Synthesis and in vitro cytotoxic evaluation of new triazole derivatives based on artemisinin via click chemistry

Article abstract of DOI:10.1007/s00044-016-1524-z

The paper presents the synthesis of new artemisinin triazole derivatives via click chemistry and their in vitro cytotoxic evaluation against four cancer cell lines including MCF-7, LU-1, HL-60 and P388. The bioassay result showed that most of the target compounds were active against four cell lines, in which compounds 11g displayed the most potent inhibitory activity against HL-60 cell line with IC₅₀ value of 2.5 μM.

Full text of DOI:10.1007/s00044-016-1524-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1524-z
ORIGINAL RESEARCH
Synthesis and in vitro cytotoxic evaluation of new triazole
derivatives based on artemisinin via click chemistry
Le Huy Binh1 Nguyen Thi Thuy Van1 Vu Tuan Kien1 Nguyen Thi Thuy My1 Luu Van Chinh2
•
•
•
•
•
Nguyen Thi Nga2 Hoang Xuan Tien1 Do Thi Thao3 Tran Khac Vu1
•
•
•
Received: 24 March 2015 / Accepted: 3 February 2016
Ó Springer Science+Business Media New York 2016
Abstract The paper presents the synthesis of new arte-
misinin triazole derivatives via click chemistry and their
in vitro cytotoxic evaluation against four cancer cell lines
including MCF-7, LU-1, HL-60 and P388. The bioassay
result showed that most of the target compounds were
active against four cell lines, in which compounds 11g
displayed the most potent inhibitory activity against HL-60
cell line with IC50 value of 2.5 lM.
bridge which is responsible for its antimalarial activity, and
therefore are expected to keep part of the pharmacological
properties of artemisinin (Klayman, 1985). In recent years,
besides the antimalarial activity, artemisinin derivatives
have received much attention in the search for new anti-
cancer agents due to the similar mechanisms underlying
both antitumor and antimalarial properties (Li et al., 2003;
Singh and Lai, 2001). Regarding this aspect, it is also
documented that artemisinin derivatives possess cytotoxic
activity against cancer cells by inducing apoptosis (Singh
and Lai, 2004), but high concentrations are required (Li
et al., 2003). Therefore, the synthesis of new artemisinin
derivatives with modified structures is essential, and a lot
of artemisinin derivatives have been synthesized and
evaluated for anticancer activity (Li et al., 2001; Yang
et al., 2005, 2006; Slade et al., 2009; Jung et al., 2009;
Chaturvedi et al., 2010; Oh et al., 2011; Xie et al., 2011;
Goswami et al., 2013; Blazqueza et al., 2013) in which
several triazole derivatives exhibited potent cytotoxic
activity to some cancer cell lines (Cho et al., 2009; Lee,
2011; Oh et al., 2010).
Keywords Artemisinin Á Anti-cancer Á Click chemistry Á
Aminobenzoic acid Á Azide
Introduction
Artemisinin (1), a sesquiterpene lactone endoperoxide,
isolated from Artemisia annua L. (Klaymann, 1993) and its
oil- and water-soluble derivatives such as artemether (2)
and arteether (3) and artesunate (4) are effective anti-
malarial agents especially against multi-drug resistant
malarial strains (Fig. 1). These derivatives belong to a class
of artemisinin-like compounds that share the endoperoxide
Click chemistry has its increasing applications found in
all aspects of drug discovery. The copper-(I)-catalyzed
1,2,3-triazole formation from azides and terminal acetyle-
nes is a very useful route to create a library of new com-
pounds for screening activity, due to its high degree of
dependability, complete specificity and the biocompatibil-
ity of the reactants. Furthermore, the triazole products are
passive linkers which readily associate with biological
targets, through hydrogen bonding and dipole interactions
(Rostovtsev et al., 2002; Kolb and Sharpless, 2003a, b). In
connection with drug design, an amide linkage, a core
structural unit in the skeleton of proteins, is often consid-
ered to be incorporated into target compounds due to their
biological compatibility and their potent application in vast
& Tran Khac Vu
Vu.trankhac@hust.edu.vn
1
Department of Pharmaceutical Chemistry and Pesticides
Technology, School of Chemical Engineering, Hanoi
University of Science and Technology, No. 1 Dai Co Viet
Street, Hai Ba Trung District, Hanoi, Vietnam
2
Institute of Natural Products Chemistry, Vietnam Academy
of Science and Technology, 18-Hoang Quoc Viet, Caugiay,
Hanoi, Vietnam
3
Laboratory for Bioassay, Institute of Biotechnology, Vietnam
Academy of Science and Technology, 18-Hoang Quoc Viet,
Caugiay, Hanoi, Vietnam
123

Med Chem Res
Fig. 1 Several antimalarial
agents
biological activities, including anti-cancer (Karolyi et al.,
2012; Chhikara et al., 2011). Accordingly, in our contin-
uous program for the search of novel anti-cancer agents,
we, therefore, continue to focus on the synthesis of new
triazole compounds containing the amide linkage based on
artemisinin via click chemistry, and evaluate the influence
of the different structural motifs on the biological activity
on some cancer cell lines.
reduced pressure to obtain azido amides 7a–i and 8a–i in
49–71 % yields, and these amides were used for the next
step without further purification. Compound 10 containing
terminal acetylene was synthesized according to the known
procedure with little modification (Aminake et al., 2012).
In this synthesis, BF3ÁEt2O in some amount of CH2Cl2 was
dropped slowly into the reaction for about 1 h to give 10 in
82 % yield.
New triazole derivatives 11a–i and 12a–i were synthe-
sized using click chemistry as illustrated in Scheme 2. In
this study, we attempted to introduce different functional
groups via triazole linker in 10 using the Cu(I)-catalyzed
Huisgen 1,3-cylcoaddition between azides 7a–i, 8a–i and
alkyne 10. In general, this reaction is known to be a simple
and efficient method for synthesizing a library of various
derivatives for bioassays (Tron et al., 2008; Kolb and
Sharpless, 2003a, b). It usually does not require much
specific precautions and proceeds at ambient temperature
in water with a variety of organic co-solvents, including
tert-butanol, ethanol, DMSO, THF or MeCN. To optimize
the copper(I)—catalyzed 1,3-dipolar cycloaddition, the
title compounds were initially supposed to be easily syn-
thesized by treating the terminal alkyne—containing arte-
misinin (10) and different azides in tert-butanol:H2O (1:1),
using CuSO4Á5H2O and sodium ascorbate as a catalyst
system. However, the reaction did not proceed at all. Then,
the reactions were carried out in different organic co-sol-
vents, including CH2Cl2, THF, MeOH, MeCN and DMSO,
but they all failed. Finally, the target compounds were
synthesized as in Scheme 2, using CuI as a catalyst in
MeCN at room temperature for 3–5 h led to a series of new
1,2,3-triazole artemisinin derivatives 12a–i, 13a–i. In
almost cases, the desired compounds were obtained in
moderate to rather good yields after column chromatogra-
phy. The regioselectivity was exclusive (Lewis et al.,
2002). Only the 1,4-regioisomer was formed, and the
Results and discussion
The synthesis of novel artemisinin triazole derivatives
11a–i and 12a–i was outlined in Schemes 1 and 2. Firstly,
azide 7a–i and 8a–i were synthesized (Scheme 1).
4-aminobenzoic acid (5a) and 3-aminobenzoic acid (5b)
were used as starting materials. These acids were firstly
diazotizated with sodium nitrite and then the sodium azide
to give azide derivatives 7a–i and 8a–i in high yields
according to document with modification (Huanan et al.,
2008). These intermediates were next reacted with a series
of amines using EDC and DMAP as a catalyst system in
CH2Cl2 at room temperature. After a work-up by dilution
with CH2Cl2, extracted consecutively with H2O, 5 %
NaHCO3, 5 % HCl and washed with H2O, the organic
phase was dried on anhydrous Na2SO4, evaporated under
1
13
structure of title compounds was confirmed by IR, H,
C-NMR and MS spectra (Table 1).
The title compound 11b was chosen as an example for
1
structural elucidation. In the H NMR spectrum, there was
appearance of all 40 protons in which the signal of 1H-
triazole appeared at 8.01 ppm as a singlet. Four aromatic
protons can be observed as a characteristic couple of
Scheme 1 Reagents and conditions: i NaNO2, HCl concentrated,
NaN3, 85–89 %, ii EDC, DMAP, amines, CH2Cl2, r.t, 2 days,
49–71 %
123

Med Chem Res
Scheme 2 Reagents and
conditions: i propargyl alcohol,
BF3ÁEt2O, 2 days, 82 %, ii CuI,
MeCN, r.t, 3–5 h, 49–66 %
doublets at 7.82 and 7.58 ppm (J = 8.50 Hz). The singlet
resonance signal at 5.45 ppm is attributed to the proton of
H-12. Two protons connected to triazole linker appeared as
two doublets at 5.02 and 4.79 ppm (J = 12.5 Hz). Besides,
the signal of H-10 proton is attributed at 4.98 ppm with
and evaluated cytotoxic activity of this hybrid compound
because of a wide range of biological activity spectrum of
quinoline skeleton including anticancer activity. The
compound 15 contains two pharmacophores. One is arte-
misinin skeleton, and the other is 7-chloroquine moiety,
which is usually used in the design of anticancer agents.
Several derivatives derived from 7-chloroquine moiety
were reported to show more potent effects on several
cancer cell lines when compared to chloroquine (Zhang
et al., 2008). Therefore, synergistic or additive pharmaco-
logical effects might be also expected in this type of hybrid
in the research.
characteristic coupling constant of
b configuration
(J = 3.50 Hz). Four protons of ethyl chain can be observed
as a broad singlet signal at 3.74 ppm. In addition, nine
protons including one methyl at position 14 and two methyl
groups of ethyl side chain appeared as a singlet at
1.45 ppm. The resonance signal of the methyl group at
position 15 was overlapped with the signal of the methyl
group at the position 16 at 0.93 ppm. The 13C NMR
showed signals of 25 carbons in the molecule in which the
characteristic signal of amide carbon appeared at the lowest
field at 168.9 ppm and four equivalent carbons of aromatic
nuclei at 128.8 and 120.5 ppm. The resonance signals at
146.1 and 120.6 ppm were attributed to two carbons of
triazole. Besides, other characteristic signals of artemisinin
skeleton were observed at 104.1 (C-3), 101.9 (C-12), 87.9
(C-10), and the signal at 66.8 was attributed to carbon of
CH2 connected to triazole. Finally, the structure of 11b was
confirmed by ESI-HRMS.
The synthesis of compound 15 was shown in Scheme 3.
4,7-dichloroquinoline (13) was first reacted with sodium
azide in DMF according to the known literature (Souza
et al., 2009) to give 14. Next, we have surveyed several co-
solvents to synthesize the hybrid compound as in the case
of triazole 11a–i, 12a–i, but failed. It was reported CH2
Cl2:H2O (1:1) together with sodium ascorbate and
CuSO4Á5H2O as a good catalyst system for triazole syn-
thesis in some cases (Lee et al., 2006). We found that this
reaction can proceed using only CH2Cl2 and sodium
ascorbate and CuSO4Á5H2O as a catalyst system to afford
15 in rather good yield (Scheme 3). Structure of this hybrid
compound was confirmed by IR, NMR and MS.
In this research, we also synthesized the hybrid of
artemisinin with a quinoline derivative 14 via click reaction
123

Med Chem Res
Table 1 Structures and yields of 11a–i, 12a–i
No
1
Compounds
R1R2
Yields (%)
62
No
10
Compounds
R1R2
Yields (%)
49
11a
12a
2
11b
59
11
12b
58
3
4
11c
11d
58
53
12
13
12c
12d
51
62
5
6
7
11e
11f
11g
66
51
49
14
15
16
12e
12f
12g
57
60
59
8
11h
55
17
12h
63
9
11i
50
18
12i
55
123

Med Chem Res
Scheme 3 Reagents and
conditions: i NaN3, DMF,
60 °C, 2 h; 75 %, ii sodium
ascorbate, CuSO4Á5H2O,
CH2Cl2, r.t, 20 h, 61 %
according to the described protocol (Monks et al., 1991;
Scudiero et al., 1988). The IC50 of the assay was carried
out using four human cancer cell lines: MCF-7 (ATCC–
HTB-22), LU-1 (ATCC–HTB-57), HL-60 (ATCC–CCL-
240) and P388 (ATCC–CCL-46). The results are shown in
Table 2 and illustrated in Fig. 2.
Table 2 In vitro cytotoxic activity of target compounds: 11a–i,
12a–i and 15
No.
Compounds
IC50 (lM)
MCF-7
LU-1
HL-60
P388
1
11a
11b
11c
[200
[200
34.4
36.2
11.2
37.8
4.7
153.0
175.9
23.0
28.6
10.0
24.3
3.0
137.0
169.6
23.5
24.2
10.3
22.0
2.5
136.3
148.9
40.2
63.6
11.3
28.6
3.8
Table 2 shows that the initial observation in structure
activity relationship in the series 11a–i showed that all com-
pounds, except 11a–b, exhibited cytotoxic inhibitory activity
against cell lines tested. Compounds 11c, 11d and 11i showed
moderate cytotoxic activity against all cell lines ranging from
23.0 to 63.6 lM. It was also observed that the effect of amide
substituents (4-methylpiperazine and 4-ethylpiperazine) in
the compounds 11c and 11d on activity was not evident, and
these compounds exhibited cytotoxic activity against LU-1
and HL-60 with IC50 values of 23.0, 23.5 and 28.6, 24.2 lM,
respectively. Similarly, the presence of piperidine and
pyrrolidine substituents in the compounds 11f and 11i showed
little difference in activity against cell lines. It seems that the
presence of more hydrophobic phenylpiperazine group in
compound 11e resulted in strong improvement in cytotoxic
activityagainstcelllineswithIC50 valuesrangingfrom10.0to
11.3 lM. Onthecontrary, compound12e containingthesame
phenylpiperazine group caused the strong reduction in activ-
ity. In this series, 2-methylpiperidine and 4-methylpiperidine
substituents had positive effect on cytotoxic activity against
four cell lines. Compound 11h possessing 2-methylpiperidine
showed rather good cytotoxic activity against cell lines with
IC50 values of 10.0, 8.5, 10.1 and 11.4 lM, respectively.
Especially, compound 11g containing 4-methylpiperidine
substituent exhibited the most potent activity against four cell
lines with IC50 values of 4.7, 3.0, 2.5 and 3.8 lM,
respectively.
2
3
4
11d
11e
5
6
11f
7
11g
11h
11i
8
10.0
61.4
36.0
46.1
65.8
28.6
58.9
37.6
19.9
26.0
108.1
19.5
84.3
3.5
8.5
10.1
27.6
28.9
33.2
42.3
21.3
39.9
29.9
13.5
13.3
49.6
5.7
11.4
36.5
38.2
43.9
50.3
40.8
68.6
33.0
14.7
16.4
57.5
12.6
39.9
2.7
9
33.2
34.0
39.8
43.6
28.4
59.0
35.8
17.3
16.9
23.8
14.2
64.9
3.1
10
11
12
13
14
15
16
17
18
19
20
12a
12b
12c
12d
12e
12f
12g
12h
12i
15
DHA
Ellipticine
53.2
1.7
The reference substance, ellipticine exhibited cytotoxic activity
against MCF-7(ATCC–HTB-22), LU-1 (ATCC–HTB-57), HL-60
(ATCC–CCL-240) and P388 (ATCC–CCL-46) cells with IC50 values
of 3.5, 3.1, 1.7 and 2.7 lM, respectively. The values shown for these
compounds are the average of three determinations
Biological results
In general, compounds in series 12a–i displayed cytotoxic
activity lower than that of series 11a–i, and there was little
effect of amide substituents on activity to cell lines tested.
Noticeably, in this series, the compound 12d possessing
4-ethylpiperazine exhibited improved activity against
The bioassay was performed at the Institute of Biotech-
nology, Vietnam Academy of Science and Technology.
The cytotoxic activity evaluation was undertaken
123

Med Chem Res
Fig. 2 In vitro cytotoxic activities of target compounds
MCF-7, LU-1, HL-60 and P388 with IC50 values of 28.6,
28.4, 31.3 and 40.8 lM, respectively. Compounds 12g and
12h revealed the strongest activity in this series ranging from
13.3 to 26.0 lM, but lower than that of compounds 11g and
11h. For the hybrid compound 15, the presence of
7-chloroquinoline skeleton via triazole linker resulted in an
interesting activity against cell lines, especially against
HL-60 with IC50 values of 5.7 lM. In comparison with the
parent compound, DHA, some new artemisinin triazole
derivatives displayed cytotoxic activity better than that of
DHA in terms of IC50 values. From SAR viewpoint, it is
possible that the 4-benzamide position is more beneficial
than 3-benzamide position on activity of target compounds
against cell lines tested. Concerning the possible mechanism
of cytotoxicity of these compounds, it could be estimated
according to previously reported studies that the endoper-
oxide-induced cell death, which is mediated by heme or a
heme-containing protein, could be of main responsibility for
the mechanism (Mercer et al., 2007, 2011).
cytotoxic activity compared with parent compound, DHA in
almostcases. Among synthesized compounds, compound11g
can be compared with standard substance, ellipticine in terms
of IC50 values against LU-1 cell line, and this compound
exhibitedthemostpotentcytotoxicactivityagainstHL-60cell
line with IC50 value of 2.5 lM.
Conclusions
We have synthesized a series of new triazole compounds
based on artemisinin 11a–i, 12a–i and a new hybrid of
artemisinin with quinoline 15 using a simplified procedure
via click chemistry. All synthesized compounds were
structurally confirmed by spectroscopic methods. A total
of 19 target compounds were screened for in vitro cyto-
toxic activity against four cell lines. The bioassay result
indicated that compound 11g showed the most potent
inhibitory activity against HL-60 cell line with IC50 value
of 2.5 lM. The biological evaluation studies may imply
that some new derivatives (11g and 11h) could be
In conclusion, it was observed in this research that the
incorporation of amide moieties into artemisinin skeleton via
triazolelinkagebrought about new compounds with improved
123

Med Chem Res
General procedure for the synthesis of triazole 11a–i
and 12a–i
identified as potential in vitro cytotoxic agents, and could
serve as a lead compounds for further design of anti-
cancer agents.
A mixture of 10 (322 mg, 1 mmol) and the corresponding
azides (7a–i, 8a–i) (1.2 eq) in MeCN (10 mL) was stirred
at room temperature for 10 min. A catalytic amount of CuI
was, then added and the reaction mixture was stirred at
room temperature for 2–5 h. The mixture was then diluted
with CH2Cl2 (15 mL) and extracted with H2O
(2 9 10 mL). The organic phase was separated, dried on
anhydrous Na2SO4 and evaporated under reduced pressure.
The target triazole 11a–i and 12a–i were obtained by
normal column chromatography using CH2Cl2:MeOH:
Et3N as eluting system.
Experimental section
Materials and measurements
All chemicals and reaction solvents were purchased from
Merck and Aldrich. Melting points were determined in
open capillaries on melting point meter KRUSS and
uncorrected. IR spectra were recorded on FT-IR IMPACT-
410 using KBr disks or film in CCl4. H and 13C NMR
1
spectra were recorded on Brucker AVANCE 500-MHz
spectrometer in CDCl3. Chemical shifts (d) are in ppm
relative to TMS, and coupling constants (J) are expressed
in hertz (Hz). High-resolution mass spectra were recorded
on FTICR MS Varian. Progress of the reaction was mon-
itored by thin-layer chromatography (TLC) using glass pre-
coated TLC sheets with ultraviolet (UV) fluorescent silica
gel. Multiplicities are shown as the abbreviations: s (sin-
glet), brs (broad singlet), d (doublet), brd (broad doublet) t
(triplet), m (multiplet).
Morpholino(4-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-trimet
hyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochro-
men-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)metha
none (11a) White solids obtained by column chro-
matography using CH2Cl2:MeOH:Et3N (99:1:0.1) as elut-
ing system; yield 62 %. Mp 131–132 °C; IR (KBr, m
(cm-1)): 1645, 1579, 1474, 1446, 1377, 1194, 1101, 1032,
1
982, 931, 878. H NMR (500 MHz, CDCl3) d (ppm): 7.98
(s, 1H, H-30), 7.81 (d, J = 8.5 Hz, 2H, H-60), 7.56 (d, J =
8.5 Hz, 2H, H-50), 5.45 (s, 1H, H-12), 5.03 (d, J = 12.
5 Hz, 1H, H-10), 4.99 (d, J = 3.5 Hz, 1H, H-10), 4.79 (d,
J = 12.5 Hz, 1H, H-10), 3.57 (brs, 4H, H-200), 3.29 (brs,
4H, H-100), 2.68 (m, 1H, H-9), 2.41–2.35 (tt, J = 14, 10.
0 Hz, 1H, H-4a), 2.07–2.02 (m, 1H, H-4b), 1.90–1.86 (m,
2H, H-8a, H-5a), 1.78 (m, 1H, H-8b), 1.64–1.59 (m, 1H,
H-7b), 1.52–1.47 (m, 2H, H-8a, H-5b), 1.45 (s, 3H, H-14),
1.27–1.25 (m, 2H, H-6, H-5a), 0.95–0.91 (overlap, 7H,
H-7a, H-15, H-16). 13C NMR (125 MHz, CDCl3) d (ppm):
168.8 (C=O), 145.0 (C-20), 136.6 (C-40), 136.4 (C-70), 126.
9 (C-60), 119.5 (C-50), 119.0 (C-30), 103.2 (C-3), 100.9 (C-
10), 87.0 (C-12), 80.0 (C-12a), 64.3 (C-200), 60.6 (C-10), 52.
3 (C-100), 51.5 (C-5a), 43.4 (C-8a), 36.4 (C-6), 35.4 (C-4),
33.6 (C-7), 29.9 (C-9), 25.1 (C-14), 23.7 (C-5), 23.4 (C-8),
19.3 (C-15), 11.9 (C-16). ESI-HRMS: calculated:
C29H39N4O7: 555.28187; found: 555.28181 [M ? H]?.
General procedure for the synthesis of 6a–b
4-Aminobenzoic acid or 3-aminobenzoic acid (5 g,
36.50 mmol) was dissolved in concentrated HCl (15 mL)
and water (15 mL) and then cooled to 0 °C. Sodium nitrite
(3.02 g, 43.80 mmol, 1.2 eq) was added, and the yellow
solution was stirred at 0 °C for 2 h. A mount of NaN3
(4.75 g, 73 mmol, 2 eq) was added slowly to the mixture,
and the mixture was stirred for 2 h and cooled to room
temperature. The crude precipitate was filtered, and washed
with distilled water and recrystallized in EtOH to give 6a
(5.3 g, 89 %) and 6b (5.05 g, 85 %), which were used for
the next step without further purification.
General procedure for the synthesis of 7a–i and 8a–i
N, N-Diethyl-4-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-trime
thyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochro
men-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)benzamide (11b)
White solids obtained by column chromatography using
CH2Cl2:MeOH:Et3N (99:1:0.1) as eluting system; yield
59 %. Mp 145–146 °C. IR (KBr, m (cm-1)): 1655, 1570,
A mixture of 4-azidobenzoic acid or 3-azidobenzoic acid
(500 mg, 3.06 mmol), EDC (703 mg, 3.67 mmol, 1.2 eq),
DMAP (186 mg, 1.53 mmol, 0.5 eq) in CH2Cl2 (15 mL)
was stirred at room temperature for 2 days. The reaction
process was monitored by TLC. The reaction mixture was
then diluted with CH2Cl2 (10 mL), and extracted consec-
utively with H2O (3 9 15 mL), 5 % NaHCO3
(2 9 15 mL), 5 % HCl (2 9 15 mL) and washed with
H2O (2 9 10 mL). The organic phase was separated, dried
on anhydrous Na2SO4 and evaporated under reduced
pressure to give 7a–i and 8a–i as solids, which were used
for the next step without further purification.
1
1471, 1440, 1371, 1193, 1106, 1030, 980, 937, 879. H
NMR (500 MHz, CDCl3) d (ppm): 7.60 (s, 1H, H-30), 7.59
(d, J = 8.5 Hz, 2H, H-60), 7.58 (d, J = 8.5 Hz, 2H, H-50),
5.45 (s, 1H, H-12), 5.02 (d, J = 12.5 Hz, 1H, H-10), 4.98
(d, J = 3.5 Hz, 1H, H-10), 4.79 (d, J = 12.5 Hz, 1H,
H-10), 3.74 (brs, 4H, H-100), 2.69–2.67 (m, 1H, H-9),
123

Med Chem Res
2.41–2.35 (tt, J = 14, 10.0 Hz, 1H, H-4a), 2.07–2.02 (m,
1H, H-4b), 1.91–1.87 (m, 2H, 8a, H-5a), 1.79–1.75 (m,
1H, H-8b), 1.64–1.59 (m, 1H, H-7b), 1.52–1.47 (m, 2H,
H-8a, H-5b), 1.45 (overlap, 9H, H-14, H-200), 1.35–1.28 (m,
1H, H-6), 1.26–1.22 (m, 1H, H-5a), 0.93 (overlap, 7H,
H-7a, H-15, H-16). 13C NMR (125 MHz, CDCl3) d (ppm):
168.9 (C=O), 146.0 (C-20), 137.9 (C-40), 135.6 (C-70), 128.
8 (C-60), 120.6 (C-50), 120.5 (C-30), 104.1 (C-3), 101.8 (C-
10), 87.9 (C-12), 81.1 (C-12a), 66.8 (C-10), 61.6 (C-100), 52.
5 (C-5a), 44.3 (C-8a), 37.3 (C-6), 36.4 (C-4), 34.5 (C-7),
30.8 (C-9), 26.1 (C-14), 24.6 (C-5), 24.4 (C-8), 20.3 (C-
15), 12.9 (C-16). ESI-HRMS: calculated: C29H41N4O6:
541.30261; found: 541.30258 [M ? H]?.
4H, H-200), 2.65 (m, 1H, H-9), 2.54 (brs, 2H, H-300), 2.40–2.
34 (m, 1H, H-4a), 2.07–2.03 (m, 1H, H-4b), 1.91–1.86 (m,
2H, H-8a, H-5a), 1.80–1.73 (m, 1H, H-8b), 1.63–1.58 (m,
1H, H-7b), 1.52–1.49 (m, 2H, H-8a, H-5b), 1.46 (s, 3H,
H-14), 1.37–1.31 (m, 1H, H-6), 1.31–1.23 (m, 1H, H-5a),
1.15 (t, J = 8.0 Hz, 3H, H-400), 0.92 (overlap, 7H, H-7a,
H-15, H-16). 13C NMR (125 MHz, CDCl3) d (ppm): 168.6
(C=O), 145.9 (C-20), 137.6 (C-40), 135.9 (C-70), 128.6 (C-
60), 120.6 (C-50), 120.3 (C-30), 103.9 (C-3), 101.7 (C-10),
87.8 (C-12), 80.9 (C-12a), 61.4 (C-10), 53.4 (C-5a), 52.3
(C-200), 48.5 (C-300), 52.0 (C-100), 44.2 (C-8a), 37.2 (C-6),
36.2 (C-4), 34.4 (C-7), 30.7 (C-9), 25.9 (C-14), 24.5 (C-5),
24.3 (C-8), 20.1 (C-15), 12.8 (C-16), 11.7 (C-400). ESI-
HRMS: calculated: C31H44N5O6: 582.32916; found: 582.
32909 [M ? H]?.
(4-Methylpiperazin-1-yl)(4-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,
3-i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)
phenyl)methanone (11c) White solids obtained by column
chromatography using CH2Cl2:MeOH:Et3N (98:2:0.1) as
eluting system; yield 58 %. Mp 92–93 °C. IR (KBr, m
(cm-1)): 1660, 1560, 1479, 1440, 1375, 1192, 1102, 1030,
(4-Phenylpiperazin-1-yl)(4-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-
i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)
methanone (11e) White solids obtained by column chro-
matography using CH2Cl2:MeOH:Et3N (99.5:0.5:0.1) as
eluting system; yield 66 %. Mp 81–83 °C. IR (KBr, m
(cm-1)): 1681, 1569, 1469, 1456, 1389, 1172, 1102, 1035,
1
988, 932, 879. H NMR (500 MHz, CDCl3) d (ppm): 8.08
(s, 1H, H-30), 7.83 (d, J = 8.5 Hz, 2H, H-60), 7.59 (d, J = 8.
5 Hz, 2H, H-50), 5.45 (s, 1H, H-12), 5.02 (d, J = 12.5 Hz,
1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d, J = 12.
5 Hz, 1H, H-10), 3.82 (brs, 4H, H-100), 3.48 (brs, 4H, H-200),
2.65 (m, 1H, H-9), 2.46–2.41 (m, 1H, H-4a), 2.34 (m, 3H,
H-300), 2.07–2.03 (m, 1H, H-4b), 1.91–1.86 (m, 2H, H-8a,
H-5a), 1.80–1.73 (m, 1H, H-8b), 1.63–1.58 (m, 1H, H-7b),
1.52–1.49 (m, 2H, H-8a, H-5b), 1.46 (s, 3H, H-14), 1.37–1.
31 (m, 1H, H-6), 1.31–1.23 (m, 1H, H-5a), 0.92 (overlap,
7H, H-7a, H-15, H-16). 13C NMR (125 MHz, CDCl3) d
(ppm): 168.8 (C=O), 146.0 (C-20), 137.7 (C-40), 136.1 (C-
70), 128.7 (C-50), 120.8 (C-60), 120.6 (C-30), 104.1 (C-3),
101.8 (C-10), 88.0 (C-12), 81.6 (C-12a), 61.6 (C-10), 53.4
(C-200), 53.4 (C-100), 52.5 (C-5a), 45.9 (C-300), 44.4 (C-8a),
37.4 (C-6), 36.4 (C-4), 34.5 (C-7), 31.5 (C-9), 26.1 (C-14),
24.6 (C-5), 24.3 (C-8), 20.3 (C-15), 13.0 (C-16). ESI-
HRMS: calculated: C30H42N5O6: 568.31351; found: 568.
31309 [M ? H]?.
1
989, 937, 872. H NMR (500 MHz, CDCl3) d (ppm): 7.85
(s, 1H, H-30), 7.83 (d, J = 8.5 Hz, 2H, H-60), 7.63 (d, J =
8.5 Hz, 2H, H-50), 7.29 (m, 2H, H-500), 6.95 (m, 3H, H-400,
H-600), 5.45 (s, 1H, H-12), 5.03 (d, J = 12.5 Hz, 1H, H-10),
4.98 (d, J = 3.5 Hz, 1H, H-10), 4.79 (d, J = 12.5 Hz, 1H,
H-10), 3.95 (brs, 4H, H-100), 3.61 (brs, 4H, H-200), 2.69–2.66
(m, 1H, H-9), 2.41–2.35 (m, 1H, H-4a), 2.09–2.02 (m, 1H,
H-4b), 1.91–1.86 (m, 2H, H-8a, H-5a), 1.80–1.75 (m, 1H,
H-8b), 1.63–1.59 (m, 1H, H-7b), 1.53–1.47 (m, 2H, H-8a,
H-5b), 1.46 (s, 3H, H-14), 1.35–1.30 (m, 1H, H-6), 1.27–1.
21 (m, 1H, H-5a), 0.94 (m, 7H, H-7a, H-15, H-16). 13C
NMR (125 MHz, CDCl3) d (ppm): 168.8 C=O), 150.7 (C-
3000), 146.0 (C-20) 137.8 (C-40), 135.8 (C-70), 129.2 (C-500),
129.2 (C-60), 128.8 (C-50), 120.7 (C-600), 120.6 (C-30), 116.
7 (C-400), 104.1 (C-3), 101.8 (C-10), 87.9 (C-12), 80.9 (C-
12a), 61.5 (C-10), 53.4 (C-5a), 52.4 (C-200), 44.3 (C-100), 43.
6 (C-8a), 37.3 (C-6), 36.3 (C-4), 34.5 (C-7), 30.7 (C-9), 26.
0 (C-14), 24.6 (C-5), 24.4 (C-8), 20.2 (C-15), 12.9 (C-16).
ESI-HRMS: calculated: C35H44N5O6: 630.32916; found:
630.32911 [M ? H]?.
(4-Ethylpiperazin-1-yl)(4-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-
i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)-
methanone (11d) White solids obtained by column chro-
matography using CH2Cl2:MeOH:Et3N (98:2:0.1) as elut-
ing system; yield 53 %. Mp 121–122 °C. IR (KBr, m
(cm-1)): 1670, 1568, 1479, 1446, 1379, 1182, 1109, 1036,
Piperidin-1-yl(4-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-trime
thyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochro-
men-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)metha-
none (11f) White solids obtained by column
chromatography using CH2Cl2:MeOH:Et3N (99:1:0.1) as
eluting system; yield 51 %. Mp 127–128 °C. IR (KBr, m
(cm-1)): 1688, 1567, 1469, 1451, 1389, 1162, 1102, 1038,
985, 937. 1H NMR (500 MHz, CDCl3) d (ppm): 8.01
(s, 1H, H-30), 8.05 (d, J = 8.0 Hz, 2H, H-60), 7.58 (d, J =
1
989, 931, 872. H NMR (500 MHz, CDCl3) d (ppm): 8.04
(s, 1H, H-30), 7.83 (d, J = 8.5 Hz, 2H, H-60), 7.60 (d, J =
8.5 Hz, 2H, H-50), 5.45 (s, 1H, H-12), 5.02 (d, J = 12.
5 Hz, 1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d,
J = 12.5 Hz, 1H, H-10), 3.82 (brs, 4H, H-100), 3.48 (brs,
123

Med Chem Res
8.0 Hz, 2H, H-50), 5.45 (s, 1H, H-12), 5.03 (d, J = 13.
0 Hz, 1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d,
J = 13.0 Hz, 1H, H-10), 3.73 (brs, 4H, H-100), 2.68 (m, 1H,
H-9), 2.38–2.35 (m, 1H, H-4a), 2.07–2.02 (m, 1H, H-4b),
1.91–1.86 (m, 2H, H-8a, H-5a), 1.80–1.75 (m, 1H, H-8b),
1.63–1.53 (m, 5H, H-7b, H-200), 1.51–1.48 (m, 4H, H-300,
H-8a, H-5b), 1.46 (s, 3H, H-14), 1.35–1.31 (m, 1H, H-6), 1.
27–1.22 (m, 1H, H-5a), 0.93 (overlap, 7H, H-7a, H-15,
H-16). 13C NMR (125 MHz, CDCl3) d (ppm): 168.7 (C=
O), 145.9 (C-20), 137.4 (C-40), 136.7 (C-70), 128.4 (C-60),
120.6 (C-50), 120.3 (C-30), 104.1 (C-3), 101.8 (C-10), 87.9
(C-12), 80.9 (C-12a), 61.6 (C-10), 53.4 (C-5a), 52.4 (C-100),
44.3 (C-8a), 37.3 (C-6), 36.3 (C-4), 34.5 (C-7), 30.8 (C-9),
26.0 (C-14), 25.5 (C-200), 24.6 (C-5, C-300), 24.3 (C-8), 20.2
(C-15), 12.9 (C-16). ESI-HRMS: calculated: C30H41N4O6:
553.30261; found: 553.30213 [M ? H]?.
5.44 (s, 1H, H-12), 5.03 (d, J = 12.5 Hz, 1H, H-10), 4.98
(d, J = 3.5 Hz, 1H, H-10), 4.77 (d, J = 12.5 Hz, 1H,
H-10), 3.52 (m, 1H, H-100), 3.06 (brs, 2H, H-500), 2.67 (m,
1H, H-9), 2.41–2.35 (m, 1H, H-4a), 2.07–2.02 (m, 1H,
H-4b), 1.91–1.85 (m, 2H, H-8a, H-5a), 1.82–1.71 (m, 1H,
H-8b), 1.64–1.57 (m, 3H, H-7b, H-200), 1.53–1.48 (m, 6H,
H-8a, H-5b, H-300, H-400), 1.46 (s, 3H, H-14), 1.36–1.30
(1H, H-6), 1.28–1.21 (m, 4H, H-600, H-5a), 0.94–0.92
(overlap, 7H, H-7a, H-15, H-16). 13C NMR (125 MHz,
CDCl3) d (ppm): 168.7 (C=O), 146.0 (C-20), 138.8 (C-40),
137.2 (C-70), 129.9 (C-60), 120.6 (C-30), 120.5 (C-50), 104.2
(C-3), 101.9 (C-10), 87.9 (C-12), 81.1 (C-12a), 61.7 (C-10),
53.4 (C-5a), 52.5 (C-100), 44.4 (C-8a, C-500), 37.3 (C-6), 36.
4 (C-4), 34.5 (C-7), 30.8 (C-9), 29.6 (C-200), 26.1 (C-14),
24.6 (C400), 24.4 (C-300), 24.2 (C-5), 24.0 (C-8), 20.3 (C-
600), 18.8 (C-15), 12.9 (C-16). ESI-HRMS: calculated:
C31H43N4O6: 567.31826; found: 567.31820 [M ? H]?.
(4-Methylpiperidin-1-yl)(4-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,
3-i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phe-
nyl)methanone (11g) Oil form obtained by column chro-
matography using CH2Cl2:MeOH:Et3N (99:1:0.1) as elut-
ing system; yield 49 %. IR (film, m (cm-1)): 1678, 1577,
Pyrrolidin-1-yl(4-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-tri-
methyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]iso-
chromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)
methanone (11i) White solids obtained by column
chromatography using CH2Cl2:MeOH:Et3N (99: 1: 0.1) as
eluting system; yield 50 %. Mp 140–141 °C. IR (KBr, m
(cm-1)): 1659, 1557, 1469, 1462, 1385, 1165, 1105, 1035,
1
1489, 1461, 1382, 1152, 1109, 1039, 988, 932. H NMR
(500 MHz, CDCl3) d (ppm): 8.01 (s, 1H, H-30), 7.81 (d,
J = 8.5 Hz, 2H, H-60), 7.58 (d, J = 8.5 Hz, 2H, H-50), 5.
45 (s, 1H, H-12), 5.03 (d, J = 12.5 Hz, 1H, H-10), 4.98 (d,
J = 3.5 Hz, 1H, H-10), 4.79 (d, J = 12.5 Hz, 1H, H-10), 3.
71 (brs, 2H, H-100), 3.05 (brs, 2H, H-100), 2.71–2.65 (m, 1H,
H-9), 2.41–2.34 (m, 1H, H-4a), 2.07–2.03 (m, 1H, H-4b),
1.91–1.86 (m, 2H, H-8a, H-5a), 1.82–1.75 (m, 3H, H-8b,
H-200), 1.72–1.59 (m, 2H, H-7b, H-300), 1.52–1.47 (m, 2H,
8a, H-5b), 1.44 (s, 3H, H-14), 1.37–1.30 (m, 1H, H-6), 1.
28–1.21 (m, 3H, H-200, H-5a), 1.0 (d, J = 6.5 Hz, 3H,
H-400), 0.94 (t, 7H, H-7a, H-15, H-16). 13C NMR
(125 MHz, CDCl3) d (ppm): 168.7 (C=O), 145.9 (C-20),
137.5 (C-40), 136.7 (C-70), 128.4 (C-60), 120.6 (C-50), 120.3
(C-30), 104.0 (C-3), 101.8 (C-10), 87.9 (C-12), 80.9 (C-
12a), 61.5 (C-10), 53.4 (C-5a), 52.4 (C-100), 44.3 (C-8a), 37.
3 (C-6), 36.3 (C-4), 34.5 (C-7), 33.7 (C-200), 30.9 (C-300),
30.7 (C-9), 26.0 (C-14), 24.6 (C-5), 24,4 (C-8), 21.6 (C-
400), 20.2 (C-15), 12.9 (C-16). ESI-HRMS: calculated:
C31H43N4O6: 567.31826; found: 567.31820 [M ? H]?.
1
989, 939. H NMR (500 MHz, CDCl3) d (ppm): 8.03 (s,
1H, H-30), 7.84 (d, J = 8.5 Hz, 2H, H-60), 7.59 (d, J = 8.
5 Hz, 2H, H-50), 5.45 (s, 1H, H-12), 5.03 (d, J = 12.5 Hz,
1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.77 (d, J = 12.
5 Hz, 1H, H-10), 3.68 (t, J = 7.0 Hz, 2H, H-100), 3.47 (t,
J = 7.0 Hz, 2H, H-100), 2.68 (m, 1H, H-9), 2.38 (dt, J = 4.
0 Hz, 14.0 Hz, 1H, H-4a), 2.35 (m, 4H, H-4b, H-100), 1.
95–1.85 (m, 4H, H-8a, H-5b, H-100), 1.64–1.59 (m, 1H,
H-7b), 1.53–1.47 (m, 2H, H-8a, H-5b), 1.46 (s, 3H, H-14),
1.35–1.27 (m, 1H, H-6), 1.26–1.22 (m, 1H, H-5a), 0.93
(overlap, 7H, H-7a, H-15, H-16).
13C NMR (125 MHz, CDCl3) d (ppm): 168.0 (C=O),
145.8 (C-20), 137.7 (C-40), 137.3 (C-70), 128.7 (C-60), 120.6
(C-50), 120.0 (C-30), 104.0 (C-3), 101.7 (C-10), 87.8 (C-
12), 80.9 (C-12a), 61.5 (C-10), 52.4 (C-5a), 49.5 (C-100),
44.2 (C-8a), 37.2 (C-6), 36.3 (C-4), 34.4 (C-7), 30.7 (C-9),
26.3 (C-14), 26.0 (C-200), 24.5 (C-5), 24.2 (C-8), 20.2 (C-
15), 12.8 (C-16). ESI-HRMS: calculated: C29H39N4O6:
539.28696; found: 539.28691 [M ? H]?.
(2-Methylpiperidin-1-yl)(4-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,
3-i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ph-
enyl)methanone (11h) Oil form obtained by column
chromatography using CH2Cl2:MeOH:Et3N (99:1:0.1) as
eluting system; yield 55 %. IR (film, m (cm-1)): 1668,
1557, 1479, 1451, 1375, 1167, 1102, 1033, 988, 939. H
NMR (500 MHz, CDCl3) d (ppm): 7.85 (s, 1H, H-30), 7.80
(d, J = 8.5 Hz, 2H, H-60), 7.56 (d, J = 8.5 Hz, 2H, H-50),
Morpholino(3-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-trime-
thyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochr-
omen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)met-
hanone (12a) Oil form obtained by column chromatog-
raphy using CH2Cl2:MeOH:Et3N (99:1:0.1) as eluting
system; yield 49 %. IR (film, m (cm-1)): 1679, 1547, 1456,
1469, 1387, 1174, 1108, 1038, 987, 939. 1H NMR
(500 MHz, CDCl3) d (ppm): 8.08 (s, 1H, H-30), 7.85–7.82
1
123

Med Chem Res
(m, 2H, H-70, H-80), 7.59 (t, J = 1.5 Hz, 1H, H-50), 7.48 (d,
J = 7.5 Hz, 1H, H-90), 5.45 (s, 1H, H-12), 5.03 (d, J = 8.
0 Hz, 1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d,
J = 8.0 Hz, 1H, H-10), 3.78 (brs, 4H, H-200), 3.58 (brs, 4H,
H-100), 2.69–2.66 (m, 1H, H-9), 2.38–2.32 (m, 1H, H-4a),
2.06–2.0 (m, 1H, H-4b), 1.91–1.86 (m, 2H, H-8a, H-5a), 1.
79–1.74 (m, 1H, H-8b), 1.64–1.60 (m, 1H, H-7b), 1.52–1.
49 (m, 1H, H-8a), 1.46 (s, 3H, H-14), 1.36–1.19 (m, 1H,
H-6), 0.95 (overlap, 7H, H-7a, H-15, H-16). 13C NMR
(125 MHz, CDCl3) d (ppm): 168.7 (C=O), 146.0 (C-20),
137.3 (C-60), 137,0 (C-90), 130.1 (C-80), 127.0 (C-40), 121.8
(C-70), 120.7 (C-50), 119.3 (C-30), 104.1 (C-3), 101.8 (C-
10), 87.9 (C-12), 81.0 (C-12a), 66.7 (C-100), 61.6 (C-10), 53.
4 (C-200), 52.4 (C-5a), 44.3 (C-8a), 37.3 (C-6), 36.3 (C-4),
34.5 (C-7), 30.8 (C-9), 26.0 (C-14), 24.6 (C-5), 23.7 (C-8),
20.2 (C-15), 12.9 (C-16). ESI-HRMS: calculated:
C29H39N4O7: 555.28187; found: 555.28181 [M ? H]?.
H-80), 7.47 (dd, J = 1.5 Hz, 8.5 Hz, 1H, H-90), 5.45 (s, 1H,
H-12), 5.03 (d, J = 13.0 Hz, 1H, H-10), 4.98 (d, J = 3.
5 Hz, 1H, H-10), 4.78 (d, J = 13.0 Hz, 1H, H-10), 3.82
(brs, 4H, H-100), 2.69–2.67 (m, 1H, H-9), 2.57 (brs, 4H,
H-200), 2.49–2.35 (m, 3H, H-300), 2.10–2.03 (m, 1H, H-4b),
1.92–1.86 (m, 2H, H-8a, H-5a), 1.79–1.74 (1H, H-8b), 1.
63–1.60 (m, 1H, H-7b), 1.52–1.47 (m, 2H, H8a, H-5b), 1.
45 (s, 3H, H-14), 1.35–1.30 (m, 1H, H-6), 1.27–1.21 (m,
1H, H-5a), 0.94 (overlap, 7H, H-7a, H-15, H-16). 13C
NMR (125 MHz, CDCl3) d (ppm): 168.5 (C=O), 146.0 (C-
20), 137.5 (C-60), 137.1 (C-90), 129.8 (C-80), 126.9 (C-40),
121.6 (C-70), 120.7 (C-50), 119.1 (C-30), 104.1 (C-3), 101.9
(C-10), 87.9 (C-12), 81.0 (C-12a), 61.6 (C-10), 55.1 (C-200),
53.4 (C-100), 52.4 (C-5a), 45.8 (C-300), 44.3 (C-8a), 37.3 (C-
6), 36.4 (C-4), 34.5 (C-7), 30.9 (C-9), 25.9 (C-14), 24.6 (C-
5), 24.4 (C-8), 20.2 (C-15), 12.9 (C-16). ESI-HRMS: cal-
culated: C30H42N5O6: 568.31351; found: 568.31309
[M ? H]?.
N,N-Diethyl-3-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-trime-
thyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochr-
omen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)benzamide
(12b) Oil form obtained by column chromatography
using CH2Cl2:MeOH:Et3N (99:1:0.1) as eluting system;
yield 58 %. IR (film, m (cm-1)): 1672, 1549, 1446, 1461,
(4-Ethylpiperazin-1-yl)(3-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,
3-i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)p-
henyl)methanone (12d) Oil form obtained by column
chromatography using CH2Cl2:MeOH:Et3N (98:2:0.1) as
eluting system; yield 62 %. IR (film, m (cm-1)): 1676,
1
1387, 1171, 1100, 1032, 989, 939. H NMR (500 MHz,
1
CDCl3) d (ppm): 8.0 (s, 1H, H-30), 7.81 (dd, J = 1.5 Hz, 8.
5 Hz, 1H, H-70), 7.76 (m, 1H, H-50), 7.58 (t, J = 9.0 Hz,
1H, H-80), 7.45 (m, 1H, H-90), 5.44 (s, 1H, H-12), 5.03 (d,
J = 12,5 Hz, 1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.
78 (d, J = 12.5 Hz, 1H, H-10), 3.58 (brs, 4H, H-100), 2.67
(m, 1H, H-9), 2.41–2.34 (m, 1H, H-4a), 2.07–2.02 (m, 1H,
H-4b), 1.91–1.86 (m, 1H, 2H, H-8a, H-5a), 1.79–1.74 (m,
1H, H-8b), 1.64–1.60 (m, 1H, H-7b), 1.53–1.49 (m, 2H,
H-8a, H-5b), 1.46 (s, 9H, H-14, H-200), 1.35–1.21 (m, 1H,
H-5a), 0.94 (overlap, 7H, H-7a, H-15, H-16). 13C NMR
(125 MHz, CDCl3) d (ppm): 169.5 (C=O), 145.9 (C-20),
138.9 (C-60), 137.1 (C-90), 129.9 (C-80), 126.3 (C-40), 121.1
(C-70), 120.7 (C-50), 118.6 (C-30), 104.1 (C-3), 101.9 (C-
10), 87.8 (C-12), 81.0 (C-12a), 61.7 (C-10), 52.4 (C-5a), 44.
3 (C-8a), 44.0 (C-100), 37.3 (C-6), 36.3 (C-4), 34.5 (C-7),
30.8 (C-9), 26.0 (C-14), 24.6 (C-5), 24.4 (C-8), 20.2 (C-
15), 13.1 (C-16), 12.9 (C-200). ESI-HRMS: calculated:
C29H41N4O6: 541.30261; found: 541.30258 [M ? H]?.
1548, 1457, 1478, 1395, 1186, 1109, 1043, 979, 935. H
NMR (500 MHz, CDCl3) d (ppm): 8.0 (s, 1H, H-30), 7.85
(dt, J = 1.5 Hz, 8.5 Hz, 1H, H-70), 7.80 (s, 1H, H-50), 7.58
(t, J = 8.5 Hz, 1H, H-80), 7.47 (dd, J = 1.5 Hz, 8.5 Hz,
1H, H-90), 5.45 (s, 1H, H-12), 5.03 (d, J = 13.0 Hz, 1H,
H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d, J = 13.
0 Hz, 1H, H-10), 3.84 (brs, 4H, H-100), 2.69–2.67 (m, 1H,
H-9), 2.55 (brs, 4H, H-200), 2.49–2.35 (m, 3H, H-4a, H-300),
2.11–2.03 (m, 1H, H-4b), 1.91–1.86 (m, 2H, H-8a, H-5a),
1.79–1.74 (m, 1H, H-8b), 1.63–1.60 (m, 1H, H-7b), 1.
52–1.47 (m, 2H, H-8a, H-5b), 1.45 (s, 3H, H-14), 1.35–1.
30 (m, 1H, H-6), 1.27–1.21 (m, 1H, H-5a), 1.12 (t, J = 7.
0 Hz, 3H, H-400), 0.94 (overlap, 7H, H-7a, H-15, H-16).
13C NMR (125 MHz, CDCl3) d (ppm): 168.4 (C=O), 145.9
(C-20), 137.6 (C-60), 137.2 (C-90), 129.9 (C-80), 126.9 (C-
40), 121.6 (C-70), 120.7 (C-50), 119.2 (C-30), 104.1 (C-3),
101.9 (C-10), 87.9 (C-12), 81.0 (C-12a), 61.7 (C-10), 53.4
(C-5a), 52.4 (C-200), 52.1 (C-100), 49.4 (C-300), 44.3 (C-8a),
37.3 (C-6), 36.3 (C-4), 34.5 (C-7), 30.8 (C-9), 26.1 (C-14),
24.6 (C-5), 24.4 (C-8), 20.2 (C-15), 12.9 (C-16), 11.8 (C-
400). ESI-HRMS: calculated: C31H44N5O6: 582.32916;
found: 582.32909 [M ? H]?.
(4-Methylpiperazin-1-yl)(3-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,
3-i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ph-
enyl)methanone (12c) Oil form obtained by column
chromatography using CH2Cl2:MeOH:Et3N (98:2:0.1) as
eluting system; yield 51 %. IR (film, m (cm-1)): 1688,
(4-Phenylpiperazin-1-yl)(3-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,
3-i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)p-
henyl)methanone (12e) Oil form obtained by column
chromatography using CH2Cl2:MeOH:Et3N (99:0.5:0.1) as
1
1541, 1444, 1468, 1385, 1176, 1106, 1033, 979, 935. H
NMR (500 MHz, CDCl3) d (ppm): 8.0 (s, 1H, H-30), 7.85
(m, 1H, H-70), 7.80 (m, 1H, H-50), 7.58 (t, J = 8.5 Hz, 1H,
123

Med Chem Res
eluting system; yield 57 %. IR (film, m (cm-1)): 1656,
1559, 1477, 1458, 1387, 1196, 1109, 1044, 978, 935. H
i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phe-
nyl)methanone (12g) Oil form obtained by column
chromatography using CH2Cl2:MeOH:Et3N (99:1:0.1) as
eluting system; yield 59 %. IR (film, m (cm-1)): 1666,
1
NMR (500 MHz, CDCl3) d (ppm): 8.02 (s, 1H, H-30), 7.85
(d, J = 9.0 Hz, 2H, H-500), 7.63 (d, J = 9.0 Hz, 2H, H-400),
7.29 (t, J = 8.0 Hz, 2H, H-80, H-70), 6.95–6.91 (m, 3H,
H-50, H-90, H-600), 5.45 (s, 1H, H-12), 5.03 (d, J = 13.0 Hz,
1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.79 (d, J = 13.
0 Hz, 1H, H-10), 3.62 (brs, 4H, H-100), 3.19 (brs, 4H, H-200),
2.68 (m, 1H, H-9), 2.41–2.34 (m, 1H, H-4a), 2.08–2.02 (m,
1H, H-4b), 1.91–1.86 (m, 2H, H-8a, H-5a), 1.81–1.75 (m,
1H, H-8b), 1.63–1.58 (m, 1H, H-7b), 1.53–1.46 (m, 2H,
H-8a, H-5b), 1.44 (s, 3H, H-14), 1.35–1.27 (m, 1H, H-6), 1.
26–1.22 (m, 1H, H-5a), 0.93 (overlap, 7H, H-7a, H-15,
H-16). 13C NMR (125 MHz, CDCl3) d (ppm): 168.6 (C=
O), 150.7 (C-300), 146.0 (C-60), 137.4 (C-90), 137.2 (C-40),
130.1 (C-80), 129.2 (C-40), 127.0 (C-70), 121.7 (C-600), 120.
7 (C-400), 119.3 (C-30), 116.7 (C-50), 104.1 (C-3), 101.9 (C-
10), 87.9 (C-12), 81.0 (C-12a), 61.6 (C-10), 53.45 (C-200),
52.5 (C-5a), 48.7 (C-100), 44.3 (C-8a), 37.3 (C-6), 36.3 (C-
4), 34.5 (C-7), 30.8 (C-9), 26.1 (C-14), 24.6 (C-5), 24.4 (C-
8), 20.2 (C-15), 12.9 (C-16). ESI-HRMS: calculated:
C35H44N5O6: 630.32916; found: 630.32911 [M ? H]?.
1
1561, 1484, 1456, 1387, 1194, 1102, 1045, 977, 935. H
NMR (500 MHz, CDCl3) d (ppm): 7.99 (s, 1H, H-30), 7.82
(m, 1H, H-70), 7.77 (m, 1H, H-50), 7.57 (t, J = 7.5 Hz, 1H,
H-80), 7.46 (d, J = 7.5 Hz, 1H, H-90), 5.45 (s, 1H, H-12), 5.
03 (d, J = 13.0 Hz, 1H, H-10), 4.98 (d, J = 3.5 Hz, 1H,
H-10), 4.77 (d, J = 13.0 Hz, 1H, H-10), 3.71 (brs, 2H,
H-100), 3.07 (brs, 2H, H-100), 2.68–2.66 (m, 1H, H-9), 2.
40–2.35 (tt, 1H, J = 14.5, 10.5 Hz, 1H, H-4a), 2.06–1.92
(m, 1H, H-4b), 1.89–1.75 (m, 2H, H-8a, H-5a), 1.73–1.61
(m, 3H, H-8b, H-300), 1.53–1.47 (m, 2H, H-8a, H-5b), 1.45
(s, 3H, H-14), 1.37–1.33 (m, 2H, H-200), 1.29–1.21 (m, 3H,
H-5a, H-200), 0.98 (d, J = 7.0 Hz, 3H, H-400), 0.93 (overlap,
7H, H-7a, H-15, H-16). 13C NMR (125 MHz, CDCl3) d
(ppm): 168.5 (C=O), 145.9 (C-20), 138.3 (C-60), 137.2 (C-
90), 129.9 (C-80), 126.8 (C-40), 121.4 (C-70), 120.7 (C-50),
119.0 (C-30), 104.1 (C-3), 101.9 (C-10), 87.9 (C-12), 81.0
(C-12a), 61.7 (C-10), 52.5 (C-5a), 48.0 (C-100), 44.3 (C-8a),
37.3 (C-6), 36.3 (C-4), 34.5 (C-7), 31.0 (C-200), 29.5 (C-300),
30.8 (C-9), 26.1 (C-14), 24.6 (C-5), 24.4 (C-8), 21.6 (C-
400), 20.2 (C-15), 12.9 (C-16). ESI-HRMS: calculated:
C31H43N4O6: 567.31826; found: 567.31820 [M ? H]?.
Piperidin-1-yl(3-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-trim-
ethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochro-
men-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)met-
hanone (12f) Oil form obtained by column chromatog-
raphy using CH2Cl2:MeOH:Et3N (99:1:0.1) as eluting
system; yield 60 %. IR (film, m (cm-1)): 1668, 1569, 1487,
1466, 1377, 1185, 1107, 1049, 977, 935. 1H NMR
(500 MHz, CDCl3) d (ppm): 8.0 (s, 1H, H-30), 7.84 (m, 1H,
H-70), 7.78 (m, 1H, H-50), 7.58 (t, J = 8.0 Hz, 1H, H-80), 7.
45 (m, 1H, H-90), 5.45 (s, 1H, H-12), 5.03 (d, J = 12.5 Hz,
1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d, J = 12.
5 Hz, 1H, H-10), 3.74 (brs, 2H, H-100), 3.38 (brs, 2H, H-100),
2.68–2.66 (m, 1H, H-9), 2.41–2.35 (m, 1H, H-4a), 2.07–2.
03 (m, 1H, H-4b), 1.91–1.86 (m, 2H, H-8a, H-5a), 1.79–1.
74 (m, 2H, H-8b, H-300), 1.64–1.59 (m, 2H, H-7b, H-300), 1.
58–1.53 (m, 4H, H-200), 1.52–1.47 (m, 2H, H-8a, H-5b), 1.
45 (s, 3H, H-14), 1.35–1.31 (m, 1H, H-6), 1.27–1.21 (m,
1H, H-5a), 0.94 (overlap, 7H, H-7a, H-15, H-16). 13C
NMR (125 MHz, CDCl3) d (ppm): 168.5 (C=O), 145.9 (C-
20), 138.2 (C-60), 137.1 (C-90), 129.8 (C-80), 126.7 (C-40),
121.3 (C-70), 120.7 (C-50), 118.9 (C-30), 104.0 (C-3), 101.8
(C-10), 87.9 (C-12), 81.0 (C-12a), 61.7 (C-10), 53.4 (C-5a),
52.4 (C-100), 44.3 (C-8a), 37.3 (C-6), 36.3 (C-4), 34.5 (C-7),
30.8 (C-9), 26.5 (C-14), 26.0 (C-200), 24.6 (C-5), 24.1 (C-
300), 23.6 (C-8), 20.2 (C-15), 12.9 (C-16). ESI-HRMS:
calculated: C30H41N4O6: 553.30261; found: 553.30259
[M ? H]?.
(2-Methylpiperidin-1-yl)(3-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,
3-i]isochromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ph-
enyl)methanone (12h) Oil form obtained by column
chromatography using CH2Cl2:MeOH:Et3N (99:1:0.1) as
eluting system; yield 63 %. IR (film, m (cm-1)): 1689,
1
1559, 1488, 1457, 1389, 1184, 1108, 1057, 979, 935. H
NMR (500 MHz, CDCl3) d (ppm): 7.99 (s, 1H, H-30), 7.83
(d, J = 7.5 Hz, 1H, H-70), 7.75 (d, J = 1.5 Hz, 1H, H-50),
7.57 (t, J = 7.5 Hz, 1H, H-80), 7.43 (d, J = 7.5 Hz, 1H,
H-90), 5.45 (s, 1H, H-12), 5.03 (d, J = 12.5 Hz, 1H, H-10),
4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d, J = 12.5 Hz, 1H,
H-10), 3.51 (m, 1H, H-100), 3.09 (m, 2H, H-500), 2.67 (m, 1H,
H-9), 2.41–2.34 (tt, 1H, J = 14.5, 10.5 Hz, 1H, H-4a), 2.
07–2.02 (m, 1H, H-4b), 1.82–1.69 (m, 3H, H-8b, H-300,
H-200), 1.64–1.58 (m, 3H, H-300, H-400, H-7b), 1.56–1.46 (m,
6H, H-8a, H-5b, H-400, H-300), 1.45 (s, 3H, H-14), 1.35–1.22
(m, 5H, H-6, H-5a, H-600), 0.94 (overlap, 7H, H-7a, H-15,
H-16). 13C NMR (125 MHz, CDCl3) d (ppm): 168.7 (C=
O), 146.0 (C-20), 138.8 (C-60), 137.2 (C-90), 129.9 (C-80),
126.4 (C-40), 121.3 (C-70), 120.8 (C-50), 118.7 (C-30), 104.1
(C-3), 101.9 (C-10), 87.9 (C-12), 81.1 (C-12a), 61.7 (C-10),
53.4 (C-100), 52.5 (C-5a), 44.6 (C-500), 44.4 (C-8a), 37.3 (C-
6), 36.4 (C-4), 34.5 (C-7), 30.8 (C-9), 29.8 (C-200), 26.1 (C-
14), 24.6 (C-400), 24.4 (C-5), 23.7 (C-8), 22.9 (C-300), 20.3
(C-15), 18.8 (C-600), 12.9 (C-16). ESI-HRMS: calculated:
C31H43N4O6: 567.31826; found: 567.31820 [M ? H]?.
(4-Methylpiperidin-1-yl)(3-(4-((((3R,6R,9R,10S,12R,12aR)-
3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-
123

Med Chem Res
12.5 Hz, 1H, H-10), 5.0 (d, J = 3.0 Hz, 1H, H-10), 4.88 (d,
J = 12.5 Hz, 1H, H-10), 2.68 (m, 1H, H-9), 2.41–2.34 (m,
1H, H-4a), 2.05–2.02 (m, 1H, H-4b), 1.90–1.86 (m, 2H,
H-8a, H-5a), 1.78–1.76 (m, 1H, H-8b), 1.67–1.56 (m, 1H,
H-7b), 1.51–1.45 (m, 2H, H-8a, H-5b), 1.44 (s, 3H, H-14),
1.31–1.21 (m, 1H, H-6), 1.25–1.19 (m, 1H, H-5a), 0.94
(overlap, 7H, H-7a, H-15, H-16). 13C NMR (125 MHz,
CDCl3) d (ppm): 151.4 (C-60), 150.3 (C-70), 146.2 (C-20),
141.1 (C-40), 136.9 (C-90), 129.5 (C-80), 129.0 (C-100), 124.
7 (C-110), 124.3 (C-120), 120.7 (C-50), 116.1 (C-30), 104.2
(C-3), 102.2 (C-10), 88.1 (C-12), 81.1 (C-12a), 61.7 (C-10),
53.1 (C-5a), 45.9 (C-8a), 37.5 (C-6), 36.4 (C-4), 34.6 (C-7),
30.9 (C-9), 26.2 (C-14), 24.7 (C-5), 24.5 (C-8), 20.3 (C-
15), 13.0 (C-16). ESI-HRMS: calculated: C27H32ClN4O5:
527.20612; found: 527.20619 [M ? H]?.
Pyrrolidin-1-yl(3-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-tri-
methyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isoc-
hromen-10-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)m-
ethanone (12i) Oil form obtained by column chro-
matography using CH2Cl2:MeOH:Et3N (99:1:0.1) as elut-
ing system; yield 55 %. IR (film, m (cm-1)): 1690, 1551,
1
1487, 1452, 1389, 1188, 1102, 1053, 977, 931. H NMR
(500 MHz, CDCl3) d (ppm): 8.03 (s, 1H, H-30), 7.92 (d,
J = 1.0 Hz, 1H, H-70), 7.86–7.84 (m, 1H, H-50), 7.60–7.56
(m, 2H, H-80, H-90), 5.45 (s, 1H, H-12), 5.03 (d, J = 12.
5 Hz, 1H, H-10), 4.98 (d, J = 3.5 Hz, 1H, H-10), 4.78 (d,
J = 12.5 Hz, 1H, H-10), 3.67 (t, J = 7.0 Hz, 2H, H-100), 3.
49 (J = 7.0 Hz, 2H, H-100), 2.69–2.66 (m, 1H, H-9), 2.
41–2.35 (tt, 1H, J = 14.5, 10.5 Hz, 1H, H-4a), 2.04–1.97
(m, 1H, H-4b), 1.95–1.86 (m, 4H, H-8a, H-5a, H-200), 1.
79–1.74 (m, 2H, H-200), 1.64–1.60 (m, 1H, H-7b), 1.50–1.
47 (m, 2H, H-8a, H-5b), 1.45 (s, 3H, H-14), 1.35–1.31 (m,
1H, H-6), 1.28–1.21 (m, 1H, H-5a), 0.94 (overlap, 7H,
H-7a, H-15, H-16). 13C NMR (125 MHz, CDCl3) d (ppm):
167.9 (C=O), 145.9 (C-20), 138.7 (C-60), 136.9 (C-90), 129.
8 (C-80), 127.1 (C-40), 121.7 (C-70), 120.7 (C-50), 119.3 (C-
30), 104.1 (C-3), 101.8 (C-10), 87.9 (C-12), 81.0 (C-12a),
61.6 (C-10), 52.4 (C-5a), 49.6 (C-100), 46.3 C-8a), 37.3 (C-
6), 36.3 (C-4), 34.5 (C-7), 30.8 (C-9), 26.3 (C-14), 26.0 (C-
200), 24.6 (C-5), 24.3 (C-8), 20.2 (C-15), 12.9 (C-16). ESI-
HRMS: calculated: C29H39N4O6: 539.28696; found: 539.
28691[M ? H]?.
Acknowledgments The authors thank Vietnam National Founda-
tion for Science and Technology Development (NAFOSTED) for
financial support via a Project 104.01.2013.01.
Compliance with ethical standards
Conflict of interest The authors have reported no conflict of
interest.
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A mixture of 10 (350 mg, 1.08 mmol) and the 4-azido-7-
chloroquinoline (14) (243 mg, 1.1 eq), L-ascorbic acid sodium
(26 mg, 0.13 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature for 10 min. CuSO4Á5H2O (20 mg, 0.066 mmol)
was then added, and the reaction mixture was stirred at room
temperature for 20 h. The mixture was then diluted with CH2
Cl2 (15 mL) and extracted with H2O (2 9 10 mL). The
organic phase was separated, dried on anhydrous Na2SO4 and
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highly functionalized Baylis–Hillman adducts of artemisinin
7-Chloro-4-(4-((((3R,6R,9R,10S,12R,12aR)-3,6,9-trimethy-
ldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-
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form obtained by column chromatography using CH2Cl2:
MeOH:Et3N (99:1:0.1) as eluting system; yield 75 %. IR
(film, m (cm-1)): 1648, 1555, 1481, 1452, 1387, 1181,
1109, 1053, 972, 939. 1H NMR (500 MHz, CDCl3) d
(ppm): 9.06 (d, J = 4.5 Hz, 1H, H-60), 8.25 (d, J = 2.
0 Hz, 1H, H-110), 8.01 (s, 1H, H-30), 7.99 (d, J = 2.0 Hz,
1H, H-80), 7.60 (dd, J = 2.0 Hz, 9.0 Hz, 1H, H-100), 7.51
(d, J = 4.5 Hz, 1H, H-50), 5.43 (s, 1H, H-12), 5.08 (d, J =
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