A short synthesis of (±)-halenaquinone

Full text of DOI:10.1021/jo010112o

J . Org. Chem. 2001, 66, 3639-3641
3639
have recently culminated4 in the synthesis of xesto-
quinone 4 and two of its methoxylated derivatives as well
as of advanced intermediates for viridin9a and morphine.9b
The convergent ABE (naphthofuranone, 3) + CD (isoben-
zofuran,10 5) plan led4 to the pentacycle 6, but we were
unable to introduce the oxygen atom at C-3, required for
the synthesis of halenaquinone from this intermediate
or others similar to it, despite many attempts to do so.
It thus became evident that if the synthesis of 1 (and
subsequently of 2) was to be attained by this common
strategy, a correctly placed oxygen or “potential oxygen”
substituent had to be incorporated in the ABE naphtho-
furanone and therefore in the dienol that precedes it. We
now report the successful implementation of this plan, a
further example of the value of o-benzoquinone mono-
ketals,11 and we illustrate this with a very short synthesis
of (()-halenaquinone.
A Sh or t Syn th esis of (()-Ha len a qu in on e
Hamish S. Sutherland, Fabio E. S. Souza, and
Russell G. A. Rodrigo*
Guelph-Waterloo Centre for Graduate Work in Chemistry
and Biochemistry, Department of Chemistry, University of
Waterloo, Waterloo, Ontario, Canada N2L 3G1
rrodrigo@sciborg.uwaterloo.ca
Received J anuary 30, 2001
In tr od u ction
Halenaquinone 1, first reported1 in 1983, was the
initial member of an expanding family of pentacyclic
metabolites isolated from tropical sponges of the genus
Xestospongia. The 1H-benzo[6,7]phenanthro[10,1-bc]-
furan ring system,2 methylated as it is at C-12b in all
members of the group, contains 20 carbon atoms and is
believed to originate from sesquiterpene (rings A, B, C,
and E) and triketide (ring D) precursors. Many of these
compounds possess potentially valuable pharmacological
properties3 and have attracted much attention from
synthetic chemists.4 (+)-Halenaquinone has been syn-
thesized twice before; in 15 steps from (-)-Wieland-
Miescher ketone5a which was itself prepared from
2-methylcyclohexanedione,5b optically pure in 50% yield,
and subsequently6 in 21 steps from 6,7-dimethoxytetra-
lone. The ABE segment, a common feature of all these
marine quinones, also occurs in the viridin (2) family7 of
furanosteroidal antibiotics and constitutes three rings of
the morphinan alkaloids.
The known12 dienol 7 prepared from propargylic alcohol
in four steps and 63% yield was subjected to our o-
benzoquinone monoketal, Diels-Alder protocol8 with
methylguaiacol 8 and [bis(trifluoroacetoxy)iodo]benzene
to provide a mixture of adducts 9 and 10 which were not
easily separated from each other. The mixture was
therefore refluxed in 1,2,4-trimethylbenzene for 48 h to
convert 10 to 9 by means of the Cope rearrangement. In
this manner 7 and 8 were combined by a sequence of
three reactions (oxidative ketalization, intramolecular
Diels-Alder addition, Cope rearrangement) to yield 9
(36% overall) in two steps without the isolation of any
intermediates. Although a recent report13 recorded the
use of phenyl vinyl sulfide as a dienophile in the
intermolecular Diels-Alder reactions with some o-ben-
zoquinone dimethyl ketals, this is the first time a hetero-
substituted dienol has been employed in our three-
reaction sequence. We were gratified therefore with the
Resu lts a n d Discu ssion
Our laboratory has concentrated its recent efforts on
the development of a rapid, general route8 to naphtho-
furanones such as 3 to serve as synthons for the eventual
preparation of all these compounds. These investigations
(1) Roll, D. M.; Scheuer, P. J .; Matsumoto, G. K.; Clardy, J . J . Am.
Chem. Soc. 1983, 105, 6177-8.
(2) Ring Systems File, entry RF70236, Chemical Abstracts Service,
1993.
(3) 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-
80.
(4) Sutherland, H. S.; Higgs, K. C.; Taylor, N. J .; Rodrigo, R.
Tetrahedron 2001, 57, 309-17 and pertinent references therein.
(5) (a) Harada, N.; Sugioka, T.; Ando, Y.; Uda, H.; Kuriki, T. J . Am.
Chem. Soc. 1988, 110, 8483-7. (b) Gutzwiller, J .; Buchschacher, P.;
Fuerst, A. Synthesis 1977, 167-8.
(6) Kojima, A.; Takemoto, T.; Sodeoka, M.; Shibasaki, M. J . Org,
Chem. 1996, 61, 4876-7. Kojima, A.; Takemoto, T.; Sodeoka, M.;
Shibasaki, M. Synthesis 1998, 581-9.
(7) Hanson, J . R. Nat. Prod. Rep. 1995, 12, 381-4.
(8) Carlini, R.; Higgs, K.; Older, C.; Randhawa, S.; Rodrigo, R. J .
Org. Chem. 1997, 62, 2330-31.
(9) (a) Souza, F. E. S.; Rodrigo, R. J . Chem. Soc., Chem. Commun.
1999, 1947-8. (b) Carlini, R.; Higgs, K. C.; Rodrigo, R.; Taylor, N. J .
J . Chem. Soc., Chem. Commun. 1998, 65-6.
(10) Lynch, V. M.; Fairhurst, R. A.; Magnus, P.; Davis, B. E. Acta
Crystallogr. 1995, C51, 780-82.
(11) Hsui, P. Y.; Liao, C. C. J . Chem. Soc., Chem. Commun. 1997,
1085-6.
(12) Grieco, P. A.; May, S. A.; Kaufman, M. D. Tetrahedron Lett.
1998, 39, 7047-50. Magriotis, P. A.; Brown, J . T.; Scott, M. E.
Tetrahedron Lett. 1991, 32, 5047-50. Kabanyane, S. T.; MaGee, D. I.
Can. J . Chem. 1992, 70, 2758-63.
(13) Gao, S.-Y.; Lin, Y.-L.; Rao, P.-D.; Liao, C.-C. Synlett 2000, 421-
3.
10.1021/jo010112o CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/19/2001

3640 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
36% yield of 9, though somewhat lower than 3 (56%),8
and pleased that the steric and electronic effects of the
thiophenyl substituent in 7 do not significantly compro-
mise the synthetic utility of the double annulation
sequence.
16.2 Hz, 1H, H-5), 2.14 (dd, J ) 6.7, 16.2 Hz, 1H, H-5), 2.57 (dd,
J ) 1.7, 9.3 Hz, 1H, H-8b), 3.08 (m, 1H, H-2a), 3.29 (s, 3H,
R-OCH3), 4.02 (dd, J ) 7.5, 8.8 Hz, 1H, H-2), 4.09 (dd, J ) 3.4,
8.8 Hz, 1H, H-2), 6.94 (dd, J ) 3.1, 6.7 Hz, 1H, H-4), 6.05 (d, J
) 10.1 Hz, 1H, H-7), 6.76 (d, J ) 10.1 Hz, 1H, H-6), 7.25-7.40
(m, 5H, R-SC6H5). 13C NMR (75 MHz, CDCl3) δ (ppm): 27.7,
35.0, 38.9, 40.8, 50.2, 54.4, 73.3, 102.8, 127.1, 127.5, 127.6, 129.2,
131.9, 133.0, 135.5, 158.5, 190.5. Anal. Calcd for C19H20O3S: C,
69.48; H, 6.14. Found: C, 69.30; H, 6.05.
7,12-Ep oxy-5a ,8,11-tr im eth oxy-12b-m eth yl-3-p h en ylth io-
3a ,4,5a ,6a ,7,12,12a -h ep ta h yd r o-1H-ben zo[6,7]p h en a n th r o-
[10,1-bc]fu r a n -6-(12bH)-on e (11). A solution of naphthofura-
none 9 (204 mg, 0.62 mmol) and isobenzofuran 5 (250 mg, 1.40
mmol) in toluene (20 mL) was refluxed for 21 h, after which the
solvent was removed under reduced pressure and the residue
purified by flash chromatography (50% ether in hexane) to give
adduct 11 as a white powder (295 mg, 0.58 mmol, 94% yield).
Mp: 155-6 °C. IR (NaCl): 2942, 1736, 1500, 1439, 1260, 1085
cm-1 1H NMR (300 MHz, CDCl3) δ (ppm): compound 11 is a
.
fluxional molecule, and the proton NMR at room temperature
consists of several very broad signals4 with a few diagnostic
peaks; 1.59 (s, R-CH3), 3.32 (s, R-OCH3), 3.78 (s, Ar-OCH3), 3.80
(s, Ar-OCH3), 6.64, 6.68 (both d, J ) 9.0 Hz, H-9, H-10), 7.23-
7.37 (m, 5H, R-SC6H5). Anal. Calcd for C29H30O6S: C, 68.75; H,
5.97. Found: C, 68.68; H, 6.13.
5a,8,11-Tr im eth oxy-12b-m eth yl-3-ph en ylth io-3a,4,5a,12c-
t e t r a h yd r o-1H -b e n zo[6,7]p h e n a n t h r o[10,1-bc]fu r a n -6-
(12bH)-on e (12). A solution of adduct 11 (403 mg, 0.80 mmol)
and NaOMe (4.00 g, 74 mol) in MeOH (100 mL) was refluxed
for 3 h, after which the solvent was removed under reduced
pressure and the residue partitioned between ether and dilute
HCl (3 M). The organic phase was washed once with water and
dried (MgSO4). Removal of the solvent under reduced pressure
and flash chromatography of the residue (35% EtOAc in hexane)
gave the pentacycle 12 as a bright yellow solid (361 mg, 0.74
mmol, 93% yield).
Naphthofuranone 9 produced the expected bridged
adduct 11 (94%) when refluxed in toluene with 4,7-
dimethoxyisobenzofuran 5. This was aromatized by re-
fluxing with sodium methoxide in methanol (93%) and
the product 12 treated briefly with trifluoroacetic acid
in dichloromethane at ambient temperature to generate
the enone 13 (97%). After aromatization of the dihydro-
furan with p-chloranil in refluxing xylene (14, 46%), the
thiophenyl group was hydrolyzed by heating with tita-
nium tetrachloride in moist acetic acid to produce the
known5a pentacyclic precursor 15 to halenaquinone in
63% yield. This compound had been previously oxidized
to (+)-halenaquinone (45%) and the latter reduced5a to
halenaquinol 16 quantitatively. Our synthesis of 15
therefore provides (()-1 and (()-16 in eight or nine steps,
respectively, in ca. 4% overall yield from 7 and 8.
Furthermore, this work extends the utility of the o-
benzoquinone monoketal methodology and promises a
similar solution to the problem of functionalizing the
highly oxygenated ring A of viridin (2).
Mp: 165-166 °C. IR (NaCl): 2938, 1704, 1628, 1471, 1267,
1090 cm-1 1H NMR (300 MHz, CDCl3) δ (ppm): 1.65 (s, 3H,
.
R-CH3), 2.02 (br dd, J ) 6.4, 17.8 Hz, 1H, H-1), 2.18 (br d, J )
17.8 Hz, 1H, H-1), 2.79 (dd, J ) 1.8, 8.4 Hz, 1H, H-12c), 3.07
(m, 1H, H-3a), 3.20 (s, 3H, R-OCH3), 3.95 (s, 3H, Ar-OCH3), 3.98
(s, 3H, Ar-OCH3), 4.05 (dd, J ) 6.1, 8.8 Hz, 1H, H-4), 4.39 (d, J
) 8.8 Hz, 1H, H-4), 6.06 (dd, J ) 1.7, 6.4 Hz, 1H, H-2), 6.71,
6.82 (both d, J ) 8.4 Hz, 1H, H-9, H-10), 7.24-7.44 (m, 5H,
R-SC6H5), 8.22 (s, 1H, H-12), 8.73 (s, 1H, H-7). 13C NMR (75
MHz, CDCl3) δ (ppm): 24.6, 35.4, 41.4, 41.5, 49.9, 55.5, 55.7,
55.8, 71.7, 103.8, 104.7, 106.3, 117.5, 123.4, 124.8, 127.3, 128.4,
129.2, 131.1, 131.3, 131.6, 132.7, 133.6, 145.0, 149.1, 150.7, 192.6.
Anal. Calcd for C29H28O5S: C, 71.29; H, 5.78. Found: C, 71.30;
H, 5.63.
8,11-Dim eth oxy-12b-m eth yl-3-p h en ylth io-3a ,4 -d ih yd r o-
1H-ben zo[6,7]p h en a n th r o[10,1-bc]fu r a n -6-(12bH)-on e (13).
To a solution of compound 12 (153 mg, 0.31 mmol) in CH2Cl2
(10 mL) was added TFA (0.5 mL). The resulting solution was
stirred for 15 min, after which the reaction mixture was diluted
with CH2Cl2 and quenched with an aqueous NaHCO3 solution.
The organic layer was washed with water and dried (MgSO4)
and the solvent removed under reduced pressure to give pen-
tacycle 13 as a bright yellow solid (138 mg, 0.30 mmol, 97% yield)
that was used without further purification.
Exp er im en ta l Section 14
8a -Me t h oxy-5a -m e t h yl-3-p h e n ylt h io-2,2a ,5,5a ,8a ,8b -
h exa h yd r on a p h th o[1,8-bc]fu r a n -8-on e (9). To a cooled (0 °C)
solution of methylguaiacol (8) (100 mg, 0.72 mmol), 3-phenylthio-
penta-2,4-dien-1-ol (7) (500 mg, 2.60 mmol), and BHT (1 crystal,
aproximately 2 mg) in THF (15 mL) was added [bis(trifluoro-
acetoxy)iodo]benzene (375 mg, 0.87 mmol), and the resulting
solution was stirred for 5 min, after which solid NaHCO3 (150
mg, 1.79 mmol) was also added. After the reaction mixture was
allowed to warm to room temperature and stir overnight, it was
partitioned between water and ether. The aqueous phase was
extracted twice more with ether, and the combined organic layers
were dried over MgSO4 and filtered through a plug of silica gel.
After removal of the solvent under reduced pressure, the
resulting dark orange oil was dissolved in 1,2,4-trimethylbenzene
and refluxed for 2 days. Removal of the solvent under vacuum
followed by flash chromatography (30% ether in hexane) gave
naphthofuranone 9 as a light yellow oil (86 mg, 0.26 mmol, 36%
yield).
Mp: 202-204 °C. IR (NaCl): 2934, 1664, 1627, 1464, 1268,
1091 cm-1 1H NMR (300 MHz, CDCl3) δ (ppm): 1.66 (s, 3H,
.
R-CH3), 2.36 (br d, J ) 17.5 Hz, 1H, H-1), 3.06 (dd, J ) 5.4,
17.5 Hz, 1H, H-1), 3.97 (s, 3H, Ar-OCH3), 3.99 (s, 3H, Ar-OCH3),
4.07 (m, 1H, H-3a), 4.33 (dd, J ) 9.1, 10.6 Hz, 1H, H-4), 4.67
(dd, J ) 9.1, 10.2 Hz, 1H, H-4), 6.08 (m, 1H, H-2), 6.70, 6.81
(both d, J ) 8.4 Hz, 1H, H-9, H-10), 7.29-7.48 (m, 5H, R-SC6H5),
8.35 (s, 1H, H-12), 9.22 (s, 1H, H-7). 13C NMR (75 MHz, CDCl3)
δ (ppm): 25.4, 36.6, 43.6, 44.2, 55.6, 55.7, 75.3, 103.3, 105.8,
119.3, 123.1, 124.8, 127.6, 127.9, 129.3, 129.6, 129.7, 131.8, 132.2,
132.9, 139.2, 145.0, 146.9, 148.6, 150.7, 176.2. Anal. Calcd for
IR (neat): 2940, 1691, 1477, 1439, 1063, 746 cm-1. H NMR
(300 MHz, CDCl3) δ (ppm): 1.22 (s, 3H, R-CH3), 1.95 (br d, J )
1
C
28H24O4S: C, 73.66; H, 5.30. Found: C, 73.85; H, 5.50.
8,11-Dim eth oxy-12b-m eth yl-3-p h en ylth io-1H-ben zo[6,7]-
p h en a n th r o[10,1-bc]fu r a n -6-(12bH)-on e (14). A solution of
pentacycle 13 (108 mg, 0.24 mmol) and p-chloranil (249 mg, 1.01
mmol) in xylenes was refluxed for 2 days, after which the solvent
was removed under vacuum and the residue purified by flash
(14) For general experimental details, see ref 4. Assignments of 1H
NMR signals were made with the aid of 2D and decoupling methods
and by comparison with spectra of similar compounds prepared earlier4
in our laboratory.

Notes
J . Org. Chem., Vol. 66, No. 10, 2001 3641
chromatography (50% EtOAc/hexane) to give furan 14 as a
bright fluorescent yellow-green solution that provided an amor-
phous solid (50 mg, 46% yield) which could not be obtained in
more than 85% purity in spite of repeated chromatography. It
was used as such for the next step.
Ha len a qu in ol Dim eth yl Eth er (15). To a solution of sulfide
14 (15 mg, 0.033 mmol) in glacial acetic acid (2 mL) were added
neat TiCl4 (1 mL) and water (50 µL), and the resulting mixture
was refluxed overnight. After being diluted with CH2Cl2, the
reaction mixture was washed with a saturated aqueous NaHCO3
solution and the organic layer was dried (MgSO4) and concen-
trated under reduced pressure. Flash chromatography of the
residue (50% Et2O/hexane) gave known pentacycle 15 (8 mg,
0.021 mmol, 63% yield), whose NMR spectrum was identical
with the previously published data for (+)-15.5a
1
IR (NaCl): 2932, 1674, 1625, 1464, 1433, 1091, 724 cm-1. H
NMR (300 MHz, CDCl3) δ (ppm): 1.59 (s, 3H, R-CH3), 2.79
(broad d, J ) 16.8 Hz, 1H, H-1), 3.27 (dd, J ) 6.4, 16.8 Hz, 1H,
H-1), 3.97 (s, 3H, Ar-OCH3), 3.98 (s, 3H, Ar-OCH3), 6.34 (m, 1H,
H-2), 6.70, 6.81 (both d, J ) 8.4 Hz, 1H, H-9, H-10), 7.20-7.44
(m, 6H, H-4, R-SC6H5), 8.24 (s, 1H, H-12), 9.27 (s, 1H, H-7).
13C NMR (75 MHz, CDCl3) δ (ppm): 32.2, 35.3, 37.5, 55.68, 55.70,
103.5, 106.2, 118.4, 121.7, 124.2, 124.3, 124.8, 127.2, 127.5, 128.7,
129.2, 130.2, 131.1, 131.8, 133.5, 142.5, 144.1, 144.9, 148.6, 150.8,
172.6. HRMS: calcd for C28H22O4S 454.1239; found 454.1249.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada for sup-
port of this work.
J O010112O