Design and synthesis of novel Vitamin D-coumarin hybrids using microwave irradiation

Article abstract of DOI:10.3184/174751917X15121208772534

A series of novel vitamin D-coumarin hybrids were synthesised by esterification of the corresponding coumarin-3-carboxylic acids and vitamin D or vitamin D CD-ring alcohol in CH₂Cl₂ under microwave irradiation. They were obtained in higher yields (from 64-81% up to 79-87%) and shorter reaction time (from 3 h down to 15 min), compared with earlier conventional methodologies. The structures of all the target compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. This provides an attractive and alternative method for the preparation of high-value vitamin D-coumarin hybrids.

Full text of DOI:10.3184/174751917X15121208772534

684 RESEARCH PAPER
VOL. 41 DECEMBER, 684–687
JOURNAL OF CHEMICAL RESEARCH 2017
Design and synthesis of novel vitamin D–coumarin hybrids using microwave
irradiation
Hengrui Zhang and Zhijie Fang*
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaoling Wei, Nanjing 210094, P.R. China
A series of novel vitamin D–coumarin hybrids were synthesised by esterification of the corresponding coumarin-3-carboxylic acids and
vitamin D or vitamin D CD-ring alcohol in CH2Cl2 under microwave irradiation. They were obtained in higher yields (from 64–81% up to
79–87%) and shorter reaction time (from 3 h down to 15 min), compared with earlier conventional methodologies. The structures of all the
target compounds were confirmed by 1H NMR, 13C NMR and HRMS. This provides an attractive and alternative method for the preparation
of high-value vitamin D–coumarin hybrids.
Keywords: vitamin D, coumarin, hybrids, microwave irradiation
Vitamin D is a sterol that not only plays a classical role in
calcium homeostasis and bone mineralisation,1,2 but also
regulates the proliferation and differentiation of various types
of cancer cells.3–5 However, inspired by the multiple bioactivity
of vitamin D, several vitamin D hybrids have been reported by
different groups. For example, the hybridisation of a calcemia-
inactivating A ring with a differentiation-activating CD-ring
side chain developed by Posner yielded a hybrid analogue
with combined powerful biological activities.6 Steinmeyer
et al. reported that the combination of phosphonate and
bisphosphonate substructures with the vitamin D skeleton can
produce biological activities.7 In recent years, several esters
linked to aromatic A-ring and CD-ring derivatives have been
identified as improved and selective hedgehog inhibitors by
Hadden and co-workers.8,9
Coumarins are an important class of naturally occurring
compounds that have attracted much attention in recent years
due to a diverse range of biological and pharmacological
properties.10–12 Many novel hybrids with coumarins have been
designed and synthesised. For example, tacrine–coumarin
hybrids have been designed as multifunctional cholinesterase
inhibitors against Alzheimer’s disease.13,14 Coumarin–pyridine
hybrids have been synthesised with promising anti-osteoporotic
activities.15 Coumarin–benzimidazole hybrids have been
evaluated as potent antibacterial and anticancer agents.16
New hybrids may have improved activity and new biological
properties compared with their individual components.
Moreover, our group has discovered novel vitamin D analogues
that have interesting biological profiles.17,18 In this study,
we hybridised vitamin D2 and coumarin using microwave
irradiation with the aim of developing new lead compounds
with efficient and selective pharmacological activities.
Results and discussion
Synthesis of coumarin-3-carboxylic acids
The synthetic strategy19–21 to obtain the coumarin-3-carboxylic
acids is outlined in Scheme 1. Salicylaldehyde derivatives
were synthesised via Reimer–Thieman formylation of the
corresponding substituted phenols 1b–h with CHCl3 and
NaOH, except for 2a, which is commercially available. At the
beginning of our study, no catalyst was used, but the reaction
was incomplete and the yield was low. When tributylamine
was used as the catalyst, the reaction was complete with
an improved yield. The resultant compounds 2a–h were
subsequently cyclised with diethylmalonate in the presence
of piperidine in ethanol solution. On reaction completion, the
mixture was hydrolysed with NaOH and acidified with HCl
at room temperature to give the corresponding coumarin-3-
carboxylic acids 3a–h.
Synthesis of vitamin D2–coumarin hybrids
The synthetic route for the vitamin D–coumarin hybrids is
depicted in Scheme 2. In a typical procedure, in the presence
O
O
R3
R3
R2
R3
R2
a
b
OH
R2
O
O
OH
OH
R1
R1
R1
3a-h
1b-h
2a-h
a
b
c
d
e
f
g
h
R1
H
H
H
H
H
H
Cl
H
H
H
H
R2
R3
H
H
CH3
H
H
OCH3
H
H
Br
Cl
Cl
NO2 OCH3
(a) CHCl3, NaOH, (n-C4H9)3N, EtOH, H2O; (b) piperidine, NaOH, HCl
Scheme 1 Synthesis of hybrids of coumarin-3-carboxylic acids.
* Correspondent. E-mail: zjfang@njust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2017 685
R1
R2
R3
O
O
O
O
e
4a-e
O
O
R3
R2
OH
O
R1
e
3a-h
O
O
O
O
R1
R3
5a-d, f-h
R2
(e) DCC, DMAP, CH2Cl2, 400 W microwave irradiation
Scheme 2 Synthesis of vitamin D–coumarin hybrids.
Table
1 Comparison between microwave-assisted and classical
min, the reaction proceeded rapidly to give the target compound
with a yield of 85%. Consequently, the other reactions were also
investigated with microwave irradiation, as shown in Table 1.
reactions in the synthesis of hybrids
Yield (%)
Entry
Hybrid
Microwave
Classical
71
73
71
64
68
80
78
81
71
72
69
69
Conclusion
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
5a
5b
5c
5d
5f
85
84
81
83
80
87
86
86
83
85
80
79
In summary, a group of vitamin D–coumarin hybrids were
successfully synthesised by microwave irradiation, following
our laboratory precedents and the principle of molecular
hybridisation. Compared with conventional methodologies,
this methodology offers attractive features, including higher
yields and shorter reaction time. We consider that the successful
synthesis of the target compound could provide an experimental
foundation for synthesising vitamin D hybrids to develop
bioactive molecules that could be used as new medicines.
9
10
11
12
5g
5h
Experimental
All operations were carried out under an atmosphere of ultrahigh-
purity argon in oven-dried glass. Most of the organic compounds
utilised in this study were commercial products of the highest purity.
The reactions were monitored by thin-layer chromatography (TLC).
Microwave irradiation was performed in a MAS-1 microwave reactor
apparatus (Shanghai Sineo Microwave Chemistry Technology Co.,
Ltd). HRMS spectra were obtained on a Bruker Apex II by means of
the ESI technique. 1H NMR spectra were recorded at 500 MHz with a
Bruker Avance III 500 NMR spectrometer in CDCl3. 13C NMR were
recorded at 125 MHz with a Bruker Avance III 500 NMR spectrometer
in CDCl3.
of N,N′-dicyclohexylcarbodiimide (DCC) as dehydrating agent
and 4-dimethylaminopyridine (DMAP) as catalyst, coumarin-3-
carboxylic acid 3h and vitamin D or vitamin D CD-ring alcohol
(which was derived from commercially available vitamin D2
using the procedures reported by our group)22 were dissolved in
CH2Cl2 and refluxed to give 4a in a yield of 71%. Extending the
reaction time did not improve the yield as was the case with the
other reactions. Recently, we have demonstrated the application
of microwave irradiation in the synthesis of aryl ketone β-C-
glycosides and novel oxime analogues of vitamin D2. This gave
high yields in very fast and clean reactions.22 Thus, when a mixture
of vitamin D, coumarin-3-carboxylic acid 3a, DCC and DMAP
in CH2Cl2 was irradiated in a microwave reactor at 400 W for 15
Synthesis of compounds 2b–h; general procedure
CHCl3 (0.5 mL) was added dropwise to a stirred mixture of the
corresponding phenol (4 mmol), tributylamine (0.08 mmol), and

686 JOURNAL OF CHEMICAL RESEARCH 2017
NaOH (14.4 mmol) in ethanol and water at 60 °C. After completion of
the addition, the reaction mixture was stirred for 40 min at 60 °C, then
cooled, and acidified to pH 2 with HCl (2 N). The organic layer was
collected and the aqueous layer was extracted with chloroform. The
combined organic solution was evaporated under reduced pressure and
purified by chromatography to give the target compounds 2b–h.
5.10 (1H, s), 4.88 (1H, d, J = 2.1 Hz), 2.83 (1H, m), 2.68 (1H, d, J =
13.5), 2.60 (2H, m), 2.34 (1H, m), 2.09 (6H, m), 1.85 (2H, d, J = 12.9),
1.68 (4H, m), 1.47 (3H, d, J = 12.9), 1.34 (3H, m), 1.02 (3H, d, J = 6.6
Hz), 0.92 (3H, d, J = 6.8 Hz), 0.87 (6H, m), 0.56 (3H, s); 13C NMR
(126 MHz, CDCl3): δ 162.60, 156.04, 153.24, 146.11, 144.34, 142.80,
135.44, 133.89, 131.33, 128.98, 127.15, 123.22, 118.75, 117.86, 117.27,
116.44, 111.85, 73.79, 55.22, 45.41, 41.83, 40.94, 39.40, 32.50, 30.86,
28.87, 26.49, 22.58, 21.26, 20.12, 18.80, 16.60, 12.42. HRMS (ESI) m/z
calcd for C38H47ClO4 [M + Na]+: 625.3055; found: 625.3059.
Synthesis of compounds 3a–h; general procedure
A stirred solution of intermediate 2 (10 mmol) in EtOH was treated
with methylmalonate (11 mmol), piperidine (50 μL) and glacial acetic
acid. The mixture was heated under reflux for 6 h. This mixture was
treated slowly with a 0.5% NaOH aqueous solution and stirred for
0.5 h at this temperature. The mixture was then poured into cool water,
acidified to pH 2 with HCl (2 N), filtered and washed with alcohol to
give the compounds 3a–h. The melting points of compounds 3a–h are
given in the ESI.
1
Compound 4d: White solid; yield 83%; m.p. 131–132 °C; H NMR
(500 MHz, CDCl3): δ 8.38 (1H, s), 7.43 (1H, d, J = 8.3 Hz), 7.11 (2H,
d, J = 5.2 Hz), 6.23 (1H, d, J = 11.2 Hz), 6.05 (1H, d, J = 11.2 Hz), 5.19
(3H, d, J = 9.0 Hz), 5.07 (1H, s), 4.85 (1H, d, J = 2.0 Hz), 2.84 (1H, m),
2.68 (1H, d, J = 13.4 Hz), 2.58 (m, 5H), 2.26 (1H, s), 2.11 (6H, m), 1.84
(1H, d, J = 6.6 Hz), 1.73 (3H, m), 1.57 (3H, m), 1.36 (6H, m), 1.00 (3H,
d, J = 6.6 Hz), 0.90 (3H, d, J = 6.8 Hz), 0.81 (6H, t, J = 7.2 Hz), 0.55
(3H, s); 13C NMR (126 MHz, CDCl3): δ 161.31, 155.91, 154.31, 147.22,
145.21, 143.47, 141.50, 134.60, 133.16, 130.95, 128.19, 125.10, 121.71,
116.48, 115.87, 114.54, 111.88, 76.10, 75.84, 72.24, 55.47, 44.85, 41.81,
41.02, 39.40, 32.10, 31.16, 30.86, 28.70, 28.06, 26.80, 22.56, 21.23,
21.12, 20.12, 18.97, 18.65, 16.60, 11.26. HRMS (ESI) m/z calcd for
C39H50O4 [M + Na]+: 605.3601; found: 605.3604.
Synthesis of compounds 4a–e, 5a–d,f–h by classical route; general
procedure
DCC (5 mmol) and DMAP (0.5 mmol) were added to a solution of the
coumarin-3-carboxylic acids (6 mmol) and vitamin D2 or vitamin D2
CD-ring alcohol (5 mmol). The resulting mixture was refluxed for
2 h to form the corresponding hybrids. On reaction completion, they
were extracted with ethyl acetate (2 × 50 mL), washed with water
(2 × 60 mL) and brine (2 × 60 mL), and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure and the product
was purified by silica gel column chromatography to yield the target
compounds.
1
Compound 4e: Yellow solid; yield 80%; m.p. 147–148 °C; H NMR
(500 MHz, CDCl3): δ 8.33 (1H, s), 7.70 (1H, d, J = 2.3 Hz), 7.48 (1H,
d, J = 2.3 Hz), 6.26 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.3 Hz),
5.30 (3H, m), 5.13 (1H, s), 4.91 (1H, d, J = 2.1 Hz), 2.82 (1H, d, J =
13.9 Hz), 2.71 (1H, d, J = 3.3 Hz), 2.63 (2H, m), 2.32 (1H, s), 2.16 (5H,
m), 1.88 (1H, d, J = 6.6 Hz), 1.80 (3H, m), 1.62 (1H, d, J = 7.6 Hz),
1.53 (3H, d, J =14.4 Hz), 1.32 (3H, d, J = 12.9 Hz), 1.05 (3H, d, J = 6.6
Hz), 0.95 (3H, d, J = 6.8 Hz), 0.91 (6H, m), 0.59 (3H, s); 13C NMR (126
MHz, CDCl3): δ 160.39, 153.77, 148.44, 145.27, 143.34, 141.80, 134.63,
132.95, 131.04, 128.89, 126.01, 121.90, 119.69, 118.67, 116.47, 112.06,
72.91, 55.53, 44.93, 41.86, 40.92, 39.44, 32.14, 30.97, 30.71, 28.14,
26.80, 22.61, 21.29, 20.15, 18.98, 18.68, 16.62, 11.29. HRMS (ESI) m/z
calcd for C38H46Cl2O4 [M + Na]+: 659.2665; found: 659.2668.
Synthesis of compounds 4a–e, 5a–d,f–h under microwave irradiation;
general procedure
A mixture of coumarin-3-carboxylic acid (6 mmol), vitamin D2 or
vitamin D2 CD-ring alcohol (5 mmol), DCC (5 mmol) and DMAP
(0.5 mmol) was irradiated in a MAS-1 microwave reactor apparatus
at 400 W for 15 min. The reaction mixture was then cooled to room
temperature and extracted with ethyl acetate (2 × 50 mL), washed with
water (2 × 60 mL) and brine (2 × 60 mL), and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
product was purified by silica gel column chromatography to give
compounds 4a–e, 5a–d,f–h.
1
Compound 5a: White solid; yield 87%; m.p. 142–143 °C; H NMR
(500 MHz, CDCl3): δ 8.43 (1H, s), 7.69 (2H, m), 7.38 (2H, m), 5.40 (1H,
d, J = 1.9 Hz), 5.17 (2H, d, J = 7.5 Hz), 2.01 (3H, d, J = 9.4 Hz), 1.87
(2H, m), 1.73 (1H, m), 1.50 (6H, d, J = 4.9 Hz), 1.25 (6H, d, J = 15.2
Hz ), 1.17 (1H, m), 1.00 (6H, d, J = 6.8 Hz), 0.89 (3H, d, J = 6.8 Hz),
0.81 (6H, t, J = 7.3 Hz);13C NMR (126 MHz, CDCl3): δ 161.92, 155.54,
154.12, 146.81, 134.47, 133.13, 131.02, 128.46, 123.73, 118.04, 116.95,
115.75, 72.54, 55.36, 50.58, 41.81, 40.82, 38.88, 32.08, 29.55, 28.70,
26.52, 21.71, 19.81, 18.96, 18.65, 17.02, 16.63, 12.47. HRMS (ESI) m/z
calcd for C29H38O4 [M + Na]+: 473.2662; found: 473.2666.
1
Compound 4a: White solid; yield 85%; m.p. 138–139 °C; H NMR
(500 MHz, CDCl3): δ 8.42 (1H, s), 7.67 (1H, m), 7.60 (1H, m), 7.33 (2H,
d, J = 8.0 Hz), 6.25 (1H, d, J = 11.2 Hz), 6.06 (1H, d, J = 11.2 Hz), 5.28
(3H, m), 5.09 (1H, s), 4.87 (1H, d, J = 1.7 Hz), 2.85 (1H, m), 2.70 (1H,
d, J = 13.4 Hz), 2.60 (2H, m), 2.35 (1H, m), 2.13 (6H, m), 1.90 (1H, m),
1.74 (3H, m), 1.56 (3H, m), 1.39 (3H, m), 1.01 (3H, d, J = 6.6 Hz), 0.91
(3H, d, J = 6.8 Hz), 0.83 (6H, t, J = 7.2 Hz), 0.56 (3H, s); 13C NMR (126
MHz, CDCl3): δ 162.34, 156.79, 155.29, 148.27, 144.60, 142.73, 135.77,
134.41, 134.27, 132.13, 129.65, 124.95, 122.92, 118.79, 118.05, 117.64,
116.94, 113.10, 77.27, 77.01, 73.60, 56.65, 46.03, 42.99, 42.17, 40.57,
33.27, 32.31, 32.02, 29.24, 27.98, 23.74, 22.41, 21.30, 20.14, 19.83,
17.77, 12.44. HRMS (ESI) m/z calcd for C38H48O4 [M + Na]+: 591.3445;
found: 591.3459.
1
Compound 5b: White solid; yield 86%; m.p. 168–169 °C; H NMR
(500 MHz, CDCl3): δ 8.34 (1H, s), 7.80 (2H, m), 7.22 (1H, d, J = 8.8
Hz), 5.39 (1H, d, J = 2.1 Hz), 5.16 (2H, d, J = 7.7 Hz), 2.09 (3H, m), 1.87
(2H, m), 1.75 (1H, d, J = 7.8 Hz), 1.73 (1H, m), 1.59 (6H, m), 1.30 (4H,
m), 1.12 (1H, t, J = 8.3 Hz), 0.98 (6H, q, J = 7.0 Hz), 0.89 (3H, d, J =
6.8 Hz), 0.83 (6H, m); 13C NMR (126 MHz, CDCl3): δ 161.49, 154.80,
152.90, 145.32, 135.73, 134.42, 131.05, 130.50, 119.14, 118.42, 117.50,
116.23, 72.89, 55.33, 50.53, 41.80, 40.80, 38.85, 32.08, 29.50, 28.69,
26.50, 21.70, 19.81, 18.97, 18.65, 16.99, 16.63, 12.49. HRMS (ESI) m/z
calcd for C29H37BrO4 [M + Na]+: 551.1767; found: 551.1769.
1
Compound 4b: White solid; yield 84%; m.p. 145–146 °C; H NMR
(500 MHz, CDCl3): δ 8.31 (1H, s), 7.72 (2H, m), 7.23 (1H, d, J = 8.7
Hz), 6.23 (1H, d, J = 11.2 Hz), 6.06 (1H, d, J = 11.2 Hz), 5.28 (3H, m),
5.09 (1H, s), 4.87 (1H, d, J = 2.0 Hz), 2.78 (1H, d, J = 13.8 Hz), 2.67
(1H, d, J = 13.5 Hz,), 2.60 (2H, m,), 2.34 (1H, m), 2.12 (5H, m), 1.85
(1H, d, J = 12.9 Hz), 1.78 (4H, m), 1.57 (3H, m), 1.36 (3H, m), 1.01
(3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 6.8 Hz), 0.86 (6H, m), 0.56 (3H, s);
13C NMR (126 MHz, CDCl3): δ 160.72, 154.90, 152.91, 145.63, 143.36,
141.74, 135.81, 134.60, 133.12, 130.99, 130.53, 121.84, 118.80, 118.37,
117.51, 116.44, 116.27, 111.97, 76.29, 75.78, 72.59, 55.48, 44.89, 41.82,
40.93, 39.39, 32.11, 30.98, 30.68, 28.09, 26.78, 22.58, 21.27, 20.12,
18.96, 18.65, 16.60, 11.27. HRMS (ESI) m/z calcd for C38H47BrO4 [M +
Na]+: 669.2550; found: 669.2551.
1
Compound 5c: White solid; yield 86%; m.p. 165–166 °C; H NMR
(500 MHz, CDCl3): δ 8.35 (1H, s), 7.57 (2H, d, J = 7.0 Hz), 7.30 (1H, d,
J = 8.5 Hz), 5.41 (1H, d, J = 2.1 Hz), 5.25 (2H, m), 2.01 (3H, m, J = 15.5
Hz), 1.90 (2H, m), 1.75 (1H, m), 1.63 (6H, m), 1.50 (3H, m), 1.33 (3H,
m), 1.14 (1H, t, J = 9.6 Hz), 1.00 (6H, d, J = 5.9 Hz), 0.91 (3H, d, J = 6.8
Hz), 0.82 (6H, m, J = 9.0 Hz); 13C NMR (126 MHz, CDCl3): δ 161.60,
154.91, 152.50, 145.38, 134.46, 132.97, 131.13, 129.09, 127.44, 119.32,
117.96, 117.29, 72.97, 55.40, 50.59, 41.85, 40.86, 38.88, 32.12, 29.56,
26.51, 21.74, 19.83, 18.98, 18.67, 17.03, 16.64, 12.51. HRMS (ESI) m/z
calcd for C29H37ClO4 [M + Na]+: 507.2278; found: 507.2178.
1
1
Compound 4c: White solid; yield 81%; m.p. 150–151 °C; H NMR
Compound 5d: White solid; yield 83%; m.p. 135–136 °C; H NMR
(500 MHz, CDCl3): δ 8.33 (1H, s), 7.58 (2H, m), 7.30 (1H, d, J = 8.8
Hz), 6.24 (1H, d, J = 11.2 Hz), 6.06 (1H, d, J = 11.3 Hz), 5.29 (3H, m),
(500 MHz, CDCl3): δ 8.42 (1H, s), 7.46 (1H, d, J = 7.7 Hz), 7.13 (2H, d,
J = 7.9 Hz), 5.40 (1H, d, J = 2.4 Hz), 5.18 (2H, m, J = 7.5 Hz), 2.47 (3H,

JOURNAL OF CHEMICAL RESEARCH 2017 687
s), 2.08 (3H, m), 1.90 (2H, m), 1.74 (2H, m), 1.59 (6H, m), 1.34 (3H, m),
1.19 (1H, m), 1.01 (6H, d, J = 6.5 Hz), 0.90 (3H, t, J = 6.2 Hz), 0.85 (6H,
m); 13C NMR (126 MHz, CDCl3): δ 162.10, 155.87, 154.33, 146.95,
145.09, 134.49, 131.02, 128.16, 125.04, 116.61, 115.90, 114.62, 72.36,
55.36, 50.60, 41.81, 40.82, 38.94, 32.09, 29.56, 26.53, 21.72, 21.11,
19.81, 18.96, 17.04, 16.62, 12.49. HRMS (ESI) m/z calcd for C30H40O4
[M + Na]+: 487.2819; found: 487.2827.
Received 8 September 2017; accepted 9 November 2017
Paper 1704988
https://doi.org/10.3184/174751917X15121208772534
Published online: 18 December 2017
References
1
2
G. Jones, Endocrinol. Metab. Clin., 2010, 39, 447.
1
Compound 5f: White solid; yield 85%; m.p. 171–172 °C; H NMR
L.J. Peppone, S. Hebl, J.Q. Purnell, M.E. Reid, R.N. Rosier, K.M. Mustian,
O.G. Palesh, A.J. Huston, M.N. Ling and G.R. Morrow, Osteoporos. Int.,
2010, 21, 1133.
(500 MHz, CDCl3): δ 8.45 (1H, s), 7.51 (1H, d, J = 8.7 Hz), 6.91 (1H,
m, J = 8.7, 2.4 Hz), 6.84 (1H, d, J = 2.3 Hz), 5.43 (1H, d, J = 2.4 Hz),
5.21 (2H, m, J = 7.5 Hz), 3.93 (3H, s), 2.11 (3H, m), 1.93 (2H, m), 1.72
(1H, m, J = 9.0 Hz), 1.63 (1H, s), 1.62 (6H, m), 1.35 (3H, m), 1.18 (1H, q,
J = 9.5 Hz), 1.08 (6H, m), 0.93 (3H, t, J = 9.5 Hz), 0.89 – 0.82 (6H, m);
13C NMR (126 MHz, CDCl3): δ 164.03, 162.28, 156.55, 155.96, 147.21,
134.54, 131.05, 129.67, 113.90, 112.54, 110.72, 99.40, 72.18, 55.43,
55.02, 50.68, 41.85, 40.86, 38.95, 32.13, 29.63, 26.56, 21.77, 19.84,
18.98, 18.67, 17.09, 16.65, 12.53. HRMS (ESI) m/z calcd for C30H40O5
[M + Na]+: 503.2768; found: 503.2774.
3
C.W. Jung, E.S. Kim, J.G. Seol, W.H. Park, S.J. Lee, B.K. Kim and Y.Y.
Lee, Leuk. Res, 1999, 23, 1105.
4
5
K.K. Deeb, D.L. Trump and C.S. Johnson, Nat. Rev. Cancer, 2007, 7, 684.
J.L. Costa, P.P. Eijk, M.A. van de Wiel, D. ten Berge, F. Schmitt, C.J.
Narvaez, J. Welsh and B. Ylstra, BMC Genomics, 2009, 10, 499.
G.H. Posner, J.K. Lee, Z. Li, K. Takeuchi, S.E. Guggino, P. Dolan and T.W.
Kensler, Bioorg. Med. Chem. Lett., 1995, 5, 2163.
A. Steinmeyer, K. Schwarz, M. Haberey, G. Langer and H. Wiesinger,
Steroids, 2001, 66, 257.
U. Banerjee, A.M. DeBerardinis and M.K. Hadden, Bioorg. Med. Chem.,
2015, 23, 548.
6
7
8
9
1
Compound 5g: White solid; yield 80%; m.p. 194–195 °C; H NMR
(500 MHz, CDCl3): δ 8.54 (1H, d, J = 2.6 Hz), 8.53 (2H, m), 7.50 (1H,
t, J = 8.8 Hz), 5.43 (1H, d, J = 2.4 Hz), 5.27 (2H, m), 2.10 (3H, m),
1.88 (2H, m), 1.62 (2H, d, J = 9.7 Hz), 1.61 (4H, m), 1.51 (3H, m), 1.31
(m, 12H), 1.06 (6H, m), 0.94 (2H, m), 0.81 (6H, m, J = 15.9, 8.6 Hz);
13C NMR (126 MHz, CDCl3): δ 161.01, 157.33, 153.81, 145.20, 143.19,
134.37, 131.14, 127.42, 124.18, 120.32, 116.98, 73.44, 55.32, 49.82,
41.81, 40.82, 38.82, 32.09, 29.49, 28.70, 26.47, 21.70, 19.82, 18.96,
18.64, 16.97, 16.62, 12.52. HRMS (ESI) m/z calcd for C29H37NO6 [M +
Na]+: 518.2513; found: 518.2517.
Compound 5h: Yellow solid; yield 80%; m.p. 154–155 °C; 1H NMR
(500 MHz, CDCl3): δ 8.41 (1H, s), 7.31 (1H, d, J = 9.1 Hz), 7.24 (1H,
m, J = 9.1, 2.9 Hz), 7.01 (1H, d, J = 2.9 Hz), 5.44 (1H, d, J = 2.5 Hz),
5.21 (2H, m, J = 7.5 Hz), 3.90 (3H, s), 2.12 (3H, m), 1.91 (2H, m), 1.77
(1H, m), 1.64 (1H, s), 1.62 (6H, m), 1.34 (3H, m), 1.22 (1H, m), 1.05
(6H, d, J = 7.9 Hz), 0.96 (3H, m), 0.86 (6H, m, J = 7.4 Hz); 13C NMR
(126 MHz, CDCl3): δ 162.08, 155.79, 155.28, 148.74, 146.54, 134.52,
131.07, 121.37, 118.39, 117.24, 116.90, 109.73, 72.58, 55.41, 54.97,
50.63, 41.85, 40.87, 38.92, 32.13, 29.60, 26.55, 21.76, 19.84, 18.98,
18.67, 17.07, 16.65, 12.53. HRMS (ESI) m/z calcd for C30H40O5 [M +
Na]+: 503.2768; found: 503.2770.
A.M. DeBerardinis, D.S. Raccuia, E.N. Thompson, C.A. Maschinot and M.
Kyle Hadden, Eur. J. Med. Chem., 2015, 93, 156.
10 J.R.S. Hoult and M. Payá, Gen. Pharmacol.Vascs. Syst., 1996, 27, 713.
11 P. Anand, B. Singh and N. Singh, Bioorg. Med. Chem., 2012, 20, 1175.
12 T.O. Olomola, R. Klein, N. Mautsa, Y. Sayed and P.T. Kaye, Bioorg. Med.
Chem., 2013, 21, 1964.
13 S.S. Xie, X.B. Wang, J.Y. Li, L. Yang and L.Y. Kong, Eur. J. Med. Chem.,
2013, 64, 540.
14 S.S. Xie, X. Wang, N. Jiang, W. Yu, K.D. Wang, J.S. Lan, Z.R. Li and L.Y.
Kong, Eur. J. Med. Chem., 2015, 95, 153.
15 K.V. Sashidhara, R.K. Modukuri, D. Choudhary, K. Bhaskara Rao, M.
Kumar, V. Khedgikar and R. Trivedi, Eur. J. Med. Chem., 2013, 70, 802.
16 M. Holiyachi, S.L. Shastri, B.M. Chougala, L.A. Shastri, S.D. Joshi, S.R.
Dixit, H. Nagarajaiah and V.A. Sunagar, ChemistrySelect, 2016, 1, 4638.
17 W. Guo, Z. Fang, H. Li and Y. Liu, J. Chem. Res., 2014, 38, 231.
18 H. Li, Z. Fang, H. Dai, H. Zhang and Y. Liu, J. Chem. Res., 2015, 39, 311.
19 M.S. Lambaa, J.K. Makrandib and S. Kumar, Heterocycl. Lett., 2013,
3,138.
20 Q. Sun, D.Y. Peng, S.G. Yang, X.L. Zhu, W.C. Yang and G.F. Yang, Bioorg.
Med. Chem., 2014, 22, 4784.
21 J. Tang and X. Huang, J. Chem. Res., 2003, 354.
Electronic Supplementary Information
The ESI is available through: http://ingentaconnect.com/
content/stl/jcr/2017/00000041/00000012/art00002
22 W. Feng, Z. Fang, J. Yang, B. Zheng and Y. Jiang, Carbohydr. Res., 2011,
346, 352.