10.1002/ejoc.201701400
European Journal of Organic Chemistry
COMMUNICATION
Sterically bulky PhBPE forms a narrow portal that restricts rhodium-substrate
interactions in the local structure (purple: rhodium, black: carbon, white:
hydrogen, red-purple: phosphorus). b) Stereochemical model for Rh-(S,S)-
PhBPE catalyst.[23] Sterically hindered and coordination sites on rhodium are
indicated by cyan circles and thin-red circles, respectively. c) Schematic
illustration of the enantioselective deuteration mechanism of β-substituted ,β-
unsaturated esters. Syn-deuteration proceeds from the Re,Re-face (the back-
side of the plane) via a less hindered complex.
window of PhBPE allowed only a limited part of the substrate,
including the ester carbonyl and olefin moieties, to coordinate to
the rhodium, while excluding the methyl mandelate group. The
stereoselectivity was explained well by following a heuristic model
introduced by Burk,[23] where the ester carbonyl oxygen atom and
alkene unit chelated to rhodium, escaping from steric interactions
between other parts of the substrate and the phosphine ligand
(Figures 3b and 3c).
On the other hand, moieties containing exchangeable hydrogen,
such as alcohol 6 (87% ee), amide 15 (69% ee), and carboxylic
acid 16 (53% ee),[21] were harmful to the reaction (Table 2b). In all
these cases, deuteration was not complete and the positions at
C2 and/or C3 were partially hydrogenated. This is probably a
consequence of labile protons that are delivered to the olefin. In
addition, the low ee values observed for carboxylic acid 16
suggested that the steric hindrance in the Si,Si-face coordination,
as shown in Figure 3c bottom, could be decreased because the
free carboxylate group is sterically smaller than amide and ester
moieties (Figure S1). These results showed that this reaction
protocol has two major limitations: 1) Exchangeable protons on
substrates interfere the catalytic deuteration. 2) The ester
protecting groups are requisite to obtain high ee values.
In conclusion, we developed a very efficient rhodium-catalyzed
deuteration process to synthesize α,β-dideuterated esters from β-
substituted α,β-unsaturated esters. After extensive investigation,
the methyl mandelate ester structure obtained the best
enantioselectivity. Rh-PhBPE emerged as the catalyst of choice,
reaching ee values up to 93%, which were achieved in a catalyst-
controlled fashion, despite the chirality of the mandelate moiety in
the substrate.
Acknowledgements
We thank Dr. F. Sato for discussion, and M. Kitajima for HPLC
analyses. This work was supported in part by JSPS KAKENHI
Grants 24681045, 24651244, 25242073, and 26560436.
Keywords: Stereoselective catalysis • Isotopic labeling •
Enantioselective Deuteration • Conformational analysis • Fatty
acids
[1]
For selected reviews, see: a) L. C. Sander, K. A. Lippa, S. A. Wise, Anal.
Bioanal. Chem. 2005, 382, 646; b) R. Mendelsohn, R. G. Snyder,
Biological Membranes (Eds.: K. Merz, B. Roux) Birkhäuser, Boston, 1996,
pp. 145–174. (c) J. Seelig, A. Seelig, Quart. Rev. Biophys. 1980, 13, 19.
S. Lethu, S. Matsuoka, M. Murata, Org. Lett. 2014, 16, 844.
[2]
[3]
For example, see: a) W. S. Knowles, Adv. Synth. Catal. 2003, 345, 3; b)
W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029; c) K. V. L. Crépy, T.
Imamoto, Adv. Synth. Catal. 2003, 345, 79; d) W. A. Nugent, T. V.
RajanBabu, M. J. Burk, Science 1993, 259, 479.
[4]
[5]
a) H.-J. LaRoche, M. Keller, H. Günther, H. Simon, Hoppe-Seyler's Z.
Physiol. Chem., 1971, 352, 399-402; b) C. Frössl, W. Boland,
Tetrahedron 1993, 49, 6613; c) G. Görgen, W. Boland, U. Preiss, H.
Simon, Helv. Chim. Acta 1989, 72, 917; d) O. Thum, C. Hertweck, H.
Simon, W. Boland, Synthesis 1999, 2145; e) C. Beckmann, J. Rattke, P.
Sperling, E. Heinz, W. Boland, Org. Biomol. Chem. 2003, 1, 2448.
For examples, see: a) H.-J. La Roche, H. Simon, M. Kellner, H. Günther,
Naturforsch. B, 1971, 26, 389-394; b) J. S. Chickos, M. Bausch, R. Alul,
J. Org. Chem. 1981, 46, 3559-3562; c) G. Dauphin, J.-G. Gourcy, H.
Veschambre, Tetrahedron Asymm. 1992, 3, 595-598..
[6]
[7]
a) J. M. Concellón, H. Rodríguez-Solla, Chem. Eur. J. 2001, 7, 4266; b)
J. M. Concellón, M. Huerta, Tetrahedron Lett. 2002, 43, 4943; c) J. M.
Concellón, H. Rodríguez-Solla, C. Concellón, Synlett 2008, 402.
a) S. G. Davies, H. Rodríguez-Solla, J. A. Tamayo, A. C. Garner, A. D.
Smith, Chem. Commun. 2004, 2502; b) S. G. Davies, H. Rodríguez-Solla,
J. A. Tamayo, A. R. Cowley, C. Concellón, A. C. Garner, A. L. Parkes, A.
D. Smith, Org. Biomol. Chem. 2005, 3, 1435.
[8]
[9]
D. Schröder, H. Schwarz, J. Am. Chem. Soc. 1993, 115, 8818.
H. Otsuka, E. Shirakawa, T. Hayashi, Chem. Commun. 2007, 1819.
[10] W. Leitner, J. M. Brown, H. Brunner, J. Am. Chem. Soc. 1993, 115, 152.
[11] For examples of asymmetric deuteration of 1,2-disubstitued olefins, see:
a) T. Ohta, H. Takaya, R. Noyori, Tetrahedron Lett. 1990, 31, 7189; b) M.
Shaharuzzaman, J. Chickos, C. N. Tam, T. A. Keiderling, Tetrahedron:
Asymmetry 1995, 6, 2929.
[12] D. Parker, J. Chem. Soc. Perkin Trans. II 1983, 83.
[13] P. L. Bock, D. M. Boschetto, J. R. Rasmussen, J. P. Demers, G. M.
Whitesides, J. Am. Chem. Soc. 1974, 96, 2814.
[14] (R)-2’ was obtained as the major product from the catalytic deuteration
of (R)-1 without chiral ligands (Figure S2).
[15] For details, see the supporting information Figure S3.
[16] T. P. Dang, H. B. Kagan, J. Chem. Soc. D Chem. Commun. 1971, 481.
[17] W. S. Knowles, M. J. Sabacky, B. D. Vineyard, D. J. Weinkauff, J. Am.
Chem. Soc., 1975, 97, 2567.
[18] M. J. Burk, J. Am. Chem. Soc. 1991, 113, 8518.
Figure 3. DFT-optimized structure of [Rh-(S,S)-PhBPE]+ complex and a model
for enantioselective deuteration of β-substituted ,β-unsaturated esters. a)
[19] C. J. Pilkington, A. Zanotti-Gerosa, Org. Lett. 2003, 5, 1273.
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