A new approach to combretastatin D₂

Abstract

A concise and convergent route to combretastatin D₂ is described together with some preliminary biological data.

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Introduction

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 potential 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 µg 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.

Results and discussion

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 triphenylphosphorane, 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.

Table 1 Selected conditions screened for the intramolecular Wittig reactions

X	Solvent	Base	C/mM	T/°C	Yield (for 3 steps)
a After isomerisation on silica gel. b After irradiation.
O=P(OMe)2	DME	tBuOK	2	0 to 20	Decomp.
O=P(OMe)2	DME	NaH	2	0 to 20	Decomp.
Ph3P^+, Cl^−	DMF	tBuOK	2	0 to 20	<10%
Ph3P^+, Br^−	DCM	K2CO3/18-C-6	2	20	31%^a
Ph3P^+, Br^−	DCM	K2CO3/18-C-6	5	20	29%^b
Ph3P^+, Br^−	DCM	K2CO3/18-C-6	10	20	26%^b
Ph3P^+, Br^−	DCM	DBU	2	0 to 20	<10%^a
Ph3P^+, Br^−	THF–DCM	NaHMDS	2.5	0 to 20	15%^a
Ph3P^+, Br^−	THF–DCM	Amberlite	2.5	20	17%^a
Ph3P^+, Br^−	DCM–H2O	Sat. K2CO3	10	Reflux	0%

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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.

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 before and both alkenes exhibited interesting ¹H NMR signals for the aryl hydrogen β 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 (Figs. 1 and 2). An X-ray crystal structure of compound (14) confirmed the relationship of the β-hydrogen to the aromatic ring (Fig. 3)‡.

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.

Fig. 3 X-Ray structure of combretastatin D₂ methyl ether.

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.

Table 2 Selected conditions for the RCM

Solvent (%cat.)	C/mM	T/°C	t	Conversion (%)^a
a Conversion determined by analysis of the NMR spectrum of the crude mixture. b Isolated yield.
DCM (I, 6%)	5	50	20 h	0
DCM (I, 10% + 50% Ti(OiPr)4)	5	50	3 d	80% (decomp.)
Toluene (I, 20% + 30% Ti(OiPr)4)	5	80	3 d	45% (decomp.)
DCM (II, 5%)	5	50	2 d	0
DCE (II, 10%)	5	90	2 d	<10
Toluene (II, 10%)	5	80	3 d	60
Toluene (II, 20%)	5	80	2 d	75 (40% yield)^b
Toluene (II, 10%)	0.5	110	1 h	0
Toluene (II, 10%)	2	80	2 d	<15
Toluene (II, 10%)	7.5	80	2 d	37
Toluene (II, 10%)	10	80	2 d	40

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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.

Biological evaluation

Compound (14) was evaluated for antiproliferative activity against MCF-7 human breast carcinoma, RKO human colon carcinoma and CRL 1730 human umbilical endothelial cells. It exhibited activity in all the cell lines at around 5–10 µM (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.

Fig. 4 Antiproliferative activity of combretastatin D₂ methyl ether against MCF-7 breast cancer cells.

Fig. 5 Antiproliferative activity of combretastatin D₂ methyl ether against RKO colon cancer cells.

Fig. 6 Antiproliferative activity of combretastatin D₂ methyl ether against human endothelial cells.

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-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), into a water insoluble formazan precipitate. Exponentially growing 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 µM) for 96 hours. MTT (50 µl 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 µl 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.

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 chromatography was used to monitor reactions using Polygram® 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. Flash column chromatography was carried out using Sorbsil® (or Fluorochem®) C60 silica gel (40–60 mesh) with the eluent or the 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–K_α 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.

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 (U_ij = 1.2U_eq for the atom to which they are bonded (1.5 for CH₃)), was used for subsequent refinements. The function minimised for wR2 was Σ[w(|F_o|² − |F_c|²)] with reflection weights w⁻¹ = [σ² |F_o|² + (g₁P)² + g₂P] where P = [max |F_o|² + 2|F_c|²]/3 for all F² and the function minimised for R1 was Σ[w(|F_o| − |F_c|)]. The 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)‡.

Synthesis of 3-(3-hydroxy-4-methoxyphenyl)-acrylic acid methyl ester cis and trans. Carbomethoxymethylidene triphenylphosphorane (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 (quantitative) of a pale yellow solid were obtained. Rf: 0.62 (trans), 0.73 (cis) (EtOAc–P.E., 4 : 6); ν_max/cm⁻¹: 3420 (OH), 1700 (C=O), 1511 (C=C), 1267 (C–O–C), 1162 (C–O–C); mp: 74–76 °C (lit.¹¹ 72.4 °C); ¹H NMR δ_H (CDCl₃): 3.68 (0.82H, s, OMe-cis), 3.79 (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, H_3′, J_trans = 18 Hz), 5.79–5.86 (1.61H, dm, H_5′-trans + Ar-cis + H₂-cis, J_o = 9 Hz), 7.01–7.04 (1H, dd, H_6′, J = 2.1 Hz, J_o = 9 Hz), 7.13–7.14 (1H, d, H_2′, J_m = 2.1), 7.22–7.25 (dd, Ar-cis), 7.32 (0.28, d, J_m = 1.8), 7.57–7.63 (1H, d, H₂, J_trans = 18 Hz); ¹³C NMR δ_C (CDCl₃): 168 (C=O), 149 (C_4′), 146 (C₃), 145 (C_3′), 129 (C_1′), 122 (C_6′), 116 (C₂), 113 (C_2′), 111 (C_5′), 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 white crystalline solid were obtained. Rf: 0.47 (EtOAc–P.E., 3 : 7); ν_max/cm⁻¹: 1733 (C=O), 1506 (Ar), 1127 (C–O–C); mp: 96–97 °C (lit.¹²: 94–95 °C); ¹H NMR δ_H (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, H_6′, J_m = 1.9 J_o = 8.2), 6.76–6.78 (m, 2H, H_2′ and H_5′); ¹³C NMR δ_C (CDCl₃): 174 (C=O), 146 (C_4′), 145 (C_3′), 134 (C_1′), 120 (C_6′), 115 (C_5′), 111 (C_2′), 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. Bromobenzaldehyde (2 g, 10.8 mmol) dissolved in toluene (10 mL) was 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 were obtained. Rf: 0.38 (P.E.–Et₂O, 9 : 1); mp: 37–38 °C (lit.¹³: 39–40 °C); ν_max/cm⁻¹: 2886 (C–H), 1595 (Ar), 1082 (C–O–C); ¹H NMR δ_H (CDCl₃): 4.00–4.03 (m, 2H, H₄ or H₅), 4.07–4.10 (2H, m, H₄ or H₅), 5.76 (s, 1H, H₂), 7.33–7.36 (d, 2H, H_2′ and H_6′, J_o = 8.4 Hz), 7.49–7.52 (dd, 2H, H_3′ and H_5′, J_o = 8.4 Hz, J_m = 1.5 Hz); ¹³C NMR δ_C (CDCl₃): 137 (C_1′), 132 (C_3′ and C_5′), 129 (C_2′ and C_6′), 124 (C_4′), 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.

Synthesis of 4-formyl phenyl boronic acid (7). 2-(4-Bromophenyl)-1,3-dioxolane (3.89 g, 16.9 mmol) was dissolved in dry THF (55 mL) under nitrogen and cooled to −78 °C with a dry 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 white solid were obtained. Rf: 0.63 (EtOAc–P.E., 6 : 4); mp: 235–237 °C (lit.: 240¹⁴ and 252 °C¹⁵); ν_max/cm⁻¹: 3210–3411 (OH), 2927–2846 (CHO), 1670 (CHO), 1507 (Ar), 1343 (B–O); ¹H NMR δ_H (DMSO): 7.92–7.94 (d, 2H, H₂ and H₆, J_o = 7.8 Hz), 8.03–8.06 (d, 2H, H₃ and H₅, J_o = 7.8 Hz), 8.40 (s, 2H, B(OH)₂), 10.09 (s, 1H, CHO); ¹³C NMR δ_C (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; ν_max/cm⁻¹: 2839–2852 (CHO), 1735 (CO₂Me), 1691 (CHO), 1512 (Ar), 1273–1230–1126 (C–O–C); ¹H NMR δ_H (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), 3.76 (s, 3H, OMe), 6.94–6.99 (m, 4H, H_6′, H_2″, H_6″ and H_2′), 7.05–7.09 (dd, 1H, H_5′, J_m = 2.1 Hz, J_o = 8.4 Hz), 7.80–7.83 (dd, 2H, H_3″ and H_5″, J_m = 2.1, J_o = 7.2 Hz), 9.90 (s, 1H, CHO); ¹³C NMR δ_C (CDCl₃): 191 (CHO), 174 (C=O), 164 (C_1″), 150 (C_3′), 143 (C_4′), 134 (C_1′), 132 (C_3″ and C_5″), 131 (C_4″), 126 (C_5′), 123 (C_6′), 117 (C_2″ and C_6″), 113 (C_2′), 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. ν_max/cm⁻¹: 2832 (CHO), 1732 (CO₂Me), 1694 (CHO), 1600–1580 (C=C), 1512 (Ar), 1273–1230–1126 (C–O–C); ¹H NMR δ_H (CDCl₃): 2.59–2.64 (t, 2H, H₃, J = 8.0 Hz), 2.85–2.94 (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 (ddt, 1H, CH=C, J_cis = 11.0 Hz, J_trans = 17.6 Hz, J = 4.6 Hz), 6.94–7.06 (m, 5H, H_6′, H_2″, H_6″, H_2′ and H_5′), 7.80–7.84 (dd, 2H, H_3″ and H_5″), 9.93 (CHO); ¹³C NMR δ_C (CDCl₃): 191 (CHO), 174 (C=O), 164 (C_1″), 150 (C_3′), 144 (C_4′), 134 (C_1′ and CH=C), 132 (C_3″ and C_5″), 131 (C_4″), 126 (C_5′), 123 (C_6′), 119 (C=CH₂), 117 (C_2″ and C_6″), 113 (C_2′), 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 allyl 3-{3-[4-(hydroxymethyl)phenoxy]-4-methoxyphenyl}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 (EtOAc–P.E., 4 : 6); ν_max/cm⁻¹: 3444 (br, OH), 1734 (CO₂Me), 1609 (C=C), 1507 (Ar), 1270–1225–1126 (C–O–C); ¹H NMR δ_H (CDCl₃): 2.60–2.65 (t, 2H, H₃, J = 7.7 Hz), 2.87–2.92 (t, 2H, H₂, J = 7.7 Hz), 3.84 (s, 3H, OMe), 4.57–4.59 (d, 2H, CH₂C=C, J = 5.7 Hz), 4.67 (s, 2H, CH₂OH), 5.22–5.33 (m, 2H, C=CH₂), 5.84–5.97 (ddt, 1H, CH=C, J_cis = 11 Hz, J_trans = 17 Hz, J = 5.7 Hz), 6.84 (d, 2H, H_2′, J_m = 1.7 Hz), 6.93–6.99 (m, 4H, H_6′, H_5′, H_2″, H_6″), 7.31–7.34 (d, 2H, H_3″ and H_5″, J_o = 8.4 Hz); ¹³C NMR δ_C (CDCl₃): 173 (C=O), 158 (C_1″), 150 (C_3′), 145 (C_4′), 135 (C_1′), 134 (C_4″), 133 (CH=C), 129 (C_3″ and C_5″), 125 (C_5′), 121 (C_6′), 119 (C=CH₂), 118 (C_2″ and C_6″), 113 (C_2′), 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 allyl 3-{3-[4-(bromomethyl)phenoxy]-4-methoxyphenyl}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%) of the bromide (11) were obtained. Rf: 0.76 (EtOAc–P.E., 3 : 7); ν_max/cm⁻¹: 1735 (CO₂Me), 1607 (C=C), 1506 (Ar), 1272–1226–1168–1126 (C–O–C); ¹H NMR δ_H (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, J_cis = 11.0 Hz, J_trans = 17.0 Hz, J = 5.7 Hz), 6.88–7.04 (m, 5H, H_2′, H_6′, H_5′, H_2″, H_6″), 7.33–7.36 (d, 2H, H_3″ and H_5″, J_o = 8.54 Hz); ¹³C NMR δ_C (CDCl₃): 173 (C=O), 159 (C_1″), 150 (C_3′), 145 (C_4′), 134 (C_1′), 133 (C_4″), 132 (CH=C), 131 (C_3″ and C_5″), 125 (C_5′), 122 (C_6′), 119 (C=CH₂), 117 (C_2″ and C_6″), 114 (C_2′), 66 (CH₂C=C), 57 (OMe), 36 (C₂), 34 (C₃), 30 (CH₂Br); m/z (EIMS): 406 (M⁺(⁸¹Br), 8), 404 (M⁺(⁷⁹Br), 8), 336 (M⁺(⁸¹Br) − CO₂CH₂CH=CH₂, 9), 334 (M⁺(⁷⁹Br) − CO₂CH₂CH=CH₂, 9), 325 (M⁺ − Br, 76), 299 (26), 253 (98), 251 (M⁺ − Br − CO₂CH₂CH=CH₂, 100), 249 (36), 211 (14), 172 (26), 149 (18), 91 (44), 79 (38); mass found: 404.060319, C₂₀H₂₁BrO₄ requires 404.062320.

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 µL, 2.5 mmol, 10 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 aldehyde (12) (120 mg, 116% (DMSO)) was used without further purification for the next step. ν_max/cm⁻¹: 2919 (ArH), 1737 (CO₂Me + CHO), 1507 (Ar), 1272–1226–1168–1126–1027 (C–O–C); ¹H NMR δ_H (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, H_2′, H_2″, H_6″, J = 8.5 Hz), 6.89–6.93 (d, 1H, H_5′, J = 8.3 Hz), 6.99–7.00 (dd, 1H, H_6′, J_o = 8.3 Hz, J_m = 1.94 Hz), 7.30–7.31 (d, 2H, H_3″ and H_5″, J_o = 8.5 Hz), 9.54 (s, 1H, CHO); ¹³C NMR δ_C (CDCl₃): 196 (CHO), 172 (C=O), 159 (C_1″), 151 (C_3′), 145 (C_4′), 134 (C_1′), 132 (C_4″), 131 (C_3″ and C_5″), 125 (C_5′), 122 (C_6′), 117 (C_2″ and C_6″), 113 (C_2′), 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.

Synthesis of (4-{2-methoxy-5-[2-(2-oxoethoxycarbonyl)-ethyl]-phenoxy}-benzyl)-triphenylphosphonium bromide (13). Triphenylphosphine (312 mg, 1.19 mmol, 1 eq.) was added to a solution of 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). ν_max/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 δ_H (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⁺, ²J_PH = 14 Hz), 6.68–6.71 (d, 2H, H_2″, H_6″, J = 8.69 Hz), 6.75–6.76 (d, 1H, H_2′, J = 1.8 Hz), 6.87–6.90 (d, 1H, H_5′, J = 8.3 Hz), 6.93–6.97 (dd, 1H, H_6′, J_o = 8.3 Hz, J_m = 1.8 Hz), 7.00–7.05 (dd, 2H, H_3″ and H_5″, J_o = 8.69 Hz, ⁴J_PH = 2.56 Hz), 7.62–7.76 (m, 15H, PPh₃), 9.55 (s, 1H, CHO); ¹³C NMR δ_C (CDCl₃): 196 (CHO), 172 (C=O), 159 (C_1″), 150 (C_3′), 145 (C_4′), 135, (s, P⁺Ph_3p), 134.8–134.9 (d, P⁺Ph_3o, ²J_PC = 9.7 Hz), 134 (C_1′), 132 (C_4″), 132 (d, C_3″ and C_5″, ³J_PC = 9.84 Hz), 130.5–130.6 (d, P⁺Ph_3m, ³J_PC = 12.6 Hz), 128 (P⁺Ph_3i, ¹J_PC = 34 Hz), 126 (C_6′), 117 (C_2″ and C_6″), 117 (C_2′), 114 (C_5′), 69 (CH₂CHO), 56 (OMe), 36 (C₃), 30.5–30.9 (d, CH₂P⁺, ¹J_PC = 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.

Synthesis of allyl 3-{3-[4-(chloromethyl)phenoxy]-4-methoxyphenyl}propanoate. Thionyl chloride (44 µL, 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 a pale yellow oil, which was used without further purification. Rf: 0.39 (EtOAc–P.E., 2 : 8); ν_max/cm⁻¹: 1735 (CO₂Me), 1609 (C=C), 1507 (Ar), 1270–1225–1126 (C–O–C); ¹H NMR δ_H (CDCl₃): 2.62–2.67 (t, 2H, H₃, J = 7.8 Hz), 2.89–2.94 (t, 2H, H₂, J = 7.8 Hz), 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, J_cis = 10.5 Hz, J_trans = 16.5 Hz, J = 5.8 Hz), 6.88–7.04 (m, 5H, H_2′, H_6′, H_5′, H_2″, H_6″), 7.32–7.35 (d, 2H, H_3″ and H_5″, J_o = 7.34 Hz); ¹³C NMR δ_C (CDCl₃): 173 (C=O), 159 (C_1″), 150 (C_3′), 145 (C_4′), 134 (C_1′), 133 (C_4″), 132 (CH=C), 130 (C_3″ and C_5″), 125 (C_5′), 122 (C_6′), 119 (C=CH₂), 117 (C_2″ and C_6″), 113 (C_2′), 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%.

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. ν_max/cm⁻¹: 2954 (Ar), 1734.7 (C=O), 1506.5 (Ar), 1270.8–1227.3–1171.0–1127.2 (C–O–C, P=O and P–O); ¹H NMR δ_H (CDCl₃): 2.60–2.65 (t, 2H, H₃, J = 7.8 Hz), 2.87–2.92 (t, 2H, H₂, J = 7.8 Hz), 3.12–3.19 (d, 2H, CH₂P, ²J_PH = 21.3 Hz), 3.68–3.72 (d, 6H, P(OMe)₂, ³J_PH = 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, J_cis = 10.7 Hz, J_trans = 17 Hz, J = 5.6 Hz), 6.84 (d, 1H, H_2′, J_m = 1.7 Hz), 6.88–7.00 (m, 4H, H_6′, H_5′, H_2″, H_6″), 7.22–7.26 (dd, 2H, H_3″ and H_5″, J_o = 8.54 Hz, J_m = 2.20 Hz); ¹³C NMR δ_C (CDCl₃): 173 (C=O), 158 (C_1″), 150 (C_3′), 145 (C_4′), 134 (C_1′), 133 (CH=C), 131 (d, C_3″ and C_5″, ³J_PC = 6.6 Hz), 130 (C_4″), 125 (C_5′), 122 (C_6′), 119 (C=CH₂), 118 (d, C_2″ and C_6″, ⁴J_PC = 2.8 Hz), 113 (C_2′), 66 (CH₂C=C), 56 (OMe), 53 (P(OMe)₂, ²J_PC = 6.9 Hz), 36 (C₂), 32–33 (CH₂P, ¹J_PC = 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.

Synthesis of 3-{3-[4-(dimethoxyphosphorylmethyl)-phenoxy]-4-methoxyphenyl}-propionic acid 2-oxoethyl ester. Ozone was bubbled 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 µL, 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. ν_max/cm⁻¹: 2957 (Ar), 1734.4 (C=O), 1507.8 (Ar), 1271–1226–1171–1127 (C–O–C); ¹H NMR δ_H (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, ²J_PH = 21.3 Hz), 3.68–3.71 (d, 6H, P(OMe)₂, ³J_PH = 10.8 Hz), 3.82 (s, 3H, OMe), 4.66 (s, 2H, CH₂CHO), 6.85–7.00 (m, 5H, H_2′, H_6′, H_5′, H_2″, H_6″), 7.22–7.24 (dd, 2H, H_3″ and H_5″, J_o = 8.54 Hz, J_m = 2.20 Hz), 9.56 (CHO); ¹³C NMR δ_C (CDCl₃): 196 (CHO), 172 (C=O), 158 (C_1″), 150 (C_3′), 145 (C_4′), 134 (C_1′), 131 (d, C_3″ and C_5″, ³J_PC = 6.6 Hz), 130 (C_4″), 125 (C_5′), 122 (C_6′), 118 (d, C_2″ and C_6″, ⁴J_PC = 3.0 Hz), 113 (C_2′), 69 (CH₂CHO), 56 (OMe), 53 (P(OMe)₂, ²J_PC = 6.9 Hz), 36 (C₂), 32–33 (CH₂P, ¹J_PC = 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.

Synthesis of combretastatin D₂ methyl ether (14).
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.
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).

(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); ν_max/cm⁻¹: 2925 (ArH), 1732 (C=O), 1586, 1519, 1502, 1265–1219–1149–1128 (C–O–C); mp: 130–131 °C (lit.⁴: 130–132), ¹H NMR δ_H (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 δ_C (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.

Synthesis of 3-[4-methoxy-3-(4-vinylphenoxy)phenyl] propionic acid methyl ester (16). A 2 M solution of NaHMDS in THF (600 µL, 1.2 mmol, 2.5 eq.) was added to a suspension of methylphosphonium 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 (EtOAc–P.E., 2 : 8); ν_max/cm⁻¹: 2849–2954 (C–H), 1734 (CO₂Me), 1605 (C=C), 1506 (Ar), 1227–1270–1127 (C–O–C); ¹H NMR δ_H (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, J_cis = 10.9 Hz), 5.55–5.60 (d, 1H, C=CH₂, J_trans = 17.6 Hz), 6.55–6.65 (dd, 1H, CH=C, J_cis = 10.9 Hz, J_trans = 17.6 Hz), 6.74–6.91 (m, 5H, H_6′, H_5′, H_2′, H_3″ and H_5″), 7.26–7.28 (dd, 2H, H_2″ and H_6″, J_m = 1.9 Hz, J_o = 6.8 Hz); ¹³C NMR δ_C (CDCl₃): 172 (C=O), 157 (C_1″), 149 (C_3′), 144 (C_4′), 135 (ArC=C), 132 (C_1′), 131 (C_4″), 127 (C_3″ and C_5″), 123 (C_5′), 120 (C_6′), 116 (C_2″ and C_6″), 112 (ArCH=CH₂), 111 (C_2′) 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); ν_max/cm⁻¹: 2918 (C–H), 1734 (CO₂Me), 1605 (C=C), 1506 (Ar), 1227–1270–1127 (C–O–C); ¹H NMR δ_H (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, 3H, OMe), 4.46–4.48 (d, 2H, CH₂–C=C, J = 4.6 Hz), 5.07–5.11 (d, 1H, ArC=CH₂, J_cis = 11.0 Hz), 5.15–5.22 (m, 2H, CH=CH₂), 5.53–5.59 (d, 1H, ArC=CH₂, J_trans = 17.6 Hz), 5.79–5.85 (ddt, 1H, CH=C, J_cis = 11.0 Hz, J_trans = 17.6 Hz, J = 4.6 Hz), 6.55–6.65 (dd, 1H, ArCH=C, J_cis 10.9 Hz, J_trans = 17.6 Hz), 6.75–6.91 (m, 5H, H_2′, H_5′, H_6′, H_2″ and H_6″), 7.20–7.28 (dd, 2H, H_3″ and H_5″, J_m = 2.0 Hz, J_o = 6.9 Hz); ¹³C NMR δ_C (CDCl₃): 171 (C=O), 156 (C_1″), 149 (C_3′), 144 (C_4′), 135 (ArC=C), 132 (C_1′), 131 (C_4″ and CH=C), 126 (C_3″ and C_5″), 123 (C_5′), 120 (C_6′), 117 (C=CH₂), 116 (C_2″ and C_6″), 112 (ArCH=CH₂), 111 (C_2′), 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 solution of the Grubbs’ catalyst 2^nd 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 product was purified by flash chromatography (EtOAc–P.E., 3 : 7). ν_max/cm⁻¹: 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 δ_H (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, J_trans = 15.9 Hz), 6.58–6.61 (d, 1H, H₄, J = 15.9 Hz), 6.59 (d, 1H, H₂₀, J_m = 1.8 Hz), 6.89–6.91 (dd, 1H, H₁₃, J_o = 8.3 Hz, J_m = 1.8 Hz), 6.92–6.93 (d, 1H, H₁₂, J_o = 8.3 Hz), 6.94–6.97 (dd, 2H, H₇, H₁₉, J_o = 8.7 Hz, J_m = 2.0 Hz), 7.30–7.32 (dd, 2H, H₆ and H₁₈, J_o = 8.7 Hz, J_m = 2.0 Hz); ¹³C NMR δ_C (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.

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Footnotes

† This paper is dedicated to Professor Steve Ley on the occasion of his 60th birthday.

‡ 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) Å, b = 10.86(4) Å, c = 21.40(10) Å, U = 3132(22) ų, Z = 8, µ = 0.092 mm⁻¹. A total of 5614 reflections were measured for the angle range 2 < 2θ < 45 and 2022 independent reflections were used in the refinement. The final parameters were wR2 = 0.2935 and R1 = 0.1041 [I > 2σI]. CCDC reference number 283472. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b513515j

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