Journal of the American Chemical Society
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the side arm can serve as an intramolecular base to deproto-
We are grateful for the generous financial support from
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nate the imino C-H of 21, which promotes the 1,3-proton
transfer and thus accelerates the transamination. Pyridoxa-
mine 11a is somewhat more active than 11f, probably because
the secondary amine (NHMe) in 11a is sterically beneficial to
access the imino C-H of 21 for deprotonation as compared to
the tertiary amine (NEt2) in 11f. The NHMe group in 11a also
likely can promote hydrolysis of Schiff bases such as from
aldimine 23 to iminium 12a and amino acid 5, as the Lys resi-
due of transaminase behaves in enzymatic transamination.
NSFC (21272158, 21472125) and the Program for New Century
Excellent Talents in University (NCET-12-1054).
REFERENCES
(1) Reviews on enzymatic transamination: (a) Taylor, P. P.; Pantaleo-
ne, D. P.; Senkpeil, R. F.; Fotheringham, I. G. Trends Biotechnol. 1998,
16, 412. (b) Mathew, S.; Yun, H. ACS Catal. 2012, 2, 993. (c) Fuchs, M.;
Farnberger, J. E.; Kroutil, W. Eur. J. Org. Chem. 2015, 2015, 6965.
(2) (a) Metzler, D. E.; Ikawa, M.; Snell, E. E. J. Am. Chem. Soc. 1954,
76, 648. (b) Matsuo, Y. J. Am. Chem. Soc. 1957, 79, 2016.
(3) (a) Humble, M. S.; Cassimjee, K. E.; Håkansson, M.; Kimbung, Y.
R.; Walse, B.; Abedi, V.; Federsel, H.-J.; Berglund, P.; Logan, D. T.
FEBS J. 2012, 279, 779. (b) Kochhar, S.; Finlayson, W. L.; Kirsch, J. F.;
Christen, P. J. Biol. Chem. 1987, 262, 11446. (c) Malashkevich, V. N.;
Jaeger, J.; Ziak, M.; Sauder, U.; Gehring, H.; Christen, P.; Jansonius, J.
N. Biochemistry 1995, 34, 405.
(4) Selected reviews on asymmetric biomimetic transamination: (a)
Breslow, R. Acc. Chem. Res. 1995, 28, 146. (b) Han, J.; Sorochinsky, A.
E.; Ono, T.; Soloshonok, V. A. Curr. Org. Synth. 2011, 8, 281. (c) Xie,
Y.; Pan, H.; Liu, M.; Xiao, X.; Shi, Y. Chem. Soc. Rev. 2015, 44, 1740.
(5) (a) Kuzuhara, H.; Komatsu, T.; Emoto, S. Tetrahedron Lett. 1978,
19, 3563. (b) Breslow, R.; Hammond, M.; Lauer, M. J. Am. Chem. Soc.
1980, 102, 421. (c) Zimmerman, S. C.; Breslow, R. J. Am. Chem. Soc.
1984, 106, 1490. (d) Ando, M.; Kuzuhara, H. Bull. Chem. Soc. Jpn. 1990,
63, 1925. (e) Zhou, W.; Yerkes, N.; Chruma, J. J.; Liu, L.; Breslow, R.
Bioorg. Med. Chem. Lett. 2005, 15, 1351. (f) Bandyopadhyay, S.; Zhou,
W.; Breslow, R. Org. Lett. 2007, 9, 1009. (g) Wei, S.; Wang, J.; Ven-
huizen, S.; Skouta, R.; Breslow, R. Bioorg. Med. Chem. Lett. 2009, 19,
5543.
(6) Kikuchi, J.-i.; Zhang, Z.-Y.; Murakami, Y. J. Am. Chem. Soc. 1995,
117, 5383.
(7) (a) Kuang, H.; Brown, M. L.; Davies, R. R.; Young, E. C.; Distefano,
M. D. J. Am. Chem. Soc. 1996, 118, 10702. (b) Kuang, H.; Distefano, M.
D. J. Am. Chem. Soc. 1998, 120, 1072. (c) Häring, D.; Distefano, M. D.
Bioconjugate Chem. 2001, 12, 385.
(8) (a) Soloshonok, V. A.; Kirilenko, A. G.; Galushko, S. V.; Kukhar, V.
P. Tetrahedron Lett. 1994, 35, 5063. (b) Willems, J. G. H.; de Vries, J.
G.; Nolte, R. J. M.; Zwanenburg, B. Tetrahedron Lett. 1995, 36, 3917. (c)
Hjelmencrantz, A.; Berg, U. J. Org. Chem. 2002, 67, 3585. (d) Svenson,
J.; Zheng, N.; Nicholls, I. A. J. Am. Chem. Soc. 2004, 126, 8554. (e)
Soloshonok, V. A.; Yasumoto, M. J. Fluorine Chem. 2007, 128, 170. (f)
Xiao, X.; Xie, Y.; Su, C.; Liu, M.; Shi, Y. J. Am. Chem. Soc. 2011, 133,
12914. (g) Wu, Y.; Deng, L. J. Am. Chem. Soc. 2012, 134, 14334. (h) Xie,
Y.; Pan, H.; Xiao, X.; Li, S.; Shi, Y. Org. Biomol. Chem. 2012, 10, 8960.
(i) Liu, M.; Li, J.; Xiao, X.; Xie, Y.; Shi, Y. Chem. Commun. 2013, 49,
1404. (j) Pan, H.; Xie, Y.; Liu, M.; Shi, Y. RSC Adv. 2014, 4, 2389. (k)
Su, C.; Xie, Y.; Pan, H.; Liu, M.; Tian, H.; Shi, Y. Org. Biomol. Chem.
2014, 12, 5856.
(9) (a) Bernauer, K.; Deschenaux, R.; Taura, T. Helv. Chim. Acta 1983,
66, 2049. (c) Knudsen, K. R.; Bachmann, S.; Jørgensen, K. A. Chem.
Commun. 2003, 2602.
(10) (a) Toth, K.; Richard, J. P. J. Am. Chem. Soc. 2007, 129, 3013. (b)
Crugeiras, J.; Rios, A.; Riveiros, E.; Richard, J. P. J. Am. Chem. Soc.
2011, 133, 3173.
(11) Selected reviews on organocatalysis: (a) Dalko, P. I.; Moisan, L.
Angew. Chem. Int. Ed. 2001, 40, 3726. (b) List, B. Chem. Rev. 2007, 107,
5413. (c) MacMillan, D. W. C. Nature 2008, 455, 304.
(12) Shi, L.; Tao, C.; Yang, Q, Liu, Y. E.; Chen, J.; Chen, J.; Tian, J.; Liu,
F.; Li, B.; Du, Y.; Zhao, B. Org. Lett. 2015, 17, 5784.
(13) Liao, S.; Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2014, 47, 2260.
(14) Liu, L.; Zhou, W.; Chruma, J.; Breslow, R. J. Am. Chem. Soc. 2004,
126, 8136.
(15) Ding, L.; Chen, J.; Hu, Y.; Xu, J.; Gong, X.; Xu, D.; Zhao, B.; Li, H.
Org. Lett. 2014, 16, 720.
(16) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(17) Suárez, R. M.; Pérez Sestelo, J.; Sarandeses, L. A. Org. Biomol.
Chem. 2004, 2, 3584.
9
The enantioselectivity of the transamination is generated
during the asymmetric 1,3-proton transfer from ketimine 21
to aldimine 23 (Scheme 4). A possible transition state (27)
has been tentatively proposed for understanding the origin of
the chirality (Figure 3). The carboxylic group of α-keto acid is
oriented towards the amine side chain probably due to acid-
base and/or hydrogen bonding interactions. Protonation of
the azaallylanion occurred at the α-C of the carboxylic group
from the up side of the pyridine ring away from the lateral
chain to give the α-amino acid with S configuration. For pyr-
idoxamines with basic side arms such as 11a, the acid-base
attraction and hydrogen bonding formed between the lateral
amine and the carboxylic acid of α-keto acid strengthen the
orientation of the α-keto acid in the transition state 27, thus
resulting in high enantioselectivity in the transamination.
For pyridoxamine 11h, the hydrogen bonding between its
NHAc chain and the α-keto acid likely accounts for the obvi-
ously higher enantioselectivity in the transamination as
compared to pyridoxamine 11i with an NMeAc side chain
(Table 1, 65% ee vs 33% ee). The proposed transition model is
also supported by transamination of 1a with stoichiometric
(R)-11a in the CD3OD-D2O (see SI). Deuterating the azaal-
lylanion proceeded via a similar way to generate the corre-
sponding α-deuterated amino acid 5a-d with the same con-
figuration (S).
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In summary, we have developed a class of axially chiral
pyridoxamines 11 bearing an amine side arm, which have
successfully mimicked multiple parameters of transaminases
including transamination activity, chiral environment, and
cooperative catalysis of the Lys residue. The pyridoxamines
displayed high catalytic activity and excellent enantioselec-
tivity in asymmetric transamination of α-keto acids, to give a
variety of optically active α-amino acids in 67-99% yields
with 83-94% ee’s under very mild conditions. Impressive
effects of the side arm on activity and enantioselectivity were
observed in the transamination.
ASSOCIATED CONTENT
Supporting Information
Procedures for synthesis of 11 and 13-18 and transamination
of α-keto acids, characterization data, NMR spectra, and X-
ray data of (R,S)-17 along with HPLC chromatograms.
AUTHOR INFORMATION
Corresponding Author
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(18) Sun, S.; Zabinski, R. F.; Toney, M. D. Biochemistry 1998, 37, 3865.
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