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Organic & Biomolecular Chemistry
Page 5 of 6
DOI: 10.1039/C7OB01803G
Journal Name
ARTICLE
Particularly, the whole-cell biocatalysts conducted by co-
expression of CgKR1 variants and GDH displayed excellent
stereoselectivity (>99.9% ee) towards N-ethyl-N-methyl-2-(3-
oxo-2,3-dihydro-1H-inden-5-yl)acetamide (5a), which is the
key intermediate of anti-Alzheimer’s drug ladostigil (TV3326).
Thus, a chemoenzymatic synthesis of enantiopure (S)-5b was
achieved via 5 steps with 34.0% overall yield starting from p-
methoxybenzaldehyde. Whole-cell biocatalysts suffered
substrate and product inhibitions at high substrate loading.
Due to this fact, further studies are needed to explore the
possibility of this chemoenzymatic method as an alternative to
chemical synthesis.
6.
7.
G. Ma, Z. Xu, P. Zhang, J. Liu, X. Hao, J. Ouyang, P.
Liang, S. You and X. Jia, Organic Process Research &
Development, 2014, 18, 1169-1174.
(a)J. S. Yadav, S. Nanda, P. T. Reddy and A. B. Rao, J.
Org. Chem., 2002, 67, 3900-3903; (b)J. Yadav, B.
Reddy, C. Sreelakshmi and A. Rao, Synthesis, 2009,
2009, 1881-1885; (c)J. S. Yadav, S. Nanda, P. T. Reddy
and A. B. Rao, US 20040082043, 2004; (d)P. Pedrini,
P. P. Giovannini, M. Mantovani, E. Andreotti and C.
Colalongo, Journal of Molecular Catalysis B:
Enzymatic, 2009, 60, 145-150; (e)D. Caron, A. P.
Coughlan, M. Simard, J. Bernier, Y. Piche and R.
Chenevert, Biotechnology letters, 2005, 27, 713-716;
(f)I. Lavandera, B. Höller, A. Kern, U. Ellmer, A.
Glieder, S. de Wildeman and W. Kroutil, Tetrahedron:
Asymmetry, 2008, 19, 1954-1958.
(a)J. A. Josey, WO 2016145045A1, 2016; (b)Y.
Kawamata, T. Hashimoto and K. Maruoka, Journal of
the American Chemical Society, 2016, 138, 5206-
5209.
M. Chorev, T. Goren, Y. Herzig, J. Sterling, M.
Weinstock-Rosin and M. Youdim, WO 9827055A1,
1998.
Acknowledgements
This work was supported by the Science and Technology
Research Projects, Ministry of Education of the People's
Republic of China (213007A), Program for Liaoning Excellent
Talents in University (LR2014028), Young Elite Scientists
Sponsorship Program by CAST (2016QNRC001), National
Natural Science Foundation of China (81602993) and Project
from the Department of Education of Liaoning Province.
8.
9.
10.
Y. Herzig, L. Lerman, W. Goldenberg, D. Lerner, H. E.
Gottlieb and A. Nudelman, Journal of Organic
Chemistry, 2006, 71, 4130-4140.
Notes and references
11.
12.
13.
L. T. Boulton, I. C. Lennon and E. Bahar, US
20060199974, 2006.
Z. Luo, F. Qin, S. Yan and X. Li, Tetrahedron:
Asymmetry, 2012, 23, 333-338.
1.
U. T. Bornscheuer, G. W. Huisman, R. J. Kazlauskas, S.
Lutz, J. C. Moore and K. Robins, Nature, 2012, 485,
185-194.
European Medicines Agency, document no.
CPMP/SWP/QWP/4446/00
February 2008,
corri-gendum
available
of
at
2.
3.
J. Wachtmeister and D. Rother, Current opinion in
biotechnology, 2016, 42, 169-177.
cument/opendocument.jsp?webContentId=WC5000
03586(retrieved on June 500003510, 500002013).
J. Sterling, Y. Herzig, T. Goren, N. Finkelstein, D.
Lerner, W. Goldenberg, I. Miskolczi, S. Molnar, F.
Rantal, T. Tamas, G. Toth, A. Zagyva, A. Zekany, G.
Lavian, A. Gross, R. Friedman, M. Razin, W. Huang, B.
Krais, M. Chorev, Moussa B.Youdim and M.
Weinstock, J. Med. Chem., 2002, 45, 5260-5279.
P. Liang, B. Qin, M. Mu, X. Zhang, X. Jia and S. You,
Biotechnology letters, 2013, 35, 1469-1473.
F. Qin, B. Qin, T. Mori, Y. Wang, L. Meng, X. Zhang, X.
Jia, I. Abe and S. You, ACS Catalysis, 2016, 6, 6135-
6140.
O. Trott and A. J. Olson, Journal of computational
chemistry, 2010, 31, 455-461.
(a)D. D. and B. S. A., J. Am. Chem. Soc., 1948, 70,
3426-3428; (b)A. N. Meldrum, J.chem.soc.trans,
1908, 93, 598-601.
J. Lowe, S. Drozda, W. Qian, M.-C. Peakman, J. Liu, J.
Gibbs, J. Harms, C. Schmidt, K. Fisher, C. Strick, A.
Schmidt, M. Vanase and L. Lebel, Bioorganic &
Medicinal Chemistry Letters, 2007, 17, 1675-1678.
(a)H. Hu, S. P. Hollinshead, S. E. Hall, K. Kalter and L.
M. Ballas, Bioorganic & Medicinal Chemistry Letters,
1996, 6, 973-978; (b)S. Ulmschneider, U. M. ller-
Vieira, C. D. Klein, I. Antes, T. Lengauer and R. W.
Hartmann, J. Med. Chem., 2005, 48, 1563-1575;
(c)M. F. Gross, S. Beaudoin, G. McNaughton-Smith,
G. S. Amato, N. A. Castle, C. Huang, A. Zou and W. Yu,
Bioorganic & Medicinal Chemistry Letters, 2007, 17,
2849-2853.
14.
15.
16.
4.
(a)L. F. S. Jr., F. A. Siqueira, E. C. Pedrozo, F. Y. M.
Vieira and A. C. Doriguetto, Org. Lett., 2007, 9, 1433-
1436; (b)F. H. lek, C. Binda, M. Li, Y. Herzig, J.
Sterling, M. B. H. Youdim, A. Mattevi and D. E.
Edmondson, J. Med. Chem., 2004, 47, 1760-1766;
(c)D. A. Gallagher and A. Schrag, CNS Drugs, 2008,
22, 563-586; (d)M. Froimowitz, K.Wu, A. Moussa, R.
M. Haidar, J. Jurayj, C. George and E. L. Gardner, J.
Med. Chem., 2000, 43, 4981-4992; (e)J. K. Ekegren, T.
Unge, M. Z. Safa, H. Wallberg, B. Samuelsson and A.
Hallberg, J. Med. Chem., 2005, 48, 8098-8102.
Y. Chen and J. Meng, Chinese Journal of Organic
Chemistry, 2016, 36, 1869.
17.
18.
19.
5.
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