An efficient synthesis of 3β,14β-dihydroxy-5α-androst-15-en-17-one

Article abstract of DOI:10.3184/174751917X14944355549168

An efficient four-step method has been developed for the synthesis of 3β,14β-dihydroxy-5α-androst-15-en-17-one from a common androstane derivative. The X-ray crystal structures of the alkenes, the epoxide and the 14-hydroxy compound have been determined.

Full text of DOI:10.3184/174751917X14944355549168

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 JUNE, 325–329
RESEARCH PAPER 325
An efficient synthesis of 3β,14β-dihydroxy-5a-androst-15-en-17-one
Xushun Qinga, Yayun Guob, Xiaojie Shana, Yue Dinga, Qi Gaoa, Yang Lia and Cunde Wanga*
aSchool of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P.R. China.
bShandong Academy of Grape, 1–27 Shanda South Road, Licheng District, Jinan 250100, P.R. China
An efficient four-step method has been developed for the synthesis of 3β,14β-dihydroxy-5a-androst-15-en-17-one from a common
androstane derivative. The X-ray crystal structures of the alkenes, the epoxide and the 14-hydroxy compound have been determined.
Keywords: 14β-hydroxysteroid, epiandrosterone, epoxide reaction, 3β,14β-dihydroxy-5a-androst-15-en-17-one, 16-bromo-5a-androstan-17-one
Results and discussion
14β-Hydroxysteroids are a large class of interesting natural
products with potential therapeutic effects.1–5 The digitalis
In this paper, we designed a synthetic route to 3β,14β-dihydroxy-
5a-androst-15-en-17-one (1) with epiandrosterone (2) as the
starting material (Scheme 1). Compound 3 was synthesised
cardiac glycosides are well-known drugs containing
a
14β-hydroxysteroid core which have been used clinically to
treat congestive heart failure (Fig. 1). They inhibit Na+, K+-
ATPase, an enzyme which is located in the cell membrane that
promotes the outward transport of Na+ and the inward transport
of K+,6 which leads to the downstream retention of Ca2+ in the
myocytes. This results in a slowing of the heart rate and a
positive inotropic response, directly counteracting the effects of
congestive heart failure.
O
O
OH
H
OH
OH
H
In addition, recent investigations have shown that
14β-hydroxysteroids possess a wide spectrum of biological
activities including anticancer,4,7,8 immunoregulatory, anti-
inflammatory and antihypertensive properties.9–11 Recently, the
drug-oriented design and synthesis of 14β-hydroxysteroids has
received considerable attention important results include12–14 the
preparation of the 17a[(aminoalkoxy)imino] alkyl analogues
of digitoxigenin by partial synthesis starting with androstane
derivatives. These are potent inhibitors of Na+, K+-ATPase (Fig.
1).15 Consequently the preparation of new 14β-hydroxysteroids
with promising biological activity by new synthetic strategies
using mild reaction conditions remains an active research area.
We now report an efficient route for the synthesis of 3β,14β-
dihydroxy-5a-androst-15-en-17-one, 1 (Fig. 1) in four steps starting
from a common androstane derivative (Scheme 1). The synthesis
is focused on stereoselective transformations to introduce the
C14 hydroxy group on the steroid ring D. This synthesis paves
the way to the synthesis of related natural compounds such as the
bufadienolides, digoxin, digitoxin, and digitoxigenin.
H
OH
H
OH
HO
HO
H
H
tomentogenin
digitoxigenin
NO(CH2)2N(CH3)2
O
H
H
H
H
OH
H
OH
HO
HO
H
17 [(aminoalkoxy)imino]
alkyl analogues of digitoxigenin
α
1
Fig. 1 Biologically active 14β-hydroxysteroids and the target molecule.
O
O
O
H
H
H
Br
a
b
H
H
H
HO
H
H
H
HO
HO
HO
HO
4a1
H
H
H
2
3
O
O
O
H
H
d
c
H
4a
H
H
O
OH
HO
H
H
4a
1
5
Reagents and conditions: (a) CuBr2, CH3OH, reflux, 8 h, 81%; (b) Li2CO3, LiBr, DMF, reflux, 4 h, 36% for 4a1 and 52% for 4a; (c) MMPP, actone, r.t., 12 h,
82%; (d) CH3CO2H, water, CH3OH, 0 °C, 12 h, 85%.
Scheme 1 Practical synthesis of 3β,14β-dihydroxy-5a-androst-15-en-17-one.
* Correspondent. E-mail: wangcd@yzu.edu.cn

326 JOURNAL OF CHEMICAL RESEARCH 2017
in a good yield by the standard procedure in our laboratory,16
by treating epiandrosterone (2) with copper(II) bromide in
methanol under reflux.
We have obtained some evidence that led us to consider the
formation of steroids 4a and 4a1 via the sequential reactions as
the most probable route. First, the reaction was carried out in
the presence of lithium bromide and lithium carbonate under
nitrogen to give the required product 4a in 51% and 4a1 in
36% yields. The result indicated there was no difference in the
reaction under air or nitrogen, and consequently the formation
of the dienone 4a1 did not need a dehydrogenation under
oxygen. Then just lithium carbonate was used in the reaction,
and the products 4a and 4a1 were not obtained. This showed
that lithium bromide and lithium carbonate were employed
together to promote synergistically a dehydrobromination of
bromosteroid 3. The required product 4a was isolated in 43%
yield together with a complex inseparable mixture when the
solvent DMF was replaced with EtOH. The dienone 4a1 was
Compound 4a and 4a1 were prepared by treating compound
3 with lithium bromide and lithium carbonate in DMF and
separated by column chromatography. The required product
4a was obtained in 52% as a white solid, and a by-product 4a1
was also was isolated as a light yellow solid, in lower yield
(36%). The molecular structure of compound 4a was elucidated
from its spectroscopic data. In the IR spectrum of compound
4a, one sharp absorption band at 1734 cm–1 and three bands at
1620, 1538 and 1452 cm–1, could be assigned to CO and C=C
stretching frequencies. The high resolution mass spectrum of
compound 4a displayed the molecular ion peak at m/z = 311.1985
[M + Na]+, which is in good agreement with the proposed
1
structure. The H NMR spectrum of compound 4a exhibited
two multiplets at 3.56–3.50 (m, 1H) and 2.95–2.75 (m, 2H) for
C3a-H and C16-H, respectively and three singlet signals at 5.42
(s, 1H), 1.04 (s, 3H) and 0.80 (s, 3H) for C15–H, C18–CH3 and
1
C19–CH3 respectively. Characteristic H chemical shifts of
C16–H, C15–H, C18–CH3, C19–CH3 and C3a–H unequivocally
revealed the specific chemical environment of these protons
1
in compound 4a. The H-decoupled 13C NMR spectrum of
compound 4a showed 19 distinct signals in agreement with the
suggested structure. The important signals which were assigned
to the CO and one C=C double bond appeared at d = 222.54,
153.54, and 112.86 ppm.
The IR spectrum of compound 4a1 contained one sharp
absorption band at 1684 cm–1 and two bands at 1530 and
1446 cm–1, which were assigned to a conjugated CO and C=C
stretching frequencies. The high resolution mass spectrum
of compound 4a1 displayed the molecular ion peak at m/z =
309.1835 [M + Na]+, which is in agreement with the proposed
structure. The 1H NMR spectrum of compound 4a1 showed two
doublet signals at 7.91 (d, J = 5.8 Hz, 1H) and 5.97 (d, J = 5.7
Hz, 1H) for C15–H and C16–H of the double bond, respectively.
The important signals in the 13C NMR which were assigned to
the conjugated CO and two C=C double bonds, appeared at d =
212.40, 153.03, 139.29, 137.00 and 127.96 ppm.
Fig. 2 Molecular structure of compound 4a, non-hydrogen atoms are
shown at the 30% probability level.
We obtained two X-ray crystal structures of 4a and 4a1 that are
shown in Fig. 2 and Fig. 3. Crystallographic data for 4a and 4a1
have been deposited with the Cambridge Crystallographic Data
Centre with the deposition number CCDC 1449075 (4a), 1477148
(4a1). The experimental details for the structure determination
are given in the electronic supplementary information.
Fig. 3 Molecular structure of compound 4a1, non-hydrogen atoms are
shown at the 30% probability level.
O
O
OH
LiBr/Li
2CO3
HO
H
H
Br
H
H
H
H
H
H
B
HO
HO
A
H
H
H
3
Br-
O
+
LiBr/Li
2CO3
Br-
O
N
O
H
Li
O
OH
H
N
H
H
C
H
H
OH
H
H
N
HO
HO
H
HO
H
H
H
4a1
4a
B
Scheme 2 Possible route in the formation of steroids 4a and 4a1.

JOURNAL OF CHEMICAL RESEARCH 2017 327
1
not obtained. This result hinted that the formation of dienone
4a1 relied on the co-operation between lithium bromide, lithium
carbonate and the solvent DMF. On the basis of the above
experimental results, the reaction route shown in Scheme 2
was proposed. First, lithium carbonate together with lithium
bromide promoted dehydrobromination to form androstenone
[A]. Then, the tautomerism of intermediate [A] gave D-ring
dienol [B], the following further tautomerism of intermediate
D-ring dienol [B] afforded the product 4a. Next, lithium
bromide-catalysed the formation of the iminium form of the
dimethylformamide by stabilising intermediate iminium [C]
in which the lithium stabilised the enol anion and the bromide
stabilised the iminium cation, the bromide ion acted as a base
abstracting a proton from the dienol [B] while the iminium
carbon accepted the 14β-hydride ion with the overall effect of
reducing the DMF to HOCH2NMe2 and the formation of the
dienone 4a1.
1,2-Epoxides serve as activated three-membered rings
leading to alcohols by ring opening reaction. 3β-Hydroxy-
14a,15a-epoxy-5a-androstan-17-one (5) was prepared by
epoxidation of intermediate 4a with appropriate epoxide
reagents (Table 1). In order to find the optimal reaction
conditions the reaction between 3β-hydroxy-5a-androst-14-en-
17-one (4a) and various epoxide reagents (Table 1). Initially, we
examined the epoxidation of 3β-hydroxy-5a-androst-14-en-17-
one (4a) with H2O2 and NaHCO3, or HCO2H, AcOH system,
respectively, but the desired product 5 was not obtained (Table
1, entries 1–3). Then the mCPBA was used at room temperature
using dichloromethane as a solvent, but the desired product 5
was only obtained in near 10% yield (Table 1, entry 4). Next
adding NaHCO3 as a basic media, we performed the reaction
under similar conditions and the reaction afforded the desired
product 4a in just 16% yield (Table 1, entry 5).
The H-decoupled 13C NMR spectrum of compound 5 showed
the important peaks were appeared at d = 214.59, 71.39, 70.98
and 55.73 ppm. The 13C NMR of 5 indicated that C=O and three
C–O existed and one C=C double bond had disappeared.
Acid-catalysed opening of the epoxide ring was used to
introduce the alcohol. It is an efficient and practical procedure
for the synthesis of 14-hydroxysteroids. The hydrolysis and
subsequent dehydration of compound 5 were straight forward.
This was achieved smoothly in an ice-water bath overnight
to afford the corresponding alcohol 1 in 85% yield. The IR
spectrum of compound 1 possessed one sharp absorption band
at 1708 cm–1 and at 1667 cm–1 which were assigned to CO and
C=C stretching frequencies. The high resolution mass spectrum
of compound 1 showed the molecular ion peak at m/z = 327.1938
[M + Na]+, which is in good agreement with the proposed
structure. The 1H NMR spectrum of compound 1 exhibited two
signals at 7.53 (d, 1H), 6.17 (d, 1H) for C16–H and C15–H of
the double bond, two singlet signals at 1.07 (s, 3H), 0.77 (s, 3H)
and one multiplet at 3.59–3.52 (m, 1H) for C19–CH3, C18–CH3
and C3–H respectively. The characteristic 1H chemical shift of
C15–H, C16–H, C19–CH3, C18–CH3 and C3–H established the
specific chemical environment of these protons in compound 1.
1
The H-decoupled 13C NMR spectrum of compound 1 showed
19 distinct signals in agreement with the suggested structure.
The important signals which were assigned to the CO and three
C=C double bonds appeared at d = 213.65, 163.58, and 131.65
ppm. Additionally, 3β-hydroxy-14a,15a-epoxy-5a-androstan-
17-one (5) and 3β,14β-dihydroxy-5a-androst-15-en-17-one (1)
were characterised by X-ray crystallography with the deposition
number CCDC 1502140 (5), 1507591 (1) (Fig. 4 and 5).
A plausible mechanism for the opening of the epoxide steroid
5 is shown in Scheme 3, protonation of the epoxide steroid 5
allowed nucleophilic ring-opening to occur with water attacking
from the opposite face of the epoxide group with the formation
of 14β,15a-diol [D]. Subsequent dehydration of this diol [D]
resulted in the formation of the desired 14β-hydroxysteroid 1.
In conclusion, this is a relatively efficient protocol to synthesise
3β,14β-dihydroxy-5a-androst-15-en-17-one. It consists of four
Although the basic media slightly improved the reaction, the
process still gave a low yield. In order to make the reaction more
efficient, magnesium monoperoxyphthalate (MMPP)17 was
used in the reaction in dichloromethane, and to our delight the
desired product 5 was obtained in 70% yield within 12 h (Table
1, entry 6). Further replacement of dichloromethane by acetone
gave the product 5 in yield of 82% at room temperature (Table
1, entry 7). Considering that higher temperature could improve
the reaction, the epoxidation was carried out at 40 °C, and the
product 5 was obtained in 75% yield within 8 h (Table 1, entry
8). The results showed higher temperature had no significant
beneficial effect on the reaction and just a short reaction time.
Table 1 Selected conditions of the epoxide reactiona
O
O
H
H
Selected conditions
HO
Fig. 4 Molecular structure of compound 5, non-hydrogen atoms are
shown at the 30% probability level.
O
H
H
HO
H
H
5
4a
Entry Reagent
Solvent
Acetone
Acetone
Acetone
CH2Cl2
T (oC)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
Time (h) Yield (%)b
1
2
3
4
5
6
7
8
H2O2+NaHCO3
H2O2+HCO2H
H2O2+AcOH
mCPBA
10
8
0
0
8
0
10
8
12
12
8
<10
16
70
82
75
mCPBA+NaHCO3 CH2Cl2
MMPP
MMPP
MMPP
CH2Cl2
Acetone
Acetone
Fig. 5 Molecular structure of compound 1, non-hydrogen atoms are
shown at the 30% probability level.
aReaction conditions: 1 mmol 4a, 1.5 mmol epoxide, 8–10 mL solvent; bIsolated yields.

328 JOURNAL OF CHEMICAL RESEARCH 2017
O
O
O
O
H
2O
H
H
H
H
-H
2O
H+
HO
H
O
H
OH
OH
H
OH
H
HO
HO
HO
HO
H
H
H
H
D
1
5
Scheme 3 Possible mechanism for the synthesis of 14β-hydroxysteroid 1.
(600 MHz, CDCl3) d 5.42 (s, 1H), 3.56–3.50 (m, 1H), 2.95–2.75 (m,
2H), 1.04 (s, 3H), 0.80 (s, 3H); 13C NMR (150 MHz, CDCl3) d 222.54,
153.54, 112.86, 71.04, 54.82, 50.90, 44.52, 41.35, 37.96, 36.80, 35.91,
35.47, 33.26, 31.32, 28.81, 28.09, 20.76, 19.87, 12.07; HRMS (ESI)
calcd for C19H28O2Na [M + Na]+: 311.1987; found: 311.1985.
steps starting from a natural androstane derivative and
provides a practical way to synthesise 14β-hydroxysteroids with
appropriate substituents.
Experimental
3β-Hydroxy-5a-androsta-8(14),15-dien-17-one (4a1): Light yellow
solid; yield 1.03 g, 36%; m.p. 184–185 °C (PE/EtOAc); IR (νmax, cm–1)
KBr: 3420, 3066, 2936, 2861, 1684, 1530, 1446, 1367, 1309, 1251,
1190, 1130, 1045, 910, 847, 613; 1H NMR (400 MHz, CDCl3) d 7.91 (d,
J = 5.8 Hz, 1H), 5.97 (d, J = 5.7 Hz, 1H), 3.67–3.60 (m, 1H), 2.79–2.75
(m, 1H), 1.14 (s, 3H), 0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) d
212.40, 153.03, 139.29, 137.00, 127.96, 70.90, 51.05, 45.70, 44.47, 38.18,
37.79, 36.17, 31.28, 29.46, 29.09, 27.14, 23.20, 19.40, 13.00; HRMS
(ESI) calcd for C19H26O2Na [M + Na]+: 309.1830; found: 309.1835.
All melting points were determined in a SGW X-4 melting point
apparatus and are uncorrected. IR spectra were recorded in a Nicolet
FT-IR 5DX spectrometer. The 1H NMR (400 or 600 MHz) and
13C NMR (100 or 150 MHz) spectra were recorded in a Bruker AV-
400 or 600 spectrometer with TMS as internal reference in CDCl3.
The J values are given in hertz. Only discrete or characteristic signals
1
for the H NMR are reported. High-resolution ESI mass spectra were
obtained on a UHR-TOF maXis (ESI) mass spectrometer. X-ray
crystallographic analysis was performed with a SMART APEX-II
diffractometer. Flash chromatography was performed on silica gel
(230–400 mesh) eluting with ethyl acetate-hexanes mixture. All
reactions were monitored by thin layer chromatography (TLC). All
reagents and solvents were purchased from commercial sources and
purified by conventional methods before use.
Synthesis of 3β-hydroxy-14a,15a-epoxy-5a-androstan-17-one (5)
A solution of 3β-hydroxy-14-androsten-17-one (4a) (0.288 g, 1.0 mmol)
in acetone (8 mL) was treated with magnesium monoperoxyphthalate
(MMPP) (0.74 g, 1.5 mmol). After being stirred overnight the mixture
was diluted with ether (20 mL), filtered, and concentrated. The residue
was dissolved in CH2C12 (60 mL), the organic phase was washed with
water (20 mL) and brine (15 mL), and dried over anhydrous sodium
sulfate. After removal of the dichloromethane, the crude product was
purified by flash chromatography (silica gel, PE:Acetone, 3:1) to give
the required product 5: White solid; yield 0.249 g, 82%; m.p. 160–161 oC
(PE/EtOAc, reported as acetate,18,19 m.p. 159–160 oC); IR (νmax, cm–1)
KBr: 3464, 2926, 2859, 1740, 1621, 1457, 1375, 1264, 1087, 1029, 967,
803, 699, 596; 1H NMR (400 MHz, CDCl3) d 3.74 (s, 1H), 3.62–3.54 (m,
1H), 2.62 (dd, J = 18.0, 1.1 Hz, 1H), 2.44 (dd, J = 18.0, 0.6 Hz, 1H), 2.13
(td, J = 11.5, 4.2 Hz, 1H), 1.08 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 214.59, 71.39, 70.98, 55.73, 50.54, 48.56, 43.85, 39.70, 37.91,
36.70, 35.59, 31.62, 31.33, 27.57, 27.43, 24.23, 20.02, 18.09, 12.05; HRMS
(ESI) calcd for C19H28O3Na [M + Na]+: 327.1936; found: 327.1938.
Synthesis of 16a-bromo-3β-hydroxy-5a-androstan-17-one (3)
A mixture of epiandrosterone (5.80 g, 20 mmol) and copper bromide
(11.20 g, 50 mmol) in methanol (100 mL) was refluxed for 8 h and the
reaction was followed by TLC analysis. After removal of methanol
under reduced pressure, the residues was added to water (20 mL)
and extracted with dichloromethane (2 × 50 mL). The organic phase
was washed with water (20 mL) and brine (15 mL), and dried over
anhydrous sodium sulfate. After removal of dichloromethane, the
crude product was purified by recrystallisation from methanol to
afford 3: White needles; yield 6.0 g, 81%; m.p. 169–170 °C (MeOH,
reported as acetate,18 m.p. 148–149 °C); IR (νmax, cm–1) KBr: 3417,
1
2923, 2853, 1747, 1628, 1454, 1372, 1255, 1036, 803, 621; H NMR
(600 MHz, CDCl3) d 4.53 (d, J = 7.2 Hz, 1H), 3.62–3.58 (m, 1H),
2.20–2.17 (m, 2H), 0.90 (s, 3H), 0.84 (s, 3H); 13C NMR (150 MHz,
CDCl3) d 212.48, 70.08, 53.26, 46.95, 46.83, 45.39, 43.77, 37.02, 35.87,
34.66, 33.33, 33.10, 31.36, 30.41, 29.75, 27.26, 19.41, 13.22, 11.28;
HRMS (ESI) calcd for C19H29BrO2Na [M + Na]+: 391.1249; found:
391.1247.
Synthesis of 3β,14β-dihydroxy-5a-androst-15-en-17-one (1)
A solution of 3β-hydroxy-14a,15a-epoxy-5a-androstan-17-one (5)
(0.453 g, 1.5 mmol) in methanol (8 mL) was treated with acetic acid
(0.054 g, 0.9 mmol) and water (0.45 mL) in an ice-water bath. The
mixture was stirred at 0°C for 12 h, and the completion of the reaction
was confirmed by TLC (Hexane/EtOAc, 1:1). The mixture was
extracted with dichloromethane (20 mL) and the organic phase was
washed with saturated sodium bicarbonate (10 mL), water (2 × 10 mL)
and brine (10 mL), and dried over anhydrous sodium sulfate. After
removal of the dichloromethane, the crude product was purified by
flash chromatography (silica gel, PE:EtOAc = 3:1) to give the required
product 1: White solid; yield 0.388 g, 85%; m.p. 133–134 °C (PE/
EtOAc, lit.19 m.p. 130–131 °C; reported as 3-monoacetate,18 m.p.
153–155 °C); IR (νmax, cm–1) KBr: 3471, 3271, 2930, 2868, 1708, 1667,
1454, 1367, 1263, 1215, 1084, 1034, 969, 903, 814, 731, 603; 1H NMR
(400 MHz, CDCl3) d 7.53 (d, J = 6.0 Hz, 1H), 6.17 (d, J = 5.9 Hz,
1H), 3.59–3.52 (m, 1H), 2.21–2.16 (m, 1H), 1.07 (s, 3H), 0.77 (s, 3H);
13C NMR (100 MHz, DMSO-d6) d 213.65, 163.58, 131.65, 82.02, 69.67,
51.84, 46.21, 44.34, 39.30, 38.43, 36.63, 36.58, 33.29, 31.45, 28.57,
26.89, 20.12, 18.17, 11.81; HRMS (ESI) calcd for C19H28O3Na [M +
Na]+: 327.1936; found: 327.1938.
Synthesis of 3β-hydroxy-5a-androst-14-en-17-one (4a) and 3β-hydroxy-
5a- androsta-8(14),15-dien-17-one (4a1)
A mixture of 16a-bromo-3β-hydroxy-5a-androstan-17-one (3) (3.69 g,
10 mmol), LiBr.H2O (2.44 g, 28 mmol) and Li2CO3 (2.10 g, 28 mmol)
in DMF (60 mL) was refluxed under nitrogen for 4 h. The completion
of the reaction was confirmed by TLC (Hexane/EtOAc, 1:1). The
mixture was cooled to room temperature and then treated with ice-
water (15 g). The resulting yellow solid was filtered and dissolved
in dichloromethane (20 mL). The solution was washed with water
(20 mL) and brine (15 mL), and dried over anhydrous sodium sulfate.
After removal of dichloromethane, the crude product was purified by
flash chromatography (silica gel, PE:EtOAc, 1:1) to give the required
product 4a together with compound 4a1.
3β-Hydroxy-5a-androst-14-en-17-one (4a): White solid; yield
1.50 g, 52%; m.p. 125–126 °C (PE/EtOAc, reported as acetate,18 m.p.
154–156 °C); IR (νmax, cm–1) KBr: 3440, 3391, 3070, 2928, 2856, 1734,
1620, 1538, 1452, 1367, 1287, 1141, 1046, 965, 899, 800, 582; 1H NMR

JOURNAL OF CHEMICAL RESEARCH 2017 329
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Acknowledgements
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged by the authors. This project was funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions. This project also was funded by
Shandong Provincial Natural Science Foundation of China (No.
ZR2015YL060) for Y. Guo.
6
7
8
9
Electronic Supplementary Information
L.M.Y. Banuls, E. Urban, M. Gelbcke, F. Dufrasne, B. Kopp, R. Kiss and
M. Zehl, J. Nat. Prod., 2013, 76, 1078.
CCDC data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax (+44)
1223 336033; E-mail: deposit@ccdc.cam.ac.uk.
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Received 23 March 2017; accepted 28 April 2017
Paper 1704670
https://doi.org/10.3184/174751917X14944355549168
Published online: 17 May 2017
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