Organometallic routes to 2,5-dihydroxy-3-(indol-3-yl)benzoquinones. Synthesis of demethylasterriquinone B4

Article abstract of DOI:10.1021/jo048126s

(Figure Presented) A method has been developed to sequentially add indole-3-mercurials to dichlorinated quinones using palladium catalysis. These reactions can be used in the modular assembly of bis(indol-3-yl)-benzoquinones, a significant natural product family.

Full text of DOI:10.1021/jo048126s

Organometallic Routes to
2,5-Dihydroxy-3-(indol-3-yl)benzoquinones. Synthesis of
Demethylasterriquinone B4
Michael C. Pirrung,* Koichi Fujita, and Kaapjoo Park
Department of Chemistry, Levine Science Research Center, Duke University,
Durham, North Carolina 27708-0317
michael.pirrung@ucr.edu
Received October 22, 2004
A method has been developed to sequentially add indole-3-mercurials to dichlorinated quinones
using palladium catalysis. These reactions can be used in the modular assembly of bis(indol-3-yl)-
benzoquinones, a significant natural product family.
Introduction
The bis-indolylquinones exhibit a range of biological
activities against cancer and diabetes.3 Asterriquinones
inhibit the interaction between the SH2 domains of
receptor tyrosine kinases, such as the epidermal growth
factor receptor, and their adapter proteins, such as Grb2,
and thereby inhibit trans-membrane signaling by this
oncogene.4 The bis-indolylquinone family has been the
subject of previous synthetic study. The first total
synthesis, of cochliodinol, used as a key step the alumina/
potassium carbonate-promoted condensation of bromanil
A large class of fungal natural products derived from
Aspergillus, Chaetomium, and Pseudomassaria species
contains the bis-indolylquinone core structure. They are
believed to arise biosynthetically by dimerization of
indolepyruvic acid, with the resulting dihydroxy-bis-
indolylquinone being variously prenylated and sometimes
methylated. Most often they are called asterriquinones,
after Aspergillus terreus, and they have been extensively
studied, primarily by the groups of Yamamoto1 and Kaji.2
Their extended conjugated systems and indole donor-
quinone acceptor structures give the asterriquinones
strong visible absorption and deep blue, purple, or red
coloring.
(2) Kaji, A.; Saito, R.; Hata, Y.; Kiriyama, N. Chem. Pharm. Bull.
1999, 47, 77-82. Kaji, A.; Saito, R.; Nomura, M.; Miyamoto, K.-i.;
Kiriyama, N. Biol. Pharm. Bull. 1998, 21, 945-949. Kaji, A.; Kimura,
K.; Teranishi, M.; Kiriyama, N.; Nomura, M.; Miyamoto, K.-i. Chem.
Pharm. Bull. 1998, 46, 1325-1329. Kaji, A.; Iwata, T.; Kiriyama, N.;
Nomura, M.; Miyamoto, K.-i. J. Antibiot. 1998, 51, 235-238. Kaji, A.;
Saito, R.; Nomura, M.; Miyamoto, K.-i.; Kiriyama, N. Anticancer Res.
1997, 17, 3675-3679. Kaji, A.; Saito, R.; Shinbo, Y.; Kiriyama, N.
Chem. Pharm. Bull. 1996, 44, 2340-2341. Kaji, A.; Kimura, K.; Iwata,
T.; Kiriyama, N. Chem. Pharm. Bull. 1995, 43, 1818-20. Kaji, A.;
Iwata, T.; Kiriyama, N.; Wakusawa, S.; Miyamoto, K.-i. Chem. Pharm.
Bull. 1994, 42, 1682-4.
* To whom correspondence should be addressed. Current address:
Department of Chemistry, University of California, Riverside, CA
92521-0403.
(1) (a) Arai, K.; Yamamoto, Y. Chem. Pharm. Bull. 1990, 38, 2929-
32. (b) Shimizu, S.; Yamamoto, Y.; Inagaki, J.; Koshimura, S. Gann
1982, 73, 642-8. (c) Shimizu, S.; Yamamoto, Y.; Koshimura, S. Chem.
Pharm. Bull. 1982, 30, 1896-9. (d) Arai, K.; Masuda, K.; Kiriyama,
N.; Nitta, K.; Yamamoto, Y.; Shimizu, S. Chem. Pharm. Bull. 1981,
29, 961-9. (e) Arai, K.; Shimizu, S.; Yamamoto, Y. Chem. Pharm. Bull.
1981, 29, 1005-12. (f) Yamamoto, Y.; Kiriyama, N.; Shimizu, S.;
Koshimura, S. Gann 1976, 67, 623-4.
(3) Zhang, B.; Salituro, G.; Szalkowski, D.; Li, Z.; Zhang, Y.; Royo,
I.; Vilella, D.; Diez, M. T.; Pelaez, F.; Ruby, C.; Kendall, R. L.; Mao,
X.; Griffin, P.; Calaycay, J.; Zierath, J. R.; Heck, J. V.; Smith, R. G.;
Moller, D. E. Science 1999, 284, 974-977.
10.1021/jo048126s CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/25/2005
J. Org. Chem. 2005, 70, 2537-2542
2537

Pirrung et al.
with 2 equiv of 5-bromoindole.5 A later study used cesium
carbonate in acetonitrile in a two-step, one-pot synthesis
of demethyltetrahydroasterriquinone E, a non-natural
product.6 Neither of these syntheses controls the rate of
the addition of the first indole versus the second indole,
making it difficult to use them to prepare unsymmetrical
derivatives, nor do they control the position of attachment
of the second indole. A late-stage convergent route
leading to the directed total synthesis of the insulin
mimetic compound demethylasterriquinone B1 has been
reported,7 as have two fully regiocontrolled modular
syntheses.8
mercurial 111 was generated from 2-methylindole. 2-tert-
Butylindole and 2-isoprenylindole (prepared by Williams’
method12) were converted to reagents 2 and 3. The
mercuration of 2-isoprenylindole is notably selective for
the more electron-rich indole and is without interference
from the adjacent monosubstituted alkene. However,
with another indole building block that would be useful
for asterriquinone synthesis, 7-prenylindole, the trisub-
stituted alkene is mercurated competitively with the
indole 3-position.
Reactions of these mercurials with 2,5-dichlorobenzo-
quinone in the presence of catalytic palladium acetate
have been conducted in two ways. Acetonitrile was used
as solvent with copper chloride as the reoxidant (vide
infra), or acetic acid was used as solvent with copper
acetate as the reoxidant. The latter process was based
on Knolker‘s report of carbazolquinone synthesis via
intramolecular Heck reaction.13 He proposed for his
reaction that acetic acid promotes electrophilic palla-
dation of an aromatic ring by protonating acetate ligands
on Pd. Using our first procedure, compound 4 (which we
had earlier produced by another route14) was obtained
in 99% yield. Using the second procedure, compound 5
(also made earlier) was obtained in 96% yield. Treatment
of 2,5-dichlorobenzoquinone with 2 equiv of 3 in the
presence of catalytic Pd(OAc)2 at room temperature in
acetonitrile gave indolylquinone 6, a valuable intermedi-
ate for asterriquinone synthesis, in excellent yield (82%).
In these reactions, little variation in efficiency was noted
regardless of the bulk of the indole 2-substituent, which
is a virtue of this methodology compared to our acid-
promoted technology for the addition of indoles to dichlo-
robenzoquinone.15
We have investigated approaches to the synthesis of
the bis-indolylquinones9 focused on the controlled, se-
quential coupling of two indoles to a quinone core using
organometallic methods. This paper reports a synthesis
of a simple, symmetrical member of the class, demethyl-
asterriquinone B4.
As a general approach to the asterriquinones, the
addition of a second indole mercurial to the mono-
indolylquinones 4-6 was examined under similar condi-
tions, and a surprising observation was made. We
expected compounds 4-6 to exhibit reactivity similar to
dichlorobenzoquinone despite the presence of the indole.
This is because the biaryl bond, with four flanking
substituents, should strongly prefer a nonplanar confor-
mation, as suggested by molecular mechanics calcula-
tions in our earlier work.14 With a nonplanar biaryl, the
electronic effect of the indole on the quinone is expected
to be small, which should translate into reactivity similar
to dichlorobenzoquinone, but does not. That is, while the
addition of the 2-methylindole mercurial to mono-indo-
lylquinone 4 gives 7 in excellent yield, poorer results are
Results
An adaptation of a method reported by Hegedus for
Heck reactions on indole-3-mercurials was investigated.10
Such reagents are readily generated in quantitative yield
by treatment of indoles with mercuric acetate (ethanol,
12 h) followed by concentration in vacuo. The known
(4) Harris, G. D.; Nguyen, A.; Strawn, L.; Fong, A.; App, H.; Le, T.;
Sutton, B.; Tang, P. C. Abstracts of Papers, 215th National Meeting of
the American Chemical Society; American Chemical Society: Wash-
ington, DC, 1998; MEDI 163. Alvi, K. A.; Pu, H.; Luche, M.; Rice, A.;
App, H.; McMahon, G.; Dare, H.; Margolis, B. J. Antibiot. 1999, 52,
215-223.
(5) Ho¨rcher, U.; Schwenner, E.; Franck, B. Liebigs Ann. Chem. 1986,
1765-71.
(6) Harris, G. D.; Nguyen, A.; App, H.; Hirth, P.; McMahon, G.; Tang,
C. Org. Lett. 1999, 1, 431.
(7) Liu, K.; Wood, H. B.; Jones, A. B. Tetrahedron Lett. 1999, 40,
5119.
(11) Mingoia, Q. Gazz. Chim. Ital. 1930, 60, 509.
(12) Sanz-Cervera, J. F.; Glinka, T.; Williams, R. M. Tetrahedron
1993, 49, 8471-8482.
(13) Knolker, H.-J.; O’Sullivan, N. Tetrahedron 1994, 50, 10893.
Knolker, H.-J., Reddy, K. R.; Wagner, A. Tetrahedron Lett. 1998, 39,
8267.
(14) Pirrung, M. C.; Park, K.; Li, Z. Org. Lett. 2001, 3, 365-7.
(15) Pirrung, M. C.; Deng, L.; Li, Z.; Park, K. J. Org. Chem. 2002,
67, 8374.
(8) Pirrung, M. C.; Li, Z.; Park, K.; Zhu, J. J. Org. Chem. 2002, 67,
7919. Tatsuta, K.; Mukai, H.; Mitsumoto, K. J. Antibiot. 2001, 54, 105-
8.
(9) Pirrung, M. C.; Park, K.; Webster, N. J. G. ChemBioChem 2003,
4, 379.
(10) Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem.
1981, 46, 2215-21.
2538 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of Demethylasterriquinone B4
SCHEME 1
identical and creates a higher symmetry compound (on
the NMR time scale). It also presumably lowers the
barrier to rotation.
seen using the more hindered mercurials 2 and 3. When
mercurial 2 is used with mono-indolylquinone 5, com-
pound 10 is obtained in only modest yield. These obser-
vations are against intuition.
The addition of 3 to indolylquinones is useful for the
synthesis of natural asterriquinones. Application of this
chemistry to demethylasterriquinone B4 required the
preparation of 12 from indolylquinone 6. This reaction
required stringent conditions (3 × 1 equiv of 3, 3 × 5
mol % Pd(OAc)2, 3 × 2 equiv CuCl2, 3 d, reflux) and gives
a mixture of reduced product and starting material. It is
unclear how the reduced materials are produced or what
is the reducing agent, but we commonly observe these
types of products in palladium-based reactions on these
quinone substrates. These reduced compounds are easily
oxidized by DDQ. Compound 12 is isolated by chroma-
tography (in meager yield). The synthesis of demethyl-
asterriquinone B4 was achieved by the alkaline hydrol-
ysis of 12. The resulting material, obtained in 20% overall
yield from the indole, exhibited NMR, IR, and UV spectra
identical to the natural product.
Compounds 8-10 exhibit doubling of NMR signals due
to atropisomers. That is, the nonplanar biaryl bond with
four different flanking substituents exhibits restricted
rotation (Scheme 1), so the two conformational diaster-
eomers are interconverted slowly on the NMR time scale.
This situation is contrasted with compound 11, prepared
by hydrolysis of 7 in refluxing 4 N KOH followed by
column chromatography on oxalic acid precoated silica
gel.16 This bis-indolyldihydroxybenzoquinone does not
exhibit NMR signal doubling. The 2,6-dihydroxybenzo-
quinone substructure undergoes rapid tautomerism that
effectively makes the two different flanking substituents
A putative mechanism is given in Scheme 2 for
coupling of a mercurated indole to give the indolylquinone
(16) Yamamoto, Y.; Nishimura, K.; Kiriyama, N. Chem. Pharm. Bull.
1976, 24, 1853-1859.
J. Org. Chem, Vol. 70, No. 7, 2005 2539

Pirrung et al.
SCHEME 2
properly operating fume hood and only while wearing ap-
propriate personal protective equipment. Residues from reac-
tions involving the generation or use of compounds 1-3 should
be disposed of in accordance with current statutes and prudent
chemical hygiene practices.
2-tert-Butyl-1H-indol-3-ylmercuric acetate (2). 2-tert-
Butylindole (1.61 g, 9.29 mmol) and Hg(OAc)2 (3.26 g,
10.2 mmol, 1.1 equiv) were dissolved in ethanol (100 mL) under
argon and stirred at room temperature for 25 h. The ethanol
was evaporated under reduced pressure, giving the product
as a gray solid (4.01 g, 100%). 1H NMR (DMSO-d6): δ 1.43
(s, 9H), 1.93 (s, 3H), 6.89 (td, J ) 0, 0 Hz, 1 H), 6.97 (dt, J )
0, 0 Hz, 1H), 7.28 (d, J ) 0 Hz, 1H), 7.60 (s, 1H), 7.78 (br s,
1H). Compound 2 was not further characterized because of
toxicity concerns.
2-(1,1-Dimethyl-allyl)-1H-indol-3-ylmercuric Acetate
(3). To a solution of 2-(1,1-dimethylallyl)-1H-indole (1.25 g,
6.76 mmol) in ethanol (100 mL) was added Hg(OAc)2 (2.17 g,
6.82 mmol) at room temperature, and the mixture was stirred
for 2 d. The solvent was evaporated to give 3 (3.00 g, 100%)
as a yellow solid. 1H NMR (CDCl3) δ 9.18 (bs, 1H), 7.41
(d, J ) 7.9 Hz, 1H), 7.27 (d, J ) 7.9 Hz, 1H), 7.03 (m, 2H),
6.05 (dd, J ) 17.4, 10.5 Hz, 1H), 5.24 (d, J ) 10.5 Hz, 1H),
5.19 (d, J ) 17.4 Hz, 1H), 2.06 (s, 3H), 1.42 (s, 6H). 13C NMR
(CDCl3): δ 176.7, 147.1, 135.3, 132.3, 128.2, 121.6, 121.2, 119.8,
114.2, 110.8, 38.4, 27.9, 22.9. Compound 3 was not further
characterized because of toxicity concerns.
2,5-Dichloro-3-(2-methyl-1H-indol-3-yl)[1,4]-
benzoquinone (4). A mixture of 2,5-dichlorobenzoquinone
(18 mg, 0.102 mmol), 2-methyl-3-indolylmercuric acetate
(84 mg, 0.216 mmol), Pd(OAc)2 (1.2 mg, 0.0054 mmol), and
CuCl2 (27 mg, 0.201 mmol) in CH3CN (2 mL) was stirred at
room temperature for 3 h. The reaction mixture was filtered
through Celite, washed with CH3CN, and the combined
filtrates were evaporated. The residue was purified by silica
gel column chromatography using hexanes-ethyl acetate
(5:1) as eluent to give 4 (36 mg, 100%) as a blue solid. 1H NMR
(CDCl3): δ 8.34 (bs, 1H), 7.35-7.10 (m, 5H), 2.32 (s, 3H). FAB-
MS: m/z 305 (M+). This is a known compound prepared earlier
in our laboratory.14
2,5-Dichloro-3-(2-tert-butyl-1H-indol-3-yl)[1,4]-
benzoquinone (5). A mixture of 2,5-dichlorobenzoquinone
(20 mg, 0.112 mmol), 2-tert-butyl-3-indolylmercuric acetate
(100 mg, 0.232 mmol), Pd(OAc)2 (2.6 mg, 0.012 mmol), Cu-
(OAc)2 (42 mg, 0.230 mmol) in AcOH (2 mL) was stirred at
room temperature for 50 h. The reaction mixture was concen-
trated under reduced pressure and purified by silica gel column
chromatography using hexanes-ethyl acetate (10:1) as eluent
to give 5 (38 mg, 96%) as a blue solid. 1H NMR (CDCl3):
δ 8.30 (bs, 1H), 7.34 (dt, J ) 8.1, 0.9 Hz, 1H), 7.24 (s, 1H),
7.18-7.12 (m, 1H), 7.08-7.02 (m, 2H), 1.33 (s, 9H). ESI-MS:
m/z 348 (M + H)+. This is a known compound prepared earlier
in our laboratory.14
involving simple modification of the conventional Heck
mechanism. Transmetalation from mercury to palladium
gives 13. Coordination to the quinone gives π-complex
14, from which syn oxidative addition gives 15. Because
this intermediate has the incorrect stereochemistry for
a syn â-hydrogen elimination, an isomerization via an
η1 f η3 f η1 equilibration that produces 16 is proposed.
A reversal of this process can occur on the other face of
the cyclohexadiene ring, giving 17 that can undergo
â-hydrogen elimination. The copper salt presumably
serves to oxidize the resulting Pd0 species to make the
reaction catalytic in noble metal.
Further experiments were aimed at increasing the
environmental friendliness of this reaction sequence by
omitting the mercuration step. The addition of 2-methyl-
indole to 4 using catalytic palladium acetate and copper
chloride in acetonitrile gives 7, though in lower yield
(50%) than from the mercurial. The direct palladation of
the indole is one mechanism that can be used to explain
this observation, which is precedented in Hegedus’
work.10 In acetic acid, the addition of 2-tert-butylindole
to 4 in excellent yield does not require palladium, but
does require copper acetate. In its absence, a large
fraction of the product mixture is 2,5-dichlorohydro-
quinone. We suggest the copper acetate plays a dual role
in promoting the conjugate addition by Lewis acidity and
oxidizing the hydroquinone to the quinone. In some
instances, this may prove to be a convenient procedure,
as it could be used in the generation of compound 12, an
intermediate in the foregoing natural product synthesis,
more efficiently than via the mercurial.
Experimental Section
Caution! Organomercury compounds are often highly toxic.
Compounds 1-3 have not been evaluated for toxicity and
therefore should be treated as if they have been shown to be
highly toxic. They should be prepared and handled in a
2540 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of Demethylasterriquinone B4
2,5-Dichloro-3-[2-(1,1-dimethylallyl)-1H-indol-3-yl][1,4]-
benzoquinone (6). To a solution of 2-(1,1-dimethylallyl)-3-
indolylmercuric acetate 3 (100 mg, 0.225 mmol) in CH3CN
(5 mL) were added 2,5-dichloro-1,4-benzoquinone (16 mg,
0.090 mmol), CuCl2 (61 mg, 1.3 mmol), and Pd(OAc)2 (2.0 mg,
9.0 µmol) at room temperature. After stirring for 48 h at room
temperature, the reaction mixture was filtered through Celite.
The filtrate was concentrated and the residue was purified by
flash column chromatography using 15% EtOAc in hexane as
eluent to afford pure 6 (26 mg, 82%) as a blue solid. Rf ) 0.33
177.7, 177.6, 146.2 (2C), 143.6, 143.6, 142.8, 142.8, 142.3,
142.3, 140.8, 140.8, 140.3, 140.2, 137.9, 137.5, 136.6, 136.5,
136.4, 136.3, 128.1, 128.0, 127.7, 127.7, 122.2, 122.2, 121.9,
121.8, 120.6, 120.4, 120.3, 120.1, 120.1, 120.0, 119.5, 119.4,
112.8, 112.7, 111.8, 111.7, 111.6, 111.5, 105.7, 105.4, 103.9
(2C), 40.0 (2C), 28.5 (2C), 26.83 (2C), 13.66 (2C). HRMS
(FAB): calcd for C28H22N2O2Cl2 [M]+ 488.1058, found 488.1063.
2,5-Dichloro-3-[2-(1,1-dimethylallyl)-1H-indol-3-yl]-6-
(2-methyl-1H-indol-3-yl)[1,4]benzoquinone (9). A mixture
of 4 (20 mg, 0.066 mmol), 3 (70 mg, 0.158 mmol), Pd(OAc)2
(1.5 mg, 0.007 mmol), and Cu(OAc)2 (24 mg, 0.132 mmol) in
AcOH (1 mL) was stirred at 80 °C for 24 h. The reaction
mixture was dissolved in ethyl acetate, passed through Celite,
washed with ethyl acetate, and the combined filtrates were
evaporated. The residue was treated again in the same way.
The crude product was purified by silica gel column chroma-
tography using hexanes-ethyl acetate (5:1) as eluent to give
9 (17 mg, 54%) as a blue solid. 1H NMR (acetone-d6, rotational
isomers (∼1:1)): δ 10.62 (bs, 1H), 10.43 (bs, 1H), 7.40-7.22
(m, 4H), 7.23-6.96 (m, 4H), 2.42 (s, 3H), 2.40 (s, 3H), 1.54
(s, 3H), 1.53 (s, 3H), 1.522 (s, 3H), 1.520 (s, 3H). 13C NMR
(acetone-d6, rotational isomers (∼1:1)): δ 179.1, 177.9, 146.5,
143.9, 143.0, 142.6, 141.0, 140.6, 140.5, 138.1, 137.8, 136.8,
136.7, 136.6, 128.4, 128.3, 127.9, 122.4, 122.1, 120.8, 120.6,
120.5, 120.2, 119.7, 119.6, 113.0, 112.9, 111.9, 111.8, 111.7,
105.9, 105.6, 104.1, 40.0, 28.5, 26.8, 13.6. ESI-MS: m/z 489
[M + H]+. HRMS (FAB): calcd for C28H24Cl2N2O2 [M + 2H]+
490.1215, found 490.1203.
2,5-Dichloro-3,6-bis-(2-tert-butyl-1H-indol-3-yl)[1,4]-
benzoquinone (10). This compound was synthesized from 5
(22% yield) in the same way as 8. 1H NMR (acetone-d6,
rotational isomers (∼3:2)): δ 10.45 (bs, 2H), 7.40-7.33 (m, 3H),
7.18-7.06 (m, 3H), 7.02-6.96 (m, 2H), 1.46 (s, 9H), 1.41
(s, 9H). 13C NMR (acetone-d6, rotational isomers (∼3:2)):
δ 179.1, 178.9, 146.3, 145.8, 143.9, 143.7, 143.6, 136.5, 128.2,
128.0, 122.3, 120.3, 120.2, 119.5, 118.8, 111.8, 111.7, 102.9,
102.7, 34.3, 30.6. ESIMS: m/z 519 [M + H]+. HRMS (FAB):
calcd for C30H30Cl2N2O2 [M + 2H]+ 520.1684, found 520.1679.
1
(1:4, EtOAc/hexane). H NMR (CDCl3): δ 8.28 (bs, NH), 7.34
(dt, J ) 8.1, 0.9 Hz, 1H), 7.21 (s, 1H), 7.20-7.07 (m, 3H), 5.98
(dd, J ) 17.4, 10.5 Hz, 1H), 5.11 (dd, J ) 17.4, 0.9 Hz, 1H),
5.07 (dd, J ) 10.5, 0.9 Hz, 1H), 1.43 (s, 3H), 1.42 (s, 3H). 13C
NMR (CDCl3): δ 177.6, 177.3, 144.9, 144.8, 142.6, 142.0, 141.8,
134.7, 132.8, 126.5, 122.3, 120.3, 118.4, 113.1, 110.9, 102.8,
39.3, 27.9, 26.7. This is a known compound prepared earlier
in our laboratory.14
2,5-Dichloro-3,6-bis-(2-methyl-1H-indol-3-yl)[1,4]-
benzoquinone (7). A mixture of 4 (20 mg, 0.066 mmol),
2-methyl-3-indolylmercuric acetate (80 mg, 0.205 mmol), Pd-
(OAc)2 (2.0 mg, 0.009 mmol), and Cu(OAc)2 (36 mg,
0.198 mmol) in AcOH (2 mL) was stirred at room temperature
for 28 h. The reaction mixture was concentrated under reduced
pressure and purified by silica gel column chromatography
using hexanes-ethyl acetate (5:1) as eluent to give 7 (28 mg,
1
99%) as a blue solid. H NMR (acetone-d6): δ 10.58 (bs, 2H),
7.40-7.27 (m, 4H), 7.13-6.99 (m, 4H), 2.41 (s, 3H), 2.39
(s, 3H). 13C NMR (acetone-d6): δ 178.2, 140.9, 140.4, 138.0,
136.8, 128.4, 122.0, 120.7, 120.4, 111.7, 106.0, 13.6. ESI-MS:
m/z 435 [M + H]+. HRMS (FAB): calcd for C24H18Cl2N2O2
-
[M + 2H]+ 436.0745, found 436.0760.
2,5-Dichloro-3-(2-methyl-1H-indol-3-yl)-6-(2-tert-butyl-
1H-indol-3-yl)[1,4]benzoquinone (8). A mixture of 4 (15 mg,
0.049 mmol), 2-tert-butyl-3-indolylmercuric acetate (64 mg,
0.148 mmol), Pd(OAc)2 (1.1 mg, 0.005 mmol), and Cu(OAc)2
(27 mg, 0.148 mmol) in AcOH (1 mL) was stirred at reflux for
24 h. The reaction mixture was concentrated under reduced
pressure and purified by silica gel column chromatography
using hexanes-ethyl acetate (5:1) as eluent to give 8 (15 mg,
2,5-Dihydroxy-3,6-bis-(2-methyl-1H-indol-3-yl)[1,4]-
benzoquinone (11). To a solution of 2,5-dichloro-3,6-bis-(2-
methyl-1H-indol-3-yl)[1,4]benzoquinone (7, 0.50 g, 1.15 mmol)
in THF/EtOH (15/30 mL) was added 4 N KOH (15 mL,
60 mmol). The reaction mixture was refluxed for 10 h. The
organic solvents were removed in vacuo, and the crude mixture
was acidified with 1 N HCl. The resulting solution was
extracted with EtOAc (3 × 50 mL). The extracts were washed
with brine and dried over Na2SO4. The residue was concen-
trated and purified by flash column chromatography using
oxalic acid-precoated silica gel [prepared by the literature
procedure:16 suspension of silica gel in 0.1 N oxalic acid
overnight, filtration, washing with H2O, and drying in an oven
at 100 °C overnight] and 30% EtOAc in hexane as eluent to
afford pure 11 (282 mg, 62%) as a dark red-purple solid. Mp:
1
64%) as a blue solid. H NMR (acetone-d6, rotational isomers
(∼1:1)): δ 10.62 (bs, 1H), 10.42 (bs, 1H), 7.40-7.25 (m, 4H),
7.15-6.95 (m, 4H), 2.43 (s, 3H), 2.39 (s, 3H), 1.44 (s, 9H), 1.43
(s, 9H). 13C NMR (acetone-d6, rotational isomers (∼1:1)):
δ 179.2, 177.9, 146.0, 143.7, 143.2, 140.9, 140.8, 140.7, 138.3,
138.1, 136.8, 136.7, 136.4, 128.3, 128.2, 122.2, 122.1, 120.9,
120.5, 120.1, 120.0, 111.8, 111.7, 105.8, 105.7, 103.0, 34.2, 30.6,
13.7. ESI-MS: m/z 477 [M + H]+. HRMS (FAB): calcd for
C27H24Cl2N2O2 [M + 2H]+ 478.1215, found 478.1213.
2,5-Dichloro-3-[2-(1,1-dimethylallyl)-1H-indol-3-yl]-6-
(2-methyl-1H-indol-3-yl)[1,4]benzoquinone (9). To a solu-
tion of 4 (188 mg, 0.614 mmol) in CH3CN (5 mL) were added
2-(1,1-dimethylallyl)-3-indolylmercuric acetate 3 (390 mg,
0.614 mmol), CuCl2 (165 mg, 1.23 mmol), and Pd(OAc)2
(7.0 mg, 0.0307 mmol) at room temperature. After the reaction
mixture was heated at reflux for 24 h, more reagents, 3
(390 mg, 0.614 mmol), CuCl2 (165 mg, 1.23 mmol), Pd(OAc)2
(7.0 mg, 0.0307 mmol), and CH3CN (2 mL), were added to the
mixture, and then the mixture was refluxed for 24 h again.
This step was repeated one more time. The reaction mixture
was cooled to room temperature and filtered through Celite.
The filtrate was concentrated and the residue was purified by
flash column chromatography using 20% EtOAc in hexane as
eluent to afford the title compound as a purple solid (152 mg,
64% based on 21% recovered starting material 4). Rf ) 0.31
(3:7, EtOAc/hexane). IR (thin film): 3398, 2971, 1670, 1574,
1
277-278 °C. IR (thin film): 3395, 2926, 1617, 1460 cm-1. H
NMR (300 MHz, CD3OD): δ 10.40 (bs, 2NH), 7.27 (d, J ) 7.8
Hz, 4H), 7.06-6.94 (m, 4H), 5.00 (bs, 2OH), 2.32 (s, 6H).
13C NMR (75 MHz, CD3OD): δ 137.0, 136.5, 129.3, 121.4,
120.3, 119.8, 112.6, 111.3, 102.7, 13.4. HRMS (FAB): calcd
for C24H19N2O4 [M + H]+ 399.1345, found 399.1340.
2,5-Dichloro-3,6-bis-[2-(1,1-dimethylallyl)-1H-indol-3-
yl][1,4]benzoquinone (12). To a solution of 6 (81 mg,
0.225 mmol) in CH3CN (5 mL) were added 2-(1,1-dimethyl-
allyl)-3-indolylmercuric acetate 3 (100 mg, 0.225 mmol), CuCl2
(60.5 mg, 0.45 mmol), and Pd(OAc)2 (2.5 mg, 0.0113 mmol) at
room temperature. After the reaction mixture was heated at
reflux for 24 h, more reagents, 3 (100 mg, 0.225 mmol), CuCl2
(60.5 mg, 0.45 mmol), Pd(OAc)2 (2.5 mg, 0.0113 mmol) and
CH3CN (2 mL), were added to the mixture, and then the
mixture was refluxed for 24 h again. This step was repeated
one more time. The reaction mixture was cooled to room
temperature, and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone, 102 mg, 0.45 mmol) was added. The mixture was
1459, 1259 cm-1 1H NMR (300 MHz, acetone-d6, rotational
.
isomers (∼1:1)): δ 10.62 (bs, 2NH), 10.45 (bs, 2NH), 7.41-
7.43 (m, 8H), 7.14-6.98 (m, 8H), 6.17 (dd, J ) 17.4, 10.5 Hz,
1H), 6.15 (dd, J ) 17.4, 10.5 Hz, 1H), 5.19-5.08 (m, 4H), 1.55
(s, 3H), 1.54 (s, 3H), 1.533 (s, 3H), 1.527 (s, 3H). 13C NMR
(75 MHz, acetone-d6, rotational isomers (∼1:1)): δ 178.9, 178.8,
J. Org. Chem, Vol. 70, No. 7, 2005 2541

Pirrung et al.
stirred for 10 h at room temperature and filtered through
Celite. The filtrate was concentrated and the residue was
purified by flash column chromatography using 20% EtOAc
in hexane as eluent to afford the title compound (32 mg, 26%)
as a purple solid. Rf ) 0.31 (3:7, EtOAc/hexane).
tography using hexanes-ethyl acetate (7:1) as eluent to give
demethylasterriquinone B4 (23 mg, 74%) as a purple amor-
phous solid. The NMR, UV, and IR data were consistent with
those reported.17 FT-IR (KBr):3408, 3332, 2969, 1640,
1346 cm-1
.
1H NMR (acetone-d6, rotational isomers (∼1:1)):
A mixture of 6 (60 mg, 0.167 mmol), 2-(1,1-dimethylallyl)-
1H-indole (70 mg, 0.378 mmol), and Cu(OAc)2 (78 mg,
0.429 mmol) in AcOH (6 mL) was stirred at 80 °C for 48 h.
The reaction mixture was concentrated under reduced pres-
sure and purified by silica gel column chromatography using
hexanes-ethyl acetate (15:1) as eluent to give 26 mg of 12 (as
a purple solid), 33% based on 13% recovered starting material
6. 1H NMR (acetone-d6, rotational isomers (∼1:1)): δ 10.46 (bs,
1H), 10.42 (bs, 1H), 7.42-7.36 (m, 2H), 7.30 (d, J ) 8.1 Hz,
1H), 7.20 (d, J ) 8.1 Hz, 1H), 7.15-6.96 (m, 4H), 6.21-6.09
(m, 2H), 5.19-5.05 (m, 4H), 1.54 (s, 6H), 1.53 (s, 6H). 13C NMR
(acetone-d6, rotational isomers (∼1:1)): δ 179.1, 178.7, 146.5,
146.4, 144.0, 143.0, 142.7, 136.6, 127.8, 122.5, 120.5, 120.3,
119.8, 119.0, 113.1, 113.0, 112.1, 111.9, 103.9, 103.8, 40.1, 40.0,
28.7, 28.5, 26.9. ESI-MS: m/z 543 [M + H]+. HR-MS (FAB):
calcd for C32H30Cl2N2O2 [M + 2H]+ 544.1684, found 544.1688.
Demethylasterriquinone B4. A solution of 12 (34 mg,
0.063 mmol) in methanol (4 mL) was heated at reflux for
10 min, and aq 10% NaOH (2 mL) was added. After an
additional 30 min of reflux, methanol was removed under
reduced pressure and the residue was acidified with 2M HCl.
The solution was extracted with ethyl acetate, washed with
brine, dried over Na2SO4 and evaporated. The crude material
was purified by oxalic acid-coated silica gel column chroma-
δ 10.11 (bs, 1H), 10.07 (bs, 1H), 9.37 (bs, 2H), 7.35 (d, J ) 8.1
Hz, 1H), 7.33 (d, J ) 8.1 Hz, 2H), 7.20 (d, J ) 8.1 Hz, 1H),
7.09-7.02 (m, 2H), 6.99-6.92 (m, 2H), 6.20 (dd, J ) 17.4,
10.5 Hz, 1H), 6.18 (dd, J ) 17.4, 10.5 Hz, 1H), 5.17-4.97
(m, 4H), 1.54 (s, 6H), 1.53 (s, 6H). 13C NMR (acetone-d6,
rotational isomers (∼1:1)): δ 146.7, 143.4, 143.2, 136.5, 136.5,
129.9, 129.8, 121.9, 119.7, 119.7, 119.2, 113.5, 111.7, 111.6,
111.4, 101.5, 40.0, 27.5. ESI-MS: m/z 505 [M - H]-.
Acknowledgment. This work was financially sup-
ported by the American Diabetes Association, the
Diabetes Action Research and Education Foundation,
and Ajinomoto Pharmaceuticals. We appreciate data
collection by L. Deng and administrative support by L.
LaBean and J. Wessels.
Supporting Information Available: 1H NMR spectra for
7-12 and demethylasterriquinone B4. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
JO048126S
(17) O’Leary, M. A.; Hanson, J. R.; Yeoh, B. L. J. Chem. Soc., Perkin
Trans. 1 1984, 567.
2542 J. Org. Chem., Vol. 70, No. 7, 2005