PhD offer (ROCS group) – Stereoselective C–C Bond Formation Catalyzed by an NHC-Zn Complex

The ROCS group, in partnership with Prof. S. Kobayashi’s group at the University of Tokyo, is looking a candidate for a PhD scholarship on the topic:

Stereoselective C–C Bond Formation
Catalyzed by an NHC-Zn Complex

Project overview :  

Offer link

Organozinc derivatives are key reagents in organic synthesis that provide carbanion equivalents with exceptional functional group tolerance. Among these, the most widely available and easy-to-handle are organozinc halides (RZnBr or RZnCl) and a wide array of functionalized reagents of such type can be prepared readily. However, a general lack of reactivity has restricted their use so far to cross-coupling chemistry. This can be ascribed to the lower Lewis acidity of the zinc atom in comparison with other more reactive organozinc species (i.e. R2Zn). In a first aspect of the project, our goal is to find methods to enhance the Lewis acidity of RZnX reagents and thereby embrace a much broader reactivity profile, including for instance the application to 1,2-additions to carbonyl derivatives, not reported to date.

In this context, Lewis base activation of organometallic reagents will be considered to increase the reactivity of organozinc halides toward carbonyl substrates. Such activation mode leads Metal–R bonds more ionic and improves Lewis acidity of metal, and the use of bidentate NHCs seems to be good candidates.4 With these systems we expect high tunability and flexibility with a possible chirality transfer for the 1,2-addition reactions (scheme, pathway 1). This kind of activation has been advantageously applied in the case of allylic substitutions with Grignard reagents (RMgX)3 and also using dialkylzinc reagents.5 However, no such activation of organozinc halides has been reported yet. Additions to aldehydes, ketones and carbon monoxide will be explored.

In another approach, the use of enolate reagents is also being considered. Indeed, the use of enolizable carbonyl derivatives offers a rapid and efficient strategy for accessing more complex molecular motifs via adolisation reactions.6 Nevertheless, enolates have the disadvantage of having to be prepared stoichiometrically, essentially in the form of silylated enol ethers. Thus, the development of a method that generates the enolate catalytically in situ has attracted a great deal of interest over the last two decades. In particular, the use of zinc enolates has required the presence of Et2Zn and a non-racemic chiral ligand, namely ProPhenol7 or a binol derivative.8
In this context and in continuity with the first approach, catalytic equimolar quantities of bidentate NHCs and zinc salts in the presence of a base are therefore envisaged for the development of enantioselective catalytic 1,2- addition reactions on aldehydes and/or imines (Scheme, pathway 2). The advantage of this approach is that it uses only safe and cheap elements that are easy to handle, unlike the pyrophoric Et2Zn.

Profiles : 

Training in organic and organometallic chemistry with an interest in methodology and multi-step synthesis.

Duration:

36 months from October 2024

Application:

– Send a cover letter
– a detailed CV
– The grade from Licence, M1, M2 (S1 of M2 if Master’s degree in progress)
Deadline : 18/05/2024

Références

  1. a) Y. Yamashita, S. Kobayashi Chem. Eur. J. 201824, 10. b) Y. Yamashita Chem. Commun202258, 1078.
  2. a) Y.Yamashita, A. Noguchi, S. Fushimi, M. Hatanaka, S. Kobayashi J. Am. Chem. Soc2021143, 5598. b) Y. Yamashita, S. Fushimi, T. Banik, T. Kimura, S. Kobayashi Org. Lett. 2024asap, DOI: 10.1021/acs.orglett.3c04326.
  3. a) O. Jackowski, A. Alexakis Angew. Chem. Int. Ed201049, 3346; b) D. Grassi, C. Dolka, O. Jackowski, A. Alexakis Chem. Eur. J201319, 1466. c) Pérez-Sevillano, R.; Ferreira, F.; Jackowski, OChem. Eur. J. 202329, e202302227.
  4. A. I. Poblador Bahamonde, S. Halbert Eur. J. Org. Chem2017, 5935.
  5. Y. Lee, L. Bo, A. H. Hoveyda J. Am. Chem. Soc. 2009, 131, 11625.
  6. Y. Yamashita, T. Yasukawa, W-J. Yoo, T. Kitanosono, S. Kobayashi Chem. Soc. Rev., 201847, 4388.
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  8. a) N. Yoshikawa, N. Kumagai, S. Matsunaga, G. Moll, T. Ohshima, T. Suzuki, M. Shibasaki, J. Am. Chem. Soc., 2001, 123, 2466. b) N. Kumagai, S. Matsunaga, N. Yoshikawa, T. Ohshima, M. Shibasaki, Org. Lett., 2001, 3, 1539. c) N. Yoshikawa, T. Suzuki, M. Shibasaki, J. Org. Chem., 2002, 67, 2556. d) N. Kumagai, S. Matsunaga, T. Kinoshita, S. Harada, S. Okada, S. Sakamoto, K. Yamaguchi, M. Shibasaki, J. Am. Chem. Soc., 2003, 125, 2169. e) H. Li, C. S. Da, Y. H. Xiao, X. Li, Y. N. Su, J. Org. Chem., 2008, 73, 7398. f) X. Li, L. Zhang, Y. H. Xiao, Q. P. Guo, C. S. Da, H. Li, X. J. Liu, X. R. Ma, Y. J. Ma, Russ. J. Gen. Chem., 2016, 86, 1922.