Isobenzofurans and ortho-benzoquinone monoketals in syntheses of xestoquinone and its 9- and 10-methoxy derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00938-8

Syntheses of (±)-xestoquinone, (±)-9-methoxyxestoquinone and (±)-10-methoxyxestoquinone are described. A convergent CD plus ABE plan using the appropriate isobenzofuran (CD) and naphthofuranone (ABE) has been implemented to provide these marine metabolite

Full text of DOI:10.1016/S0040-4020(00)00938-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 309±317
Isobenzofurans and ortho-benzoquinone monoketals in
syntheses of xestoquinone and its 9- and
10-methoxy derivatives
*
Hamish S. Sutherland, Kerianne C. Higgs, Nicholas J. Taylor and Russell Rodrigo
Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo,
Waterloo, Ontario, Canada, N2L 3G1
Received 7 April 2000; revised 30 May 2000; accepted 10 July 2000
AbstractÐSyntheses of (^)-xestoquinone, (^)-9-methoxyxestoquinone and (^)-10-methoxyxestoquinone are described. A convergent CD
plus ABE plan using the appropriate isobenzofuran (CD) and naphthofuranone (ABE) has been implemented to provide these marine
metabolites in overall yields of 18.3, 9.5 and 8.5%, respectively. The latter pair of compounds, previously evaluated as inhibitors of
Topoisomerase II as an inseparable mixture, are now available separate and pure for the ®rst time. q 2000 Elsevier Science Ltd. All rights
reserved.
Halenaquinone 1 was the ®rst member1 of a group of penta-
cyclic marine quinones isolated from tropical sponges of the
genus Xestospongia. In succeeding years, this genus2 and
the related Adocia3,4 have yielded many more compounds of
the group including xestoquinone 2, methoxyhalenaquinone
3 and adociaquinones 4, 5 and 6. More recently, an investi-
gation5 of sponges collected from the seas off the northern
coast of the Philippine Islands resulted in the isolation of
two inseparable isomeric methoxyxestoquinones 7 and 8,
chloro-hydroxy quinones 9 and 10, adociaquinones 4 and
5 and their corresponding seco derivatives. Partially reduced
derivatives, quinols and various hydrogenated quinones
have also been found in these investigations on some occa-
sions2,4 and all these marine metabolites are now recognised
as a structurally discrete group based on the parent penta-
cyclic ring system6 1H-benzo[6,7]phenanthro[10,1-bc]-
furan. It has been conjectured4 that the quinone ring D is
triketide in origin and the rest of the molecule (14 carbons)
comes from a sesquiterpene that has suffered demethylation
to form the furan ring (E).
PTK antagonist, but a subsequent study5 established that
quinones 2, 7±10 were inhibitors of Topoisomerase II, an
enzyme found at elevated levels in cancer cells. A separate
study determined7 that both 1 and 2 bound to Topoiso-
merase I and prevented the unwinding of DNA during cell
division though neither compound intercalated with the
DNA helix. Xestoquinone was also found to be a useful
modi®er of myosin. It was suggested8 that the quinone
ring (D) interacted with speci®c SH groups of the protein
and altered its conformation. In support of this hypothesis a
xestoquinone-mercaptoethanol adduct 11 was prepared in
vitro. In addition, xestoquinone activated actomyosin
ATP-ase by enhancement of the interaction between actin
and myosin. It had been previously shown to be a potential
cardiotonic agent because of its positive inotropic effect on
cardiac muscle.
The quinones of the group have signi®cant and potentially
valuable pharmacological properties; 1 and 3 have proven4
to be powerful irreversible inhibitors of some cytoplasmic
and receptor protein tyrosine kinases (PTK) but not all
PTK's are affected. It was suggested that Michael addition
of the PTK to electrophilic sites at the A, E and D rings was
responsible. These ®ndings are relevant to the development
of PTK antagonists as anti-proliferative agents in the treat-
ment of cancer and psoriasis. Xestoquinone 2 was not a
Keywords: antitumour compounds; cycloadditions; quinones; sponges.
* Corresponding author. Fax: 11-519-746-0435; e-mail: rrodrigo@wlu.ca
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00938-8

310
H. S. Sutherland et al. / Tetrahedron 57 (2001) 309±317
was obtained16 in good yield from guaiacol it could not be
converted into a suitable dienophile for further progress
towards (^) 2. A completely new route to such a tricyclic
target was therefore devised and successfully implemented.
It involved oxidative functionalisation of 4-methylguaiacol
14 through an o-quinone monoketal, led to 15 in two steps
and subsequently to (^)-xestoquinone.17 This general intra-
molecular Diels±Alder, Cope rearrangement sequence was
pro®tably applied to more complex systems by us18,19 and
others.20 In this report we provide full details of the synth-
esis of (^) 2 modi®ed slightly to provide a better overall
yield, and adapt our synthetic route to afford 9-methoxy and
10-methoxyxestoquinones (7 and 8) separately for the ®rst
time. Furthermore, an X-ray crystallographic structure of a
pure synthetic intermediate has been obtained in order to
conclusively assign structures to this pair of isomers which
had been isolated in small quantities (15 mg) and charac-
terised previously only as an inseparable 70:30 mixture.
These marine metabolites have also attracted much attention
from synthetic chemists. Beginning with optically pure
Wieland±Mischler ketone (as rings A and B) Harada and
co-workers completed syntheses of halenaquinone,9 xesto-
quinone10 and adociaquinones A and B11 in 14±16 steps and
yields of 4±6%. Rings C and D were af®xed by a Diels±
Alder reaction with dimethoxybenzocyclobutene, while ring
E was built up from the tetracyclic adduct. After oxidative
generation of the ring D quinone to produce (1)-xesto-
quinone,10 reaction with 2-aminoethanesul®nic acid (hypo-
taurine) gave the adociaquinones11 which were separated by
HPLC. Two different syntheses published contempor-
aneously,12,13 employed methoxynaphthalene precursors as
the CD-ring synthons. In the ®rst of these, the starting mat-
erials
2-bromo-3-carbethoxy-5,8-dimethoxynaphthalene
and 2-t-butyldimethylsilyl-3-hydroxymethylfuran (ring E)
were converted to (1)-xestoquinone (68% e.e.) in eleven
steps and 11.3% overall yield. The key step which fabri-
cated rings A and B of the homochiral pentacyclic precursor
in `one pot' was an intramolecular asymmetric Heck reac-
tion±polyene cyclisation sequence catalysed by a Pd(0)
species complexed with (S)-BINAP. A subsequent retracing
of essentially the same reaction scheme with silver salts as
additives in the polyene cyclisation step also resulted14 in
the preparation of (1) 2 in comparable yield. In the second
asymmetric synthesis from a naphthalene starting material
(1)-halenaquinone (85% e.e.) was obtained in 21 steps and
low yield (ca. 2%). The key step this time was an inter-
molecular tandem Suzuki coupling Heck reaction (catalysed
by palladium acetate-(S)-BINAP) between the naphthalene
2,3-ditri¯ate and an alkylborane to provide the BCD tricycle
in 85% e.e. and 20% yield. Subsequent elaboration of this
product incorporated the requisite 3-keto group and rings A
and E of (1)-halenaquinone. In a completely different
approach (^)-xestoquinone was synthesised by a conver-
gent ABE1CD, Diels±Alder reaction.15 The CD segment
was a dimethoxy o-quinomethide again, but the novelty and
attraction of this work lay in the ®rst synthesis of a complete
ABE tricyclic naphthofuranone used as the dienophile in the
assembly of the pentacycle. This fragment was prepared by
means of a novel protocol called `furan ring transfer' by the
authors, and although the chemistry of those particular steps
was ingeniously conceived, the synthesis of the tricycle (12)
took 11 steps to complete in moderate (6.3%) yield from
a-furylmethanol.
The synthesis of (^)-xestoquinone began with the prepar-
ation17 of 15 in two steps from 4-methylguaiacol and
2,4-pentadienol in 56% yield. This tricycle, representing
rings AB and E of the quinones reacted with the known21
4,7-dimethoxyisobenzofuran 16 to provide the adduct 17 in
78% yield.22 The isobenzofuran 16 was prepared this time as
1
a stable solid23 by the dipyridyl-s-tetrazine route.24 The H
NMR spectrum of 17 in CDCl3 at ambient temperature
showed very broad signals for all protons associated with
the ABE segment. A spectrum in benzene-d6 at 678C was
satisfactory but it still provided little information about the
relative stereochemistry of the Diels±Alder adduct. An
X-ray structure of 17 established that it was formed by
Our laboratory has had a long-standing interest in such
a convergent plan and had devoted considerable effort
to elaborating a similar tricyclic system for use as a dien-
ophile in the syntheses of xestoquinone and related
naturally occurring pentacycles. Although a tricycle 13

H. S. Sutherland et al. / Tetrahedron 57 (2001) 309±317
311
Figure 1. X-Ray structure of 17.
face-selective exo-addition of the two reactants and the site
of conformational disorder was identi®ed as the methylene
group at C-4 (Fig. 1).
Aromatisation via a 5-endo-trig cleavage25 of the oxygen
bridge and subsequent dehydration of the resulting 12-
hydroxy derivative was accomplished in `one pot' to
provide an 85% yield of 18 by re¯uxing with methanolic
sodium methoxide. The 5a-methoxyl group was eliminated
by brief treatment with tri¯uoroacetic acid in methylene
chloride at room temperature (19, 90%), and the furan 20
(ring E) was generated in 87% yield by dehydrogenation
with chloranil in re¯uxing p-xylene. Catalytic hydrogena-
tion of the 2,3-alkene was virtually quantitative and the ®nal
oxidation at ring D with ceric ammonium nitrate released
(^)-xestoquinone 2 in 63% yield. This synthesis of (^) 2 is
complete in eight steps and 18.3% overall yield from
4-methylguaiacol and is easily the most ef®cient route to
this pentacyclic natural product to date.
5-endo-trig oxygen bridge cleavage.
Trimethoxybenzene 27 was brominated in 97% yield to
the known28 bromide 28 which reacted with redistilled
furan in the presence of sodamide to provide the benzyne-
furan adduct 29 in 76% yield. The trimethoxyisobenzofuran
30 was generated from 29 by the dipyridyl-s-tetrazine route
via the intermediate adduct 31. In this instance however,
the isobenzofuran was of marginal stability and the pro-
cedure had to be conducted in the presence of tricyclic
dienophile 15. A 61% yield of a 1:1 mixture of adducts
The presence of a methoxyl group at C-9 (as in 7) or C-10
(as in 8) complicates the syntheses of these sponge meta-
bolites5 by any existing route because it introduces dissym-
metry into the CD synthons hitherto employed. In
embarking on a synthesis of these quinones it was our belief
that the route described above for (^) 2 could be adapted at
the 5-endo-trig oxygen bridge cleavage step to differentiate
isomers 21 and 22. Our experience with this reaction in
natural product synthesis26,27 had persuaded us that the
alcohol intermediates 23 and 24 would dehydrate to the
aromatics 25 and 26, respectively, at different rates. The
dehydration of the para methoxylated benzyl alcohol 23
would be assisted by the C-9 methoxyl group, in contrast
to 24 where the C-10 methoxyl group was meta to the
alcoholic function at C-12 but conjugated with the enone
function C6±C6a±C7. These effects would be expected to
stabilise alcohol 24 but de-stabilise 23 with respect to the
dehydration/aromatisation step. Such differences could
not be observed of course, in the reaction of 17 and these
postulates could only be veri®ed by preparing bridged
adducts 21 and 22 and subjecting them to the base-catalysed
1
was produced and the similarity of the H NMR spectrum
of this mixture with that of 17 enabled structures 21 and
22 to be assigned with con®dence, to the individual com-
ponents. Treatment of these mixed adducts with methoxide
in re¯uxing methanol resulted in an approximately 1:1
mixture of alcohol 24 and naphthalene 25 as expected.
They were easily separated by simple column chroma-
tography on silica. Occasionally a small amount of naph-
thalene 26 was also detected in the product but it was
removed from 25 by crystallisation. Conversion of 24 to
the naphthalene 33 and 25 to 32 were then effected in almost
quantitative yields by treatment of these substrates with
tri¯uoroacetic acid. In this manner the two isomeric penta-
cycles 32 and 33 were obtained separate, pure and crystal-
line. The structural assignments were unequivocally settled
by an X-ray crystallographic determination on intermediate
25, the naphthalene formed directly by methoxide treatment

312
H. S. Sutherland et al. / Tetrahedron 57 (2001) 309±317
Figure 2. X-Ray structure of 25.
of the bridged adduct mixture. Fig. 2 shows the methoxyl
group in this compound at C-9, thus validating our original
hypothesis and eventually permitting a secure structural corre-
lation with one of the natural methoxyxestoquinones in the
inseparable mixture isolated5 from the Philippine sponge.
for an overall yield of 8.5%. Thus the combined yield of 7
and 8 from trimethoxybenzene is 18%.
The ®nal correlation with the natural quinones was made by
comparison of the 1H and 13C NMR spectra of our synthetic
samples with published data.5 Since that data was obtained
from a 70:30 mixture we prepared a similar mixture of our
synthetic materials for a 1H NMR spectrum (Fig. 3). We can
now con®rm that 9-methoxyxestoquinone whose structure
is secured by X-ray analysis of 25, is identical with the
major constituent of the natural mixture (previously
named 14-methoxyxestoquinone5). The minor isomer of
that mixture is identical with 10-methoxyxestoquinone
Subsequent processing of each of these naphthalenes sepa-
rately (32!34 and 33!35) proceeded as before in com-
parable yields. Hydrogenation of 34 produced 36 and
oxidation with ceric ammonium nitrate converted it to
9-methoxyxestoquinone 7 in an overall yield of 9.5%
from trimethoxybenzene in 8 steps while 35 was hydro-
genated to 37 and oxidised to 10-methoxyxestoquinone 8
Figure 3. The aromatic regions of the 1H NMR spectra; (a) 9-methoxyxestoquinone (7); (b) 10-methoxyxestoquinone (8); (c) a ca. 70:30 mixture of 7 and 8.

H. S. Sutherland et al. / Tetrahedron 57 (2001) 309±317
313
(previously 15-methoxyxestoquinone). These assignments
also validate the original structural postulates made on the
basis of heteronuclear HMBC relationships detected in
spectra of the natural mixture. Our synthetic route to the
individual methoxyxestoquinones now makes it possible
to evaluate these compounds separately as inhibitors of
Topoisomerase II.
Sodium (102 mg, 4.44 mMol) was added to a solution of
the bridged compound (17) (354 mg, 0.89 mMol) in metha-
nol (10 mL) at room temperature. The resulting mixture was
heated under re¯ux for 4.5 h then concentrated in vacuo.
The yellow residue was treated with 3N HCl (2 mL) and
the aqueous layer extracted with ethyl acetate. Column
chromatography gave the aromatic compound (18)
(305 mg, 90%) as a yellow crystalline solid from ether/
hexanes. mp 228±2298C (Found: C, 72.4; H, 6.3.
C23H24O5 requires C, 72.6; H, 6.3%) nmax (KBr) 2928,
1704, 1454, 1268 cm21; dH (500 MHz, CDCl3) 1.64 (3H,
s, C12b-CH3), 1.87 (1H, dd, Jˆ17.9, 5.8 Hz, H-1), 2.04 (1H,
dd, Jˆ17.9, 2.2 Hz, H-1), 2.74 (1H, dd, Jˆ8.2, 1.8 Hz, H-
12c), 3.12 (1H, m, H-3a), 3.21 (3H, s, C5a-OCH3), 3.91 (1H,
d, Jˆ8.3 Hz, H-4), 3.95 and 3.97 (s, C8-OCH3 and C11±
OCH3), 4.15 (1H, dd, Jˆ8.3, 5.9 Hz, H-4), 5.69 (1H, dt,
Jˆ10.1 Hz, 3.0 Hz, H-3), 5.78 (1H, bd, Jˆ10.1 Hz, H-2),
6.70 and 6.81 (1H each, d, Jˆ8.4 Hz, H-9 and H-10), 8.21
(1H, s, H-12), 8.72 (1H, s, H-7). dC (125 MHz, CDCl3) 24.5
(C12b±CH3), 35.6 (C-12b), 37.9 (C-3a), 39.8 (C-1), 50.0
(5a-OCH3), 54.3 (C-12c), 55.8 and 55.9 (OCH3), 72.5 (C-
4), 103.8 and 106.3 (C-9 and C-10), 105.5 (C-5a), 117.3
(C-12), 123.3 (C-7), 124.8, 128.5 and 131.8 (C-6a, C-7a
and C-11a), 126.3 and 126.8 (C-2 and C-3), 146.2, 149.3
and 150.8 (C-12a, C-8, C-11), 193.2 (C-6). m/z 380 (M1,
100), 365 (8), 349 (5), 281 (22), 253 (22).
1. Experimental
1.1. General
All glassware and syringes were dried in an oven, and then
cooled in a dry box before use. All temperatures are in 8C.
Tetrahydrofuran (THF) was distilled from potassium ben-
zophenone ketyl, all other solvents were used as received.
All reagents were purchased from Aldrich Chemical
Company. Thin layer chromatography was carried out on
Merck 5554 pre-coated silica gel 60 F254 aluminium sheets.
After development, the sheets were viewed under UV light
or with an oxidising stain consisting of ceric ammonium
sulfate and hexammonium heptamolybdate in 1.8 M
H2SO4. Flash chromatography was performed using
Merck 9385 silica gel 60 (230±400 mesh). Fourier trans-
form infrared spectra (FT-IR) were recorded on a Bomem
MB-100 spectrometer or a Perkin±Elmer Spectrum RX
spectrometer as neat ®lms between NaCl plates, or KBr
1.1.3.
3,4-Dihydro-12b-methyl-8,11-dimethoxy-1H-
1
discs. H and 13C NMR spectra were obtained on Bruker
benzo[6,7]phenanthro[10,1-bc]furan-6-(12bH)-one (19)
and 12b-methyl-8,11-dimethoxy-1H-benzo[6,7]phenan-
thro[10,1-bc]furan-6-(12bH)-one (20). Tri¯uoroacetic
acid (0.5 mL) was added to a solution of the ketone (18)
(112 mg, 0.29 mMol) in dichloromethane (3 mL) and the
mixture was stirred at room temperature for 15 min.
NaHCO3 was added in small portions followed by water
(10 mL). The dienone (19) was extracted into ethyl acetate
and isolated as a yellow oil. (Found: M1, 348.1355.
C22H20O4 requires M, 348.1361), nmax 2947, 2835, 1666,
1624, 1242 cm21; dH (250 MHz, CDCl3) 1.65 (3H, s,
C12b±CH3), 2.30 (1H, d, Jˆ17.1 Hz, H-1), 2.98 (1H, dd,
Jˆ17.1, 4.1 Hz, H-1), 3.97 and 3.99 (s, C8±OCH3 and C11-
OCH3), 4.05 (2H, m, H-3a and H-4), 4.94 (1H, dd, Jˆ8.5,
6.8 Hz, H-4), 5.80 (2H, m, H-2 and H-3), 6.68 (1H, d,
Jˆ8.3 Hz, H-9 or H-10), 6.80 (1H, d, Jˆ8.3 Hz, H-9 or
H-10), 8.35 (1H, s, H-12), 9.22 (1H, s, H-7). dC (62 MHz,
CDCl3) 25.2 ((12b-CH3), 37.6 (C-12b), 41.3 (C-3a), 43.4
(C-1), 55.7 (2£OCH3), 76.0 (C-4), 103.1 and 105.6 (C-9
and C-10), 119.1 (C-12), 122.9 (C-7), 124.8, 127.7 and
129.9 (C-6a, C-12a and C-11a), 125.9 and 127.1 (C-2 and
C-3), 140.4 (C-12c), 146.0, 146.8, 148.6 and 150.8 (C-5a, C-
8, C-11 and C-7a), 176.4 (C-6). m/z 348 (M1, 100), 333
(33), 318 (14), 303 (22). This oil was re¯uxed in xylenes
(10 mL) with p-chloranil (145 mg, 0.59 mMol) for 48 h.
Column chromatography of the concentrated reaction
mixture gave the aromatic furan (20) as a yellow crystalline
AM-300 and AMX-500 instruments. Chemical shifts for
NMR were determined relative to the internal standard tetra-
methylsilane (d 0.00), C6H6 (d 7.15) or CHCl3 (d 7.26) for 1H
spectra, and CDCl3 (d 77.0) for 13C spectra. All 1H NMR data
listed have the following order: chemical shift (ppm),
(number of protons, multiplicity, coupling constants, assign-
ment). The 13C NMR data listed have the following order:
chemical shift (ppm), (assignment). Mass spectra were run at
the McMaster Regional Centre for Mass Spectrometry,
McMaster University, Hamilton, Ontario. Elemental analyses
were performed by MHW Laboratories, Phoenix, Arizona.
1.1.1. 7,12-Epoxy-3a,4,5a,6a,7,12,12a-heptahydro-12b-
methyl-5a,8,11-trimethoxy-1H-benzo[6,7]phenanthro[10,1-
bc]furan-6-(12bH)-one (17).A solution of the naphtho-
furan17 (15) (2.48 g, 11.3 mMol) and 4,7-dimethoxyisoben-
zofuran21 (16) (2.50 g, 14.0 mMol) in toluene (100 mL) was
re¯uxed for 42 h. Removal of solvent followed by column
chroma-tography (30% ethyl acetate/hexanes) gave the
bridged compound (17) (3.50 g, 78%) as a white solid.
Mp 182±1848C (Found: C, 69.5; H, 6.5. C23H26O6 requires
C, 69.3; H, 6.6%) nmax 2939, 1731, 1479, 1262 cm21; dH
(500 MHz, 340 K, C6D6) 1.07 (s, C12b-CH3), 1.52 (1H, dd,
Jˆ17.4, 2.4 Hz, H-1), 1.97 (1H, dd, Jˆ17.4, 5.3 Hz, H-1),
2.42 (1H, d, Jˆ9.4 Hz, H-12c), 2.51 (1H, d, Jˆ9.5 Hz, H-
12a), 2.68 (1H, bd, Jˆ7.5 Hz, H-3a), 2.95 (1H, d, Jˆ9.5 Hz,
H-6a), 3.20 (1H, t, Jˆ7.7 Hz, H-4), 3.37, 3.43 and 3.45
(s, C5a-OCH3, C8-OCH3 and C11-OCH3), 3.82 (1H, t,
Jˆ8.3 Hz, H-4), 5.25 and 5.46 (2H, m, H-2 and H-3), 5.51
(1H, s, H-12), 6.31 (1H, s, H-7), 6.42 (2H, s, H-9 and H-10).
m/z 398 (M1, 1), 209 (17), 178 (100), 163 (29).
1
solid (88 mg, 86%). The H NMR spectrum was identical
with the literature spectrum.12
1.1.4. 12b-Methyl-8,11-dimethoxy-1H-benzo[6,7]phen-
anthro[10,1-bc]furan-6-(12bH)-one (38). Palladium on
carbon (10%, 4.3 mg) and NaHCO3 (50 mg) was added to
a solution of the furan (20) (33.0 mg, 0.095 mMol) in ethyl
acetate (15 mL), then treated with hydrogen (1 atmosphere)
1.1.2. 3a,4,5a,12c-Tetrahydro-5a,8,11-trimethoxy-1H-
benzo[6,7]phenanthro[10,1-bc]furan-6-(12bH)-one (18).

314
H. S. Sutherland et al. / Tetrahedron 57 (2001) 309±317
for 4 h. The reaction mixture was ®ltered and concentrated
to give an oil which on column chromatography (silica gel,
ethyl acetate/hexanes) gave xestoquinol dimethyl ether (38)
as yellow crystals (32.3 mg, 97%). The H NMR spectrum
was identical with the literature spectrum.10
mixture (1:1) of the coupled products (21) and (22)
(4.093 g, 61%). (Found: M1, 428.1804. C24H28O7 requires
M, 428.1835) nmax (NaCl) 2941, 2840, 1738, 1498 cm21. dH
(300 MHz, C6D6, 340K) 1.06 (s, C12b-CH3), 1.07 (s, C12b-
CH3), 1.56 (1H, dd, Jˆ17.4, 2.6 Hz, H-1), 1.57 (1H, dd,
Jˆ17.4, 2.6 Hz, H-1), 1.97 (1H, dd, Jˆ17.4, 5.3 Hz, H-1),
1.98 (1H, dd, Jˆ17.4 Hz, 5.3 Hz, H-1), 2.44-2.52 (2H, m,
H-12c and H-12a), 2.65-2.75 (1H, m, H-3a), 2.98 (1H, d,
Jˆ9.6 Hz, H-6a), 3.21-3.28 (1H, m, H-4), 3.35, 3.40, 3.41
and 3.47 (s, C5a-OCH3, C8-OCH3 and C11±OCH3), 3.61 (s,
C9-OCH3 or C10±OCH3), 3.68 (s, C9-OCH3 or C10-
OCH3), 3.83 (1H, dd, Jˆ8.4 Hz, H-4), 5.22-5.32 (1H, m,
H-2), 5.40±5.50 (1H, m, H-3), 5.45 and 5.46 (1H, s, H-12),
6.13 and 6.15 (1H, s, H-7), 6.28 (1H, bs, H-9 or H-10). m/z
428 (M1, 7), 400 (38), 385 (18), 293 (29), 245 (47), 165
(100).
1
1.1.5. Xestoquinone (2). The hydrogenated furan (38)
(33 mg, 0.09 mMol) was dissolved in acetonitrile (2 mL)
and ceric ammonium nitrate (153 mg, 0.28 mMol) in
water (3 mL) was added dropwise at 08C. The solution
was stirred for 5 min at 08C, then water (10 mL) was
added. Extraction with ethyl acetate gave the crude product
which was puri®ed by column chromatography on silica gel
using ethyl acetate/hexanes to give xestoquinone (2)
1
(19 mg, 63%) as ¯aky orange crystals. The H NMR spec-
trum was identical with the literature spectrum.12
1.1.6. Bromo-2,4,5-trimethoxybenzene (28). Bromine
(1.59 mL, 30.9 mMol) in dichloromethane (50 mL) was
added dropwise to a solution of 1,2,4-trimethoxybenzene
(27) (4.945 g, 29.4 mMol) in dichloromethane (200 mL) at
08C. The resulting mixture was washed with aqueous
sodium bisul®te, aqueous sodium bicarbonate and water.
Removal of the solvent gave bromo-2,4,5-trimethoxyben-
zene (28) (7.057 g, 97%) as a white solid, mp 53±548C
(lit.28 mp 54±55.58C).
1.2. Aromatisation of the B ring
Sodium methoxide (0.354 g, 6.55 mMol) was added to a
solution of a 1:1 mixture of (21) and (22) (0.704 g,
1.64 mMol) in methanol (100 mL), then the solution was
heated under re¯ux for 4 h. The mixture was concentrated,
then acidi®ed with 3N HCl. The aqueous solution was
extracted with ethyl acetate to provide a yellow oil. Column
chromatography on silica gel using ethyl acetate/hexanes
followed by ethyl acetate as eluents gave in order of elution
the aromatic compound (25) (0.289 g, 43%) and the alcohol
(24) (0.275 g, 39%). 12b-Methyl-3a,4,5a,12c-tetrahydro-
5a,8,9,11-tetramethoxy-1H-benzo[6,7]phenanthro[10,1-
bc]furan-(12bH)-one (25). Mp 202±2038C. (Found: C,
70.45; H, 6.49. C24H26O6 requires C 70.23; H, 6.38%)
nmax 2938, 1703, 1599, 1463, 1359 cm21. dH (250 MHz,
CDCl3) 1.62 (3H, s, C12b-CH3), 1.87 (1H, dd, Jˆ17.7,
5.4 Hz, H-1), 2.05 (dd, 1H, dd, Jˆ18.0, 2.0 Hz, H-1), 2.73
(1H, dd, Jˆ8.2, 1.7 Hz, H-12c), 3.12 (1H, m, H-3a), 3.21
(3H, s, C5±OCH3), 3.93 (1H, d, Jˆ8.6 Hz, H-4), 3.95, 4.01
and 4.02 (s, C(8)±OCH3, C(9)±OCH3 and C(11)±OCH3),
4.16 (1H, dd, Jˆ8.4, 5.9 Hz, H-4), 5.69 (1H, ddd, Jˆ10.1,
2.9, 2.9 Hz, H-3), 5.78 (1H, dddd, Jˆ10.1, 5.5, 1.8, 1.8 Hz,
H-2), 6.74 (1H, s, H-10), 8.16 (1H, s, H-12), 8.54 (1H, s,
H-7). dC 24.4 (12b-CH3), 35.2 (C-12b), 37.8 (C-3a), 39.6
(C-1), 49.8 (5a-OCH3), 54.2 (C-12c), 54.2, 55.8 and 61.5
(OCH3), 72.4 (C-4), 97.9 (C-10), 104.9 (C-5a), 117.5
(C-12), 122.1 (C-7), 123.1 (C-11a), 126.1 and 126.6 (C-2
and C-3), 127.8 and 132.9 (C-6a and C-7a), 138.0, 143.4,
148.6 and 152.2 (C-8, C-9, C-11 and C-12a), 193.3 (C-6).
m/z 410 (100), 395 (63), 367 (25), 311 (31), 99 (40); and 12-
hydroxy-12b-methyl-3a,4,5a,12,12c-pentahydro-5a,8,10,11-
tetramethoxy-1H-benzo[6,7]phenanthro[10,1-bc]furan-
6-(12bH)-one (24) as a yellow foam. (Found: M1,
428.1846. C24H28O7 requires M 428.1835), nmax 3479,
2932, 1699, 1593, 1468, 1328, 1224 cm21. dH (250 MHz,
CDCl3) 1.36 (3H, s, C12b-CH3), 1.64 (1H, dd, Jˆ18.0,
4.1 Hz, H-1), 2.05 (1H, d, Jˆ18.0 Hz, H-1), 2.45 (1H, dd,
Jˆ2.8, 2.8 Hz, H-12a), 2.90 (1H, m, H-3a), 2.96 (1H, d,
Jˆ7.6 Hz, H-12c), 3.07 (3H, s, C5a-OCH3), 3.85 (1H,
concealed, H-4), 3.80, 3.82 and 3.88 (s, C8-OCH3, C10-
OCH3 and C11-OCH3), 3.95 (1H, dd, Jˆ8.4, 5.4 Hz, H-4),
5.20 (1H, dd, Jˆ10.2, 3.0 Hz, H-12), 5.54 (1H, d,
Jˆ10.1 Hz, H-3), 5.68 (1H, m, H-2), 6.41 (1H, s, H-9),
7.54 (1H, d, Jˆ2.7 Hz, H-7). dC (50 MHz, CDCl3) 24.1
(C12b±CH3), 31.9 (C-12b), 35.0 (C-1), 37.9 (C-3a), 49.4,
1.1.7. 1,4-Dihydro-5,6,8-trimethoxy-1,4-epoxynapthal-
ene (29). Bromo-2,4,5-trimethoxybenzene (28) (13.924 g,
56.4 mMol) in THF (100 mL) was added dropwise to a
mixture of furan (70 mL, 0.96 mol) and sodium amide
(9.20 g, 0.24 mol) in THF (140 mL) at 508C under argon.
The mixture was stirred at 558C for 11 h, ®ltered and parti-
tioned between water and ethyl acetate. The organic layer
was dried, evaporated and the residue was chromatographed
on silica gel (9:1 hexanes:ethyl acetate) to give 1,4-dihydro-
5,6,8-trimethoxy-1,4-epoxynapthalene (29) (10.006 g,
76%). Recrystallisation from hexanes gave colourless
prisms, mp 84±858C. (Found: C, 67.21; H, 5.90. C13H14O4
requires C, 66.66; H, 6.50%) nmax (NaCl) 2940, 2839, 1631,
1614, 1491, 1464 cm21. dH 3.81(5), 3.82 and 3.85 (s,
OCH3), 5.92 (1H, d, Jˆ1.3 Hz, H-1 or H-4), 5.96 (d,
Jˆ1.3 Hz, H-1 or H-4), 6.12 (1H, s, H-7), 7.00 (1H, dd,
Jˆ5.5, 1.7 Hz, H-2 or H-3), 7.05 (1H, dd, Jˆ5.5, 1.7 Hz,
H-2 or H-3). dC 56.3, 56.7 and 61.2 (OCH3), 80.1, 80.6 (C-1
and C-4), 95.9 (C-7), 125.9, 138.6, 140.0, 148.2, 151.2 (C-
4a, C-5, C-6, C-8, C-8a), 141.5, 143.0 (C-2 and C-3). m/z
234 (M1, 73), 206 (34), 193 (77), 191 (100), 165 (21).
1.1.8. 7,12-Epoxy-3a,4,5a,6a,7,12,12a-heptahydro-12b-
methyl-5a,8,9,11-tetramethoxy-1H-benzo[6,7]phenan-
thro[10,1-bc]furan-6-(12bH)-one (21) and 7,12-Epoxy-
3a,4,5a,6a,7, 12,12a-heptahydro-12b-methyl-5a,8,10,11-
tetramethoxy-1H-benzo[6,7]phenanthro[10,1-bc]furan-
6-(12bH)-one
(22).
3,6-(Dipyridin-20-yl)tetrazine24
(3.724 g, 15.8 mMol) was added to a solution of the bridged
ether (29) (3.680 g, 15.7 mMol) in chloroform (180 mL).
The reaction mixture was stirred for 1 h at room tempera-
ture. A solution of the naphthofuran17 (15) (2.875 g,
1.31 mMol) in toluene (300 mL) was added and the result-
ing solution was re¯uxed for 25 h. The solution was concen-
trated in vacuo and the residue was chromatographed on
silica (1:1 hexanes:ethyl acetate) to give an inseparable

H. S. Sutherland et al. / Tetrahedron 57 (2001) 309±317
315
50.5 and 61.8 (OCH3), 55.2 and 55.8 (C-12a and C-12c),
61.8 (OCH3), 62.5 (C-12), 72.0 (C-4), 96.1 (C-9), 104.7
(C-5a), 112.4 (C-10), 125.8, 126.4 and 127.0 (C-2, C-3
and C-7), 130.4, 133.5 and 139.7 (C-6a, C-7a and C-11a),
154.5 and 155.3 (C-8 and C-11), 195.0 (C-6). m/z 428 (M1,
2), 209 (46), 208 (100), 193 (54).
ethyl acetate/hexanes) gave the xestoquinol dimethyl ether
(36) (114 mg, 93%) as a yellow solid. mp 193±1958C
(Found: C, 72.82; H, 5.78. C23H22O5 requires C, 73.00; H,
5.86%) nmax 2940, 1670, 1626, 1595 cm21. dH (300 MHz,
CDCl3) 1.53 (3H, s, C12b-CH3), 1.80 (1H, ddd, Jˆ13.2, 4.4,
4.4 Hz, H-1), 2.11-2.15 (2H, m, H-2), 2.54-2.68 (2H, m, H-1
and H-3), 2.87 (1H, dd, Jˆ17.1, 7.5 Hz, H-3), 3.96 (3H, s,
OCH3), 4.00 (6H, s, OCH3), 6.75 (1H, s, H-10), 7.47 (1H, t,
Jˆ1.3 Hz, H-4), 8.23 (1H, s, H-12), 9.10 (1H, s, H-7); dC
(75 MHz, CDCl3) 17.2 (C-3), 18.7 (C-2), 32.1 (C-1), 33.8
(C12b±CH3), 36.1 (C-12b), 55.8, 57.5 and 61.6 (OCH3),
98.0 (C-10), 117.8 (C-12), 121.2 and 122.3 (C-3a and
C-11a), 123.2 (C-7), 127.7 and 132.5 (C-7a and C-12a),
138.2 (C-8), 143.8, 144.2 and 144.7 (C-4, C-5a and
C-12c), 146.8, 148.4 and 151.8 (C-6a, C-9 and C-11),
172.9 (C-6). m/z 378 (M1, 86), 363 (100), 333 (19), 319
(20), 189 (19), 174 (37).
1.2.1. 3,4-Dihydro-12b-methyl-8,9,11-trimethoxy-1H-
benzo[6,7]phenanthro[10,1-bc]furan-6-(12bH)-one (32).
Tri¯uoroacetic acid (2.5 mL) was added to a solution of
the ketone (25) (450 mg, 1.10 mMol) in dichloromethane
(40 mL) and the mixture was stirred at room temperature
for 15 min. NaHCO3 was added in small portions followed
by water (40 mL), the product was extracted with ethyl ace-
tate, removal of solvent gave the dienone (32) (409 mg,
99%) as a yellow oil. (Found: M1, 378.1436. C23H22O5
requires M 378.1467), nmax (NaCl) 2966, 2936, 1662,
1624, 1596 cm21; dH (300 MHz, CDCl3) 1.64 (3H, s,
C12b±CH3), 2.29 (1H, bd, Jˆ17.5 Hz, H-1), 2.91 (1H, dd,
Jˆ17.5, 3.6 Hz, H-1), 3.97, 4.02 and 4.03 (9H, s, 8-OCH3,
9-OCH3, 11-OCH3), 4.03 (1H, concealed, H-3a), 4.12 (1H,
dd, Jˆ6.7, 2.0 Hz, H-4), 4.94 (1H, dd, Jˆ8.5, 6.7 Hz, H-4),
5.80 (2H, m, H-2 and H-3), 6.75 (1H, s, H-10), 8.32 (1H, s,
H-12), 9.05 (1H, s, H-7). dC (75 MHz, CDCl3) 25.3 (12b-
CH3), 36.9 (C-12b), 41.3 (C-3a), 43.5 (C-1), 55.8, 57.5 and
61.6 (OCH3), 75.9 (C-4), 97.9 (C-10), 119.5 (C-12), 121.8
(C-7), 122.8 (C-11a), 125.8, 127.1 (C-2 and C-3), 127.9 and
130.9 (C-7a and C-12a), 137.9, 140.7, 143.4, 146.8, 148.3
and 151.8 (C-5a, C-6a, C-8, C-9, C-11 and C-12c), 176.4
(C-6). m/z 378 (M1, 25), 363 (16), 152 (27), 120 (49), 49
(100).
1.2.4. 9-Methoxyxestoquinone (7). The dimethyl ether (36)
(100 mg, 0.26 mMol) was dissolved in acetonitrile (30 mL)
and ceric ammonium nitrate (435 mg, 0.79 mMol) in water
(20 mL) was added dropwise at 08C. The solution was stir-
red for 5 min at 08C, then water (30 mL) was added. Extrac-
tion with ethyl acetate gave the crude product which was
puri®ed by column chromatography on silica gel using ethyl
acetate/hexanes (4:1) to give 9-methoxyxestoquinone (7)
(55 mg, 60%) as ®ne yellow needles from acetonitrile. mp
307±3108C (Found: M1z, 348.0966. C21H16O5 requires M,
348.0998) nmax (NaCl) 2948, 1693, 1665, 1648, 1605 cm21
;
dH (300 MHz, CDCl3) 1.54 (3H, s, 12b-CH3), 1.76 (1H, ddd,
Jˆ13.0, 4.5, 4.5 Hz, H-1), 2.11-2.37 (2H, m, H-2), 2.52-
2.62 (1H, m, H-1), 2.66 (1H, dd, Jˆ17.0, 9.0 Hz, H-3),
2.89 (1H, dd, Jˆ17.0, 7.6 Hz, H-3), 3.94 (3H, s, OCH3),
6.24 (1H, s, H-10), 7.54 (1H, dd, Jˆ1.3, 1.3 Hz, H-4),
8.25 (1H, s, H-12), 9.10 (1H, s, H-7). dC (75 MHz,
CDCl3) 16.9 (C-3), 18.4 (C-2), 31.2 (C-1), 32.5 (12b-
CH3), 37.4 (C-12b), 56.6 (OCH3), 110.1 (C-10), 121.5
(C-3a), 123.0 (C-12), 127.3 (C-7), 129.5 (C-7a), 133.5
(C-11a), 137.6 (C-6a), 144.0 (C-5a), 144.9 (C-4), 147.2
(C-12c), 156.7 (C-12a), 161.0 (C-9), 170.3 (C-6), 178.9
(C-8), 184.4 (C-11). m/z 348 (M1, 40), 333 (100), 249
(11), 221 (10), 193 (10).
1.2.2. 12b-methyl-8,9,11-trimethoxy-1H-benzo[6,7]phenan-
thro-[10,1-bc]furan-6-(12bH)-one (34). A solution of the
dienone (32) (260 mg, 0.69 mMol) and p-chloranil (345 mg,
1.40 mMol) in xylenes (30 mL) was re¯uxed for 52 h.
Column chromatography of the concentrated reaction
mixture gave the aromatic furan (34) (227 mg, 88%) as
orange crystals from ethyl acetate/hexanes. mp 167±
1688C (Found: C, 73.52; H, 5.32. C23H20O5 requires C,
73.39; H, 5.36%) nmax (NaCl) 2973, 2941, 1675, 1624,
1596 cm21; dH (300 MHz, CDCl3) 1.56 (3H, s, 12b-CH3),
2.56 (1H, ddd, Jˆ16.8, 3.0, 3.0 Hz, H-1), 3.13 (1H, dd,
Jˆ16.8, 6.1 Hz, H-1), 3.99, 4.02 and 4.03 (s, C8-OCH3,
C9±OCH3 and C11-OCH3), 6.11 (1H, ddd, Jˆ9.7, 6.2,
1.8 Hz, H-2), 6.62 (1H, dd, Jˆ9.7, 3.1 Hz, H-3), 6.76 (1H,
s, H-10), 7.57 (1H, s, H-4), 8.22 (1H, s, H-12), 9.13 (1H, s,
H-7). dC (75 MHz, CDCl3) 32.2 (12b-CH3), 35.2 (C-12b),
35.4 (C-1), 55.8, 57.4 and 61.6 (OCH3), 98.0 (C-10), 117.5
(C-2), 118.6 (C-12), 121.0 and 122.4 (C-3a and C-11a),
123.2 (C-7), 127.7 (C-7a), 128.8 (C-3), 132.4 (C-12a),
138.0 (C-8), 141.5 (C-4), 143.1 and 144.2 (C-5a and
C-12c), 144.4, 148.5 and 151.8 (C-6a, C-9 and C-11),
172.7 (C-6). m/z 376 (M1, 87), 361 (100), 331 (21), 303
(14), 145 (24).
1.2.5.
3,4-Dihydro-12b-methyl-8,10,11-trimethoxy-1H-
benzo-[6,7]phenanthro[10,1-bc]furan-6-(12bH)-one (33).
Tri¯uoroacetic acid (5.0 mL) was added to a solution of the
alcohol (24) (0.902 g, 2.11 mMol) in dichloromethane
(60 mL) and the mixture was stirred at room temperature
for 15 min. NaHCO3 was added in small portions followed
by water (50 mL). The product was extracted into ethyl ace-
tate and removal of the solvent gave the dienone (33) as an
orange crystalline solid (0.770 g, 97%). mp 178±1798C
(Found: C, 72.88; H, 5.79. C23H22O5 requires C, 73.00; H,
5.86%) nmax (NaCl) 2968, 2940, 1676, 1656, 1618 cm21; dH
1.65 (3H, s, 12b-CH3), 2.32 (1H, bd, Jˆ17.1 Hz, H-1), 2.92
(1H, dd, Jˆ17.1, 4.4 Hz, H-1), 3.95, 4.02 and 4.05 (s, C8-
OCH3, C10-OCH3, C11-OCH3), 4.03 (concealed, H-3a), 4.14
(1H, d, Jˆ7.5 Hz, H-4), 4.95 (1H, dd, Jˆ8.8, 7.5 Hz, H-4),
5.80 (2H, m, H-2 and H-3), 6.63 (1H, s, H-9), 8.14 (1H, s, H-
12), 9.19 (1H, s, H-7). dC (75 MHz, CDCl3) 25.2 (12b-CH3),
36.9 (C-12b), 41.2 (C-3a), 43.3 (C-1), 55.6, 56.8 and 61.0
(OCH3), 75.9 (C-4), 94.6 (C-9), 117.7 (C-12), 119.6 (C-11a),
123.5 (C-7), 125.9 (C-3), 126.9 (C-2), 127.7, 130.6 (C-7a and
1.2.3. 12b-Methyl-8,9,11-trimethoxy-1H-benzo[6,7]phenan-
thro-[10,1-bc]furan-6-(12bH)-one (36). Palladium on
carbon (10%, 20 mg) and NaHCO3 (1.0 g) was added to a
solution of the furan (34) (121 mg, 0.32 mMol) in ethyl
acetate (50 mL), then treated with hydrogen (1 atm) for
4 h. The reaction mixture was ®ltered and concentrated to
give an oil which on column chromatography (silica gel,

316
H. S. Sutherland et al. / Tetrahedron 57 (2001) 309±317
C-12a), 135.5 and 139.8 (C-11 and C-12c), 146.6, 146.9,
150.6 and 154.2 (C-5a, C-6a, C-8 and C-10), 176.2 (C-6).
m/z 378 (M1, 100), 363 (82), 335 (28), 305 (15).
Jˆ13.2, 4.4, 4.4 Hz, H-1), 2.11±2.35 (2H, m, H-2), 2.58±
2.70 (2H, m, H-1 and H-3), 2.88 (dd, Jˆ17.1, 7.5 Hz, H-3),
3.93 (s, OCH3), 6.26 (1H, s, H-9), 7.54 (1H, dd, Jˆ1.3,
1.3 Hz, H-4), 8.29 (1H, s, H-12), 9.05 (1H, s, H-7). dC
16.9 (C-3), 18.4 (C-2), 31.2 (C-1), 32.5 (C12b-CH3), 42.3
(C-12b), 56.6 (OCH3), 110.6 (C-9), 121.5 (C-3a), 123.5
(C-12), 126.7 (C-7), 130.5 (C-7a), 132.4 (C-11a), 138.3
(C-6a), 144.0 (C-5a), 144.9 (C-4), 147.2 (C-12c), 155.7
(C-12a), 160.5 (C-10), 170.3 (C-6), 179.9 (C-11), 183.6
(C-8). m/z 348 (M1, 39), 333 (100), 305 (6), 249 (11).
1.2.6. 12b-methyl-8,10,11-trimethoxy-1H-benzo[6,7]phenan-
thro-[10,1-bc]furan-6-(12bH)-one (35). A solution of the
dienone (33) (757 mg, 2.00 mMol) and p-chloranil (995 mg,
4.05 mMol) in xylenes (50 mL) was re¯uxed for 48 h.
Column chromatography of the concentrated reaction
mixture gave the aromatic furan (35) (708 mg, 94%) as
orange crystals from ethyl acetate/hexanes. mp 170±
1718C (Found: C, 73.13; H, 5.54. C23H20O5 requires C,
73.39; H, 5.36%) nmax (NaCl) 2966, 2937, 1671,
1618 cm21; dH 1.56 (3H, s, 12b-CH3), 2.65 (1H, ddd,
Jˆ16.7, 2.6, 2.6 Hz, H-1), 3.14 (1H, dd, Jˆ16.7, 6.1 Hz,
H-1), 3.95, 4.03 and 4.05 (s, C8±OCH3, C10-OCH3 and
C11-OCH3), 6.11 (1H, ddd, Jˆ9.7, 6.2, 1.8 Hz, H-2), 6.62
(1H, dd, Jˆ9.7, 3.1 Hz, H-3), 6.65 (1H, s, H-9), 7.56 (1H, s,
H-4), 8.05 (1H, s, H-12), 9.26 (1H, s, H-7). dC 32.2 (12b-
CH3), 35.2 (C-12b and C-1), 55.7, 56.8 and 61.1 (OCH3),
94.7 (C-9), 116.8 (C-2), 117.5 (C-12), 119.4 (C-11a), 120.9
(C-3a), 124.8 (C-7), 128.6 (C-3), 129.0 (C-7a), 130.5
(C-12a), 135.7 (C-11), 141.2 (C-4), 143.7 (C-5a), 144.2
(C-12c), 146.7 (C-6a), 151.0 (C-10), 154.3 (C-8), 172.6
(C-6). m/z 376 (M1, 93), 361 (100), 346 (23), 331 (16),
303 (16).
Acknowledgements
We thank the Natural Sciences and Engineering Research
Council of Canada for support of this work.
References
1. Roll, D. M.; Scheuer, P. J.; Matsumoto, G. K.; Clardy, J. J.
Am. Chem. Soc. 1983, 105, 6177±6178.
2. Nakamura, H.; Kobayashi, J.; Kobayashi, M.; Ohizumi, Y.;
Harata, Y. Chem. Lett. 1985, 713±716; Kobayashi, M.;
Shimizu, N.; Kyogoku, Y.; Kitagawa, I. Chem. Pharm. Bull.
1985, 33, 1305±1308.
1.2.7.
12b-Methyl-8,10,11-trimethoxy-1H-benzo[6,7]-
3. Schmitz, F. J.; Bloor, S. J. J. Org. Chem. 1988, 53, 3922±
3925. Later investigators have suggested4 that voucher speci-
mens of Adocia species studied in this report are more prop-
erly classi®ed as Xestospongia cf. carbonaria.
phenanthro-[10,1-bc]furan-6-(12bH)-one (37). Palladium
on carbon (10%, 30 mg) and NaHCO3 (1.5 g) were added to
a solution of the furan (35) (339 mg, 9.01 mMol) in ethyl
acetate (50 mL), then treated with hydrogen (1 atmosphere)
for 4 h. The reaction mixture was ®ltered and concentrated
to give an oil which on column chromatography (silica gel,
ethyl acetate/hexanes) gave the xestoquinol dimethyl ether
(37) (297 mg, 87%) as a yellow solid. Mp 210±2128C
(Found C, 73.00; H, 6.03. C23H22O5 requires C, 73.00; H,
5.86%) nmax 2967, 1670, 1656, 1609 cm21. dH 1.54 (3H, s,
12b-CH3), 1.85 (1H, ddd, Jˆ13.2, 4.2, 4.2 Hz, H-1), 2.10±
2.30 (2H, m, H-2), 2.57±2.68 (2H, m, H-1 and H-3), 2.87
(1H, dd, Jˆ17.1, 7.5 Hz, H-3), 3.94, 4.02 and 4.04 (s, 8-
OCH3, 10-OCH3 and 11-OCH3), 6.63 (1H, s, H-9), 7.46 (1H,
t, Jˆ1.3 Hz, H-4), 8.07 (1H, s, H-12), 9.23 (1H, s, H-7). dC
17.2 (C-3), 18.7 (C-2), 31.9 (C-1), 33.8 (12b-CH3), 36.2
(C-12b), 55.7, 56.9 and 61.1 (OCH3), 94.6 (C-9), 116.1
(C-12), 119.4 and 121.1 (C-3a and C-11a), 124.8 (C-7),
129.2 and 130.4 (C-7a and C-12a), 135.9 (C-11), 143.5
(C-4), 144.7, 146.2, 147.8, 150.9 and 154.3 (C-5a, C-6a,
C-8, C-10 and C-12c), 172.8 (C-6). m/z 378 (M1, 77), 363
(100), 348 (35), 333 (19), 305 (16), 174 (42).
4. Alvi, K. A.; Rodriguez, J.; Diaz, M. C.; Moretti, R.; Wilhelm,
R. S.; Lee, R. H.; Slate, D. L.; Crews, P. J. Org. Chem. 1993,
58, 4871±4880.
Â
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6. Name and numbering according to the 1993 Edition of the
Ring Systems File (entry RF 70236) published by the Chemi-
cal Abstracts Service of the American Chemical Society.
Xestoquinone 2 can then be named systematically as 12b-
methyl-2,3-dihydro-1H-benzo[6,7]phenanthro[10,1-bc]furan-
6,8,11-trione. Compounds 7 and 8 previously named 14- and
15- methoxyxestoquinones are named as 9- and 10- methoxy
derivatives, respectively in this manuscript.
7. Bae, M.-A.; Tsuji, T.; Kondo, K.; Hirasi, T.; Ishibashi, M.;
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1.2.8. 10-Methoxyxestoquinone (8). The dimethyl ether
(37) (284 mg, 0.75 mMol) was dissolved in acetonitrile
(60 mL) and ceric ammonium nitrate (1.23 g, 2.24 mMol)
in water (40 mL) was added dropwise at 08C. The solution
was stirred for 5 min at 08C, then water (60 mL) was added.
Extraction with ethyl acetate gave the crude product was
puri®ed by column chromatography on silica gel using
ethyl acetate/hexanes (4:1) to give 10-methoxyxesto-
quinone (8) (157 mg, 60%) as ®ne yellow needles from
acetonitrile. mp 268±2708C (Found: C, 72.38; H, 4.90.
C21H16O5 requires C, 72.41; H, 4.63%) nmax (NaCl) 2946,
1676, 1605 cm21. dH 1.54 (3H, s, 12b-CH3), 1.76 (1H, ddd,
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