Oxidative cyclisation of cis- and trans-2,3-dibenzylbutyrolactones using ruthenium tetra(trifluoroacetate)

Article abstract of DOI:10.1016/S0040-4020(01)00273-3

A series of cis- and trans-2,3-dibenzylbutyrolactones have been synthesised and subjected to oxidative cyclisation using ruthenium tetra(trifluoroacetate) affording dibenzocyclooctadiene lactones belonging to the stegane and isostegane series of lignans.

Full text of DOI:10.1016/S0040-4020(01)00273-3

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 4015±4022
Oxidative cyclisation of cis- and trans-2,3-dibenzylbutyrolactones
using ruthenium tetraꢀtri¯uoroacetate)
Robert S. Wardp and David D. Hughes
University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK
Received 14 December 2000; revised 2 February 2001; accepted 22 February 2001
AbstractÐAseries of cis- and trans-2,3-dibenzylbutyrolactones have been synthesised and subjected to oxidative cyclisation using
ruthenium tetra)tri¯uoroacetate) affording dibenzocyclooctadiene lactones belonging to the stegane and isostegane series of lignans.
q 2001 Elsevier Science Ltd. All rights reserved.
1.Introduction
other methods of oxidative coupling, and Schlessinger5 and
Cambie6 have reported the synthesis of )7) and )8) from )5)
and )6), respectively, using the vanadium and thallium
reagents )Scheme 1). The synthesis of an aza analogue of
isopicrostegane has also been reported utilising VOF3 as the
oxidising reagent.7
The biaryl unit is a key building block in the structures of a
large number of important natural products.1 Steganone )1),
steganol )2), steganacin )3) and steganangin )4) are of inter-
est owing to their antitumour and antiviral properties.2
The use of ruthenium tetra)tri¯uoroacetate) was ®rst
reported by Landais and Robin8 for the synthesis of the
isosteganes )11) and )12) from the butyrolactones )9) and
)10) )Scheme 2). Improved yields were obtained when the
ruthenium reagent was employed.
The aims of the work described in this paper were ®rstly to
study the cyclisation, using ruthenium tetra)tri¯uoro-
acetate), of trans-2,3-dibenzylbutyrolactones in which a
phenolic group is located in either the 2- or the 3-benzyl
group, and secondly to extend the scope of the methodology
to cis-2,3-dibenzylbutyrolactones.
2.Results and discussion
Successful methods that have been reported for the
construction of the biaryl bond in such compounds include
oxidative coupling using heavy metal oxidants, the use of
hypervalent iodine reagents, and dehydrogenation by `high
potential' quinones. In this paper we report the results of our
work on the oxidative cyclisation of cis- and trans-2,3-
dibenzylbutyrolactones using ruthenium tetra)tri¯uoro-
acetate). Other oxidants that have been reported for such
purposes include vanadium)V) oxyhalides and thallium)III)
tri¯uoroacetate )TTFA). Thus, Kupchan3 and Taylor and
McKillop4 have reported that vanadium)V) oxyhalides and
TTFAgive signi®cant improvements when compared with
The trans-compounds )6) and )13±15) were ®rst studied.
Compound )6)6 was treated with ruthenium tetra)tri¯uoro-
acetate), generated in situ from 2 equivalents of RuO2´2H2O
in a mixture of TFA±TFAA containing a trace of BF 3´Et2O.
The mixture was stirred at room temperature for 24 h,
affording a single product in 89% yield. The structure of
the product was identi®ed as )8) by comparison with the
data reported in the literature.6
The dibenzylbutyrolactones )13±15)9 were similarly treated
with ruthenium tetra)tri¯uoroacetate) and stirred at room
temperature for 24 h affording )16±18),9 as single dia-
stereoisomers, in 78±82% yield )Scheme 3). The structures
Keywords: lignans; lactones; oxidation; ruthenium and compounds.
Corresponding author. Tel.: 144-1792-295274; fax: 144-1792-295747;
e-mail: r.s.ward@swan.ac.uk
of )16±18) were assigned by analysis of their H and 13C
1
p
NMR spectra. The aliphatic region of the 1H NMR spectrum
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00273-3

4016
R. S. Ward, D. D. Hughes / Tetrahedron 57 %2001) 4015±4022
Scheme 1. Reagents: )a) VOF3, TFA; )b) TTFA, BF3´Et2O.
Scheme 2. Reagents: )a) RuO2´2H2O, TFA±TFAA, BF3´Et2O; )b) Tl2O3, TFA±TFAA, BF3´Et2O; )c) VOF3, TFA±TFAA.
was in each case retained while the aromatic region was
greatly simpli®ed, showing just four singlets for )16) and
)17) and ®ve singlets for )18), consistent with the
dibenzocyclooctadiene skeleton. The stereochemistry
about the biaryl bond was established by comparison with
the data for )8). Thus, zero coupling was observed between
H-5a and H-6 and between H-8b and H-7, characteristic of
the isostegane series,10±12 while the coupling between H-6
and H-7 [13.2 Hz for )16) and )17), and 13.3 Hz for )18)],
indicated that the lactone was trans-fused.10±12
for C-6 and C-7 in the 13C NMR spectra with those for
compound )8) )Fig. 1). The values for )16) )46.9 and
50.4), )17) )46.9 and 50.1), and )18) )46.8 and 50.4) were
almost identical to those for )8) )46.8 and 50.0), and differed
from those of the stegane isomer )19), which come at
39.7 ppm )C-6) and 43.4 ppm )C-7), respectively.13
The position of the phenolic group in )16±18) was
con®rmed by examination of the H NMR spectra, and by
1
n.O.e experiments. The signal due to H-9 in compound )8) is
moved down®eld )6.74 ppm) due to its close proximity to
the carbonyl group. Evidence for this assignment comes
from comparison with the corresponding tetrahydrofuran,14
Further proof that the dibenzocyclooctadienes belonged to
the isostegane series came from a comparison of the signals
Scheme 3. Reagents: )a) RuO2´2H2O, TFA±TFAA, BF3´Et2O )80±90%).

R. S. Ward, D. D. Hughes / Tetrahedron 57 %2001) 4015±4022
4017
compounds )16±18) showed that the phenolic group was
located at C-11, C-10 and C-11, respectively. The observed
n.O.e effects between H-5b and H-7 and H-5a and H-4 were
also consistent with the structures of )16±18), as shown in
Fig. 2.
The oxidation of the dibenzylbutyrolactones )20±22),15
under the same reaction conditions, afforded the dibenzo-
cyclooctadienes )23±25), as single diastereoisomers, in
81±87% yield )Scheme 4).
Evidence for their structures was based on comparison with
the spectral data for the previous compounds. The aliphatic
regions of the NMR spectra were retained, while the
aromatic regions were simpli®ed, showing four singlets,
corresponding to H-1, H-4, H-9 and H-12. Evidence that
the dibenzocyclooctadienes possessed an isostegane struc-
ture came from the zero coupling observed between H-5a
and H-6 and H-8b and H-7, while the signals due to C-6 and
C-7 were almost identical to those for the previous
compounds, resonating at 47.1 and 50.1, 47.0 and 50.1,
and 46.9 and 50.3 ppm, respectively. The coupling between
H-6 and H-7 was in line with previous results, and was
found to be 13.2 Hz for all 3 compounds, indicating that
the lactone was trans-fused.
Figure 1.
The position of the phenolic moiety in each compound was
con®rmed from observations similar to those for compounds
)8), )16±18), including n.O.e experiments. Other evidence
came from the IR spectra, which showed the necessary
g-lactone and hydroxyl peaks, while high-resolution mass
spectrometry con®rmed molecular formulas as C21H22O6 for
compounds )23) and )24) and C20H20O6 for compound )25).
Figure 2.
where the corresponding proton appears at 6.65 ppm. The
presence of a hydroxyl group also results in a down®eld
shift of the proton located next to it, with the result that in
When yatein )5)5 was treated with ruthenium tetra)tri¯uoro-
acetate) and stirred at room temperature for 24 h, the
dibenzocyclooctadiene )7) was obtained, as a single dia-
stereoisomer, in 59% yield )Scheme 5). The structure of
the product was established by comparison with the data
for )8), )16±18), and )23±25), and with the data given in
the literature.5
1
the H NMR spectrum of )16), where the hydroxyl group
is located at C-11, two singlets, corresponding to H-9
and H-12, appear down®eld, while in the 1H NMR
spectrum of )17), where the hydroxyl group is located at
C-10, only one singlet, corresponding to H-9, is moved
down®eld.
1
The H NMR spectrum of )18) re¯ected the fact that it has
It is of interest to note, however, that Robin et al.16 reported
that oxidation of )5), using ruthenium tetra)tri¯uoroacetate),
gave only degradation products, probably due to the clea-
vage of the methylenedioxy group. The same authors16
reported that when the reaction was carried out using
TTFA, the isostegane )7) was obtained, but in only 30%
only one substituent located on the phenolic ring. However,
the presence of two doublets, at 6.63 and 6.75 ppm, and a
double doublet at 7.11 ppm is consistent with the hydroxyl
group being located at C-11. Furthermore, the observation
of a clear n.O.e between H-9 and H-8b in all three
Scheme 4. Reagents: )a) RuO2´2H2O, TFA±TFAA, BF3´Et2O )81±87%).

4018
R. S. Ward, D. D. Hughes / Tetrahedron 57 %2001) 4015±4022
Scheme 5. Reagents: )a) RuO2´2H2O, TFA±TFAA, BF3´Et2O )59%).
yield. Schlessinger et al.5 reported that the reaction of )5)
with vanadium oxy¯uoride, in TFAand BF 3´Et2O, afforded
)7) in 65±70% yield, while the use of thallium)III) oxide as
the oxidising agent, in TFAand BF ´Et2O, afforded )7) in
3
65% yield.
using the route reported by Moritani et al.15,18
Treatment of )28±30) with ruthenium tetra)tri¯uoroacetate)
at room temperature for 24 h afforded, in each case, a
mixture of products. Puri®cation by ¯ash chroma-
tography afforded one major fraction containing two
components having almost identical Rf values. Further
attempts to separate these compounds by chroma-
tography failed. The 13C NMR spectra showed two car-
bonyl peaks, in each case, which led to the conclusion
that both the stegane and isostegane isomers had been
formed )Scheme 6).
Cambie et al.17 reported that oxidation of )5) in neat TFA,
without BF3´Et2O, afforded deoxypodophyllotoxin )26) as
the major product. Treatment of the isostegane )7) with
thallium)III) oxide in TFAcleaved the methylenedioxy
group to give the o-benzoquinone )27) in 61% yield. In
the current work )27) was not isolated, even though the
yield of )7) was only 59%.
Further evidence that oxidative coupling had taken place
came from the high-resolution mass spectra which
con®rmed the molecular formulas of the products.
1
It was evident from the aromatic regions in the H NMR
spectra, that coupling of the phenolic dibenzylbutyro-
lactones )29) and )30) afforded a mixture of the stereo-
isomers in an approximate 1:1 ratio, whereas coupling of
the non-phenolic dibenzylbutyrolactone )28) afforded the
stereoisomers in a 1.6:1 ratio.
The coupling of )28±30) is in marked contrast to the
®ndings of Robin et al.16 who reported that the
coupling of )37) using ruthenium tetra)tri¯uoroacetate)
and TTFAafforded only the stegane isomer ) 38)
)Scheme 7).
The cis-dibenzylbutyrolactones )28±30) were synthesised
Scheme 6. Reagents: )a) RuO2´2H2O, TFA±TFAA, BF3´Et2O )80±91%).

R. S. Ward, D. D. Hughes / Tetrahedron 57 %2001) 4015±4022
4019
Scheme 7. Reagents: )a) RuO2´2H2O, TFA±TFAA, BF3´Et2O; )b) TTFA, BF3´Et2O.
3.Experimental
d, J 13.2 Hz, H-5a), 2.35 )1 H, dd, J 9.7, 13.2 Hz, H-5b),
2.26 )1 H, dd, J 9.1, 13.4 Hz, H-8b), 2.17 )1 H, m, H-6), 2.09
)1 H, dd, J 9.1, 13.2 Hz, H-7); dC )100.6 MHz, CDCl3)
176.7 )C-14), 148.9 )C-3), 148.7 )C-2), 147.3 )C-11),
147.2 )C-10), 132.4 )C-12a), 132.0 )C-8a), 131.7 )C-4a),
130.9 )C-1a), 114.2 )C-9), 114.0 )C-12), 112.0 )C-4),
111.7 )C-7), 70.1 )C-13), 56.1 )4£OMe), 50.2 )C-7), 46.9
)C-6), 34.3 )C-5), 32.1 )C-8); m/z: )EI) 385 )4), 384 )M1,
18), 207 )4%); )CI) 402 )M1NH41, 100), 372 )16), 152 )9),
117 )33%); [Found: )M1NH4)1 402.1923, C22H24O6
requires 402.1917].
1H and 13C NMR spectra were recorded on a Bruker AC 400
instrument and were run in CDCl3 unless otherwise stated.
Mass spectra were recorded on a VG 12-250 low-resolution
quadrupole instrument or on a VG Micromass Quattro II
instrument. Accurate mass measurements were made
using either a ZAB-E high-resolution double-focusing
instrument or a Finnigan Mat 900 instrument. IR spectra
were recorded on a Perkin±Elmer FT 1725X spectrometer
and were measured using KBr discs unless otherwise stated.
Melting points were recorded on an Electrothermal 9100
apparatus and are uncorrected.
3.2. Preparation of trans-11-hydroxy-6-ꢀhydroxymethyl)-
2,3,10-trimethoxydibenzo[1a,4a:8a,12a]cyclooctadiene-7-
carboxylic acid lactone ꢀ16) using ruthenium tetra-
ꢀtri¯uoroacetate)
Flash chromatography was performed on silica gel )Fisons
Matrex, 35±70m). Ether and dichloromethane were dried by
passing them down an alumina column and distillation from
calcium hydride. Ethyl acetate was dried over anhydrous
potassium carbonate and distilled from calcium hydride.
TFE was dried by distillation from calcium hydride and
stored over molecular sieves.
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )13)9 )0.152 g,
0.409 mmol). Puri®cation via ¯ash chromatography on
silica using a gradient elution of CH2Cl2/EtOAc )80:20),
followed by crystallisation from EtOAc, afforded )16) as a
white solid )0.121 g, 80%), m.p. 240±2438C )Lit.9 245±
2508C); IR )®lm): 3438 cm21 )OH), 1770 cm21 )g-lactone);
dH )400 MHz, CDCl3) 6.73 )1 H, s, H-12), 6.72 )1 H, s,
H-9), 6.61 )1 H, s, H-4), 6.60 )1 H, s, H-1), 5.50 )1 H, s,
OH), 4.34 )1 H, dd, J 6.7, 8.4 Hz, H-13a), 3.86 )3 H, s,
OMe), 3.85 )3 H, s, OMe), 3.78 )3 H, s, OMe), 3.73 )1 H,
dd, J 8.4, 11.2 Hz, H-13b), 3.09 )1 H, d, J 13.4 Hz, H-8a),
2.59 )1 H, d, J 13.2 Hz, H-5a), 2.35 )1 H, dd, J 9.7, 13.2 Hz,
H-5b), 2.25 )1 H, dd, J 9.2, 13.4 Hz, H-8b), 2.17 )1 H, m,
H-6), 2.08 )1 H, dd, J 9.2, 13.2 Hz, H-7); dC )100.6 MHz,
CDCl3) 177.4 )C-14), 147.5 )C-3), 146.2 )C-2), 145.5
)C-11), 142.9 )C-10), 133.8 )C-12a), 132.5 )C-8a), 131.9
)C-4a), 130.6 )C-1a), 116.9 )C-12), 114.2 )C-9), 112.0
)C-4), 111.1 )C-7), 70.1 )C-13), 56.1 )OMe), 56.0
)2£Me), 50.4 )C-7), 46.9 )C-6), 34.3 )C-5), 32.1 )C-8);
m/z: )EI) 371 )20), 370 )M1, 100), 151 )24), 137 )25%);
)CI) 388 )M1NH41, 100), 370 )11), 358 )4%); [Found:
)M1NH4)1 388.1764, C21H22O6 requires 388.1760].
3.1. Preparation of trans-6-ꢀhydroxymethyl)-2,3,10,11-
tetramethoxydibenzo[1a,4a:8a,12a]cyclooctadiene-7-
carboxylic acid lactone ꢀ8) using ruthenium tetra-
ꢀtri¯uoroacetate)
To a stirred solution of RuO2´2H2O )0.064 g, 0.480 mmol,
2 mol equiv.), in CH2Cl2 )15 ml), TFA)1 ml) and TFAA
)0.5 ml) was added, at 2108C, a solution of )6)6 )0.091 g,
0.240 mmol) in CH2Cl2 )10 ml) followed immediately by
BF3´Et2O )0.2 ml). The mixture was stirred at room
temperature overnight before addition of a cold saturated
solution of NaHCO3 )10 ml). The mixture was then passed
through a short celite column to remove the metallic salts.
The organic layer was decanted and the aqueous layer was
extracted with EtOAc )4£40 ml). The combined organic
extracts were washed with brine )2£40 ml), water
)2£40 ml), dried )MgSO4), ®ltered and evaporated in
vacuo to afford an off-white foam. Puri®cation via ¯ash
chromatography on silica and elution with CH2Cl2/EtOAc
)90:10), followed by crystallisation from diethyl ether,
afforded )8) as a white solid )0.083 g, 90%), m.p.
208±2108C )Lit.16 212±2138C); IR )®lm): 1795 cm21
)g-lactone); dH )400 MHz, CDCl3) 6.74 )1 H, s, H-9),
6.63 )2 H, s, H-1,4), 6.62 )1 H, s, H-12), 4.35 )1 H, dd, J
6.7, 8.5 Hz, H-13a), 3.87 )3 H, s, OMe), 3.86 )3 H, s, OMe),
3.80 )3 H, s, OMe), 3.78 )3 H, s, OMe), 3.73 )1 H, dd, J 8.5,
11.3 Hz, H-13b), 3.11 )1 H, d, J 13.4 Hz, H-8a), 2.60 )1 H,
3.3. Preparation of trans-10-hydroxy-6-ꢀhydroxymethyl)-
2,3,11-trimethoxydibenzo[1a,4a:8a,12a]cyclooctadiene-7-
carboxylic acid lactone ꢀ17) using ruthenium tetra-
ꢀtri¯uoroacetate)
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )14)9 )0.126 g,
0.339 mmol). Puri®cation via ¯ash chromatography on

4020
R. S. Ward, D. D. Hughes / Tetrahedron 57 %2001) 4015±4022
silica using a gradient elution of CH2Cl2/EtOAc )80:20),
followed by crystallisation from EtOAc, afforded )17) as
a white solid )0.103 g, 82%), m.p. 213±2158C )Lit.9
210±2158C); IR )®lm): 3434 cm21 )OH), 1771 cm21
)g-lactone); dH )400 MHz, CDCl3) 6.80 )1 H, s, H-9),
6.63 )1 H, s, H-12), 6.62 )1 H, s, H-4), 6.61 )1 H, s, H-1),
5.63 )1 H, s, OH), 4.32 )1 H, dd, J 6.7, 8.4 Hz, H-13a), 3.86
)3 H, s, OMe), 3.81 )3 H, s, OMe), 3.80 )3 H, s, OMe), 3.70
)1 H, dd, J 8.4, 11.1 Hz, H-13b), 3.06 )1 H, d, J 13.5 Hz,
H-8a), 2.60 )1 H, d, J 13.3 Hz, H-5a), 2.34 )1 H, dd, J 9.7,
13.3 Hz, H-5b), 2.20 )1 H, dd, J 9.2, 13.5 Hz, H-8b), 2.13 )1
H, m, H-6), 2.06 )1 H, dd, J 9.2, 13.2 Hz, H-7); dC
)100.6 MHz, CDCl3) 176.5 )C-14), 148.7 )C-3), 147.3
)C-2), 145.5 )C-11), 144.9 )C-10), 132.8 )C-12a), 132.5
)C-8a), 132.0 )C-4a), 131.0 )C-1a), 114.9 )C-12), 114.3
)C-9), 113.3 )C-4), 112.0 )C-7), 70.0 )C-13), 56.1 )3£
OMe), 50.1 )C-7), 46.9 )C-6), 34.2 )C-5), 31.7 )C-8); m/z:
)EI) 371 )25), 370 )M1, 100), 281 )15), 207 )84), 191 )11),
165 )15%); )CI) 388 )M1NH41, 100), 372 )8), 358 )7%);
[Found: )M1NH4)1 388.1759, C21H22O6 requires
388.1760].
)OH), 1770 cm21 )g-lactone); [Found: C, 67.41; H, 6.00.
C21H22O6 requires C, 68.10; H, 5.99%]; dH )400 MHz,
CDCl3) 6.72 )1 H, s, H-9), 6.71 )1 H, s, H-1), 6.61 )1 H,
s, H-12), 6.60 )1 H, s, H-4), 5.53 )1 H, s, OH), 4.33 )1 H, dd,
J 6.7, 8.4 Hz, H-13a), 3.87 )3 H, s, OMe), 3.85 )3 H, s,
OMe), 3.78 )3 H, s, OMe), 3.72 )1 H, dd, J 8.4, 11.0 Hz,
H-13b), 3.09 )1 H, d, J 13.6 Hz, H-8a), 2.58 )1 H, d, J
13.3 Hz, H-5a), 2.33 )1 H, dd, J 9.6, 13.3 Hz, H-5b), 2.26
)1 H, dd, J 9.1, 13.6 Hz, H-8b), 2.16 )1 H, m, H-6), 2.09 )1
H, dd, J 9.1, 13.2 Hz, H-7); dC )100.6 MHz, CDCl3) 176.8
)C-14), 147.1 )C-3,11), 146.3 )C-10), 143.9 )C-2), 133.3
)C-12a), 132.2 )C-8a), 131.7 )C-4a), 130.4 )C-1a), 117.3
)C-1), 114.0 )C-9), 111.3 )C-4,12), 70.1 )C-13), 56.1
)OMe), 56.0 )2£OMe), 50.1 )C-7), 47.1 )C-6), 34.3 )C-5),
32.1 )C-8); m/z: )EI) 371 )22), 370 )M1, 100), 271 )9), 165
)11), 149 )14%); )CI) 388 )M1NH41, 100), 358 )9), 279
)19), 170 )15), 152 )21), 116 )35%); [Found: )M1NH4)1
388.1765, C21H22O6 requires 388.1760].
3.6. Preparation of trans-3-hydroxy-6-ꢀhydroxymethyl)-
2,10,11-trimethoxydibenzo[1a,4a: 8a,12a]cyclooctadiene-
7-carboxylic acid lactone ꢀ24) using ruthenium
tetraꢀtri¯uoroacetate)
3.4. Preparation of trans-11-hydroxy-6-ꢀhydroxymethyl)-
2,3-dimethoxydibenzo[1a,4a:8a,12a]cyclooctadiene-7-
carboxylic acid lactone ꢀ18) using ruthenium tetra-
ꢀtri¯uoroacetate)
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )21)15 )0.128 g,
0.344 mmol). Puri®cation via ¯ash chromatography on
silica and elution with CH2Cl2/EtOAc )98:2), followed by
crystallisation from EtOAc, afforded )24) a white gum
)0.103 g, 81%); IR )®lm): 3438 cm21 )OH), 1770 cm21
)g-lactone); dH )400 MHz, CDCl3) 6.73 )1 H, s, H-9),
6.70 )1 H, s, H-4), 6.62 )1 H, s, H-12), 6.61 )1 H, s, H-1),
5.56 )1 H, s, OH), 4.31 )1 H, dd, J 6.7, 8.5 Hz, H-13a), 3.85
)3 H, s, OMe), 3.81 )3 H, s, OMe), 3.80 )3 H, s, OMe), 3.71
)1 H, dd, J 8.5, 11.0 Hz, H-13b), 3.09 )1 H, d, J 13.4 Hz,
H-8a), 2.56 )1 H, d, J 13.2 Hz, H-5a), 2.29 )1 H, dd, J 9.5,
13.2 Hz, H-5b), 2.26 )1 H, dd, J 9.3, 13.4 Hz, H-8b), 2.16 )1
H, m, H-6), 2.06 )1 H, dd, J 9.3, 13.2 Hz, H-7); dC
)100.6 MHz, CDCl3) 176.8 )C-14), 148.9 )C-2), 147.2
)C-3), 145.3 )C-11), 144.9 )C-10), 132.5 )C-12a), 132.1
)C-8a), 131.9 )C-4a), 131.7 )C-1a), 114.9 )C-9), 114.1
)C-4), 113.4 )C-12), 111.7 )C-1), 70.1 )C-13), 56.1 )3£
OMe), 50.1 )C-7), 47.0 )C-6), 33.9 )C-5), 32.1 )C-8); m/z:
)EI) 371 )21), 370 )M1, 100), 207 )12), 165 )16), 152 )16
%); )CI) 388 )M1NH41, 100), 372 )10), 279 )11), 152 )15),
116 )27%); [Found: )M1NH4)1 388.1761, C21H22O6
requires 388.1760].
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )15)9 )0.118 g,
0.346 mmol). Puri®cation via ¯ash chromatography on
silica using a gradient elution of CH2Cl2/EtOAc )80:20),
followed by crystallisation from EtOAc, afforded )18) as a
white solid )0.094 g, 80%), m.p. 194±1958C )Lit.9 190±
1928C); IR )®lm): 3400 cm21 )OH), 1745 cm21 )g-lactone);
dH )400 MHz, CDCl3) 7.11 )1 H, d, J 8.3 Hz, H-9), 6.75 )1
H, dd, J 2.7, 8.3 Hz, H-10), 6.63 )1 H, d, J 2.7 Hz, H-12),
6.61 )1 H, s, H-4), 6.60 )1 H, s, H-1), 5.23 )1 H, s, OH), 4.33
)1 H, dd, J 6.7, 8.5 Hz, H-13a), 3.86 )3 H, s, OMe), 3.79 )3
H, s, OMe), 3.72 )1 H, dd, J 8.5, 11.3 Hz, H-13b), 3.15 )1 H,
d, J 13.6 Hz, H-8a), 2.60 )1 H, d, J 13.2 Hz, H-5a), 2.34 )1
H, dd, J 9.8, 13.2 Hz, H-5b), 2.24 )1 H, dd, J 9.3, 13.6 Hz,
H-8b), 2.13 )1 H, m, H-6), 2.05 )1 H, dd, J 9.3, 13.3 Hz,
H-7); dC )100.6 MHz, CDCl3) 176.6 )C-14), 152.8 )C-11),
148.8 )C-3), 147.2 )C-2), 142.4 )C-8a), 132.3 )C-12a), 131.7
)C-4a), 130.5 )C-1a), 130.4 )C-9), 117.6 )C-10), 115.3
)C-12), 114.0 )C-4), 112.0 )C-1), 70.0 )C-13), 56.0
)2£OMe), 50.4 )C-7), 46.8 )C-6), 34.2 )C-5), 31.5 )C-8);
m/z: )EI) 341 )21), 340 )M1, 100), 255 )26), 181 )25), 165
)33), 152 )29%); )CI) 358 )M1NH41, 100), 342 )15), 328
)12), 116 )34%); [Found: )M1NH4)1 358.1654, C20H20O5
requires 358.1654].
3.7. Preparation of trans-3,11-dihydroxy-6-ꢀhydroxy-
methyl)-2,10-dimethoxydibenzo[1a,4a: 8a,12a]cyclo-
octadiene-7-carboxylic acid lactone ꢀ25) using
ruthenium tetraꢀtri¯uoroacetate)
3.5. Preparation of trans-2-hydroxy-6-ꢀhydroxymethyl)-
3,10,11-trimethoxydibenzo[1a,4a:8a,12a]cyclo-
octadiene-7-carboxylic acid lactone ꢀ23) using
ruthenium tetraꢀtri¯uoroacetate)
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )22)15 )0.127 g,
0.355 mmol). Puri®cation via ¯ash chromatography on
silica and elution with CH2Cl2/EtOAc )98:2), followed by
crystallisation from EtOAc, afforded )25) as white crystals
)0.110 g, 87%), m.p. 208±2118C; IR )®lm): 3431 cm21
)OH), 1781 cm21 )g-lactone); dH )400 MHz, CDCl3) 6.71
)1 H, s, H-9), 6.70 )1 H, s, H-12), 6.67 )1 H, s, H-4), 6.57 )1
H, s, H-1), 5.60 )2 H, br.s, OH), 4.30 )1 H, dd, J 6.6, 8.5 Hz,
H-13a), 3.85 )3 H, s, OMe), 3.78 )3 H, s, OMe), 3.70 )1 H,
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )20)15 )0.109 g,
0.293 mmol). Puri®cation via ¯ash chromatography on
silica and elution with CH2Cl2/EtOAc )98:2), followed by
crystallisation from EtOAc, afforded )23) as a white solid
)0.092 g, 85%), m.p. 232±2348C; IR )®lm): 3435 cm21

R. S. Ward, D. D. Hughes / Tetrahedron 57 %2001) 4015±4022
4021
dd, J 8.5, 11.0 Hz, H-13b), 3.08 )1 H, d, J 13.6 Hz, H-8a),
2.54 )1 H, d, J 13.1 Hz, H-5a), 2.28 )1 H, dd, J 9.6, 13.1 Hz,
H-5b), 2.23 )1 H, dd, J 9.2, 13.6 Hz, H-8b), 2.15 )1 H, m,
H-6), 2.05 )1 H, dd, J 9.2, 13.2 Hz, H-7); dC )100.6 MHz,
CDCl3) 176.9 )C-14), 146.4 )C-11), 145.3 )C-2), 144.9
)C-10), 143.7 )C-3), 133.4 )C-12a), 131.7 )C-8a), 131.6
)C-4a), 131.5 )C-1a), 117.0 )C-12), 114.9 )C-4), 113.7
)C-9), 111.2 )C-1), 70.2 )C-13), 56.1 )OMe), 56.0 )OMe),
50.3 )C-7), 46.9 )C-6), 33.9 )C-5), 32.2 )C-8); m/z: )EI) 357
)21), 356 )M1, 100), 271 )9), 257 )11), 152 )10%); )CI) 374
)M1NH41, 57), 222 )11), 154 )26), 116 )72%); [Found:
)M1NH4)1 374.1596, C20H20O5 requires 374.1604].
3.82 )3 H, s, OMe), 3.79 )3 H, s, OMe), 2.41-3.10 )6 H, m);
dC )100.6 MHz, CDCl3) major isomer: 177.3 )C-14), 148.7
)C-2), 147.5 )C-3,10), 147.4 )C-11), 130.2 )C-1a), 129.7
)C-4a), 128.5 )C-8a), 127.6 )C-12a), 115.9 )C-1), 111.6
)C-4,9), 111.4 )C-12), 73.1 )C-13), 56.1 )2£OMe), 56.0
)2£OMe), 42.5 )C-6), 40.2 )C-7), 35.6 )C-8), 28.9 )C-5);
minor isomer: 179.4 )C-14), 149.0 )C-2), 148.2 )C-3), 147.8
)C-10,11), 133.6 )C-1a), 133.1 )C-4a,8a), 133.0 )C-12a),
113.6 )C-1), 112.5 )C-4), 111.8 )C-9,12), 69.4 )C-13),
56.2 )2£OMe), 55.9 )2£OMe), 44.5 )C-7), 37.2 )C-6),
30.3 )C-8), 30.0 )C-5); m/z: )EI) 385 )22), 384 )M1, 100),
226 )8), 165 )8), 152 )8%); )CI) 402 )M1NH41, 100), 384
)6), 372 )5%); [Found: )M1NH4)1 402.1922, C22H24O6
requires 402.1917].
3.8. Preparation of trans-6-ꢀhydroxymethyl)-10,11,12-
trimethoxy-2,3-methylenedioxy-dibenzo[1a,4a:8a,12a]
cyclooctadiene-7-carboxylic acid lactone ꢀ7) using
ruthenium tetraꢀtri¯uoroacetate)
3.10. Preparation of cis-10-hydroxy-6-ꢀhydroxymethyl)-
2,3,11-trimethoxydibenzo[1a,4a:8a,12a]cyclooctadiene-
7-carboxylic acid lactone ꢀ32) and cis-10-hydroxy-6-
ꢀhydroxymethyl)-2,3,11-trimethoxydibenzo
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )5)5 )0.083 g,
0.209 mmol). Puri®cation via ¯ash chromatography on
silica and elution with CH2Cl2/EtOAc )98:2), followed by
crystallisation from EtOAc/hexane, afforded )7) as a white
foam )0.049 g, 59%), m.p. 169±1718C )Lit.6 172±172.58C);
IR )®lm): 1777 cm21 )g-lactone); dH )400 MHz, CDCl3)
6.63 )1 H, s, H-9), 6.56 )1 H, s, H-1), 6.55 )1 H, s, H-4),
5.93 )1 H, d, J 1.4 Hz, OCH2O), 5.91 )1 H, d, J 1.4 Hz,
OCH2O), 4.35 )1 H, dd, J 6.6, 8.4 Hz, H-13a), 3.83 )6 H,
s, 2£OMe), 3.82 )3 H, s, OMe), 3.70 )1 H, dd, J 8.4,
11.0 Hz, H-13b), 3.05 )1 H, d, J 13.2 Hz, H-8a), 2.57 )1
H, d, J 13.1 Hz, H-5a), 2.32 )1 H, dd, J 9.6, 13.1 Hz,
H-5b), 2.22 )1 H, dd, J 9.1, 13.2 Hz, H-8b), 2.12 )1 H, m,
H-6), 2.03 )1 H, dd, J 8.8, 13.2 Hz, H-7); dC )100.6 MHz,
CDCl3) 176.2 )C-14), 153.1 )C-10), 151.6 )C-12), 147.4
)C-3), 145.6 )C-2), 140.6 )C-11), 135.7 )C-4a), 130.9
)C-1a), 128.8 )C-12a), 126.5 )C-8a), 113.0 )C-9), 111.7
)C-1), 108.4 )C-4), 103.1 )OCH2O), 72.6 )C-13), 56.0
)3£OMe), 50.1 )C-7), 46.8 )C-6), 34.2 )C-5), 31.9 )C-8);
m/z: )EI) 398 )M1, 100), 383 )8), 181 )15), 152 )7%); )CI)
416 )M1NH41, 26), 391 )87), 296 )19), 279 )100), 152 )24),
136 )53%); [Found: )M1NH4)1 416.1705, C22H22O7
requires 416.1709].
[1a,4a:8a,12a]cyclooctadiene-7-carboxylic acid lactone
ꢀ35) using ruthenium tetraꢀtri¯uoroacetate)
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )29)15 )0.134 g,
0.360 mmol). Puri®cation via ¯ash chromatography on
silica and elution with CH2Cl2/EtOAc )95:5) afforded a
mixture of the two isomers )32) and )35), in a 1:1 ratio, as
a gum )0.108 g, 81%); IR )®lm): 3440 cm21 )OH), 1774
cm21 )g-lactone); dH )400 MHz, CDCl3) 7.20 )1 H, s),
6.90 )1 H, s), 6.73 )2 H, s), 6.70 )1 H, s), 6.66 )1 H, s),
6.62 )1 H, s), 6.48 )1 H, s), 5.68 )1 H, br.s, OH), 5.54 )1 H,
br.s, OH), 4.36 )2 H, m, H-13), 4.06 )1 H, m, H-13), 3.99 )1
H, d, J 9.2 Hz, H-13), 3.85 )3 H, s, OMe), 3.84 )6 H, s,
OMe), 3.83 )6 H, s, OMe), 3.80 )3 H, s, OMe), 2.40±3.08
)12 H, m); dC )100.6 MHz, CDCl3) 179.3, 177.3 )C-14),
148.7, 148.2 )C-2), 147.8, 147.4 )C-3), 145.6, 145.4
)C-10), 145.2, 144.6 )C-11), 133.8, 133.3 )C-1a), 132.9,
132.6 )C-4a), 130.5, 130.3 )C-8a), 129.2, 127.7 )C-12a),
119.0, 114.9 )C-1), 113.6, 112.6 )C-4), 111.8, 111.7 )C-9),
111.1, 110.9 )C-12), 73.1, 69.3 )C-13), 56.2, 56.1, 56.1,
56.0, 56.0, 56.0 )OMe), 44.4, 40.2 )C-7), 42.4, 37.2 )C-6),
35.6, 30.3 )C-8), 30.0, 28.9 )C-5); m/z: )EI) 371 )19), 370
)M1, 90), 211 )12), 165 )13%); )CI) 388 )M1NH41, 100),
358 )9), 152 )13), 124 )17%); [Found: )M1NH4)1
388.1758, C21H22O6 requires 388.1760].
3.9. Preparation of cis-6-ꢀhydroxymethyl)-2,3,10,11-
tetramethoxydibenzo[1a,4a:8a,12a]cyclooctadiene-7-
carboxylic acid lactone ꢀ31) and cis-6-ꢀhydroxymethyl)-
2,3,10,11-tetramethoxydibenzo-[1a,4a:8a,12a] cyclo-
octadiene-7-carboxylic acid lactone ꢀ34) using
ruthenium tetraꢀtri¯uoroacetate)
3.11. Preparation of cis-11-hydroxy-6-ꢀhydroxymethyl)-
2,3-dimethoxydibenzo[1a,4a:8a,12a]cyclooctadiene-7-
carboxylic acid lactone ꢀ33) and cis-11-hydroxy-6-
ꢀhydroxymethyl)-2,3-dimethoxydibenzo[1a,4a:8a,12a]
cyclooctadiene-7-carboxylic acid lactone ꢀ36) using
ruthenium tetraꢀtri¯uoroacetate)
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )28)15 )0.097 g,
0.252 mmol). Puri®cation via ¯ash chromatography on
silica and elution with CH2Cl2/EtOAc )95:5) afforded a
mixture of the two isomers )31) and )34), in a 1.6:1 ratio,
as a gum )0.088 g, 91%); IR )®lm): 1778 cm21 )g-lactone);
dH )400 MHz, CDCl3) major isomer: 7.17 )1 H, s), 6.73 )1
H, s), 6.71 )1 H, s), 6.63 )1 H, s), 4.37 )1 H, m, H-13a), 3.99
)1 H, d, J 9.1 Hz, H-13b), 3.86 )3 H, s, OMe), 3.85 )3 H, s,
OMe), 3.83 )3 H, s, OMe), 3.82 )3 H, s, OMe), 2.41-3.10 )6
H, m); minor isomer: 6.83 )1 H, s), 6.73 )1 H, s), 6.69 )1 H,
s), 6.48 )1 H, s), 4.37 )1 H, m, H-13a), 4.08 )1 H, dd, J 8.8,
11.8 Hz, H-13b), 3.86 )3 H, s, OMe), 3.85 )3 H, s, OMe),
The above experimental procedure was employed using as
starting material the dibenzylbutyrolactone )30)15 0.113 g,
0.331 mmol). Puri®cation via ¯ash chromatography on
silica and elution with CH2Cl2/EtOAc )95:5) afforded a
mixture of the two isomers )33) and )36), in a 1:1 ratio, as
a gum )0.090 g, 80%); IR )®lm): 3410 cm21 )OH),
1745 cm21 )g-lactone); dH )400 MHz, CDCl3) 7.10 )1 H,
d, J 8.3 Hz, H-9), 7.00 )1 H, d, J 8.4 Hz, H-9), 6.79 )1 H, dd,
J 2.7, 8.3 Hz, H-10), 6.75 )1 H, dd, J 3.0, 8.4 Hz, H-10), 6.71
)1 H, d, J 3.0 Hz, H-12), 6.68 )1 H, d, J 2.7 Hz, H-12), 6.66

4022
R. S. Ward, D. D. Hughes / Tetrahedron 57 %2001) 4015±4022
V. J. Org. Chem. 1976, 41, 4047. )b) Kupchan, S. M.; Dhingra,
O. P.; Kim, C. K. J. Org. Chem. 1976, 41, 4049.
4. )a) McKillop, A.; Hunt, J. D.; Zelesko, M. J.; Fowler, J. S.;
Taylor, E. C.; McGillivray, G.; Kienzle, F. J. Am. Chem. Soc.
1971, 93, 4841. )b) Taylor, E. C.; Kienzle, F.; Robey, R. L.;
McKillop, A.; Hunt, J. D. J. Am. Chem. Soc. 1971, 93, 4845.
5. Schlessinger, R. H.; Damon, R. E.; Blount, J. F. J. Org. Chem.
1976, 41, 3772.
)1 H, s), 6.65 )2 H, s), 6.60 )1 H, s), 5.33 )2 H, br.s, OH),
4.37 )2 H, m, H-13), 4.09 )1 H, m, H-13), 4.01 )1 H, d, J
9.3 Hz, H-13), 3.86 )3 H, s, OMe), 3.84 )3 H, s, OMe), 3.81
)3 H, s, OMe), 3.79 )3 H, s, OMe), 2.42±3.15 )12 H, m); dC
)100.6 MHz, CDCl3) 179.5, 177.5 )C-14), 154.5, 154.3
)C-11), 148.8, 147.5 )C-3), 145.6, 142.3 )C-2), 134.3,
133.1 )C-1a), 130.9, 130.5 )C-4a), 130.4, 129.9 )C-8a),
129.6, 128.2 )C-12a), 117.6 115.6 )C-1), 115.5, 115.2
)C-4), 114.3, 113.6 )C-9), 112.5, 112.0 )C-12), 73.3, 69.4
)C-13), 56.2, 56.0, 55.9 )4£OMe), 44.9, 40.2 )C-7), 42.7,
37.1 )C-6), 35.6, 30.0 )C-8), 29.7, 28.5 )C-5); m/z: )EI) 341
)19), 340 )M1, 100), 255 )13), 181 )11), 165 )9%); )CI) 358
)100), 342 )20), 328 )13), 152 )11), 116 )45%); [Found: M1
340.1307, C20H20O5 requires 340.1311].
6. Cambie, R. C.; Clark, G. R.; Craw, P. A.; Rutledge, P. S.;
Woodgate, P. D. Aust. J. Chem. 1984, 37, 1775.
7. Tomioka, K.; Kubota, Y.; Kawasaki, H.; Koga, K.
Tetrahedron Lett. 1989, 30, 2949.
8. Landais, Y.; Robin, J.-P. Tetrahedron Lett. 1986, 27, 1785.
9. Ward, R. S.; Pelter, A.; Abd-El-Ghani, A. Tetrahedron 1996,
52, 1303.
10. Taafrout, M.; Rouessac, F.; Robin, J.-P. Tetrahedron Lett.
1983, 24, 197.
Acknowledgements
11. Taafrout, M.; Rouessac, F.; Robin, J.-P. Tetrahedron Lett.
1983, 24, 2983.
Funding from the Evans Davies Cancer Trust Fund and
from Swansea University Chemistry Department, in the
form of a research studentship )to D. D. H.), is gratefully
acknowledged. Discussion with Dr A. El-Sharkawi of the
Oncology Department at Singleton Hospital in the planning
of this project is also gratefully acknowledged.
12. Hicks, R. P.; Sneden, A. T. Tetrahedron Lett. 1983, 24, 2987.
13. Buckleton, J. S.; Cambie, R. C.; Clark, G. R.; Craw, P. A.;
Rickard, C. E. F.; Rutledge, P. S.; Woodgate, P. D. Aust. J.
Chem. 1988, 41, 305.
14. Ward, R. S.; Hughes, D. D. Tetrahedron 2001, 57, 2057±
2064.
15. Prepared using the method described in Refs 9 and 18; for
details see D. D. Hughes, Ph.D. thesis, Swansea University,
2001.
References
1. For leading references on both the synthesis and natural occur-
rence of biaryls, see: Bringmann, G.; Walter, R.; Weirich, R.
Angew. Chem., Int. Ed. Engl. 1990, 29, 977.
16. Landais, Y.; Robin, J.-P.; Lebrun, A. Tetrahedron 1991, 47,
3787.
17. Cambie, R. C.; Craw, P. A.; Rutledge, P. S.; Woodgate, P. D.
Aust. J. Chem. 1988, 41, 897.
2. Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Gilmore, C. J.;
Restivo, R. J.; Bryan, R. F. J. Am. Chem. Soc. 1973, 95, 1335.
3. )a) Kupchan, S. M.; Dhingra, O. P.; Kim, C. K.; Kameswaran,
18. Moritani, Y.; Miyagishima, T.; Fukushima, C.; Ukita, T.;
Ohmizu, H.; Iwasaki, T. J. Org. Chem. 1996, 61, 6923.