Synthesis of dihydrodehydrodiconiferyl alcohol: The revised structure of lawsonicin

Article abstract of DOI:10.1039/b918179b

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. 10.1039/b918179b The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b918179b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of dihydrodehydrodiconiferyl alcohol: the revised structure
of lawsonicin†
Junxiu Meng,a,b Tao Jiang,b Huma Aslam Bhatti,c Bina S. Siddiqui,c Sally Dixon*a and Jeremy D. Kilburn*a
Received 3rd September 2009, Accepted 29th September 2009
First published as an Advance Article on the web 28th October 2009
DOI: 10.1039/b918179b
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.
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
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 conclu-
sively established. Lawsonicin is of unknown biosynthesis;2 how-
ever, 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. 2 Schematised biosynthesis of dihydrodehydrodiconiferyl alcohol
via 8-5¢ radical coupling.
Fig. 1 Structures of racemic 2,3-trans epimers of lawsonicin (1) and
dihydrodehydrodiconiferyl alcohol (2).
8-5¢-Dimerisation leads to an intermediate p-quinone me-
thide, 4,8,9 intramolecular cyclisation of which installs the di-
hydrobenzo[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) can-
not be rationalised within these established pathways for mono-
lignol dimerisation, and we herein propose structural revision of
lawsonicin, to the known neolignan, dihydrodehydrodiconiferyl
alcohol11–14 (rac-trans-2,15 Fig. 1).
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 (phenyl-
propene) 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
aSchool of Chemistry, University of Southampton, Southampton, UK SO17
1BJ. E-mail: sd5@soton.ac.uk, jdk1@soton.ac.uk; Fax: +44(23)80594182;
Tel: +44(23)80593596
bKey Laboratory of Marine Drugs, Ministry of Education of China, School
of Pharmacy, Ocean University of China, Qingdao, 266003, China
Results and discussion
cH.E.J Research Institute of Chemistry, International Centre for Chemical
Sciences, University of Karachi, Karachi-75270, Pakistan
A comparison of 1H and 13C NMR data for rac-trans-1 with
† 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
1
that reported for rac-trans-2 was first made (Table 1). H NMR
data is similar for the two molecules, although small differences
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Table 1 Reported 1H and 13C NMR data (CDCl3)a of lawsonicin (rac-trans-1)1 and dihydrodehydrodiconiferyl alcohol (rac-trans-2)17
1
d H/ppm
rac-trans-1
d
13C/ppmc
Positionb
rac-trans-2
rac-trans-1
rac-trans-2
2
3
3a
4
5
6
7
7a
5.41 (1H, d, J = 7.0 Hz)
5.54 (1H, d, J = 7.6 Hz)
88.0
53.8
87.9
53.8
3.45 (1H, ddd, J = 8.0, 7.0, 5.0 Hz)
3.60 (1H, q, J = 7.6 Hz)
—
—
127.9
116.1
133.1
112.8
144.2
146.7
55.9
127.7
116.0
133.0
112.4
144.2
146.6
56.0
6.56 (1H, s)
—
6.60 (1H, s)
—
6.67 (1H, s)
—
6.67 (1H, s)
—
—
—
7-OMe
3.77 (3H, s)
3.88 (3H, s)
8
9
10
11
2.54 (2H, t, J = 7.5 Hz)
1.70 (2H, tt, J = 7.5, 6.5 Hz)
3.53 (2H, t, J = 6.5 Hz)
3.74 (2H, m)
2.67 (2H, t, J = 7.3 Hz)
1.88 (2H, tt, J = 7.3, 6.6 Hz)
3.69 (2H, t, J = 6.6 Hz)
3.90 (2H, d, J = 7.6 Hz)
—
32.0
34.5
62.3
64.0
135.5
108.9
146.5
56.0
145.7
114.5
119.5
32.0
34.6
62.3
63.9
135.4
108.8
146.6
56.0
145.6
114.3
119.4
1¢
—
2¢
6.85 (1H, d, J = 1.9 Hz)
6.94 (1H, d, J = 1.7 Hz)
3¢
—
—
3¢-OMe
3.75 (3H, s)
—
3.86 (3H, s)
—
4¢
5¢
6¢
6.72 (1H, d, J = 8.1 Hz)
6.87 (1H, d, J = 8.1 Hz)
6.77 (1H, dd, J = 8.1, 1.9 Hz)
6.91 (1H, dd, J = 8.1, 1.7 Hz)
1
a Chemical shifts are referenced to residual solvent (d H) or solvent (d13C) 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-2.2 c 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.
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,
4JH4-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 dCH
values support the structural assignment of rac-trans-2. Firstly,
13
those of the benzofuran ring: d CH-4 (116.0 ppm) is expected
13
to be similar for either molecule; however, d CH-7 (rac-trans-
13
1) is expected at higher field than d CH-6 (rac-trans-2), and
13
13
Scheme 1 Synthesis of a (2-aryl)-3¢,4¢-disubstituted analogue of law-
sonicin. 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 observed d CH = 112.8 ppm is consistent with a d CH-
6 (rac-trans-2) assignment.16 Secondly, the 2-aryl substituent:
13
13
d CH-5¢ (rac-trans-1) is expected at lower field than d CH-5¢
13
13
13
(rac-trans-2), i.e.d CH-5¢ > d CH-2¢/d CH-6¢ (rac-trans-1) and
the 13C NMR data support the (2-aryl)-3¢-methoxy-4¢-hydroxy-
substitution pattern of rac-trans-2.
13
In order to model d CH-5¢, -2¢ and -6¢ of rac-trans-1, we pre-
pared 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 conden-
sation 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).
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).
Observed differences, Dd (ppm), are as expected for the compari-
son 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
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Table 2 13C NMR dataa of (2-aryl)-3¢,4¢-disubstituted analogue, 8
Position
d
13C/ppm (8)
Dd (8 vs. rac-trans-1)
1¢
2¢
3¢
4¢
5¢
6¢
141.04
107.95
157.86
130.14
130.50
118.21
+5.54
-0.95
+11.36
-15.56
+16.0
-1.0
a Chemical shifts are referenced to solvent signal (CDCl3).
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). There-
fore, a synthetic approach to rac-trans-2 involving intramolecular
C–H insertion of an a-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 a-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 treat-
ment 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%).
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,
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
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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.
2-{[4-(Benzyloxy)-3-methoxybenzyl]oxy}-5-bromo-3-methoxy-
benzaldehyde (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,
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, ace-
tonitrile and triethylamine were freshly distilled from CaH2. N,N-
Dimethylformamide and hexamethyldisilazane were distilled from
1
br) cm-1. H NMR (400 MHz, CDCl3): d = 10.09 (1H, s), 7.48
˚
CaH2 and stored over 4 A molecular sieves. Reactions requiring
(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): d = 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.
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
1
spectrometers. H 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.
(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): d = 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): d = 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.
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): d = 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): d = 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-{2-[4-(Benzyloxy)-3-methoxybenzyloxy]-5-bromo-3-methoxy-
phenyl}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
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(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): d = 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):
d = 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.
(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.
a-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): d = 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): d = 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.
2-{2-[4-(Benzyloxy)-3-methoxybenzyloxy]-5-bromo-3-methoxy-
phenyl}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
t
solution in THF, 8.0 mmol) in BuOH (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): d = 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),
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 a-diazoester
13 (52 mg, 0.099 mmol) in toluene (2 mL) was added a solution
of tetrakis[(S)-(-)-N-(p-dodecylphenylsulfonyl)prolinato] dirho-
dium(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):
d = 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): d =
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]+
5.13 (2H, s), 4.92 (2H, s), 3.85 (2 ¥ 3H, s), 3.48 (2H, s) ppm. 13
C
NMR (100.5 MHz, CDCl3): d = 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-methoxy-
phenyl}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),
1
1734 (m), 1591 (m), 697 (w) cm-1. H NMR (400 MHz, CDCl3):
d = 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): d = 172.08 (s), 153.97 (s), 150.24
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calcd for C25H23BrNaO6: 521.0576; found 521.0573. rac-trans-14:
MS (ES+): m/z (%) = 411 (100%) [M+Na]+. HRMS (ES+): m/z
m.p. 70 ◦C (EtOH). IR (solid): 2953 (w), 1738 (m), 1261 (m, br),
[M+Na]+ calcd for C21H24NaO7: 411.1420; found 411.1425.
1
733 (w) cm-1. H NMR (400 MHz, CDCl3): d = 7.41 (2H, d,
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%).
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): d = 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-(benzyl-
oxy)prop-1-ynyl)-7-methoxy-(2,3-trans)-dihydrobenzofuran-3-car-
boxylate (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): d = 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): d = 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.
Acknowledgements
This work was supported by the Education Commission Pakistan
under the Split Ph.D. program (HAB) and the Chinese Govern-
ment Scholarship Programme 2007-2009 (JM).
Notes and references
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rac-Methyl-(2,3-trans)-5-(3-hydroxypropyl)-2-(4-hydroxy-3-
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late (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):
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10 To our knowledge, presumed reductase catalysis of this transformation
has not yet been specified. For a discussion of the overall oxidoreductive
biosynthesis, see: M. Nose, M. A. Bernards, M. Furlan, J. Zajicek, T. L.
Eberhardt and N. G. Lewis, Phytochemistry, 1995, 39, 71.
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1
2926 (w), 1734 (m, br), 755 (w, br) cm-1. H NMR (400 MHz,
CDCl3): d = 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): d = 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.
112 | Org. Biomol. Chem., 2010, 8, 107–113
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3
3
12 P. M. Pauletti, A. R. Araujo, M. C. M. Young, A. M. Giesbrecht and
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3
13 (a) T. Deyama, T. Ikawa, S. Kitagawa and S. Nishibe, Chem. Pharm.
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15 For elucidation of the 2,3-trans-configuration of dihydrodehydrodi-
coniferyl alcohol, see: ref. 13 and 14.
16 Compare the 7-methoxy-5-methyl-2,3-dihydrobenzofuran analogue of
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M. Z. Zhu, Chem. Commun., 2003, 526and the 5-hydroxy-6-methoxy-
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J. W. Benbow and R. Katoch-Rouse, J. Org. Chem., 2001, 66, 4965.
17 Data reproduced in Table 1 is from the isolated natural product, see: ref.
14. Corresponding data and structural verification has been reported
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(a) W. Kurosawa, T. Kan and T. Fukuyama, Synlett, 2003, 7, 1028;
(b) W. Kurosawa, H. Kobayashi, T. Kan and T. Fukuyama, Tetrahedron,
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27 H. Saito, H. Oishi, S. Kitagaki, S. Nakamura, M. Anada and S.
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20 M. S. Khanna, O. V. Singh, C. P. Garg and R. P. Kapoor, Synth.
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29 S. Y. Lin, C. L. Chen and Y. J. Lee, J. Org. Chem., 2003, 68, 2968.
30 C3-Epimerisation of a similar 2,3-cis-precursor to dihydrodehydrodi-
coniferyl alcohol during reduction with NaBH4/MeOH, and stability
to epimerisation under LiAlH4/THF reducing conditions at -60 ◦C,
has been reported, see: ref. 32.
31 J. W. Bode, M. P. Doyle, M. N. Protopova and Q.-L. Zhou, J. Org.
3
21 JH2,H3 Coupling constants are diagnostic in the assignment of rela-
Chem., 1996, 61, 9146.
tive trans-configuration from the 1H NMR spectrum of 7 (CDCl3,
32 S. Garc´ıa-Mun˜oz, L. Jimenez-Gonzalez, M. Alvarez-Corral, M.
Munoz-Dorado and I. Rodriguez-Garcia, Synlett, 2005, 3011.
3
300 MHz); d = 6.27 (1H, d, JH2,H3 = 7.7 Hz, H2), 4.42 (1H,
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 107–113 | 113
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