Traceless synthesis of hydantoin fused tetrahydro-β-carboline on ionic liquid support in green media

Article abstract of DOI:10.1021/ol901857h

A novel Ionic liquid (IL) supported, green synthetic protocol has been developed toward the synthesis of oxo and thio hydantoin analogues tethered with tetrahydro-β-carboline by the use of focused microwave irradiation. IL-bound tryptophan underwent a Pic

Full text of DOI:10.1021/ol901857h

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4826-4829
Traceless Synthesis of Hydantoin Fused
Tetrahydro-ꢀ-carboline on Ionic Liquid
Support in Green Media
Barnali Maiti, Kaushik Chanda, and Chung-Ming Sun*
Laboratory of Combinatorial Drug DiscoVery, Department of Applied Chemistry,
National Chiao Tung UniVersity, Hsinchu 300-10, Taiwan
cmsun@mail.nctu.edu.tw
Received August 10, 2009
ABSTRACT
A novel ionic liquid (IL) supported, green synthetic protocol has been developed toward the synthesis of oxo and thio hydantoin analogues
tethered with tetrahydro-ꢀ-carboline by the use of focused microwave irradiation. IL-bound tryptophan underwent a Pictet-Spengler reaction
with various carbonyl compounds to generate the IL- immobilized tetrahydro-ꢀ-carbolines in aqueous isopropanol media. Subsequent reaction
of substituted tetrahydro-ꢀ-carboline derivatives with various isocyanates and isothiocyanate provided a three-dimensional combinatorial
library in a traceless fashion.
Tetrahydro-ꢀ-carbolines (1a), a key constituent of most
naturally occurring indole alkaloids, have received consider-
able attention by medicinal chemists owing to their important
bioproperties including antiaggregation, in vitro trypanocidal
activity, antimalarial, and anticonvulsant activity.1 Recently,
it has been found that hydantoin and thio hydantoin deriva-
tives (1b) also possess several pharmacological properties
including dual action for anticonvulsant and antimuscarinic
activity, insulinotropic properties, and antifungal activity.2
However, the ring system 2 as the conceptual derivation of
a new scaffold, which represents the amalgamation of two
important pharmacophores, is much less known (Figure 1).
The generation of tetracyclic skeletons with tetrahydro-ꢀ-
carboline and hydantoin thus has a substantial intellectual
appeal due to their resemblance to drug-like molecules. This
type of compound has been documented for the inhibition
of cGMP-phosphodiesterase (2a, 2b), a chemical messenger
in the body that activates cGMP kinase, and as a novel
antimitotic agent (2c) and a novel Eg5 inhibitor (2d).3,6
Because of their diverse array of biological activities, these
(1) (a) Zhao, M.; Bi, L.; Bi, W.; Wang, C.; Yang, Z.; Ju, J.; Peng, S.
Bioorg. Med. Chem. 2006, 14, 4761. (b) Valdez, R. H.; Tonin, L. T. D.;
Ueda-Nakamura, T.; Dias Filho, B. P.; Morgado-Diaz, J. A.; Sarragiotto,
M. H.; Nakamura, C. V. Acta Trop. 2009, 110, 7. (c) Tonin, L. T. D.;
Barbosa, V. A.; Bocca, C. C.; Ramos, E. R. F.; Nakamura, C. V.; Costa,
W. F.; Basso, E. A.; Nakamura, T. U.; Sarragiotto, M. H. Eur. J. Med.
Chem. 2009, 44, 1745. (d) Jenkins, P. R.; Wilson, J.; Emmerson, D.; Garcia,
M. D.; Smith, M. R.; Gray, S. J.; Britton, R. G.; Mahale, S.; Chaudhuri, B.
Bioorg. Med. Chem. 2008, 16, 7728. (e) Gupta, L.; Srivastava, K.; Singh,
S.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett. 2008, 18, 3306.
(2) (a) Hudkins, R. L.; DeHaven-Hudkins, D. L.; Doukas, P. Bioorg.
Med. Chem. Lett. 1997, 7, 979. (b) Sergent, D.; Wang, Q.; Sasaki, N. A.;
Ouazzani, J. Bioorg. Med. Chem. Lett. 2008, 18, 4332. (c) Tan, C; Wei,
L.; Ottensmeyer, F. P.; Goldfine, I.; Maddux, B. A.; Yip, C. C.; Batey,
R. A.; Kotra, L. P. Bioorg. Med. Chem. Lett. 2004, 14, 1407.
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Daugan, A.; Grondin, P.; Ruault, C.; Gouville, A. M.; Coste, H.; Kirilovsky,
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10.1021/ol901857h CCC: $40.75
Published on Web 10/06/2009
 2009 American Chemical Society

novel drug-like molecules are interesting to explore in early
screening (Figure 2). The advent of combinatorial chemistry
for the rapid generation of numerous collections of small
molecules has greatly helped in the design and choice of
lead structures in the drug discovery process.7
combinatorial synthesis.11 Significant interest has recently
been garnered in the development of organic reactions in
aqueous medium.12,14 Water, a profuse and non-toxic solvent,
could be a greener option because of its nonflammable,
nonhazardous properties. Due to numerous favorable proper-
ties, isopropyl alcohol (IPA) was preferred as the cosolvent
by lessening the polarity of the reaction medium and thus
enhancing the solubility of organic substrates. It is cheap,
safe, and easily biodegradable via the acetone pathway and
a predominantly favorable organic cosolvent.15 Higher yields
and shorter reaction times are the two features that make
microwave irradiation superior to meet the increased de-
mands of high-throughput synthesis.16 Ionic liquid support
in aqueous systems increases the power of microwave
irradiation and makes the reaction sequences more attractive
in terms of aqueous chemistry perspective. Herein, we
describe a simple and efficient synthetic protocol for the fast
synthesis of substituted indole alkaloids under microwave
irradiation in aqueous IPA media.
Figure 1
.
Conceptual derivation of a new scaffold.
To attain the target compound on ionic liquid support, the
most essential reaction involves the coupling of Boc-
protected L-tryptophan 4 to hydroxyl ethyl methyl imida-
zolium tetrafluoroborate 3c17 (Scheme 1). For comparison
purposes, this coupling reaction was carried out under a set
of different conditions, involving (i) room temperature for
48 h; (ii) thermal heating at refluxing temperature for 12 h;
and (iii) microwave irradiation in a closed vessel system
under pressure (80 °C, 2 bar) which reduced the time to 12
min. After completion of the reaction, the dicyclohexyl urea
(DCU) was filtered off and IL-conjugates 5 were precipitated
with addition of cold ether, which was then filtered to obtain
the IL-conjugates 5. Unlike other solid supports, the main
advantage of using ionic liquid soluble support was its direct
monitoring capacity by standard analytical technique such
Figure 2
.
Representative examples of biologically active hydantoin
analogues tethered with tetrahydro-ꢀ-carbolines.
Ionic liquids are used as ecofriendly solvents as well as
catalysts in organic synthesis because of their unique
chemical and physical properties.8,9 On the basis of the
choice of cations and anions, ionic liquids can be reused,
and the solubility can be adjusted readily for phase separation
from organic as well as aqueous media.10 When the hydroxyl
group is on the cation of an ionic liquid, these ionic liquid
have been used as synthetic equivalents of classical low
molecular weight soluble polymer supports in combinatorial
synthesis of structurally diverse small molecules. There are
some literature reports regarding the employment of alcohol-
functionalized ILPs as a soluble support in liquid-phase
1
as H and 13C NMR and mass spectroscopy. For the first
time, we have demonstrated here that the product conversion
was quantitative, monitored by regular proton NMR spec-
troscopy in each intermediate step with an attached IL-tag.
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Org. Lett., Vol. 11, No. 21, 2009
4827

It has been found that protons of the -CH2CH2OH group
of the free IL appeared at 3.94 ppm in proton NMR spectra
A (Figure 3), whereas the same protons were shifted to 4.48
ppm after attachment to the Boc-protected L-tryptophan 4
as a result of the electron-withdrawing nature of the ester
linkage to the IL-tag in spectra B. The generation of
ꢀ-carbolines by [5 + 1] approach could be realized by the
NHBoc deprotection and subsequent Pictet-Spengler cy-
clization with carbonyl compounds in aqueous acidic me-
dium.18,19 It is noteworthy that NHBoc deprotection and
subsequent cyclization were carried out in one pot manner
using 20% TFA in H2O-IPA (1:1) under microwave
irradiation (80 °C, 2 bar) for 20-30 min. The NHBoc
deprotection was achieved in 10 min under microwave
irradiation, which was further confirmed from the disap-
pearance of tert-butyl group around 1.44 ppm in spectra C.
The in situ generated amine was subsequently reacted with
various carbonyl compounds in the same reaction media to
generate imines that subsequently underwent intramolecular
cyclization to achieve the tetrahydro-ꢀ-carbolines 6 with the
IL-tag remaining intact. When ketones were used in the
Pictet-Spengler cyclization, more harsh reaction conditions
(130 °C, 9 bar, 20 min) were required to complete cyclization
owing to the deactivating nature of the ketone functionality.
Moreover, the same set of reactions was finished in 18 h
under refluxing condition. After the reaction was finished,
the water and IPA were removed from the reaction mixtures
under reduced pressure, and the residue remaining was
redissolved in CH3CN, further precipitated with ether, and
filtered through a fritted funnel to remove unreacted carbonyl
compounds and other side products to obtain the IL-
conjugates 6.
Scheme 1
.
Ionic Liquid Supported Synthesis of Hydantoin
Fused Tetrahydro-ꢀ-carbolines
The formation of the IL-immobilized tetrahydro-ꢀ-carbo-
line was evident from 1H NMR spectra, which indicates the
appearance of a NH proton of ꢀ-carboline moiety at 10.5
ppm and two methyl group absorbances manifested at 2.0
ppm in spectra D. The formation of cis and trans diastere-
omers in various ratios of IL-bound ꢀ-carboline 6 is
determined through proton NMR analysis.
To create the second diversity point in target structures,
the terminal hydantoin moiety is constructed across IL-
immobilized ꢀ-carbolines by the reaction with various
isocyanates and thioisocyanates under microwave irradiation
to form urea intermediate 7. Simultaneous intramolecular
cyclization of IL-conjugated urea 7 in water/IPA cosolvents
followed by cleavage of the ionic liquid support led to a
traceless synthesis of tetracyclic scaffold 8 in high yield and
high purity. The cyclization of the hydantoin ring and
subsequent traceless cleavage of the ionic liquid support was
performed in one step under mild basic conditions in
triethylamine. The reaction was eventually completed in 12
Figure 3. Stepwise monitoring toward the formation of tetrahydro-
ꢀ-carboline fused oxo and thio hydantoin analogues on ionic liquid
support.
min (80 °C, 2 bar) as compared to requiring 10 h in refluxing
conditions. Reaction progress was directly monitored by
TLC, which indicated the complete release of the desired
compound 8 from the IL support to confirm the traceless
nature of the reaction. The solvents were removed, and the
residue remaining was redissolved in CH3CN and further
purified by precipitation in ether to obtain the targeted
compounds 8. The formation was achieved from proton
NMR spectra, which clearly indicated the nullifying of the
signal at 10.5 ppm and the disappearance of the characteristic
signal of the IL-tag at 4.8-4.7 ppm (-CH2CH2-). Moreover,
all intermediates of IL-supported products could be confirmed
(18) (a) Chang, W. J.; Kulkarni, M. V.; Sun, C. M. J. Comb. Chem.
2006, 8, 141. (b) Lee, S. C.; Choi, S. Y.; Chung, Y. K.; Park, S. B.
Tetrahedron Lett. 2006, 47, 6843. (c) Lin, M. J.; Zhang, W.; Sun, C. M.
J. Comb. Chem. 2007, 9, 951. (d) Chen, C. H.; Chang, C. M.; Chen, H. Y.;
Lai, J. J.; Sun, C. M. J. Comb. Chem. 2007, 9, 618
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Suzuki, K.; Takayama, H. Org. Lett. 2006, 8, 4605. (c) Bandini, M.; Melloni,
A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem.
Soc. 2006, 128, 1424
.
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Org. Lett., Vol. 11, No. 21, 2009

with mass spectra (MS). The analytical data including crude
yield and purity are reported in Table 1.
took the 1D NOE analysis of compound 8l, which showed
that there is no correlation between C2-Ha and C12-Hb
protons, which demonstrates clearly the trans stereochemistry
(Figure 4). Moreover, the irradiation of Hf caused the
enhancement of He and Hb by 9.00% and 2.03% respectively
which further enhanced the Hd by 2.70%. Similarly, the
irradiation of Hd caused the enhancement of Ha and Hc by
4.86% and 23.48%. In the same way, the irradiation of He
caused the enhancement of Hb and Hf signals by 1.81 and
12.4% respectively. We also obtained the signal enhancement
of Hc by 3.18% followed by irradiation of Ha.
Table 1. Microwave-Assisted, IL-Supported Synthesis of
Tetrahydro-ꢀ-carboline Hydantoin and Thio Hydantoins
(8a-8n)
Figure 4. Some important NOE interactions in the 8l trans isomer.
In this study, an efficient and green methodology for the
gram-scale synthesis of pharmacologically interesting trisub-
stituted indole alkaloids through the use of commercially
available building blocks has been demonstrated. Final
libraries are usually obtained in high purity and yield just
by simple precipitation and washings of each IL-attached
intermediate with minimum column purification. In contrast
to the solid-phase synthesis, the reaction progress of IL-
bound support was successfully monitored by a conventional
analytical technique without the “cleave-&-analyze” method.
Moreover, the aqueous chemistry provides a practical
prospect for the sustainable development of future science
and technologies in drug discovery.
a LRMS were detected with ESI ionization source. b Yields are based
on loading of ionic liquid soluble support. c Determined by HPLC analysis
at UV 254 nm of the crude product. d Isolated as only the trans isomer.
Acknowledgment. The authors thank the National Science
Council of Taiwan for the financial assistance.
OL901857H
The predominantly trans stereochemistry of tetrahydro-
ꢀ-carboline hydantoins 8h-8m is based on spectral data
through comparison with earlier works by Cook’s research
group.20 To further confirm the obtained results, we under-
(20) (a) Ungemach, F.; Soerens, D.; Weber, R.; DiPierro, M.; Campos,
O.; Morkry, P.; Cook, J. M.; Silverton, J. V. J. Am. Chem. Soc. 1980, 102,
6976.
Org. Lett., Vol. 11, No. 21, 2009
4829