Natural product inspired diversity oriented synthesis of tetrahydroquinoline scaffolds as antitubercular agent

Article abstract of DOI:10.1021/co100022h

An efficient natural product inspired diversity oriented syn thesis of tetrahydroquinoline analogues has been developed using the natural carbohydrate derived solid acid catalyst via multicomponent aza-Diels-Alder reaction of imine (generated in situ from

Full text of DOI:10.1021/co100022h

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Natural Product Inspired Diversity Oriented Synthesis of
Tetrahydroquinoline Scaffolds as Antitubercular Agent
,†
†
†
‡
‡
§
Atul Kumar,* Suman Srivastava, Garima Gupta, Vinita Chaturvedi, Sudhir Sinha, and R. Srivastava
†
‡
§
Medicinal and Process Chemistry Division, Drug Target Discovery Division, and Division of Microbiology, Central Drug Research
Institute, CSIR, Lucknow, India
S Supporting Information
b
ABSTRACT: An efficient natural product inspired diversity oriented syn-
thesis of tetrahydroquinoline analogues has been developed using the
natural carbohydrate derived solid acid catalyst via multicomponent aza-Diels-
Alder reaction of imine (generated in situ from aromatic amine and
aldehyde) with dienophile in acetonitrile in a diastereoselective manner.
The use of water as solvent reverses the diastereoselectivity toward the cis
isomer. Interestingly, tricyclic pyrano/furano benzopyran with cis diastereo-
selectivity is obtained when salicylaldehyde is used as an alternative of
aromatic aldehyde under the same condition. These synthesized quinolines
and benzopyrans analogues have been evaluated for their Antitubercular
activity against M. tuberculosis H Ra, and M. tuberculosis H Rv, and some
37
37
of the analogues shows better activity profile than their natural product
analogues. The protocol is not only mild, efficient, ecofriendly, but also
involves reusable and biodegradable catalyst and provides route for both the
diastereoisomer.
KEYWORDS: natural product inspired synthesis, diversity oriented synthesis, antitubercular agent, tetrahydroquinoline,
benzopyran, cellulose sulfuric acid
’
INTRODUCTION
Natural products have played a critical role in the identifica-
tion of several medicines including antibacterial, antifungal,
antitubercular, and antitumor compounds. These biologically
Mother Nature is about 3.8 billion year old lab which has
4
produced an amazing library of chemical structures unparalleled
in number, supreme in diversity and function. These molecular
structures are a real treasure and contain diverse information
which is encoded in the language of chemistry. Collectively these
molecules cover the chemical genome of our planet. With
modern knowledge tools in medicinal chemistry we can better
use them for the benefit of health. More significantly we can use
these resources by making copies of the natural products by
doing total synthesis and also by putting the right pharmaco-
phore at the right position for getting more beneficial effects in
active heterocycles have been synthesized by total synthesis.
Though total synthesis plays a crucial role in the medicinal
5
chemistry efforts, it is time-consuming, impractical, and may
lack structural variability. For a lead discovery rationale which is
the key of drug discovery, a more rapid solution may be provided
by diversity-oriented synthesis (DOS) of natural product-like
molecules. A compromise between total synthesis and combina-
torial chemistry, DOS concerns molecules displaying sufficient
molecular complexity to resemble natural products, but features a
more straightforward synthesis, thus allowing introduction of
1
terms of the biological profile. Natural products always inspired
6
significant structural diversity.
the medicinal chemist for discoveries of new drugs. About 70% of
the new chemical entities (NCEs) introduced in the past 25 years
were natural products obtained from sources such as plants and
animals, derived from natural products, or chemically designed
Quinoline alkaloids such as graveolinine, 4-methoxy-2-phenyl-
quinoline, and kokusagine (Figure 1) isolated from Lunasia
amara exhibit significant in vitro antitubercular activity against M.
7
2
tuberculosis H Rv. SAR confirmed that the presence of an aryl
37
mimics of natural products.
group, that is, phenyl or a methylenedioxyphenyl ring at the C-2
position, methoxy group at the C-4 position and quinoline nucleus,
enhances inhibitory activity. Apart from this, several natural products
The drug discovery process targeted toward natural products
is very tedious, time-consuming, and difficult. The modern drug
discovery by applying the tools of synthetic chemistry is an
innovative approach, and diversity oriented synthesis has exhibi-
ted considerable promise to explore the biologically active chemi-
Received: September 29, 2010
Published: November 10, 2010
3
cal space with more density quickly.
r 2010 American Chemical Society
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ACS Combinatorial Science
RESEARCH ARTICLE
Figure 1. Quinoline Alkaloids exhibiting promising antitubercular activity.
Figure 2. Biologically active quinoline alkaloids.
Figure 3. Sulfonated cellulose and starch.
containing tetrahydroquinoline moiety such as martinelline,
virantmycin, Oxamniquine, and L-689,560, a very potent N-methyl-
D-aspartate (NMDA) antagonist (Figure 2) exhibits relevant
Several synthetic methods have been developed for these
12,13
compounds,
among them the aza-Diels-Alder reaction
between N-arylimine with electron rich dienophile is a powerful
8
pharmacological properties.
method for the construction of tricyclic tetrahydroquinoline ring
14
In continuation of our ongoing research toward the develop-
ment of diversity oriented or biology oriented synthesis of
systems. Since the pioneering work of Povarov, BF -OEt has
3
2
been the most commonly used catalyst for this reaction. How-
ever, many of these catalysts are not fully satisfactory with regard
to operational simplicity and isolated yield, and some of the
previous methods would bring metals or other undesired chem-
ical species into the environment. Hence, there is a quest to find a
better and improved methodology for the synthesis of quinoline
derivatives.
9
-11
bioactive analogues with potential pharmacological value
and inspired from the antitubercular activity of 2-phenylquino-
line analogues, we have been interested in designing and
synthesizing the diversity oriented 2-phenyl tetrahydroquinoline
analogues as an active antitubercular agent. Herein we wish to
report an efficient diversity oriented synthesis of antitubercular
tetrahydroquinoline via multicomponent synthesis using cellu-
lose sulphuric acid as proton source.
In view of our ongoing quest for sustainable processes toward the
development of environmentally benign synthetic procedures for
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RESEARCH ARTICLE
Figure 4. Representative examples of quinolines and benzopyrans prepared using our diversity-oriented synthetic approach using cellulose sulfuric acid,
A = Acetonitrile, B = Water.
Scheme 1. Multicomponent Synthesis of Pyranoquinoline
Figure 5. Dienophile used in diversity oriented synthesis of quinolines
and benzopyrans.
15
multicomponent reactions, we headed for the development of
16,9c
new ecofriendly catalyst.
Natural biopolymers are attractive candidates in the search for
17
new solid support catalysts. In this regard, the two most abundant
natural supramolecular carbohydrates (NSCar), cellulose and
starch molecules, are selected for catalytic purposes because these
are biodegradable, cost-effective, and obtainable from renewable re-
sources. To accomplish these effective catalytic properties, cellulose
and starch were converted to their sulfonic acid derivatives (Figure 3).
We have selected sulfonic acid derivatives of carbohydrates as
catalyst because many sulfonated active site containing immobi-
(
Figure 5) greatly improved the molecular diversity of the adduct
formed, thereby allowing admittance to diversified tetrahydro-
quinoline derivatives with considerable biological activities. There-
fore, the process is worthwhile for the preparation of libraries of
tetrahydroquinoline compounds.
18
lized solid catalyst have exhibited promising results.
In the Povarov reaction either an aromatic amine, a carbonyl
usually an aldehyde), and an activated olefin react together to
’
RESULTS AND DISCUSSION
In this endeavor we desire to report a facile route for the
(
yield a tetrahydroquinoline adduct (multicomponent) or an aro-
matic amine, a carbonyl (usually an aldehyde) react together to
form imine, and this in situ form imine reacts with an activated
olefin to yield a tetrahydroquinoline adduct (Scheme 1). This
stepwise process can be explained mechanistically through the
synthesis of tetrahydroquinoline analogues via Povarov reaction.
In the Povarov reaction the in situ generated imines react with
a variety of dienophiles yielded a wide range of quinoline het-
erocycles (Figure 4). The use of cyclic or acyclic enol ethers
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RESEARCH ARTICLE
Figure 6. Tentative reaction mechanism for the formation of pyranoquinoline and furanoquinoline.
was observed. Thus, using 0.03 g as an optimized catalyst
concentration, the reaction time was set up to 2 h. No reaction
(
NR) took place in the absence of catalyst. Also, with an increase
in the temperature (80 °C) no effect on the reaction pace and
substrate conversion was noticed; however at room temperature,
conversion was cleaner and at 0 °C reaction conversion was
much cleaner than at higher temperature. The reusability of the
catalyst was also investigated, and it is noteworthy that no
obvious decrease in the efficiency was observed for the successive
Figure 7. Cis and trans isomer.
16
uses of the recovered catalysts.
generation of an imine, which is attacked by the electron rich
nucleophile under acid activation, followed by an intramolecular
cyclization (Figure 6).
In this study it was found that cellulose sulfuric acid is a more
efficient catalyst over other catalysts with respect to reaction
time, yield, and consistency of the desired product. Extending the
methodology further similar reaction conditions were also ap-
plied on the reaction of benzaldehyde and aniline with 2,3-
dihydrofuran, cyclopentadiene, pyrrole, and ethyl vinyl ether. It
was observed that 2,3-dihydrofuran, cyclopentadiene, pyrrole,
and ethyl vinyl ether show faster reactivity and higher selectivity
(because of less steric hindrance of the five membered and acyclic
enol ether). Cis and trans compounds produced in similar man-
ner, and trans was the major isomer and cis was the minor isomer
when acetonitrile was used as solvent. After the optimized con-
ditions were established, the feasibility of this reaction was exam-
ined using several substituted anilines and substituted benzalde-
hyde. We were pleased to report that in all cases, the reactions
gave the corresponding products in good to excellent yield (Table 1).
Besides this, unexpected results were obtained when salicylde-
hyde was used as aromatic aldehyde; in this three-component
reaction under same reaction condition functionalized cis-fused
N-arylamino furanobenzopyrans as a mixture of cis/trans dia-
stereomers was obtained (Scheme 2). In this case cis is the major
isomer and trans is the minor one.
The diastereoselectivity of quinoline alkaloids strongly de-
pends on solvent. The product was obtained as a mixture of cis
and trans isomers. The trans one is formed as the major isomer
with organic solvents like acetonitrile. If water is used along with
19
acetonitrile cis selectivity is increased. It is interesting to report
here that when water is used as solvent alone, cis isomer was
obtained as the major product. The product ratio was determined
1
by H NMR spectroscopic analysis. The most diagnostic param-
eter for the structural assignment is the scalar coupling con-
stant between protons H-4a and H-5. As depicted in Figure 7, the
cis isomer has a small coupling constant (JH-4a, H-5) = 5.0-6.0 Hz
consistent with an all cis configuration of the hydrogen atoms 4a,
5
, and 10b. In the trans isomer, the value of (JH-4a, H-5) =
1
0.0-11.0 Hz is large and indicative of the antiorientation of
protons H-4a and H-5. The coupling constant (J
) in all
H-4a, H-10b
products (2.2-2.9 Hz) indicates the cis- fusion of the pyran- and
1
2b
quinoline rings.
As an initial stride in the development of the solid acid
catalyzed methodology, we tried to prepare tetrahydroquinoline
from the reaction of benzaldehyde (1.0 mmol), aniline (1.0
mmol), and 3,4 dihydro-2H-pyran (2.0 mmol) as a model in the
absence and presence of cellulose and starch sulfuric acid under
different temperature conditions (Scheme 1). To optimize the
amount of catalyst needed the reaction was carried out by varying
amount of the catalyst, and maximum yield was obtained with
Recently, Wang et al. have describe a diastereoselective syn-
2
0
thesis of cis-fused pyranobenzopyrans and furanobenzopyrans
using preformed o-hydroxybenzaldimines with 3,4-dihydro-2H-
pyran and 2,3-dihydrofuran. Here one pot multicomponent
synthesis of cis-fused furanobenzopyrans using cellulose sulfuric
acid is described. To optimize the reaction condition we have
performed the reaction of salicylaldehyde and several aromatic
amines with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran also.
The optimum condition was same as in pyranoquinoline. The
corresponding pyranobenzopyrans were obtained as a mixture of
cis and trans diastereoisomers in good to excellent yield
(54-96%). In most of the cases, the cis isomer was the major
product. The ratio of cis and trans isomers was determined from
0
.03 g of catalyst. Further increase in the amount of catalyst in the
mentioned reaction did not have any significant effect on the
product yield. First, the reaction was carried out with 0.05 g of
catalyst, and 60-80% conversion was observed within 2 h at
room temperature. Further experiments revealed that even with
decreases in the catalyst amount down to 0.03 g, a good con-
version (90%) was achieved in 4 h. However, when the catalyst
concentration was reduced to 0.01 g, only 35-45% conversion
1
the H NMR spectra of the crude products.
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RESEARCH ARTICLE
a,b
Table 1. Diversity Oriented Synthesis of Tetrahydroquinoline and Benzopyran Derivatives
antitubercular activity-MIC(μg/mL)
d
e
H37Ra
H37Rv
0
0
c
c
R
(R -CHO) R = dienophile yield (%) trans/cis (CH
3
CN) cis/trans (H
2
O) time (h)
cis
trans
cis
trans
H
H
Cl
Ph
I
89
82
76
75
88
85
89
80
71
83
86
76
71
80
79
64
69
80
65:35
59:41
55:45
66:34
67:33
51:49
56:44
69:31
65:35
62:38
58:42
52:38
59:41
63:37
55:45
79:21
29:71
35:65
85:15
89:11
81:19
88:12
75:25
81:19
76:16
69:31
89:11
72:28
68:32
61:49
74:26
79:21
83:17
76:16
2.0
2.0
2.8
3.5
3.0
3.2
2.5
2.5
2.8
3.0
3.9
3.2
2.5
2.5
2.7
3.0
3.0
3.8
12.5
25
>25
>25
>50
12.5
>25
>50
25
>25
6.25
>25
>25
12.5
>25
>25
>25
>25
>50
g25
>50
25
>25
>25
>25
>25
>50
50
2-OCH
3
Ph
I
Ph
I
12.5
25
CH
3
Ph
I
H
4-OCH
3
3
Ph
Ph
I
6.25
>25
>25
>50
12.5
>25
25
H
Ph
II
II
III
III
III
III
IV
V
V
V
V
II
I
H
4-OCH
Ph
12.5
f
f
H
nd
nd
f
f
4-OCH
3
Ph
nd
nd
f
f
Cl
H
H
H
Ph
nd
nd
H
>50
>50
f
f
Ph
>50
25
nd
nd
Ph
>25
25
f
f
4
4
4
-OCH
3
Ph
12.5
25
nd
12.5
>25
>25
>25
>25
nd
f
f
-Cl
Ph
nd
nd
f
f
-CH
3
Ph
>25
>50
>25
nd
nd
H
H
2-OH Ph
2-OH Ph
>25
>50
12.5
>50
Kokusagine
16
16
Graveolinine
a
b
3
Reaction conditions: aldehyde (5 mmol), aromatic amine (5 mmol), dienophile (10 mmol), CellSA (0.03 g), solvent (CH CN/water). All products
d
1
13
c
1
were characterized by H and C NMR spectroscopy. Product ratio was determined from the H NMR spectra of the crude products. MABA MIC
e
37 37
f
(
μg/mL) Against M. tuberculosis H Ra. Agar micro dilution MIC (μg/mL) against M. tuberculosis H Rv. Not determined.
Scheme 2. Multicomponent Synthesis of cis Fused Furano
and Pyrano Benzopyran
some of the synthesized compound show better minimum inhibitory
concentrations (MIC) values (6.25 μg/mL and 12.5 μg/mL) in
comparison with natural products used for the design, for
example, Kokusagine and Graveolinine. The results of antituber-
cular activity are depicted in Table 1.
’
CONCLUSION
A diversity-oriented synthetic approach has been developed
for the diastereoselective synthesis of tetrahydroquinoline li-
braries using cellulose sulfuric acid as catalyst which yields skel-
etally diverse natural product-like compounds. These natural
products-like libraries represent an effort to influence the structural
features of natural products to target biologically significant
regions of chemical structure space. The developed methodology
is efficient, and the catalyst used is eco-friendly, reusable, bio-
degradable, and easily synthesized. We have also reported the
synthesis of linear tricyclic pyrano/furano benzopyran with cis
diaseteroselectivity using cellSA from salicylaldehyde. These syn-
thesized quinolines and benzopyrans analogues have been eval-
uated for their antitubercular activity against M. tuberculosis
H Ra, and M. tuberculosis H Rv. We believe this methodol-
A plausible mechanistic approach is given in Figure 8. It is
proposed that, with o-hydroxybenzaldehyde, the reaction prob-
ably followed through the formation of an o-quinonemethide
intermediate, which consequently undergoes cycloaddition
with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran leading to the
formation of linear pyranobenzopyran and furanobenzopyran,
respectively.
3
7
37
ogy is superior to existing methodologies for the synthesis of
both the diastereoisomers of tetrahydroquinolines, which are
of immense importance as bioactive molecules.
All the synthesized compounds were screened for their
antitubercular activity using the microalamar blue (MABA)
’
EXPERIMENTAL SECTION
21
method against M. tuberculosis H Ra, while the agar micro-
37
dilution method was used for the determination of activity
General Experimental Procedure for the Synthesis of
Pyranoquinolines/Furanoquinolines, Cyclopentaquinolines,
22
against M. tuberculosis H Rv. It is interesting to report that
37
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RESEARCH ARTICLE
Figure 8. Plausible mechanism for the formation of pyranobenzopyran and furanobenzopyran.
Pyrroloquinolines, 4-Ethoxy-2-phenyl-1,2,3,4-tetrahydro-
quinoline, cis-Fused Pyranobenzopyrans, and Furanobenzo-
pyrans As Exemplified for Pyranoquinolines/Furanoquinolines.
A mixture of aldehyde (5 mmol), aromatic amine (5 mmol),
and 3,4-dihydro-2H-pyran/2,3-dihydrofuran (10 mmol) was stirred
vigorously at 0 °C with cellulose sulfuric acid (0.03 g) in acetonitrile/
water (5 mL) for an appropriate amount of time given in Table 1.
After completion of the reaction, as indicated on TLC, the reaction
mixture was filtered and residue was washed with DCM. The residue
containing cellulose sulfuric acid was used for the subsequent
reactions. The filtrate was evaporated under reduced pressure to
obtain residue. Then water and ethyl acetate was added to the above
residue. The organic phase was separated, dried (Na SO ), and
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’
ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and compound characterization data for products. This material
is available free of charge via the Internet at http://pubs.acs.org.
’
AUTHOR INFORMATION
Corresponding Author
*
9
E-mail: dratulsax@gmail.com. Phone: 91-522-2612411. Fax:
1-522-2623405.
’
ACKNOWLEDGMENT
(9) (a) Kumar, A.; Maurya, R. A.; Ahmad, P. Diversity oriented
synthesis of benzimidazole and benzoxa/(thia)zole libraries through
polymer-supported hypervalent iodine reagent. J. Comb. Chem. 2009,
Authors S.S. and G.G. thank CSIR-UGC New Delhi for the
award of a senior research fellowship. The authors also acknowl-
edge SAIF-CDRI for providing the spectral and analytical data.
11, 198–201. (b) Kumar, A.; Sharma, S.; Maurya, R. A.; Sarkar, J.
Diversity Oriented Synthesis of Benzoxanthene and Benzochromene
Libraries via One-Pot, Three-Component Reactions and Their Anti-
proliferative Activity. J. Comb. Chem. 2010, 12, 20–24. (c) Kumar, A.;
Gupta, G.; Srivastava, S. Diversity Oriented Synthesis of Pyrrolidines via
Natural Carbohydrate Solid Acid Catalyst. J. Comb. Chem 2010, 12,
458–462.
(10) (a) Kumar, A.; Maurya, R. A.; Sharma, S.; Ahmad, P.; Singh,
A. B.; Tamrakar, A. K.; Srivastava, A. K. Design and synthesis of 3,5-
diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid
lowering agents. Bioorg. Med. Chem. 2009, 17, 5285–5292. (b) Kumar,
A.; Maurya, R. A.; Sharma, S.; Kumar, M.; Bhatia, G. Synthesis and
biological evaluation of N-aryl-1,4-dihydropyridines as novel antidyslipi-
demic and antioxidant agents. Eur. J. Med. Chem. 2010, 45, 501–509.
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dx.doi.org/10.1021/co100022h |ACS Comb. Sci. 2011, 13, 65–71