A new approach to combretastatin D2

Article abstract of DOI:10.1039/b513515j

A concise and convergent route to combretastatin D₂ is described together with some preliminary biological data. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b513515j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A new approach to combretastatin D2†
David Cousin,a John Mann,*a Mark Nieuwenhuyzena and Hendrik van den Bergb
Received 23rd September 2005, Accepted 25th October 2005
First published as an Advance Article on the web 25th November 2005
DOI: 10.1039/b513515j
A concise and convergent route to combretastatin D2 is described together with some preliminary
biological data.
Introduction
Results and discussion
Shrubs and trees of the Combretaceae family are much used in
Africa and India as a source of medicinal products, and the
constituent combretastatins have been extensively studied as po-
tential drugs.1 Of these, combretastatin A4 (1a) and its phosphate
ester (1b) have shown particular promise as potential anti-cancer
agents. The latter is currently undergoing phase II clinical trials as
an inhibitor of angiogenesis.2
All of the combretastatins are acyclic with the exception of
combretastatins D1 (2) and D2 (3) and the recently described
combretastatins D3 (4) and D4 (5).3 Several syntheses of D1 and
D2 have been described4 but none of the routes was efficient,
and only one cytotoxicity study has been reported (using mouse
leukaemia P388) which showed modest activity (ED50 3–5 lg ml−1)
for these compounds.5 Our interest in the design and synthesis of
angiogenesis inhibitors prompted us to design a new, convergent
route to this class of compounds with a view to further study of
the biological properties of both the natural products and their
analogues.
Our synthetic route is shown in Scheme 1 and uses a copper-
catalysed coupling of the phenol (6) and boronic acid (7) to provide
the key ether linkage of combretastatin D2. The phenol (6) was
synthesised from 3-hydroxy-4-methoxybenzaldehyde by means of
a Wittig reaction with carbomethoxymethylidene triphenylphos-
phorane, with subsequent catalytic transfer hydrogenation of
the resultant alkene (85% overall). In a parallel synthesis, the
ethylene ketal of 4-bromobenzaldehyde was converted into the
aryl lithium and then reacted with triisopropyl borate followed by
acid hydrolysis (70–75% overall). The coupling was accomplished
using a modification of the method of Evans et al.6 using
copper(II) acetate to provide the required diaryl ether (8). This
reaction was somewhat capricious with yields ranging from 32–
81% but could be optimised to around 70% on the multigram
scale. Transesterification using allyl alcohol and dibutyltin oxide7
produced the allyl ester (9) in excellent yield (88–95%), and
this was reduced to the alcohol (10) using NaBH4 and then
converted into the bromide (11) using CBr4 and Ph3P (overall
yield 60%). Ozonolysis followed by cleavage of the ozonide
(Me2S) yielded aldehyde (12) (ca. 60–70% crude) which could
be converted into the phosphonium salt (13) over a period of
2 days (quantitative yield). This participated in an intramolecular
Wittig reaction following treatment with potassium carbonate in
dichloromethane containing 18-crown-6. The yield of the methyl
ether of combretastatin D2 (14) was only 30% and has not yet
been optimised, although a large number of other bases, solvents
and reaction conditions have been investigated (Table 1). Stronger
bases than potassium carbonate invariably caused hydrolysis of
the ester group. Since compound (14) has been converted into
combretastatin D2 by Boger et al. (using BI3 and dimethylaniline
in benzene),4 this constitutes a formal total synthesis of the natural
product. However, our approach is both shorter and more efficient
than the other published routes, and should allow access to a range
of analogues for biological evaluation.
Interestingly, in the product mixture from the Wittig reaction
the trans-alkene (15) could be seen, though this isomerised to
the cis-alkene during silica chromatography (isomerisation was
also effected using light). This isomer has never been reported
aSchool of Chemistry, Queenꢀs University Belfast, Stranmillis Rd., Belfast,
UK BT9 5AG
1
before and both alkenes exhibited interesting H NMR signals
for the aryl hydrogen b to the methoxy group. For the cis-
alkene this resonated at 5.11 ppm while for the trans-isomer
it appeared at 4.59 ppm, providing evidence in both cases of
significant diamagnetic shielding by the aromatic ring current
bDepartment of Oncology, Queen’s University Belfast, Belfast City Hospital,
Lisburn Rd., Belfast, UK BT9 7AB
† This paper is dedicated to Professor Steve Ley on the occasion of his
60th birthday.
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Table 1 Selected conditions screened for the intramolecular Wittig reactions
X
Solvent
Base
C/mM
T/◦C
Yield (for 3 steps)
=
=
O
O
P(OMe)2
P(OMe)2
DME
DME
DMF
DCM
DCM
DCM
DCM
THF–DCM
THF–DCM
DCM–H2O
tBuOK
2
2
2
2
5
10
2
2.5
2.5
10
0 to 20
0 to 20
0 to 20
20
20
20
0 to 20
0 to 20
20
Decomp.
Decomp.
<10%
31%a
NaH
Ph3P+, Cl−
Ph3P+, Br−
Ph3P+, Br−
Ph3P+, Br−
Ph3P+, Br−
Ph3P+, Br−
Ph3P+, Br−
Ph3P+, Br−
tBuOK
K2CO3/18-C-6
K2CO3/18-C-6
K2CO3/18-C-6
DBU
29%b
26%b
<10%a
15%a
NaHMDS
Amberlite
Sat. K2CO3
17%a
Reflux
0%
a After isomerisation on silica gel. b After irradiation.
=
Scheme 1 Synthesis of combretastatin D2 methyl ether via intramolecular Wittig reaction. (a) Ph3P CHCO2Me, DCM, r.t., overnight, 95%,
(b) HCO2NH4, 10% Pd/C, MeOH, reflux 3 h, 91%, (c) ethylene glycol, PhCH3, pTsOH, 18 h, 75–89%, (d) i) nBuLi, THF, B(OiPr)3, −78 ◦C to r.t.
overnight, ii) 3 N HCl, THF, 2 h, r.t., 70–75% overall, (e) Et3N, Cu(OAc)2, DCM, 4A molecular sieves, r.t., 18 h, 55–70%, (f) allyl alcohol, Bu2SnO, reflux,
20 h, 88–95%, (g) NaBH4, MeOH, r.t., 3 h, 65%, (h) CBr4, PPh3, DCM, r.t, 3 h, 85–90%, (i) O3, DCM, −78 ◦C, then Me2S, DCM, −78 ◦C to r.t., 4 h,
(j) PPh3, MeCN, r.t., 2 d, (k) K2CO3–18-C-6, DCM, slow addition, 20 ◦C, overnight, 26–31% from 11, (l) light, CCl4–CHCl3, overnight, quantitative.
(Figs. 1 and 2). An X-ray crystal structure of compound (14)
confirmed the relationship of the b-hydrogen to the aromatic ring
(Fig. 3)‡.
An alternative approach to (14) is shown in Scheme 2 and
involved an attempted ring-closing metathesis reaction. The
aldehydo-ester (8) was converted into the styrene (16) via a
Wittig reaction (80–87%), and transesterification as before with
allyl alcohol produced the diene (17) (85–95%). Attempted RCM
reactions with Grubbs’ catalyst I under a variety of conditions
(Table 2) provided no products, while reaction with Grubbs’
catalyst II yielded the dimeric product (18). The best conditions
employed 20% of catalysts in toluene at 80 ◦C with a 75%
conversion and 40% yield of the dimer. To date, other metathesis
catalysts (e.g. Schrock catalyst) have not been tried.
‡ Crystal data for C19H18O4: the crystals are small and show very weak
diffraction and hence a low ratio of observed reflections (approx. 25%).
However, we were able to establish the atomic connectivity from this
crystal. M = 310.33, orthorhombic, space group Pbca, a = 13.47(5)
3
˚
˚
˚
˚
A, b = 10.86(4) A, c = 21.40(10) A, U = 3132(22) A , Z = 8, l =
0.092 mm−1. A total of 5614 reflections were measured for the angle range
2 < 2h < 45 and 2022 independent reflections were used in the refinement.
The final parameters were wR2 = 0.2935 and R1 = 0.1041 [I > 2rI].
CCDC reference number 283472. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b513515j
Biological evaluation
Compound (14) was evaluated for antiproliferative activity against
MCF-7 human breast carcinoma, RKO human colon carcinoma
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Table 2 Selected conditions for the RCM
Solvent (%cat.)
DCM (I, 6%)
C/mM
T/◦C
t
Conversion (%)a
5
5
5
5
5
5
5
0.5
2
7.5
10
50
50
80
50
90
80
80
110
80
80
80
20 h
3 d
3 d
2 d
2 d
3 d
2 d
1 h
2 d
2 d
2 d
0
DCM (I, 10% + 50% Ti(OiPr)4)
80% (decomp.)
45% (decomp.)
0
<10
Toluene (I, 20% + 30% Ti(OiPr)4)
DCM (II, 5%)
DCE (II, 10%)
Toluene (II, 10%)
Toluene (II, 20%)
Toluene (II, 10%)
Toluene (II, 10%)
Toluene (II, 10%)
Toluene (II, 10%)
60
75 (40% yield)b
0
<15
37
40
a Conversion determined by analysis of the NMR spectrum of the crude mixture. b Isolated yield.
Fig. 3 X-Ray structure of combretastatin D2 methyl ether.
Fig. 1 NMR spectrum of the cis–trans mixture obtained after attempted
isolation of the trans-isomer on neutralized silica gel.
Fig. 2 NMR spectrum of combretastatin D2 methyl ether.
and CRL 1730 human umbilical endothelial cells. It exhibited
activity in all the cell lines at around 5–10 lM (IC50 values,
see Figs. 4–6). No comparable data is available for (14) or
combretastatin D2 using these cell lines. The other products
produced in this work have not yet been evaluated.
Scheme 2 Attempted synthesis of combretastatin D2 methyl ether via
ring-closing metathesis. a) Ph3P+CH3, Br−, NaHMDS, THF, 0 ◦C to r.t.,
20 h, 80–87%, b) allyl alcohol, Bu2SnO, reflux, 20 h, 85–95%, c) Grubbs’
catalyst II, toluene, 80 ◦C, 30–75% conversion, 30–40% yield.
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dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT),
into a water insoluble formazan precipitate. Exponentially grow-
ing cells (MCF-7 human breast carcinoma, RKO human colon
carcinoma and CRL 1730 human umbilical endothelial cells) were
seeded 24 hours prior to treatment into sterile flat-bottomed 96
well plates, at varied seeding densities determined by their growth
characteristics. Cells were exposed to combretastatin (0.5–100 lM)
for 96 hours. MTT (50 ll of a 2 mg ml−1 solution) was then
added to each well. The plates were incubated for a further
four hours and then the medium and any unconverted MTT was
aspirated from the wells. The remaining formazan precipitate was
dissolved in 100 ll DMSO and the absorbance read at 570 nm
using a Molecular Devices plate reader. IC50 values (compound
concentration that produces a 50% reduction in the growth of
the cells) were determined from plots of absorbance vs. drug
concentration.
Fig. 4 Antiproliferative activity of combretastatin D2 methyl ether
against MCF-7 breast cancer cells.
General experimental procedures
All solvents were dried before use. Acetonitrile, dichloromethane
and methanol were either distilled from calcium hydride under
nitrogen or argon or used after drying on a high pressure alumina
column device (MBRAUN). Tetrahydrofuran was either dried
by distillation in the presence of sodium and benzophenone or
used after drying on a high pressure alumina column device
(MBRAUN). Dry DMF was purchased from Aldrich. Thin layer
R
chromatography was used to monitor reactions using Polygramꢀ
SIL G/UV254 precoated plastic sheets with a 0.2 mm layer of silica
gel containing fluorescent indicator UV254. Plates were visualised
using a 254 nm UV lamp and potassium permanganate stain.
R
Flash column chromatography was carried out using Sorbsilꢀ (or
R
Fluorochemꢀ) C60 silica gel (40–60 mesh) with the eluent or the
Fig. 5 Antiproliferative activity of combretastatin D2 methyl ether
against RKO colon cancer cells.
gradient of eluents reported. NMR spectra were recorded using
Bruker Avance300 or Bruker DRX500 spectrometers. Samples
were dissolved in CDCl3 with tetramethylsilane as a reference. IR
spectra were recorded using a Perkin-Elmer RXI FT-IR system
spectrometer. Mass spectra were recorded on a VG Autospec
spectrometer and were carried out by ASEP (Queen’s University
of Belfast). Elemental analyses were carried out by ASEP (Queen’s
University of Belfast). Melting points were recorded on a Stuart
melting point apparatus and are uncorrected.
X-Ray crystallography
X-Ray crystallographic data for combretastatin D2 methyl ether
were collected using a Bruker SMART diffractometer with
graphite monochromated Mo–Ka radiation. Data were collected
at low temperature, ca. 153 K. Omega/phi scans were employed
for data collection and absorption, Lorentz and polarisation
corrections were applied.
Fig. 6 Antiproliferative activity of combretastatin D2 methyl ether
against human endothelial cells.
The structure was solved by direct methods and ordered non-
hydrogen atoms were refined with anisotropic atomic displacement
parameters. Hydrogen-atom positions were added, and idealised
positions and a riding model with fixed thermal parameters
(Uij = 1.2Ueq for the atom to which they are bonded (1.5 for CH3)),
was used for subsequent refinements. The function minimised for
wR2 was R[w(|Fo|2 − |Fc|2)] with reflection weights w−1 = [r2
|Fo|2 + (g1P)2 + g2P] where P = [max |Fo|2 + 2|Fc|2]/3 for all
F2 and the function minimised for R1 was R[w(|Fo| − |Fc|)]. The
Experimental
In vitro drug sensitivity as determined by MTT dye-exclusion assay
In vitro drug sensitivity was determined as previously described.8
Combretastatin was dissolved in dimethyl sulfoxide (DMSO) to
yield a stock solution of 10 mM. The fraction of viable cells
remaining after drug treatment was determined by the ability of
the cells to metabolise the water-soluble tetrazolium salt, 3-[4,5-
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SAINT9 and SHELXTL10 packages were used for data collection,
reduction, structure solution and refinement. Additional material
available from the Cambridge Structural Database includes atomic
co-ordinates, thermal parameters, remaining bond lengths and
angles, and structure factors (CCDC no. 283472)‡.
added and the mixture was refluxed for 20 h. The cooled reaction
mixture was quenched with saturated NaHCO3 and the product
was extracted with EtOAc (3 × 40 mL). The combined organic
layers were washed with brine and dried with MgSO4. The crude
product was purified by flash chromatography (Et2O–P.E., 1 : 9)
and 2.209 g (89%) of a pale yellow solid wer◦e obtained. Rf: 0.38
(P.E.–Et2O, 9 : 1); mp: 37–38 ◦C (lit.13: 39–40 C); mmax/cm−1: 2886
(C–H), 1595 (Ar), 1082 (C–O–C); 1H NMR dH (CDCl3): 4.00–4.03
(m, 2H, H4 or H5), 4.07–4.10 (2H, m, H4 or H5), 5.76 (s, 1H, H2),
Synthesis of 3-(3-hydroxy-4-methoxyphenyl)-acrylic acid methyl
ester cis and trans. Carbomethoxymethylidene triphenylphos-
phorane (12.09 g, 36.1 mmol, 1.1 eq.) was added to a solution
of isovanillin (5 g, 32.9 mmol) in DCM (110 mL) under argon,
and the mixture was stirred at room temperature for 20 h, then
refluxed for 2 h. The solvent was removed under vacuum and the
crude product was purified by flash chromatography (EtOAc–P.E.,
4 : 6). The cis- and trans-isomers were not separated and 6.94 g
ꢀ
ꢀ
7.33–7.36 (d, 2H, H2 and H6 , Jo = 8.4 Hz), 7.49–7.52 (dd, 2H,
H3 and H5 , Jo = 8.4 Hz, Jm = 1.5 Hz); 13C NMR dC (CDCl3): 137
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(C1 ), 132 (C3 and C5 ), 129 (C2 and C6 ), 124 (C4 ), 103 (C2), 66
(C4 and C5); m/z (EIMS): 229 (M+(81Br), 12), 227 (M+(79Br), 12),
203 (48), 201 (48), 185 (96), 183 (97), 157 (37), 155 (37), 76 (40),
74 (18); mass found 227.978709, C9H9O2Br requires 227.978591.
(quantitative) of a pale yellow solid were obtained. Rf: 0.62 (trans),
−1
=
0.73 (cis) (EtOAc–P.E., 4 : 6); mmax/cm : 3420 (OH), 1700 (C O),
◦
11
Synthesis of 4-formyl phenyl boronic acid (7). 2-(4-Bromo-
=
1511 ◦(C C), 1267 (C–O–C), 1162 (C–O–C); mp: 74–76 C (lit.
1
phenyl)-1,3-dioxolane (3.89 g, 16.9 mmol) was dissolved in dry
72.4 C); H NMR dH (CDCl3): 3.68 (0.82H, s, OMe-cis), 3.79
◦
THF (55 mL) under nitrogen and cooled to −78 C with a dry
(3H, s, OMe-trans), 3.91 (0.82H, s, OMe-cis), 3.92 (3H, s, OMe-
trans), 5.63 (0.28H, s, OH-cis), 5.72 (1H, s, OH), 5.26–5.32 (d, 2H,
ice–acetone bath. n-Butyllithium (2.5 M in hexanes, 10.1 mL,
25.3 mmol, 1.5eq.) was added dropwise and the mixture was
stirred at −78 ◦C for 45 min. Triisopropyl borate (11.7 mL,
50.6 mmol, 3eq.) was added dropwise and the mixture was allowed
to heat slowly to room temperature and was stirred overnight. The
reaction was quenched with 3 N HCl and was stirred at room
temperature for 2 h. The crude product was extracted with ethyl
acetate and the combined organic layers were washed with brine
then dried with MgSO4. The crude product was purified by flash
chromatography (EtOAc–P.E., 5 : 5, then MeOH) and 1.63 g (64%)
of a whit◦e solid were obtained.◦Rf: 0.63 (EtOAc–P.E., 6 : 4); mp:
235–237 C (lit.: 24014 and 252 C15); mmax/cm−1: 3210–3411 (OH),
2927–2846 (CHO), 1670 (CHO), 1507 (Ar), 1343 (B–O); 1H NMR
dH (DMSO): 7.92–7.94 (d, 2H, H2 and H6, Jo = 7.8 Hz), 8.03–8.06
(d, 2H, H3 and H5, Jo = 7.8 Hz), 8.40 (s, 2H, B(OH)2), 10.09 (s,
ꢀ
ꢀ
H3 , Jtrans = 18 Hz), 5.79–5.86 (1.61H, dm, H5 -trans + Ar-cis +
ꢀ
H2-cis, Jo = 9 Hz), 7.01–7.04 (1H, dd, H6 , J = 2.1 Hz, Jo = 9 Hz),
ꢀ
7.13–7.14 (1H, d, H2 , Jm = 2.1), 7.22–7.25 (dd, Ar-cis), 7.32 (0.28,
d, Jm = 1.8), 7.57–7.63 (1H, d, H2, Jtrans = 18 Hz); 13C NMR dC
=
ꢀ
ꢀ
ꢀ
(CDCl3): 168 (C O), 149 (C4 ), 146 (C3), 145 (C3 ), 129 (C1 ), 122
ꢀ
ꢀ
ꢀ
(C6 ), 116 (C2), 113 (C2 ), 111 (C5 ), 56 (OMe), 52 (CO2Me); m/z
(EIMS): 208 (M+, 100), 193 (13), 177 (52), 149 (11), 133 (20), 117
(11), 105 (12), 89 (17), 78 (14); mass found 208.073877, C11H12O4
requires 208.073559; found: C: 63.98, H: 5.66, C11H12O4 requires
C: 63.45, H: 5.81, O: 30.74%.
Synthesis of 3-(3-hydroxy-4-methoxyphenyl)-propionic acid
methyl ester (6). Pd/C (200 mg, 10% of the weight of the
olefin) and ammonium formate (6.06 g, 96 mmol, 10 eq.) were
added to a solution of the alkene (2 g, 9.61 mmol) in methanol
(50 mL). The mixture was refluxed under nitrogen for 3 h. The
cooled reaction mixture was filtered over Celite and the methanol
was removed under vacuum. Chloroform (20 mL) was added to
precipitate the excess of ammonium formate, which was removed
by filtration. After removal of the solvent and short purification
by flash chromatography (EtOAc–P.E., 4 : 6), 1.81 g (90%) of a
1H, CHO); 13C NMR dC (DMSO): 194 (C O), 137 (C4), 135 (C3
=
and C5), 129 (C2 and C6), 116 (C1); m/z (EIMS): 150 (M+, 25), 149
(M+ − H+, 64), 121 (M+ − H+ − CO, 100), 105 (M+ − B(OH)2, 16);
mass found: 150.048187, C7H7BO3 requires 150.048824; found C:
55.41, H: 4.68, C7H7BO3 requires C: 56.07, H: 4.71, B: 7.21, O:
32.01%.
Synthesis of 3-[3-(4-formylphenoxy)-4-methoxyphenyl]-propionic
acid methyl ester (8). The phenol (6) (984 mg, 4.68 mmol) was
dissolved in dry DCM (25 mL) and powdered molecular sieves
(6 g) were added. The boronic acid (7) (1.75 g, 11.7 mmol,
2.5 eq.), copper(II) acetate (935 mg, 5.15 mmol, 1.1 eq.) and
triethylamine (3.26 mL, 23.4 mmol, 5 eq.) were successively added.
The mixture was vigorously stirred at room temperature for 24 h
under ambient atmosphere. The mixture was filtered over Celite
and 5% Na2EDTA was added. The organic layer was separated
and washed with 1 N HCl. The aqueous layer was extracted
with DCM. The combined organic layers were washed with brine
and dried with MgSO4. The crude product was purified by flash
chromatography and 1.005 g (68%) of a pale cream solid were
obtained. Rf: 0.39 (EtOAc–P.E., 2 : 8); mp: 52–54 ◦C; mmax/cm−1:
2839–2852 (CHO), 1735 (CO2Me), 1691 (CHO), 1512 (Ar), 1273–
1230–1126 (C–O–C); 1H NMR dH (CDCl3): 2.59–2.64 (t, 2H, H3,
J = 7.8 Hz), 2.86–2.91 (t, 2H, H2, J = 7.8 Hz), 3.66 (s, 3H, OMe),
white crystalline solid were obtained. Rf: 0.47 (EtOAc–P.E., 3 : ◦7);
−1
=
mmax/cm : 1733 (C O), 1506 (Ar), 1127 (C–O–C); mp: 96–97 C
(lit.12: 94–95 ◦C); 1H NMR dH (CDCl3): 2.57–2.62 (t, 2H, H3, J =
8.1 Hz), 2.83–2.89 (t, 2H, H2, J = 8.1), 3.67 (s, 3H, OMe), 3.86
ꢀ
(s, 3H, OMe), 5.58 (s, 1H, OH), 6.66–6.69 (dd, 1H, H6 , Jm = 1.9
Jo = 8.2), 6.76–6.78 (m, 2H, H2 and H5 ); 13C NMR dC (CDCl3):
ꢀ
ꢀ
=
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
174 (C O), 146 (C4 ), 145 (C3 ), 134 (C1 ), 120 (C6 ), 115 (C5 ), 111
ꢀ
(C2 ), 56 (OMe), 52 (OMe), 36 (C2), 31 (C3); m/z (EIMS): 211
(M+ + H+, 11), 210 (M+, 63), 179 (9), 150 (34), 137 (100), 135 (20),
122 (9), 107 (14), 94 (9), 91 (14), 79 (11), 77 (13), 65 (10); mass
found 210.088452, C11H14O4 requires 210.089209; found C: 63.09,
H: 6.62, C11H14O4 requires C: 62.85, H: 6.71, O: 30.44%.
Synthesis of 2-(4-bromophenyl)-1,3-dioxolane. Ethylene glycol
(1.2 mL, 21.6 mmol, 2eq.) and p-toluenesulfonic acid (catalytic
amount) were dissolved in dry toluene (20 mL) under nitrogen in
a Dean Stark apparatus. The mixture was vigorously refluxed for
1.5 h to remove the water from the ethylene glycol. Bromobenz-
aldehyde (2 g, 10.8 mmol) dissolved in toluene (10 mL) was
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
3.76 (s, 3H, OMe), 6.94–6.99 (m, 4H, H6 , H2 , H6 and H2 ), 7.05–
ꢀ
7.09 (dd, 1H, H5 , Jm = 2.1 Hz, Jo = 8.4 Hz), 7.80–7.83 (dd, 2H,
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H3 and H5 , Jm = 2.1, Jo = 7.2 Hz), 9.90 (s, 1H, CHO); 13C NMR
ꢀꢀ
ꢀꢀ
Synthesis of allyl 3-{3-[4-(bromomethyl)phenoxy]-4-methoxy-
phenyl}propanoate (11). Triphenylphosphine (91 mg, 0.35 mmol,
1.2 eq.) was added in small portions to a solution of the benzylic
alcohol (10) (100 mg, 0.29 mmol) and carbon tetrabromide
(194 mg, 0.58 mmol, 2 eq.) in DCM (1.5 mL) at room temperature.
The resulting mixture was stirred at room temperature for 2 h and
the reaction was quenched with a saturated solution of NaHCO3.
The crude product was extracted with DCM and the combined
organic extracts were washed with brine, then dried with MgSO4.
After evaporation of the solvent, the crude product was purified
by flash chromatography (EtOAc–P.E., 3 : 7), and 147 mg (91%)
=
ꢀꢀ
ꢀ
ꢀ
dC (CDCl3): 191 (CHO), 174 (C O), 164 (C1 ), 150 (C3 ), 143 (C4 ),
134 (C1 ), 132 (C3 and C5 ), 131 (C4 ), 126 (C5 ), 123 (C6 ), 117 (C2
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
and C6 ), 113 (C2 ), 61 (OMe), 52 (OMe), 36 (C2), 30 (C3); m/z
(CIMS): 333 (M+ + H+ + NH4 ), 332 (M+ + NH4 ), 315 (M+ +
H+), 314 (M+), 241, 228, 210; mass found: 314.116638, C18H18O5
requires 314.115424; found C: 68.47, H: 5.83, C18H18O5 requires
C: 68.78, H: 5.77, O: 25.45%.
+
+
Synthesis of allyl 3-[3-(4-formylphenoxy)-4-methoxyphenyl]-
propanoate (9). The ester (8) (150 mg, 0.48 mmol) was dissolved
in allyl alcohol (4 mL), and dibutyltin oxide (24 mg, 0.096 mmol,
0.2 eq.) was added. The mixture was refluxed for 20 h. Saturated
Na2CO3 was added to the cooled reaction mixture and the aqueous
layer was extracted with EtOAc. The combined organic layers
were filtered over Celite and dried with MgSO4. The solvents were
evaporated under vacuum and the crude product was purified
by flash chromatography (EtOAc–P.E., 3 : 7) to give 143 mg
of a yellow oil. mmax/cm−1: 2832 (CHO), 1732 (CO2Me), 1694
of the bromide (11) were obtained. Rf: 0.76 (EtOAc–P.E., 3 : 7);
−1
=
mmax/cm : 1735 (CO2Me), 1607 (C C), 1506 (Ar), 1272–1226–
1168–1126 (C–O–C); 1H NMR dH (CDCl3): 2.61–2.67 (t, 2H, H3,
J = 7.7 Hz), 2.89–2.94 (t, 2H, H2, J = 7.7 Hz), 3.83 (s, 3H, OMe),
=
4.53 (s, 2H, CH2Br), 4.58–4.60 (d, 2H, CH2C C, J = 5.8 Hz),
=
=
5.23–5.33 (m, 2H, C CH2), 5.84–5.97 (ddt, 1H, CH C, Jcis
=
ꢀ
11.0 Hz, Jtrans = 17.0 Hz, J = 5.7 Hz), 6.88–7.04 (m, 5H, H2 ,
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
H6 , H5 , H2 , H6 ), 7.33–7.36 (d, 2H, H3 and H5 , Jo = 8.54 Hz);
13
=
=
ꢀꢀ
ꢀ
ꢀ
(CHO), 1600–1580 (C C), 1512 (Ar), 1273–1230–1126 (C–O–C);
C NMR dC (CDCl3): 173 (C O), 159 (C1 ), 150 (C3 ), 145 (C4 ),
1H NMR dH (CDCl3): 2.59–2.64 (t, 2H, H3, J = 8.0 Hz), 2.85–
=
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀ
134 (C1 ), 133 (C4 ), 132 (CH C), 131 (C3 and C5 ), 125 (C5 ), 122
(C6 ), 119 (C CH2), 117 (C2 and C6 ), 114 (C2 ), 66 (CH2C C), 57
(OMe), 36 (C2), 34 (C3), 30 (CH2Br); m/z (EIMS): 406 (M+(81Br),
=
=
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
2.94 (t, 2H, H2, J = 7.9 Hz), 3.77 (s, 3H, OMe), 4.55–4.60 (d,
=
=
2H, CH2C C, J = 4.6 Hz), 5.19–5.30 (m, 2H, C CH2), 5.83–5.87
+
79
+ 81
=
=
(ddt, 1H, CH C, Jcis = 11.0 Hz, Jtrans = 17.6 Hz, J = 4.6 Hz),
8), 404 (M ( Br), 8), 336 (M ( Br) − CO2CH2CH CH2, 9), 334
+
79
+
=
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
6.94–7.06 (m, 5H, H6 , H2 , H6 , H2 and H5 ), 7.80–7.84 (dd, 2H,
(M ( Br) − CO2CH2CH CH2, 9), 325 (M − Br, 76), 299 (26),
H3 and H5 ), 9.93 (CHO); 13C NMR dC (CDCl3): 191 (CHO), 174
+
=
ꢀꢀ
ꢀꢀ
253 (98), 251 (M − Br − CO2CH2CH CH2, 100), 249 (36), 211
=
=
ꢀꢀ
ꢀ
ꢀ
ꢀ
(C O), 164 (C1 ), 150 (C3 ), 144 (C4 ), 134 (C1 and CH C), 132
(14), 172 (26), 149 (18), 91 (44), 79 (38); mass found: 404.060319,
C20H21BrO4 requires 404.062320.
=
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
(C3 and C5 ), 131 (C4 ), 126 (C5 ), 123 (C6 ), 119 (C CH2), 117
=
ꢀꢀ
ꢀꢀ
ꢀ
(C2 and C6 ), 113 (C2 ), 66 (CH2C C), 56 (OMe), 36 (C2), 30 (C3);
m/z (CIMS): 359 (M+ + H+ + NH4 , 22), 358 (M+ + NH4 , 100),
342 (27), 341 (M+ + H+, 96); mass (calculated for M + H+) found:
341.140213, C20 H21 O5 requires 341.138899.
+
+
Synthesis of 2-oxoethyl-3-{3-[4-(bromomethyl)phenoxy]-4-
methoxyphenyl}propanoate (12). Ozone was bubbled through a
solution of the benzylic bromide (11) (100 mg, 0.25 mmol) in DCM
(15 mL) at −78 ◦C for 2 min. Nitrogen was bubbled through the
resulting blue solution until the colour faded, and dimethyl sulfide
(130 lL, 2.5 mmol, 10 eq.) was added. The mixture was stirred at
Synthesis of allyl 3-{3-[4-(hydroxymethyl)phenoxy]-4-methoxy-
phenyl}propanoate (10). Sodium borohydride (60 mg,
1.58 mmol, 2 eq.) was added to a solution of the aldehyde
(9) (268 mg, 0.79 mmol) in MeOH (2.5 mL) at 0 ◦C and the
resulting mixture was stirred at this temperature for 1.5 h. The
reaction was quenched with 2 N HCl and the crude product
was extracted with EtOAc. The combined organic extracts were
washed with brine and dried over MgSO4. The crude product was
purified by flash chromatography (EtOAc–P.E., 4 : 6) and 106 mg
(65% from ester 8) of a colourless oil were obtained. Rf: 0.42
◦
−78 C for 1 h, then at room temperature for 4 h. The volatiles
were removed under vacuum and the aldehyde (12) (120 mg, 116%
(DMSO)) was used without further purification for the next step.
mmax/cm−1: 2919 (ArH), 1737 (CO2Me + CHO), 1507 (Ar), 1272–
1226–1168–1126–1027 (C–O–C); 1H NMR dH (CDCl3): 2.70–2.73
(t, 2H, H3, J = 7.6 Hz), 2.90–2.93 (t, 2H, H2, J = 7.6 Hz), 3.79 (s,
3H, OMe), 4.49 (s, 2H, CH2Br), 4.63 (s, 2H, CH2CHO), 6.85–6.87
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
(m, 3H, H2 , H2 , H6 , J = 8.5 Hz), 6.89–6.93 (d, 1H, H5 , J = 8.3
(EtOAc–P.E., 4 : 6); mmax/cm−1: 3444 (br, OH), 1734 (CO2Me),
1609 (C C), 1507 (Ar), 1270–1225–1126 (C–O–C); H NMR dH
ꢀ
Hz), 6.99–7.00 (dd, 1H, H6 , Jo = 8.3 Hz, Jm = 1.94 Hz), 7.30–
1
=
7.31 (d, 2H, H3 and H5 , Jo = 8.5 Hz), 9.54 (s, 1H, CHO); 13C
ꢀꢀ
ꢀꢀ
(CDCl3): 2.60–2.65 (t, 2H, H3, J = 7.7 Hz), 2.87–2.92 (t, 2H,
=
ꢀꢀ
ꢀ
NMR dC (CDCl3): 196 (CHO), 172 (C O), 159 (C1 ), 151 (C3 ),
=
H2, J = 7.7 Hz), 3.84 (s, 3H, OMe), 4.57–4.59 (d, 2H, CH2C C,
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀ
145 (C4 ), 134 (C1 ), 132 (C4 ), 131 (C3 and C5 ), 125 (C5 ), 122
=
J = 5.7 Hz), 4.67 (s, 2H, CH2OH), 5.22–5.33 (m, 2H, C CH2),
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
(C6 ), 117 (C2 and C6 ), 113 (C2 ), 69 (CH2CHO), 56 (OMe), 36
(C2), 34 (CH2Br), 30 (C3); m/z (EIMS): 407 (M+(81Br), 22), 406
(M+(81Br) − H+, 98), 405 (M+(79Br), 22), 404 (M+(79Br) − H+, 98),
391 (39), 380 (M+(81Br) − H+ − CO, 46), 378 (M+(79Br) − H+ −
CO, 46), 370 (37), 366 (M+(81Br) − CH2CHO, 43), 364 (M+(79Br) −
CH2CHO), 360 (58), 333 (10), 325 (14), 299 (14), 241 (13), 185 (17),
167 (16), 149 (54), 78 (58); mass found: 405.033638, C19H19BrO5
requires 405.033760.
=
5.84–5.97 (ddt, 1H, CH C, Jcis = 11 Hz, Jtrans = 17 Hz, J = 5.7 Hz),
ꢀ
ꢀ
ꢀ
ꢀꢀ
6.84 (d, 2H, H2 , Jm = 1.7 Hz), 6.93–6.99 (m, 4H, H6 , H5 , H2 ,
H6 ), 7.31–7.34 (d, 2H, H3 and H5 , Jo = 8.4 Hz); 13C NMR dC
ꢀꢀ
ꢀꢀ
ꢀꢀ
=
ꢀꢀ
ꢀ
ꢀ
ꢀ
(CDCl3): 173 (C O), 158 (C1 ), 150 (C3 ), 145 (C4 ), 135 (C1 ),
=
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
134 (C4 ), 133 (CH C), 129 (C3 and C5 ), 125 (C5 ), 121 (C6 ),
119 (C CH2), 118 (C2 and C6 ), 113 (C2 ), 66 (CH2OH), 65
=
ꢀꢀ
ꢀꢀ
ꢀ
+
=
(CH2C C), 56 (OMe), 36 (C2), 30 (C3); m/z (EIMS): 342 (M ,
100), 256 (15), 243 (M+ − CH2 CHCH2 − CO2, 58), 239 (39),
=
197 (11), 153 (14), 137 (26), 134 (17), 121 (13), 105 (17), 77 (25);
mass found: 342.146004, C20H22O5 requires 342.146724; found C:
69.56, H: 6.50, C20H22O5 requires C: 70.16, H: 6.48, O: 23.36%.
Synthesis of (4-{2-methoxy-5-[2-(2-oxoethoxycarbonyl)-ethyl]-
phenoxy}-benzyl)-triphenylphosphonium bromide (13). Triphenyl-
phosphine (312 mg, 1.19 mmol, 1 eq.) was added to a solution of
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the bromide (12) (485 mg, 1.19 mmol) in acetonitrile (6 mL),
and the mixture was stirred for 2 days when a TLC of the
crude mixture showed completion of the reaction. The solvents
were removed under vacuum. A small amount of Et2O was
added, and the crude product was dried under high vacuum to
remove the DMSO, present in the crude starting material. A pale
cream hygroscopic crystalline compound was obtained (800 mg,
quantitative). mmax/cm−1: 2924.4 (ArH), 1734.7 (CO + CHO),
1506.3 (Ar), 1438.5 (PPh), 1272–1194.8, 1112.4–1058.2 (C–O–C);
mp: 81–83 ◦C; 1H NMR dH (CDCl3): 2.66–2.71 (t, 2H, H3, J = 7.4
Hz), 2.85–2.90 (t, 2H, H2, J = 7.4 Hz), 3.77 (s, 3H, OMe), 4.64
(s, 2H, CH2CHO), 5.34–5.38 (d, 2H, CH2P+, 2JPH = 14 Hz), 6.68–
H3, J = 7.8 Hz), 2.87–2.92 (t, 2H, H2, J = 7.8 Hz), 3.12–3.19 (d,
2
3
2H, CH2P, JPH = 21.3 Hz), 3.68–3.72 (d, 6H, P(OMe)2, JPH
=
=
10.8 Hz), 3.82 (s, 3H, OMe), 4.57–4.58 (d, 2H, CH2C C, J =
=
=
5.6 Hz), 5.22–5.32 (m, 2H, C CH2), 5.83–5.96 (ddt, 1H, CH C,
ꢀ
Jcis = 10.7 Hz, Jtrans = 17 Hz, J = 5.6 Hz), 6.84 (d, 1H, H2 , Jm = 1.7
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
Hz), 6.88–7.00 (m, 4H, H6 , H5 , H2 , H6 ), 7.22–7.26 (dd, 2H, H3
and H5 , Jo = 8.54 Hz, Jm = 2.20 Hz); 13C NMR dC (CDCl3): 173
ꢀꢀ
=
=
ꢀꢀ
ꢀ
ꢀ
ꢀ
(C O), 158 (C1 ), 150 (C3 ), 145 (C4 ), 134 (C1 ), 133 (CH C), 131
3
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
(d, C3 and C5 , JPC = 6.6 Hz), 130 (C4 ), 125 (C5 ), 122 (C6 ),
4
=
ꢀꢀ
ꢀꢀ
ꢀ
119 (C CH2), 118 (d, C2 and C6 , JPC = 2.8 Hz), 113 (C2 ),
2
=
66 (CH2C C), 56 (OMe), 53 (P(OMe)2, JPC = 6.9 Hz), 36 (C2),
32–33 (CH2P, 1JPC = 139 Hz), 30 (C3); m/z (EIMS): 434 (M+, 8),
360 (10), 348 (6), 325 (7), 261 (8), 239 (18), 211 (15), 134 (15),
109 (100), 89 (27), 78 (33); mass found: 434.149195, C22H27O7P
requires: 434.149442.
ꢀꢀ
ꢀꢀ
ꢀ
6.71 (d, 2H, H2 , H6 , J = 8.69 Hz), 6.75–6.76 (d, 1H, H2 , J =
ꢀ
1.8 Hz), 6.87–6.90 (d, 1H, H5 , J = 8.3 Hz), 6.93–6.97 (dd, 1H,
ꢀ
ꢀꢀ
ꢀꢀ
H6 , Jo = 8.3 Hz, Jm = 1.8 Hz), 7.00–7.05 (dd, 2H, H3 and H5 ,
Jo = 8.69 Hz, 4JPH = 2.56 Hz), 7.62–7.76 (m, 15H, PPh3), 9.55 (s,
1H, CHO); 13C NMR dC (CDCl3): 196 (CHO), 172 (C O), 159
Synthesis of 3-{3-[4-(dimethoxyphosphorylmethyl)-phenoxy]-4-
methoxyphenyl}-propionic acid 2-oxoethyl ester. Ozone was bub-
bled through a solution of the phosphonate (85 mg, 0.20 mmol) in
DCM (15 mL) at −78 ◦C for 2 min. Nitrogen was bubbled through
the resulting blue solution until the colour faded, and dimethyl
sulfide (300 lL, 4 mmol, 20 eq.) was added. The mixture was stirred
at −78 ◦C for 1 h, then at room temperature for 4 h. The volatiles
were removed under vacuum and the product (85 mg, 98%) was
used without further purification for the next step. mmax/cm−1: 2957
=
+
+
ꢀꢀ
ꢀ
ꢀ
(C1 ), 150 (C3 ), 145 (C4 ), 135, (s, P Ph3p), 134.8–134.9 (d, P Ph3o,
2
3
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
JPC = 9.7 Hz), 134 (C1 ), 132 (C4 ), 132 (d, C3 and C5 , JPC
=
9.84 Hz), 130.5–130.6 (d, P+Ph3m, JPC = 12.6 Hz), 128 (P+Ph3i,
3
1
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
JPC = 34 Hz), 126 (C6 ), 117 (C2 and C6 ), 117 (C2 ), 114 (C5 ),
69 (CH2CHO), 56 (OMe), 36 (C3), 30.5–30.9 (d, CH2P+, JPC
=
1
50.3 Hz), 30 (C3); m/z (FAB+): 607 (M+ + H2O, 17), 589 (M+, 52),
561 (31), 547 (33), 503 (14), 455 (15), 369 (56), 293 (28), 279 (100),
262 (52), 183 (33), 154 (49), 136 (41); mass found: 589.214401,
C37H34O5P+ requires 589.214388.
=
(Ar), 1734.4 (C O), 1507.8 (Ar), 1271–1226–1171–1127 (C–O–C);
1H NMR dH (CDCl3): 2.70–2.76 (t, 2H, H3, J = 7.6 Hz), 2.88–2.95
(t, 2H, H2, J = 7.6 Hz), 3.12–3.19 (d, 2H, CH2P, 2JPH = 21.3 Hz),
Synthesis of allyl 3-{3-[4-(chloromethyl)phenoxy]-4-methoxy-
phenyl}propanoate. Thionyl chloride (44 lL, 0.60 mmol, 2eq.)
was added dropwise to a solution of the alcohol (10) (100 mg,
0.29 mmol) in DCM (1.5 mL) at 0 ◦C. The resulting mixture was
stirred at this temperature for 2 h. The volatile compounds were
removed under vacuum to yield the pure chloride (94 mg, 90%) as
3
3.68–3.71 (d, 6H, P(OMe)2, JPH = 10.8 Hz), 3.82 (s, 3H, OMe),
ꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
4.66 (s, 2H, CH2CHO), 6.85–7.00 (m, 5H, H2 , H6 , H5 , H2 , H6 ),
ꢀꢀ
ꢀꢀ
7.22–7.24 (dd, 2H, H3 and H5 , Jo = 8.54 Hz, Jm = 2.20 Hz),
9.56 (CHO); 13C NMR dC (CDCl3): 196 (CHO), 172 (C O), 158
=
3
ꢀꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
(C1 ), 150 (C3 ), 145 (C4 ), 134 (C1 ), 131 (d, C3 and C5 , JPC = 6.6
4
a pale yellow oil, which was used without further purification. Rf:
ꢀꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
Hz), 130 (C4 ), 125 (C5 ), 122 (C6 ), 118 (d, C2 and C6 , JPC = 3.0
−1
=
2
0.39 (EtOAc–P.E., 2 : 8); mmax/cm : 1735 (CO2Me), 1609 (C C),
ꢀ
Hz), 113 (C2 ), 69 (CH2CHO), 56 (OMe), 53 (P(OMe)2, JPC = 6.9
1507 (Ar), 1270–1225–1126 (C–O–C); 1H NMR dH (CDCl3): 2.62–
2.67 (t, 2H, H3, J = 7.8 Hz), 2.89–2.94 (t, 2H, H2, J = 7.8 Hz),
Hz), 36 (C2), 32–33 (CH2P, 1JPC = 139 Hz), 30 (C3); m/z (EIMS):
436 (M+, 10), 408 (27), 394 (28), 348 (46), 334 (23), 327 (17), 299
(46), 285 (62), 261 (30), 239 (47), 216 (100), 211 (75); mass found:
436.129509, C21H25O8P requires 436.128707.
=
3.83 (s, 3H, OMe), 4.58–4.60 (d, 2H, CH2C C, J = 5.8 Hz), 4.61
=
(s, 2H, CH2Cl), 5.23–5.33 (m, 2H, C CH2), 5.85–5.98 (ddt, 1H,
=
CH C, Jcis = 10.5 Hz, Jtrans = 16.5 Hz, J = 5.8 Hz), 6.88–7.04 (m,
ꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
Synthesis of combretastatin D2 methyl ether (14).
5H, H2 , H6 , H5 , H2 , H6 ), 7.32–7.35 (d, 2H, H3 and H5 , Jo =
7.34 Hz); 13C NMR dC (CDCl3): 173 (C O), 159 (C1 ), 150 (C3 ),
=
ꢀꢀ
ꢀ
Procedure with tBuOK–DMF. Potassium t-butoxide was added
at 0 ◦C to a dilute solution of the phosphonium salt (13) in
DMF. The resulting yellow solution was allowed to warm to room
temperature and was stirred overnight. The reaction was quenched
with saturated NH4Cl and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed several times
with brine, then dried with MgSO4.
=
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
145 (C4 ), 134 (C1 ), 133 (C4 ), 132 (CH C), 130 (C3 and C5 ),
125 (C5 ), 122 (C6 ), 119 (C CH2), 117 (C2 and C6 ), 113 (C2 ), 66
(CH2C C), 56 (OMe), 46 (CH2Cl), 36 (C2), 30 (C3); m/z (EIMS):
=
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
ꢀ
=
362 (M+(37Cl), 36), 360 (M+(35Cl), 100), 325 (M+, 35), 319 (M+, 15),
261 (40), 241 (26), 136 (32), 215 (27), 153 (32), 137 (43), 113 (20),
91 (22); mass found: 360.112236, C20H21ClO4 requires 360.112837;
found C: 65.58, H: 5.72, C20H21ClO4 requires C: 66.57, H: 5.87, O:
17.73, Cl: 9.83%.
General procedure for intramolecular Wittig reactions with
K2CO3–18-C-6. A slurry of potassium carbonate (4 eq.) and 18-
crown-6 (4 eq.) in DCM (15 mL mmol−1) was stirred at room
temperature for 3 h before the slow addition of a solution of
the phosphonium salt (13) via a syringe pump (3 mL h−1). The
resulting yellow solution was stirred overnight and the mixture
was concentrated under vacuum. The reaction was quenched
with saturated NH4Cl, and the aqueous layer was extracted with
DCM. The combined organic extracts were washed with brine,
then dried with MgSO4. The crude product was purified by flash
chromatography (EtOAc–hexane, 2 : 8).
Synthesis of 3-{3-[4-(dimethoxyphosphorylmethyl)-phenoxy]-4-
methoxyphenyl}-propionic acid allyl ester. A solution of the
chloride (94 mg, 0.26 mmol) in trimethyl phosphite (484 mg,
3.9 mmol, 15 eq.) was refluxed for 20 h. The excess of trimethyl
phosphite was co-evaporated with toluene under vacuum, and
103 mg of a yellow oil (91%) were obtained. The crude product was
used without further purification for the next step. mmax/cm−1: 2954
=
(Ar), 1734.7 (C O), 1506.5 (Ar), 1270.8–1227.3–1171.0–1127.2
1
=
(C–O–C, P O and P–O); H NMR dH (CDCl3): 2.60–2.65 (t, 2H,
6 0 | Org. Biomol. Chem., 2006, 4, 54–62
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=
3H, OMe), 4.46–4.48 (d, 2H, CH2–C C, J = 4.6 Hz), 5.07–5.11
(The same procedure was used for the intramolecular Wittig
reactions with the other bases listed in Table 1.)
Combretastatin D2 methyl ether data:
white powder; Rf: 0.43 (EtOAc–hexane, 2 : 8); mmax/cm−1: 2925
=
=
(d, 1H, ArC CH2, Jcis = 11.0 Hz), 5.15–5.22 (m, 2H, CH CH2),
=
5.53–5.59 (d, 1H, ArC CH2, Jtrans = 17.6 Hz), 5.79–5.85 (ddt, 1H,
=
CH C, Jcis = 11.0 Hz, Jtrans = 17.6 Hz, J = 4.6 Hz), 6.55–6.65
=
=
(dd, 1H, ArCH C, Jcis 10.9 Hz, Jtrans = 17.6 Hz), 6.75–6.91 (m,
(ArH), 1732 (C O), 1586, 1519, 1502, 1265–1219–1149–1128 (C–
◦
O–C); mp: 130–131 C (lit.4: 130–132), H NMR dH (CDCl3):
2.28–2.30 (t, 2H, H16, J = 5.4 Hz), 2.88–2.90 (t, 2H, H15, J = 5.4
Hz), 3.95 (s, 3H, OMe), 4.65–4.67 (d, 2H, H2, J = 6.68 Hz), 5.12
(d, 1H, H20, J = 1.99 Hz), 6.03–6.08 (dt, 1H, H3, J1 = 11.1 Hz,
J2 = 6.68 Hz), 6.67–6.69 (dd, 1H, H13, J1 = 8.2 Hz, J2 = 1.99
Hz), 6.82–6.84 (d, 1H, H12, J = 8.2 Hz), 7.09–7.12 (m, 3H, H4 H7
H19), 7.31–7.32 (d, 2H, H6 H18, J = 8.2 Hz); 13C NMR dC (CDCl3):
173 (C17), 156 (C8), 151 (C10), 146 (C11), 138 (C3), 135 (C4), 133
(C5), 129 (C6/C14), 125 (C18), 121 (C7/C19), 122 (C13), 113 (C12),
112 (C20), 59 (C2), 56 (OMe), 31 (C16), 27 (C15); m/z (EIMS): 310
(M+, 100), 253 (16), 239 (35), 183 (37), 149 (39), 123 (44), 115 (36),
112 (21), 97 (23), 91 (20), 83 (26), 71 (37), 57 (65); mass found:
310.120979, C19H18O4 requires 310.120509.
5H, H2 , H5 , H6 , H2 and H6 ), 7.20–7.28 (dd, 2H, H3 and H5 ,
1
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Jm = 2.0 Hz, Jo = 6.9 Hz); 13C NMR dC (CDCl3): 171 (C O), 156
=
=
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(C1 ), 149 (C3 ), 144 (C4 ), 135 (ArC C), 132 (C1 ), 131 (C4 and
=
=
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CH C), 126 (C3 and C5 ), 123 (C5 ), 120 (C6 ), 117 (C CH2),
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116 (C2 and C6 ), 112 (ArCH CH2), 111 (C2 ), 64 (CH2C C),
55 (OMe), 35 (C2), 29 (C3); m/z (CIMS): 339 (M+ + H+); mass
(calculated for M + H+) found: 339.160606, C21H23O4 requires:
339.159634; found C: 74.12, H: 7.02, C21H22O4 requires: C: 74.54,
H: 6.55, O: 18.91%.
Synthesis of the dimer (18). Representative procedure: a solu-
tion of the Grubbs’ catalyst 2nd generation (10 mol%) in toluene
(0.003 M) was added to a solution of the diene (17) in toluene
at 80 ◦C. The resulting brown/pink solution was stirred at 80 ◦C
for 2 days and the solvent was removed under vacuum. The crude
Synthesis of 3-[4-methoxy-3-(4-vinylphenoxy)phenyl] propionic
acid methyl ester (16). A 2 M solution of NaHMDS in THF
(600 lL, 1.2 mmol, 2.5 eq.) was added to a suspension of methyl-
phosphonium bromide (429 mg, 1.2 mmol) in THF (1.5 mL) under
nitrogen at 0 ◦C. After stirring for 1 h at this temperature, a solution
of the aldehyde (8) (150 mg, 0.48 mmol) in THF (1.5 mL) was
added dropwise and the mixture was stirred for 20 h. The reaction
was quenched with water and the crude product was extracted with
EtOAc. The combined organic layers were washed with brine then
dried with MgSO4. After evaporation of the solvents, the crude
product was purified by flash chromatography (EtOAc–P.E., 2
: 8) and 130 mg (87%) of a yellow oil were obtained. Rf: 0.65
product was purified by flash chromatography (EtOAc–P.E., 3 : 7).
−1
=
mmax/cm : 2925.6, 1729.9 (CO2Me), 1602.7 (C C), 1515.6 (Ar),
1506.4 (Ar), 1269.0–1230.2–1123.0 (C–O–C); mp: 216–217 ◦C; 1H
NMR dH (CDCl3): 2.49–2.54 (t, 2H, H16, J = 8.8 Hz), 2.78–2.84
(t, 2H, H15, J = 8.8 Hz), 3.88 (s, 3H, OMe), 4.65–4.67 (dd, 2H,
H2, J1 = 6.9 Hz, J2 = 0.9 Hz), 6.07–6.17 (dt, 1H, H3, Jtrans = 15.9
Hz), 6.58–6.61 (d, 1H, H4, J = 15.9 Hz), 6.59 (d, 1H, H20, Jm
= 1.8 Hz), 6.89–6.91 (dd, 1H, H13, Jo = 8.3 Hz, Jm = 1.8 Hz),
6.92–6.93 (d, 1H, H12, Jo = 8.3 Hz), 6.94–6.97 (dd, 2H, H7, H19,
Jo = 8.7 Hz, Jm = 2.0 Hz), 7.30–7.32 (dd, 2H, H6 and H18, Jo =
8.7 Hz, Jm = 2.0 Hz); 13C NMR dC (CDCl3): 29.3 (C15), 35.3 (C16),
55.1 (OMe), 64.3 (C2), 112 (C13), 117 (C20), 118 (C7 and C19), 121
(C3), 123 (C12), 127 (C6 and C18), 130 (C5), 132 (C14), 134 (C4), 145
(C11), 148 (C10), 156 (C8), 171 (C17); m/z (FAB): 621 (M+, 36), 391
(6), 311 (23), 307 (16), 251 (34), 195 (17), 176 (14), 154 (100), 136
(85), 131 (46), 121 (33); mass found: 620.241592, C38H36O8 requires
620.241019.
(EtOAc–P.E., 2 : 8); mmax/cm−1: 2849–2954 (C–H), 1734 (CO2Me),
1
=
1605 (C C), 1506 (Ar), 1227–1270–1127 (C–O–C); H NMR dH
(CDCl3): 2.47–2.54 (t, 2H, H3, J = 7.5 Hz), 2.76–2.81 (t, 2H, H2,
J = 7.5 Hz), 3.57 (s, 3H, OMe), 3.74 (s, 3H, OMe), 5.07–5.11 (d,
=
=
1H, C CH2, Jcis = 10.9 Hz), 5.55–5.60 (d, 1H, C CH2, Jtrans
=
=
=
17.6 Hz), 6.55–6.65 (dd, 1H, CH C, Jcis = 10.9 Hz, Jtrans
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17.6 Hz), 6.74–6.91 (m, 5H, H6 , H5 , H2 , H3 and H5 ), 7.26–
7.28 (dd, 2H, H2 and H6 , Jm = 1.9 Hz, Jo = 6.8 Hz); 13C NMR dC
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References
=
=
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(CDCl3): 172 (C O), 157 (C1 ), 149 (C3 ), 144 (C4 ), 135 (ArC C),
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132 (C1 ), 131 (C4 ), 127 (C3 and C5 ), 123 (C5 ), 120 (C6 ), 116 (C2
1 A. Cirla and J. Mann, Combretastatins: from natural products to drug
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=
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and C6 ), 112 (ArCH CH2), 111 (C2 ) 55 (OMe), 51 (CO2Me),
35 (C2), 29 (C3); m/z (CIMS): 313 (M+ + H+), 281 (M+ + H+ −
OMe); mass (calculated for M + H+) found: 313.143349, C19H21O4
requires 313.143984.
Synthesis of 3-[4-methoxy-3-(4-vinylphenoxy)phenyl] propionic
acid allyl ester (17). The ester (16) (190 mg, 0.61 mmol) was
dissolved in allyl alcohol (5 mL), and dibutyltin oxide (15 mg,
0.06 mmol, 0.1 eq.) was added. The mixture was refluxed for
20 h. Saturated Na2CO3 was added to the cooled reaction mixture
and the crude product was extracted with EtOAc. The combined
organic layers were filtered over Celite and dried with MgSO4. The
solvents were evaporated under vacuum and the crude product
was purified by flash chromatography (EtOAc–P.E., 2 : 8) to
yield 143 mg (71%) of a yellow oil. Rf: 0.36 (EtOAc–P.E., 1 : 8);
−1
=
mmax/cm : 2918 (C–H), 1734 (CO2Me), 1605 (C C), 1506 (Ar),
1
1227–1270–1127 (C–O–C); H NMR dH (CDCl3): 2.50–2.55 (t,
2H, H3, J = 7.9 Hz), 2.77–2.82 (t, 2H, H2, J = 7.9 Hz), 3.73 (s,
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The Royal Society of Chemistry 2006
©