Enantioselective synthesis and antioxidant activity of 3,4,5-substituted piperidine derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.04.092

In this study, 3,4,5-trisubstituted piperidines were synthesized enantioselectively, and their antioxidant activity was evaluated. The 3,4,5-trisubstituted piperidines containing TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) and a spatially proximal hydroxy group showed good antioxidant activity. Some of these compounds showed IC₅₀ values in a nanomolar range, comparable to that of TEMPO. Probably the TEMPO generated from the homolysis of the C-ON bond of 3,4,5-trisubstituted piperidines functions as a radical-scavenging entity, and the hydroxy group of piperidines has a synergistic effect to the antioxidant activity.

Full text of DOI:10.1016/j.bmcl.2016.04.092

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Enantioselective synthesis and antioxidant activity
of 3,4,5-substituted piperidine derivatives
b,c,
Jin Ho Kim a, Pranab K. Shyam b, Mi Jeong Kim a, Hwa-Jung Lee b, Jeong Tae Lee a, , Hye-Young Jang
⇑
⇑
a Department of Chemistry and Institute of Applied Chemistry, Hallym University, Chuncheon 24252, Republic of Korea
b Division of Energy Systems Research, Ajou University, Suwon 16499, Republic of Korea
c Korea Carbon Capture & Sequestration R&D Center, Deajeon 305-343, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, 3,4,5-trisubstituted piperidines were synthesized enantioselectively, and their antioxidant
activity was evaluated. The 3,4,5-trisubstituted piperidines containing TEMPO (2,2,6,6-tetram-
ethylpiperidine-1-oxyl) and a spatially proximal hydroxy group showed good antioxidant activity.
Some of these compounds showed IC50 values in a nanomolar range, comparable to that of TEMPO.
Probably the TEMPO generated from the homolysis of the CAON bond of 3,4,5-trisubstituted piperidines
functions as a radical-scavenging entity, and the hydroxy group of piperidines has a synergistic effect to
the antioxidant activity.
Received 15 December 2015
Revised 28 April 2016
Accepted 30 April 2016
Available online xxxx
Keywords:
Piperidine
TEMPO
Ó 2016 Elsevier Ltd. All rights reserved.
Enantioselective reaction
Antioxidant
ABTS assay
Reactive oxygen species (ROS) encompass both the oxygen rad-
icals such as superoxide anion radicals (OÅ2-) and hydroxyl radicals
(ÅOH), and some nonradical derivatives of oxygen such as hydrogen
peroxide (H2O2) and singlet oxygen (1O2).1 ROS are generated dur-
ing the routine metabolic processes of normal cells such as energy-
generating catabolism or external stimuli such as radiation.
Although ROS play some beneficial roles in diverse physiological
processes, e.g., bactericidal action,2 detoxification,3 prostaglandin
production and certain cell-signaling processes,4 they are infamous
for their negative roles such as cellular damage by inducing lipid
and protein peroxidation and damage of nucleic acids to trigger
inflammation and mutations.5,6 Therefore, if these ROS are not
scavenged by antioxidants such as vitamin C and resveratrol,7 they
can cause rapid ageing and various diseases that originate from
oxidative stress.8 Moreover, the use of antioxidants has shown to
reduce the accumulation of amyloid-b protein in the mouse Alzhei-
mer’s disease (AD) model, resulting in a slow functional decline in
clinical studies.9
routes to control the regio- and stereoselectivity have been pro-
posed.15–18 For example, lithiation of piperidines renders the sub-
stitution at the 2-position, and the carbonyl ene and Prins
cyclizations afford the corresponding 3,4-disubstituted piperi-
dines.19–24 Although numerous reactions of piperidines including
enantioselective reactions have been reported,25–33 the regio- and
stereoselective reactions can still be improved, affording diverse
pharmaceuticals containing piperidine units. Recently, we have
reported a highly enantioselective and diastereoselective synthesis
of
a,b-substituted aldehydes in the presence of transition-metal
and chiral cyclic amine catalysts (Scheme 1).34–36
In this study, we report the stereoselective synthesis of various
3,4,5-trisubstituted piperidines and their antioxidant activity. It
would be interesting to study the antioxidant activity of 3,4,5-sub-
stituted
ethylpiperidine-1-oxyl) as
knowledge, this is the first synthesis of nonradical TEMPO-bearing
piperidines
containing
TEMPO
(2,2,6,6-tetram-
a
substituent. To the best of our
Synthesis of piperidine derivatives has attracted much interest
because of their biological activities and the importance of
piperidines in natural product synthesis.10–14 Depending on the
regio- and stereochemistry of substituents, different synthetic
EtO2C
O
CO2Et
R
Ph
OSiMe3
N
H
O
Ph
H
+
O
photocatalyst
or copper catalyst
H
R
N
TEMPO + CH2(CO2Et)2
⇑
Corresponding authors. Tel.: +82 33 248 2071 (J.T.L.); tel.: +82 31 219 2555
(H.-Y.J.).
single diastereomer, 88-99% ee
E-mail addresses: leo900516@gmail.com (J.T. Lee), hyjang2@ajou.ac.kr
Scheme 1. Enantioselective reactions for the synthesis of a,b-substituted
(H.-Y. Jang).
aldehydes.
http://dx.doi.org/10.1016/j.bmcl.2016.04.092
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kim, J. H.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.092

2
J. H. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
piperidines that exhibit antioxidant activity, although the radical-
scavenging activity of TEMPO and related compounds has been
reported.37–41 The antioxidant activity of these piperidines was
evaluated by the ABTS (2,20-azinobis-(3-ethylbenzothiazoline-6-
sulfonic acid)) test, a free-radical scavenging assay.
IC50 values of compounds 1b–3e, ascorbic acid, quercetin, and TEMPO by ABTS assaya
Compound
IC50
(
lM)
Compound
IC50 (lM)
1b
1c
1d
1e
2b
2c
2d
2e
12.25 2.499
0.093 0.008
>100
3b
3c
3d
3e
98.35 5.687
0.090 0.013
85.34 7.517
>100
Diethyl
2-((1R,2S)-3-oxo-1-phenyl-2-(2,2,6,6-tetramethyl-
>100
piperidin-1-yloxy)propyl)malonate 1a was synthesized using (S)-
2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine (20 mol %) and
CuCl (10 mol%) with 99% enantiomeric excess (ee) in a single
diastereomeric form. Following the Jørgensen’s protocol for
cyclization,42 1a was subjected to the reductive amination condi-
tions involving benzyl amine and sodium cyanoborohydride,
affording (3S,4R,5S)-ethyl 1-benzyl-2-oxo-4-phenyl-5-(2,2,6,6-
tetramethylpiperidin-1-yloxy)piperidine-3-carboxylate 1b in 92%
yield (Scheme 2). The subsequent reduction of 1b using lithium
aluminum hydride (LAH) afforded ((3S,4R,5S)-1-benzyl-4-phenyl-
5-(2,2,6,6-tetramethylpiperidin-1-yloxy)piperidin-3-yl) methanol
1c in 57% yield. To cleave the OAN bond of 1c, zinc dust was used,
affording (3S,4R,5S)-1-benzyl-5-(hydroxymethyl)-4-phenyl-piperi-
din-3-ol 1d in 80% yield. (3S,4R,5S)-Ethyl 1-benzyl-5-hydroxy-2-
oxo-4-phenylpiperidine-3-carboxylate 1e was synthesized from
1b via OAN bond cleavage in 34% yield. The fluoro-, and methyl-
substituted compounds were subjected to the same conditions,
affording diverse piperidine derivatives in moderate-to-good yield
as shown in Scheme 2.
The IC50 values of compounds 1b–3e, ascorbic acid, quercetin,
and TEMPO obtained from ABTS assay are shown in Table 1. The
majority of b and c series compounds (1b–3b and 1c–3c) showed
superior antioxidant activity than ascorbic acid, one of the refer-
ence compounds. In contrast, most of the d and e series com-
pounds except 2d, did not show significant activity. In b and c
series, there is a CAON connected TEMPO group. Therefore, the
radical-scavenging activity of b and c series compounds can be
attributed to the in situ generation of TEMPO radical by the homo-
lytic cleavage of CAON bond during the ABTS assay. Although the
homolysis of CAON bond occurs at 130 °C affording TEMPO radi-
cals,43,44 in this study, the TEMPO radical may have been produced
by homolytic cleavage at room temperature to some extent. Previ-
ously reported TEMPO NAOÅ radical intact compounds showed
radical-scavenging activity.45,46 However, the originally nonradical
c series compounds showed a similar antioxidant activity with
TEMPO, indicating the release of TEMPO radicals from these com-
pounds. Based on the results of previous studies on the cleavage of
COAN versus CAON bonds of simple alkoxyamines, CAON homol-
ysis is usually easier than COAN homolysis, as shown by bond-dis-
sociation energies (BDEs).47–50 Therefore, the observed radical-
scavenging activity can be attributed to the dissociation of TEMPO
radicals from nonradical b and c series compounds.
15.93 2.258
0.095 0.003
9.61 0.507
>100
Ascorbic acid
Quercetin
TEMPO
25.63 0.838
5.57 0.365
0.026 0.005
a
The assay were performed in triplicate.
group and TEMPO showed better IC50 values (60–95 nM), much
better than that of quercetin, and comparable to that of TEMPO
(26 nM). To the best of our knowledge, the IC50 values of c series
compounds are the best values reported for nonradical com-
pounds. Compared to b series piperidines, c series piperidines have
a hydroxy group in close proximity to the TEMPO group; this may
be responsible for the higher activity of c series piperidines than b
series piperidines. The presence of a hydroxy group near TEMPO
may accelerate the homolytic cleavage of CAON bond, generating
TEMPO radicals.
To confirm the importance of TEMPO for the antioxidant activ-
ity, compounds 1f and 1g without TEMPO (Fig. 1) were synthe-
sized, and their antioxidant activity was evaluated. As expected,
these compounds did not show significant antioxidant activity
(Table 2). Thus, regardless of other substituents such as an ester
or a hydroxy group, the compounds without TEMPO do not show
antioxidant activity. Because the dissociation of TEMPO from 1b
and 1c could form 1f and 1g, respectively, during the assay involv-
ing CAON bond cleavage, the ABTS assay mixtures of 1b and 1c
were analyzed. Compounds 1f and 1g were not detected by NMR
and GC–MS analysis. Presumably, after the homolysis of 1b and
1c, the resulting radical species are degraded.
Because c series compounds bearing a hydroxy group showed
much better antioxidant activity than the corresponding b series
compounds bearing an ethyl ester group, the role of the hydroxy
group in influencing the antioxidant activity was investigated.
Compound 1h in which the hydroxy group of 1c was protected
by an acetyl group (Fig. 1) was synthesized, and the antioxidant
activity was evaluated. Although this compound showed some
activity, it was less active than 1c in terms of the IC50 values
(Table 2). Therefore, it can be concluded that the hydroxy group
enhances the antioxidant activity by assisting the homolytic cleav-
age of the CAON bond generating TEMPO radicals, the major con-
tributor to the antioxidant activity. The actual radical-scavenging
entity can be attributed to the TEMPO dissociated from the parent
compounds.
By comparing the antioxidant activity between b and c series
compounds, clearly c series compounds possessing both a hydroxy
O
O
O
Bn
E
E
R
Bn
N
OH
O
N
OEt
Bn
NH2Bn
NaBH3(CN)
LAH
Zn
N
OH
R
H
R
O
O
R
N
N
N
OH
a
b
c
d
E= CO2Et
Zn
O
O
R
entry
R
b (yield)
c (yield)
d (yield)
e (yield)
Bn
N
OEt
1
2
3
-C6H5
-pF-C6H4
-pCH3-C6H4
1b (92%) 1c (57%) 1d (80%)
1e (34%)
2b
3b
2c
3c
2d
3d
2e
3e
(77%)
(79%)
(58%)
(82%)
(69%)
(71%)
(61%)
(55%)
OH
e
Scheme 2. Synthesis of 3,4,5-trisubstituted piperidine derivatives.
Please cite this article in press as: Kim, J. H.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.092

J. H. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
6. Slater, T. F. Biochem. J. 1984, 222, 1.
3
O
7. Kim, M. J.; Jung, S. H.; Moon, I.; Jun, J. G.; Lee, J. T. Bull. Korean Chem. Soc. 2014,
35, 1549.
8. Lagouge, M.; Larsson, N.-G. J. Intern. Med. 2013, 273, 529.
9. Sung, S.; Yao, Y.; Uryu, K.; Yang, H.; Lee, V. M.-Y.; Trojanowski, J. Q.; Pratico, D.
FASEB J. 2003, 18, 323.
10. Elbein, A.; Molyneux, R. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; John Wiley & Son: New York, 1987.
11. Pinder, A. R. Nat. Prod. Rep. 1986, 3, 171.
O
O
N
O
N
OH
N
O
O
N
1g
1f
1h
12. Pinder, A. R. Nat. Prod. Rep. 1992, 9, 491.
13. Plunkett, A. O. Nat. Prod. Rep. 1994, 11, 581.
Figure 1. Structures of 1f, 1g and 1h used for control experiments.
14. O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
15. Nadin, A. J. Chem. Soc., Perkin Trans. 1 1998, 3493.
16. Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003,
59, 2953.
Table 2
IC50 values of compounds 1f, 1g, and 1h by ABTS assaya
17. Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
18. Bailey, P. D.; Millwood, P. a.; Smith, P. D. Chem. Commun. 1998, 633.
19. Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155.
20. Sun, H.; Ma, D. Org. Lett. 2000, 2, 2503.
Compound
IC50 M)
1f
>100
1g
>100
1h
0.573 0.123
(
l
21. Guilloteau-Bertin, B.; Compe, D.; Gil, L.; Marazano, C.; Das, B. C. Eur. J. Org.
Chem. 2000, 1391.
a
The assay were performed in triplicate.
22. Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
23. Dwyer, M. P.; Lamar, J. E.; Meyers, A. I. Tetrahedron Lett. 1999, 40, 8965.
24. Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
25. Williams, J. T.; Bahia, P. S.; Kariuki, B. M.; Spencer, N.; Philp, D.; Snaith, J. S. J.
Org. Chem. 2006, 71, 2460.
26. Cariou, C. A. M.; Kariuki, B. M.; Snaith, J. S. Org. Biomol. Chem. 2008, 6, 3337.
27. Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004.
28. Amat, M.; Bosch, J.; Hidalgo, J.; Cantó, M.; Perez, M.; Llor, N.; Molins, E.;
Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074.
29. Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu, J.; Cacchio, T. Tetrahedron Lett. 2000, 41,
5647.
In conclusion, novel 3,4,5-trisubstituted piperidines were suc-
cessfully synthesized enantioselectively from enantiomerically
enriched ,b-substituted aldehydes, and their antioxidant activity
was evaluated. Among these compounds, those containing both
TEMPO and a hydroxy group showed the best IC50 values, compa-
rable to that of TEMPO. This confirms that the hydroxy group-
assisted homolysis of CAON bond accelerates the release of
TEMPO. These results may pave the way to develop nonradical
antioxidant moieties.
a
30. Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.
31. Davis, F. A.; Zhang, J. Y.; Li, Y. X.; Xu, H.; DeBrosse, C. J. Org. Chem. 2005, 70,
5413.
32. Hedley, S. J.; Moran, W. J.; Price, D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68,
4286.
33. Amat, M.; Escolano, C.; Lozano, O.; Llor, N.; Bosch, J. Org. Lett. 2003, 5, 3139.
34. Yoon, H.-S.; Ho, X.-H.; Jang, J.; Lee, H.-J.; Kim, S.-J.; Jang, H.-Y. Org. Lett. 2012, 14,
3272.
35. Ho, X.-H.; Oh, H.-J.; Jang, H.-Y. Eur. J. Org. Chem. 2012, 2012, 5655.
36. Kim, J.-H.; Park, E.-J.; Lee, H.-J.; Ho, X.-H.; Yoon, H.-S.; Kim, P.; Yun, H.; Jang, H.-
Y. Eur. J. Org. Chem. 2013, 2013, 4337.
37. Belekian, D.; Beyou, E.; Chaumont, P.; Cassagnau, P.; Flat, J. J.; Quinebèche, S.;
Guillaneuf, Y.; Gigmes, D. Eur. Polym. J. 2015, 66, 342.
38. Cicco, S. R.; Vona, D.; De Giglio, E.; Cometa, S.; Mattioli-, M.; Palumbo, F.; Ragni,
R.; Farinola, G. M. ChemPlusChem 2015, 80, 1104.
Acknowledgements
This study was supported by the National Research Foundation
of Korea (NRF) (No. 2013008819) and ICT & Future Planning (No.
2015M3D3A1065436) to Hye-Young Jang, and by Basic Science
Research Program through the National Research Foundation of
Korea (NRF) funded by the Ministry of Education, Science and
Technology (2012R1A1A1013930) to Jeong Tae Lee.
39. Winiarska, K.; Jarzyna, R.; Dzik, J. M.; Jagielski, A. K.; Grabowski, M.;
Nowosielska, A.; Focht, D.; Sierakowski, B. Free Radical Biol. Med. 2015, 81, 13.
40. Chatterjee, P. K.; Cuzzocrea, S.; Brown, P. a. J.; Zacharowski, K.; Stewart, K. N.;
Mota-Filipe, H.; Thiemermann, C. Kidney Int. 2000, 58, 658.
41. Samuni, M.; Barenholz, Y. Free Radical Biol. Med. 2003, 34, 177.
42. Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 4305.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data and antioxidant assay data for all compounds, as well
as copies of 1H and 13C NMR spectra) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/j.
bmcl.2016.04.092.
43. Studer, A.; Schulte, T. Chem. Rec. 2005, 5, 27.
44. Sciannamea, V.; Jérôme, R.; Detrembleur, C. Chem. Rev. 2008, 108, 1104.
45. Maki, T.; Soh, N.; Fukaminato, T.; Nakajima, H.; Nakano, K.; Imato, T. Anal. Chim.
Acta 2009, 639, 78.
46. Ivan Marius, G.; Scaiano, J. C. Photochem. Photobiol. 2003, 78, 416.
47. Hodgson, J. L.; Roskop, L. B.; Gordon, M. S.; Lin, C. Y.; Coote, M. L. J. Phys. Chem. A
2010, 114, 10458.
48. Gryn’ova, G.; Ingold, K. U.; Coote, M. L. J. Am. Chem. Soc. 2012, 134, 12979.
49. Ciriano, M. V.; Korth, H.; van Scheppingen, W. B.; Mulder, P. J. Am. Chem. Soc.
1999, 121, 6375.
References and notes
_
1. Ak, T.; Gülçin, I. Chem. Biol. Interact. 2008, 174, 27.
2. Anas, A. A.; Wiersinga, W. J.; de Vos, A. F.; van der Poll, T. Neth. J. Med. 2010, 68,
147.
50. Ma, Y.; Loyns, C.; Price, P.; Chechik, V. Org. Biomol. Chem. 2011, 9, 5573.
3. Webster, N. R.; Nunn, J. F. Br. J. Anaesth. 1988, 60, 98.
4. Cadenas, E. Mol. Aspects Med. 2004, 25, 17.
5. Valko, M.; Izakovic, M.; Mazur, M.; Rhodes, C. J.; Telser, J. Mol. Cell. Biochem.
2004, 266, 37.
Please cite this article in press as: Kim, J. H.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.092