjugate addition. This could be achieved with triorganoaluminium, under copper catalysis, with chiral phosphoramidite ligands. Alternatively, Grignard reagents could also be used under copper catalysis, but with chiral N-heterocyclic carbenes as chiral ligands. Recently, we found that our new family of phosphinamine ligands (called SimplePhos) were also excellent for the aluminium chemistry. Besides the high enantioselectivity they provide, they are not sensitive to cleavage as phosphoramidite are. Among the challenges in this type of reaction, the introduction of aryl nucleophiles is problematic. We recently found that aryl dialkylaluminium reagents could be generated and used in this reaction, with very high enantioselectivities (ee >98%). The reaction is also atom economical, as the two alkyl groups on aluminium are not transferred. More recently, we found that Rh-catalysis can also be used for such reactions. Although Rhodium is more expensive than Copper, the chiral ligand (BINAP) is commercially available. In addition, the scope of the reaction is much wider, with higher enantioselectivities. Closely related to aryl nucleophiles are vinylic nucleophiles. The same Cu methodology seems very successful with these nucleophiles. The scope and limitations are, presently, actively studied, with applications to some natural products. Finally, we have started a new study on dienic Michael acceptors. The challenge is, now, to control the regioselectivity, in addition to the enantioselectivity. The first results are very encouraging. Grignard reagents, associated with chiral N-heterocyclic carbenes, afford the 1,4 adduct with high ee's (>98%), whereas triorganoaluminium and dirorganozinc species afford the 1,6 adduct, also in excellent enantioselectivities ((>98%), but with different chiral ligand. The reaction has successfully been extended to enynes. This new topic is presently actively studied and applications to the synthesis of natural products is underway.
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