Pd-N-heterocyclic carbene catalyzed synthesis of piperidine alkene-alkaloids and their anti-cancer evaluation

Article abstract of DOI:10.1016/j.bmcl.2013.12.108

A facile synthesis of piperidine alkene-alkaloids including natural (+)-Caulophyllumine B in high yields has been developed by Heck cross-coupling reaction catalyzed by simple in situ formed palladium-N-heterocyclic carbenes (Pd-NHCs). Formation of Pd(0) nanoparticles has been noticed during the reaction course. The synthesized piperidine alkene-alkaloids were evaluated for in vitro anti-cancer activity against a panel of human tumor cell lines of lung, breast and ovarian. Several of these piperidine alkene-alkaloids were found to possess highest growth inhibition activity than the standard drug cisplatin and support the concept to modulate drug receptor interaction.

Full text of DOI:10.1016/j.bmcl.2013.12.108

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1180–1183
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pd-N-heterocyclic carbene catalyzed synthesis of piperidine
alkene–alkaloids and their anti-cancer evaluation
b
c
Shravankumar Kankala a, , Ranjith Kumar Kankala , Ramesh Balaboina ,
⇑
Narasimha Swamy Thirukovela a, Ravinder Vadde a, , Chandra Sekhar Vasam c,
⇑
⇑
a Department of Chemistry, Kakatiya University, Warangal, India
b Institute of Biotechnology, National Dong-Hwa University, Shou-Feng, Hualien 974, Taiwan, ROC
c Department of Chemistry, Satavahana University, Karimnagar, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of piperidine alkene–alkaloids including natural (+)-Caulophyllumine B in high yields
has been developed by Heck cross-coupling reaction catalyzed by simple in situ formed palladium-
N-heterocyclic carbenes (Pd-NHCs). Formation of Pd(0) nanoparticles has been noticed during the
reaction course. The synthesized piperidine alkene–alkaloids were evaluated for in vitro anti-cancer
activity against a panel of human tumor cell lines of lung, breast and ovarian. Several of these piperidine
alkene–alkaloids were found to possess highest growth inhibition activity than the standard drug
cisplatin and support the concept to modulate drug receptor interaction.
Received 27 August 2013
Revised 11 December 2013
Accepted 26 December 2013
Available online 3 January 2014
Keywords:
Piperidine alkene–alkaloids
Heck coupling
Ó 2013 Elsevier Ltd. All rights reserved.
N-Heterocyclic carbene
Natural products
Anti-cancer activity
Cancer remains a major public health problem in the developed
countries. One in four deaths on earth is caused by cancer, which
stood as the utmost dangerous disease and needs more attention
towards its therapy. Substituted piperidine structural motifs are
present in numerous bioactive natural alkaloids,1–5 these are most
widely prescribed drug categories and their synthesis in a stereo-
defined manner with appropriate building blocks represents a sig-
nificant synthetic task.6–9 In this context, the stereoselective
synthesis of alkene substituted piperidines would be worth study-
ing since both the functionalities are known to be highly selective
against various drug metabolizing enzymes like cytochrome P450
and provides combined effect.10–12 The important metabolic
pathways of piperidine and alkenes include hydration, oxidation,
peroxidation, and reduction. Besides, the alkene group can undergo
many useful synthetic transformations such as cycloaddition,
Wacker oxidation, metathesis and polymerization13–17 that can
further enhance the application of piperidine–alkene derivatives
vastly in fine chemicals, medicine and material science. There are
some natural piperidine alkaloids9,18–22 composed of either termi-
nal or internal alkene linkage shown in Figure 1.
synthesized by transition metal catalyzed C–C bond forming
cross-coupling or metathesis or Witting reactions,15–17,23–25 and
(ii) the alkene function is useful in cycloadditions to construct
other heterocycles14,26–28 those can be linked to piperidine.
Recently we have reported organo-NHC catalyzed 1,3-dipolar
cycloadditions of both terminal and internal alkynes.29
Palladium catalyzed C–C bond forming cross-coupling reactions
have gained immense importance in the stereocontrolled synthesis
of natural products.30–33 Specifically, the Heck, Suzuki and Negishi
couplings are of vital importance for such synthesis.34–37 Among
the various Pd-organometallic catalysts designed, those with
strong
r-donating NHCs increases electron density around the
palladium, accelerating the oxidative addition of the catalyst (i.e.
Pd-NHCs) to the substrate during the cross-coupling.38,39
Herein we describe the aptness of Heck cross-coupling reaction,
catalyzed by in situ generated Pd-NHCs, as key step in the stereo-
selective synthesis of a variety of piperidine alkene–alkaloids
including natural Caulophyllumine B (Fig. 1). The reaction outlined
in Scheme 1 describes the selection of starting materials to develop
Heck coupling reaction in the synthesis of piperidine alkene–
alkaloids (4a–j). These starting materials were easily accessed from
commercially available N-Boc-piperidine (1), which are competent
enough to provide stereoselectively the crucial (E)-olefin (4a–j).
We described the optimization of reaction conditions to
synthesize the crucial (E)-olefin (4a) of alkaloid Caulophyllu-
mine B as shown in Scheme 1. At first we have synthesized
This manuscript describes a facile route for the stereoselective
synthesis of piperidines with internal alkene linkage (vinyl
substituted piperidines) duly because; (i) they can be efficiently
⇑
Corresponding authors.
E-mail address: shravankankala@yahoo.com (S. Kankala).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.108

S. Kankala et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1180–1183
1181
(v) mesityl
R = (i) tert-butyl
(ii) iso-propyl
(iii) cyclohexyl
(iv) adamentyl
Cl
(vi) 4-chlorophenyl
N
N
R
R
N
Me
N
H
Me
Me
N
H
Me
(vii) 2,6-diipropylphenyl
H
Me
OH
(+)-Caulophyllumine B
(+)-Pinidine
(-)-Pinidine
Figure 2. NHC Precursors (imidazolium salts) used in the present work.
OH
N
We applied a simple protocol to a catalytic system consisting of
1:2 Pd(OAc)2 + Im-Cl (i), and slightly excess of base (Et3N or
K2CO3), in aq ethanol (9:1) at 80 °C. This system proved to be highly
efficientin Heckcouplingof 2 with 3a thanligandfree Pd(II)catalytic
systemandreachedalmostcompletionin ꢀ9 h to give86%yield(GC)
of selectively 4a specifically in the presence of Et3N. This combina-
tion (Pd(OAc)2 + NHC + Et3N) is further supplemented by adding a
phase transfer catalyst (PTC, TBAB) that has produced a maximum
yield of 93% in short reaction time of ꢀ5 h. Besides, there was no
Pd-block observed, but the in situ formation of Pd(0) nanoparticles
(PdNPs) was noticed by UV–visible spectrum. The role of a PTC to
form and stabilize the metal nanoparticles including PdNPs is
known.47,48 The roleof PdNPs in catalyzing Heckcouplingis also well
established.47,49,50 Further, the controlled formation of PdNPs from
Pd-NHCs during the Heck reaction was also reported.50–52 Neverthe-
less, the catalytic cycle for the Heck coupling involving either Pd(II)
or Pd(0) i.e. PdNPs is the same.
H
N
H
Ph
HO
(-)-histrionicotoxin 235A
(+)-dienomycin C
Figure 1. Examples of natural Piperidine alkene–alkaloids.
b
a
Ar-I (3a-j)
N
N
N
Ar
Ar
Br
Boc
Boc
Boc
4a-j
1
2
Ar = 4-OAcC H (4a), Ar = 4-OHC H , R = Me (5a),
Ar = C H , R = H (5b), Ar = 4-MeC H , R = H (5c),
6
4
6 4
LiAlH4/THF
6
5
6 4
Ar = 4-OMeC H , R = H (5d), Ar = 2-OMeC H , R = H (5e),
Ar = 2,6-di-MeC H , R = H (5f), Ar = 4-C H C H , R = H (5g),
Ar = 4-NO C H , R = H (5h), Ar = 4-CH COC H , R = H (5i),
6
4
6 4
6
3
2 5 6 4
2
6
4
3
6 4
N
R
Ar = 4-CF C H , R = H (5j).
3
6 4
5a-j
In order to generalize the utility of NHC ligands, we have also
employed Im-Cls (ii–vii) to produce stable Pd(II)-NHC catalysts
in situ in the Heck coupling of substrate 2 with 3a. The details of
the results are shown in ESI. Almost same yields ꢀ90% of
compound 4a were noted in an average reaction time of ꢀ5 h
and indicated that Im-Cls (i–vii) all are also useful NHC ligand pre-
cursors to provide stable Pd(II)-NHC catalysts during Heck cou-
pling. The structural analysis of the cross-coupled product i.e.
(E)-olefin target (4a) is consistent with spectral data obtained.
The 1H NMR spectrum of 4a obtained by Heck coupling has dis-
played the olefinic protons at ꢀd 6.12 ppm and at d 6.33 ppm indi-
cating the trans orientation of the olefinic protons. The Mass
spectrum of compound 4a show a single peak m/z = 345 belongs
to the molecular ion peak.
Complementary to the stereoselective synthesis of the (E)-olefin
of Caulophyllumine B, we next extended our work to synthesize
the analogues of Caulophyllumine B i.e. synthetic piperidine al-
kene–alkaloids by extending the protocol developed for Heck cou-
pling. Under the optimized the conditions, the Heck coupling
performed between (S)-2-vinyl-N-Boc-piperidine (2) and various
other aryl iodides (3b–j) using Pd(OAc)2 + NHC + PTC catalytic
system along with Et3N base produced stereoselectively the
(E)-olefins i.e. (S)-2-vinyl-N-Boc-pepiridine containing derivatives
(4b–j) in high yields. The details of the reactants employed and
products obtained are listed in Table 1. The reaction was found
to be general for a variety of substituted aromatic iodides, and suc-
cessful couplings were achieved with both electron-donating and
electron-withdrawing aryl substituents. (E)-olefin 4a on reaction
with LiAlH4 in the one-pot deprotection of the acetyl group and
the transformation of Boc group into the methyl functionality to
achieve the Caulophyllumine B 5a as reported previously.53 After
this, the deprotections of 4b–j were also carried out under the
same conditions to obtain 5b–j (Scheme 1, Table 1).
Scheme 1. Reagents and conditions: (a) s-BuLi/(+)-Sparteine, Et2O, À78 °C to rt,
6 h; (b) NHC-precursor (i), Pd(OAc)2, NEt3, TBAB, Water/Ethanol (9:1), reflux, 5 h.
(S)-2-vinyl-N-Boc-pepiridine (2), a critical starting material for
Heck coupling by treating N-Boc-piperidine with s-BuLi/(+)-Sparte-
ine.40 After having, (S)-2-vinyl-N-Boc-pepiridine in hand, we have
then worked on the optimization of conditions for catalytic Heck
coupling with 4-acetoxy iodo benzene (3a) in aqueous ethanol to
obtain (E)-olefin (4a) i.e. an immediate precursor of Caulophyllu-
mine B (see Table 1 ESI).
It has been established that active Pd(II)-NHC catalysts can be
formed in situ (under basic conditions) by treating an imidazolium
salt directly with Pd(II) salt41,42 or via transmetallation of Ag(I)-
NHCs43–45 in various C–C coupling reactions, depending on the
nature of imidazolium salts. In the present work, some simple
imidazolium chlorides (Im-Cls) depicted in Figure 2, synthesized
easily by Arduengo’s procedure,46 were employed as precursors
to NHCs to produce Pd(II)-NHC catalysts in situ.
Table 1
Results of synthesis of piperidine-alkenes (5a–j)a
Entry
Compound
Ar
R
Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-AcOC6H4
C6H5
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Me
H
H
H
H
H
H
H
H
H
93
90
92
92
90
88
92
93
92
92
71
88
92
86
90
84
90
90
85
90
4-MeC6H4
4-OMeC6H4
2-MeC6H4
2,6-di-MeC6H4
4-C2H5C6H4
4-NO2C6H4
4-CH3COC6H4
4-CF3C6H4
4-OHC6H4
C6H5
4-MeC6H4
4-OMeC6H4
2-OMeC6H4
2,6-di-MeC6H4
4-C2H5C6H4
4-NO2C6H4
4-CH3COC6H4
4-CF3C6H4
9
10
11
12
13
14
15
16
17
18
19
20
4j
5a
5b
5c
5d
5e
5f
5g
5h
5i
In vitro cytotoxic activity: The in vitro cytotoxic property in
terms of IC50 values i.e. growth inhibition of human cancer cell
lines (i) A-549 (Lung), (ii) MCF-7 (Breast) and (iii) OVCAR-3 (Ovar-
ian) of piperidine alkene–alkaloids (5a–j) were evaluated and
compared with cisplatin as working standard, and the final inhib-
itory concentration to an extent of 50% was calculated using the
reported methods.54
The cell viability values presented in Table 2 point out that the
piperidine alkene–alkaloids (5a–j) has revealed strong growth
inhibition and fit for this activity against all the tested fanatic
5j
a
All products were characterized by 1H/13C NMR and mass spectral analysis.
Isolated yields after chromatography.
b

1182
S. Kankala et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1180–1183
Table 2
In vitro cytotoxic activity of piperidine alkene–alkaloids (5a–j) on human cancer cell linesa (IC50
l
g/mL)b
Entry
Compound
A-549 (Lung)
MCF-7 (Breast)
OVACR-3 (Ovarian cancer)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
3.45 0.06
9.99 0.07
8.56 0.25
4.33 0.05
4.94 0.11
7.28 0.07
5.94 0.02
3.27 0.07
3.69 0.05
2.82 0.07
3.76 0.01
1.51 0.06
9.15 0.07
5.35 0.01
3.57 0.03
3.81 0.02
4.29 0.01
4.13 0.05
2.15 0.02
2.70 0.02
1.25 0.0
1.94 0.02
10.47 0.32
8.48 0.09
3.31 0.13
4.78 0.08
6.27 0.09
5.07 0.08
1.02 0.02
2.18 0.05
0.99 0.04
2.48 0.06
9
10
11
5i
5j
Cisplatin
2.75 0.08
a
Data represent as mean SEM values. Cytotoxicity as IC50 for each cell line, is the concentration of compound which reduced by 50% the optical density of treated cell
with respect to untreated cells using the MTT assay.
b
Data represent as mean SEM values of these independent determinations.
perilous cancer cell lines. On comparision with the standard some
of the derivaties predominantly 5j, 5a, 5h, 5i (in the same
descending sequence) has shown comparable strong inhibition
against all the three cell lines duly because of electron withdraw-
ing nature of tested derivatives. In General most of these alkaloids
effectively took action strongly on human cancer cell lines almost
close to the concentration of standard and exhibited better
inhibitory nature. As far as the structure activity relationship is
concerned, numerous correlations can be established from this
data to support the nature of cytotoxic activity based on not only
steric but also electronic properties of piperidine moiety and
aromatic ring substituents. This might be one of the promising
reasons for the improvement in the activity of piperidine
alkene–alkaloids is duly because of drug-receptor interaction
i.e. ligational properties.
In addition to, the fascinating piece of evidence at this point is,
the aryl substituent on piperidine alkene afforded a chance to aug-
ment the cancer growth suppression. Trifluoromethyl substituted
aryl derivative of piperidine–alkene alkaloid (5j) has shown the
prominent activity among all the derivatives tested against all
the cell lines as of the electronic effect by fluoro substituent on
cytotoxicity has already been reported.55,56 In contrast, compound
5a with O-acetyl functionalised derivative of aryl substituent fol-
lowed the order of improved activity especially against breast can-
cer cell line MCF-7. The compounds 5d, with 4-OCH3C6H4 (entry 4),
and 5e, with 2-OCH3C6H4 (entry 5) substituent are next to the stan-
dard drug Cisplatin (entry 11) has shown relatively better activity
in all cases.
Supplementary data
Supplementary data (experimental procedures for 4a–j, 5a–j
and Spectral data of compounds 4a–j and 5a–j) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2013.12.108.
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Acknowledgments
S.K. and N.S.T. thank CSIR, New Delhi for the award of Research
Associate and JRF.

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