Enantiomers of an indole alkaloid containing unusual dihydrothiopyran and 1,2,4-thiadiazole rings from the root of isatis indigotica

Article abstract of DOI:10.1021/ol302660t

A pair of enantiomers (1a and 1b) of an indole alkaloid containing dihydrothiopyran and 1,2,4-thiadiazole rings was isolated from an aqueous extract of the root of Isatis indigotica. The structures and absolute configurations of the enantiomers were determined by extensive spectroscopic analysis, especially 2D NMR, modified Moshers method, and electronic CD (ECD). The proposed biosynthetic pathway and preliminary investigations of the biological activity of compounds 1a and 1b against influenza virus A/Hanfang/359/95 (H3N2) and HSV-1 are also discussed.

Full text of DOI:10.1021/ol302660t

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5668–5671
Enantiomers of an Indole Alkaloid
Containing Unusual Dihydrothiopyran
and 1,2,4-Thiadiazole Rings from the Root
of Isatis indigotica
Minghua Chen,† Sheng Lin,† Li Li,† Chenggen Zhu,† Xiaoliang Wang,† Yanan Wang,†
Bingya Jiang,† Sujuan Wang,† Yuhuan Li,‡ Jiandong Jiang,†,‡ and Jiangong Shi*,†
State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing 100050, People’s Republic of China, and Institute of Medicinal
Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing 100050, People’s Republic of China
shijg@imm.ac.cn
Received September 26, 2012
ABSTRACT
A pair of enantiomers (1a and 1b) of an indole alkaloid containing dihydrothiopyran and 1,2,4-thiadiazole rings was isolated from an aqueous
extract of the root of Isatis indigotica. The structures and absolute configurations of the enantiomers were determined by extensive spectroscopic
analysis, especially 2D NMR, modified Mosher’s method, and electronic CD (ECD). The proposed biosynthetic pathway and preliminary
investigations of the biological activity of compounds 1a and 1b against influenza virus A/Hanfang/359/95 (H3N2) and HSV-1 are also discussed.
Isatis indigotica Fort. (Cruciferae) is a biennial herba-
ceous plant widely distributed and cultivated in China. Its
dried roots and leaves (named “ban lan gen” and “da qing
ye” in Chinese, respectively) are usedin traditional Chinese
medicine for the treatment of various diseases, especially
influenza, cold, fever, and infections.1 Diverse structures
and significant biological activities from extracts of this
plant have attracted considerable interest. Chemical and
pharmacological studies have resulted in the characteriza-
tion of constituents with different structural features and
biological activities from ethanol extracts of the roots and
leaves of I. indigotica, including alkaloids,2 lignans,3
ceramides,4 flavonoids,5 2-hydroxy-3-butenyl thiocyanate,
† Institute of Materia Medica.
‡ Institute of Medicinal Biotechnology.
(1) Jiangsu New Medical College. Dictionary of Traditional Chinese
Medicine; ShanghaiScience and Technology PublishingHouse: Shanghai,
1986; pp 126 and 1250.
(3) (a) Li, B.; Chen, W. S.; Zhao, Y.; Zhang, H. M.; Dong, J. X.; Qiao,
C. Z. Chin. Tradit. Herb. Drugs 2005, 36, 326. (b) He, L. W.; Li, X.; Chen,
J. W.; Sun, D. D.; Ju, W. Z.; Wang, K. C. Acta Pharm. Sin. 2006, 41,
1193. (c) Zuo, L.; Li, J. B.; Xu, J.; Yang, J. Z.; Zhang, D. M.; Tong, Y. L.
Chin. J. Chin. Mater. Med. 2007, 32, 688.
(4) Sun, D. D.; Dong, W. W.; Li, X.; Zhang, H. Q. Sci. China. Ser. B:
Chem. 2009, 52, 621.
(5) (a) He, Y.; Lu, J.; Lin, R. C. Chin. Tradit. Herb. Drugs 2003, 34,
777. (b) Liu, J. F.; Zhang, X. M.; Xue, D. Q.; Jiang, Z. Y.; Gu, Q.; Chen,
J. J. Chin. J. Chin. Mater. Med. 2006, 31, 1961.
(6) (a) Huang, Q. S.; Yoshihira, K.; Natori, S. Planta Med. 1981, 42,
308. (b) Xie, Z.; Shi, Y.; Wang, Z.; Wang, R.; Li, Y. J. Agric. Food Chem.
2011, 59, 12467.
(2) (a) Zhang, S. H. Chin. Tradit. Herb. Drugs 1983, 14, 247. (b) Wu,
X.; Qin, G.; Cheung, K. K.; Cheng, K. F. Tetrahedron 1997, 53, 13323.
(c) Wu, X.; Liu, Y.; Sheng, W.; Sun, J.; Qin, G. Planta Med. 1997, 63, 55.
(d) Li, B.; Chen, W. S.; Zheng, S. Q.; Yang, G. J.; Qiao, C. Z. Acta.
Pharm. Sin. 2000, 35, 508–510. (e) Chen, W. S.; Li, B.; Zhang, W. D.;
Yang, G. J.; Qiao, C. Z. Chin. Chem. Lett. 2001, 12, 501. (f) Wei, X. Y.;
Leung, C. Y.; Wong, C. K.; Shen, X. L.; Wong, R. N.; Cai, Z. W.; Mak,
N. K. J. Nat. Prod. 2005, 68, 427. (g) Liu, J. F.; Jiang, Z. Y.; Wang, R. R.;
Zheng, Y. T.; Chen, J. J.; Zhang, X. M.; Ma, Y. B. Org. Lett. 2007, 9,
4127. (h) Sun, D. D.; Dong, W. W.; Li, X.; Zhang, H. Q. Chem. Nat.
Compd. 2010, 46, 763. (i) Wu, Y.; Zhang, Z.-X.; Hu, H.; Li, D.; Qiu, G.;
Hu, X.; He, X. Fitoterapia 2011, 82, 288.
r
10.1021/ol302660t
Published on Web 11/06/2012
2012 American Chemical Society

Table 1. NMR Data for 1a
1 (DMSO-d6)
1 (acetone-d6)
no.
δH
δC
δH
δC
2
3
176.8
48.4
177.7
49.5
3a
4
129.1
130.3
125.2
7.02 dd (7.8, 1.2)
124.1 7.07 dd (7.8, 1.2)
5
6.88 ddd (1.2, 7.8, 7.8) 121.9 6.90 ddd (1.2, 7.2, 7.8) 122.9
7.24 ddd (1.2, 7.8, 7.8) 129.6 7.24 ddd (1.2, 7.2, 7.8) 130.5
Figure 1. Structures of 1, 1a, and 1b.
6
7
6.91 dd (7.8, 1.2)
110.0 6.99 dd (7.8, 1.2)
142.7
110.9
143.7
128.6
142.1
27.8
and sulfur-containing epigoitrin, goitrin, proepigoitrin,
and progoitrin.6 As part of a program to assess the
chemical and biological diversity of traditional Chinese
medicines, an aqueous extract of the roots of I. indigotica
has been investigated. In our previous study, 31 indole
alkaloids were isolated from the aqueous extract.7 Some
of them showed antiviral activity against influenza virus
A/Hanfang/359/95 (H3N2) or Coxsackie virus B3, as well
as protective activity against D,L-galactosamine (GalN)-
induced hepatocyte (WB-F344 cell) damage. Subsequent
investigation of the same extract led to the characterization
of 1, an indole alkaloid containing unusual dihydrothio-
pyran and 1,2,4-thiadiazole rings (Figure 1). Herein, we
report details of the isolation and structure elucidation of
a pair of enantiomers of 1, 1a and 1b. The postulated
biogenetic pathway and biological activity of the enantio-
mers are also discussed.8
7a
30
40
50a
50b
60a
60b
300
500
126.7
7.38 dd (5.4, 3.0)
2.79 m
141.6 7.40 dd (4.8, 4.2)
26.5 2.84 m
2.84 m
2.79 m
3.56 ddd (4.8, 10.8, 15.6) 21.1 3.76 ddd (13.8, 8.4, 6.6) 22.2
2.77 m
2.74 ddd (13.8, 4.2, 3.6)
172.9
185.7
174.1
187.3
41.5
1
000a
2.86 dd (13.8, 6.6)
2.70 dd (13.8, 7.2)
4.17 m
40.7 2.88 dd (14.4, 6.6)
2.79 dd (14.4, 6.6)
69.8 4.31 m
1000
2000
3000
b
71.1
5.47 ddd (16.2, 10.8, 5.4) 140.8 5.63 ddd (16.8, 10.8, 5.4) 141.5
4.79 ddd (10.8, 1.8, 1.8) 113.6 4.98 ddd (16.8, 1.8, 1.2) 114.0
4
4
000a
000b
4.77 ddd (16.2, 1.8, 1.8)
4.86 ddd (10.8, 1.8, 1.2)
9.68 brs
NH-1 10.74 brs
OH-2000 4.93 d (5.4)
3.95 d (4.2)
a NMR data (δ) were measured at 600 MHz for 1H and at 150 MHz
for 13C. Proton coupling constants (J) in Hz are given in parentheses.
Compound 1 was obtained as a colorless gum with [R]D20
ꢀ14.1 (c 0.22, MeOH). The IR spectrum of 1 showed
absorption bands for hydroxy and/or amino (3256 cmꢀ1),
carbonyl (1715 cmꢀ1), and aromatic ring (1619 and
1474 cmꢀ1) functionalities. The positive mode ESIMS of
1 exhibited quasimolecular ion peaks at m/z 372 [M þ H]þ,
394 [M þ Na]þ, and 410 [M þ K]þ. The molecular formula
of C18H17N3O2S2, with 12 degrees of unsaturation, was
determined from HRESIMS at m/z 372.0844 [M þ H]þ
(calcdforC18H17N3O2S2, 372.0835) and 394.0659 [M þ Na]þ
(calcd for C18H17N3O2S2Na, 394.0654), combined with
1
1
The assignments were based on DEPT, Hꢀ H gCOSY, gHSQC, and
gHMBC experiments.
2.77(m, H-60b), 2.86(dd, J= 13.8 and6.6Hz, H-1000a), and
2.70 (dd, J = 13.8 and 7.2 Hz, H-1000b)]. It also displayed
exchangeable resonances assignable to an amide proton at
δH 10.74 (brs, NH-1) and a secondary hydroxy proton at
δH 4.93 (d, J = 5.4 Hz, OH-2000). The 13C NMR and DEPT
spectra of 1 showed 18 carbon resonances, corresponding
to the above units and four additional quaternary carbons
including an sp3-hybridized carbon [δC 48.4 (C-3)] and
three sp2-hybridized carbons [δC 176.8 (C-2), 172.9 (C-300),
and 185.7 (C-500)] (Table 1). These spectroscopic data
suggested that 1 was an aromatic alkaloid possessing
unusual heterocycles.
1
the NMR data (Table 1). The H NMR spectrum of 1
in DMSO-d6 displayed resonances attributable to (a) an
ortho-disubstituted benzene ring [δH 7.02 (dd, J = 7.8 and
1.2 Hz, H-4), 6.88 (ddd, J = 1.2, 7.8, and 7.8 Hz, H-5), 7.24
(ddd, J = 1.2, 7.8, and 7.8 Hz, H-6), and 6.91 (dd, J = 7.8
and 1.2 Hz, H-7)]; (b) a trisubstituted double bond
attached to an aliphatic methylene unit [δH 7.38 (dd, J =
5.4 and 3.0 Hz, H-40)], of which the methylene protons
resonated at δH 2.79 (m, H-50a and H-50b); (c) a terminal
double bond connected to an oxymethine [δH 5.47 (ddd,
J = 16.2, 10.8, and 5.4 Hz, H-3000), 4.79 (ddd, J = 10.8, 1.8,
and 1.8 Hz, H-4000a), 4.77 (ddd, J = 16.2, 1.8, and 1.8 Hz,
H-4000b), and 4.17 (m, H-2000)]; and (d) two other methylene
units [δH 3.56 (ddd, J = 4.8, 10.8, and 15.6 Hz, H-60a),
The structure of 1 was further elucidated by compre-
hensive 2D NMR data analysis in both DMSO-d6 and
acetone-d6. The gHSQC spectrum furnished assignments
of the proton-bearing carbon and corresponding proton
resonances in the NMR spectra. In the Hꢀ H gCOSY
spectrum of 1, the homonuclear coupling correlations of
H-4/H-5/H-6/H-7, H-40/H2-50/H2-60, and H2-1000/H-2000/
H-3000/H2-4000 revealed the presence of structural units
containing the vicinally coupled protons (Figure 2, thick
lines). In the HMBC spectrum, two- and three-bond
correlations of H-4/C-3, C-5, C-6, and C-7a; H-5/C-3a,
C-4, and C-7; H-6/C-4 and C-7a; H-7/C-5 and C-3a; and
1
1
(7) Chen, M.; Gan, L.; Lin, S.; Wang, X.; Li, L.; Li, Y.; Zhu, C.; Wang,
Y.; Jiang, B.; Jiang, J.; Yang, Y.; Shi, J. J. Nat. Prod. 2012, 75, 1167.
(8) For plant material, experimental procedures, and physicalꢀchemical
properties for compounds 1a and 1b, see Supporting Information.
Org. Lett., Vol. 14, No. 22, 2012
5669

NH/C-2, C-3, C-3a, and C-7a were observed. These corre-
lations, in combination with the shifts of these proton and
carbon resonances and the quaternary nature of C-3,
demonstrated the presence of a 3,3-disubstituted indolin-
2-one moiety in 1. HMBC correlations of H-40/C-3, C-50,
C-60, and C-500; H2-50/C-30, C-40, and C-60; and H2-60/C-40
and C-50, in combination with the shifts of these proton
and carbon resonances, indicated that the C-3 of the
indolin-2-one moiety and quaternary sp2-hybridized C-500
were linked to one end (C-30) of the trisubstituted double
bond with the two methylene units (CH2-50 and CH2-60) at
the other end. Meanwhile, HMBC correlations from H2-60
to C-3, together with the shifts of these proton and carbon
resonances including C-60 and the coupling patterns of
H-60a and H-60b, revealed that C-3 linked to C-60 through
a sulfur atom, forming an unusual 50,60-dihydrospiro-
[indoline-3,20-thiopyran]-2-one moiety in 1. In addition,
HMBC correlations of H2-1000/C-2000, C-300, and C-3000;
H-2000/C-1000, C-3000, C-4000, and C-300; H-3000/C-2000; H-4000/
C-3000 and C-2000; and OH-2000/C-1000, C-2000, and C-3000 indi-
cated the presence of a 2000-hydroxybut-3000-en-1000-yl unit
connected by the remaining quaternary sp2 hybridized
carbon, C-300. The chemical shifts of C-300 and C-500 in the
aforementioned moieties, along with the molecular compo-
sition and degree of unsaturation of 1, indicated that the two
quaternary carbons must be connected by the two remain-
ing nitrogen atoms and the remaining sulfur atom to
construct a 100,200,400- or 100,300,400-thiadiazole ring. The chem-
ical shifts of C-300 and C-500 were consistent with those
of the corresponding carbons in 1,2,4-thiadiazole deriva-
tives9 but significantly different from those in 1,3,4-
thiadiazole analogues,10 suggesting the presence of a
100,200,400-thiadiazole ring in 1. Therefore, the gross structure of
1was determined to be 30-[300-(2000-hydroxybut-3000-en-1000-yl)-
100,200,400-thiadiazol-500-yl]-50,60-dihydrospiro[indoline-3,20-
thiopyran]-2-one.
Figure 3. Δδ values (δR ꢀ δS, black data in ppm) for 1a-(R)-
MPA and 1a-(S)-MPA.
were identical to those of 1 prior to HPLC separation. This
confirmed that1wasa mixtureofenantiomerswitha 1a/1b
ratio of ∼2:1. The absolute configuration at C-2000 in 1a
was determinedbyMosher’smethod.11 Esterification of 1a
with (R)-(ꢀ)- and (S)-(þ)-R-methoxyphenylacetic acid
(MPA) gave the corresponding derivatives 1a-(R)-MPA
1
and 1a-(S)-MPA. The H NMR data of the diastereo-
1
mers were assigned on the basis of 1Hꢀ H COSY experi-
ments. From the MPA determination rule based on the
Δδ values11 (Figure 3), the configuration of 1a was deter-
mined to be 2000S and that of the enantiomer (1b) was
assigned as 2000R. The absolute configurations at C-3 in 1a
and 1bweredeterminedbycomparison ofthe experimental
ECD spectra with those predicted from quantum mechan-
ical time dependent density functional theory (TDDFT)
calculations.12 In the ECD calculation, the flexible 2000-
hydroxybut-3000-enyl unit was replaced by a methyl group
to simplify the computation since this unit may generate
various conformations but has little effect on the ECD
data.13 A pair of enantiomers (1A and 1B) was proposed
as the model compounds. The theoretically calculated
ECD spectra of 1A and 1B were in good agreement with
the experimental ECD spectra of 1a and 1b (Figure 4),
respectively. This indicated that 1a and 1b had the
3S- and 3R-configurations, respectively. Therefore, com-
pounds 1a and 1b were determined as (ꢀ)-(2000S,3S)- and
(þ)-(2000R,3R)-30-{300-[2000-hydroxybut-3000-en-1000-yl]-100,200,400-
thiadiazol-500-yl}-50,60-dihydrospiro[indoline-3,20- thiopyran]-
2-one, respectively.14
Since the stereoisomers of the proposed biosynthetic
precursors, epiprogoitrin and progoitrin, were presented
in I. indigotica in a 2:1 ratio,6b it was suspected that 1 was
a mixture of two enantiomers in unequal amounts, which
resulted in the optical activity. This was supported by
HPLC analysis of 1 on an analytical chiral column, show-
ing two peaks with an integration of about 2:1 ratio. Sub-
sequent separation of 1 yielded 1a {[R]2D0 ꢀ29.1 (c 0.15,
MeOH)} and 1b {[R]2D0 þ28.9 (c 0.07, MeOH)}, which had
opposite specific rotations and ECD data, but NMR data
Compounds 1a and 1b are characterized by the 50,60-
dihydrospiro[indoline-3,20-thiopyran]-2-one and 300-(2000-
hydroxybut-3000-en-1000-yl)-100,200,400-thiadiazole moieties,
(9) (a) Cameron, T. S.; Decken, A.; Fang, M.; Parsons, S.; Passmore,
J.; Wood, D. J. Chem. Commun. 1999, 1801. (b) Ren, F.; Den, G.; Wang,
H.; Luan, L.; Meng, Q.; Xu, Q.; Xu, H.; Xu, X.; Zhang, H.; Zhao, B.; Li,
C.; Guo, T.; Yang, J.; Zhao, W.; Zhao, Y.; Jia, Q.; Lu, H.; Xiang, J.;
Elliott, J. D.; Lin, X. J. Med. Chem. 2012, 55, 4286.
(10) Lebrini, M.; Bentiss, F.; Lagrenee, M. J. Heterocycl. Chem.
2005, 42, 991.
(11) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17.
(12) (a) Li, X.-C.; Ferreira, D.; Ding, Y.-Q. Curr. Org. Chem. 2010,
14, 1678. (b) Chianese, G.; Fattorusso, E.; Aiyelaagbe, O. O.; Luciano,
P.; Schroder, H. C.; Muller, W. E. G.; Taglialatela-Scafati, O. Org. Lett.
2011, 13, 316.
(13) Berova, N.; Di Bari, L.; Pescitelli, G. Chem. Soc. Rev. 2007, 36, 914.
(14) For enantiomeric natural products, see: Finefield, J. M.; Sherman,
D. H.; Kreitman, M.; Williams, R. M. Angew. Chem., Int. Ed. 2012, 51,
4802.
1
Figure 2. 1Hꢀ H COSY (thick lines) and main HMBC (red
arrows, from proton to carbon) correlations for 1.
5670
Org. Lett., Vol. 14, No. 22, 2012

Scheme 1. Plausible Biosynthetic Pathways of 1a and 1b
Figure 4. Measured ECD spectra of 1a (blue) and 1b (red) and
the calculated ECD spectra of 1A (blue dash) and 1B (red dash).
which have never been presented in a natural product.
However, dendrodoine, 5-[3-(N,N-dimethylamino-1,2,4-
thiadiazolyl)-3-indolylmethanone which contains a similar
thiadiazole ring, was reported from the marine tunicate
Dendrodoa grossularia.15 Two plausible biosynthetic path-
ways for 1a and 1b are proposed in Scheme 1 (shown as red
and black arrows, respectively). The biosynthetic precur-
sors are proposed to be glucosinolates, epiprogoitrin (2)
for 1aand progoitrin (3) for 1b, aswellasglucobrassicin(4)
for both. These compounds are abundant in cruciferous
plants16 including I. indigotica.6b Myrosinase catalyzed
hydrolysis of 2ꢀ46b liberates intermediates 2aꢀ4a, respec-
tively. Condensation of two molecules of 2a or 3a (or one
molecule each of 2a and 3a) followed by dehydration
would generate 2b or 3b, which is possibly mediated by
coupling between a nitrile and an imidothioate, the known
breakdown products of 2a and/or 3a.17 An enzyme-
catalyzed DielsꢀAlder [4 þ 2] cycloaddition18 of 2b and
3b with 3-thioxoindolin-2-one (4b, a decomposition pro-
duct of 4a), followed by a simultaneous or sequential double
bond rearrangement, would then give 1a and 1b.
which would undergo oxidation and coupling with
3-mercaptopropanal (6, a possible plant metabolite19) to
generate 1a and 1b.20
In preliminary in vitro assays,21 compounds 1a and 1b
showed antiviral activity against the herpes simplex virus 1
(HSV-1) with IC50 values of 33.33 and 25.87 μM and SI
values of 2.0 and 3.9, respectively (the positive control
acyclovir gave IC50 = 0.41 μM and SI = 241.9). Com-
pound 1a also inhibited the influenza virus A/Hanfang/
359/95 (H3N2), with IC50 and SI values of 33.33 μM
and 3.0, respectively, but 1b was inactive (IC50 > 100)
(the positive control, oseltamivir, gave IC50 = 1.62 μM
and SI = 777.8).
Alternatively, the condensation of the nitrile from 2a or
3a with the imidothioate from 4a would produce 5a or 5b,
Acknowledgment. Financial support from the National
Natural Sciences Foundation of China (NNSFC; Grant
Nos. 30825044 and 20932007), the Program for Changjiang
Scholars and Innovative Research Team in University
(PCSIRT, Grant No. IRT1007), and the National Science
and Technology Project of China (No. 2011ZX09307-002-01)
is acknowledged.
(15) Heiz, S.; Durgeat, M.; Guyot, M.; Brassy, C.; Bachet, B.
Tetrahedron Lett. 1980, 21, 1457.
(16) (a) Fahey, J. W.; Zalcmann, A. T.; Talalay, P. Phytochemistry
2001, 56, 5. (b) Frechard, A.; Fabre, N.; Pean, C.; Montaut, S.; Fauvel,
M.-T.; Rollin, P.; Fouraste, I. Tetrahedron Lett. 2001, 42, 9015.
(17) Polat, U. J. Biol. Environ. Sci. 2010, 4, 39.
(18) For biosynthetic DielsꢀAlder reactions, see: (a) Kim, H. J.;
Ruszczycky, M. W.; Choi, S.-H.; Liu, Y.-N.; Liu, H.-W. Nature 2011,
473, 109. (b) Townsend, C. A. ChemBioChem 2011, 12, 2267. (c) Kim,
H. J.; Ruszczycky, M. W.; Liu, H.-W. Cur. Opin. Chem. Biol. 2012, 16,
124.
(19) Vermeulen, C.; Collin, S. J. Agric. Food Chem. 2002, 50, 5654.
(20) The similarity of the ratios between the precursors (2/3) and the
final products (1a/1b) suggests that the alcohol is formed first and the
spiro-center then follows. The spiro-center would be likely formed in a
nonenantioselective manner, and this process would not be affected by
the first because the chiral alcohol is away from the spiro-center. In
addition, the presence of diastereoisomers of 1a and 1b in this material is
speculated based on the isolation of a pair of enantiomers with a similar
indoline moiety (see ref 7).
Supporting Information Available. Plant material, ex-
perimental procedures; physicalꢀchemical properties;
the measured and calculated ECD spectra; copies of IR,
MS, HRMS, and 1D and 2D NMR spectra of 1, 2, 1a-(R)-
MPA, and 1a-(S)-MPA. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) He, W.-Y.; Gao, R.-M.; Li, X.-Q.; Jiang, J.-D.; Li, Y.-H. Acta
Pharm. Sin. 2010, 45, 395.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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