A concise diastereoselective approach to enantioenriched substituted piperidines and their in vitro cytotoxicity evaluation

Article abstract of DOI:10.1016/j.bmcl.2014.08.003

A library of diversely stereo-oriented, highly substituted 2,6-cis piperidine derivatives were synthesized, and evaluated for their anticancer activity in cancer cells that included A549 (lung cancer, CCL-185), MCF7 (breast cancer (HTB-22), DU145 (prostate cancer (HTB-81), and HeLa (cervical cancer, CCL-2). One stereo-variant emerged as a promising candidate for further design based structure-activity studies.

Full text of DOI:10.1016/j.bmcl.2014.08.003

Accepted Manuscript
A concise diastereoselective approach to enantioenriched substituted piperi-
dines and their in vitro cytotoxicity evaluation
Gullapalli Kumaraswamy, Rangaraju Satish Kumar, Bitla Sampath, Y.
Poornachandra, C. Ganesh Kumar, Sahithya Phani Babu Vemulapalli,
Jagadeesh Bharatam
PII:
S0960-894X(14)00834-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.08.003
BMCL 21901
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
20 May 2014
12 July 2014
2 August 2014
Please cite this article as: Kumaraswamy, G., Kumar, R.S., Sampath, B., Poornachandra, Y., Ganesh Kumar, C.,
Vemulapalli, S.P.B., Bharatam, J., A concise diastereoselective approach to enantioenriched substituted piperidines
and their in vitro cytotoxicity evaluation, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/
10.1016/j.bmcl.2014.08.003
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A concise diastereoselective approach to
enantioenriched substituted piperidines and their
in vitro cytotoxicity evaluation
Gullapalli Kumaraswamy,*a Rangaraju Satish Kumara, Bitla Sampatha, Y. Poornachandra,b C. Ganesh Kumar,b Sahithya Phani
Babu Vemulapallic and Jagadeesh Bharatamc

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
A concise diastereoselective approach to enantioenriched substituted piperidines
and their in vitro cytotoxicity evaluation
Gullapalli Kumaraswamy,*a Rangaraju Satish Kumara, Bitla Sampatha Y. Poornachandra,b C. Ganesh
,
Kumar,b Sahithya Phani Babu Vemulapallic and Jagadeesh Bharatamc
a Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
b Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
c Center for NMR & Structural Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A library of diversely stereo-oriented, highly substituted 2,6-cis piperidine derivatives
were synthesized, and evaluated for their anticancer activity in cancer cells that
included A549 (lung cancer, CCL-185), MCF7 (breast cancer (HTB-22), DU145
(prostate cancer (HTB-81), and HeLa (cervical cancer, CCL-2). One stereo-variant
emerged as a promising candidate for further design based structure-activity studies.
Keywords:
Anti-tumor activity
piperidine scaffolds
cytotoxic activity
asymmetric Mannich reaction
Grubbs cross-metathesis.
2009 Elsevier Ltd. All rights reserved.
The configuration of stereogenic centers in the piperdine ring has
The non-racemic functionalized piperidine scaffolds have
received renewed attention owing to their broad spectrum of
biological and pharmaceutical properties.1 Functionalized
piperidine sub-units are found to be part of naturally occurring
alkaloids and anti-tumor antibiotic molecules.2 Simple derivatives
of the substituted piperidine molecule L-pipecolic acid, are a
constituents of plants, fungi and human physiological fluids.3 In
particular, C-2 and C-6 substituted piperidine molecules
originated from extracts of Dendrobatesspeciosus (Panamanian
poison frogs) have showed a range of activities such as cytotoxic,
antifungal, hemolytic and anti-HIV properties4 (Figure 1).
considerable influence on its biological and pharmaceutical
activity. Stereogenic functional group variations in 6-membered
azacycles are expected to accrue good activity; as a consequence,
they are exhibiting noteworthy differences in their biological
profiles.5 The development of simple and efficient methods for
the synthesis of enantiomerically pure substituted piperidine
derivatives from readily available starting materials is always a
demanding task. Consistent with our continued interest in
developing catalytic enantioselective routes to enantioenriched
small molecules,6 we describe the preparation of new variants of
highly substituted non-racemic functionalized homopipecolic
derivatives and chemotherapeutical activity.
 Corresponding author. Tel: + 91-40-27193154; Fax: + 91-40-27193275, Email Address: gkswamy_iict@yahoo.co.in

RESULTS AND DISCUSSIONS
A number of impressive methods have been reported
with the same high level of diastereoselectivity. Compounds 3b-
3e, were generated using L-proline catalyst under otherwise
identical conditions. Next, to prepare anti-syn and anti-anti
variants, we employed a previously described anti-Mannich
strategy10b using amido-sulfone 1f and 2 in the presence of 20
for accessing enantioenriched substituted piperidine molecules.
Included among them are i) the use of readily available resident
chiral amine as a nitrogen source7 ii) chiral pool derived routes8
and iii) various catalytic routes.9 While exploring numerous
methods, we have focused on the organocatalyzed asymmetric
Mannich reaction that constitutes one of the atom-economic
efficient strategies for providing the chiral -amino carbonyl
motif in either syn- or anti-selective fashion.10 Organocatalyzed
asymmetric reaction products having formyl functionality that
could be used for tandem reactions with appropriate pro-
nucleophiles are especially interesting.11 In principle, three
stereogenic centers could be realized using a tandem Mannich /
indium promoted allylation sequence. Further, a Grubbs cross-
metathesis with methyl acrylate and aza-Michael reaction is
expected to provide highly substituted optically active piperidine
derivatives.
mol%
of
(S)-,
-bis[3,5-bis(trifluoromethyl)phenyl]-2-
pyrrolidine methanol and subsequent indium promoted allylation
under identical conditions as reported (vide infra). The resulting
products, anti-syn 3f and anti-anti 3ff, showed similar diastereo
selctivities (Figure 3).
Figure 2. Synthesis of -amino allyl alcohols produced by
Mannich / indium promoted allylationa
OH
N
CO2H
H
N
CO2H
H
L-Pipecolic acid
S
R
(2 ,4 )-4-hydroxypipecolic acid
OH
OH
a) Isolated yield.
H
CO2H
N
Following successful preparation of diastereo divergent
hydroxyl-methyl-amino variant compounds, we have focused on
one-pot Grubbs cross-metathesis and aza-Michael reaction.13 The
cross metathesis reaction between 3a and methylacrylate using
second-generation Grubbs catalyst proved to be ineffective in
several organic solvents. However, the use of 5 mol% of second-
generation Grubbs catalyst in the absence of solvent gave the
-unsaturated ester in 85% yield (Figure 4).
N
H
n-C4H9
N
H
MeO
OMe
(-)-Lasubin
Alkaloid-241D
L
-HomoPipecolic acid
Figure 1. Substituted piperidine molecules
At the outset, we envisaged that a one-pot reaction could be used
to install a hydroxy-methyl-amino stereogenic centers with
pendant terminal olefin functionality. To this end, an
organocatalyzed asymmetric Mannich reaction developed by List
et. al.10a followed by Barbas11 Mannich-allyation reaction
sequence was adopted. After some experimentation (Supporting
Information), the desired transformation was achieved to give
syn-anti (3a) and syn-syn (3aa) products as separable
diastereomers (Figure 2). The ratio of syn-anti to syn-syn product
(66:34) ratio was determined from the weight of the isolated
diastereomers. A stepwise reaction sequence showed that the
stereochemical information introduced in the first organocatalytic
step was preserved in the reaction9d by yielding syn Mannich
products in 99:1 dr with 98% ee.12 Thus, it is the indium
promoted allylation that provided poor diastereoselectivity. The
relative stereochemistry of the 3a and 3aa were not assigned at
this juncture but advanced further.
i)
20 mol%
CF3
F3C
CF3
N
CF
OTMS
3
Boc
NH
H
KF (5 equiv)
CHCl3
OH
NHBoc
SO2Tol
O
30 0C, 4 days
H
+
In0
ii)
Br
3f, (Major isomer, 70% yield)
2
1f
H2O
3ff(Minor isomer, 30% yield)
Figure 3. Synthesis of -amino allyl alcohols from anti-Mannich
reaction.
Finally, the one-pot Grubbs cross metathesis / aza-Michael
reaction sequence between terminal olefin 3a and methylacrylate
was performed by the exposer of the metathesis product to acidic
and then basic conditions. The initial product 4a was obtained in
an encouraging 40% yield. In a survey of bases, aqueous
ammonia was found to increase the yield of 4a to 85% as a single
diastereomer. Various other substrates were submitted to the
successful conditions and the results are shown in Figure 4. In all
cases, exclusive cis diastereomer was obtained.
With the optimized reaction conditions, the scope of the
transformation was examined with various substituted aromatic
aldehydes. As shown in Figure 2, substituted aromatic aldehydes
with electron rich and poor functional groups were reacted
smoothly, affording the desired products in fair to good yields

The relative stereochemistry of C2, C3, C4 and C6 centers of 4a
were assigned by NMR studies such as 1D including selective
1H-1H homo-nuclear decoupling NMR, and 2D-NOESY and
HSQC analysis. In compound 4a, the observed strong nOe cross-
peaks of Ha-Hc, Hc-Hf, and Hf-Ha protons and the scalar coupling
Figure 5. Nuclear Overhauser effect (nOe) analysis of 4a and
Aza-Michael reaction by 6-exo-trig cyclization of 4a and 4b.
constants (3Jab = 2.87 Hz, Jef = 11.88 Hz, and Jdf = 4.65 Hz)
unequivocally showed that Ha and Hf protons are in a syn
orientation (Figure 5). The stereochemical outcome of 3a can be
explained on the basis of 6-exo-trig cyclization wherein,
substituents at positions 2 and 5 are likely to adopt the equatorial
orientations TS-1, leading to the cis-diastereomer 4a (Figure
5).7c In case of 3b, the substituents at positions 2 and 5 are likely
to adopt the axial orientations TS-2, leading to the cis-
diastereomer 4b.
3
3
CH3
CH3
Ph
Ph
NH
e
H
H
NH2
2
H
b
3
6
HO
H
O
5
4
HO
3a
COOMe
H
H
d
a
H
c
H
H
f
H
H
OMe
3Jef = 11.88 Hz
3Jdf = 4.65 Hz
4a
TS-1
CO2Me
O
OMe
Ar
OH
Ar
H
H
OH
NH2
N
H
H
H3C
3b
H
H3C
H
Figure
4.
Synthesis
of
enantioenriched
piperedine
H
H
Ar = 4-MePh
derivativesa,b,c,d
4b
H
H
TS-2
O
i)
OH
OMe
BOC
5 mol% Grubbs
2nd generation
catalyst, rt, 5 h
O
NH OH
ACTIVITY AGAINST CANCER CELLS
N
H
OMe
ii) 2M HCl, THF,
rt, 6 h
4a, 85% yield
dr = > 99
3a
The stereo-divergent substituted homopipecolic ester derivatives
4a, 4aa-4f, and 4ff were screened for cytotoxicity activity against
a panel of tumor cell lines. In vitro growth inhibition was
assessed in 96-well plates by the standard MTT assay using
doxorubicin as a standard. Four human tumor cell lines were
used: A549 derived from human alveolar adenocarcinoma
epithelial cells (ATCC No.CCL-185), HeLa derived from human
cervical cancer cells (ATCC No. CCL-2), DU-145 derived from
human prostate adenocarcinoma cells (ATCC No. HTB-81) and
iii) Basification
with aq. NH3 solution
OH
OH
OH
O
O
O
N
OMe
N
H
OMe
N
H
OMe
H
4aa, dr = > 99; 83%
4bb, dr = > 99; 81%
4b, dr = > 99; 80%
OH
OH
OH
O
O
O
N
OMe
N
H
N
OMe
OMe
H
H
Table 1. Cytotoxicity results of various enantioenriched
MeO
substituted piperidine derivatives
4d, 83%
4cc, 81%
4c, 83%
OH
OH
OH
Entry
Test
Substrate
IC50valuesa
in (μM)
O
O
O
N
H
OMe
N
H
OMe
N
H
OMe
F
F
MeO
A549 DU145
HeLa
14.2
6.5
MCF7
12.3
5.4
4ee, 72%
4e, 75%
OH
4dd, 81%
OH
1
2
4a
4aa
4b
20.5
8.5
11.3
6.3
O
O
N
H
OMe
N
H
OMe
4ff, 83%
4f, 80%
3
29.0
97.6
NA
49.7
330.3
110.4
27.4
12.6
6.5
13.4
NA
12.2
NA
4
4bb
4c
a) All reactions were carried out using 2 mmol scales. b) Isolated yield.
c) The relative stereochemistry of C2, C3, C4 and C6 centers of 3a was
unambiguously assigned by NMR studies and all other by analogy.
d) In all cases, exclusive one diastereomer was observed.
5
NA
NA
6
4cc
4d
NA
18.2
11.5
5.3
17.1
10.4
5.1
7
23.5
5.4
8
4dd
4e
9
26.6
17.2
51.7
NA
19.8
17.4
15.6
18.2
10
4ee

11
12
13
14
15
16
4f
4ff
5a
5b
6a
6b
34.6
69.2
31.2
28.9
17.6
20.1
0.6
64.1
NA
35.2
41.1
31.5
33.4
16.5
19.9
0.7
35.6
NA
The activity results of 5a, 6a, 5b and 6b were shown in Table 1.
The results indicate the polar functional groups shown
deleterious to activity.
In conclusion, we have accomplished
a
concise
41.6
46.5
14.8
15.7
0.6
39.8
23.1
13.7
12.5
0.6
diastereoselective approach for a library of enantioenriched
substituted piperidine molecules. Strategic transformation of this
two-step sequence includes a catalytic enantioselective Mannich
reaction that is either syn- or anti-selective as the genesis of
chirality / indium promoted allylation, and Grubbs cross-
metathesis / aza-Michael reaction. Moreover, this strategy can be
used for the synthesis of various derivatives of stereo-divergent
substituted aza-cyclic small molecules which can be evaluated
for biological activity. Interestingly, promising data presented in
this study reveals that the configuration of stereogenic center
plays an important role in anticancer activity. This study also
provides the impetus for the next generation design and synthesis
of enantioenriched substituted homopipecolic esters and amides.
Further study aimed at a comprehensive understanding of
stereogenicity-structure activity relationships is currently in
progress.
Doxorubicinb
(Standard control)
i. Not active; A549-Lung cancer (CCL-185); MCF7-Breast cancer (HTB-
22); DU145-Prostate cancer (HTB-81); HeLa-Cervical cancer (CCL-2)
ii. (a) The IC50 values (50% inhibitory concentration) were calculated
from the plotted absorbance data from the dose-response curves. IC50 values
(in μM) were expressed as the average of two independent experiments. (b)
Reference compound for positive control profile, MCF7 derived from human
breast adenocarcinoma cells (ATCC No.HTB-22) using the MTT assays.14
IC50 values (50% inhibitory concentration) were determined as a
preliminary screen, with results shown in Table 1. Compounds
4aa and 4dd had excellent activity against all four cell types. By
comparing the 4-fluorophenyl and 4-methoxyphenyl analogues,
the substitution pattern on the aromatic nucleus was shown to
have an effect on the activity profile. Similarly, the configuration
of piperidine stereogenic centers had an influence on the activity
profile compound 4aa and 4dd being more cytotoxic than the
corresponding diastereomers of 4a and 4d, respectively.
ACKNOWLEDGMENT: Financial support was provided by
the DST, New Delhi, India (Grant No: SR/S1/OC-08/2011), ORGIN
(CSC-0108) programme (CSIR) of XII Five year plan. UGC & CSIR
(New Delhi) is gratefully acknowledged for awarding the fellowship
to R. S. K, B. S, Y. P, and S. P. B. V.
Supplementary data
Supplementary data associated (detailed experimental procedures for
the synthesis and the nOe studies) with this article can be found, in
the online version,
The substituted piperidine molecules have three strategic sub-
structures for modifications; hence we aimed at for further
improvement of activity based on the lead molecular structures of
4aa and 4dd that showed good activity in preliminary screening.
Reduction of the ester group of 4aa and 4dd to the primary
alcohols 5a and 6a, and saponification to the carboxylic acids 5b
and 6b, was accomplished in good yields (Scheme 1). These
more polar compounds possessing hydrogen bond donors were
less active than the parent esters (Table 1).
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