Asymmetric synthesis and anti-protozoal activity of the 8,4′-oxyneolignans virolin, surinamensin and analogues

Article abstract of DOI:10.1016/j.ejmech.2012.12.013

The asymmetric synthesis of 8,4′-oxyneolignans (-)-virolin, (-)-surinamensin and a number of analogues has been achieved. A divergent synthesis was used, with all compounds being elaborated from a single chiral aldehyde derived from ethyl lactate. In the

Full text of DOI:10.1016/j.ejmech.2012.12.013

European Journal of Medicinal Chemistry 60 (2013) 240e248
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Asymmetric synthesis and anti-protozoal activity of the 8,40-
oxyneolignans virolin, surinamensin and analogues
*
Claire E. Rye, David Barker
School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
The asymmetric synthesis of 8,40-oxyneolignans (ꢀ)-virolin, (ꢀ)-surinamensin and
a number of
Article history:
Received 20 November 2012
Received in revised form
5 December 2012
Accepted 10 December 2012
Available online 16 December 2012
analogues has been achieved. A divergent synthesis was used, with all compounds being elaborated from
a single chiral aldehyde derived from ethyl lactate. In the 15 compounds that were tested, the level of
substitution on the A-ring was found to directly influence the activity against Leishmania donovani whilst
the activity against Plasmodium falciparum was influenced by numerous substitution and stereochemical
factors.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
8,40-Oxyneolignans
Leishmania
Malaria
1. Introduction
a synthetic route which allows for the complete exploration of
these features. We herein we report the enantioselective synthesis
Lignans and neolignans are secondary metabolites found widely
distributed throughout the plant kingdom and considerable
research into these natural products has been instigated due to
their widespread biological activity [1]. The 8,40-oxyneolignans,
found predominantly in the Myristicaceae or nutmeg plant family
are a relatively small subclass of neolignans [2]. Despite this, they
are known to have potent and varied biological activity, ranging
from antileishmanial [3], antimalarial [4] and antiparasitic [5] to
antifungal [6] and antioxidant [7]. Structurally they are dimers from
the coupling of two C6C3 fragments through oxygen between the C-
8 and C-40 positions. Variation is seen in the ether type and
distribution on the two aromatic rings, the nature of the propyl
fragment and the stereochemistry at the C-7 and C-8 positions
(Fig. 1). This immediately gives rise to great diversity within the
class; representative examples include virolin 1, surinamensin 2,
polysphorin 3 and odoratisol B 4 (Fig. 1).
of two natural 8,40-oxyneolignans, virolin 1 and surinamensin 2
along with a range of analogues.
Biological testing of these compounds has until now, been
carried out on either small amounts of isolated material or racemic
synthetic material [4e7]. As a result, while several groups have
endeavoured to carry out SAR studies, it has been difficult to ach-
ieve an overall view of the exact structural motifs required for the
various biological activities associated with these molecules.
Further to this, there has been limited follow up testing based on
the conclusions from the early studies this is particularly the case
for activity against neglected diseases such as malaria and leish-
mania [3,4]. We therefore decided to synthesize a range of enan-
tiomerically pure lignans and analogues using a divergent synthesis
that easily allows for alteration in multiple sites in the 8,40-oxy-
neolignan framework.
There have been several syntheses of members of the 8,40-
oxyneolignan family, although early work suffered from poor
stereospecificity [8]. More recent syntheses [9e11] have been both
concise and stereospecific, however they are not easily adaptable to
analogue synthesis where all the structural features of these
natural products could be investigated. Thus we wished to develop
2. Results and discussion
2.1. Chemistry
The two main sites of difference in 8,40-oxyneolignans are the
change in substitution pattern of the aromatic A-ring and different
functionalities in the C3 sidechain off the B-ring (Fig. 2). We
envisaged that aldehyde 5 would allow for easy alteration of both
sites, with variation in the A-ring by addition of different aryl
organometallic reagents. The aryl bromide moiety in 5, or
* Corresponding author. Tel.: þ64 9 373 7599; fax: þ64 9 373 7422.
E-mail address: d.barker@auckland.ac.nz (D. Barker).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.12.013

C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
241
OH
OH
OH
2
1
8
MeO
MeO
MeO
MeO
MeO
HO
OMe
OMe
OMe
7
O
O
R
O
2'
4
4'
OMe
7'
virolin
1
R = H, surinamensin 2
R = OMe, polysphorin
odoratisol B 4
9'
3
Fig. 1. Examples of natural 8,40-oxyneolignans.
subsequent products, would allow for introduction of different
sidechains via the use of palladium mediated couplings.
The synthesis of aldehyde 5 began from (S)-ethyl lactate 6 which
was converted to mesylate 7 [12] in 98% yield (Scheme 1).
boronic acid gave virolin 1 and surinamensin 2, with the spectro-
scopic data for both 1 and 2 matching the literature values [9,16].
Similarly bromides 12e16 were coupled with trans-propenyl
boronic acid to give 8,40-oxyneolignan analogues 19e23. This
method was also shown to be applicable to the coupling of other
boronic acids with the reaction of bromide 12a with phenyl boronic
acid giving bi-aryl analogue 24 in 63% yield.
Displacement of the mesylate in
7
using 4-bromo-2-
methoxyphenol 8 was initially attempted using the method of
Curti et al. [9], where pre-treatment of a phenol with caesium
carbonate under sonication forms the active phenoxide, prior to
addition of mesylate 7 and 18-crown-6. However for phenol 8 this
method gave the desired ether 9 in only 14% yield. Thermal pre-
treatment of phenol 8 with caesium carbonate at 80 ꢁC for
30 min, however, followed by a further 24 h after addition of
mesylate 7 gave ether 9 in 89% yield. Reduction of ester 9 without
contaminant debromination proved surprisingly difficult, with
LiAlH4, NaBH4 and ZnBH4 all giving alcohol 10 and debromo-
alcohol 11 in various yields. Oxidation of 10 to aldehyde 5 also
proved troublesome, with PCC on silica [13] giving the best result
but affording aldehyde 5 in a moderate 55% yield. Fortunately,
reduction of 9 with DIBALeH gave aldehyde 5 directly, without
debromination, in 98% yield and with no appearance of over
reduction products.
A range of aryllithium or aryl Grignard reagents were then
added to aldehyde 5 to give alcohols 12a/be16a/b in 31e86% yield.
In all cases a mixture of anti and syn isomers were formed with the
anti isomer 12ae16a being the major product. The two isomers
proved to be difficult to separate using flash chromatography. In
many cases only the less polar anti isomer could be separated with
the syn isomer never effectively separated from the anti isomers. In
many cases it was easier to react a purified mixture of isomers in
subsequent reactions and separate thereafter. However, to prepare
virolin 1 and to examine the biological difference between pure syn
and anti isomers we sought to prepare the syn isomer selectively.
Whilst there is literature precedent [14], we found that addition of
chelating agents such as MgBr2 and ZnCl2 to the organometallic
additions to aldehyde 5 failed to significantly improve the amount
of the syn isomers produced. Oxidation of the anti/syn mixtures
14a/b and 15a/b with DesseMartin periodinane afforded ketones
17 and 18, in 84% and 90% yields respectively, which were then
reduced using 15-crown-5 chelated NaBH4 giving alcohols 14b and
15b in excellent yields [7,15].
2.2. Biology
Fifteen compounds, including virolin 1 and surinamensin 2 and
a range of the synthetic analogues were tested for their activity
against amastigote form of leishmania Leishmania donovani and
malarial strain Plasmodium falciparum along with their general
cytotoxicity (L6 cells) (Table 1).
Results showed that leishmania activity is effected by the level
of substitution of the A-ring, with little or no effect seen when the
B-ring sidechain was altered. Compounds 19a and 24a with no
substituents on the A-ring showed the greatest activity. Addition of
a single methoxy group (13a, 20a) decreased the activity by
approximately 50% and addition of dimethoxy (1, 14b, 17, 21a) or
methylenedioxy (15b, 22a, 22b) groups reduced the activity by
a further 50%. Compounds with trimethoxy substitution on ring A
(2, 16a) were slightly less active than those with disubstitution. The
stereochemistry at C-7 had little significance and the alcohol can be
substituted for a keto group (17) with little effect. However when
the alcohol was converted to a methoxymethyl (MOM) ether the
compounds (MOM-14b, MOM-19a) were inactive. All the
compounds except 2 were more toxic against leishmania than L6
cells with the compounds with no A-ring substitution (19a, 24) not
only showing the best activity but also the best selectivity.
The correlation with level of substitution on the A-ring with
bioactivity was not seen against malarial strain P. falciparum. In this
case compounds with dimethoxy-substituted A-rings (1, 14b, 17,
21a) were the most active followed by 4-methoxy and methyl-
enedioxy. Compounds with no substitution on the A-ring (19a, 24)
were less active. Alteration of the sidechain on the B-ring had
a clear effect on the bioactivity. Changing from the propenyl group
found in the natural compounds (e.g. 1) to a bromide resulted in
compounds with 4e5 times less activity (e.g. 1 vs 14b, 20a vs 13a,
22b vs 15b). The stereochemistry and substitution of the C-7
alcohol also effected the activity with syn substituted compounds
being more active than their corresponding anti isomers (1 vs 21a,
22b vs 22a) whilst MOM ethers (MOM-14b, MOM-19a) were again
inactive.
The final step was functionalisation of the aryl bromide moiety.
Suzuki coupling of bromides 14b and 16b with trans-propenyl
OH
O
OMe
H
OMe
A
3. Conclusions
O
O
In conclusion the synthesis of a number of natural 8,40-oxy-
neolignans and analogues using aldehyde 5 as the key intermediate
has been achieved. The bromide in 5 allows for the incorporation of
natural and non natural sidechains via palladium mediated
couplings. The activity against leishmania is predominately
B
R
Br
5
Fig. 2. Generic structure of 8,40-oxyneolignans.

242
C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
O
O
O
iii
ii
HO
OMe
H
OMe
EtO
OMe
EtO
O
O
O
OR
6, R = H
i
Br
X
Br
7, R = Ms
9
5
10 R = Br
11 R = H
iv
OH
OH
12 R1, R2, R3 = H
R1
R2
R1
OMe
OMe
13 R1, R3 = H, R2 = OMe
OMe
OMe
R , R2 = OMe, R3 = H
O
1
chromatography
O
14
R2
R , R2 = -OCH2O-, R3 = H
1
15
R3
R3
1
2
3
Br
Br
Br
Br
16
R , R , R = OMe
12a-16a
v
OH
R1
R2
O
R1
R2
vi
17 R1, R2 = OMe
O
18 R1, R2 = -OCH2O-
O
R3
14b,15b
OH
OH
19 R1, R2, R3 = H
R1
R2
R1
vii
OMe
OMe
20 R1, R3 = H, R2 = OMe
OR
O
O
1
R , R2 = OMe, R3 = H
R2
21
1
R , R2 = -OCH2O-, R3 = H
R3
R3
22
1
2
R , R , R3 = OMe
23
19a-23a
1, 2, 19b, 22b
OH
OH
OMe
OMe
viii
OR
O
O
24b
24a
Scheme 1. Reagents and conditions: i) MsCl, toluene, 0 ꢁC to rt, 1 h, 98%; ii) 4-bromo-2-methoxyphenol 8, Cs2CO3, DMF, 80 ꢁC, 30 min, then add 7, 18-cr-6, DMF, 80 ꢁC, 24 h; 89%; iii)
DIBALeH, DCM, ꢀ78 ꢁC, 20 min, 98%; iv) Grignard or aryllithium species, THF, ꢀ78 ꢁC to rt, 18 h, 31e86%; v) DesseMartin periodinane, DCM, rt, 17 h, 84e90%; vi) NaBH4, 15-cr-5, i-
PrOH, 84e96%; vii) trans-propenyl boronic acid, CsF, Pd(PPh3)4, THF, reflux, 18 h, 69e73%.; viii) using 12, PhB(OH)2, K2CO3, Pd(PPh3)4, THF, reflux, 18 h, 63%.
determined by the substitution on the A-ring, with stereochemistry
and substitution on the B-ring being secondary whilst anti-malarial
activity is influenced by substitution on both the A- and B-rings and
also by stereochemistry with the natural product (ꢀ)-virolin 1
being the most active.
chromatography, unless otherwise stated. All optical rotation
measurements were determined at 20 ꢁC on the sodium D line
(
l
¼ 589 nm, 0.1 dm cell). All NMR spectra were recorded on either
Bruker Avance DRX 300 MHz or 400 MHz spectrometer at ambient
temperatures. Chemical shifts are reported relative to the solvent
peak of chloroform (
reported as position (d), relative integral, multiplicity (s, singlet; d,
d d
7.26 for 1H and 77.0 for 13C). 1H NMR data are
4. Experimental section
doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; qd,
4.1. General experimental
quartet of doublets), coupling constant (J, Hz), and the assignment of
the atom. 13C NMR data are reported as position (
d) and assignment
All reactions were carried out under a nitrogen atmosphere in
dry, freshly distilled solvents unless otherwise noted. All reactions
were monitored by thin layer chromatography (TLC) carried out on
Merck F-254 silica glass plates with UV light (254 nm) as the primary
visualisation method with supplementary visualisation by staining
with vanillin in 95% ethanol or iodine on silica gel. Flash chroma-
tography was carried out on silica gel, particle size 0.032e0.063 mm.
Retention values (Rf) are reported using the solvent mixture used for
of the atom. NMR assignments were performed using HSQC and
HMBC experiments. The numbering and assignment of the natural
products (1, 2 and isomers 21a, 23a) is done in accordance with
lignan nomenclature, which numbers each lignan fragment from C1
to C9 [1]. High-resolution mass spectroscopy (HRMS) was carried
out byeither chemical ionization (CI) or electrospray ionization (ESI)
on a MicroTOF-Q mass spectrometer. Unless noted, chemical
reagents were used as purchased.

C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
243
Table 1
IC50
g/mL) values of 8,40-oxyneolignans against Leishmania donovani, Plasmodium
falciparum and cytotoxicity against L6 cells.
for a further 24 h. The mixture was cooled to room temperature
before sat. ammonium chloride (5 mL) and brine (5 mL) were added
and the aqueous mixture was extracted with ethyl acetate
(3 ꢂ 30 mL). The combined organic extracts were washed with
water (2 ꢂ 50 mL), brine (40 mL), dried (MgSO4) and the solvent
removed in vacuo. The crude product was purified by flash chro-
matography (9:1 hexanes/ethyl acetate) to yield the title product 9
(
m
Compound
L. donovani
P. falciparum
L6
Virolin 1 (21b)
10.9
13.9
0.608
2.52
11.5
7.32
Surinamensin
2 (23b)
13a
14b
15b
16a
17
19a
20a
4.79
10.8
9.2
4.31
2.50
10.8
8.47
3.12
3.23
1.33
1.71
4.59
1.73
5.99
49.3
47.3
13.5
20.9
48.2
20.3
41.6
11.9
15.5
13.2
15.3
14.7
11.2
50.6
52.3
(0.51 g, 89%) as a colourless oil. Rf ¼ 0.45; [
a
]
¼ þ31 (c 0.90, CHCl3);
D
1H NMR (400 MHz; CDCl3) 1.26 (3H, m, OCH2CH3), 1.61 (3H, d,
J ¼ 6.8 Hz, 3-CH3), 3.84 (3H, s, OCH3), 4.20 (2H, m, OCH2), 4.71 (1H,
m, 2-H), 6.72 (1H, d, J ¼ 8.4 Hz, 60-H), 6.98 (2H, m, AreH); 13C NMR
(75 MHz; CDCl3) 13.9 (OCH2CH3), 18.3 (C-3), 55.8 (OCH3), 61.0
(OCH2), 74.0 (C-2), 114.4 (C-40), 115.5, 117.4, 124.7 (C-30, C-50, C-60),
146.1 (C-10), 150.7 (C-20), 171.6 (C-1); IR: nmax (film)/cmꢀ1; 3078,
2983, 2936, 1673, 1589, 1389, 1200, 1142, 783; m/z (EIþ): 304 (81Mþ,
90%), 302 (79Mþ, 90), 282 (100), 280 (53), 204 (65). HRMS (EIþ)
found (Mþ): 304.01334C12H1581BrO4 requires 304.01332. Found
(Mþ): 302.0153, C12H1579BrO4 requires 302.0154.
11.3
12.1
2.29
5.54
10.6
6.82
10.2
2.48
60.3
52.5
21a
22a
22b
24a
MOM-14ba
MOM-19aa
a
The 7-hydroxy group was converted to the methoxymethyl (MOM) ether, see
Experimental section for details.
4.5. (2R)-2-(40-Bromo-20-methoxyphenoxy)propan-1-al 5
4.2. (2S)-Ethyl 2-(methylsulfonyloxy)propionate 7
To a solution of ester 9 (1.25 g, 4.0 mmol) in DCM (30 mL) under
an atmosphere of nitrogen, at ꢀ78 ꢁC, was added DIBAL (4.0 mL,
4.0 mmol,1 M solution in hexane) dropwise and the mixture stirred
for 20 min. The reaction was quenched, at ꢀ78 ꢁC, with the addition
of methanol (20 mL). Rochelle’s salt (30 mL), followed by brine
(30 mL) and 2 M HCl (20 mL) were added the organic layer separated
and the aqueous layer further extracted with DCM (4 ꢂ 30 mL). The
combined organic fractions weredried (Na2SO4) and the solvent was
removed in vacuo to give the crude product which was purified by
flash chromatography (4:1 hexanes/ethyl acetate) to give the title
product 5 (1.00 g, 98%) as a colourless solid. Rf (2:1 hexanes, ethyl
To a solution of (S)-ethyl lactate 6 (3.4 g, 29 mmol) in toluene
(45 mL) under an atmosphere of nitrogen at 0 ꢁC, was added trie-
thylamine (6.4 mL, 46 mmol) followed by the dropwise addition of
methanesulfonyl chloride (2.45 mL, 32 mmol). The resulting solu-
tion was stirred for 1 h at 0 ꢁC, after which it was allowed to warm to
room temperature. The reaction mixture was then filtered and the
solvent was removed in vacuo. The crude product was purified by
flash chromatography (9:1 hexane/ethyl acetate) to give the title
product 7 (5.57 g, 98%) as a colourless oil. [
a
]
¼ ꢀ49 (c 1.24, CHCl3);
D
1H NMR (400 MHz; CDCl3) 1.32 (3H, s, OCH2CH3), 1.62 (3H, d,
J ¼ 6.9 Hz, 3-CH3), 3.15 (3H, s, SeCH3), 4.25 (2H, m, OCH2), 5.12 (1H, q,
J ¼ 6.7 Hz, 2-H); 13C NMR (100 MHz; CDCl3) 14.0 (OCH2CH3),18.3 (C-
3), 39.1 (SeCH3), 62.0 (OCH2), 74.3 (C-2) and 169.5 (C-1). The 1H and
13C NMR data were in agreement with the literature values [12].
acetate) ¼ 0.45; m.p.: 47e49 ꢁC (ethyl acetate); [
a]
¼ þ11.2 (c 1.96,
D
CHCl3); 1H NMR (300 MHz; CDCl3) 1.47 (3H, d, J ¼ 6.9 Hz, 3-CH3), 3.86
(3H, s, OCH3), 4.52 (1H, m, 2-H), 6.87e7.03 (3H, m, AreH), 9.81 (1H, s,
1-H); 13C NMR (75 MHz; CDCl3) 15.8 (C-3), 56.0 (OCH3), 80.1 (C-2),
112.4 (C-30 and C-40),120.9,123.8 (C-50, C-6),147.3 (C-10),151.1 (C-20),
202.8 (C-1); IR: nmax (film)/cmꢀ1; 2932, 2852,1733,1664,1587,1492,
1218, 1120, 1025, 837, 697; m/z (EIþ): 260 (81Mþ, 60%), 258 (79Mþ,
60), 231 (96), 229 (100), 94 (98); HRMS (EIþ) found (Mþ): 259.9882
C10H1381BrO3 requires 259.9881. Found (Mþ): 257.9882
C10H1379BrO3 requires 257.9890.
4.3. 4-Bromo-2-methoxyphenol 8
To a stirred solution of 2-methoxyphenol (5.00 g, 40 mmol) in
DMF (25 mL) under an atmosphere of nitrogen at 0 ꢁC, was added
a solution of N-bromosuccinimide (7.2 g, 40 mmol) in DMF (25 mL).
The resulting mixture was stirred for 30 min. Ice cold water (50 mL)
was added and the mixture was warmed to room temperature. The
aqueousmixturewasextractedwithdiethylether(3ꢂ30mL)andthe
combined organic extracts were washed with water (50 mL), brine
(50 mL) and then dried (Na2SO4). The crude product was purified by
flash chromatography (3:1 hexanes/ethyl acetate) to give the title
product 8 (7.41 g, 91%) as a yellow oil. 1H NMR (300 MHz; CDCl3) 3.87
(3H, s, 2-OCH3), 5.70 (1H, br s, OH), 6.78 (1H, d, J ¼ 6.2 Hz, 6-H), 6.98
(2H, m, 2 ꢂ AreH); 13C NMR (75 MHz; CDCl3) 56.2 (OCH3),111.5 (C-4),
4.6. (2R)-2-(40-Bromo-20-methoxyphenoxy)propan-1-ol 10
To a stirred suspension of ester 9 (0.37 g,1.2 mmol) inTHF(20 mL),
sodium borohydride (0.9 g, 25 mmol) was added portion wise, the
resultant suspension was stirred at room temperature under an
atmosphere of nitrogen for 22 h. Excess sodium borohydride was
quenched by the dropwise addition of water (10 mL), followed ethyl
acetate (15 mL). The layers were separated and the aqueous layer
further extracted with ethyl acetate (3 ꢂ 15 mL). The combined
organicfractionswerewashedwithbrine(30 mL)anddried(MgSO4).
Thesolventwasremovedinvacuoandthecrudeproductwaspurified
by flash chromatography (2:1 hexanes/ethyl acetate) to give the title
114.1,115.7 and 124.1 (AreCH),144.8 (C-1),147.2 (C-2). The 1H and 13
C
NMR data were in agreement with the literature values [16].
4.4. (2R)-Ethyl 2-(40-bromo-20-methoxyphenoxy)propanoate 9
product 10 (0.23 g, 71%) as a colourless oil. Rf ¼ 0.2; [ ]D ¼ ꢀ37 (c 0.52,
a
CHCl3); 1H NMR (300 MHz; CDCl3) 1.31 (3H, d, J ¼ 6.5 Hz, 3-CH3), 3.08
(1H, br, s, OH), 3.66 (2H, d, J ¼ 3.8 Hz, 1-CH2), 3.84 (3H, s, OCH3), 4.28
(1H, m, 2-H), 6.88 (1H, m, AreH), 7.01 (2H, m, AreH); 13C NMR
(75 MHz; CDCl3) 16.3 (C-3), 55.7 (OCH3), 65.9 (C-1), 78.9 (C-2), 112.8
(C-30, C-40), 121.1, 123.8 (C-50, C-60), 147.2 (C-10), 151.0 (C-20); IR: nmax
(film)/cmꢀ1; 3477, 2974, 1591 1252, 1179, 841, 796; m/z (EIþ): 262
To a stirred solution of phenol 8 (0.5 g, 2.5 mmol) in DMF
(10 mL) was added caesium carbonate (0.8 g, 2.5 mmol) and the
resulting suspension was placed under an atmosphere of nitrogen
and stirred at 80 ꢁC for 30 min. The mixture was cooled to room
temperature and the solid was allowed to settle, the supernatant
solution was decanted and added dropwise to a stirred solution of
mesylate 7 (0.37 g, 1.9 mmol) in DMF (3 mL). 18-Crown-6 (0.65 g,
2.5 mmol) was added and the resultant mixture was heated at 80 ꢁC
(
81Mþ, 18%), 260 (79Mþ, 18), 204 (96), 202 (100); HRMS (EIþ) found
(Mþ): 262.0031, C10H1381BrO3 requires 262.0029. Found (Mþ):
260.0048, C10H1379BrO3 requires 260.0049.

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C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
4.7. (2R)-2-(2-Methoxyphenoxy)propan-1-ol 11
4.8.2. (1S,2R)-1-(400-Methoxyphenyl)-1-hydroxy-2-(40-bromo-20-
methoxyphenoxy)propane 13a and (1R,2R)-1-(400-methoxyphenyl)-
1-hydroxy-2-(40-bromo-20-methoxyphenoxy)propane 13b
To a stirred suspension of lithium aluminium hydride (0.02 g,
0.42 mmol) in THF (1 mL), was added ester 9 (0.032 g, 0.14 mmol)
in THF (1 mL), the resultant suspension was stirred at room
temperature under an atmosphere of nitrogen for 3½ h. Excess
lithium aluminium was quenched by the dropwise addition of
water (5 mL), followed by Rochelle’s salt (5 mL). The layers were
separated and the aqueous layer further extracted with ethyl
acetate (3 ꢂ 5 mL). The combined organic fractions were washed
with brine (20 mL) and dried (MgSO4). The solvent was removed
in vacuo and the crude product was purified by flash chroma-
tography (2:1 hexanes/ethyl acetate) to give the title product 11
To a solution of 4-bromoanisole (0.15 g, 0.9 mmol) in THF (5 mL)
under an atmosphere of nitrogen at ꢀ78 ꢁC, was added n-butyl-
lithium (0.63 mL, 1.0 mmol, 1.6 M in n-hexanes) and the resultant
solution was stirred for 5 min. A solution of aldehyde 5 (0.2 g,
0.78 mmol) in THF (5 mL) was then added dropwise and the
mixture was warmed to room temperature and stirred for 23 h.
Saturated NH4Cl solution (20 mL) was added and the aqueous
mixture was extracted with ethyl acetate (3 ꢂ 10 mL). The
combined organic extracts were washed with brine (20 mL), dried
(MgSO4) and the solvent was removed in vacuo. The crude product
was purified by flash chromatography (3:1 hexanes/ethyl acetate)
to afford the title product 13 as a poorly separable 1.5:1 mixture of
anti 13a to syn 13b diastereomers (0.086 g, 31%) as a pale yellow oil.
A sample of the anti isomer 13a was separated from the mixture.
(0.023 g, 88%) as a colourless oil. Rf ¼ 0.25; [
a
]
¼ ꢀ38.2 (c 0.34,
D
CHCl3); 1H NMR (400 MHz; CDCl3) 1.33 (3H, d, J ¼ 6.2 Hz, 3-CH3),
2.96 (1H, br s, OH), 3.66 (2H, d, J ¼ 4.9 Hz, 1-CH2), 3.86 (3H, s,
OCH3), 4.29 (1H, m, 2-H), 6.88e6.92 (2H, m, AreH), 6.99e7.03
(2H, m, AreH); 13C NMR (100 MHz; CDCl3) 16.6 (C-3), 55.8
(OCH3), 66.0 (C-1), 79.1 (C-2), 112.1 (C-30), 119.3, 121.1, 123.1 (C-40,
C-50, C-60), 147.3 (C-10), 151.1 (C-20); IR: nmax (film)/cmꢀ1; 3478,
2935, 1591, 1249, 1178, 876, 741; m/z (EIþ): 182 (MHþ, 25%), 124
(100); HRMS (EIþ) found (MHþ): 182.09411, C10H14O3 requires
182.0943.
Compound 13a: Rf ¼ 0.5; [
a]
¼ ꢀ43.1 (c 0.58, CHCl3); 1H NMR
D
(300 MHz; CDCl3) 1.16 (3H, d, J ¼ 6.3 Hz, 3-CH3), 3.22 (1H, d,
J ¼ 3.0 Hz, OH), 3.80 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.33 (1H, m, 2-
H), 4.84 (1H, t, J ¼ 2.7 Hz, 1-H), 6.85e6.89 (3H, m, 300-H and AreH),
7.02e7.06 (2H, m, AreH), 7.24 (1H, m, 200-H); 1C NMR (75 MHz;
CDCl3) 13.3 (C-3), 55.2, 56.1 (OCH3), 73.7 (C-2), 82.3 (C-1), 113.5 (C-
300), 115.7 (C-30), 120.8, 123.9 (C-50 and C-60), 127.4 (C-200), 131.7 (C-
100), 146.0 (C-400), 152.2, 158.9 (C-10, C-20). Compound 13b: Rf ¼ 0.45;
1H NMR (300 MHz; CDCl3) 1.12 (3H, d, J ¼ 6.4 Hz, 3-CH3), 3.52 (1H,
d, J ¼ 3.0 Hz, OH), 3.80 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.13 (1H, m,
2-H), 4.66 (1H, t, J ¼ 2.7 Hz, 1-H), 6.85e6.89 (3H, m, 300-H, AreH),
7.02e7.06 (2H, m, AreH), 7.24 (1H, m, 200-H); 13C NMR (75 MHz;
CDCl3) 16.2 (C-3), 55.2, 56.0 (2 ꢂ OCH3), 73.6 (C-2), 82.3 (C-1), 113.6
(C-300), 115.3 (C-30), 121.0, 123.8 (C-50, C-60), 127.3 (C-200), 131.6 (C-
100), 146.1 (C-400), 152.1, 158.9 (C-10, C-20); IR: nmax (film)/cmꢀ1; 3464,
2937, 2835, 1611, 1586, 1497, 1029, 837; m/z (EIþ): 368 (81BrMþ, 4%),
366 (79BrMþ, 4), 232 (6), 202 (31), 189 (6), 187 (6), 137 (100), 135
(31); HRMS (EIþ) found (Mþ): 368.0445, C17H1981BrO4 requires
368.0446. Found (Mþ): 366.0466, C17H1979BrO4 requires 366.0468.
4.8. Synthesis of alcohols 12e16
General procedure A: Grignard addition to aldehyde 5: To a stirred
solution of aldehyde 5 (1.0 mmol) in THF (10 mL) under an atmo-
sphere of nitrogen, cooled to ꢀ78 ꢁC was added the appropriate
Grignard reagent (3.0 mmol) dropwise. The resulting solution was
stirred at ꢀ78 ꢁC for a further 10 min before being slowly warmed
to room temperature and stirred for 21 h. Saturated NH4Cl solution
(10 mL) was added and the layers were separated. The aqueous
mixture was further extracted with ethyl acetate (3 ꢂ 20 mL). The
combined organic fractions were dried (MgSO4) and the solvent
removed in vacuo. The crude product was purified by flash chro-
matography to afford the corresponding alcohols.
4.8.3. (1S,2R)-1-(300,400-Dimethoxyphenyl)-1-hydroxy-2-(40-bromo-
20-methoxyphenoxy) propane 14a
4.8.1. (1S,2R)-1-Phenyl-1-hydroxy-2-(40-bromo-20-
The reaction was carried out according to the general procedure
methoxyphenoxy)propane 12a and (1R,2R)-1-phenyl-1-hydroxy-2-
A, using aldehyde 9 (0.89 g, 3.5 mmol) and 3,4-dimetho-
(40-bromo-20-methoxyphenoxy)propane 12b
xyphenylmagnesium bromide (10.4 mL, 0.5 M solution in THF,
5.2 mmol). Purification using flash chromatography (3:1 hexanes/
ethyl acetate) gave the title product (1.1 g, 80%) in a poorly separable
2.5:1 mixture of anti to syn diastereomers, as a pale yellow oil. A
sample of the anti isomer 14a was separated from the mixture. Data
for 14b given below. Compound 14a: Rf (2:1 hexanes, ethyl
acetate) ¼ 0.3; 1H NMR (400 MHz; CDCl3) 1.16 (3H, d, J ¼ 6.4 Hz, 3-
CH3), 3.27 (1H, br s, OH), 3.87 (6H, s, OCH3), 3.89 (3H, s, OCH3), 4.34
(1H, m, 2-H), 4.85 (1H, d, J ¼ 1.2 Hz, 1-H), 6.83e7.06 (6H, m, AreH);
13C NMR (100 MHz; CDCl3) 13.4 (C-3), 56.1 (OCH3), 73.9 (C-1), 82.3
(C-2), 109.5 (C-200), 110.8 (C-500), 115.6 (C-30, C-40), 118.5 (C-600), 120.8
(C-60), 124.0 (C-50), 132.2 (C-100), 146.9, 148.3, 151.2 (C-10, C-20, C-300,
C-400); IR: nmax (film)/cmꢀ1; 3504, 2935, 1587, 1516, 1258, 1138, 840,
The reaction was carried out according to general procedure A,
using aldehyde 5 (0.52 g, 2.0 mmol) and phenyl magnesium chlo-
ride (4.0 mL, 2.0 M in THF, 6.0 mmol). A solvent mixture of 9:1
hexanes/ethyl acetate was used for flash chromatography to give
the title products in a 2.6:1 mixture of anti 12a to syn 12b diaste-
reomers (0.53 g, 77%) as a pale yellow oil. The anti isomer was
separated from the mixture. Compound 12a: Rf ¼ 0.6; [
a
]
¼ ꢀ21.9
D
(c 4.34, CHCl3); 1H NMR (300 MHz; CDCl3) 1.16 (3H, d, J ¼ 6.3 Hz, 3-
CH3), 3.23 (1H, d, J ¼ 2.7 Hz, OH), 3.88 (3H, s, OCH3), 4.37 (1H, m, 2-
H), 4.91 (1H, t, J ¼ 2.7 Hz, 1-H), 6.88 (1H, d, J ¼ 9.0 Hz, 60-H), 7.03e
7.07 (2H, m, 30-H, 50-H), 7.28e7.34 (5H, m, AreH); 13C NMR
(75 MHz; CDCl3) 13.2 (C-3), 56.1 (OCH3), 73.9 (C-2), 82.4 (C-1), 115.5
(C-40), 115.7 (C-30), 121.1, 124.0 (C-50, C-60), 126.2, 127.4, 128.2 (Are
CH), 139.6 (AreC), 152.3, 158.9 (C-10, C-20). Compound 12b:
Rf ¼ 0.55; 1H NMR (300 MHz; CDCl3) 0.96 (3H, d, J ¼ 6.6 Hz, 3-CH3),
3.80 (1H, d, J ¼ 1.5 Hz, OH), 3.89 (3H, s, OCH3), 4.16 (1H, m, 2-H),
4.71 (1H, d, J ¼ 6.0,1-H), 6.85 (1H, d, J ¼ 9.0 Hz, 60-H), 7.03e7.07 (2H,
m, 30-H, 50-H), 7.28e7.34 (4H, m, AreH); IR: nmax (film)/cmꢀ1; 3484,
2983, 2935, 1586, 1494, 1445, 1134, 1027, 996, 701; m/z (EIþ): 338
735; m/z (EIþ): 398
( (
81Br Mþ, 5%), 396 79Br Mþ, 5), 167
(M ꢀ C9H10O2Br, 100), 165 (45), 77 (6); HRMS (EIþ) found (Mþ):
396.0575, C18H2179BrO5 requires 396.0573. Found (Mþ): 398.0553,
C18H2181BrO5 requires 398.0552.
4.8.4. (1S,2R)-1-(300,400-Methylenedioxyphenyl)-1-hydroxy-2-(40-
bromo-20-methoxyphenoxy) propane 15a
The reaction was carried out according to the general procedure
A, using aldehyde 5 (0.1 g, 0.39 mmol) and 3,4-methylenedioxy
magnesium bromide (0.78 mL, 1.0 M solution in THF, 0.78 mmol).
Purification using flash chromatography (4:1 hexanes/ethyl acetate)
(
81Mþ, 8%), 336 (79Mþ, 8), 231 (21), 229 (21), 204 (100), 202 (100),
63 (11), 43 (19); HRMS (EIþ) found (Mþ): 338.0341, C16H17 81BrO3
requires 338.0341. Found (Mþ): 336.0362, C16H17 79BrO3 requires
336.0361.

C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
245
gave the title product 15a (0.13 g, 86%) as a 2:1 mixture of 15a to 15b
as a pale yellow oil. A sample of the anti isomer 15a was separated
from the mixture. Data for 15b given below. Compound 15b: Rf (4:1
hexanes/ethyl acetate) ¼ 0.55; 1H NMR (300 MHz; CDCl3) 1.16 (3H, d,
J ¼ 8.4 Hz, 3-CH3), 3.23 (1H, br s, OH), 3.86 (3H, s, 20-OCH3), 4.33 (1H,
m, 2-H), 4.80 (1H, d, J ¼ 3.0 Hz, 1-H), 5.94 (2H, s, OCH2), 6.74e7.01
(6H, m, AreH); 13C NMR (75 MHz; CDCl3) 13.4 (C-3), 56.1 (OCH3),
73.9 (C-1), 82.3 (C-2), 100.9 (OCH2O), 106.9, 107.9 (C-200, C-500), 115.5
(C-40), 115.6 (C-30), 119.6, 120.9, 124.0 (C-300, C-50, C-60), 133.6 (C-100),
C-600), 127.2 (C-100), 146.2, 149.1, 150.6, 153.8 (C-10, C-20, C-300, C-400),
197.1 (C-1); IR: nmax (film)/cmꢀ1; 3411, 2935, 1680 (C]O), 1593,
1514, 1501, 1264, 1223, 1171, 1139, 767; m/z (EIþ): 396 (81Br Mþ, 9%),
394 (79Br Mþ, 9), 165 (M ꢀ C9H10O2Br, 100); HRMS (EIþ) found
(Mþ): 396.0396, C18H1981BrO5 requires 396.0395. Found (Mþ):
394.0416, C18H1979BrO5 requires 394.0416.
4.10. (2R)-1-(300,400-Methylenedioxyphenyl)-2-(40-bromo-20-
methoxyphenoxy)propan-1-one 18
142.3,144.9,147.3,152.2 (C-10, C-20, C-300, C-400); IR: nmax (film)/cmꢀ1
;
3501, 2945, 2872,1258,1232,1042, 892, 758; m/z (EIþ): 382 (81BrMþ,
7%), 380 (79Br Mþ, 7), 204 (21), 202 (22), 151 (100), 149 (63); HRMS
(EIþ) found (Mþ): 382.0236, C17H17 81BrO5 requires 382.0239. Found
(Mþ): 380.0255, C17H17 79BrO5 requires 380.0259.
The reaction was carried out using the same procedure as
ketone 17, using alcohols 15a/b (0.1 g, 0.26 mmol) with a reaction
time of 17 h. A solvent mixture of 3:1 hexanes/ethyl acetate was
used for flash chromatography to give the title product 18 (0.089 g,
90%) as a red oil. Rf (4:1 hexanes, ethyl acetate) ¼ 0.5; [
a
]
¼ þ39 (c
D
4.8.5. (1S,2R)-1-(300,400,500-Trimethoxyphenyl)-1-hydroxy-2-(40-
bromo-20-methoxyphenoxy)propane 16a and (1R,2R)-1-(300,400,500-
trimethoxyphenyl)-1-hydroxy-2-(40-bromo-20-methoxyphenoxy)
propane 16b
1.23, CHCl3); 1H NMR (300 MHz; CDCl3) 1.67 (3H, d, J ¼ 6.9 Hz, 3-
CH3), 3.82 (3H, s, 20-OCH3), 5.31 (1H, m, 2-H), 6.03 (2H, s,
OCH2O), 6.63 (1H, d, J ¼ 8.5 Hz, 60-H), 6.82 (1H, d, J ¼ 8.0 Hz, 500-H),
6.89 (1H, dd, J ¼ 2.8, 5.7 Hz, 50-H), 6.93 (1H, d, J ¼ 2.3 Hz, 30-H), 7.55
(1H, d, J ¼ 1.7 Hz, 200-H), 7.73 (1H, dd, J ¼ 1.9,10.1 Hz, 600-H); 13C NMR
(75 MHz; CDCl3) 18.3 (C-3), 55.5 (OCH3), 77.3 (C-2), 101.4 (OCH2O),
107.5, 107.9 (C-200, C-500), 113.7 (C-40), 115.2, 117.0, 122.8, 124.7 (C-30,
C-40, C-50, C-600),128.3 (C-100),145.8, 147.8, 150.4, 151.7 (C-300, C-400, C-
10, C-20), 195.8 (C-1); IR: nmax (film)/cmꢀ1; 2911, 1685, 1604, 1589,
1138, 749; m/z (EIþ): 380 (81Br Mþ, 14%), 378 (79Br Mþ, 14), 149
The reaction was carried out according to the general procedure
A, using aldehyde 5 (0.1 g, 0.39 mmol) and 2,3,4-trimethoxy
magnesium bromide (1.56 mL, of a 0.5 M solution in THF,
0.78 mmol). A solvent mixture of 4:1 hexanes/ethyl acetate was
used for flash chromatography to give the title product 16 in a 1.2:1
mixture of anti 16a to syn 16b diastereomers (0.055 g, 33%) as
a yellow oil. A sample of the anti isomer 16a was separated from the
mixture. Compound 16a: Rf ¼ 0.35; 1H NMR (300 MHz; CDCl3) 1.16
(3H, d, J ¼ 6.0 Hz, 3-CH3), 3.85, 3.90, 3.92 (12H, s, 4 ꢂ OCH3), 4.26
(1H, m, 2-H), 4.93 (1H, d, J ¼ 3.0 Hz, 1-H), 6.58e7.04 (5H, m, AreH);
13C NMR (75 MHz; CDCl3) 12.6 (C-3), 55.2, 55.4, 55.6 (OCH3), 73.7
(C-2), 83.4 (C-1), 103.1 (C-200, C-600), 112.1 (C-30), 118.8, 119.1 (C-50, C-
60), 130.1 (C-40), 133.2 (C-10), 146.5, 146.7 (C-10, C-20), 151.8, 151.9,
152.2 (C-300, C-400, C-500). Compound 16b: Rf ¼ 0.30; 1H NMR
(300 MHz; CDCl3) 0.97 (3H, d, J ¼ 6.0 Hz, 3-CH3), 3.85, 3.90, 3.92
(12H, s, OCH3), 4.11 (1H, m, 2-H), 4.53 (1H, m, 1-H), 6.59e7.05 (5H,
m, AreH); 13C NMR (75 MHz; CDCl3) 15.8 (C-3), 55.2, 55.4, 55.6
(OCH3), 78.2 (C-2), 82.3 (C-1), 103.1 (C-200 and C-600), 112.1 (C-30),
118.8, 119.1 (C-50, C-60), 130.1 (C-40), 133.2 (C-10), 146.5, 146.7 (C-10,
(M
ꢀ
C9H10O2Br, 100); HRMS (EIþ) found (Mþ): 380.0084,
C17H1581BrO5 requires 380.0082. Found (Mþ): 378.0105,
C17H1579BrO5 requires 378.0103.
4.11. (1R,2R)-1-(300,400-Dimethoxyphenyl)-1-hydroxy-2-(40-bromo-
20-methoxyphenoxy)propane 14b
A solution of NaBH4 (1.0 g, 26 mmol) and 15-crown-5 (5.2 mL,
26 mmol) in isopropanol (40 mL) was stirred for 48 h, then cooled
to ꢀ78 ꢁC and a solution of ketone 17 (2.6 g, 6.6 mmol) in methanol
(5 mL) was added and stirred for a further 48 h. Water (5 mL) was
added and the methanol was removed in vacuo. Further water
(5 mL) was added and the mixture extracted with ethyl acetate
(3 ꢂ 15 mL). The combined organic extracts were dried (MgSO4)
and the solvent was removed in vacuo, the crude product was
purified by flash chromatography (3:1 hexanes/ethyl acetate) to
give the title product 14b (2.5 g, 96%) as a pale yellow oil. Rf (2:1
hexanes, ethyl acetate) ¼ 0.25; 1H NMR (400 MHz; CDCl3) 1.14 (3H,
d, J ¼ 6.4 Hz, 3-CH3), 3.89 (9H, s, OCH3), 4.12 (1H, m, 2-H), 4.63 (1H,
d, J ¼ 8.4 Hz, 1-H) and 6.80e7.05 (6H, m, AreH); 13C NMR
(100 MHz; CDCl3) 16.8 (C-3), 56.0 (OCH3), 78.4 (C-1), 83.7 (C-2),
109.5 (C-200), 110.8 (C-500), 115.6 (C-30, C-40), 119.5 (C-600), 119.7 (C-60),
124.0 (C-50), 132.3 (C-100), 146.8, 148.9 (C-300, C-400), 149.0 (C-20),
151.5 (C-10); IR: nmax (film)/cmꢀ1; 3504, 2935, 2835, 1587, 1516,
1258, 1157, 1138, 765, 735; m/z (EIþ): 398 (81Br Mþ, 5%), 396 (79Br
Mþ, 5), 194 (24), 167 (100), 77 (6); HRMS (EIþ) found (Mþ):
396.0575, C18H2179BrO5 requires 396.0573. Found (Mþ): 398.0564,
C18H2181BrO5 requires 398.0552.
C-20), 151.8, 151.9, 152.2 (C-300, C-400, C-500); IR: nmax (film)/cmꢀ1
;
3506, 2933, 2839, 1589, 1576, 1494, 1462, 1397, 1252, 1224, 1056,
1027, 1004, 831; m/z (ESIþ): 451 (81BrMNaþ, 80%), 449 (79BrMNaþ,
80), 208 (100); HRMS (ESIþ) found (MNaþ): 451.0552,
C19H2381BrNaO6 requires 451.0551. Found (MNaþ): 449.0578,
C19H2379BrNaO6 requires 449.0576.
4.9. (2R)-1-(300,400-Dimethoxyphenyl)-2-(40-bromo-20-
methoxyphenoxy)propan-1-one 17
To a stirred solution of alcohols 14a/b (1.1 g, 2.8 mmol) in DCM
(85 mL), was added DesseMartin periodinane (1.78 g, 4.2 mmol),
the reaction mixture was left open to atmosphere stirring for 18 h.
Saturated Na2S2O5 solution (50 mL) was added followed by NaHCO3
(50 mL), the mixture was shaken until no further gas evolved. The
layers were separated and the aqueous mixture was extracted with
DCM (3 ꢂ 50 mL). The combined organic fractions were washed
with brine (100 mL), dried (MgSO4) and the solvent was removed in
vacuo. The crude product was purified by flash chromatography
(2:1 hexanes/ethyl acetate) to give the title product 17 (0.93 g, 84%)
4.12. (1R,2R)-1-(300,400-Methylenedioxyphenyl)-1-hydroxy-2-(40-
bromo-20-methoxyphenoxy)propane 15b
A solution of NaBH4 (0.03 g, 0.8 mmol) and 15-crown-5 (0.16 mL,
0.8 mmol) in isopropanol (5 mL) was stirred for 24 h, then cooled
to ꢀ78 ꢁC and a solution of ketone 18 (0.075 g, 0.2 mmol) in
methanol (5 mL) was added and stirred for a further 48 h. Water
(5 mL) was added and the methanol was removed in vacuo. Further
water (5 mL) was added to the residue was extracted with ethyl
acetate (3 ꢂ 15 mL). The combined organic extracts were dried
(MgSO4) and the solvent was removed in vacuo, the crude product
as a yellow oil. Rf ¼ 0.25; [
a
]
¼ þ32 (c 1.02, CHCl3); 1H NMR
D
(300 MHz; CDCl3) 1.72 (3H, d, J ¼ 6.8 Hz, 3-CH3), 3.87 (3H, s, 20-
OCH3), 3.96 (6H, s, OCH3), 6.38 (1H, q, J ¼ 6.9 Hz, 2-H), 6.64 (1H, d,
J ¼ 8.6 Hz, 500-H), 6.87e6.97 (3H, m, 30-H, 50-H, 60-H), 7.64 (1H, d,
J ¼ 1.9 Hz, 200-H), 7.77 (1H, dd, J ¼ 1.9, 8.4 Hz, 600-H); 13C NMR
(75 MHz; CDCl3) 19.1 (C-3), 56.1 (OCH3), 78.2 (C-2), 110.0, 111.4 (C-
200 and C-500), 114.2 (C-40), 115.7, 117.0, 123.5, 123.5 (C-30, C-40, C-50,

246
C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
was purified by flash chromatography (4:1 hexanes/ethyl acetate)
to give the title product 15b (0.063 g, 84%) as a pale yellow oil.
Rf ¼ 0.50; 1H NMR (300 MHz; CDCl3) 1.13 (3H, d, J ¼ 6.0 Hz, 3-CH3),
3.82 (1H, br s, OH), 3.89 (3H, s, 20-OCH3), 4.11 (1H, m, 2-H), 4.61 (1H,
(12H, s, OCH3), 4.23 (1H, m, 8-H), 4.53 (1H, m, 7-H), 6.15 (1H, m,
80-H), 6.34 (1H, m, 70-H), 6.58e6.90 (5H, m, AreH); 13C NMR
(100 MHz; CDCl3) 16.9 (C-9), 18.2 (C-90), 55.6 (OCH3), 78.5 (C-8),
83.1 (C-7), 104.0 (C-2, C-6), 109.4 (C-20), 118.8, 119.0 (C-50, C-60),
124.6 (C-80), 130.2 (C-70), 133.5 (C-10), 135.2 (C-1), 146.4, 150.1 (C-
30, C-40), 151.9, 152.3 (C-3, C-4, C-5). All spectral data were in
agreement with the literature values [10,11]. Compound 23a: Rf
(4:1 hexanes/ethyl acetate) ¼ 0.35; 1H NMR (400 MHz; CDCl3) 1.20
(3H, d, J ¼ 6.0 Hz, 9-CH3), 1.88 (3H, d, J ¼ 4.0 Hz, 90-CH3), 3.82,
3.89, 3.92 (12H, s, OCH3), 4.33 (1H, m, 8-H), 4.93 (1H, d, J ¼ 3.0 Hz,
7-H), 6.15 (1H, m, 80-H), 6.39 (1H, m, 70-H), 6.58e6.92 (5H, m, Are
d, J ¼ 9.0 Hz,1-H), 5.95 (2H, s, OCH2O), 6.76e7.03 (6H, m, AreH); 13
C
NMR (75 MHz; CDCl3) 16.6 (C-3), 56.0 (20-OCH3), 78.2 (C-1), 83.7 (C-
2), 101.0 (OCH2O), 107.5, 108.1 (C-200, C-500), 115.5 (C-40), 115.6 (C-30),
120.1, 121.0, 123.8 (C-300, C-50, C-60), 133.7 (C-100), 146.7, 147.4, 147.8,
151.6 (C-10, C-20, C-300, C-400); IR: nmax (film)/cmꢀ1; 3500, 2945, 2872,
1532, 1258, 1232, 1042, 892, 789; m/z (EIþ): 382 (81Br Mþ, 7%), 380
(
79Br Mþ, 7), 204 (21), 202 (22), 178 (41), 151 (100), 149 (63); HRMS
(EIþ) found (Mþ): 382.0236, C17H17 81BrO5 requires 382.0239. Found
(Mþ): 380.0255, C17H17 79BrO5 requires 380.0259.
H); C NMR (100 MHz; CDCl3) 13.4 (C-9), 18.2 (C-90), 55.6, 55.9
13
(OCH3), 73.8 (C-8), 83.4 (C-7), 104.0 (C-2 and C-6), 109.4 (C-20),
118.8, 119.0 (C-50, C-60), 124.6 (C-80), 130.2 (C-70), 133.5 (C-10), 135.2
(C-1), 146.4, 150.1 (C-30, C-40), 151.9 (C-4), 152.3 (C-3 and C-5). All
spectral data were in agreement with the literature values [2a]; m/
z (ESIþ): 411 (MNaþ, 100%); HRMS (ESIþ) found (MNaþ): 411.1787,
C22H28NaO6 requires 411.1784.
4.13. Suzuki coupling to form 8,40-oxyneolignans and analogues
4.13.1. (ꢀ)-Virolin 1 (21b)
To a stirred solution of aryl bromide 14b (14 mg, 0.05 mmol) in
THF (2 mL) was added trans-propenyl boronic acid (0.013 g,
0.15 mmol), followed by caesium fluoride (0.03 g, 0.2 mmol). The
resulting mixture was heated to reflux placed under an atmosphere
of nitrogen and tetrakis(triphenylphosphine)palladium(0) (1.4 mg,
3 mol%) was added. The resulting suspension was heated for 48 h,
before being cooled to room temperature. Ethyl acetate (5 mL) was
added, followed by brine (5 mL), the layers were separated and the
aqueous mixture was further extracted with ethyl acetate
(3 ꢂ 15 mL). The combined organic fractions were dried (MgSO4)
and the solvent was removed in vacuo. The crude product was
purified by flash chromatography (4:1 hexanes/ethyl acetate) to
give the title product 1 (12.7 mg, 64%) as a colourless oil. Rf ¼ 0.60;
4.13.4. 2-Methoxy-1-(((10S,20R)-10-hydroxy-10-phenylpropan-20-yl)
oxy)-4-((E)-prop-1-en-yl)benzene 19a
Using the same procedure as for compound 1, bromide 12a
(0.05 g, 0.15 mmol) with a reaction time of 24 h, after purification
by flash chromatography (9:1 DCM/hexanes) gave the title
product 19a (0.033 g, 73%) as
a
colourless oil. Rf
¼
0.65;
[a
]
¼ ꢀ37.5 (c 0.8, CHCl3); 1H NMR (300 MHz; CDCl3) 1.17 (3H,
D
d, J ¼ 6.3 Hz, 30-CH3), 1.87 (3H, dd, J ¼ 6.6, 1.5 Hz, CH]CHCH3),
3.49 (1H, d, J ¼ 2.7 Hz, OH), 3.90 (3H, s, 2-OCH3), 4.38 (1H, m, 20-
H), 4.91 (1H, d, J ¼ 3.0 Hz, 10-H), 6.17 (1H, m, CH]CHCH3), 6.35
(1H, dd, J ¼ 1.5, 15.9 Hz, CH]CHCH3), 6.87e6.98 (3H, m, 2-, 5-
and 6-H) and 7.22e7.39 (5H, m, AreH); 13C NMR (75 MHz; CDCl3)
13.1 (C-30), 18.1 (CH]CHCH3), 55.9 (OCH3), 73.3 (C-10), 82.5 (C-20),
109.4 (C-3), 119.0, 120.3 (C-5, C-6), 123.9 (C-4), 125.1 (CH]
CHCH3), 126.1, 127.2, 128.2 (AreCH), 130.5 (CH]CHCH3), 139.8
(AreC), 145.6 (C-1), 151.7 (C-2); IR: nmax (film)/cmꢀ1; 3471, 2934,
1604, 1581, 1506, 1450, 1415, 1256, 1219, 1062, 908; m/z (EI): 298
(Mþ, 12%), 164 (100); HRMS (EI) found (Mþ): 298.156, 3C19H22O3
requires 298.1563.
[
a
]
¼ ꢀ94 (c 0.6, CHCl3) [lit. [9] [
a
]
¼ ꢀ99.6 (c 1.0, CHCl3); 1H NMR
D
D
(400 MHz; CDCl3) 1.14 (3H, d, J ¼ 6.4 Hz, 9-CH3), 1.86 (3H, m, 90-
CH3), 3.86 and 3.89 (9H, s, OCH3), 4.07 (1H, m, 8-H), 4.60 (1H, d,
J ¼ 8.4 Hz, 7-H), 6.12 (1H, m, 80-H), 6.32 (1H, m, 70-H), 6.80e7.05
13
(6H, m, AreH); C NMR (100 MHz; CDCl3) 17.3 (C-9), 18.6 (C-90),
56.1 (OCH3), 78.5 (C-7), 84.4 (C-8), 109.2 (C-2), 110.1 (C-5), 111.1 (C-
20), 119.5 (C-6), 119.7 (C-50), 120.2 (C-60), 125.1 (C-80), 130.6 (C-70),
132.7,133.7 (C-40, C-1),146.9, 149.0,149.2,151.0 (C-10, C-3, C-30, C-4).
All spectral data were in agreement with the literature values [9].
4.13.5. 2-Methoxy-1-(((10S,20R)-10-hydroxy-10-(400-methoxyphenyl)
propan-20-yl)oxy)-4-((E)-prop-1-en-yl)benzene 20a
4.13.2. 7-epi-Virolin 21a
Using the same procedure as for compound 1, bromide 14a
(15 mg, 0.05 mmol) with a reaction time of 48 h, after purification
by flash chromatography (4:1 hexanes/ethyl acetate) gave the title
product 21a (12 mg, 62%) as a colourless oil. Rf (2:1 hexanes, ethyl
Using the same procedure as for compound 1, bromide 13a
(0.08 g, 0.22 mmol) with a reaction time of 20 h, after purification
by flash chromatography (3:1 hexanes/ethyl acetate) gave the title
product 20a (0.05 g, 71%) as a yellow oil. Rf ¼ 0.5; [
a]
¼ ꢀ38 (c 1.3,
D
1
acetate) ¼ 0.40; [
a
]
¼ ꢀ72 (c 1.0, CHCl3) [lit. [9] [
a
]
¼ ꢀ44.8 (c
CHCl3); H NMR (300 MHz; CDCl3) 1.16 (3H, d, J ¼ 6.3 Hz, 30-CH3),
1.87 (3H, dd, J ¼ 6.3, 1.5 Hz, CH]CHCH3), 3.48 (1H, br s, OH), 3.79
(3H, s, 400-OCH3), 3.89 (3H, s, 2-OCH3), 4.33 (1H, m, 20-H), 4.85 (1H,
d, J ¼ 2.4 Hz, 10-H), 6.16 (1H, m, CH]CHCH3), 6.35 (1H, m, CH]
CHCH3), 6.85e6.95 (5H, m, 300-, 3-, 5- and 6-H) and 7.22e7.39 (2H,
m, 200-H); 13C NMR (75 MHz; CDCl3) 13.3 (C-30), 18.3 (CH]CHCH3),
55.2 (2-OCH3), 55.8 (40-OCH3), 73.4 (C-10), 82.5 (C-20), 109.4 (CH, C-
300), 113.6 (C-3), 119.0 (C-6), 120.0 (C-5), 124.9 (CH]CHCH3), 127.3
(C-200), 130.5 (CH]CHCH3), 132.0 (C-100), 133.7 (C-4), 145.7 (C-1),
151.5 (C-2), 158.8 (C-400); IR: nmax (neat)/cmꢀ1; 3484 (OH), 2932,
1609, 1581, 1507, 1461, 1246, 1137, 1060 (CeO), 1032, 961; m/z
(ESIþ): 351 (MNaþ, 100%), 311 (18) and 163 (22); HRMS (ESIþ) found
(MNaþ): 351.1559, C20H24NaO4 requires 351.1567.
D
D
0.9, CHCl3); 1H NMR (400 MHz; CDCl3) 1.12 (3H, d, J ¼ 6.4 Hz, 9-
CH3), 1.85 (3H, m, 90-CH3), 3.85 (9H, s, OCH3), 4.31 (1H, m, 8-H),
4.81 (1H, d, J ¼ 4.0 Hz, 7-H), 6.12 (1H, m, 80-H), 6.35 (1H, m, 70-H),
6.82e6.94 (6H, m, AreH); 13C NMR (100 MHz; CDCl3) 13.4 (C-9),
18.4 (C-90), 55.9 (OCH3), 73.5 (C-8), 82.5 (C-7), 109.3, 110.8 (C-2, C-
5), 115.3 (C-20) 118.4, 119.0, 120.0 (C-50, C-60, C-6), 125.0 (C-80),
130.4 (C-70), 132.2 (C-10, C-40), 146.0, 148.3 (C-3, C-30, C-4, C-10);
IR: nmax (neat)/cmꢀ1; 3509, 2932, 1584, 1500, 1454, 1261, 1225,
1134, 803. All spectral data were in agreement with the literature
values [9].
4.13.3. (ꢀ)-Surinamensin 2 (23b) and 7-epi-surinamensin 23a
Using the same procedure as for compound 1, a mixture of
bromides 16a/b (0.055 g, 0.13 mmol) with a reaction time of 20 h,
after purification by flash chromatography (9:1 hexanes/ethyl
acetate) gave the title products as a separable 1.2:1 mixture of anti
23a to syn 2 (17 mg, 34%) as a pale yellow oil. Compound 2: Rf (4:1
hexanes, ethyl acetate) ¼ 0.45; 1H NMR (400 MHz; CDCl3) 1.16
(3H, d, J ¼ 6.0 Hz, 9-CH3), 1.88 (3H, d, J ¼ 4.0 Hz, 90-CH3), 3.89, 3.92
4.13.6. 2-Methoxy-1-(((10S,20R)-1-hydroxy-10-(300,400-
methylenedioxyphenyl)propan-20-yl)oxy)-4-((E)-prop-1-en-yl)
benzene 22a
Using the same procedure as for compound 1, bromide 15a
(0.1 g, 0.26 mmol) with a reaction time of 20 h, after purification by
flash chromatography (3:1 hexanes/ethyl acetate) gave the title

C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
247
product 22b (0.062 g, 70%) as a colourless oil. Rf (4:1 hexanes/ethyl
357 (MNaþ, 100%) and 317 (23); HRMS (ESIþ) found (MNaþ):
357.1462, C22H22NaO3 requires 357.1461.
acetate) ¼ 0.5; [
a
]
¼ ꢀ46 (c 2.54, CHCl3); 1H NMR (400 MHz;
D
CDCl3) 1.18 (3H, d, J ¼ 6.0 Hz, 30-CH3),1.88 (3H, m, CH]CHCH3), 3.88
(3H, s, 2-OCH3), 4.31 (1H, m, 20-H), 4.79 (1H, m, 10-H), 5.94 (2H, s,
OCH2O), 6.14 (1H, m, CH]CHCH3), 6.37 (1H, m, CH]CHCH3), 6.76e
4.13.9. (1R,2R)-1-(300,400-Dimethoxyphenyl)-1-(methoxymethoxy)-
2-(40-bromo-20-methoxyphenoxy)propane MOM-14b
13
6.96 (6H, m, AreH); C NMR (100 MHz; CDCl3) 13.5 (C-30), 18.4
To a stirred solution of 14b (0.59 g, 1.5 mmol) in DCM (30 mL)
under an atmosphere of nitrogen, at 0 ꢁC was added diisopropy-
lethylamine (0.58 g, 3.5 mmol), followed by the dropwise addition
of methyl methoxy chloride (0.18 g, 2.3 mmol). The resulting
solution was allowed to warm to room temperature and stirred for
7 days. Saturated NH4Cl solution (20 mL) was added, the layers
were separated and the aqueous mixture was further extracted
with DCM (3 ꢂ 30 mL). The combined organic fractions were dried
(MgSO4) and the solvent was removed in vacuo. The crude product
was purified by flash chromatography (2:1 hexanes, ethyl acetate)
to give the title product MOM-14b (0.47 g, 72%) as a pale yellow oil.
Rf ¼ 0.8; 1H NMR: (400 MHz; CDCl3) 1.13 (3H, d, J ¼ 6.2 Hz, 3-CH3),
3.36 (3H, s, CH2OCH3), 3.88 (9H, s, 3 ꢂ OCH3), 4.48 (1H, m, 2-H), 4.71
(1H, d, J ¼ 6.6 Hz, 1-H), 5.29 (2H, s, OCH2O), 6.83e7.04 (6H, m, Are
H); 13C NMR (100 MHz; CDCl3) 16.6 (C-3), 55.8, 55.9 (OCH3), 78.2
(C-1), 80.4 (C-2), 94.3 (OCH2O), 110.0,110.7 (C-200, C-500), 115.4 (C-30),
115.6 (C-40), 116.9, 120.5, 123.8 (C-600, C-50, C-60), 130.9 (C-100), 147.3,
(CH]CHCH3), 55.7 (OCH3), 73.6 (C-20), 84.1 (C-10), 100.9 (OCH2O),
107.6, 108.1, 109.3 (C-3, C-200 and C-500), 119.0, 119.5, 121.1 (C-5, C-6
and C-600), 125.1 (CH]CHCH3), 130.5 (CH]CHCH3), 133.8 (C-1 and
C-100), 145.6, 147.6 (C-4, C-300 and C-400), 151.5 (C-2); IR: nmax (neat)/
cmꢀ1; 3480, 2935, 1504, 1443, 1029, 965, 854; m/z (ESIþ): 365
(MNaþ, 100), 325 (46); HRMS (ESIþ) found (MNaþ): 365.1356,
C20H22NaO5 requires 365.1359.
4.13.7. 2-Methoxy-1-(((10R,20R)-1-hydroxy-10-(300,400-
methylenedioxyphenyl)propan-20-yl)oxy)-4-((E)-prop-1-en-yl)
benzene 22b
Using the same procedure as for compound 1, bromide 15b
(0.06 g, 0.16 mmol) with a reaction time of 20 h, after purification
by flash chromatography (3:1 hexanes/ethyl acetate) gave the title
product 22b (0.037 g, 69%) as a yellow oil. Rf ¼ 0.7; [
a
]
¼ ꢀ71 (c
D
1.42, CHCl3); 1H NMR (400 MHz; CDCl3) 1.14 (3H, d, J ¼ 6.4 Hz, 30-
CH3), 1.88 (3H, m, CH]CHCH3), 3.51 (1H, br s, OH), 3.90 (3H, s, 2-
OCH3), 4.08 (1H, m, 20-H), 4.60 (1H, d, J ¼ 8.4 Hz, 10-H), 5.93 (2H,
s, OCH2O), 6.15 (1H, m, CH]CHCH3), 6.37 (1H, m, CH]CHCH3),
148.8, 148.9, 151.0 (C-300, C-400, C-10, C-20); IR: nmax (film)/cmꢀ1
;
2934, 2835, 1587, 1516, 1258, 1225, 1179, 1139, 1102, 847, 810, 764;
m/z (EIþ): 442 (81Br Mþ, 4%), 440 (79Br Mþ, 4), 211 (60), 108 (100);
HRMS (EIþ) found (Mþ): 442.0811, C20H2581BrO6 requires 442.0814.
Found (Mþ): 440.0831, C20H2579BrO6 requires 440.0835.
13
6.76e6.96 (6H, m, AreH); C NMR (100 MHz; CDCl3) 16.8 (C-30),
18.3 (CH]CHCH3), 55.6 (OCH3), 78.3 (C-20), 83.9 (C-10), 100.9
(OCH2O), 107.5, 108.0 (C-200, C-500), 118.5, 118.7, 119.1, 121.0 (C-3, C-5,
C-6, C-600), 124.8 (CH]CHCH3), 130.4 (CH]CHCH3), 133.9 (C-100),
138.3 (C-1), 146.5, 147.7 (C-4, C-300 and C-400), 150.8 (C-2); IR: nmax
(neat)/cmꢀ1; 3485, 2935, 1598, 1504, 1443, 1248, 1028, 965, 854; m/
z (ESIþ): 365 (MNaþ, 100), 325 (46); HRMS (ESIþ) found (MNaþ):
365.1355, C20H22NaO5 requires 365.1359.
4.13.10. 2-Methoxy-1-(((10S,20R)-10-(methoxymethoxy)-10-
phenylpropan-20-yl)oxy)-4-((E)-prop-1-en-yl)benzene MOM-19b
Using the same procedure as for MOM-14b, using alcohol 19a
(0.2 g, 0.6 mmol) and a reaction time of 5 days. A solvent mixture of
9:1 DCM/hexanes was used for flash chromatography to give the title
product MOM-19b (0.13 g, 58%) as a colourless oil. Rf ¼ 0.25;
4.13.8. 2-Methoxy-1-(((10S,20R)-10-hydroxy-10-phenylpropan-20-yl)
oxy)-4-(phenyl)benzene 24a and 2-methoxy-1-(((10R,20R)-10-
[
a
]
¼ þ21 (c 0.62, CHCl3); 1H NMR (300 MHz; CDCl3) 1.32 (3H, d,
D
J ¼ 6.3 Hz, 30-CH3),1.84 (3H, dd, J ¼ 1.5, 6.6 Hz, CH]CHCH3), 3.39 (3H,
s, CH2OCH3), 3.79 (3H, s, 2-OCH3), 4.43 (1H, m, 20-H), 4.63 and 4.70
(2 ꢂ1H, d, J ¼ 6.6 Hz, OCH2), 4.89 (1H, d, J ¼ 4.5 Hz,10-H), 6.07 (1H, m,
CH]CHCH3), 6.32 (1H, dd, J ¼ 1.5, 15.6 Hz, CH]CHCH3), 6.71e6.85
(3H, m, 3-H, 5-H, and 6-H), 7.23e7.41 (5H, m, AreH); 13C NMR
(75 MHz; CDCl3) 14.6 (C-30), 18.3 (CH]CHCH3), 55.6, 55.9 (OCH3),
79.3, 79.4 (C-10, C-20), 94.8 (OCH2O),117.0,118.6,124.0,124.5 (C-3, C-
5, C-6, CH]CHCH3),127.5,127.6,128.1 (AreCH),130.6 (CH]CHCH3),
132.2 (C-4), 139.0, 146.5 (C-1, AreC), 150.7 (C-2); IR: nmax (film)/
cmꢀ1; 3023, 2932, 2848,1601,1580,1261,1223,1146,1070,1036, 961,
701; m/z (EI): 342 (Mþ, 3%), 103 (13), 91 (41), 45 (100); HRMS (EI)
found (Mþ): 342.1826, C21H26O4 requires 342.1831.
hydroxy-10-phenylpropan-20-yl)oxy)-4-(phenyl)benzene 24b
To a stirred solution of bromides 12a/b (0.05 g, 0.15 mmol) in
THF (5 mL) was added phenyl boronic acid (0.054 g, 0.45 mmol),
followed by potassium carbonate (0.082 g, 0.6 mmol). The resulting
mixture was brought to reflux under an atmosphere of nitrogen;
and tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol%) was
added. The resulting suspension was heated at reflux for 36 h,
before being cooled to room temperature. Ethyl acetate (5 mL) was
added, followed by brine (5 mL), the layers were separated and the
aqueous mixture was further extracted with ethyl acetate
(3 ꢂ 15 mL). The combined organic fractions were dried (MgSO4)
and the solvent was removed in vacuo. The crude product was
purified by flash chromatography (3:1 hexanes/ethyl acetate) to
give the title products in a separable 2:1 mixture of anti 24a to syn
24b diastereomers (31 mg, 63%) as an orange oil. Compound 12a: Rf
(9:1 hexanes/ethyl acetate) ¼ 0.55; 1H NMR (400 MHz; CDCl3)
1.19e1.21 (3H, m, 30-CH3), 3.54 (1H, s, OH), 3.93 (3H, s, 2-OCH3),
4.45 (1H, m, 20-H), 4.97 (1H, br s, 10-H), 7.05e7.37 (13H, m, AreH);
13C NMR (75 MHz; CDCl3) 13.4 (C-30), 56.0 (OCH3), 73.9 (C-20), 82.4
(C-10), 111.3 (C-3), 119.1, 120.3 (C-5, C-6), 126.2, 127.3, 128.1, 128.4,
128.8 (AreCH), 139.9, 140.0, 140.9 (C-4, AreC), 146.8 (C-1), 151.8 (C-
2). Compound 12b: Rf (9:1 hexanes/ethyl acetate) ¼ 0.45 1H NMR
(400 MHz; CDCl3) 1.19e1.20 (3H, m, 3-CH3), 3.54 (1H, s, OH), 3.93
(3H, s, OCH3), 4.22 (1H, m, 20-H), 4.73 (1H, d, J ¼ 12.0 Hz, 10-H),
4.14. Biological assays
Complete details of the whole organism parasite assay protocols
used are reported elsewhere [17]. Parasite strains, cell lines and
positive controls for the assays were L. donovani, MHOM-ET-67/L82
strain, amastigote stage (positive control miltefosine, IC50 0.144
mL), P. falciparum, K1 strain, IEF stage (positive control chloroquine,
IC50 0.54 g/mL) and L6 rat skeletal myoblast cell line for cytotox-
mg/
m
icity (positive control podophyllotoxin, IC50 0.005 mg/mL).
Acknowledgements
13
7.00e7.32 (13H, m, AreH); C NMR (75 MHz; CDCl3) 16.9 (C-30),
We thank the Royal Society of New Zealand, Marsden Fund for
funding this research and the University of Auckland for additional
financial assistance and a doctoral scholarship (C.E.R.). We also
acknowledge Dr. Marcel Kaiser and the Swiss Tropical and Public
Health Institute for the biological results.
55.9 (OCH3), 78.6 (C-20), 83.9 (C-10), 111.2 (C-3), 119.8, 120.3 (C-5, C-
6), 126.1, 127.3, 128.1, 128.4 and 128.8 (AreCH), 140.0, 140.9 (C-4,
AreC), 146.8 (q, C-1), 151.9 (C-2); IR: nmax (neat)/cmꢀ1; 3490, 3030,
2934, 1603, 1517, 1487, 1243, 1211, 1142, 1034, 759, 699; m/z (ESIþ):

248
C.E. Rye, D. Barker / European Journal of Medicinal Chemistry 60 (2013) 240e248
[4] H.-J. Zhang, P.A. Tamez, V.D. Hoang, G.T. Tan, N.V. Hung, L.T. Xuan, L.M. Huong,
Appendix A. Supplementary data
N.M. Cuong, D.T. Thao, D.D. Soejarto, H.H.S. Fong, J.M. Pezzuto, J. Nat. Prod. 64
(2001) 772e777.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2012.12.
013. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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