Synthesis of dihydrodehydrodiconiferyl alcohol: the revised structure of lawsonicin

Abstract

Structural revision of lawsonicin, a natural product of Lawsonia alba, is reported based upon comparison of its spectral data with that of the naturally occurring dihydrobenzo[b]furan neolignan (rac)-trans-dihydrodehydrodiconiferyl alcohol, which is found to be identical. A concise synthesis of dihydrodehydrodiconiferyl alcohol, via Rh₂[S-DOSP]₄-catalysed intramolecular C–H insertion, is described.

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Introduction

Isolation and structural elucidation of lawsonicin (rac-trans-1), a natural product of Lawsonia alba, was reported by one of us in 2003¹ (Fig. 1). Although the assignment of a core 2-aryl-(3′,4′-substituted)-2,3-trans-dihydrobenzo[b]furan is unambiguous, the 5,6-substitution pattern of the benzofuran ring was not conclusively established. Lawsonicin is of unknown biosynthesis;² however, its formula, C₂₀H₂₄O₆, implies that the molecule may derive from dimerisation of coniferyl alcohol (C₁₀H₁₂O₃) and belong to a class of known 2-aryl-2,3-dihydrobenzo[b]furan lignans.

Fig. 1 Structures of racemic 2,3-trans epimers of lawsonicin (1) and dihydrodehydrodiconiferyl alcohol (2).

Lignans constitute a large group of plant secondary metabolites whose biosynthesis involves the dimerisation of phenylpropenes.³ Resonance stabilisation of a radical formed from a (phenylpropene) monolignol facilitates oxidative coupling of radical partners (or electrophilic attack of a single radical upon a second monolignol molecule),⁴ to give structurally diverse products, of which 8-8′-linked lignans are the most common. The established biosynthesis of dehydrodiisoeugenols, via bimolecular coupling of phenoxy radicals derived from laccase-catalysed oxidation of 2-methoxy-4-trans-propenylphenol (isoeugenol),^5,6 is widely applied to 8-5′-linked lignan (neolignan) biosynthesis and can be delineated for dimerisation of coniferyl alcohol (3) (Fig. 2).^6,7

Fig. 2 Schematised biosynthesis of dihydrodehydrodiconiferyl alcohol via 8-5′ radical coupling.

8-5′-Dimerisation leads to an intermediate p-quinone methide, 4,^8,9 intramolecular cyclisation of which installs the dihydrobenzo[b]furan core, prior to an enzymatic allylic alcohol reduction.¹⁰ Dihydrodehydrodiconiferyl alcohol, 2, is furnished in this overall oxidoreductive process. Added structural classes of lignan may be defined, featuring an 8-O4′, 8-3′, 8-2′ or 8-1′ linkage and potentially involving further post-dimerisation modifications. However, the ascribed connectivity of lawsonicin (rac-trans-1) cannot be rationalised within these established pathways for monolignol dimerisation, and we herein propose structural revision of lawsonicin, to the known neolignan, dihydrodehydrodiconiferyl alcohol^11–14 (rac-trans-2,¹⁵Fig. 1).

Results and discussion

A comparison of ¹H and ¹³C NMR data for rac-trans-1 with that reported for rac-trans-2 was first made (Table 1). ¹H NMR data is similar for the two molecules, although small differences in reported chemical shift are difficult to attribute. Integral, multiplicity of resonance and coupling constants are largely consistent, and discrepancies appear only for assignment of the ¹H-11 multiplicity in a spectral region of substantial overlap, and also as disparate assignment of the ¹H-3 multiplicity. Importantly, ⁴J_H4-H6 coupling is not observed for rac-trans-2, indicating that the para-relationship, inferred on this basis between aromatic protons of the benzofuran ring for rac-trans-1, may be mistaken. ¹³C NMR data is an excellent match for the two molecules and aromatic δCH values support the structural assignment of rac-trans-2. Firstly, those of the benzofuran ring: δ¹³CH-4 (116.0 ppm) is expected to be similar for either molecule; however, δ¹³CH-7 (rac-trans-1) is expected at higher field than δ¹³CH-6 (rac-trans-2), and the observed δ¹³CH = 112.8 ppm is consistent with a δ¹³CH-6 (rac-trans-2) assignment.¹⁶ Secondly, the 2-aryl substituent: δ¹³CH-5′ (rac-trans-1) is expected at lower field than δ¹³CH-5′ (rac-trans-2), i.e.δ¹³CH-5′ > δ¹³CH-2′/δ¹³CH-6′ (rac-trans-1) and the ¹³C NMR data support the (2-aryl)-3′-methoxy-4′-hydroxy-substitution pattern of rac-trans-2.

Table 1 Reported ¹H and ¹³C NMR data (CDCl₃)^a of lawsonicin (rac-trans-1)¹ and dihydrodehydrodiconiferyl alcohol (rac-trans-2)¹⁷

Position^b	δ^1H/ppm		δ^13C/ppm^c
	rac-trans-1	rac-trans-2	rac-trans-1	rac-trans-2
a Chemical shifts are referenced to residual solvent (δ^1H) or solvent (δ^13C) for rac-trans-1, and to tetramethylsilane for rac-trans-2.b Refers to the numbering of rac-trans-2 (Fig. 1) and reported assignments for rac-trans-2.^2c Literature chemical shifts for both molecules were reported to 0.1 ppm. Correction of reported chemical shifts, C4 (−0.4 ppm), C10 (+0.8 ppm), C11 (+0.4 ppm) and 3′-OMe (+2.3 ppm) for rac-trans-1,^1 is based upon the actual ^13C NMR spectrum of lawsonicin.
2	5.41 (1H, d, J = 7.0 Hz)	5.54 (1H, d, J = 7.6 Hz)	88.0	87.9
3	3.45 (1H, ddd, J = 8.0, 7.0, 5.0 Hz)	3.60 (1H, q, J = 7.6 Hz)	53.8	53.8
3a	—	—	127.9	127.7
4	6.56 (1H, s)	6.67 (1H, s)	116.1	116.0
5	—	—	133.1	133.0
6	6.60 (1H, s)	6.67 (1H, s)	112.8	112.4
7	—	—	144.2	144.2
7a	—	—	146.7	146.6
7-OMe	3.77 (3H, s)	3.88 (3H, s)	55.9	56.0
8	2.54 (2H, t, J = 7.5 Hz)	2.67 (2H, t, J = 7.3 Hz)	32.0	32.0
9	1.70 (2H, tt, J = 7.5, 6.5 Hz)	1.88 (2H, tt, J = 7.3, 6.6 Hz)	34.5	34.6
10	3.53 (2H, t, J = 6.5 Hz)	3.69 (2H, t, J = 6.6 Hz)	62.3	62.3
11	3.74 (2H, m)	3.90 (2H, d, J = 7.6 Hz)	64.0	63.9
1′	—	—	135.5	135.4
2′	6.85 (1H, d, J = 1.9 Hz)	6.94 (1H, d, J = 1.7 Hz)	108.9	108.8
3′	—	—	146.5	146.6
3′-OMe	3.75 (3H, s)	3.86 (3H, s)	56.0	56.0
4′	—	—	145.7	145.6
5′	6.72 (1H, d, J = 8.1 Hz)	6.87 (1H, d, J = 8.1 Hz)	114.5	114.3
6′	6.77 (1H, dd, J = 8.1, 1.9 Hz)	6.91 (1H, dd, J = 8.1, 1.7 Hz)	119.5	119.4

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In order to model δ¹³CH-5′, -2′ and -6′ of rac-trans-1, we prepared derivative 8, bearing the (2-aryl)-3′,4′-disubstitution pattern of lawsonicin, via a B-ring-substituted flavanone 6. 3′-Methoxy-4′-hydroxyflavanone¹⁸ (6) was prepared via Claisen–Schmidt condensation of vanillin benzyl ether (5) and 2′-hydroxy acetophenone,¹⁹ followed by cyclisation of the resulting hydroxychalcone derivative and benzyl ether hydrogenolysis. Conversion of 6 to a triflic ester was straightforward and oxidative ring contraction²⁰ proceeded to give the expected rac-trans-dihydrobenzo[b]furan derivative 7 in moderate yield.²¹ Low-yielding Heck coupling with methyl acrylate, catalytic hydrogenation and methyl ester reduction steps furnished 8 (Scheme 1).

Scheme 1 Synthesis of a (2-aryl)-3′,4′-disubstituted analogue of lawsonicin. Reagents and conditions: (a) 2′-hydroxyacetophenone, dioxane, 50% w/v KOH (aq.), EtOH, △ (75%); (b) NaOAc, MeOH, △ (70%); (c) H₂ (1 atm), 10% Pd/C, CH₂Cl₂–MeOH, rt (100%); (d) Tf₂O, Et₃N, CH₂Cl₂, −78 °C→rt (67%); (e) HClO₄, trimethyl orthoformate, Tl(NO₃)₂·3H₂O, rt (46%); (f) PdCl₂, PPh₃, methyl acrylate, Et₃N, DMF, 110 °C (30%); (g) H₂ (1 atm), 10% Pd/C, CH₂Cl₂–MeOH, rt (100%); (h) LiAlH₄, Et₂O, rt (94%).

The ¹³C NMR spectrum of model compound 8 (CDCl₃, 400 MHz) correlates poorly with that of lawsonicin; ¹³C-1′, ¹³C-3′ and ¹³CH-5′ appear substantially downfield of the corresponding nuclei in lawsonicin, whilst ¹³C-4′ is upfield (Table 2).

Table 2 ¹³C NMR data^a of (2-aryl)-3′,4′-disubstituted analogue, 8

Position	δ^13C/ppm (8)	Δδ (8vs. rac-trans-1)
a Chemical shifts are referenced to solvent signal (CDCl3).
1′	141.04	+5.54
2′	107.95	−0.95
3′	157.86	+11.36
4′	130.14	−15.56
5′	130.50	+16.0
6′	118.21	−1.0

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Observed differences, Δδ (ppm), are as expected for the comparison of a 3′-methoxy-4′-(3-hydroxypropyl)-aryl substituent with the 3′-methoxy-4′-hydroxy aryl group of dihydrodehydrodiconiferyl alcohol. However, due to small inconsistencies in the ¹³C NMR data reported elsewhere for rac-trans-2,^12,22 we wished to finally verify the structural revision of lawsonicin by comparison of authentic samples.

Although the oxidative rearrangement of a simple flavanone had proved successful (Scheme 1), attempted rearrangement of various 6,7-disubstituted flavanones failed to yield a functionalised 2,3-dihydrobenzo[b]furan core precursor to the reported structure of lawsonicin, and so we wished to avoid the potentially difficult cyclisation of an A-ring-substituted flavanone for preparation of rac-trans-dihydrodehydrodiconiferyl alcohol (rac-trans-2). Therefore, a synthetic approach to rac-trans-2 involving intramolecular C–H insertion of an α-diazoester, as the key step for formation of the dihydrobenzo[b]furan ring, was adopted. The presence of a (pivaloate) protected 5-(3-hydroxypropyl) side chain was detrimental to the yield in preparation of a closely related α-diazo methyl ester,²³ and we chose, therefore, to prepare a 5-bromo-2,3-dihydrobenzo[b]furan, trans-14, in order to later introduce the 3-hydroxypropyl side chain under Pd⁰ catalysis.

Benzyl iodide 10 was prepared in 77% yield from 4-hydroxy-3-methoxybenzyl alcohol. Coupling of 10 with 5-bromo-2-hydroxy-3-methoxybenzaldehyde (9) was carried out, followed by Wittig olefination, enol ether hydrolysis, oxidation and methylation with diazomethane, yielding methyl ester 12. Diazo transfer, using p-acetamidobenzenesulfonyl azide (p-ABSA) and DBU,²⁴ enabled conversion of 12 to 13 in good yield. Catalysis of the intramolecular C–H insertion of 13 was effected upon treatment with Rh₂[S-DOSP]₄,^25,26 and a 1.3 : 1 (trans : cis) ratio of separable 2,3-dihydroxybenzo[b]furan isomers, 14, resulted, also in good yield. Pleasingly, epimerisation of cis-14 to its thermodynamically more stable trans-14 isomer proceeded smoothly upon treatment with sodium methoxide, following Hashimoto's conditions²⁷ (Scheme 2). Sonogashira coupling between trans-14 and prop-2-ynyloxymethyl benzene²⁸ (15) took place to give 16 in good yield.²⁹ Corresponding alkyne reduction and benzyl ether hydrogenolysis was then carried out, and required careful control of conditions in order to avoid dihydrobenzofuran ring-opening. Finally, methyl ester reduction using LiAlH₄ resulted in partial C3-epimerisation³⁰ and dihydrodehydrodiconiferyl alcohol 2 was obtained as a 10 : 3 (2,3-trans : 2,3-cis) diastereomeric product mixture, which we were unable to separate using HPLC (Scheme 3). Nonetheless, direct comparison of ¹H and ¹³C NMR, and EIMS data for the product mixture, 2, with that of lawsonicin, indicated the major isomer rac-trans-2 to be identical to lawsonicin.

Scheme 2 Synthesis of an aryl bromide functionalised precursor to dihydrodehydrodiconiferyl alcohol. Reagents and conditions: (a) KH, 18-crown-6, THF, 60 °C, 1.5 h (98%); (b) ⁿBuLi, (methoxymethyl) triphenylphosphonium chloride, THF, −78 °C→rt, 5 h (70%); (c) Hg(OAc)₂, MeCN–H₂O, rt, 1 h (67%); (d) NaClO₂, 2-methyl-2-butene, NaH₂PO₄·2H₂O, ^tBuOH–H₂O, 0 °C→rt then rt, 14 h (86%); (e) CH₂N₂, Et₂O–THF, −78 °C→rt (95%); (f) p-ABSA, DBU, MeCN, 0 °C→rt then rt, 24 h (90%); (g) Rh₂[S-DOSP]₄ (1.3 mol%), toluene, 0 °C, 2 h (95%); (h) NaOMe, MeOH, −60 °C, 26 h (96%).

Scheme 3 Synthesis of dihydrodehydrodiconiferyl alcohol. Reagents and conditions: (a) Pd(PPh₃)₄ (13 mol%), CuI (0.53 equiv.), Et₃N, 90 °C, 6 h (73%); (b) H₂ (1 atm), 10% Pd/C, MeOH, rt, 3 h; then formic acid, 20 min (97%); (c) LiAlH₄, THF, −15 °C→0 °C, 3 h (100%).

Conclusions

An efficient synthesis of dihydrodehydrodiconiferyl alcohol 2, in twelve linear steps and 16% yield, has been completed, although attenuated by partial C3-epimerisation in the final step. Valuable advantages of the described route are high-yielding diazo transfer and C–H insertion, for formation of the 2,3-dihydrobenzo[b]furan core, and a late-stage Pd⁰-catalysed functionalisation, which permits the synthesis of analogues with varying C5-substitution. Of most importance, the major 2,3-trans-epimer of 2 has identical spectral data to the 2,3-dihydrobenzo[b]furan natural product, lawsonicin, whose earlier reported structure is revised to 2,3-trans-dihydrodehydrodiconiferyl alcohol (rac-trans-2). The identity of (rac-trans-2) as a constituent of Lawsonia alba is confirmed.

Experimental

General techniques

Reagents and solvents were obtained from commercial suppliers and, if necessary, dried and distilled before use. THF was freshly distilled from sodium benzophenone ketal under argon. Toluene was distilled from sodium under argon. Dichloromethane, acetonitrile and triethylamine were freshly distilled from CaH₂. N,N-Dimethylformamide and hexamethyldisilazane were distilled from CaH₂ and stored over 4 Å molecular sieves. Reactions requiring a dry atmosphere were conducted in oven dried glassware under argon. Petrol refers to the fraction boiling between 40 and 60 °C. ¹H and ¹³C NMR spectra were recorded on Bruker 300 or 400 MHz spectrometers. ¹H chemical shifts are reported as values in ppm referenced to residual solvent. The following abbreviations are used to denote multiplicity and may be compounded: s = singlet, d = doublet, t = triplet, q = quartet, qn = quintuplet, sext = sextet. Coupling constants, J, are measured in Hertz (Hz). ¹³C spectra were proton decoupled and referenced to solvent. Signals are reported as s, d, t, q, depending on the number of directly attached protons (0, 1, 2 and 3, respectively), this being determined by DEPT experiments. Infra-red spectra were recorded either as neat solids or as oils on a Bio-Rad Golden Gate ATR FT–IR spectrometer fitted with an ATR accessory. Absorptions are given in wavenumbers (cm⁻¹) and the following abbreviations used to denote peak intensities: s = strong, m = medium, w = weak and/or br (broad). Low resolution mass spectra were recorded on a Micromass platform single quadrupole mass spectrometer in methanol or acetonitrile. Accurate mass spectra were recorded on a double focusing mass spectrometer.

Synthetic procedures

1-(Benzyloxy)-4-(iodomethyl)-2-methoxybenzene (10). To a stirred solution of 4-benzyloxy-3-methoxybenzyl alcohol³¹ (2.33 g, 9.54 mmol) in THF (50 mL) at 0 °C was added I₂ (2.68 g, 10.56 mmol), imidazole (0.85 g, 12.49 mmol) and PPh₃ (2.82 g, 10.75 mmol). The mixture was stirred for 50 min at 0 °C before addition of a solution of Na₂S₂O₃·5H₂O (1.90 g) in H₂O (15 mL) followed by Et₂O (50 mL). The organic phase was separated and the aqueous phase extracted with Et₂O (2 × 50 mL). The combined organic extracts were then washed with Na₂S₂O₃ (15 mL of an 11% w/v aqueous solution) dried over MgSO₄ and concentrated in vacuo. Purification by column chromatography (SiO₂ eluted with petrol/EtOAc, 20 : 1) gave the title compound 10 as white needles (2.70 g, 80%). m.p. 82–83 °C. IR (solid): 2877 (w), 1587 (m), 1513 (m, br), 1257 (s) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 7.43-7.29 (5H, m), 6.90 (1H, d, J = 2.0 Hz), 6.89 (1H, dd, J = 2.0, 8.1 Hz), 6.76 (1H, d, J = 8.1 Hz), 5.13 (2H, s), 4.45 (2H, s), 3.88 (3H, s) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 149.83 (s), 148.17 (s), 137.09 (s), 132.31 (s), 128.76 (d), 128.08 (d), 127.40 (d), 121.19 (d), 113.93 (d), 112.60 (d), 71.15 (t), 56.19 (q), 7.12 (t) ppm. MS (ES+): m/z (%) = 377 (100%) [M+Na]⁺.

2-{[4-(Benzyloxy)-3-methoxybenzyl]oxy}-5-bromo-3-methoxybenzaldehyde (11). To a suspension of KH (0.57 g, 14.12 mmol) in THF (30 mL) was added a solution of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (9) (1.64 g, 7.09 mmol) in THF (10 mL) at 0 °C. The mixture was stirred for 5 min before addition of a solution of benzyl iodide 10 (3.00 g, 8.47 mmol) and 18-crown-6 (1.04 g, 3.93 mmol) in THF (20 mL). The mixture was stirred at 60 °C for 1.5 h before addition of H₂O (20 mL) followed by EtOAc (50 mL). The organic phase was separated and the aqueous phase extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over MgSO₄ and concentrated in vacuo. Purification by column chromatography (SiO₂ eluted with petrol/EtOAc, 12 : 1) gave the title compound 11 as a white solid (3.17 g, 98%). m.p. 126 °C. IR (solid): 2938 (w), 1684 (m), 1475 (m, br), 736 (m, br) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 10.09 (1H, s), 7.48 (1H, d, J = 2.1 Hz), 7.42-7.25 (5H, m), 7.23 (1H, d, J = 2.1 Hz), 6.89 (1H, d, J = 1.3 Hz), 6.81 (1H, t, J = 8.0 Hz), 6.77 (1H, dd, J = 8.0, 1.3 Hz), 5.13 (2H, s), 5.07 (2H, s), 3.92 (3H, s), 3.85 (3H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 188.89 (d), 154.09 (s), 150.28 (s), 149.94 (s), 148.81 (s), 137.07 (s), 131.40 (s), 129.10 (s), 128.73 (d), 128.06 (d), 127.44 (d), 121.89 (d), 121.72 (d), 120.95 (d), 117.23 (s), 113.98 (d), 112.75 (d), 76.63 (t), 71.18 (t), 56.57 (q), 56.22 (q) ppm. MS (ES+): m/z (%) = 479 (98%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₃H₂₁BrNaO₅: 479.0470; found 479.0469.

(E)-2-{[4-(Benzyloxy)-3-methoxybenzyl]oxy}-5-bromo-1-methoxy-3-(2-methoxyvinyl)benzene (17). To a stirred suspension of (methoxymethyl) triphenylphosphonium chloride (3.37 g, 9.84 mmol) in THF (30 mL) was added ⁿBuLi (4.5 mL of a 1.5M solution in hexane, 6.75 mmol). The mixture was stirred at room temperature for 30 min before cooling to −78 °C. A solution of aldehyde 11 (1.50 g, 3.28 mmol) in THF (15 mL) was added and the mixture stirred for 5 h, warming to room temperature during this time. The mixture was then concentrated in vacuo. Purification by column chromatography (SiO₂ eluted with petrol/EtOAc, 15 : 1) gave the title compound 17 as a white solid (1.11 g, 70%). m.p. 87 °C. IR (solid): 2935 (w), 2832 (w), 1638 (m), 1585 (w), 1513 (m), 1463 (s), 1265 (s, br), 736 (m) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (2H, d, J = 7.4 Hz), 7.35 (2H, t, J = 7.4 Hz), 7.29 (1H, t, J = 7.4 Hz), 7.28 (1H, m), 7.03 (1H, d, J = 13.0 Hz), 7.01 (1H, s), 6.86-6.82 (3H, m), 5.87 (1H, d, J = 13.0 Hz), 5.16 (2H, s), 4.84 (2H, s), 3.89 (3H, s), 3.83 (3H, s), 3.55 (3H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 153.90 (s), 150.74 (d), 149.81 (s), 148.28 (s), 143.60 (s), 137.29 (s), 132.81 (s), 130.84 (s), 128.71 (d), 128.00 (d), 127.41 (d), 121.21 (d), 120.11 (d), 116.87 (s), 113.99 (d), 113.03 (d), 112.66 (d), 99.40 (d), 75.02 (t), 71.23 (t), 56.62 (q), 56.21 (q), 56.16 (q) ppm. MS (ES+): m/z (%) = 507 (93%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₅H₂₅BrNaO₅: 507.0783; found 507.0778.

2-{2-[4-(Benzyloxy)-3-methoxybenzyloxy]-5-bromo-3-methoxyphenyl}acetaldehyde (18). To a stirred solution of enol ether 17 (202 mg, 0.42 mmol) in MeCN (20 mL) at 0 °C, was added H₂O (2 mL) and Hg(OAc)₂ (407 mg, 1.28 mmol). The mixture was stirred at room temperature for 1 h before addition of a solution of KI (0.67 g, 4.04 mmol)) in H₂O (20 mL). The resulting white precipitate was collected by filtration. Purification by column chromatography (SiO₂ eluted with petrol/EtOAc, 15 : 1) gave the title compound 18 as a white solid (133 mg, 67%). m.p. 125 °C. IR (solid): 2938 (w), 2727 (w), 1721 (m), 1591 (m), 1514 (m), 1265 (s), 1206 (m), 849(w, br) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 9.53 (1H, t, J = 1.8 Hz), 7.43-7.33 (2H, m), 7.28 (1H, t, J = 7.5 Hz), 7.27–7.20 (2H, m) 6.95 (1H, d, J = 2.5 Hz), 6.85 (1H, d, J = 1.5 Hz), 6.80 (1H, d, J = 2.1 Hz), 6.76 (1H, d, J = 8.1 Hz), 6.73 (1H, dd, J = 8.1, 1.5 Hz), 5.15 (2H, s), 4.90 (2H, s), 3.89 (2 × 3H, s), 3.46 (2H, d, J = 1.8 Hz) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 198.97 (d), 153.68 (s), 149.87 (s), 148.44 (s), 145.53 (s), 137.21 (s), 130.29 (s), 128.81 (s), 128.72 (d), 128.03 (d), 127.44 (d), 125.69 (d), 121.29 (d), 116.66 (s), 115.61 (d), 114.00 (d), 112.64 (d), 74.89 (t), 71.22 (t), 56.28 (q), 56.21 (q), 45.18 (t) ppm. MS (ES+): m/z (%) = 493 (87%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₄H₂₃BrNaO₅: 493.0627; found 493.0621.

2-{2-[4-(Benzyloxy)-3-methoxybenzyloxy]-5-bromo-3-methoxyphenyl}acetic acid (19). To a stirred suspension of aldehyde 18 (588 mg, 1.24 mmol) and 2-methyl-2-butene (4 mL of a 2M solution in THF, 8.0 mmol) in ^tBuOH (45 mL) was added a solution of NaClO₂ (283 mg, 2.5 mmol) and NaH₂PO₄·2H₂O (2 mL of a 1.56M aqueous solution) dropwise at 0 °C. The mixture was warmed to room temperature and stirred for 14 h before addition of EtOAc (30 mL) and brine (15 mL). The organic phase was separated and the aqueous phase extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over MgSO₄ and concentrated in vacuo. Purification by column chromatography (SiO₂ eluted with 2% MeOH in CH₂Cl₂) gave the title compound as a white solid (527 mg, 86%). m.p. 133–134 °C. IR (solid): 2939 (m, br), 1709 (s), 1592 (m), 1514 (s), 736 (w, br) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.42-7.39 (2H, m), 7.25 (2H, t, J = 7.6 Hz), 7.31 (1H, d, J = 7.3 Hz), 6.99–6.96 (2H, m), 6.94 (1H, d, J = 2.0 Hz), 6.81-6.79 (2H, m), 5.13 (2H, s), 4.92 (2H, s), 3.85 (2 × 3H, s), 3.48 (2H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 176.57 (s), 153.51 (s), 149.81 (s), 148.34 (s), 145.37 (s), 137.25 (s), 130.46 (s), 129.74 (s), 128.71 (d), 128.01 (d), 127.48 (d), 125.61 (d), 121.24 (d), 116.41 (s), 115.56 (d), 113.97 (d), 112.56 (d), 74.93 (t), 71.19 (t), 56.24 (q), 56.13 (q), 35.50 (t) ppm. MS (ES−): m/z (%) = 485 (78%) [M − H]⁻. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₄H₂₃BrNaO₆: 509.0576; found 509.0543.

2-{2-[4-(Benzyloxy)-3-methoxybenzyloxy]-5-bromo-3-methoxyphenyl}acetate (12). To a stirred solution of N-methyl-N-nitroso-p-toluenesulfonamide (0.69 g 3.22 mmol) in Et₂O (20 mL) at 0 °C, was added KOH in EtOH (10 mL of a 4% w/v solution) in a flask fitted with reflux condenser. The mixture was warmed to 40 °C and a yellow solution of CH₂N₂ in Et₂O collected, cooling the receiver vessel at −78 °C. This fresh solution of CH₂N₂ in Et₂O was added to a stirred solution of carboxylic acid 19 in THF (10 mL) at −78 °C, via cannula until a yellow colour persisted. The mixture was then warmed to room temperature and stirred for 30 min before addition of Et₂O/AcOH (40 mL of a 9 : 1 mixture) dropwise. Concentration in vacuo gave a yellow residue. Purification by column chromatography (SiO₂ eluted with EtOAc/petrol, 1 : 8→1 : 4) gave the title compound 12 as a white solid (184 mg, 95%). m.p. 98 °C. IR (solid): 2948 (w), 1734 (m), 1591 (m), 697 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.42-7.40 (2H, m), 7.35 (2H, t, J = 7.5 Hz), 7.30 (1H, d, J = 7.0 Hz), 6.96–6.95 (2H, m), 7.00-6.94 (3H, m), 5.15 (2H, s), 4.90 (2H, s), 3.90 (3H, s), 3.86 (3H, s), 3.60 (3H, s), 3.50 (2H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 172.08 (s), 153.97 (s), 150.24 (s), 148.66 (s), 145.91 (s), 137.71 (s), 131.13 (s), 130.84 (s), 129.12 (d), 128.42 (d), 127.85 (d), 126.00 (d), 121.46 (d) 116.77 (s), 115.74 (d), 114.39 (d), 112.87 (d), 75.21 (t), 71.64 (t), 56.65 (q), 56.58 (q), 52.61 (q), 36.00 (t) ppm. MS (ES+): m/z (%) = 523 (73%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na] ⁺ calcd for C₂₅H₂₅BrNaO₆: 523.0732; found 523.0729.

α-Diazoester 13. To a stirred solution of carboxylic ester 12 (55 mg, 0.11 mmol) and 4-acetamidobenzenesulfonyl azide (76 mg, 0.316 mmol) in MeCN (6 mL) at 0 °C, was added DBU (0.12 mL, 0.874 mmol). The mixture was warmed to room temperature and stirred for 24 h before concentration in vacuo. Purification by column chromatography (SiO₂ eluted with EtOAc/petrol, 1 : 8) gave the title compound 13 as a yellow oil (52 mg, 90%). IR (film): 2951 (w), 1701 (m), 1268 (m, br), 740 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.43-7.27 (6H, m), 6.94-6.93 (2H, m), 6.81 (1H, d, J = 8.0 Hz), 6.74 (1H, d (fine splitting), J = 8.0 Hz), 5.13 (2H, s), 4.87 (2H, s), 3.87 (3H, s), 3.86 (3H, s), 3.75 (3H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 165.78 (s), 153.40 (s), 149.75 (s), 148.58 (s), 142.88 (s), 137.24 (s), 129.52 (s), 128.73 (d), 128.02 (d), 127.43 (d), 123.91 (d), 122.47 (s), 121.57 (d), 117.15 (s), 114.67 (d), 113.72 (d), 112.47 (d), 75.69 (t), 71.16 (t), 56.35 (q), 56.04 (q), 52.21 (q) ppm. MS (ES+): m/z (%) = 549 (93%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₅H₂₃BrN₂NaO₆: 549.0637; found 549.0632.

Methyl-2-(4-(benzyloxy)-3-methoxyphenyl)-5-bromo-7-methoxy-[(2,3-cis)- and (2,3-trans)-]dihydro benzofuran-3-carboxylate (rac-cis-14 and rac-trans-14). To a stirred solution of α-diazoester 13 (52 mg, 0.099 mmol) in toluene (2 mL) was added a solution of tetrakis[(S)-(−)-N-(p-dodecylphenylsulfonyl)prolinato] dirhodium(II) (2.5 mg, 1.3 mol%) in toluene (1 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h before warming to room temperature and concentration in vacuo. Purification by column chromatography (SiO₂ eluted with EtOAc/hexane, 1 : 8) gave the title compound, a colourless oil, as a 1.3 : 1 (2,3-trans : 2,3-cis) ratio of isomers, which were separated by column chromatography (SiO₂ eluted with hexane/EtOAc, 10 : 1), (47 mg, 95%). To effect epimerisation of rac-cis-14; to a solution of rac-cis-14 (23 mg, 0.046 mmol) in THF (1 mL) was added NaOMe (0.2 mL of a 1.11 M solution in MeOH, 0.22 mmol) at −60 °C. The mixture was stirred at −60 °C for 26 h before dropwise addition of 0.2 mL of sodium phosphate buffer (1 M, pH 7). The mixture was then warmed to room temperature and EtOAc (10 mL) was added. The organic phase was separated and the aqueous phase extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over MgSO₄ and concentrated in vacuo. Purification by flash column chromatography (SiO₂ eluted with EtOAc/petrol, 1 : 4) gave rac-trans-14 as a white solid (22 mg, 96%). rac-cis-14: m.p. 102–104 °C. IR (solid): 2947 (w), 1736 (m), 1616 (w), 1261 (m, br), 1202 (m, br), 733 (m, br) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.40 (2H, d J = 7.5 Hz), 7.33 (2H, t, J = 7.5 Hz), 7.28 (1H, m), 6.96 (2H, m), 6.89 (1H, m), 6.82 (2H, m), 5.93 (1H, d, J = 9.8 Hz), 5.13 (2H, s), 4.50 (1H, d, J = 9.8 Hz), 3.89 (3H, s), 3.84 (3H, s), 3.22 (3H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 170.05 (s), 149.66 (s), 148.44 (s), 148.32 (s), 145.34 (s), 137.12 (s), 129.43 (s), 128.69 (d), 128.04 (d), 127.48 (d), 120.85 (d), 119.20 (d), 116.18 (d), 113.87 (d), 113.20 (s), 110.29 (d), 87.01 (d), 71.13 (t), 56.47 (q), 56.27 (q), 54.29 (d), 52.13 (q) ppm. MS (ES+): m/z (%) = 521 (99%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₅H₂₃BrNaO₆: 521.0576; found 521.0573. rac-trans-14: m.p. 70 °C (EtOH). IR (solid): 2953 (w), 1738 (m), 1261 (m, br), 733 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (2H, d, J = 7.5 Hz), 7.36 (2H, t, J = 7.5 Hz), 7.29 (1H, m), 7.09 (1H s), 6.95 (1H, s), 6.92 (1H, s), 6.87 (1H, broad d, J = 8.5 Hz), 6.83 (1H, d, J = 8.5 Hz), 6.05 (1H, d, J = 8.3 Hz), 5.14 (2H, s), 4.30 (1H, d, J = 8.3 Hz), 3.86 (2 × 3H, s), 3.81 (3H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 170.75 (s), 150.09 (s), 148.65 (s), 147.32 (s), 145.27 (s), 137.13 (s), 132.73 (s), 128.72 (d), 128.03 (d), 127.38 (d), 126.54 (s), 120.12 (d), 118.83 (d), 116.13 (d), 114.16 (d), 112.83 (s), 110.00 (d), 87.02 (d), 71.18 (t), 56.49 (q), 56.29 (q), 55.78 (d), 53.04 (q) ppm. MS (ES+): m/z (%) = 521 (99%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₅H₂₃BrNaO₆: 521.0576; found 521.0557.

rac-Methyl-2-(4-(benzyloxy)-3-methoxyphenyl)-5-(3-(benzyloxy)prop-1-ynyl)-7-methoxy-(2,3-trans)-dihydrobenzofuran-3-carboxylate (16). A solution of aryl bromide rac-trans-14 (40 mg, 0.08 mmol), Pd(PPh₃)₄ (12 mg, 13 mol%), CuI (8 mg, 53 mol%) and prop-2-ynyloxymethyl benzene (15) (58 mg, 0.40 mmol) in Et₃N (2.5 mL) was stirred at 90 °C for 6 h and then filtered. Concentration of the filtrate in vacuo gave a brown residue, which was purified by column chromatography (EtOAc/hexane, 1 : 9) to give the title compound 16 as a light yellow oil (33 mg, 73%). IR (film): 2951 (w), 1739 (m), 1597 (m), 1225 (s), 741 (m, br) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.42-7.27 (10H, m), 7.11 (1H, s), 6.95 (1H, s), 6.93 (1H, d, J = 1.6 Hz), 6.88 (1H, dd, J = 8.0, 1.6 Hz) 6.84 (1H, d, J = 8.3 Hz), 6.08 (1H, d, J = 8.4 Hz), 5.14 (2H, s), 4.67 (2H, s), 4.39 (2H, s), 4.31 (1H, d, J = 8.4 Hz), 3.87 (3H, s), 3.86 (3H, s), 3.81 (3H, s) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 170.92 (s), 150.09 (s), 148.65 (s), 144.36 (s), 137.71 (s), 137.15 (s), 132.81 (s), 128.73 (d), 128.64 (d), 128.28 (d), 128.06 (d), 128.05 (d), 127.39 (d), 125.31 (s), 121.33 (d), 118.88 (d), 116.35 (d), 115.78 (s), 114.17 (d), 110.04 (d), 87.17 (d), 86.66 (s), 83.62 (s), 71.94 (t), 71.20 (t), 58.20 (t), 56.30 (2 × q), 55.70 (d), 53.01 (q) ppm. MS (ES+): m/z (%) = 587 (100%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₃₅H₃₂NaO₇: 587.2046; found 587.2050.

rac-Methyl-(2,3-trans)-5-(3-hydroxypropyl)-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-2,3-dihydro-1-benzofuran-3-carboxylate (20). A solution of benzyl ether 16 (9 mg, ∼0.016 mmol) in MeOH (5 mL) was treated with 10% Pd/C (14 mg, 0.13 mmol) and stirred under H₂ (1 atm) for 3 h before filtration and concentration of the filtrate in vacuo. The resulting residue was taken into MeOH (5 mL), and fresh 10% Pd/C (14 mg, 0.13 mmol) and formic acid (0.1 mL of a 99% solution) was added. The mixture was then stirred for a further 20 min under H₂ (1 atm) before filtration and concentration of the filtrate in vacuo. Purification by column chromatography (SiO₂ eluted with hexane/EtOAc, 1 : 2) gave the title compound 20 as a colourless oil (6 mg, 97%). IR (film): 2926 (w), 1734 (m, br), 755 (w, br) cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 6.88–6.84 (2H, m), 6.81 (1H, d, J = 8.0 Hz), 6.78 (1H, s), 6.68 (1H, s), 6.02 (1H, d, J = 8.5 Hz), 5.60 (1H, s)), 4.30 (1H, d, J = 8.5 Hz), 3.88 (3H, s), 3.87 (3H, s), 3.80 (3H, s), 3.71 (2H, t, J = 6.5 Hz), 2.69 (2H, m), 1.91 (2H, tt, J = 7.5, 6.5 Hz) ppm. ¹³C NMR (100.5 MHz, CDCl₃): δ = 171.49 (s), 146.84 (s), 146.28 (s), 146.06 (s), 144.46 (s), 135.75 (s), 132.21 (s), 125.32 (s), 119.68 (d), 116.72 (d), 114.60 (d), 113.22 (d), 109.01 (d), 86.98 (d), 62.50 (t), 56.35 (2 × q), 56.23 (d), 52.83 (q), 34.83 (t), 32.21 (t) ppm. MS (ES+): m/z (%) = 411 (100%) [M+Na]⁺. HRMS (ES⁺): m/z [M+Na]⁺ calcd for C₂₁H₂₄NaO₇: 411.1420; found 411.1425.

Dihydrodehydrodiconiferyl alcohol (2). To a suspension of LiAlH₄ (17 mg, 0.448 mmol) in THF (2 mL) at −15 °C was added a solution of methyl ester 20 (3 mg, 0.0077 mmol) in THF (1 mL) dropwise. The mixture was stirred for 3 h, warming from −15 °C to 0 °C during this time. Et₂O (5 mL) and EtOAc (10 mL) were then added and the resulting suspension was warmed to room temperature and stirred for 15 min. H₂O (5 mL) and EtOAc (10 mL) were added and the organic phase separated. The aqueous phase was extracted with EtOAc (2 × 10 mL) and the combined organic phases washed with brine (15 mL), dried over MgSO₄ and concentrated in vacuo. Purification by column chromatography (SiO₂ eluted with hexane/EtOAc, 1 : 2) gave the title compound 2, a colourless oil, as a 10 : 3 (2,3-trans : ¹⁷ 2,3-cis³²) diastereomeric product mixture (3 mg, ca. 100%).

Acknowledgements

This work was supported by the Education Commission Pakistan under the Split Ph.D. program (HAB) and the Chinese Government Scholarship Programme 2007-2009 (JM).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹³C NMR spectra for compounds 2, 8, 10–14, 16–20 and the isolated natural product. See DOI: 10.1039/b918179b

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