Total syntheses of demethylasterriquinone B1, an orally active insulin mimetic, and demethylasterriquinone A1.

Article abstract of DOI:10.1021/jo020182a

Two total syntheses of the unsymmetrical bis-indolylquinone natural product demethylasterriquinone B1 (also known as L-783,281) have been accomplished. The first exploits a known base-promoted condensation of indoles with bromanil, which stops at monoaddition using the sterically hindered 2-isoprenylindole. This permits addition of the second indole, 7-prenylindole, which gives both meta- and para-substituted bis-indolylquinone products. This regiochemical control problem was solved by extension of a method we recently developed for acid-promoted addition of indoles to 2,5-dichlorobenzoquinone. Under our original mineral acid conditions, reaction of 2-isoprenylindole with dichlorobenzoquinone fails, but it succeeds with 3-bromo-2,5-dichlorobenzoquinone using acetic acid as the promoter. The regiochemistry established in such selectively bromine-substituted quinones can be exploited in Stille couplings. As a model system, the synthesis of demethylasterriquinone A1 was accomplished using as the key step a Stille coupling of a 2,5-dibromobenzoquinone with an (N-isoprenylindol-3-yl)tin, producing the para-substituted bis-indolylquinone exclusively. Use of a (7-prenylindole)tin in coupling with a bromo-2,5-dichloro-4-indolylbenzoquinone gives the demethylasterriquinone B1 precursor. The dihaloquinone products of these indole/quinone coupling processes can be hydrolyzed to the dihydroxyquinone natural products. Demethylasterriquinone B1 is of high recent interest as a small molecule insulin mimetic with oral anti-diabetic activity in mice.

Full text of DOI:10.1021/jo020182a

VOLUME 67, NUMBER 23
NOVEMBER 15, 2002
© Copyright 2002 by the American Chemical Society
Tota l Syn th eses of Dem eth yla ster r iqu in on e B1, a n Or a lly Active
In su lin Mim etic, a n d Dem eth yla ster r iqu in on e A1
Michael C. Pirrung,* Zhitao Li, Kaapjoo Park, and J in Zhu
Department of Chemistry, Levine Science Research Center, Duke University,
Durham, North Carolina 27708-0317
pirrung@chem.duke.edu
Received March 15, 2002
Two total syntheses of the unsymmetrical bis-indolylquinone natural product demethylaster-
riquinone B1 (also known as L-783,281) have been accomplished. The first exploits a known base-
promoted condensation of indoles with bromanil, which stops at monoaddition using the sterically
hindered 2-isoprenylindole. This permits addition of the second indole, 7-prenylindole, which gives
both meta- and para-substituted bis-indolylquinone products. This regiochemical control problem
was solved by extension of a method we recently developed for acid-promoted addition of indoles to
2,5-dichlorobenzoquinone. Under our original mineral acid conditions, reaction of 2-isoprenylindole
with dichlorobenzoquinone fails, but it succeeds with 3-bromo-2,5-dichlorobenzoquinone using acetic
acid as the promoter. The regiochemistry established in such selectively bromine-substituted
quinones can be exploited in Stille couplings. As a model system, the synthesis of demethylaster-
riquinone A1 was accomplished using as the key step a Stille coupling of a 2,5-dibromobenzoquinone
with an (N-isoprenylindol-3-yl)tin, producing the para-substituted bis-indolylquinone exclusively.
Use of a (7-prenylindole)tin in coupling with a bromo-2,5-dichloro-4-indolylbenzoquinone gives the
demethylasterriquinone B1 precursor. The dihaloquinone products of these indole/quinone coupling
processes can be hydrolyzed to the dihydroxyquinone natural products. Demethylasterriquinone
B1 is of high recent interest as a small molecule insulin mimetic with oral anti-diabetic activity in
mice.
In tr od u ction
kinases, such as the epidermal growth factor receptor,
and their adapter proteins, such as Grb2, an interaction
mediated through the SH2 domains of Grb2. These
demethylasterriquinones thereby inhibit trans-mem-
brane signaling by the EGF oncogene product.3 Dem-
ethylasterriquinone B1 (DAQ B1 or L-783,281) was
recently isolated from a Congo fungus classified as a
A large class of fungal natural products derived from
Aspergillus, Chaetomium, and Pseudomassaria species
is based upon a dihydroxy-bis-indolylquinone unit that
is variously prenylated and sometimes O-methylated.
Most often, they are called asterriquinones (Figure 1),
after Aspergillus terreus, and they have been extensively
studied, primarily by the groups of Yamamoto1 and Kaji.2
The bis-indolylquinones exhibit a range of medicinal
activities. They have antitumor activity, with aster-
riquinone A1 forming DNA interstrand cross-links (IC50
1 µM), causing arrest of the cell cycle at G1 and apoptotic
cell death. Members of the family also inhibit the
interaction between phosphorylated receptor tyrosine
(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.
(3) 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.
(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.
10.1021/jo020182a CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/18/2002
J . Org. Chem. 2002, 67, 7919-7926
7919

Pirrung et al.
and it alters the proteolysis pattern of the insulin
receptor near the ATP binding site. Like insulin, activa-
tion of insulin receptor in â-cells by DAQ B1 stimulates
insulin gene transcription (EC50 50 nM),7 but unlike
insulin, DAQ B1 does not cause undesirable proliferation
of vascular smooth muscle cells.8 Further studies have
shown that DAQ B1 alone does not result in hypoglyce-
mia in the streptozotocin-induced diabetic mouse model
(similar to type I diabetes) or in lean non-diabetic mice,
but causes glucose lowering in diabetic mice in the
presence of a sub-effective dose of insulin.9 The biology
of DAQ B1 is thus a bit unclear, as it is a full insulin
mimetic in cells expressing insulin receptor but is an
insulin receptor activator with utility as an insulin
sensitizer in animal models.
Simple structure-activity relationships based on modi-
fications of the natural product have been reported.10
Reduction or hydroxylation of the prenyl groups or
N-methylation are tolerated, but the only change permit-
ted in the quinone is methylation of one hydroxyl.
Further medicinal chemistry has led to related active
structures.11
F IGURE 1. Asterriquinones from Aspergillus terreus.
DAQ B1 is also an agonist of the neurotrophin recep-
tors TrkA, B, and C, which like the insulin receptor are
tyrosine kinases.12 DAQ B1 activates Trk phosphoryla-
tion in neuronal cells and in Chinese hamster ovary
(CHO) cells transfected with Trk, and it was suggested
that DAQ B1 interacts with the intracellular domain of
Trk and noncovalently triggers receptor dimerization.
Key steps in many signal transduction pathways medi-
ated by growth factor receptors (such as those for insulin
and neurotrophin) are receptor dimerization followed by
autophosphorylation. The ability of DAQ B1 to promote
receptor dimerization would therefore be crucial and
unique. It is reasonable to suggest that the extended
molecular structure of DAQ B1 may accomplish this
through the two structural domains of its indole rings,
each of which might interact with one chain of a tyrosine
kinase receptor. In other words, DAQ B1 might act as a
chemical inducer of dimerization.13 The asterriquinone
family of natural products thus seems to be able to affect,
either positively or negatively, members of the receptor
tyrosine kinase family. Access to diverse structures based
on the bis-indolylquinone scaffold could therefore be
valuable in discovery of ligands not only for the insulin
receptor, but for other growth factor receptors. A total
Pseudomassaria, but DAQ B1 was already known as a
synthetic material from earlier work.1e A Merck group
discovered the compound in nature by screening for
insulin receptor tyrosine kinase activators.4 Small mol-
ecule agonists of growth factor receptors are quite rare,5
with the only other example being a granulocyte-colony-
stimulating factor mimic,6 so its activity as an insulin
receptor activator was remarkable. DAQ B1 shows cel-
lular activity in triggering the insulin receptor tyrosine
kinase with a 3-6 µM IC50, and its action is specific. It
induces phosphorylation of the insulin receptor â (in its
tyrosine kinase domain), but not insulin-like growth
factor receptor or epidermal growth factor receptor. A
related natural product (demethylasterriquinone B4)
shows no insulin receptor activation. DAQ B1 stimulates
glucose uptake in rat adipocytes and mouse soleus muscle
and shows oral anti-diabetic activity in ob/ ob mice (a
noninsulin dependent diabetes mellitus (NIDDM) model).
DAQ B1 is believed to bind to the intracellular domain
of the receptor because it does not compete with insulin
(7) Xu, G. G.; Gao, Z.-y.; Borge, P. D., J r.; J egier, P. A.; Young, R.
A.; Wolf, B. A. Biochemistry 2000, 39, 14912-9.
(8) Weber, M. A.; Lidor, A.; Arora, S.; Salituro, G. M.; Zhang, B. B.;
Sidawy, A. N. J . Vasc. Surg. 2000, 32, 1118-26.
(9) Qureshi, S. A.; Ding, V.; Li, Z.; Szalkowski, D.; Biazzo-Ashnault,
D. E.; Xie, D.; Saperstein, R.; Brady, E.; Huskey, S.; Shen, X.; Liu, K.;
Xu, L.; Salituro, G. M.; Heck, J . V.; Moller, D. E.; J ones, A. B.; Zhang,
B. B. J . Biol. Chem. 2000, 275, 36590-5.
(10) Wood, H. B., J r.; Black, R.; Salituro, G.; Szalkowski, D.; Li, Z.;
Zhang, Y.; Moller, D. E.; Zhang, B.; J ones, A. B. Bioorg. Med. Chem.
Lett. 2000, 10, 1189-92.
(11) Liu, K.; Xu, L.; Szalkowski, D.; Li, Z.; Ding, V.; Kwei, G.;
Huskey, S.; Moller, D. E.; Heck, J . V.; Zhang, B. B.; J ones, A. B. J .
Med. Chem. 2000, 43, 3487-3494.
(4) 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.
(5) Boger, D. L.; Goldberg, J . Bioorg. Med. Chem. 2001, 9, 557-
562.
(6) Tian, S. S.; Lamb, P.; King, A. G.; Miller, S. G.; Kessler, L.;
Luengo, J . I.; Averill, L.; J ohnson, R. K.; Gleason, J . G.; Pelus, L. M.;
Dillon, S. B.; Rosen, J . Science 1998, 281, 257-9.
(12) Wilkie, N.; Wingrove, P. B.; Bilsland, J . G.; Young, L. Harper,
S. J .; Hefti, F.; Ellis, S.; Pollack, S. J . J . Neurochem. 2001, 78, 1135-
1145.
(13) Belshaw, P. J .; Spencer, D. M.; Crabtree, G. R.; Schreiber, S.
L. Chem. Biol. 1996, 3, 731-8. Belshaw, P. J .; Ho, S. N.; Crabtree, G.
R.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 4604-7.
Perez-Sestelo, J .; Mourino, A.; Sarandeses, L. A. Org. Lett. 1999, 1,
1005-7.
7920 J . Org. Chem., Vol. 67, No. 23, 2002

Synthesis of Demethylasterriquinone B1
SCHEME 1
chemical synthesis of the most prominent member of the
family, DAQ B1, is a first step toward that goal.
The bis-indolylquinone family has been the subject of
previous synthetic study. The first total synthesis of an
asterriquinone was directed toward cochliodinol and used
as a key step the alumina/potassium carbonate-promoted
condensation of bromanil with 2 equiv of 5-bromoindole.14
A later study used cesium carbonate in acetonitrile in a
two-step, one-pot synthesis of demethyltetrahydroaster-
riquinone E, a nonnatural product that was obtained in
reasonable efficiency after purification by reversed-phase
HPLC.15 Several related symmetric asterriquinones were
also obtained from 2-substituted indoles. Neither of these
syntheses controls the rate of the addition of the first
indole versus the second indole, making it difficult to use
either synthesis to prepare unsymmetrical derivatives,
nor do they control the position of attachment of the
second indole. A recent synthesis of DAQ B1 addressed
this issue utilizing a p-substituted quinone bearing
leaving groups of differential reactivity.16 The first re-
ported total synthesis of DAQ B1 (Scheme 1) comprised
a late-stage convergent route wherein indole carbox-
aldehyde 2 and pyrandione 4 were united in a Kno¨ve-
nagel condensation to give 5. A base-catalyzed rearrange-
ment led to the natural product. This synthesis requires
about a dozen steps and proceeds in about 20% overall
yield.17
diversification. With increasing interest in the use of
library methods that form carbon-carbon bonds to access
natural products and complex natural product-like com-
pounds,19 this “divergent” or modular approach is likely
to become more important in natural products synthesis
design. The asterriquinones are inherently modular
molecules that should be amenable to a modular synthe-
sis design20 and, potentially, combinatorial synthetic
approaches to molecular libraries. Indeed, two syntheses
of the asterriquinones14,15 are modular. Our modular
synthesis design for the asterriquinones focuses on
controlled addition of indoles to a central quinone unit,
any of which could be varied to create a family of bis-
indolylquinone compounds for investigation. One of the
modular synthetic approaches to DAQ B1 described in
full detail here was communicated earlier.21
Resu lts
Convergency,18 as represented in Scheme 1, has tra-
ditionally been accorded high value in natural products
synthesis owing to its ability to permit parallel processing
in the production of advanced intermediates used in late-
stage coupling. While convergency is a virtue in most
efficiently providing a single target, it impairs efficiency
when the goal is gaining a family of structurally variant
targets. For example, applying the foregoing synthesis
toward DAQ B1 derivatives with modified indoles could
require a unique synthetic route to be executed from
modified starting materials to each target. As has long
been appreciated in medicinal chemistry, a more efficient
strategy in generating many targets involves synthesis
of a common late-stage intermediate and substitution of
a readily available set of modules into the synthesis for
Initial efforts focused on obtaining the two indoles
required for the total synthesis, 2-isoprenylindole (6) and
7-prenylindole (10), which are known. Williams prepared
the former in two steps and 25% overall yield from prenyl
bromide via the Fisher indole synthesis.22 This process
proved adequate for obtaining multigram quantities of
6 and was applied to the preparation of several meth-
ylated analogues.23 A reported four-step synthesis of 1024
was replicated, with some difficulty in controlling the
initial mono-BOC protection of o-iodoaniline. While mul-
tigram lots of 10 were also obtained, this route was not
very versatile or scalable. Subsequently, a method based
on the fascinating Bartoli reaction25 was developed that
permitted 7-prenylindole to be obtained in two steps and
(19) Hung, D. T.; J amison, T. F.; Schreiber, S. L. Chem. Biol. 1996,
3, 623-39.
(20) For example: Paquette, L. A.; Pissarnitski, D.; Barriault, L. J .
Org. Chem. 1998, 63, 7389-7398. Sinha, S. C.; Sinha-Bagchi, A.;
Yazbak, A.; Keinan, E. Tetrahedron Lett. 1995, 36, 9257-60.
(21) Pirrung, M. C.; Park, K.; Zhao, Y.; Webster, N. J . G. ChemBio-
Chem, in press.
(14) Ho¨rcher, U.; Schwenner, E.; Franck, B. Liebigs Ann. Chem.
1986, 1765-71.
(15) Harris, G. D.; Nguyen, A.; App, H.; Hirth, P.; McMahon, G.;
Tang, C. Org. Lett. 1999, 1, 431-33.
(16) Tatsuta, K.; Mukai, H.; Mitsumoto, K. J . Antibiot. 2001, 54,
105-108.
(17) Liu, K.; Wood, H. B.; J ones, A. B. Tetrahedron Lett. 1999, 40,
5119.
(22) Sanz-Cerveral, J . F.; Glinka, T.; Williams, R. M. Tetrahedron
1993, 49, 8471.
(18) Velluz, L.; Ralls, J .; Nomine´, G. Angew. Chem., Int. Ed. 1965,
4, 181. Ireland, R. E. Organic Synthesis; Prentice-Hall: Englewood
Cliffs, 1969; p 29. For a recent review covering convergent synthetic
approaches to one interesting class, see: Smith, A. B., III; Empfield,
J . R. Chem. Pharm. Bull. 1999, 47, 1671-1678.
(23) Pirrung, M. C.; Halstead, D. Unpublished results.
(24) Kondo, Y.; Kojima, S.; Sakamoto, T. Heterocycles 1996, 43,
2741-2746.
(25) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni,
E. J . Chem. Soc., Perkin Trans. 1 1991, 2757-61.
J . Org. Chem, Vol. 67, No. 23, 2002 7921

Pirrung et al.
SCHEME 2
SCHEME 4
SCHEME 3
ted without isolation to the Heck conditions with 7.
However, the desired 12 was obtained only in low yield.
An expedient, first-generation synthetic route to DAQ
B1 was then executed (Scheme 4) on the basis of the
known base-catalyzed nucleophilic addition methods.
While the addition of 10 to bromanil was difficult to
control, 2-isoprenylindole (6) undergoes slow (1 d) but
clean monoaddition to give the purple 13 in 100% yield
(with 56% recovered 6). Attempts to improve the conver-
sion by longer reaction times, refluxing, and/or using
excess p-bromanil were not fruitful. Treatment of 13 with
10 under similar conditions rapidly gives a ∼1:1 mixture
of the meta- and para-substituted indolylquinones that
could be rectified by silica gel chromatography. The
seemingly straightforward hydrolysis of 14 to DAQ B1
required some investigation. Use of the 4 N KOH
conditions reported by Harris15 completely destroyed the
compound. Saturated sodium formate in refluxing MeOH
gives a regioisomeric mixture of monohydroxy/mono-
methoxy bis-indolylquinones that could be hydrolyzed in
2 N KOH in MeOH at reflux (quantitative for two steps),
but this method was slow when the scale was increased.
A procedure developed in our syntheses of dihydroxyin-
dolylquinones27 involving addition of 10% aqueous NaOH
to a warm, dilute solution of 14 in MeOH and heating at
reflux for 30 min provided DAQ B1 that was purified by
chromatography on oxalic acid precoated silica gel (65%
yield). Spectroscopic data of synthetic 1 were directly
compared to data obtained on an authentic sample of
DAQ B1; they proved identical. The synthetic compound
was also evaluated for its ability to cause phosphorylation
of the insulin receptor â-tyrosine kinase domain in a rat
fibroblast cell line overexpressing human insulin receptor
(hIRcB cells).18 At 30 µM, synthetic 1 resulted in levels
of insulin receptor phosphorylation that were comparable
to insulin at 10 ng/mL.
∼50% yield from o-bromonitrobenzene and prenyl bro-
mide.26 A number of 7-prenylindole relatives can also be
prepared by analogous two-step procedures.
The acid-promoted condensation of indoles with 2,5-
dichlorobenzoquinone27 (8) was investigated for applica-
tion to the synthesis of DAQ B1. However, 2-isoprenylin-
dole does not undergo reaction with 8 when promoted
by HCl. Though 2-tert-butylindole does give an addition
product in 54% yield, the steric demand of 6 is evidently
too great. An alternative process was investigated (Scheme
2) for adding very sterically hindered indoles to 8 based
on Hegedus’s report on the conversion of indoles to their
3-mercurio derivatives and their use in Heck reactions
with acrylates.28 These methods have been useful in
approaches to other sterically hindered asterriquinones.29
The conversion of 6 to the mercurial proceeds quantita-
tively without interference from the terminal alkene, and
7 requires no purification. Upon treatment with 2,5-
dichlorobenzoquinone in the presence of catalytic pal-
ladium acetate with cuprous chloride as reoxidant, the
quinone 9 is obtained in excellent yield. However, it did
not prove possible to add 10 to 6 with mineral acid as
the promoter. An alternative strategy (Scheme 3) would
first add 7-isoprenylindole and then perform the Heck
reaction on 11. While the initial condensation is success-
ful,27 the product is relatively unstable, so it was submit-
This synthesis was short and modular but suffered
from a lack of regiocontrol, so improvements were sought
in a second-generation route. It was thought that pre-
determination of the para regiochemistry of DAQ B1
could be accomplished by initial addition of 6 to 3-bromo-
2,5-dichlorobenzoquinone and use of a bromide-selective
Stille coupling reaction for installation of the second
indole. This general approach was validated through the
preparation of a simple symmetrical asterriquinone, DAQ
(26) Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143.
(27) Pirrung, M. C.; Park, K.; Li, Z. Org. Lett. 2001, 3, 365-7.
(28) Harrington, P. J .; Hegedus, L. S. J . Org. Chem. 1984, 49, 2658.
(29) Pirrung, M. C.; Park, K. Unpublished results.
7922 J . Org. Chem., Vol. 67, No. 23, 2002

Synthesis of Demethylasterriquinone B1
SCHEME 5
SCHEME 6
synthesis proceeds in an overall yield of 25% for five
steps. One shortcoming of this synthetic approach is that
it cannot be applied to asterriquinones bearing 2-isopre-
nylindoles because steric factors prevent stannylation of
the lithium reagents derived from them (Zhu, J ., unpub-
lished results).
A1 (Scheme 5), which required indole-tin reagent 16. The
challenging introduction of the N-isoprenyl group was
addressed using a method from Wipf’s muscoride syn-
thesis30 that was developed originally by Hansen.31 While
the mechanism of alkylations with dimethylpropargyl
chloride is unknown, limiting possibilities include direct
SN2 substitution, more permissible at a tertiary center
than is ordinarily expected due to the reduced steric
demands of an ethyne group or an elimination/addition
mechanism via the vinylidene. The efficiency of the
dimethylpropargylation of 3-bromoindole is adequate,
and the two remaining steps in the route to 16 are
efficient. It was generally used in crude (though quite
clean) form as obtained following KF treatment of the
stannylation reaction mixture to remove tin residues. The
bromoquinone reactant 17 for the Stille coupling was
obtained from bromanil by ethanolysis in the presence
of potassium fluoride.32 The Stille coupling was performed
under standard conditions, with the notable feature that
at shorter reaction times the monoindolylquinone 18
dominates the reaction mixture, implying that it should
be possible to substitute a different 3-indolyltin at this
intermediate stage to produce an unsymmetrical bis-
indolylquinone. In this instance, coupling was simply
allowed to proceed with excess 16 to generate 19 in
excellent yield for two steps (90% yield per coupling).
Hydrolysis to give demethylasterriquinone A1 followed
literature precedent,33 giving material that was spectro-
scopically identical34 to the natural compound. This
A total synthesis of DAQ B1 was performed exploiting
the precedents from the DAQ A1 synthesis (Scheme 6).
A tin reagent was prepared from 10 by selective iodina-
tion at the 3-position, protection of the nitrogen with a
Boc group (f 20) and metal-halogen exchange followed
by trapping of the 3-indolyllithium with tri-n-butyltin
chloride (∼55% overall). To form a reactant suitable for
Stille coupling with 21, a method was needed to add 6 to
a brominated quinone. The mercurial chemistry used to
prepare 9 could have been used, but limiting the sto-
ichiometric use of heavy metals was desirable. It was
discovered that while 6 does not undergo addition to 8
under the influence of mineral acid, it does add to bromo-
2,5-dichlorobenzoquinone in acetic acid, giving 22 in 79%
yield. The substitution pattern of this compound is built
into the starting quinone and directs selective production
of the para-bis-indolylquinone regiochemistry based on
the reactivity of vinyl bromides vs vinyl chlorides in the
Stille coupling.35 The Stille coupling was adequate under
conventional conditions (Pd(Ph3P)4), but could be im-
proved using bulky phosphines,36 producing 23 in 76%
yield. The hydrolysis of the carbamate and vinyl halides
(35) Both 22 and its isomer i were examined in base-catalyzed
condensations with 10, and both gave mixtures.
(30) Wipf, P.; Venkatraman, S. J . Org. Chem. 1996, 61, 6517-6522.
(31) Barmettler, P.; Hansen, H. J . Helv. Chim. Acta 1990, 73, 1515-
73.
(32) Wallenfels, K.; Draber, W. Chem. Ber. 1957, 90, 2819.
(33) Arai, K.; Shimizu, S.; Taguchi, Y.; Yamamoto, Y. Chem. Pharm.
Bull. 1981, 29, 991-9.
(34) Yamamoto, Y.; Nishimura, K.; Kiriyama, N. Chem. Pharm. Bull.
1976, 24, 1853.
(36) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067.
J . Org. Chem, Vol. 67, No. 23, 2002 7923

Pirrung et al.
under basic conditions using our earlier procedure27 gives
the natural product in 73% yield.
by flash column chromatography using 10% EtOAc in hexane
as eluent to afford pure 2,3,5-tribromo-6-[2-(1,1-dimethylallyl)-
1H-indol-3-yl][1,4]benzoquinone as a purple solid (1.26 g, 100%
based on recovered 6 (56%)). Rf ) 0.31 (1:4 EtOAc/hexane).
Intermediates from these syntheses provide access to
chemical reagents useful for studying the biochemical
properties of DAQ. For example, the monohydroxy/
monomethoxy quinones derived from 14 react with
methylaziridine to give the monoaziridinylquinone 24,
which may prove useful as an affinity label to identify
proteins with which DAQ interacts.
IR (thin film): 3423, 2971, 1677, 1562, cm-1 1H NMR
.
(CDCl3): δ 8.28 (bs, NH), 7.33 (dt, J ) 8.1, 0.9 Hz, 1H), 7.20-
7.05 (m, 3H), 5.98 (dd, J ) 17.4, 10.5 Hz, 1H), 5.12 (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 175.0, 171.3, 145.9, 144.8,
142.4, 140.2, 137.6, 135.4, 134.7, 122.4, 120.3, 118.6, 113.4,
110.9, 105.3, 39.3, 28.0, 26.7. Mp: 90 °C dec. Anal. Calcd for
C
19H14NO2Br3: C, 43.21; H, 2.65; N, 2.65. Found: C, 43.48;
H, 2.81; N, 2.65.
2,5-Dib r om o-3-[2-(1,1-d im et h yla llyl)-1H -in d ol-3-yl]-6-
[7-(3-m e t h ylb u t -2-e n yl)-1H -in d ol-3-yl][1,4]b e n zoq u i-
n on e (14). To a solution of 2,3,5-tribromo-6-[2-(1,1-dimethyl-
allyl)-1H-indol-3-yl][1,4]benzoquinone (13, 150 mg, 0.284 mmol)
in CH3CN (1 mL) were added Cs2CO3 (185 mg, 0.568 mmol)
and 7-(3-methylbut-2-enyl)-1H-indole (63 mg, 0.341 mmol) at
room temperature. After being stirred for 2 h, the reaction
mixture was diluted with EtOAc (20 mL). The organic solution
was washed with 0.5 N HCl (2 × 20 mL) and brine (2 × 20
mL) and dried over Na2SO4. The residue was concentrated and
purified by careful flash column chromatography using 15%
EtOAc in hexane as eluent to afford pure 3,6-bisindolyl-2,5-
dibromobenzoquinone 14 (85 mg, 47%) and its regioisomer, 3,5-
bisindolyl-2,6-dibromobenzoquinone (79 mg, 44%), as purple
solids. Data for 14. Rf ) 0.38 (3:7 EtOAc/hexane). IR (thin
Discu ssion a n d Con clu sion
The two total syntheses of DAQ B1 described here have
longest linear sequences from commercially available
materials of five and seven steps, respectively. The former
proceeds in 12% yield, the latter in 13% yield (average
of the two linear routes); the latter requires no isomer
separations. Using these syntheses, gram quantities of
DAQ B1 have been prepared, and its biological activity
has been verified. The first-generation route should be
generally applicable to asterriquinone synthesis on the
basis of the work of Harris.13 However, these routes do
not represent ideal syntheses for families of asterriquino-
nes, due to the lack of regiocontrol or the necessity to
convert one indole to its tin derivative to gain regiocon-
trol. Coupling reactions that proceed with indoles (or
other heterocycles) without pre-functionalization would
permit the wide variety of commercially available het-
erocycles to be used directly in the creation of molecular
libraries. An ideal asterriquinone synthesis would involve
only two steps: selective condensation of a quinone core
with first one and then a second indole. Completion of a
third generation synthesis of the asterriquinones reflect-
ing this ideal is thus a high priority.
film): 3410, 2971, 1667, 1570, 1431, 1244 cm-1 1H NMR
.
(CDCl3): δ 8.77 (bs, NH), 8.27 (bs, NH), 7.53 (d, J ) 2.7 Hz,
1H), 7.34 (dd, J ) 8.1, 0.9 Hz, 2H), 7.25-7.06 (m, 5H), 6.06
(dd, J ) 17.4, 10.8 Hz, 1H), 5.44 (m, 1H), 5.18 (dd, J ) 17.4,
1.2 Hz, 1H), 5.14 (dd, J ) 10.8, 0.9 Hz, 1H), 3.60 (d, J ) 7.2
Hz, 2H), 1.83 (s, 3H), 1.81 (s, 3H), 1.47 (s, 6H). 13C NMR
(CDCl3): δ 177.5, 145.5, 145.0, 141.9, 141.7, 137.1, 134.8, 134.7,
133.8, 133.0, 128.7, 126.4, 124.9, 124.7, 122.3, 122.2, 121.8,
120.8, 120.1, 119.7, 118.7, 113.1, 110.9, 109.2, 105.9, 39.4, 30.7,
27.8, 26.8, 25.8, 18.1. HRMS (FAB): calcd for C32H30Br2N2O2
[M + 2H]+ 632.0674, found 632.0673. Mp: 134 °C dec.
2-[2-(1,1-Dim et h yl-a llyl)-1H -in d ol-3-yl]-3-h yd r oxy-6-
m et h oxy-5-[7-(3-m et h ylb u t -2-en yl)-1H -in d ol-3-yl][1,4]-
ben zoqu in on e a n d 2-[2-(1,1-Dim eth yla llyl)-1H-in d ol-3-
yl]-6-h yd r oxy-3-m et h oxy-5-[7-(3-m et h ylb u t -2-en yl)-1H -
in d ol-3-yl][1,4]ben zoqu in on e. To a solution of 3,6-bisindolyl-
2,5-dibromobenzoquinone 14 (30 mg, 47.4 µmol) in MeOH (10
mL) was added saturated NaCO2H or NaOAc solution (5 mL),
and the mixture was refluxed for 3 d (monitored by TLC). The
reaction mixture was concentrated in vacuo to remove MeOH,
and the resulting crude mixture was extracted with EtOAc (3
× 10 mL). The organic solution was washed with brine (10
mL), dried over Na2SO4, and concentrated. The residue was
purified by flash column chromatography using 20% EtOAc
in hexane as eluent to afford pure 2,5-bisindolyl-3-hydroxy-
6-methoxy-1,4-benzoquinone and 2,5-bisindolyl-6-hydroxy-3-
methoxy-1,4-benzoquinone (regioisomers, 23 mg, 94%) as red-
purple solids. Rf ) 0.28 (3:7 EtOAc/hexane). IR (thin film):
Exp er im en ta l Section
Gen er a l Meth od s. Oxalic-acid precoated silica gel was
prepared by a literature procedure:37 suspension of silica gel
60 (230-400 mesh) in 0.1 N oxalic acid overnight, filtration,
washing with H2O, and drying in an oven at 100 °C overnight.
2,3,5-Tr ibr om o-6-[2-(1,1-d im eth yla llyl)-1H-in d ol-3-yl]-
[1,4]b en zoq u in on e (13). To a solution of 2-(1,1-dimethyl-
allyl)-1H-indole (1.0 g, 5.40 mmol) in CH3CN (10 mL) were
added Cs2CO3 (3.52 g, 10.8 mmol) and tetrabromo-1,4-benzo-
quinone (2.41 g, 5.40 mmol) at room temperature. After the
reaction mixture was stirred for 12 h at room temperature,
Cs2CO3 (1.76 g, 5.40 mmol) and tetrabromo-1,4-benzoquinone
(1.21 g, 2.70 mmol) were added to the reaction mixture. After
further stirring for 12 h at room temperature, the mixture was
diluted with EtOAc (100 mL). The organic solution was washed
with 0.5 N HCl (2 × 100 mL) and brine (2 × 100 mL) and
dried over Na2SO4. The residue was concentrated and purified
3396, 2970, 2919, 1642, 1605, 1301, 1270 cm-1 1H NMR
.
(CDCl3, regioisomers (∼1:1)): δ 8.61 (bs, NH), 8.59 (bs, NH),
8.26 (bs, NH), 8.22 (bs, NH), 7.71 (bs, OH), 7.55 (d, J ) 2.4
Hz, 1H), 7.49 (d, J ) 7.8 Hz, 1H), 7.46 (bs, OH), 7.43 (d, J )
2.7 Hz, 1H), 7.40 (d, J ) 7.8 Hz, 1H), 7.31-7.25 (m, 4H), 7.17-
7.01 (m, 8H), 6.11 (dd, J ) 17.1, 10.2 Hz, 1H), 6.05 (dd, J )
17.4, 10.5 Hz, 1H), 5.42 (m, 2H), 5.20-5.08 (m, 4H), 3.85 (s,
3H), 3.71 (s, 3H), 3.56 (d, J ) 6.6 Hz, 4H), 1.81 (s, 3H), 1.791
(s, 3H), 1.788 (s, 3H), 1.78 (s, 3H), 1.47 (s, 6H), 1.46 (s, 6H).
13C NMR (CDCl3): δ 188.7, 183.3, 183.1, 182.3, 157.7, 156.0,
151.4, 149.1, 145.4, 144.9, 142.3, 142.2, 134.8, 134.7, 134.6,
134.3, 133.4, 133.3, 129.7, 128.4, 127.1, 126.9, 126.5, 125.9,
124.2, 124.0, 122.0, 121.91, 121.87, 121.8, 120.6, 120.2, 120.1,
119.73, 119.66, 118.79, 118.77, 118.5, 118.4, 116.7, 114.1,
113.1, 112.3, 111.9, 110.7, 105.1, 104.9, 100.7, 100.1, 61.2, 60.2,
(37) Yamamoto, Y.; Nishimura, K.; Kiriyama, N. Chem. Pharm. Bull.
1976, 24, 1853-9.
7924 J . Org. Chem., Vol. 67, No. 23, 2002

Synthesis of Demethylasterriquinone B1
39.2, 30.61, 30.56, 27.2, 27.0, 26.8, 26.7, 25.78, 25.76, 18.0.
HRMS (FAB): calcd for C33H32N2O4 [M]+ 520.2362, found
520.2365.
m), 0.82 (9H, m). The crude material was azeotroped with
benzene before being used in the Stille coupling.
2,5-Bis[1-(1,1-dim eth ylallyl)-1H-in dol-3-yl]-3,6-dieth oxy-
[1,4]ben zoqu in on e (19). A solution of quinone 17 (52 mg,
0.15 mmol) and tetrakis(triphenylphosphine)palladium (20 mg,
0.017 mmol) in toluene was bubbled with nitrogen for 10 min.
Crude compound 16 was added in portions (255 mg, 0.54
mmol), and the solution was brought to 110 °C. The reaction
mixture was stirred for 18 h and filtered through Celite. The
solvent was removed in vacuo, and the residue was purified
by silica gel chromatography (hexane, then benzene). Com-
pound 19 (68 mg, 82%) was obtained as a purple solid. Mp:
179-181 °C. 1H NMR (CDCl3): δ 7.77 (2H, s), 7.60 (2H, m),
7.54 (2H, m), 7.15 (4H, m), 6.20 (2H, dd, J ) 10.8, 17.7 Hz),
5.27 (2H, d, J ) 10.8 Hz), 5.22 (2H, d, J ) 17.7 Hz), 3.95 (4H,
q, J ) 7.2 Hz), 1.83 (12H, s), 1.13 (6H, t, J ) 7.2 Hz). 13C NMR
(CDCl3): δ 184.5, 152.7, 143.9, 135.5, 129.5, 128.7, 124.3, 122.4,
121.2, 119.9, 114.1, 103.9, 69.2, 59.9, 28.4, 16.1. IR (thin
film): 2959, 2929, 1727, 1651, 1458 cm-1. HRMS: calcd for
Dem eth yla ster r iqu in on e B1 (1). To a solution of 2,5-
bisindolyl-3-hydroxy-6-methoxy-1,4-benzoquinone and 2,5-bis-
indolyl-6-hydroxy-3-methoxy-1,4-benzoquinone (65 mg, 0.125
mmol) in MeOH (20 mL) was added 2 N NaOH (10 mL), and
the mixture was refluxed for 2 h (monitored carefully by TLC).
The reaction mixture was concentrated in vacuo to remove
MeOH, and the resulting solution was acidified with 2 N HCl.
The crude mixture was extracted with EtOAc (3 × 20 mL).
The organic solution was washed with brine (10 mL), dried
over Na2SO4, and concentrated. The residue was purified by
flash column chromatography using oxalic acid precoated silica
gel and 10% EtOAc in hexane as eluent to afford pure
demethylasterriquinone B1 (DAQ B1) 1 (61 mg, 96%) as a dark
red-purple solid. Rf ) 0.43 (1:4, EtOAc/hexane, reversed phase
RP-18). IR (thin film): 3416, 3345, 2970, 2928, 1637, 1343
1
cm-1. H NMR (acetone-d6): δ 10.41 (bs, NH), 10.05 (bs, NH),
9.36 (bs, 2OH), 7.62 (d, J ) 2.7 Hz, 1H), 7.44 (dd, J ) 6.9, 2.1
Hz, 1H), 7.33 (dt, J ) 8.1, 0.9 Hz, 1H), 7.28 (dt, J ) 8.1, 0.9
Hz, 1H), 7.07-6.91 (m, 4H), 6.17 (dd, J ) 17.4, 10.5 Hz, 1H),
5.48 (m, 1H), 5.10 (dd, J ) 17.4, 1.2 Hz, 1H), 5.01 (dd, J )
10.5, 1.2 Hz, 1H), 3.64 (d, J ) 6.9 Hz, 2H), 1.78 (s, 3H), 1.76
(s, 3H), 1.52 (s, 6H). 13C NMR (acetone-d6): δ 146.4, 143.1,
136.3, 135.7, 133.2, 129.7, 127.8, 127.5, 125.0, 122.9, 121.7,
121.4, 120.4, 120.0, 119.5, 119.4, 113.0, 112.1, 111.4, 111.3,
105.8, 101.3, 39.9, 30.6-29.0 (2C, overlapping with solvent
peaks), 27.5, 25.9, 17.9. HRMS (FAB): calcd for C32H31N2O4
[M + H]+ 507.2284, found 507.2283.
C
36H38N2O4 562.2832, found 562.2831 (M+).
Dem eth yla ster r iqu in on e A1. Compound 19 (8 mg, 0.014
mmol) was dissolved in 1 N potassium hydroxide (1 mL) and
ethanol (2 mL). The solution was heated at 70 °C for 1 h. The
mixture was acidified with 1 N HCl to pH 2. The precipitate
was extracted with ethyl acetate (10 mL × 2). The organic
phases were combined and dried over sodium sulfate. After
removal of the solvent, the residue was purified with column
chromatography on oxalic acid precoated silica gel (benzene).
The title compound (5.1 mg, 70%) was obtained as a dark
purple solid. 1H NMR (CDCl3): δ 8.11 (2H, s), 7.74 (2H, s),
7.60 (4H, m), 7.16 (4H, m), 6.21 (2H, dd, J ) 10.8, 17.7 Hz),
5.28 (2H, d, J ) 10.8 Hz), 5.25 (2H, d, J ) 17.7 Hz),1.83 (12H,
s). 13C NMR (CDCl3): δ 144.0, 135.6, 128.5, 128.2, 122.2, 121.4,
119.9, 114.2, 114.1, 111.1, 102.6, 59.9, 28.2. These data are
consistent with data reported in the literature.
3-Br om o-2,5-d ich lor o[1,4]ben zoqu in on e. To 7.03 g (40
mmol) of 2,5-dicholoro[1,4]benzoquinone in 120 mL of acetic
acid was added 2.68 mL (1.1 equiv) of bromine. The mixture
was stirred at room temperature for 4 h and poured into 300
mL of water. The precipitate formed was collected and
recrystallized from ethanol to give the product (9.03 g, 92%)
as yellow crystals. Mp: 164-165 °C (lit.39 mp 168 °C).
3-Br om o-1-(1,1-d im et h ylp r op -2-yn yl)-1H -in d ole. To a
mixture of 3-bromoindole (196 mg, 1 mmol, prepared by the
literature procedure38 in 97% yield) and 3-chloro-3-methylbut-
1-yne (204 mg, 2 mmol) in 2 mL of DMF, at 0 °C, was added
60% NaH (100 mg, 2.5 mmol) suspended in 1 mL of DMF. The
mixture was stirred at room temperature for 12 h. After
workup, the crude compound was purified by silica gel chro-
matography (1:6 ethyl acetate/hexane) to give a yellow oil (157
1
mg, 60%). H NMR (CDCl3): δ 7.86 (d, J ) 8.1 Hz, 1H), 7.57
(d, J ) 8.1 Hz, 1H), 7.35 (s, 1H), 7.18-7.24 (m, 2H), 2.60 (s,
1H), 1.95 (s, 6H). 13CNMR (CDCl3): δ 134.6, 128.9, 123.8,
122.5, 120.6, 119.8, 90.3, 85.7, 73.2, 53.0, 30.3.
3-Br om o-1-(1,1-d im eth yla llyl)-1H-in d ole (15). A mixture
of 3-bromo-1-(1,1-dimethylprop-2-ynyl)-1H-indole (96 mg, 0.37
mmol), quinoline (0.04 mL), and 5% Pd/BaSO4 (10 mg) in
benzene (10 mL) was stirred under an H2 atmosphere at room
temperature for 29 h. The reaction mixture was filtered
through Celite and purified by flash chromatography (hexane).
The product was obtained as a yellow oil (84 mg 87% yield).
1H NMR (CDCl3): δ 7.56 (1H, m), 7.49 (1H, m), 7.31 (1H, s),
7.16 (2H, m), 6.12 (1H, dd, J ) 10.5, 17.4 Hz), 5.24 (1H, d, J
) 10.5 Hz), 5.17 (1H, d, J ) 17.4 Hz), 1.74 (6H, s). 13C NMR
(CDCl3): δ 143.8, 135.0, 128.8, 124.5, 122.0, 120.1, 119.5, 114.1,
89.0, 60.0, 28.3. IR: 3086, 2982, 1568, 1451. Anal. Calcd for
C13H14BrN: C, 59.11; H, 5.34; N, 5.30. Found: C, 59.07; H,5.47;
N, 5.13.
3-Iod o-7-(3-m eth ylbu t-2-en yl)in d ole-1-ca r boxylic Acid
ter t-Bu tyl Ester (20). To a solution of 7-prenylindole (7 mmol)
in 26 mL of DMF was added potassium hydroxide pellets (1
g, 18 mmol). A solution of iodine (7 mmol) in 26 mL of DMF
was added to the reaction mixture in 20 min under stirring.
The reaction mixture was stirred for 1 h at room temperature
and poured into 400 mL of ice-water containing 0.5% am-
monia and 0.1% sodium metabisulfite. The mixture was
extracted with a 1:1 solution of ethyl acetate/hexanes until no
product was left in the aqueous phase. The organic phases
were combined, washed with cold water, and dried with
anhydrous sodium sulfate. The solvent was removed in vacuo,
and the crude product was dissolved in 100 mL of dichlo-
romethane. Boc2O (1.57 g, 7 mmol), K2CO3 (1.2 g, 9 mmol),
and DMAP (100 mg, 0.8 mmol) were added. The mixture was
stirred at room temperature for 12 h and filtered. The crude
product was purified by chromatography (0.5% ethyl acetate
in hexane) to yield 2.00 g (69%) of the title compound as a
colorless oil. IR (thin film): 2977, 2927, 1754, 1746, 1370, 1309,
1-(1,1-Dim eth yl-allyl)-3-(tr ibu tylstan n yl)-1H-in dole (16).
To a solution of 15 (254 mg, 0.96 mmol) in diethyl ether at
-78 °C was added tert-butyllithium (1.18 mL of a 1.7 M
solution, 2.01 mmol). The solution was stirred for 20 min, and
tributyltin chloride (0.27 mL, 0.99 mmol) was added. The
mixture was allowed to warm to room temperature and stirred
for 10 h. A saturated aqueous solution of KF was poured into
the reaction and stirred for 30 min. The aqueous phase was
extracted with ethyl acetate (30 mL × 3). The combined
organic phase was dried with sodium sulfate, and the solvent
was removed in vacuo. Compound 16 was obtained as a yellow
1150 cm-1 1H NMR (CDCl3): δ 7.67 (s, 1H), 7.30-7.23 (m,
.
3H), 5.25 (m, 1H), 3.81 (d, J ) 6.6 Hz, 2H), 1.73 (s, 3H), 1.72
(s, 3H), 1.64 (s, 9H). 13C NMR (CDCl3): δ 148.6, 133.7, 133.0,
132.5, 129.5, 127.6, 126.4, 124.1, 123.4, 123.1, 119.8, 84.2, 33.7,
28.4, 26.1, 18.4. HRMS (FAB): calcd for C18H22INO2 [M]+
411.0695, found 411.0696.
7-(3-Met h ylb u t -2-en yl)-3-t r ib u t ylst a n n a n ylin d ole-1-
ca r boxylic Acid ter t-Bu tyl Ester (21). Compound 20 (1.3
g, 3.2 mmol) was dissolved in 65 mL of anhydrous ethyl ether.
1
oil in 85% yield. H NMR (CDCl3): δ 7.55 (2H, m), 7.18 (1H,
s), 7.05 (2H, m), 6.15 (1H, dd, J ) 11.0, 17.7 Hz), 5.25 (1H, d,
J ) 11.0), 5.16 (1H, d, J ) 17.7 Hz), 1.78 (6H, s), 1.40 (18H,
(38) Bocchi, B.; Palla, G. Synthesis 1982, 1096-1097.
(39) Ling, A. R. J . Chem. Soc. 1892, 61, 558-567.
J . Org. Chem, Vol. 67, No. 23, 2002 7925

Pirrung et al.
tert-Butyllithium (3.7 mL of a 1.7 M solution) was added at
-78 °C under argon. The solution was stirred for 20 min, and
tributyltin chloride (1.1 mL) was added. The solution was
allowed to warm to room temperature and stirred for 10 h.
Saturated KF solution (50 mL) was poured into the reaction
mixture, which was stirred for 30 min. The solution was
extracted three times with ethyl acetate (30 mL). The com-
bined organic phase was washed with brine and dried with
sodium sulfate, and the solvent was removed in vacuo. The
crude compound 21 was obtained as a yellow oil that was used
in the next step without further purification (chromatography
caused protiodestannylation). The yield was estimated to be
80% on the basis of NMR.
(76%) of the title compound. IR (KBr): 3417, 2973, 2930, 1754,
1
1675, 1594, 1145 cm-1. H NMR (CDCl3): δ 8.32 (s, 1H), 7.84
(s, 1H), 7.37 (d, J ) 7.5 Hz, 1H), 7.28-7.12 (m, 6H), 6.08 (dd,
J ) 10.8, 17.4 Hz, 1H), 5.31 (m, 1H), 5.19 (d, J ) 17.4 Hz,
1H), 5.17 (d, J ) 10.8 Hz, 1H), 3.84 (d, J ) 7.2 Hz, 2H), 1,77
(s, 3H), 1.75 (s, 3H), 1.68 (s, 9H), 1.50 (s, 3H), 1.49 (s, 3H). 13
C
NMR (CDCl3): δ 177.9, 177.4, 149.0, 145.3, 142.9, 142.4, 142.1,
141.0, 137.4, 135.0, 134.2, 133.2, 131.7, 129.9, 129.4, 127.1,
127.0, 123.7, 123.1, 122.6, 120.6, 119.2, 118.9, 113.4, 111.3,
110.9, 103.4, 84.7, 39.7, 33.8, 28.4, 28.2, 27.1, 26.2, 18.4. HRMS
(FAB): calcd for C37H38Cl2N2O4 [M + 2H]+ 644.2209, found
644.2208. Mp: 126-127 °C.
2-[2-(1,1-Dim et h yla llyl)-1H -in d ol-3-yl]-3,6-d ih yd r oxy-
5-[7-(3-m et h ylb u t -2-en yl)-1H -in d ol-3-yl][1,4]b en zoq u i-
n on e, DAQ B1 (1). To a refluxing solution of compound 23
(380 mg) in methanol (36 mL) was added 18 mL of 10% NaOH.
The solution was refluxed for 30 min and poured into 20 mL
of water. The mixture was acidified to pH 1 with 10% H2SO4
and extracted three times with ethyl acetate (25 mL). The
combined organic phase was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was removed
in vacuo, and the crude product was purified on oxalic acid
precoated silica gel (15% ethyl acetate/hexane) to yield 218
mg (73%) of the natural product. 1H NMR (acetone-d6): δ 10.46
(s, 1H), 10.10 (s, 1H), 9.8-9.0 (br, 2H), 7.63 (d, J ) 2.7 Hz,
1H), 7.45 (d, J ) 7.2 Hz, 1H), 7.34 (d, J ) 8.1 Hz, 1H), 7.29 (d,
J ) 8.1 Hz, 1H), 7.08-6.93 (m, 4H), 6.18 (dd, J ) 10.8, 17.4
Hz, 1H), 5.49 (m, 1H), 5.11(d, J ) 17.4 Hz, 1H), 5.02 (d, J )
10.8 Hz, 1H), 3.65 (d, J ) 6.9 Hz, 2H), 1.79 (s, 3H), 1.77 (s,
3H), 1.53 (s, 6H).13C NMR (CDCl3): δ 146.0, 142.7, 135.8,
135.2, 132.7, 129.2, 127.4, 127.0, 124.5, 122.4, 121.2, 120.9,
119.9, 119.5, 119.0, 118.9, 112.5, 111.7, 110.9, 110.9, 105.4,
100.8, 39.4, 27.0, 25.4, 17.5.
2-Br om o-3,6-d ich lor o-5[2-(1,1-d im eth yla llyl)-1H-in d ol-
3yl][1,4]ben zoqu in on e (22). A mixture of 2-isoprenylindole
(0.93 g, 5 mmol) and 2.55 g (10 mmol) of bromo-2,5-dichloro-
benzoquinone in 20 mL of acetic acid was stirred at 50 °C for
2 h and then at room temperature for another 10 h. DDQ (1.15
g, 5 mmol) was added, and the mixture was stirred at room
temperature for 2 h. The solvent was removed in vacuo, and
the residue was dissolved in 50 mL of ethyl acetate. The
solution was washed twice with 50 mL of saturated sodium
bicarbonate, followed by 50 mL of water and 50 mL of brine.
The resulting solution was dried with anhydrous sodium
sulfate, and the solvent was removed in vacuo. The crude
product was purified by chromatography (ethyl acetate/hexane,
15/85) to yield 1.72 g (79%) of the title compound and 1.27 g
of the starting quinone. IR (KBr): 3426, 2969, 1673, 1565,
1
1459, 1432, 1055 cm-1. H NMR (CDCl3): δ 8.26 (s, 1H), 7.37
(d, J ) 8.1 Hz, 1H), 7.20 (m, 1H), 7.10 (m, 2H), 5.99 (dd, J )
10.8, 17.7 Hz, 1H), 5.12 (d, J ) 17.7 Hz, 1H), 5.09 (d, J ) 10.8
Hz, 1H), 1.44 (s, 6H).13C NMR (CDCl3): δ 175.5, 172.0, 145.4,
145.1, 143.3, 142.4, 140.9, 135.0, 134.7, 126.7, 122.8, 120.8,
118.8, 113.7, 111.3, 102.9, 39.6, 28.3, 27.1. HRMS (FAB): calcd
for C19H14BrCl2NO2 [M]+ 436.9585, found 436.9587. Mp: 189-
190 °C (benzene).
Ack n ow led gm en t. Financial support was provided
by the American Diabetes Association and Diabetes
Action Research and Education Foundation. We thank
Dr. H. Blair Wood of Merck for a comparison sample of
DAQ B1. The cover images were provided courtesy of
Dr. R. A. Shoemaker and J . McCarthy, Agriculture and
Agri-Food Canada, Ottawa.
3-[2,5-Dich lor o-4-[2-(1,1-d im eth yla llyl)-1H-in d ol-3-yl]-
3,6-d ioxocycloh exa -1,4-d ien yl]-7-(3-m eth ylbu t-2-en yl)in -
d ole-1-ca r boxylic Acid ter t-Bu tyl Ester (23). A mixture of
tri(o-tolyl)phosphine (22 mg) and Pd2(dba)3 (39 mg) in 10 mL
of anhydrous toluene was stirred under nitrogen for 15 min.
To this solution were added compound 22 (160 mg) and crude
compound 21 (400 mg) in 10 mL of anhydrous toluene. The
mixture was degassed by nitrogen bubbling for 10 min and
heated to 90 °C for 30 min, when reaction was complete. The
reaction mixture was filtered through Celite, and the solvent
was removed in vacuo. The crude product was purified by
chromatography (20% ethyl acetate/hexane) to yield 180 mg
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of 14,
19, 20, 22, and 23. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O020182A
7926 J . Org. Chem., Vol. 67, No. 23, 2002