Highly diastereoselective crystallization-induced asymmetric transformation of 1,3-disubstituted-tetrahydro-β-carbolines in water

Article abstract of DOI:10.1039/c7ra08811f

A green and highly stereoselective method for the synthesis of cis or trans-1,3-disubstituted-tetrahydro-β-carbolines has been developed using water as the solvent. A mixture of cis and trans-1,3-disubstituted-tetrahydro-β-carboline hydrochlorides can be converted to a single cis or trans isomer via a crystallization-induced asymmetric transformation process. It is possible to get both isomers using this method by incorporating different additives in water. This method has advantages such as environmental friendliness, high stereoselectivity, suitability for industrialization, and non-toxicity.

Full text of DOI:10.1039/c7ra08811f

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Highly diastereoselective crystallization-induced
asymmetric transformation of 1,3-disubstituted-
tetrahydro-b-carbolines in water†
Cite this: RSC Adv., 2017, 7, 47753
*
Tian-Zhuo Meng, Xiao-Xin Shi,
and Qi-Qi Fan
Hui-Ya Qu, Yi Zhang, Zhong-Shou Huang
A green and highly stereoselective method for the synthesis of cis or trans-1,3-disubstituted-tetrahydro-b-
carbolines has been developed using water as the solvent. A mixture of cis and trans-1,3-disubstituted-
Received 9th August 2017
Accepted 27th September 2017
tetrahydro-b-carboline hydrochlorides can be converted to
a single cis or trans isomer via
a crystallization-induced asymmetric transformation process. It is possible to get both isomers using this
method by incorporating different additives in water. This method has advantages such as environmental
friendliness, high stereoselectivity, suitability for industrialization, and non-toxicity.
DOI: 10.1039/c7ra08811f
rsc.li/rsc-advances
100% via simple crystallization under appropriate conditions.4
It can in principle be divided into two types: crystallization-
Introduction
induced
enantiomer
transformations
(CIETs)
and
Water is one of the most common resources on earth, and has
played an important role in humanity’s development and
engenders life. As we know, enzymatic processes in nature can
only occur in an aqueous environment. Water is not only
a medium for biochemical reactions, but is also a reagent in
some oxidation and reduction reactions in the body. As people
pay more and more attention to environmental protection,
there is a tendency to implement green chemistry in organic
synthesis.1 Chemists have devoted a lot of research effort to
replacing harmful and toxic solvents with more environmen-
tally friendly alternatives in the past two decades. Water is
considered a green solvent for organic reactions, having
advantages like non-toxicity, non-ammability, non-volatility,
cheapness, and ready availability. One of the earliest examples
was reported by Diels and Alder in 1931, for the Diels–Alder
reaction of furan and maleic anhydride.2 More and more
researchers have carried out various organic reactions using
water as a solvent in recent years.3 Nevertheless, it is still
a highly challenging task to nd practical reactions which use
water as solvent because of the drawbacks such as the insolu-
bility of organic reactants and high surface tension.
crystallization-induced diastereomer transformations (CIDTs).
As CIAT processes are consistent with the requirements of
“atom-economy” and green chemistry, and as the synthesis of
chiral compounds becomes more and more important, there
has been an explosion of research activities utilizing CIAT
techniques to prepare chiral compounds in the last few deca-
des.5,4c–e However, new, efficient and highly stereoselective CIAT
processes remain highly desirable.
The tetrahydro-b-carboline scaffold exists widely in natural
products and medicinal compounds, so the asymmetric
syntheses of chiral tetrahydro-b-carbolines have attracted much
attention.6
1,3-Disubstituted-tetrahydro-b-carbolines
(1,3-
disubstituted-THbCs) are an important kind of compound due
to their various biological activities7 including antitumor,7a
antioxidant,7b antiparasitic,7c anti-inammatory,7d antith-
rombotic,7e fungicidal,7f antiviral7g properties and their use in
the treatment of type 2 diabetes mellitus.7h Several methods
have been reported for the preparation of optically pure 1,3-
disubstituted-THbCs.8 However, most of them have drawbacks
such as poor stereoselectivity,8a the introduction and removal of
sterically hindered groups,8b–e low yield8f,8g and using harmful
solvents.8h Herein, we describe the rst highly stereoselective
method for the synthesis of cis or trans 1,3-disubstituted-THbCs
via a CIAT process in water.
Crystallization-induced
asymmetric
transformations
(CIATs), which are also referred to as crystallization-induced
stereoisomer transformations (CISTs), are a highly practical
means for converting enantiomeric or diastereomeric mixtures
into a single stereoisomeric product with a theoretical yield of
Results and discussion
Department of Pharmaceutical Engineering, School of Pharmacy, East China
University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, P. R.
China. E-mail: xxshi@ecust.edu.cn
Our investigation commenced with the preparation of mixtures
of cis and trans 1,3-disubstituted-THbCs via the classical Pictet–
Spengler reaction. We obtained the mixtures of cis and trans 1,3-
disubstituted-THbCs hydrochlorides in 85–98% yields via the
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra08811f
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 47753–47757 | 47753

View Article Online
RSC Advances
Paper
Table 1 Highly stereoselective synthesis of cis or trans 1,3-disubsti-
tuted-THbCs via a CIAT process in watera
Scheme
1 Synthesis of mix-1$HCl from L-tryptophan ester
hydrochloride.
condensation of L-tryptophan ester hydrochlorides with
different aldehydes under reux for 2–12 hours in isopropanol.
The diastereomeric ratio of the cis and trans-isomers ranged
from 11 : 89 to 92 : 8 (see Scheme 1). We then tried to convert
the mixtures of 1,3-disubstituted-THbCs to a single isomer via
a CIAT process in water. We began our study with mix-1a$HCl
[mixtures of (1S,3S) and (1R,3S)-diastereomers] as the model
substrate. The starting diastereomeric ratio of the cis and trans-
isomers was 46 : 54 aer the Pictet–Spengler reaction. We
initially put mix-1a$HCl in pure water and heated it to 95 ꢀC. We
found that part of the solid dissolved with a quick conversion of
the cis-isomer to the trans-isomer at the beginning. However,
the rate of conversion slowed down rapidly and equilibrium
between the cis and trans-isomers was reached aer two hours.
The diastereomeric ratio of the cis and trans-isomers changed to
16 : 84.
We thought that the high solubility of the materials probably
resulted in the poor stereoselectivity of the CIAT process.
Inspired by the salting-out effect and ionic equilibrium theory,
we used 5% sodium chloride aqueous solution as the solvent.
To our surprise, the diastereomeric ratio of the cis and trans-
isomers changed to 6 : 94 when equilibrium was reached aer 6
hours. Experiments were then performed to investigate the
inuence of the concentration of sodium chloride on the
a
Reaction conditions: mix-1a–u$HCl (1 g), NaCl aqueous solution (8
b
c
mL), 95 ꢀC. Isolated yields. Cis/trans ratios were determined by
HPLC, the relative congurations of products were assigned by 1H–1H
NOESY.8h
Fig.
1 Influence of the concentration of NaCl on the diaster-
eoselectivity and reaction rate of CIAT processes for mix-1a$HCl.
47754 | RSC Adv., 2017, 7, 47753–47757
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 2 The effect of additives on the CIAT stereoselectivity of mix- Table
1a$HCl
3
The effect of different additive salts on the diaster-
eoselectivities of CIATsa
Entry
Additivea
Time (h)
Productsb (cis : trans)
Yieldc (%)
1
2
3
4
5
6
7
8
NaCl
KCl
LiCl
CaCl2
MgCl2
BaCl2
ZnCl2
AlCl3
10
12
10
12
11
10
14
10
6
6
6
10
8
4
5
4
3
12
10
10
1 : 99
3 : 97
1 : 99
2 : 98
4 : 96
2 : 98
10 : 90
3 : 97
98 : 2
98 : 2
5 : 95
9 : 91
3 : 97
99 : 1
96 : 4
97 : 3
97 : 3
13 : 87
6 : 94
5 : 95
96
92
96
94
92
93
81
93
94
95
83
81
80
96
91
94
93
73
84
86
9
NaBr
KBr
10
11
12
13
14
15
16
17
18
19
20
Na2SO4
K2SO4
Mg2SO4
NaNO3
NaI
a
Reaction conditions: mix-1$HCl (1 g), 10% additive salt aqueous
b
c
solution (8 mL), 95 ꢀC. Isolated yields. Cis/trans ratios were
determined by HPLC, the relative congurations of the products were
KI
NaBF4
Na2SO3
CH3CO2Na
HCO2Na
assigned by H–1H NOESY.8h
1
a
Reaction conditions: 10% (w/w) aqueous solutions were used for
the additive salts could change the conguration of the major
product (comparing entries 1, 9, 11, 14, 15 and 17–20), whereas
the different cations of the additive salts could not change the
conguration of the major product (comparing entries 1–8 or
11–13). This is probably due to the fact that the different anions
b
c
various salts. Cis/trans ratios were determined by HPLC. Isolated
yields.
diastereomeric ratio and reaction rate (see Fig. 1). As can be
seen from Fig. 1, when the concentration of sodium chloride
was increased from 0% to 15%, the purity of the trans-isomer
was improved from 84% to >99% aer the equilibrium was
nally reached. On the other hand, increasing the concentra-
tion of sodium chloride signicantly decreased reaction rate.
When a 10% sodium chloride aqueous solution was used as the
solvent, a great diastereoselectivity (99 : 1) was obtained aer 10
hours.
Next, we attempted to extend the scope of the above CIAT
process (see Table 1). We found that the above CIAT process
could be applied to almost all substrates; the CIAT of some
substrates produced trans-isomers with high diaster-
eoselectivities, while the CIAT of other substrates produced cis-
isomers with high diastereoselectivities. We also found that the
optimized concentrations of sodium chloride were different for
various substrates, ranging from 0% to 20%.
We have also investigated the inuence of various salts on
the above CIAT process using mix-1a$HCl; a total of twenty salts
were examined and the results are summarized in Table 2. To
our surprise, the addition of some salts produced trans-1a$HX
as the major product (entries 1–8, 11–13 and 18–20), while the
addition of other salts produced cis-1a$HX as the major product
(entries 9, 10 and 14–17). We found that the different anions of
Scheme 2 Syntheses of Tadalafil and HR22C16 from the 1,3-disub-
stituted-THbCs cis-1i and trans-1f, respectively.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 47753–47757 | 47755

View Article Online
RSC Advances
Paper
diastereoselectivities and rate of the CIAT process. The above
CIAT protocol has the following advantages: (1) it was success-
fully carried out in pure water, so it is environmentally benign;
(2) all the products have good to excellent diastereoselectivities;
(3) the scope of the CIAT process is very wide, it was applicable
to all the tested substrates; (4) the experiments were carried out
on a gram scale; (5) it is practical because the starting materials
are easy to obtain and operation is very simple.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Scheme 3 Proposed mechanism for the CIAT process of mix-1a$HCl
in aqueous NaCl solution.
We are grateful to the National Natural Science Foundation of
China (No. 20972048) and the Shanghai Educational Develop-
ment Foundation (The Dawn Program: No. 03SG27) for the
nancial support of this work.
(XÀ) of the additive salts might exchange with the ClÀ of mix-
1a$HCl to crystallize out less soluble trans (or cis)-1a$HX.
We then investigated the CIAT processes of other substrates
by adding different salts. We examined the CIAT processes of all
twenty-one substrates shown in Table 1. It was found that the
conguration of the major products from the CIAT processes of
six substrates could be changed by adding different salts (see
Table 3). Therefore we can obtain both the cis and trans-isomers
of these six substrates by incorporating different additive salts
in water.
It is worth noting that cis or trans 1,3-disubstituted-THbCs,
which can be readily obtained by the above CIAT process, are
very useful for drug synthesis. For example, (+)-cis-1i was
synthesized from D-tryptophan methyl ester hydrochloride via
the same CIAT process, which is an important intermediate for
the synthesis of Tadalal (see Scheme 2),9 a selective PDE5
inhibitor. Additionally, trans-1f was successfully used herein for
the synthesis of HR22C16 (see Scheme 2), which is a potent
mitotic kinesin Eg5 inhibitor.10
Notes and references
1 (a) R. A. Sheldon, Green Chem., 2017, 19, 18; (b)
F. Roschangar, R. A. Sheldon and C. H. Senanayake, Green
Chem., 2015, 17, 752; (c) R. A. Sheldon, Chem. Soc. Rev.,
2012, 41, 1437; (d) K. Sanderson, Nature, 2011, 469, 18; (e)
P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39, 301;
(f) E. S. Beach, Z. Cui and P. T. Anastas, Energy Environ.
Sci., 2009, 2, 1038; (g) M. Poliakoff and P. Licence, Nature,
2007, 450, 810; (h) I. T. Horvath and P. T. Anastas, Chem.
Rev., 2007, 107, 2169; (i) J. H. Clark, Green Chem., 2006, 8,
17; (j) B. Horton, Nature, 1999, 400, 797; (k) P. T. Anastas
and J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, UK, 1998.
2 O. Diels and K. Alder, Liebigs Ann. Org. Bioorg. Chem., 1931,
490, 243.
3 (a) M. B. Gawande, V. D. B. Bonifacio, R. Luque, P. S. Branco
and R. S. Varma, Chem. Soc. Rev., 2013, 42, 5522; (b)
M. O. Simon and C. J. Li, Chem. Soc. Rev., 2012, 41, 1415;
(c) R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110,
6302; (d) D. Dallinger and C. O. Kappe, Chem. Rev., 2007,
107, 2563; (e) C. I. Herrerias, X. Yao, Z. Li and C. J. Li,
Chem. Rev., 2007, 107, 2546; (f) C. J. Li and L. Chen, Chem.
Soc. Rev., 2006, 35, 68; (g) M. H. Shinde and
U. A. Kshirsagar, Green Chem., 2016, 18, 1455; (h) L. Tang,
Y. Yang, L. Wen, X. Yang and Z. Wang, Green Chem., 2016,
18, 1224; (i) W. Zhao, C. Yang, Z. Cheng and Z. Zhang,
Green Chem., 2016, 18, 995; (j) T. Mizugaki, Y. Nagatsu,
K. Togo, Z. Maeno, T. Mitsudome, K. Jitsukawa and
K. Kaneda, Green Chem., 2015, 17, 5136; (k) V. S. Shende,
S. H. Deshpande, S. K. Shingote, A. Joseph and
A. A. Kelkar, Org. Lett., 2015, 17, 2878; (l) M. C. Pirrung and
K. D. Sarma, J. Am. Chem. Soc., 2004, 126, 444; (m)
W. J. Ang, Y. S. Chng and Y. Lam, RSC Adv., 2015, 5, 81415;
(n) S. Paul, M. M. Islam and S. M. Islam, RSC Adv., 2015, 5,
42193; (o) C. Yang, W.-Q. Su and D.-Z. Xu, RSC Adv., 2016,
6, 99656.
Some people have proposed that the least soluble diaste-
reomer will crystallize preferentially during a CIAT process.5b,11
Based on this assumption, a plausible mechanism for the above
CIAT process of mix-1$HCl in aqueous NaCl solution is
proposed in Scheme 3. Both the solid cis and trans-1$HCl would
partially dissolve into the aqueous solution phase by dissoci-
ating into cis and trans-1 cations and chloride anions, the cis
and trans-1 cations would interchange via cleavage and forma-
tion of the C–N bond.12 Crystallization of the less soluble isomer
would shi the equilibrium to afford the less soluble isomer as
the major product of the CIAT process.
Conclusions
In conclusion, we have developed the rst protocol for a highly
diastereoselective CIAT process of 1,3-disubstituted-THbCs in
water. This protocol provides efficient access to a single isomer
of either cis or trans-1,3-disubstituted-THbCs, which are very
useful for drug synthesis. It was also observed that addition of
different salts in water exhibits an obvious inuence on the
47756 | RSC Adv., 2017, 7, 47753–47757
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
4 (a) K. Sakai, N. Hirayama and R. Tamura, in Novel Optical
Resolution Technologies, ed. R. Yoshioka, Springer-Verlag
Berlin Heidelberg, New York, 2007, pp. 83–132; (b)
E. M. Carreia and H. Yamamoto, in Comprehensive
Chirality, ed. R. M. Kellogg and M. Leeman, Elsevier Ltd.,
Groningen, 2012, vol. 9, pp. 367–399; (c) N. G. Anderson,
Org. Process Res. Dev., 2005, 9, 800; (d) K. M. J. Brands and
A. J. Davies, Chem. Rev., 2006, 106, 2711; (e) S. Caddick and
K. Jenkins, Chem. Soc. Rev., 1996, 25, 447.
5 (a) F. Belanfger, C. E. Chase, A. Endo, F. G. Fang, J. Li,
S. R. Mathieu, A. Z. Wilcoxen and H. Zhang, Angew. Chem.,
Int. Ed., 2015, 54, 5108; (b) F. A. Kortmann, M.-C. Chang,
E. Otten, E. P. A. Couzijn, M. Lutz and A. J. Minnaard,
Chem. Sci., 2014, 5, 1322; (c) D. L. Jameson, T. Field,
M. R. Schmidt, A. K. DeStefano, C. J. Stiteler, V. J. Venditto,
B. Krovic, C. M. Hoffman, M. T. Ondisco and
M. E. Belowich, J. Org. Chem., 2013, 78, 11590; (d) A. Duris,
T. Wiesenganger, D. Moravcikova, P. Baran, J. Kozisek,
A. Daich and D. Berkes, Org. Lett., 2011, 13, 1642; (e)
T. Ueda, N. Kanomata and H. Machida, Org. Lett., 2005, 7,
2365; (f) K. M. J. Brands, J. F. Payack, J. D. Rosen,
T. D. Nelson, A. Candelario, M. A. Huffman, M. M. Zhao,
J. Li, B. Craig, Z. J. Song, D. M. Tschaen, K. Hansen,
P. N. Devine, P. J. Pye, K. Rossen, P. G. Dormer,
R. A. Reamer, C. J. Welch, D. J. Mathre, N. N. Tsou,
J. M. Mcnamara and P. J. Reider, J. Am. Chem. Soc., 2003,
125, 2129; (g) E. Vedejs, R. W. Chapman, S. Lin, M. Muller
and D. R. Powell, J. Am. Chem. Soc., 2000, 122, 3047; (h)
M. Petit, A. J. B. Lapierre and D. P. Curran, J. Am. Chem.
Soc., 2005, 127, 14994; (i) O. Hamelin, J. Pecaut and
M. Fontecave, Chem.–Eur. J., 2004, 10, 2548.
20, 4437; (b) S. M. Lin, J. Y. Wu, C. Su, S. Ferng, C. Y. Lo
and R. Y. Y. Chiou, J. Agric. Food Chem., 2012, 60, 9856; (c)
R. Brokamp, B. Bergmann, I. B. Muller and S. Bienz,
Bioorg. Med. Chem., 2014, 22, 1832; (d) X. Hu, M. Zhao,
Y. Wang, Y. Wang, S. Zhao, J. Wu, X. Li and S. Peng, J.
Mater. Chem. B, 2016, 4, 1384; (e) C. Li, X. Zhang, M. Zhao,
Y. Wang, J. Wu, J. Liu, M. Zheng and S. Peng, Eur. J. Med.
Chem., 2011, 46, 5598; (f) H. J. Song, Y. X. Liu, Y. X. Liu,
Y. Q. Huang, Y. Q. Li and Q. M. Wang, Bioorg. Med. Chem.
Lett., 2014, 24, 5228; (g) H. Song, Y. Liu, Y. Liu, L. Wang
and Q. Wang, J. Agric. Food Chem., 2014, 62, 1010; (h)
A. Pasternak, Z. Feng, R. Jesus, Z. Ye, S. He, P. Dobbelaar,
S. A. Bradley, G. G. Chicchi, K. L. Tsao, D. Trusca,
G. J. Eiermann, C. Li, Y. Feng, M. Wu, Q. Shao,
B. B. Zhang, R. Nargund, S. G. Mills, A. D. Howard, L. Yang
and Y. P. Zhou, ACS Med. Chem. Lett., 2012, 3, 289.
8 (a) P. D. Bailey, M. A. Beard and T. R. Phillips, Tetrahedron
Lett., 2009, 50, 3645; (b) J. Dong, T. Z. Meng, X. X. Shi,
W. H. Zou and X. Lu, Tetrahedron: Asymmetry, 2013, 24,
883; (c) S. Yu, O. M. Berner and J. M. Cook, J. Am. Chem.
Soc., 2000, 122, 7827; (d) J. Sandrin, S. P. Hollinshead and
J. M. Cook, J. Org. Chem., 1989, 54, 5636; (e) F. Ungemach,
M. Dipierro, R. Weber and J. M. Cook, J. Org. Chem., 1981,
46, 164; (f) V. F. Vavsari, V. Dianati, S. Ramezanpour and
S. Balalaie, Synlett, 2015, 26, 1955; (g) L. Alberch,
P. D. Bailey, P. D. Clingan, T. J. Mills, R. A. Price and
R. G. Pritchard, Eur. J. Org. Chem., 2004, 9, 1887; (h)
S. Xiao, X. Lu, X. X. Shi, Y. Sun, L. L. Liang, X. H. Yu and
J. Dong, Tetrahedron: Asymmetry, 2009, 20, 430.
9 A. Daugan, P. Grondin, C. Ruaut, A. C. L. M. Gouville,
H. Coste, J. M. Linget, J. Kirilovsky, F. Hyal and
R. Labaudiniere, J. Med. Chem., 2003, 46, 4533.
¨
6 (a) J. Stockigt, A. P. Antonchick, F. Wu and H. Waldmann,
Angew. Chem., Int. Ed., 2011, 50, 8538; (b) S.-G. Wang, 10 S. Hotha, J. C. Yarrow, J. G. Yang, S. Garrett,
Z.-L. Xia, R.-Q. Xu, X.-J. Liu, C. Zheng and S.-L. You, Angew.
Chem., 2017, 129, 7548; (c) S.-L. You, Q. Cai and M. Zeng,
K. V. Renduchintala, T. U. Mayer and T. M. Kapoor, Angew.
Chem., Int. Ed., 2003, 42, 2379.
Chem. Soc. Rev., 2009, 38, 2190; (d) R. N. Rao, B. Maiti and 11 (a) D. Berkes, P. Jakubec, D. Winklerova, F. Povazanec and
K. Chanda, ACS Comb. Sci., 2017, 19, 199; (e) Q. Yin,
S.-G. Wang and S.-L. You, Org. Lett., 2013, 15, 2688; (f)
T. Arai, M. Wasai and N. Yokoyama, J. Org. Chem., 2011,
76, 2909; (g) M. Jida, D. Tourwe and S. Ballet, RSC Adv.,
2014, 4, 38159; (h) H.-L. Zhu, J.-B. Ling and P.-F. Xu, J. Org.
A. Daich, Org. Biomol. Chem., 2007, 5, 121; (b) D. Berkes,
A. Kolarovic, R. Manduch, P. Baran and F. Povazanec,
Tetrahedron: Asymmetry, 2005, 16, 1927; (c) T. Shiraiwa,
S. Sakata, K. Fujishima and H. Kurokawa, Bull. Chem. Soc.
Jpn., 1991, 64, 191.
Chem., 2012, 77, 7737; (i) Q. Yin, S.-G. Wang and S.-L. You, 12 (a) M. L. V. Linn and J. M. Cook, J. Org. Chem., 2010, 75, 3587;
Org. Lett., 2013, 15, 2688; (j) W. Dai, H. Lu, X. Li, F. Shi and
S.-J. Tu, Chem.–Eur. J., 2014, 20, 11382.
(b) H. J. Kumpaty, M. L. V. Linn, M. S. Kabir,
F. H. Forsterling, J. R. Deschamps and J. M. Cook, J. Org.
Chem., 2009, 74, 2771; (c) X. X. Shi, S. L. Liu, W. Xu and
Y. L. Xu, Tetrahedron: Asymmetry, 2008, 19, 435; (d)
M. J. Earle, M. Noe, A. Perosa and K. R. Seddon, RSC Adv.,
2014, 4, 1204.
7 (a) R. Yamanokuchi, K. Imada, M. Miyazaki, H. Kato,
T. Watanabe, M. Fujimuro, Y. Sadki, S. Yoshinaga,
H. Terasawa, N. Iwasaki, H. Rotinsulu, F. Losung,
R. E. P. Mangindaan, M. Namikoshi, N. J. Voogd,
H. Yokosawa and S. Tsukamoto, Bioorg. Med. Chem., 2012,
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 47753–47757 | 47757