The synthesis of the anti-malarial natural product polysphorin and analogues using polymer-supported reagents and scavengers.

Article abstract of DOI:10.1039/b308761a

A general asymmetric route to both enantiomers of polysphorin has been developed. The route utilizes polymer-supported reagents, catalysts and scavengers to minimise the need for aqueous work-up and chromatography. This includes application of a method to scavenge 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and a "catch-and-release" procedure to extract the resultant diol following Sharpless asymmetric dihydroxylation. A novel enzymatic selective protection and investigations of a new asymmetric dihydroxylation using microencapsulated osmium tetroxide were also investigated during the course of this study.

Full text of DOI:10.1039/b308761a

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The synthesis of the anti-malarial natural product polysphorin and
analogues using polymer-supported reagents and scavengers
Ai-Lan Lee and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: ϩ44 (0) 1223 336442;
Tel: ϩ44 (0) 1223 336398
Received 28th July 2003, Accepted 8th September 2003
First published as an Advance Article on the web 8th October 2003
A general asymmetric route to both enantiomers of polysphorin has been developed. The route utilizes polymer-
supported reagents, catalysts and scavengers to minimise the need for aqueous work-up and chromatography. This
includes application of a method to scavenge 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and a “catch-and-
release” procedure to extract the resultant diol following Sharpless asymmetric dihydroxylation. A novel enzymatic
selective protection and investigations of a new asymmetric dihydroxylation using microencapsulated osmium
tetroxide were also investigated during the course of this study.
between H-7 and H-8 correctly corresponds to the threo (syn)
compound as the anti compound should display a H NMR
Introduction
1
The neolignan polysphorin (1) was isolated from Piper poly-
coupling constant of approximately 2.5 Hz, based on IR, NMR
sphorum C in China,1 and from the leaves and stems of
and conformational studies.6 Also, since the optical rotation of
Rhaphidopora decursiva in Vietnam.2 Biological screening has
the sample of polysphorin isolated from natural sources was
since shown polysphorin (1) to possess in vitro anti-malarial
zero, it was presumed that this material is racemic.
activity.2 Several other members of this family of neolignans
In previous synthetic studies the neolignans were syn-
have also been shown to display interesting biological proper-
thesized by oxidative coupling to give rise to racemic mixtures
ties: rhaphidecursinol B (2) shows activity against Plasmodium
of syn and anti products.5–7 Herein the development of a
falciparum, the parasite responsible for the most severe forms
new general asymmetric route towards both enantiomers of
polysphorin, plus a small collection of unnatural analogues
of malaria,3 but is ten times less active than polysphorin (1);2
neolignans virolin (3) and surinamensin (4) both show activity
is described. Polymer-supported reagents and scavengers
against leishmaniasis, another vector-borne disease;4 a number
have been used throughout to facilitate reaction work-up
of neolignans including (5) have also been shown to exhibit
and purification, requiring only filtration to isolate reaction
potent anti-fungal activity.5
products.8,9
Results and discussion
Initial studies were aimed towards producing the anti- diastereo-
isomer of polysphorin (1Ј), based on the published structure.
Although it is known that ring opening of secondary epoxides
using phenols can sometimes be difficult, the possible reaction
of epoxide 6 with phenol 7 posed a strategically attractive route
to 1Ј. Numerous methods were examined to open model
epoxide 8 with phenol 9, but all proved unsuccessful. Altern-
ative attempts to open a cyclic sulfite 10 also failed to produce
the desired product.10
Consequently, the target molecule was approached via an
alternative SN2 inversion of mono-protected diol 11. Selective
Although the published structure of polysphorin (1Ј) shows
an anti-relationship between the two chiral centres,2 our
synthetic studies and crystal structures have confirmed that
polysphorin in fact possesses a syn relationship between the two
1
centres. The published H NMR coupling constant of 8.17 Hz
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
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Scheme 1
Table 1 Asymmetric dihydroxylations using Os EnCata
were encountered whilst conducting experiments using (DH-
QD)2PHAL and NMO in acetone–water (10 : 1) solvent system.
Conversely, when the reagent was recycled using achiral con-
ditions the microcapsules appeared to maintain good activity
over five recycles.13 Overall, the unreliability observed upon
recycling of the microcapsules, combined with the fact that
chromatography was still required when using Os EnCat,
prompted us to seek an alternative strategy.
A polymer-supported boronic acid 14, which had previously
been applied by Fréchet to separate cis and trans-cyclo-
hexanediol was considered.15 It was envisaged that Fréchet’s
protocol could be adopted for a “catch-and-release” method
to purify diol 15Ј synthesized by conventional Sharpless
asymmetric dihydroxylation (Scheme 1). Following aqueous
work-up, diol 15Ј was heated to reflux with boronic acid resin
14. When TLC analysis indicated that all the diol had been
effectively captured by the polymer, the solution of impurities
was removed by filtration and the remaining polymer beads
washed with excess toluene. Subsequent washing using 10 : 1
acetone–water was then used to cleave purified diol 15Ј. Release
of the diol was much easier on a smaller scale than on a gram
scale, where several washes were needed to release all of the
clean diol.
Substrate
Yield (%, isolated)
Ee (%)b
97–99
94
91
88
97
97
>99
90
96
89
82
87
94
>99
Selective protection of diol 15 was investigated: cleavage of a
cyclic silyl ether using BuLi;16 cleavage of an acetonide using
MeMgBr;17 and reductive cleavage of an orthoester18 all failed
to achieve appreciable selectivity due to difficulty differentiating
between the two secondary alcohols.
Consequently, an enzymatic selective protection was investi-
gated. Seven enzymes were screened in combination with
racemic diol 16 (Table 2). As anticipated, most lipases only
acylated one enantiomer, but at the undesired C-8 position.
However, the result using PS–C Amano II from Pseudomonas
cepacia immobilized on ceramic particles was more successful;
one enantiomer was selectively protected at the desired C-7
position and the other enantiomer on the C-8 hydroxyl.
The enzyme was tested on enantiomerically enriched diols 15
and 15Ј (Scheme 2), made by a Sharpless dihydroxylation
83
51
a Reagents and conditions: Os EnCat 5 mol%, (DHQD)2PHAL
5 mol%, MeSO2NH2 1 eq., K3Fe(CN)6 3 eq., K2CO3 3 eq., 1 : 1
THF–water, RT, 24–48 h. b Ee determined by 1H-NMR analysis of the
bis-Mosher ester
isomerisation of phenol 9 to trans alkene 7 was effected using a
polymer-supported iridium catalyst 129,11 (Scheme 1). Sub-
sequent O-methylation using polymer-supported Schwesinger
base PS-BEMP and MeI afforded 13 in 98% yield. The asym-
metric centres were then installed using a Sharpless asymmetric
dihydroxylation.12 Methods for asymmetric dihydroxylation
using polyurea microencapsulated osmium tetroxide (Os
EnCat)13 were developed for intended application in this step.
Prior to this work, Kobayashi et al. had reported a similar
catalytic asymmetric dihydroxylation using phenoxyethoxy-
methyl-polystyrene microencapsulated osmium tetroxide.14
Optimisation studies using Os EnCat with trans-β-methyl-
styrene showed that the best yield and ee could be achieved
using 5 mol% of catalyst in THF–water (Table 1). This reaction
was observed to exhibit a high level of solvent dependency;
water–tBuOH mixtures gave no reaction, while water–acetone
mixtures provided only 44–50% yield. Eight substrates were
screened successfully using the optimized conditions (Table 1).
Experiments were also conducted with trans-β-methylstyrene
to test catalyst recycling and these gave near quantitative yields
with no drop in ees over the first three runs. However, on the
fourth cycle, the yield dropped dramatically to 19%, indicating
that the recycling of the Os EnCat was not consistently
reproducible for asymmetric application. Similar observations
Scheme 2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
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Table 2 Lipase screeninga
Entry
Lipase
Result
1
2
3
Type VII, Candida rugosa
A ϩ C (trace B)
A ϩ C
A ϩ B
PS “Amano” from Pseudomonas cepacia
PS -C “Amano” II from Pseudomonas cepacia immobilised on
ceramic particles
4
5
6
7
Type II, Porcine pancreas
Candida cylindrica, immobilised on Sol–Gel-AK
Rhizopus delemar
A ϩ C (trace B)
No reaction
No reaction
Candida cylindrica
A ϩ C (trace B)
a Reagents and conditions: lipase (292 mg), diol 16 (0.33 mmol), vinyl acetate (3.5 mmol), TBME (4.5 ml), RT, 17 h.
(∼96% ee). Reaction with the 7R, 8R diol 15 led to the acylation
at the undesired C-8 position 18. Fortunately, reaction with
its enantiomer 15Ј resulted in selective acylation at the C-7
hydroxyl (17). Although we have used enantiomerically
enriched diols for the purpose of our synthesis, this novel
enzymatic protection could potentially complement existing
methods for enzymatic kinetic resolution of racemic diols.19
The Mitsunobu reaction between 17 and 9 was investigated.
Unfortunately, all tested conditions failed to give any desired
product, owing to the low reactivity of phenol 9. There-
fore, stepwise mesylation followed by SN2 displacement was
investigated as an alternative. Most conventional methods
for displacing the mesylate failed to initiate a reaction. The
only successful conditions applied Cs2CO3 and 18-crown-6
(Scheme 3).20 Unfortunately this led to the wrong diastereo-
isomer of the natural product rhaphidecursinol B (2), exhibit-
ing a 1H-NMR coupling constant of 2.2 Hz between H-7
and H-8.
Scheme 4
while polymer-supported bicarbonate was used concurrently
to scavenge DDQH, resulting in a clear colourless solution
(Scheme 5).
Tosylation of α-hydroxy ketone 20 was achieved in 94% yield
using toluenesulfonic anhydride and pyridine, followed by
filtration through silica gel. Since a high concentration of both
reactants was found to be essential for this reaction, application
of PS-DMAP or diethylaminomethyl-polystyrene failed to
provide complete conversions as a large amount of solvent was
necessary to swell the polymer-supported reagents. Alternative
conversion of the α-hydroxy ketone 20 to the corresponding
mesylate, bromide or iodide did not give sufficiently clean
reactions.
The SN2 coupling of phenol 7 with tosylate 21 was accom-
plished in quantitative yield using PS-BEMP phosphazene
base. Finally, a non-chelation control polymer-supported
borohydride reduction of the resulting ketone 22 yielded the
natural product (7S, 8S)-polysphorin (1) in a 13 : 1 to 32 : 1
diastereomeric ratio.24 A chromatographic separation was
carried out at this stage to yield 90% of the desired pure poly-
sphorin (1); the NMR spectra matched that of the isolated
natural product.2
Scheme 3
It was envisaged that a secondary mesylate would be further
activated for displacement if formed on the alcohol adjacent
to a carbonyl centre. A stereoselective reduction could then
permit access to polysphorin (1). Both chelation and non-
chelation controlled reductions of similar compounds are
known.5,21 The α-hydroxy ketone 20 was produced by selectively
oxidising the benzylic position of diol 15. Transition metal
oxidants such as MnO2 and tetra-N-propylammonium per-
ruthenate (TPAP) unfortunately resulted in diol cleavage in
preference to selective oxidation (Scheme 4). Application of
dimethyldioxirane (DMDO) to the diol or the corresponding
acetonide led to a complex mixture of products, even though
the same oxidation was successful when used in combination
with diol 16 (Scheme 4).22
Fortunately, application of DDQ gave the desired α-hydroxy
ketone 20 in 89–94% yield without significant racemisation. As
DDQ is notoriously difficult to remove using column chroma-
tography, a mixed resin-bed scavenging method was success-
fully applied to extract excess DDQ.23 Polymer-supported
ascorbate resin was used to reduce any excess DDQ to DDQH,
Application of the devised route permitted the synthesis of
both enantiomers of polysphorin. Interestingly, these enantio-
mers displayed complementary optical activity, further con-
firming that the samples of polysphorin isolated from
nature were racemic. A small collection of analogues, including
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
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Scheme 5
Fig. 1
rhaphidecursinol B (2) (Fig. 1) was synthesized under the
generic conditions varying the phenol subunit incorporated in
the penultimate step.
The relative stereochemistry of this family was proven by the
acquisition of a crystal structure of rhaphidecursinol B (2)
(Fig. 2), which clearly displays a syn relationship between the
two stereogenic centres. A crystal structure of hydrazone
derivative 31 (Fig. 3), synthesized by oxidative cleavage of the
double bond in 1, followed by reaction with p-toluenesulfonyl
hydrazide (Scheme 6), proved the absolute stereochemistry of
(7R, 8R)-polysphorin.
In conclusion, we have developed a general enantioselective
route towards polysphorin and various analogues. Only one
aqueous work-up and one chromatographic purification were
necessary throughout the whole synthesis due to the multi-
step application of polymer-supported reagents, scavengers and
catalysts. During the course of this study a novel enzymatic
protection was discovered and asymmetric dihydroxylations
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
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sodium benzophenone ketyl; acetonitrile (MeCN), benzene,
dichloromethane (CH2Cl2), methanol (MeOH) and toluene
from calcium hydride. All other solvents and reagents were
used as supplied unless otherwise specified. Analytical thin
layer chromatography (TLC) was performed using pre-coated
glass-backed plates (Merck Kieselgel 60 F254) and visualised
by ultra-violet radiation (254 nm), acidic ammonium
molybdate() or acidic potassium permanganate() solu-
tions. Optical rotations were determined on a Perkin-Elmer
polarimeter Model 343. Infra-red spectra were obtained on
Perkin-Elmer Spectrum One FT-IR Universal ATR Sampling
Accessory, deposited neat or as a chloroform solution to a
diamond/ZnSe plate. 1H-NMR spectra were recorded in CDCl3
on a Bruker Advance DPX-400 spectrometer at 400 MHz with
residual chloroform as the internal reference (δH = 7.25 ppm).
13C-NMR spectra were recorded in CDCl3 on the same spec-
trometer at 100 MHz with the central peak of chloroform as
the internal reference (δC = 77.0 ppm). Where DEPT was taken,
the CH and CH3 carbons are denoted (ϩ) and CH2 carbons
(Ϫ). Mass spectra were obtained on a Kratos MS890MS spec-
trometer (ϩEI) or a Micromass Q-TOF spectrometer (ϩESI)
at the Department of Chemistry, University of Cambridge.
Optical rotations were measured on a Perkin-Elmer 343
polarimeter using a sodium lamp (λ 589 nm, D-line); [α]λT ЊC
Fig. 2
values are reported in 10Ϫ1deg cm2
g
Ϫ1, concentration (c)
in g per 100 ml. Microanalyses were performed by Medac
Ltd., Surrey. X-ray crystal structures were determined at the
Department of Chemistry, Lensfield Road, Cambridge.
Polymer-supported iridium catalyst 12 was prepared following
the previously published procedure.9
Fig. 3
Preparation of 2,6-dimethoxy-4-(E )-propenyl-phenol 76
Hydrogen was bubbled through a suspension of catalyst 12
(1.27 g, 0.8 mmol based on Ir content) and THF (17 ml) until
the polymer turned from red to chrome yellow. The suspension
was flushed with argon before addition of 4-allyl-2,6-di-
methoxyphenol (2 g, 10 mmol) and the resulting suspension
was agitated under an atmosphere of argon at RT. After 24 h,
the polymer was removed by filtration and washed with THF.
The filtrate was concentrated in vacuo to give the title com-
pound as a colourless oil with a 60 : 1 trans : cis selectivity.
Crude mass recovery was quantitative. νmax /cmϪ1 3470 br (OH),
1653 (alkene C᎐C), 1603, 1516 (Ar C᎐C), 961 (trans HC᎐CH);
᎐
᎐
᎐
δH(400 MHz, CDCl3) 6.55 (2 H, s, Ar–H), 6.29 (1 H, dq, J 15.7,
1.8, CH᎐CHCH ), 6.07 (1 H, dq, J 15.7, 6.6, CH᎐CHCH ), 5.46
᎐
᎐
3
3
(1 H, s, OH ), 3.87 (6 H, s, OCH ), 1.85 (3 H, dd, J 6.6, 1.8, CH᎐
᎐
3
CHCH3); δC(CDCl3) 147.1, 134.0, 130.9, 129.6, 123.8, 102.7,
56.2, 18.2; Found (ESI): [M ϩ Na]ϩ 217.0841, C11H14O3Na
requires 217.0838.
Preparation of 1,2,3-trimethoxy-5-(E )-propenyl-benzene 1325
PS-BEMP (Fluka, 2.2 mmolgϪ1 base, 14 g, 31 mmol) and
iodomethane (0.71 ml, 11 mmol) was added to a solution of
2,6-dimethoxy-4-(E)-propenyl-phenol 7 (2 g, 10 mmol) in
acetonitrile (40 ml). The resulting suspension was agitated
under an atmosphere of argon at RT. After 2 h, the spent
polymer was removed by filtration to yield the title compound
Scheme 6
as a yellow oil (2.1 g, 98%); νmax /cmϪ1 1580 (Ar C᎐C), 1505 (Ar
᎐
using OsEnCat were investigated, though these were not
utilised in the final synthesis.
C᎐C); δ (400 MHz, CDCl ) 6.55 (2 H, s, Ar–H), 6.32 (1 H, d,
᎐
H
3
J 15.7, CH=CHCH ), 6.14 (1 H, dq, J 15.7, 6.5, CH᎐CHCH ),
᎐
3
3
3.85 (6 H, s, OCH3), 3.82 (3 H, s, OCH3), 1.87 (3 H, d, J 6.6,
CH3); δC(CDCl3) 153.3, 137.3, 133.8, 130.9ϩ, 125.3ϩ, 103.0ϩ,
60.9ϩ, 56.1ϩ, 18.3ϩ; Found (ESI): [M ϩ Na]ϩ 231.0992,
C12H16O3Na requires 231.0997.
Experimental
Unless otherwise specified, reactions involving polymers were
carried out on a laboratory shaker IKA 125 at 250 rpm.
Moisture sensitive reactions were carried out under an argon
atmosphere using oven-dried glassware. Commercially available
resins were washed and dried in vacuo prior to use. Diethyl
ether (Et2O) and tetrahydrofuran (THF) were distilled from
Preparation of polymer-supported boronic acid 1426
Bromopolystyrene (Fluka 1% DVB, 4 mmolgϪ1 Br, 40 g, 160
mmol) was swelled in THF (250 ml) and nBuLi (192 mmol)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
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added slowly at RT. The beads were allowed to stir at RT for
3 h. Approximately 50 ml of the solution was removed via
syringe before the remaining suspension was cooled to Ϫ78 ЊC.
Trimethyl borate (22.4 g, 216 mmol) was added dropwise over
45 min at Ϫ78 ЊC and the resulting suspension allowed to warm
to RT and stir for 24 h. The reaction was quenched by addition
of 1 M HCl (150 ml). The beige beads were washed with 1 M
HCl, water, THF and ether before they were dried under
vacuum. Elemental analysis indicated 0.53% B corresponding
to a loading of 0.49 mmol gϪ1 B.
this solution and the resulting suspension was agitated at RT
After 17 h, the lipase beads were removed by filtration and the
resulting filtrate concentrated in vacuo to yield a colourless oil.
Purification by silica gel chromatography (3 : 1 EtOAc : petrol
ether) yielded the title product as a colourless oil (33 mg, 94%).
Rf (3 : 1 EtOAc : petroleum ether) = 0.30. [α]2D5 Ϫ31.0 (c 0.8,
CHCl3); νmax /cmϪ1 3488 br (OH), 1735 (C᎐O), 1592 (Ar C᎐C),
᎐
᎐
1506 (Ar C᎐C); δ (400 MHz, CDCl ) 6.57 (2 H, s, Ar–H), 5.05
᎐
H
3
(1 H, dq, J 7.3, 6.6, H-8), 4.52 (1 H, dd, J 7.3, 3.3, H-7), 3.85
(6 H, s, OCH3), 3.83 (3 H, s, OCH3), 2.47 (1 H, d, J 3.3, OH ),
Polymer-supported boronic acid is also commercially avail-
able from Lancaster Synthesis, catalogue number 19459.
2.09 (3 H, s, C᎐OCH ), 1.10 (3 H, d, J 6.6, H-9); δ (CDCl )
᎐
3 C 3
170.8, 153.4, 138.0, 135.7, 104.0ϩ, 77.3ϩ, 74.6ϩ, 60.8ϩ,
56.2ϩ, 21.3ϩ, 16.6ϩ; Found (ESI): [M ϩ Na]ϩ 307.1140,
C14H20O6Na requires 307.1158.
Preparation of 1-(3,4,5-trimethoxy-phenyl)-propane-1R,2R diol
15
Preparation of polymer-supported ascorbate23
A suspension of AD-mix-β (10.1 g), methanesulfonamide
(685 mg, 7.2 mmol) in water (21 ml) and BuOH (21 ml) was
Ambersep 900 OHϪ (Acros, 35 g) was placed in a sintered
funnel and washed with a 0.4 M ascorbic acid solution (1.2 l)
over a 1.5 h period. The resulting beige beads were then washed
with water (1 l), MeOH (500 ml) and acetone (500 ml) and dried
t
cooled to 0 ЊC before 1,2,3-trimethoxy-5-(E)-propenyl-benzene
(13) (1.5 g, 7.2 mmol) was added. The reaction was allowed
to warm to RT and stir over 16 h before it was quenched by
addition of sodium sulfite (10.5 g). After the suspension was
stirred for 20 min, the product was extracted with ethyl acetate
and methanesulfonamide removed with 2 M KOH. The com-
bined organic layers were dried (brine, Na2SO4) and concen-
trated in vacuo to yield a yellow oil. The crude yellow oil was
dissolved in toluene (110 ml) and polymer-supported boronic
acid added (15.6 g) before the suspension was heated to relux
with a Dean–Stark apparatus for 24 h. When TLC analysis
showed that no diol product was present in the solution, the
polymer beads were isolated and washed with toluene. Finally,
the polymer beads were washed with a 10 : 1 acetone : water
solution until all the diol product has been cleaved from the
polymer beads. The filtrate was dried with MgSO4 and concen-
trated in vacuo to yield a colourless oil (1.44 g, 83%); [α]2D5 Ϫ28
in vacuo for 24 h; νmax /cmϪ1 3281 br (OH), 1788 (C᎐O), 1725
᎐
(C᎐O).
᎐
Preparation of polymer-supported bicarbonate
Chloride on polymer-support (Fluka, 4 mmol gϪ1, 50 g) was
placed in a sintered funnel and washed with a saturated
NaHCO3 solution until the filtrate tested negative for ClϪ. The
polymer beads were washed with water, acetone, ether and
dried in vacuo for 24 h.
(Polystyrylmethyl)trimethylammonium bicarbonate is also
available from Merck Biosciences, catalogue number
01–64–0419.
Preparation of 2R-hydroxy-1-(3,4,5-trimethoxy-phenyl)-propan-
1-one 20
(c 0.805, CHCl3); νmax /cmϪ1 3446 br (OH), 1592 (Ar C᎐C), 1508
(Ar C᎐C); δ (400 MHz, CDCl ) 6.52 (2H, s, Ar–H), 4.25 (1 H,
᎐
᎐
H
3
Diol 15 (1.3 g, 5.36 mmol) was dissolved in dioxane (26 ml).
DDQ (1.83 g, 8 mmol) was added and the resulting mixture was
allowed to stir at 60 ЊC for 12 h. The solution was concentrated
in vacuo and redissolved in CH2Cl2 (100 ml). Polymer-
supported ascorbate (18.9 g) and polymer-supported bicarb-
onate (15.2 g) were added to the solution and the resulting
suspension was allowed to stir at RT for 2 h, when TLC analysis
indicated that all DDQ and DDQH had been scavenged by the
polymers. The purple and yellow polymer beads were removed
by filtration to leave a pale yellow filtrate. Concentration in
vacuo yielded a pale yellow oil (1.14 g, 89%); [α]2D5 ϩ48 (c 0.8,
CHCl3); νmax /cmϪ1 3475 br (OH), 1678 (C᎐O), 1585 (Ar C᎐C),
d, J 7.3, ArCHOH), 3.81 (1 H, m, CH3CHOH), 3.81 (6 H, s,
OCH3), 3.79 (3 H, s, OCH3), 3.36 (1 H, br s, OH ), 3.07 (1 H, br
s, OH ), 1.04 (3 H, d, J 6.59, CH3); δC(CDCl3) 153.2, 137.7,
136.8, 103.8, 79.5, 72.1, 60.8, 56.1, 18.9; Found (EI): [M]ϩ
242.1158, C12H18O5 requires 242.1154.
The (1S, 2S)-enantiomer 15Ј was prepared in the same way
using AD-mix-α; [α]2D5 ϩ25 (c 1.081, CHCl3).
Preparation of acetic acid 2S-hydroxy-1S-(3,4,5-trimethoxy-
phenyl)-propyl ester 17
t
Diol 15Ј (780 mg, 3.2 mmol) was dissolved in butyl methyl
᎐
᎐
ether (30 ml). Lipase PS-C Amano II immobilized on ceramic
particles (3.2 g) and vinyl acetate (2.77 g, 32 mmol) was added
to this solution and the resulting suspension was allowed to stir
at RT. After 48 h, the lipase beads were removed by filtration
and the resulting filtrate concentrated in vacuo to yield a colour-
less oil. Purification by silica gel chromatography (3 : 1 EtOAc :
petrol ether) yielded the title product as a colourless oil (755
mg, 83%). Rf (1 : 1 EtOAc : petroleum ether) = 0.12. [α]2D0 ϩ59.0
1505 (Ar C᎐C); δ (400 MHz, CDCl ) 7.15 (2 H, s, Ar–H), 5.10
᎐
H
3
(1 H, dq, J 7.0, 6.6, CHOHMe), 3.92 (3 H, s, OCH3), 3.90 (6 H,
s, OCH3), 3.74 (1 H, d, J 6.6, OH ), 1.44 (3 H, d, J 7.0, CH3);
δC(CDCl3) 201.1, 153.2, 143.4, 128.3, 106.2ϩ, 69.0ϩ, 60.9ϩ,
56.4ϩ, 22.6ϩ; Found (EI): [M]ϩ 240.1004, C12H16O5 requires
240.0998.
The 2S enantiomer was prepared in the same way using
1-(3,4,5-trimethoxy-phenyl)-propane-1S,2S diol 15Ј as the
starting material. [α]2D5 Ϫ45 (c 1.143, CHCl3).
(c 0.583, CHCl3); νmax /cmϪ1 3474 br (OH), 1735 (C᎐O), 1592
᎐
(Ar C᎐C), 1508 (Ar C᎐C); δ (400 MHz, CDCl ) 6.53 (2H, s,
᎐
᎐
H
3
Ar–H), 5.45 (1H, d, J 7.0, H-7), 4.02 (1H, dq, J 7.0, 6.6, H-8),
3.85 (6H, s, OCH ), 3.82 (3H, s, OCH ), 2.13 (3H, s, C᎐OCH ),
1.10 (3H, d, J 6.6, H-9); δC(CDCl3) 170.3, 153.4, 138.1, 133.2,
104.3ϩ, 80.6ϩ, 70.1ϩ, 60.8ϩ, 56.2ϩ, 21.2ϩ, 18.9ϩ; Found
(ESI): [M ϩ Na]ϩ 307.1146, C14H20O6Na requires 307.1158.
Preparation of toluene-4-sulfonic acid 1R-methyl-2-oxo-2-(3,4,5-
trimethoxy-phenyl)-ethyl ester 21
᎐
3
3
3
A solution of 2R-hydroxy-1-(3,4,5-trimethoxy-phenyl)-propan-
1-one (20) (293 mg, 1.22 mmol) in pyridine (1.5 ml) was cooled
to 0 ЊC before p-toluenesulfonic anhydride (600 mg, 1.85 mmol)
was added to the solution. The resulting suspension was
allowed to stir at 0 ЊC for 1 h. Filtration through a plug of
silica (1 : 1 CHCl2 : ether) and concentration in vacuo yielded a
yellow oil (455 mg, 94%); [α]2D5 Ϫ3.1 (c 2.0, CHCl3); νmax /cmϪ1
Preparation acetic acid 2R-hydroxy-1R-methyl-2-(3,4,5-tri-
methoxy-phenyl)-ethyl ester 18
Diol 15 (30 mg, 0.12 mmol) was dissolved in tbutyl methyl ether
(2 ml). Lipase PS-C Amano II immobilized on ceramic particles
(131 mg) and vinyl acetate (113 mg, 1.31 mmol) was added to
1695 (C᎐O), 1583 (Ar C᎐C), 1505 (Ar C᎐C), 1128 (SO O);
᎐
᎐
᎐
2
δH(400 MHz, CDCl3) 7.75 (2 H, d, J 8.4, Ar–H), 7.28 (2 H, d,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
3962

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J 8.4, Ar–H), 7.21 (2 H, s, Ar–H), 5.76 (1 H, q, J 7.0, CHMe-
OTs), 3.92 (3 H, s, OCH3), 3.89 (6 H, s, OCH3), 2.41 (3 H, s,
Ar–CH3), 1.55 (3 H, d, J 7.0, CH3); δC(CDCl3) 193.3, 153.1,
145.0, 143.4, 133.6, 129.8ϩ, 128.7, 127.8ϩ, 106.6ϩ, 77.06ϩ,
60.9ϩ, 56.4ϩ, 21.6ϩ, 18.4ϩ; Found (ESI): [M ϩ Na]ϩ
417.0992, C19H22O7SNa requires 417.0984.
The 1S enantiomer was prepared in the same way using
2S-hydroxy-1-(3,4,5-trimethoxy-phenyl)-propan-1-one as the
starting material; [α]2D5 ϩ3.0 (c 0.713, CHCl3).
of these analogues using polymer-supported borohydride
produced analogues of 1.
Preparation of 2R-(4-allyl-2,6-dimethoxy-phenoxy)-1-(3,4,5-
trimethoxy-phenyl)-propane-1-one 2327
Phenol 9 (100 mg, 0.52 mmol) and PS-BEMP (Fluka, 2.2 mmol
gϪ1 base, 282 mg, 0.62 mmol) was added to a solution of
toluene-4-sulfonic acid 1S-methyl-2-oxo-2-(3,4,5-trimethoxy-
phenyl)-ethyl ester (204 mg, 0.52 mmol) in acetonitrile (5 ml)
and the resulting suspension was allowed to stir at RT. After
15 h, the polymer beads were removed by filtration and washed
with ether and CH2Cl2. The filtrate was concentrated in vacuo to
yield a yellow oil. Crude mass recovery was quantitative. The
crude product was used directly in the next reaction. A small
amount of material was purified by column chromatography
(100 : 1 CH2Cl2 : ether) for characterisation. Rf (100 : 1 CH2Cl2 :
ether) = 0.09. [α]2D5 ϩ44.5 (c 1.47, CHCl3); νmax /cmϪ1 1683
Preparation of 2S-(2,6-dimethoxy-4-propenyl-phenoxy)-1-
(3,4,5-trimethoxy-phenyl)-propane-1-one 22
Phenol 6 (33 mg, 0.17 mmol) and PS-BEMP (Fluka, 2.2 mmol
g
Ϫ1 base, 94 mg, 0.21 mmol) was added to a solution of toluene-
4-sulfonic acid 1R-methyl-2-oxo-2-(3,4,5-trimethoxy-phenyl)-
ethyl ester (21) (68 mg, 0.17 mmol) in acetonitrile (3 ml).
The resulting suspension was allowed to stir at RT. After 15 h,
the polymer beads were removed by filtration and washed with
ether and CH2Cl2. The filtrate was concentrated in vacuo to
yield a yellow oil. Crude mass recovery was quantitative. The
crude product was used directly in the next reaction. A small
amount of material was purified by column chromatography
(100 : 1 CH2Cl2 : ether) for characterisation. Rf (1 : 1 ether :
petroleum ether) = 0.14. [α]2D5 Ϫ59 (c 2.35, CHCl3); νmax /cmϪ1
1683 (C᎐O), 1582 (Ar C᎐C), 1503 (Ar C᎐C); δ (400 MHz,
(C᎐O), 1588 (Ar C᎐C), 1504 (Ar C᎐C); δ (400 MHz, CDCl )
᎐
᎐
᎐
H
3
7.51 (2 H, s, Ar–H), 6.37 (2 H, s, Ar–H), 5.93 (1 H, m, H-8Ј),
5.24 (1 H, q, J 6.6, H-8), 5.10 (1 H, d, J 17.2, H-9Ј), 5.08 (1 H, d,
J 8.1, H-9Ј), 3.90 (3 H, s, OCH3), 3.87 (6 H, s, OCH3), 3.72 (6 H,
s, OCH3), 3.31 (2 H, d, J 7.0, H-7Ј), 1.54 (3 H, d, J 7.0, H-9);
δC(CDCl3) 197.5, 153.2, 152.8, 142.2, 134.1ϩ, 136.11, 133.8,
130.5, 116.1–, 107.2ϩ, 105.4ϩ, 80.8ϩ, 60.9ϩ, 56.2ϩ, 55.9ϩ,
40.5–, 17.9ϩ; Found (ESI): [M ϩ Na]ϩ 439.1713, C23H28O7Na
requires 439.1733.
᎐
᎐
᎐
H
CDCl3) 7.49(2 H, s, Ar–H), 6.52 (2 H, s, Ar–H), 6.30 (1 H, d,
J 15.7, H-7Ј), 6.13 (1 H, dq, J 15.7, 6.2, H-8Ј), 5.27 (1 H, q,
J 7.0, H-8), 3.90 (3 H, s, OCH3), 3.87 (6 H, s, OCH3), 3.74 (6 H,
s, OCH3), 1.85 (3 H, d, J 6.2, H-9Ј), 1.54 (3 H, d, J 7.0, H-9);
δC(CDCl3) 197.4, 153.2, 152.8, 142.5, 134.6, 134.0, 130.8ϩ,
130.5, 125.4ϩ, 107.1ϩ, 102.8ϩ, 80.7ϩ, 60.9ϩ, 56.2ϩ, 55.8ϩ,
18.3ϩ, 17.8ϩ; Found (ESI): [M ϩ Na]ϩ 439.1747, C23H28O7Na
requires 439.1733.
The 2R enantiomer was prepared in the same way using
toluene-4-sulfonic acid 1S-methyl-2-oxo-2-(3,4,5-trimethoxy-
phenyl)-ethyl ester as the starting material; [α]2D5 ϩ60 (c 0.88,
CHCl3).
(7R, 8R)-Rhaphidecursinol B 22
Polymer-supported borohydride (Aldrich, 2.5 mmol gϪ1 on
Amberlite IRA-400, 529 mg, 1.3 mmol) was added to a
solution of 2R-(4-allyl-2,6-dimethoxy-phenoxy)-1-(3,4,5-tri-
methoxy-phenyl)-propane-1-one (23) (110 mg, 2.6 mmol) in
methanol (2.5 ml) and the resulting suspension was stirred at
RT. After 16h, the polymer beads were removed by filtration
and washed with methanol. The filtrate was concentrated in
vacuo to give a 25 : 1 mixture of diastereoisomers in favour of
the title product. The diastereoisomers were separated by pre-
parative TLC (eluent: 2.5 : 1 ether : petroleum ether) to yield
the title product as a white solid (86 mg, 79%). Rf (3 : 1 ether :
petroleum ether) = 0.23. Mp 81–82 ЊC; [α]2D5 Ϫ58.2 (c 5.26,
(7S, 8S )-Polysphorin 12
Polymer-supported borohydride (Aldrich, 2.5 mmolgϪ1 on
Amberlite IRA-400, 82 mg, 0.2 mmol) was added to a
solution of 2S-(2,6-dimethoxy-4-propenyl-phenoxy)-1-(3,4,5-
trimethoxy-phenyl)-propane-1-one (22) (17 mg, 0.041 mmol) in
methanol (0.8 ml) and the resulting suspension was stirred at
RT. After 16 h, the polymer beads were removed by filtration
and washed with methanol. The filtrate was concentrated in
vacuo to give a 32 : 1 mixture of diastereoisomers in favour
of the title product. The diastereoisomers were separated by
preparative TLC (eluent: 3 : 1 ether : petroleum ether) to yield
the title product as a viscous white oil (16 mg, 96%). Rf (3 : 1
ether : petroleum ether) = 0.23. Mp 107–108 ЊC; [α]2D5 ϩ95 (c 0.8,
CHCl3); νmax /cmϪ1 3469 br (OH), 1589 (Ar C᎐C), 1502 (Ar
᎐
C᎐C); δ (400 MHz, CDCl ) 6.57 (2 H, s, Ar–H), 6.43 (2 H, s,
᎐
H
3
Ar–H), 5.95 (1 H, m, H-8Ј), 5.11 (1 H, dd, J 16.8, 1.5, H-9Ј),
5.01 (1 H, dd, J 8.4, 1.5, H-9Ј), 4.91 (1 H, s, OH ), 4.58 (1 H, d,
J 8.1, H-7), 3.95 (1 H, dq, J 8.1, 6.2, H-8), 3.85 (6 H, s, OCH3),
3.83 (6 H, s, OCH3), 3.80 (3 H, s, OCH3), 3.33 (2 H, d, J 7.0,
H-7Ј), 1.20 (3 H, d, J 6.2, H-9); δC(CDCl3) 153.1, 152.7, 137.0ϩ,
136.4, 135.9, 135.2, 134.6, 116.1–, 105.5ϩ, 104.4ϩ. 86.2ϩ,
79.3ϩ, 60.7ϩ, 56.1ϩ, 55.9ϩ, 40.4Ϫ, 17.6ϩ; Found (ESI):
[M ϩ Na]ϩ 441.1895, C23O7H30Na requires 441.1889.
Crystal data: C23H30O7, M = 418.47, monoclinic, a =
12.334(3), b = 12.813(3), c = 14.026(3), β = 91.62(3)Њ, U =
2215.9(8) Å3, T = 180(2) K, space group P2(1), Z = 4, µ = 0.092
mmϪ1, 10958 reflections collected, 6652 independent reflections
(Rint = 0.0959). The final wR(F 2) was 0.1715.†
CHCl3); νmax /cmϪ1 3471 br (OH), 1582 (Ar C᎐C), 1503 (Ar
᎐
C᎐C); δ (400 MHz, CDCl ) 6.58 (2 H, s, Ar–H), 6.57 (2 H, s,
᎐
H
3
Ar–H), 6.33 (1 H, d, J 15.7, H-7Ј), 6.16 (1 H, dq, J 15.7, 6.6,
H-8Ј), 4.88 (1 H, s, OH ), 4.58 (1 H, d, J 8.4, H-7), 3.96 (1 H, dq,
J 8.4, 6.2, H-8), 3.88 (6 H, s, OCH3), 3.84 (6 H, s, OCH3), 3.81
(3 H, s, OCH3), 1.88 (3 H, d, J 6.6, H-9Ј), 1.21 (3 H, d, J 6.2,
H-9); δC(CDCl3) 153.1, 152.8, 137.6, 136.4, 136.1, 133.9, 130.8,
125.6ϩ, 104.4ϩ, 103.0ϩ, 86.4ϩ, 79.4ϩ, 60.8ϩ, 56.1ϩ, 56.0ϩ,
18.3ϩ, 17.7ϩ; Found (ESI): [M ϩ Na]ϩ 441.1907, C23H30O7Na
requires 441.1889.
2-Methoxy-4-propenyl-phenol28
Hydrogen was bubbled through a suspension of catalyst 12
(225 mg, 0.15 mmol) and THF (4 ml) until the polymer turned
from red to chrome yellow. The suspension was flushed with
argon before eugenol (300 mg, 1.83 mmol) was added and the
resulting suspension was agitated under an atmosphere of
argon at RT. After 24 h, the polymer was removed by filtration
and washed with THF. The filtrate was concentrated in vacuo to
The 7R, 8R enantiomer was prepared in the same way
using
2R-(2,6-dimethoxy-4-propenyl-phenoxy)-1-(3,4,5-tri-
methoxy-phenyl)-propane-1-one as starting material. The
diastereoisomeric ratio was 15:1 in favour of the 7R, 8R isomer;
[α]2D5 Ϫ87 (c 0.34, CHCl3).
The following analogues of compounds 22 and 1 were made
using the same general methods. The coupling phenol was
varied to produce analogues of 22 and subsequent reduction
† CCDC reference numbers 216370–216371. See http://www.rsc.org/
suppdata/ob/b3/b308761a/ for crystallographic data in .cif or other
electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
3963

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give the title compound as a yellow oil with a 50 : 1 trans : cis
selectivity. Crude mass recovery was quantitative; νmax /cmϪ1
filtration and washed with ether and CH2Cl2. The filtrate was
concentrated in vacuo to yield a colourless oil. Crude mass
recovery was quantitative. The crude product was filtered
3507 br (OH), 1596 (Ar C᎐C), 1510 (Ar C᎐C); δ (400 MHz,
᎐
᎐
H
CDCl3) 6.89 (1 H, s, Ar–H), 6.84 (2 H, s, Ar–H), 6.33 (1 H, dd,
J 15.7, 1.5, CH=CHCH ), 6.59 (1 H, dq, J 15.7, 6.6, 1.46, CH᎐
through a plug of silica (eluent: 100 : 1 CH2Cl2 : ether); [α]2D5
0
(c 0.2, CHCl3); νmax /cmϪ1 1688 (C᎐O), 1582 (Ar C᎐C), 1507
᎐
᎐
᎐
3
CHCH3), 5.57 (1 H, s, OH ), 3.90 (3 H, s, OCH3), 1.86 (3 H,
(Ar C᎐C); δ (400 MHz, CDCl ) 7.21–7.46 (9 H, m, Ar–H),
᎐
H 3
dd, J 6.6, 1.5, CH᎐CHCH ); δ (CDCl ) 146.5, 144.8, 130.7,
6.86–7.03 (4 H, m, Ar–H and HC᎐CH ), 5.88 (1H, q, J 6.8,
᎐
᎐
3
C
3
130.7, 123.4, 119.3, 114.3, 107.9, 55.8, 18.3; Found (EI): [M]ϩ
164.0837, C10H12O2 requires 164.0837.
H-8), 3.91 (3H, s, OCH3), 3.87 (6 H, s, OCH3), 1.73 (3 H, d, J
6.8, H-9); δC(CDCl3) 197.6, 157.1, 153.1, 143.3, 137.5, 131.0,
128.9, 128.6ϩ, 127.9ϩ, 127.3ϩ, 127.1ϩ, 126.3ϩ, 115.2ϩ,
106.6ϩ, 77.4ϩ, 60.9ϩ, 56.3ϩ, 19.0ϩ; Found (ESI): [M ϩ Na]ϩ
419.1844, C26H26O5Na requires 419.1858.
(8R)-Oxo-surinamensin 429
PS-BEMP (Fluka, 2.2 mmol gϪ1 base, 90 mg, 0.20 mmol) and
2-methoxy-4-propenyl-phenol (27 mg, 0.17 mmol) was added to
a solution of toluene-4-sulfonic acid 1S-methyl-2-oxo-2-(3,4,5-
trimethoxy-phenyl)-ethyl ester (65 mg, 0.165 mmol) in aceto-
nitrile (3 ml) and the resulting suspension was allowed to stir at
RT. After 15 h, the polymer beads were removed by filtration
and washed with ether and CH2Cl2. The filtrate was concen-
trated in vacuo to yield a yellow oil. Crude mass recovery was
quantitative. The crude product was used directly in the next
reaction. A small amount of material was purified by column
chromatography (100 : 1 CH2Cl2 : ether) for characterisation. Rf
(100 : 1 CH2Cl2 : ether) = 0.40 (streaks). [α]2D5 ϩ1.2 (c 0.325,
CHCl3); νmax /cmϪ1 1686 (C᎐O), 1582 (Ar C᎐C), 1506 (Ar C᎐C);
Preparation of 2S-[4-((E )-styryl)-phenoxy]-1-(3,4,5-trimethoxy-
phenyl)-propan-1S-ol 25
Polymer-supported borohydride (Aldrich, 2.5 mmolgϪ1 on
Amberlite IRA-400, 86 mg, 0.22 mmol) was added to a solution
of
2S-[4-((E)-styryl)-phenoxy]-1-(3,4,5-trimethoxy-phenyl)-
propan-1-one (26) (18 mg, 0.04 mmol) in methanol (0.4 ml)
and CH2Cl2 (0.4 ml) and the resulting suspension was stirred at
RT. After 16 h, the polymer beads were removed by filtration
and washed with methanol. The filtrate was concentrated in
vacuo to give a colourless oil with a 3 : 1 mixture of inseparable
diastereoisomers in favour of the title product. The crude yield
᎐
᎐
᎐
was quantitative; νmax /cmϪ1 3436 br (OH), 1594 (Ar C᎐C), 1507
δH(400 MHz, CDCl3) 7.45 (2 H, s, Ar–H), 6.85 (1 H, s, Ar–H),
6.74 (2 H, s, Ar–H), 6.27 (1 H, d, J 15.7, H-7Ј), 6.06 (1 H, dq,
J 15.7, 6.4, H-8Ј), 5.32 (1 H, q, J 6.8, H-8), 3.89 (3 H, s, OCH3),
3.86 (6 H, s, OCH3), 3.82 (3 H, s, OCH3), 1.82 (3 H, d, J 6.4,
H-9Ј), 1.71 (3 H, d, J 6.8, H-9); δC(CDCl3) 198.0, 152.9, 149.7,
145.8, 142.9, 132.6, 130.4ϩ, 120.1, 124.4ϩ, 118.6ϩ, 115.6ϩ,
109.4ϩ, 106.7ϩ, 78.8ϩ, 60.8ϩ, 55.1ϩ, 55.6ϩ, 19.0ϩ, 18.3ϩ;
Found (ESI): [M ϩ Na]ϩ 409.1628, C22H26O6Na requires
409.1627.
8S-Oxo-surinamensin (4Ј) was prepared in the same way
using toluene-4-sulfonic acid 1R-methyl-2-oxo-2-(3,4,5-tri-
methoxy-phenyl)-ethyl ester as starting material; [α]2D5 Ϫ1.5
(c 0.7, CHCl3).
᎐
(Ar C᎐C); δ (400 MHz, CDCl ) 7.53–6.91 (9 H, m, Ar–H and
᎐
H
3
CH᎐CH ), 6.66 (2 H, s, H-2 and H-6), 4.64 (1 H, dd, J 7.3, 2.2,
᎐
H-7), 4.44 (1 H, m, H-8), 3.89 (6 H, s, OCH3), 3.85 (3 H, s,
OCH3), 2.98 (1 H, d, J 2.2, OH ), 1.18 (3 H, d, J 6.1, H-9);
δC(CDCl3) 157.3, 153.3, 138.0, 137.5, 135.4, 131.0, 128.7ϩ,
128.0ϩ, 127.8ϩ, 127.4ϩ, 127.2ϩ, 126.3ϩ, 116.5ϩ, 104.4ϩ,
79.0ϩ, 78.2ϩ, 60.8ϩ, 56.2ϩ, 16.0ϩ; Found (ESI): [M ϩ Na]ϩ
443.1831, C26H28O5Na requires 443.1834.
Preparation of (E )-3-{3-methoxy-4-[1S-methyl-2-oxo-2-(3,4,5-
trimethoxy-phenyl)-ethoxy-phenyl}-acrylic acid ethyl ester 28
Ethyl-4-hydroxy-3-methoxy-cinnamate (22 mg, 0.098 mmol)
and PS-BEMP (Fluka, 2.2 mmol gϪ1 base, 55 mg, 0.12 mmol)
was added to a solution of toluene-4-sulfonic acid 1R-methyl-2-
oxo-2-(3,4,5-trimethoxy-phenyl)-ethyl ester (21) (39 mg, 0.098
mmol) in acetonitrile (2 ml) and the resulting suspension was
allowed to stir at RT. After 15 h, the polymer beads were
removed by filtration and washed with ether and CH2Cl2. The
filtrate was concentrated in vacuo to yield a colourless oil.
Crude mass recovery was quantitative. The crude product was
used directly in the next reaction. A small amount of material
(؊)-Surinamensin 24
Polymer-supported borohydride (Aldrich, 2.5 mmol gϪ1 on
Amberlite IRA-400, 160 mg, 0.4 mmol) was added to a solution
of 8R-surinamensin (4) (30 mg, 0.078 mmol) in methanol (1 ml)
and the resulting suspension was stirred at RT. After 16 h,
the polymer beads were removed by filtration and washed
with methanol. The filtrate was concentrated in vacuo to give an
8 : 1 mixture of inseparable diastereoisomers in favour of the
title product. A small proportion of pure title compound was
isolated (8 mg) by preparative TLC (eluent: 1 : 1 ethyl acetate :
petroleum ether) to yield the title product as a colourless oil. Rf
(2 : 1 ether : petroleum ether) = 0.20. [α]2D5 Ϫ3.9 (c 0.615, CHCl3);
νmax /cmϪ1 3496 br (OH), 1591 (Ar C᎐C), 1508 (Ar C᎐C); δ (400
was purified by column chromatography (100 : 1 CH2Cl2
:
ether) to yield an amorphous white solid for characterisation.
Rf (100 : 1 CH2Cl2 : ether) = 0.04. [α]2D5 Ϫ2.6 (c 0.765, CHCl3);
νmax /cmϪ1 1705 (C᎐O), 1583 (Ar C᎐C), 1508 (Ar C᎐C); δ (400
᎐
᎐
᎐
H
᎐
᎐
H
MHz, CDCl3) 7.55 (1 H, d, J 15.9, H-8Ј), 7.42 (2 H, s, Ar–H),
7.02(1H, d, J 1.6, H-6Ј), 6.97 (1 H, dd, J 8.3, 1.6, H-2Ј), 6.76
(1 H, d, J 8.3, H-3Ј), 6.26 (1 H, d, J 15.9, H-7Ј), 5.39 (1 H, q,
J 6.9, H-8), 4.22 (2 H, q, J 7.1, CH2), 3.89 (3 H, s, OCH3), 3.87
(6 H, s, OCH3), 3.85 (3 H, s, OCH3), 1.74 (3 H, d, J 6.9, H-9),
1.30 (3 H, t, J 7.1, CH2CH3); δC(CDCl3) 197.4, 167.0, 153.0,
149.7, 148.7, 144.1ϩ, 143.2, 128.8, 128.6, 122.2ϩ, 116.6ϩ,
114.6ϩ, 110.6ϩ, 106.7ϩ, 78.6ϩ, 60.9ϩ, 60.3Ϫ, 56.2ϩ, 55.8ϩ,
19.1ϩ, 14.3ϩ; Found (ESI): [M ϩ Na]ϩ 467.1678, C24H28O8Na
requires 467.1682.
MHz, CDCl3) 6.94 (1 H, d, J 8.2, H-3Ј), 6.92 (1 H, d, J 1.6,
H-6Ј), 6.86 (1 H, dd, J 8.2, 1.6, H-2Ј), 6.61 (2 H, s, H-2), 6.36
(1 H, d, J 15.9, H-7Ј), 6.15 (1 H, dq, J 15.9, 6.6, H-8Ј), 4.60 (1 H,
d, J 8.2, H-7), 4.10 (2 H, m, OH and H-8), 3.92 (3 H, s, OCH3),
3.86 (6 H, s, OCH3), 3.83 (3 H, s, OCH3), 1.88 (3 H, d, J 6.6,
H-9Ј), 1.20 (3 H, d, J 6.0, H-9); δC(CDCl3) 153.2, 150.8, 146.7,
135.6, 133.6, 130.4, 125.0, 119.1, 118.8, 109.2, 104.4, 84.1, 78.7,
60.8, 56.1, 55.7, 18.3, 17.2; Found (ESI): [M ϩ Na]ϩ 411.1788,
C22H28O6Na requires 411.1784.
Preparation of 2S-[4-((E )-styryl)-phenoxy]-1-(3,4,5-trimethoxy-
phenyl)-propan-1-one 26
Preparation of (E )-3-(4-[2S-hydroxy-1S-methyl-2-(3,4,5-tri-
methoxy-phenyl)-ethoxy]-3-methoxy-phenyl}-acrylic acid ethyl
ester 27
Polymer-supported borohydride (Aldrich, 2.5 mmolgϪ1 on
Amberlite IRA-400, 157 mg, 0.39 mmol) was added to a
solution of (E)-3-{3-methoxy-4-[1S-methyl-2-oxo-2-(3,4,5-tri-
methoxy-phenyl)-ethoxy-phenyl}-acrylic acid ethyl ester (28)
PS-BEMP (Fluka, 2.2 mmol gϪ1 base, 55 mg, 0.122 mmol) and
trans-4-hydroxystilbene (20 mg, 0.101 mmol) was added to a
solution of toluene-4-sulfonic acid 1R-methyl-2-oxo-2-(3,4,5-
trimethoxy-phenyl)-ethyl ester (21) (40 mg, 0.101 mmol) in
acetonitrile (2 ml) and the resulting suspension was allowed to
stir at RT. After 15 h, the polymer beads were removed by
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 9 5 7 – 3 9 6 6
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(35 mg, 0.08 mmol) in methanol (1 ml) and CH2Cl2 (0.2 ml) and
the resulting suspension was stirred at RT. After 16 h, the poly-
mer beads were removed by filtration washed with methanol.
The filtrate was concentrated in vacuo to give a colourless oil
with a 6 : 1 mixture of inseparable diastereoisomers in favour of
the title product. The crude yield was quantitative; νmax /cmϪ1
sodium periodate (31 mg, 0.14 mmol) in THF (0.4 ml) and
water (0.2 ml). The resulting mixture was allowed to stir at RT.
After 20 min, the reaction was diluted with CH2Cl2 and
quenched with a saturated solution of Na2S2O3. The aqueous
layer was separated, extracted with CH2Cl2, washed with brine
and dried (MgSO4) before the solvent was removed in vacuo
and the resulting residue was filtered through a plug of silica
(3 : 1 ether : petroleum ether). A portion of the crude product
(9.6 mg, 0.02 mmol) was dissolved in dry methanol (0.3 ml) and
p-toluenesulfonyl hydrazide (4.4 mg, 0.02 mmol) was added to
this solution. The reaction mixture was allowed to stir at RT for
45 min before the solvent was removed under a gentle stream
of air and the resulting residue was purified by silica gel column
chromatography (5 : 1 ether : hexane) to yield a white solid (12
mg, 88%). Single crystals of the title compound were obtained
by evaporation from a solution of ethyl acetate. Rf (5 : 1 ether :
hexane) = 0.08. [α]2D5 Ϫ42 (c 0.17, CHCl3); νmax /cmϪ1 3472 br
3484 br (OH), 1705 (C᎐O), 1633 (alkene C᎐C), 1594 (Ar C᎐C),
᎐
᎐
᎐
1508 (Ar C᎐C); δ (400 MHz, CDCl ) 7.62 (1 H, d, J 16.1,
᎐
H
3
H-8Ј), 7.10–7.05 (2 H, m, Ar–H), 6.96 (1 H, d, J 8.8, Ar–H),
6.61 (2 H, s, Ar–H), 6.32 (1 H, d, J 16.1, H-7Ј), 4.64 (1 H, d,
J 6.9, H-7), 4.50–4.41 (3 H, m, OCH2CH3 and H-8), 3.91 (3 H,
s, OCH3), 3.85 (6 H, s, OCH3), 3.82 (3 H, s, OCH3), 3.72 (1 H, s,
OH ), 1.33 (3 H, t, J 7.1, OCH2CH3), 1.21 (3 H, d, J 6.2, H-9);
δC(CDCl3) 167.0, 153.3, 150.8, 149.6, 144.1ϩ, 138.0, 135.3,
129.3, 122.2ϩ, 117.5ϩ, 116.9ϩ, 110.6ϩ, 104.4ϩ, 82.9ϩ, 78.4ϩ,
60.8ϩ, 60.4Ϫ, 56.2ϩ, 55.9ϩ, 16.8ϩ, 14.3ϩ; Found (ESI):
[M ϩ Na]ϩ 469.1821, C24H30O8Na requires 469.1838.
(OH), 1592 (C᎐N/Ar C᎐C), 1579 (Ar C᎐C), 1501 (Ar C᎐C),
᎐
᎐
᎐
᎐
1333 (–SO2–N), 1166 (–SO2–N); δH(600 MHz, CDCl3) 7.86
(2 H, d, J 8.2, H-14, H-18), 7.69 (1 H, s, H-7Ј), 7.66 (1 H, s,
NH ), 7.32 (2 H, d, J 8.2, H-15, H-17), 6.85 (2 H, s, Ar–H), 6.56
(2 H, s, Ar–H), 4.66 (1 H, br s, OH ), 4.60 (1 H, d, J 8.2, H-7),
4.03 (1 H, dq, J 6.6, 8.2, H-8), 3.89 (6 H, s, OCH3), 3.84 (6 H, s,
OCH3), 3.81 (3 H, s, OCH3), 2.42 (3 H, s, H-19), 1.22 (3 H, d,
J 6.6, H-9); δC(CDCl3) 153.1, 152.9, 147.5ϩ, 144.4, 139.1,
137.6, 136.0, 135.2, 129.7ϩ, 128.6, 127.9ϩ, 104.5ϩ, 104.2ϩ,
86.5ϩ, 79.2ϩ, 60.8ϩ, 56.2ϩ, 56.1ϩ, 21.6ϩ, 17.7ϩ; Found
(ESI): [M ϩ Na]ϩ 597.1903, C23H34N2O9SNa requires 597.1883.
Crystal data: C23H34N2O9S, M = 574.63, monoclinic, a =
22.4427(4), b = 11.0768(3), c = 12.8817(2), β = 114.475(2)Њ, U =
2914.55(10) Å3, T = 180(2) K, space group C2, Z = 4, µ = 0.166
mmϪ1, 14205 reflections collected, 6477 independent reflections
(Rint = 0.0345). Flack parameter30 = 0.05(7). The final wR(F 2)
was 0.0951.†
Preparation of 2S-((E )-2-ethoxy-5-propenyl-phenoxy)-1-(3,4,5-
trimethoxy-phenyl)-propane-1-one 30
PS-BEMP (Fluka, 2.2 mmol gϪ1 base, 90 mg, 0.198 mmol) and
trans-2-ethoxy-5-(1-propenyl)-phenol (29 mg, 0.165 mmol)
was added to a solution of toluene-4-sulfonic acid 1R-methyl-
2-oxo-2-(3,4,5-trimethoxy-phenyl)-ethyl ester (21) (65 mg,
0.165 mmol) in acetonitrile (3 ml) and the resulting suspension
was allowed to stir at RT. After 15 h, the polymer beads were
removed by filtration and washed with ether and CH2Cl2. The
filtrate was concentrated in vacuo to yield a yellow oil. Crude
mass recovery was quantitative. The crude product was filtered
through a plug of silica (eluent: 100 : 1 CH2Cl2 : ether); [α]2D5
(c 0.67, CHCl3); νmax /cmϪ1 1689 (C᎐O), 1582 (Ar C᎐C), 1507
0
᎐
᎐
(Ar C᎐C); δ (400 MHz, CDCl ) 7.44 (2 H, s, Ar–H), 6.82 (3 H,
᎐
H
3
m, Ar–H), 6.23 (1 H, dd, J 15.7, 1.6, H-7Ј), 6.00 (1 H, dq, J 15.7,
6.6, H-8Ј), 5.33 (1 H, q, J 6.9, H-8), 4.034 (1 H, q, J 7.0, OCH-
HЈCH3), 4.028 (1 H, q, J 7.0, OCHHЈCH3), 3.90 (3 H, s, OCH3),
3.86 (6 H, s, OCH3), 1.80 (3 H, d, J 6.6, 1.6, H-9Ј), 1.70 (3 H,
d, J 6.9, H-9), 1.35 (3 H, t, J 7.0, OCHHЈCH3); δC(CDCl3)
198.2, 152.9, 148.5, 147.3, 142.9, 131.4, 130.2ϩ, 129.4, 124.2ϩ,
120.4ϩ, 114.4ϩ, 113.91ϩ, 106.89ϩ, 79.39ϩ, 64.55Ϫ, 60.89ϩ,
56.24ϩ, 19.12ϩ, 18.30ϩ, 14.83ϩ; Found (ESI): [M ϩ Na]ϩ
423.1801, C23H28O6Na requires 423.1784.
Acknowledgements
We would like to thank Dr Peter Moore (AstraZeneca) and
Dr Chandrashekar Ramarao for helpful discussions. We
gratefully acknowledge the financial support from Cambridge
Commonwealth Trust, The British Council, The Committee
of Vice-Chancellors and Principals and AstraZeneca for PhD
funding (to ALL), the BP endowment and the Novartis
Research Fellowship (to SVL). We thank Dr John Davies for
the X-ray structure determination.
Preparation of 2R-((E )-2-ethoxy-5-propenyl-phenoxy)-1-(3,4,5-
trimethoxy-phenyl)-propan-1R-ol 29
Polymer-supported borohydride (Aldrich, 2.5 mmol gϪ1 on
Amberlite IRA-400, 582 mg, 1.45 mmol) was added to a
solution of 2R-((E)-2-ethoxy-5-propenyl-phenoxy)-1-(3,4,5-tri-
methoxy-phenyl)-propane-1-one (30) (117 mg, 0.29 mmol) in
methanol (5 ml) and the resulting suspension was stirred at
RT. After16 h, the polymer beads were removed by filtration
and washed with methanol. The filtrate was concentrated in
vacuo to give, as a colourless oil, a 7 : 1 mixture of inseparable
diastereoisomers in favour of the title product; νmax /cmϪ1 3483
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