10.1002/anie.201905623
Angewandte Chemie International Edition
COMMUNICATION
To gain insight into the reaction mechanism, we studied the
effect of the proton source on the conversion and stereochemical
outcome (Table 3). In the absence of a proton source, a
conversion equal to the catalyst loading was observed (Entries 1
and 2), suggesting that the catalyst is the actual proton source.
Turnover was only observed upon adding a stoichiometric amount
of proton source (Entries 3 and 4). Notably, enantioselectivities
consistently proved to be independent of the proton source
(Entries 4-9), suggesting that the stoichiometric PS is not involved
in the enantiodetermining step. Further, even a sub-stoichiometric
amount of water enables full conversion (Entry 10), as the 0.5
equiv. of silanol, formed during the protodesilylation of the SKA,
functions as an efficient proton source, ultimately generating
hexamethyldisiloxane.
Brønsted acid-catalyzed protonation of the corresponding bis-silyl
ketene acetals in the presence of methanol or water. The
operationally simple protocol allows a facile transformation under
mild reaction conditions and exclusively furnishes the
enantioenriched products in quantitative yields starting from the
corresponding racemic acid without the need for additional
purification. We suggest that the bifunctional activation mode of
the DSI catalyst enables a highly efficient catalytic cycle that in
turn circumvents racemic background reactivity with the achiral,
stoichiometric PS. The late stage deracemization of NSAIDs on
gram scale and the simple direct enantioselective deuteration of
bis-silyl ketene acetals using CD3OD or D2O as deuterium source
demonstrate applicability of the developed system.
Table 3. Reaction mechanism investigation.[a]
Acknowledgements
Entry
1
2
3
4
5
6
7
8
Cat. (mol%)
Proton source (equiv)
-
Conv.(%)[b]
~50
er[c]
nd
95.5:4.5
95.5:4.5
95.5:4.5
95.5:4.5
95:5
95:5
95.5:4.5
95:5
95:5
95.5:4.5
Generous support from the Max Planck Society, the Deutsche
Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of
Excellence RESOLV, EXC 1069), and the European Research
Council (Advanced Grant “C–H Acids for Organic Synthesis,
CHAOS”) are gratefully acknowledged. We thank the technicians
of our group and the MS, HPLC and NMR departments, especially
Dr. M. Leutzsch of the Max-Planck-Institut (MPI) für
Kohlenforschung for analytics and A. Antenucci for the
preparation of some starting material.
50
100
50
1
1
1
1
1
1
1
-
Full
Full
Full
Full
Full
Full
Full
Full
MeOH (1.0)
MeOH (1.1)
EtOH (1.1)
iPrOH (1.1)
tBuOH (1.1)
DMP (1.1)
H2O (1.1)[e]
H2O (0.55) [e]
CD3OD (1.1)
9
10
11
Full
Full
1
[a] Reactions were performed on a 0.02 mmol scale. [b] Determined by 1H-NMR.
[c] Determined by chiral phase HPLC, see the SI. [e] Addition of water as stock
solution in dichloromethane (2%, V/V).
Keywords: Brønsted acids · deracemization · bis-silyl ketene
acetals · disulfonimide (DSI) · protonation · deuteration ·
organocatalysis ·
We speculate that the high efficiency of our catalytic system,
compared to that of the racemic background reaction, is a result
of a relatively fast protodesilylation event depicted in the proposed
transition state (TS) (Figure 2), which likely exploits the
bifunctionality of the DSI with its high N–H acidity and concomitant
Lewis-basicity of the S=O bond, in combination with the
oxophilicity of the silicon group. An analogous protodesilylation
event can be envisioned for the re-protonation of 3 by the achiral
PS, overall resulting in a fast and efficient enantioselective
protonation. In this scenario, the background reaction between 1a
and the achiral PS can be avoided by the high efficiency of the
catalytic system without the need of a bulky PS, thereby improving
the atom economy of the protonation step.
[1]
[2]
C. Ballatore, D. M. Huryn, A. B. Smith III, ChemMedChem 2013, 8,
385-395.
a) D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982,
104, 1737-1739; b) D. A. Evans, F. Urpi, T. C. Somers, J. S. Clark,
M. T. Bilodeau, J. Am. Chem. Soc. 1990, 112, 8215-8216; c) A. G.
Myers, B. H. Yang, H. Chen, J. L. Gleason, J. Am. Chem. Soc. 1994,
116, 9361-9362; d) A. I. Meyers, G. Knaus, K. Kamata, M. E. Ford,
J. Am. Chem. Soc. 1976, 98, 567-576; e) A. G. Myers, B. H. Yang,
H. Chen, L. McKinstry, D. J. Kopecky, J. L. Gleason, J. Am. Chem.
Soc. 1997, 119, 6496-6511; f) P. E. Sonnet, R. R. Heath, J. Org.
Chem. 1980, 45, 3137-3139; g) D. A. Evans, J. M. Takacs,
Tetrahedron Lett. 1980, 21, 4233-4236; h) Y. Kawanami, Y. Ito, T.
Kitagawa, Y. Taniguchi, T. Katsuki, M. Yamaguchi, Tetrahedron Lett.
1984, 25, 857-860; i) W. Oppolzer, R. Moretti, S. Thomi,
Tetrahedron Lett. 1989, 30, 5603-5606; j) A. Abiko, O. Moriya, S. A.
Filla, S. Masamune, Angew. Chem. In. Ed. 1995, 34, 793-795; k) J.
Lin, W. H. Chan, A. W. M. Lee, W. Y. Wong, Tetrahedron 1999, 55,
13983-13998.
Figure 2. Proposed catalytic cycle.
[3]
[4]
L. Duhamel, J.-C. Plaquevent, Tetrahedron Lett. 1977, 18, 2285-
2288.
a) J.-W. Lee, B. List, J. Am. Chem. Soc. 2012, 134, 18245-18248;
b) J. Guin, G. Varseev, B. List, J Am Chem Soc 2013, 135, 2100-
2103.
[5]
[6]
a) S. Oudeyer, J.-F. Brière, V. Levacher, Eur. J. Org. Chem. 2014,
2014, 6103-6119; b) C. Fehr, Angew. Chem. In. Ed. 1996, 35, 2566-
2587; c) L. Duhamel, P. Duhamel, J.-C. Plaquevent, Tetrahedron:
Asymmetry 2004, 15, 3653-3691.
a) K. Ishihara, S. Nakamura, M. Kaneeda, H. Yamamoto, J. Am.
Chem. Soc. 1996, 118, 12854-12855; b) S. Nakamura, M. Kaneeda,
K. Ishihara, H. Yamamoto, J. Am. Chem. Soc. 2000, 122, 8120-
8130; c) C. H. Cheon, H. Yamamoto, J. Am. Chem. Soc. 2008, 130,
9246-9247; d) E. M. Beck, A. M. Hyde, E. N. Jacobsen, Org. Lett.
2011, 13, 4260-4263; e) C. H. Cheon, O. Kanno, F. D. Toste, J. Am.
Chem. Soc. 2011, 133, 13248-13251.
[7]
M. Morita, L. Drouin, R. Motoki, Y. Kimura, I. Fujimori, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2009, 131, 3858-3859.
In summary, we have developed a deracemization of -
branched aryl carboxylic acids based on the asymmetric
This article is protected by copyright. All rights reserved.