Structural modification of oridonin: Via DAST induced rearrangement

Article abstract of DOI:10.1039/c8ra05728a

A simple and efficient protocol was developed for the syntheses of oridonin analogues, i.e. 6,20-epoxy ent-kaurane diterpenoid analogues from oridonin via diethylaminosulfur trifluoride (DAST) promoted rearrangement, most of which exhibited superior anticancer activities compared with their precursor.

Full text of DOI:10.1039/c8ra05728a

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Structural modification of oridonin via DAST
induced rearrangement†
Cite this: RSC Adv., 2018, 8, 29548
a
a
a
b
Dong-Dong Luo,‡ Kai Peng,‡ Jia-Yu Yang, Pawinee Piyachaturawat,
b
c
c
a
Witchuda Saengsawang, Lei Ao, Wan-Zhou Zhao, Yu Tang
and Sheng-Biao Wan*a
*
Received 5th July 2018
Accepted 10th August 2018
A simple and efficient protocol was developed for the syntheses of oridonin analogues, i.e. 6,20-epoxy ent-
kaurane diterpenoid analogues from oridonin via diethylaminosulfur trifluoride (DAST) promoted
rearrangement, most of which exhibited superior anticancer activities compared with their precursor.
DOI: 10.1039/c8ra05728a
rsc.li/rsc-advances
cyclopentanone in the D-ring. The strong hydrogen bonding
interaction exists between 6b-OH and carbonyl group at C-15
Introduction
Oridonin, an ent-kaurane diterpenoid extracted from Isodon (Fig. 1). It's difficult for 6b-OH and 7b-OH to participate in
rubescens (Chinese name “Donglingcao”), has received partic- nucleophilic reaction due to the adjacent steric hindrance and
1,2
ular interest from the pharmaceutical community due to its the intramolecular hydrogen bonding interaction. The previous
pharmacological utilities, e.g. unique and prominent anticancer studies of oridonin on the structure–activity relationship (SAR)
3
22,23
activity as well as its safety. It has been demonstrated that have proved that D-ring is crucial to anti-cancer activity,
and
24
oridonin could signicantly suppress cancer cell migration via any modication of enone moiety would lead to loss of anti-
regulation of non-muscle myosin IIA. The anticancer mecha- cancer activity. As shown in Fig. 1, previous efforts on struc-
4
25
5–13
nism of oridonin in vitro may involve multiple pathways,
instance, oridonin can not only inhibit the proliferation of the ring,
breast cancer cell McF-7, but also induce apoptosis through the ring opening via oxidative cleavage of C–C bond between C-6
for tural modication of oridonin were mainly focused on A
2,26–28 29 17,30,31
6-O positions and 14-O positions
as well as B-
31
pathways of hampering the cell cycle and activation of mito- and C-7.
chondria.
9,14–18
Targeting AML1-ETO (AE) fusion protein which
Diethylaminosulfur triuoride (DAST) has been employed as
plays a critical role in leukemogenesis shows potent antitumor a versatile uorinating agent for various uorination reac-
32–34
activity with low adverse effects on t(8;21) leukemia in vitro and tions,
e.g. uorination of carbohydrate in which structural
19
in vivo. However, the clinical application of oridonin has been
signicantly impeded by its poor aqueous solubility, moderate
20
21
potency, low bioavailability and metabolic instability. Thus
it's highly desirable to synthesize the oridonin analogues via
rational chemical modication of its structure for better phar-
macological properties such as anticancer activity.
Oridonin belongs to the class of 7,20-epoxy ent-kaurane
diterpenoid structures, which features 1,6,14-trihydroxy groups,
7-hemiacetal moiety in the B-ring and the a-methylene
a
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for
Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of
Education, School of Medicine and Pharmacy, Ocean University of China, Yushan
Road 5, Qingdao 266003, China. E-mail: biaowan@ouc.edu.cn; tangyu@ouc.edu.cn;
Tel: +86-532-82031087
b
Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400,
Thailand
c
The Nanjing Han & Zaenker Cancer Institute (NHZCI), Nanjing OGpharma Co. Ltd.,
Nanjing 210036, China
†
Electronic supplementary information (ESI) available: CCDC 1590323. For ESI
and crystallographic data in CIF or other electronic format see DOI:
1
0.1039/c8ra05728a
Fig. 1 Structures of oridonin and biologically active analogues.
‡
These authors contributed equally to this work.
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Scheme 1 Synthesis of 14-acyl oridonin analogues 11.
34–37
rearrangements could be observed.
Therefore, it can be entry 6). Subsequently, various solvents were screened, and DCM
envisioned that the similar structural rearrangements of ori- was identied as the optimal one which furnished 12b in highest
donin could occur in the presence of DAST, yielding new ori- yield (Table 1, entry 4). The employment of other solvents such as
donin analogues. As a continuation of our research works on THF, MeCN, DMF and DMSO resulted in inferior yields (Table 1,
38,39
pharmaceutical molecules,
herein, we disclosed a simple entry 7–11), and notably, only a trace amount of 12b was observed
and efficient method for preparation of novel 6,20-epoxy ent- using acetone as solvent (Table 1, entry 11).
kaurane diterpenoid analogues from oridonin, in which 6,20-
Other strategies for this rearrangement were also investi-
endo ring was formed via DAST promoted rearrangement.
gated for more efficient transformation and more environ-
mentally benign conditions. Intriguingly, a trace amount of 12b
could be observed under Swern oxidation condition using
Results and discussion
DMSO, (COCl)
2
and i-Pr
2
NEt (for details, see the ESI† control
Our currently ongoing research works indicated that new potent
antitumor agents could be produced via installing protected
amino acid residues or cinnamyl group at C-14 position of ori-
donin analogues. Thus, oridonin analogues 11a–11r were
prepared in good yields through esterication of oridonin, 1-
acetyl-oridonin and 1-oxo-oridonin derivatives with 4-methoxy
cinnamylic acid, 3,4-dimethoxy cinnamic acid, 3,4,5-trimethoxy
cinnamic acid, Boc-Gly, Boc-L-Val, Boc-L-Leu, Boc-L-Ile, Boc-L-
Pro, Boc-L-Phe, N-Fmoc-L-Asp-1-OtBu, Fmoc-L-Phe (Scheme 1),
which would be exploited as substrates for rearrangement.
Initially, the feasibility of rearrangement was investigated using
readily accessed 1-oxo-14-acyl oridonin analogue 11b as the model
substrate in the presence of DAST (1 equiv.) with dichloromethane
a
Table 1 Optimization of the reaction conditions
b
Entry
Reagent (equiv.)
Solvent
Yield (%)
1
2
3
DAST (1)
DAST (3)
DAST (5)
DAST (10)
DAST (12)
DAST (10)
DAST (10)
DAST (10)
DAST (10)
DAST (10)
DAST (10)
DCM
DCM
DCM
DCM
DCM
DCM
THF
31
40
57
80
77
68
61
54
c
4
(DCM) as solvent, and gratifyingly the desired product 12b was
c
5
furnished in 31% yield, the structure of which was determined
unambiguously by X-ray crystallography (CCDC 1590323) (Table 1,
entry 1). Aerwards, the impact of DAST amount on the reaction
was examined, and the yields of 12b could be increased to 40%,
d
6
e
7
e
8
MeCN
DMF
e
9
61
36
f
1
1
0
1
DMSO
Acetone
57% and 80%, respectively with 3 equivalents, 5 equivalents and 10
e
Trace
equivalents of DAST employed (Table 1, entries 2–4). However,
further increasing the amount of DAST led to inferior yield (Table
a
ꢁ
Reaction condition: 11b (0.09 mmol), solvent (5.0 mL), ꢀ78 C for
b
1
0 min, then warmed up to room temperature for 8 h. Yield of
1
, entry 5). The reaction temperature was also evaluated, and the
reaction could be signicantly accelerated at higher temperature,
which, however, had a detrimental inuence on the yield (Table 1, 10 min, then warmed up to rt for 3 h. Room temperature for 3 h.
c
ꢁ
isolated products. ꢀ78 C for 10 min, then warmed up to rt for 2 h.
d
ꢁ
ꢁ
e
ꢁ
ꢀ
78 C for 10 min, then warmed up to 40 C for 1 h. ꢀ78 C for
f
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suggested that the acidic additive could thoroughly block the
transformation.
Under the optimal conditions, the generality of this protocol
was investigated with sterically and electronically diverse
substrates subjected to this rearrangement reaction. Gratify-
ingly, most of the substrates 11a–11r, were well tolerated,
furnishing a series of 6,20-epoxy-14-acyl ent-kaurane diterpe-
noids 12a–12j in 79–84% yields (Scheme 2). Notably, the
incorporated functionalities had a trivial impact on the trans-
formation. Subsequently, aiming to prepare oridonin analogues
carrying unprotected hydroxyl at C-14, the substrate 13 was
synthesized via protection of 7,14-dihydroxyl of oridonin with
2
2,2-dimethoxypropane followed by acetylation with Ac O, and
satisfyingly the correspondingly 6,20-epoxy-14-OH ent-kaurane
diterpenoid 14 was delivered in 89% yield with 13 treated with
DAST (Scheme 3).
Interestingly, when 11d was treated with DAST in the pres-
ence of (E)-3-(3,4-dimethoxyphenyl)acrylic acid, the 1-acetyl-
6
,14-diacyl oridonin analogue 15 was isolated as the main
Scheme 2 Synthesis of novel 6,20-epoxy ent-kaurane diterpenoid 12.
product instead in 83% yield and only trace of 12d was obtained
(Scheme 4).
Based on these experimental results, a plausible mechanism
was proposed (Scheme 5). Initially, 11d reacts with DAST to
produce the intermediate 16, which undergoes an intramolecular
nucleophilic substitution to furnish the bicyclic oxiranium ion
intermediate 17. Due to the basic nature of uorine anion and
comparative strong acidity of 7-OH, the hydroxyl group is readily
deprotonated, followed by the opening of oxiranium ion moiety
to yield 12d (route a). In contrast, an alternative reaction pathway
Scheme 3 Synthesis of 6,20-epoxy-14-OH ent-kaurane diterpenoid 14.
(route b) might operate in the presence of 3,4-dimethoxycin-
namic acid, the oxiranium ion moiety can be preferentially
attacked by the more nucleophilic carboxylate anion of 3,4-
dimethoxycinnamic acid to give the product 15.
The in vitro cytotoxicity of some products were determined by
the methylthiazol tetrazolium (MTT) assay on the human
hepatic carcinoma cell (HepG2), human multiple myeloma cell
(RPMI-8226), human lung carcinoma (A549) cell lines with the
commercial anticancer drug, paclitaxel (PTX), as the positive
control. The results were summarized in Table 2. Notably, 11i
Scheme 4 Synthesis of 1-acetyl-6,14-diyl oridonin analogue 15.
experiments). Aerwards, 11b was subjected to Mitsunobu
(
IC50 ¼ 0.98 mM) and 14 (IC50 ¼ 2.07 mM) exhibited potent
condition using 3,4,5-trimethoxybenzoic acid, PPh
in anhydrous THF, whereas no 12b was found. Finally, various
Brønsted and Lewis acids, e.g. p-TsOH, CF SO H, HCl, AlCl (for
details see the ESI Table S-1†), were evaluated as catalyst for
dehydroxylation, however, no 12b could be detected, which
3
and DIAD
inhibitory activities against HepG2 cell line. Compound 11e
(
against A549 cell lines (Fig. 2). In addition, to obtain the cyto-
toxicity of these new compounds on normal human cells, the
IC50 ¼ 7.60 mM) was found to be a potent cytotoxic agent
3
3
3
Scheme 5 A possible reaction mechanism.
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Table 2 Cytotoxicity values of some compounds towards three
selected tumor cell lines for 72 h
a
Conclusions
In summary, we report a novel and concise protocol for
syntheses of 6,20-epoxy ent-kaurane diterpenoid analogues
from oridonin with a-methylene cyclopentanone core intact.
The reaction features mild conditions and good yield.
Remarkably, the prepared 14-acyl oridonin analogues 11e, 11i
and 6,20-epoxy ent-kaurane diterpenoid analogue 14 exhibited
Cytotoxicity (IC50, mM)
Compounds
HepG2
RPMI-8226
A549
Oridonin
PTX
7.93 ꢃ 1.25
0.19 ꢃ 0.03
13.81 ꢃ 2.27
10.75 ꢃ 1.21
16.07 ꢃ 0.53
0.98 ꢃ 0.10
15.28 ꢃ 1.90
15.28 ꢃ 1.90
8.71 ꢃ 1.25
13.53 ꢃ 3.16
14.62 ꢃ 1.68
45.00 ꢃ 3.59
11.37 ꢃ 0.77
23.68 ꢃ 2.25
13.96 ꢃ 0.68
16.07 ꢃ 1.26
18.13 ꢃ 1.20
9.42 ꢃ 1.03
11.00 ꢃ 2.68
9.37 ꢃ 0.65
16.58 ꢃ 2.93
21.60 ꢃ 3.17
2.07 ꢃ 0.29
9.02 ꢃ 0.80
9.84 ꢃ 0.41
1.40 ꢃ 0.50
19.55 ꢃ 2.07
>100
10.96 ꢃ 1.06
11.53 ꢃ 1.33
>100
22.64 ꢃ 1.28
0.44 ꢃ 0.26
7.60 ꢃ 0.74
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1e
1g
1h
1i
1j
1k
1l
1m
1o
1p
1q
1r
2a
2b
2d
2e
2g
2h
2i
21.14 ꢃ 1.43 superior anticancer activities compared to oridonin in vitro.
19.35 ꢃ 1.05 Oridonin was endowed with more potent bioactivities via
19.82 ꢃ 1.14
chemical modication, which will open a new avenue for
development of novel anticancer agents. The further anticancer
activity investigation of oridonin analogues is under the way.
18.13 ꢃ 3.20
>100
18.13 ꢃ 3.20
10.23 ꢃ 0.40
9.87 ꢃ 0.97
14.52 ꢃ 0.90
17.98 ꢃ 1.38
16.61 ꢃ 2.04
9.57 ꢃ 0.92
9.66 ꢃ 1.50
7.33 ꢃ 1.42
19.66 ꢃ 1.8
33.21 ꢃ 3.87
10.05 ꢃ 1.31
10.62 ꢃ 0.95
14.64 ꢃ 1.75
11.95 ꢃ 1.34
9.54 ꢃ 0.57
6.94 ꢃ 0.41
15.08 ꢃ 1.46
14.01 ꢃ 1.61
14.81 ꢃ 1.99
72.22 ꢃ 4.38 Experimental
21.08 ꢃ 3.53
Chemistry section
23.80 ꢃ 2.05
23.56 ꢃ 2.76 Unless otherwise stated, all commercial reagents were used
16.73 ꢃ 1.73
11.03 ꢃ 1.70
18.06 ꢃ 2.29
13.34 ꢃ 1.95
without additional purication and solvents were distilled prior
to use. All reactions were carried out under nitrogen atmo-
1
13
sphere. H NMR and C NMR spectra were recorded in CDCl at
3
14.13 ꢃ 2.01 500 MHz, using CDCl as a reference standard (d ¼ 7.26 ppm)
3
1
13
12.85 ꢃ 2.20 for H NMR and (d ¼ 77.00 ppm) for C NMR or DMSO-d6 as
2j
4
5
17.58 ꢃ 2.32
14.95 ꢃ 3.57
10.31 ꢃ 1.89
1
a reference standard (d ¼ 2.50 ppm) for H NMR and (d ¼ 39.52
13
ppm) for C NMR. Melting points were measured with a Labo-
ratory Device MEL-TEMP and were uncorrected. TLC was per-
formed using commercially prepared silica gel plates (GF254),
and visualization was effected at 254 nm and 365 nm. High
resolution mass spectra (HRMS) were recorded on the Exact
Mass Spectrometer equipped with ESI ionization source.
a
IC50 values were presented as the mean ꢃ SD (standard error of the
mean) from three separated experiments.
effect of compounds 11e, 11i, 14 and oridonin was evaluated in
human liver cancer cell line HepG2 and normal liver cell line L-
2 2
O . Compared with LO cells, oridonin was approximately 2-fold
General procedure for the synthesis of compounds 11a–11r
more selective in inhibiting the growth of HepG2 cells. The
tested analogues 11i (8.84-fold) and 14 (3.43-fold) exhibited
higher selectivity than oridonin (see ESI Table S-2†). Particu-
larly, compound 11i seemed to be more selective than oridonin,
with an SI (selectivity index, IC50 of normal cells/IC50 of tumor
cells) value of 8.84. These results suggest that these 14-acyl
oridonin analogues and novel 6,20-epoxy ent-kaurane diterpe-
noid analogues may serve as promising antitumor agents.
To a stirring solution of oridonin (500 mg, 1.37 mmol) in
acetone (40 mL) was added Jones reagent (0.6 mL) dropwise at
ice-water bath. The resulting mixture was stirred at 0 C for
ꢁ
20 min, and isopropyl alcohol was added to quench excess Jones
reagent. Then the mixture was diluted with water and extracted
with dichloromethane (3 ꢂ 10 mL). The extract was then
4
washed with brine, dried over anhydrous MgSO , ltered, and
evaporated to give a solid crude product. The crude residue was
recrystallized from acetone–hexane to give compound 10a as
a white solid, 440 mg, 88% yield.
Treatment of oridonin (500 mg, 1.37 mmol) with 2,2-dime-
thoxypropane in the presence of p-TsOH in acetone afforded
7
,14-(1-methylethylene)-dioxy-oridonin derivative (498 mg, 1.23
mmol) in 90% yield. Subsequently, this derivative (200 mg, 0.50
mmol) was treated with Ac O (0.05 mL, 0.50 mmol), Et N (1 mL)
2
3
and DMAP (183 mg, 1.50 mmol) in 15 mL dichloromethane to
yield the corresponding compound 13 (221 mg, 91% yield).
Deprotection of compound 13 (200 mg, 0.44 mmol) with 2%
HCl solution in 10 mL tetrahydrofuran gave the corresponding
compound 10b (155 mg, 87% yield).
Compound 10a (100 mg, 0.25 mmol) was mixed with 4-
methoxycinnamic acid (50 mg, 0.25 mmol), EDCI (143 mg, 0.75
mmol) and DMAP (92 mg, 0.75 mmol) in 10 mL anhydrous
dichloromethane, and the resulting mixture was stirred under
Fig. 2 Comparison of the activity and IC50 of 1, 11e in inhibiting A549
and 1, 11i, 14 in inhibiting HepG2.
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nitrogen atmosphere at room temperature overnight. The reac- dichloromethane (10 mL) and the resulting mixture was stirred
ꢁ
tion was poured into 1 M HCl solution, and the mixture was under nitrogen atmosphere at ꢀ78 C for 10 min, then warmed
extracted with dichloromethane (3 ꢂ 5 mL). The organic layers up to room temperature and stirred for 2 h. The mixture was
were combined, washed with water and saturated NaCl solution, poured into water, and the mixture was extracted with
dried over anhydrous MgSO
The crude product was puried by column chromatography combined, washed with brine, dried over anhydrous MgSO
SiO , DCM/MeOH) to give the compound 11a. White solid, mp ltered and concentrated in vacuo. The crude product was
36–137 C. 121 mg, 83% yield. R
4
, ltered, and concentrated in vacuo. dichloromethane thrice (3 ꢂ 5 mL). The organic layers were
4
,
(
2
ꢁ
1
f
¼ 0.35 (1: 25 MeOH in CH
2 2
Cl ); puried by column chromatography (6 : 1 petroleum ether/
1
H NMR (500 MHz, CDCl
3
) d 7.60 (d, J ¼ 15.9 Hz, 1H), 7.44 (d, J ¼ ethyl acetate) to give the compound 14. Yellow solid, mp 115–
ꢁ
8
1
8
1
(
2
1
(
(
.7 Hz, 2H), 6.88 (t, J ¼ 5.8 Hz, 2H), 6.27 (s, 1H), 6.20 (d, J ¼ 116 C. 77 mg, 89% yield. R ¼ 0.27 (1 : 1 petroleum ether/ethyl
f
1
5.9 Hz, 1H), 5.92 (s, 1H), 5.62 (d, J ¼ 0.9 Hz, 1H), 5.47 (d, J ¼ acetate); H NMR (500 MHz, CDCl ) d 6.13 (s, 1H), 5.53 (s, 1H),
3
.8 Hz, 1H), 4.32 (dd, J ¼ 10.6, 1.0 Hz, 1H), 4.05 (dd, J ¼ 10.6, 4.88 (dd, J ¼ 10.9, 6.0 Hz, 1H), 4.88 (dd, J ¼ 10.9, 6.0 Hz, 1H),
.5 Hz, 1H), 3.83 (d, J ¼ 6.1 Hz, 3H), 3.25 (d, J ¼ 9.6 Hz, 1H), 2.62 4.74 (s, 2H), 4.58 (s, 1H), 4.17 (s, 1H), 4.12 (d, J ¼ 10.0 Hz, 1H),
dt, J ¼ 14.0, 8.8 Hz, 1H), 2.47 (ddd, J ¼ 15.4, 10.9, 6.6 Hz, 1H), 4.10 (q, J ¼ 10.0 Hz, 2H), 4.09 (d, J ¼ 10.0 Hz, 1H), 3.83 (dd, J ¼
.38–2.24 (m, 3H), 2.08–2.01 (m, 1H), 1.99 (d, J ¼ 8.6 Hz, 1H), 43.1, 15.7 Hz, 1H), 3.11 (d, J ¼ 8.7 Hz, 1H), 3.11 (d, J ¼ 8.7 Hz,
.95–1.87 (m, 1H), 1.74 (ddd, J ¼ 13.8, 8.8, 6.7 Hz, 2H), 1.68–1.60 1H), 2.44–2.35 (m, 1H), 2.45–2.33 (m, 1H), 2.19 (dd, J ¼ 12.2,
1
3
m, 1H), 1.37–1.30 (m, 1H), 1.21 (s, 3H), 1.01 (s, 3H). C NMR 6.1 Hz, 1H), 2.19 (dd, J ¼ 12.2, 6.1 Hz, 1H), 1.99 (s, 3H), 1.89 (s,
125 MHz, CDCl ) d 211.78, 204.97, 165.43, 161.79, 149.32, 1H), 1.64–1.57 (m, 2H), 1.49 (s, 1H), 1.41 (d, J ¼ 8.7 Hz, 1H), 1.21
3
1
3
1
6
3
46.32, 130.08, 126.56, 122.20, 114.37, 114.06, 97.13, 75.54, 73.03, (s, 1H), 1.04 (s, 3H), 1.01 (s, 3H). C NMR (125 MHz, CDCl )
3
4.93, 61.18, 60.35, 55.39, 50.77, 48.56, 41.32, 38.54, 35.83, 32.89, d 205.36, 203.22, 169.94, 149.04, 120.20, 82.53, 76.74, 73.59,
0.53, 30.00, 29.69, 23.30, 19.05. HRMS (m/z) (ESI): calcd for 68.21, 64.94, 55.04, 52.97, 51.04, 43.79, 36.97, 32.26, 30.83,
523.2326 [M + H] found 523.2318.
29 6
All of the products 11b–11r were synthesized according to for C22H O 389.1959 [M + H] found 389.1959.
+
C
H O
30 35 8
29.68, 29.37, 24.60, 22.45, 21.40, 18.95. HRMS (m/z) (ESI): calcd
+
above described procedure.
General procedure for the synthesis of compound 15
General procedure for the synthesis of compounds 12a–12k
Compound 11d (50 mg, 0.08 mmol) was mixed with (E)-3-(3,4-
dimethoxyphenyl)acrylic acid (33 mg, 0.16 mmol), 0.11 mL
DAST (diethylaminosulfur triuoride) in anhydrous dichloro-
methane (10 mL) and the resulting mixture was stirred under
Compound 11a (94 mg, 0.18 mmol) was mixed with 0.24 mL
DAST (diethylaminosulfur triuoride) in anhydrous dichloro-
methane (10 mL), and the resulting mixture was stirred under
ꢁ
nitrogen atmosphere at ꢀ78 C for 10 min, then warmed up to
ꢁ
nitrogen atmosphere at ꢀ78 C for 10 min, then warmed up to
room temperature and stirred for 2 h. The mixture was poured
into water, and extracted with dichloromethane (3 ꢂ 5 mL). The
organic layers were combined, washed with water and saturated
room temperature and stirred overnight. The mixture was
poured into water, and the mixture was extracted with
dichloromethane thrice (3 ꢂ 5 mL). The organic layers were
4
NaCl solution, dried over anhydrous MgSO , ltered, and
concentrated in vacuo. The crude product was puried by column
chromatography (petroleum ether/ethyl acetate) to give the
4
combined, washed with brine, dried over anhydrous MgSO ,

ltered and concentrated in vacuo. The crude product was
puried by column chromatography (6 : 1 petroleum ether/
ethyl acetate) to give the compound 15. White solid, mp 125–
ꢁ
compound 12a. White solid, mp 119–120 C. 73 mg, 81% yield. R
f
1
¼
0.46 (1 : 1 petroleum ether/ethyl acetate); H NMR (500 MHz,
ꢁ
1
26 C. 52 mg, 83% yield. R ¼ 0.63 (1 : 1 petroleum ether/ethyl
f
CDCl ) d 7.58 (d, J ¼ 15.9 Hz, 1H), 7.44 (d, J ¼ 8.7 Hz, 2H), 6.86 (d,
3
1
acetate); H NMR (500 MHz, CDCl
3
) d 7.88 (d, J ¼ 15.9 Hz, 1H),
J ¼ 8.7 Hz, 2H), 6.20 (d, J ¼ 15.9 Hz, 1H), 6.16 (s, 1H), 5.72 (s, 1H),
7
7
(
6
1
(
6
1
6
1
3
1
1
1
4
.59 (d, J ¼ 15.9 Hz, 1H), 7.18 (d, J ¼ 8.3 Hz, 1H), 7.15 (s, 1H),
5
3
2
2
1
2
1
6
3
5
.50 (s, 1H), 4.38 (d, J ¼ 9.7 Hz, 1H), 4.31–4.26 (m, 2H), 3.82 (s,
H), 3.23 (d, J ¼ 7.9 Hz, 1H), 2.74 (ddd, J ¼ 14.6, 11.7, 6.3 Hz, 1H),
.56–2.45 (m, 2H), 2.35 (dt, J ¼ 14.6, 4.6 Hz, 1H), 2.18–2.10 (m,
H), 1.96–1.81 (m, 3H), 1.77–1.69 (m, 1H), 1.66 (s, 1H), 1.19 (d, J ¼
.04 (d, J ¼ 8.3 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J ¼ 8.2 Hz, 1H), 6.81
t, J ¼ 9.1 Hz, 1H), 6.56 (d, J ¼ 15.9 Hz, 1H), 6.20 (dd, J ¼ 15.8,
.4 Hz, 1H), 6.01 (d, J ¼ 13.7 Hz, 2H), 5.36–5.31 (m, 2H), 5.02 (s,
H), 4.73 (dd, J ¼ 11.2, 5.5 Hz, 1H), 4.41 (d, J ¼ 10.6 Hz, 1H), 4.28
1
3
3
5.1 Hz, 3H), 1.05 (s, 3H). C NMR (125 MHz, CDCl ) d 209.87,
t, J ¼ 8.9 Hz, 1H), 3.93 (d, J ¼ 6.4 Hz, 6H), 3.89 (d, J ¼ 5.4 Hz,
02.56, 199.65, 166.04, 161.48, 147.69, 145.74, 129.98, 126.97,
19.22, 114.68, 114.21, 83.31, 77.27, 77.01, 76.76, 75.61, 70.10,
4.24, 61.58, 61.31, 55.34, 47.17, 42.05, 41.18, 36.37, 31.96, 31.33,
0.17, 29.68, 23.23, 19.17. HRMS (m/z) (ESI): calcd for C H O
05.2221 [M + H] found 505.2218.
All of the products 12b–12j were synthesized according to
H), 3.17 (d, J ¼ 9.9 Hz, 1H), 2.61–2.53 (m, 1H), 2.36–2.31 (m,
H), 2.04 (d, J ¼ 7.4 Hz, 3H), 1.90–1.78 (m, 2H), 1.71 (d, J ¼
.1 Hz, 1H), 1.56 (d, J ¼ 12.9 Hz, 1H), 1.46 (t, J ¼ 12.7 Hz, 1H),
.40–1.30 (m, 3H), 1.21 (d, J ¼ 8.9 Hz, 3H), 0.90 (d, J ¼ 8.9 Hz,
3
0
33 7
+
1
3
3
H). C NMR (125 MHz, CDCl ) d 200.70, 169.93, 168.85,
65.90, 151.30, 151.20, 150.25, 149.16, 146.21, 146.05, 127.58,
27.10, 123.20, 117.17, 115.70, 114.89, 110.93, 110.86, 109.77,
09.31, 96.81, 75.94, 75.16, 74.05, 63.40, 60.14, 56.04, 52.18,
1.97, 40.46, 40.23, 37.70, 33.68, 31.65, 30.37, 29.68, 27.00,
above described procedure.
General procedure for the synthesis of compound 14
Compound 13 (100 mg, 0.22 mmol) was mixed with 0.30 mL 25.17, 21.58, 21.38, 17.82. HRMS (m/z) (ESI): calcd for
+
DAST
(diethylaminosulfur
triuoride)
in
anhydrous
44
C H51NO13 787.3324 [M + H] found 787.3342.
29552 | RSC Adv., 2018, 8, 29548–29554
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1
1
Conflicts of interest
There are no conicts to declare.
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Science Foundation of China (81561148012, 21572154,
21772181), NSFC-Shandong Joint Fund for Marine Science
Research Centers (U1606403) and the Fundamental Research
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