An approach to 3,6-disubstituted 2,5-dioxybenzoquinones via two sequential Suzuki couplings. Three-step synthesis of leucomelone

Article abstract of DOI:10.1021/ol802645f

(Chemical Equation Presented) Two sequential Suzuki coupling reactions have been developed for efficient synthesis of synthetically and biologically important 3,6-disubstituted 2,5-dioxybenzoquinone architectures in a highly chemoselective controlled mann

Full text of DOI:10.1021/ol802645f

ORGANIC
LETTERS
2009
Vol. 11, No. 3
589-592
An Approach to 3,6-Disubstituted
2,5-Dioxybenzoquinones via Two
Sequential Suzuki Couplings. Three-Step
Synthesis of Leucomelone
Xianwen Gan,† Wei Jiang,‡ Wei Wang,*,‡,§ and Lihong Hu*,†,§
Shanghai Research Center for Modernization of Traditional Chinese Medicine,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 199 Guoshoujing
Road, Shanghai 201203, People’s Republic of China, Department of Chemistry &
Chemical Biology, UniVersity of New Mexico, Albuquerque, New Mexico 87131-0001,
and School of Pharmacy, East China UniVersity of Science & Technology,
130 Mei-Long Road, Shanghai 200237, People’s Republic of China
wwang@unm.edu; simmhulh@mail.shcnc.ac.cn
Received November 16, 2008
ABSTRACT
Two sequential Suzuki coupling reactions have been developed for efficient synthesis of synthetically and biologically important 3,6-disubstituted
2,5-dioxybenzoquinone architectures in a highly chemoselective controlled manner. The method serves as a key step in the total synthesis
of leucomelone in three steps and in 61% overall yield.
The 3,6-disubstituted 2,5-dioxybenzoquinone framework
and its reductive phenol form are widely distributed in a large
collection of natural products (Figure 1).1-7 Significantly,
they display a broad spectrum of intriguing biological
† Chinese Academy of Sciences.
‡ University of New Mexico.
§ East China University of Science & Technology.
Figure 1. Naturally occurring 3,6-disubstituted 2,5-dioxybenzo-
quinone architecture (1) and its reduced phenol form (2).
(1) Xie, C.; Koshino, H.; Esumi, Y.; Onose, J.; Yoshikawa, K.; Abe,
N. Bioorg. Med. Chem. Lett. 2006, 16, 5424
.
(2) (a) Lee, I. K.; Yun, B. S.; Cho, S. M.; Kim, W. G.; Kim, J. P.;
Ryoo, I. J.; Koshino, H.; Yoo, I. D. J. Nat. Prod. 1996, 59, 1090. (b) Yun,
B. S.; Lee, I. K.; Kim, J. P.; Yoo, I. D. J. Antibiot. 2000, 53, 114. (c)
Tsukamoto, S.; Macabalang, A. D.; Abe, T.; Hirota, H.; Ohta, T.
Tetrahedron 2002, 58, 1103. (d) Quang, D. N.; Hashimoto, T.; Nukada,
M.; Yamamoto, I.; Tanaka, M.; Asakawa, Y. Plant Med. 2003, 69, 1063.
(e) Quang, D. N.; Hashimoto, T.; Nukada, M.; Yamamoto, I.; Tanaka, M.;
Asakawa, Y. Chem. Pharm. Bull. 2003, 58c, 452. (f) Liu, J. K.; Hu, L.;
Dong, Z. J.; Hu, Q. Chem. BiodiVers. 2004, 1, 601. (g) Xie, C.; Koshino,
H.; Esumi, Y.; Takahashi, S.; Yoshikawa, K.; Abe, N. Biosci. Biotechnol.
activities including potent immunosuppressant,1 antioxida-
tive,2 neuroprotective,3 anticogulant,4 antidiabetic,5 antican-
cer,6 and specific 5-lipoxygenase inhibitory activities.7
(5) 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, A. V.; Smith, R. G.; Moller,
D. E. Science 1999, 284, 974. (b) Westerlund, J.; Wolf, B. A.; Bergsten, P.
Diabetes 2002, 51 (Suppl. 1), S50.
Biochem. 2005, 69, 2326
(3) Lee, I. K.; Yun, B. S.; Kim, J. P.; Ryoo, I. J.; Kim, Y. H.; Yoo,
I. D. Biosci. Biotechnol. Biochem. 2003, 67, 1813
(4) Khanna, J. M.; Malone, M. H.; Euler, K. L.; Brady, L. R. J. Pharm.
Sci. 1965, 54, 1016
.
.
(6) Puder, C.; Wagner, K.; Vettermann, R.; Hauptmann, R.; Potterat,
O. J. Nat. Prod. 2005, 68, 323.
.
10.1021/ol802645f CCC: $40.75
Published on Web 01/08/2009
2009 American Chemical Society

Moreover, notably, most of the terphenyls are plentiful in
edible mushrooms, indicating their relatively low toxicity
profile.2 Accordingly, these molecules serve as attractive
leads for the development of new therapeutic agents.
As a result of a wide range of bioactivities of this class of
compounds,5 in the recent past, their syntheses have received
increasing interest. The terphenylquinone nucleus was gener-
ally built up via substitution with diazonium salt but in low
yield.8 The alumina/potassium carbonate-promoted conden-
sation was developed as a key step for the synthesis of
asterriquinones.9a-c An improved protocol using cesium
carbonate was disclosed.9d However, these approaches were
limited to the preparation of symmetric asterriquinones.
Recently, Pirrung and co-workers reported a Pd-catalyzed
Heck reaction, which enabled introduction of different indole
moieties in a chemoselective controlled mode.10 Neverthe-
less, toxic mercuric indole reagents were employed with a
limited scope.
was described.13 However, highly toxic Tl2CO3 as base was
used, and the approach failed to react with aromatic boronic
acids.14 Moreover, controlled chemoselective introduction
of two different aromatic moieties into the central quinone
unit was a challenging task. Herein, we wish to report an
efficient protocol enabling to construct the differentially 3,6-
disubstituted 2,5-dioxybenzoquinones via two sequential
Suzuki-coupling reactions in high efficiency. We also suc-
cessfully applied the strategy for three-step synthesis of
natural product leucomelone in 61% overall yield.
Initial efforts focused on the optimization of the first
Suzuki coupling reaction conditions aimed at improving the
reaction yield and controlled generation of monosubstituted
product without forming bis-aryl product. A model reaction
of 3 (1.0 equiv) with 4-methoxyphenylboronic acid (4a, 1.4
equiv) was carried out in dixoane in the presence of K2CO3
as base at 110 °C (Table 1). It was found the reaction
We were interested in developing a general approach to
unsymmetrical 3,6-disubstituted 2,5-dioxybenzoquinones. A
convergent strategy is particularly attractive in medicinal
chemistry since it is a more efficient way of generating
structural diversity from readily available common late-stage
intermediates. We envisioned that Suzuki cross-coupling
reaction with 3,6-dibromo-2,5-dimethoxybenzoquinone (3)
was an ideal solution as a result of a large number of boronic
acids available (Scheme 1).11 Furthermore, the intermediate
Table 1. Optimization of Suzuki Coupling of
2,5-Dibromo-3,6-dimethoxy-1,4-benzoquinone (3) with
4-Methoxyphenylboronic Acid (4a)a
T
time SMb yieldc
solvent (°C) (h) (%) (%)
entry
catalyst
base
Scheme 1. Convergent Approach to Unsymmetrical
3,6-Disubstituted 2,5-Dimethoxybenzoquinone via Two
Sequential Suzuki Cross-Coupling Reactions
1
2
3
4
5
6
7
8
Pd(PPh3)4
K2CO3 dioxane 110 18
8
2
11
8
14
11
0
52
44
73
78
73
48
0
Pd(OAc)2/PCy3 K2CO3 dioxane 110 18
PdCl2(PPh3)2 K2CO3 dioxane 110 18
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
K2CO3 dioxane 110 18
K2CO3 THF 70 18
K2CO3 toluene 120 18
K2CO3 DMF 110 18
K2CO3 dioxane/ 100 18
water
0
0
9
PdCl2(dppf)
Na2CO3 dioxnae 110 18
Cs2CO3 dioxane 110 12
63
0
0
4
2
20
50
68
80
76
10 PdCl2(dppf)
11 PdCl2(dppf)
12 PdCl2(dppf)
13 PdCl2(dppf)
3 can be conveniently prepared in a large scale in two steps
from commercially available starting matereial.12 However,
the challenges were also realized. Examples of Suzuki cross-
couplings of quinones with boronic acids were extremely
rare. To the best of our knowledge, only a single study
involved reaction of dihalobenzoquinone with indolylboron
Cs2CO3 dioxane
rt 16
K2CO3 dioxane 110 24
K2CO3 dioxane 110 30
a 2,5-Dibromo-3,6-dimethoxy-1,4-benzoquinone (3, 0.10 mmol), 4-meth-
oxyphenylboronic acid (4a, 0.14 mmol), catalyst (0.005 mmol), base (0.20
mmol), solvent (1 mL). b Calculated based on recovered starting material
(SM) 3. c Isolated yield.
(7) Takahashi, A.; Kudo, R.; Kusano, G.; Nozoe, S. Chem. Pharm. Bull.
1992, 40, 3194.
(8) Kvalnes, D. E. J. Am. Chem. Soc. 1934, 56, 2478.
(9) (a) Lohrisch, H. J.; Schmidt, H.; Steglich, W. Liebigs Ann. Chem.
1986, 195. (b) Pattenden, G.; Pegg, N. A.; Kenyon, R. W. Tetrahedron
Lett. 1987, 28, 4749. (c) Pattenden, G.; Pegg, N. A.; Kenyon, R. W. J. Chem.
Soc., Perkin Trans. 1 1991, 2363. (d) Harris, C. D.; Nguyen, A.; App, H.;
Hirth, P.; McMahon, G.; Tang, C. Org. Lett. 1999, 1, 431.
(10) Pirrung, M. C.; Li, Z.; Park, K.; Zhu, J. J. Org. Chem. 2002, 67,
7919.
efficiency was highly catalyst dependent (entries 1-4).
Among the catalysts probed, PdCl2(dppf) was most effective.
In this case, monosubstituted product 4a was generated in
78% yield (entry 4). Importantly, under the reaction condi-
tions, a very small amount of bis-substitution product (<5%)
was observed. The effect of solvents on the reaction was
(11) For recent reviews of Suzuki cross-couplings, see: (a) Doucet, H.
Eur. J. Org. Chem. 2008, 2013. (b) Corbet, J.-P.; Mignani, G. Chem. ReV.
2006, 106, 2651. (c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633.
(13) (a) Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett.
1993, 34, 7637. (b) Kasahara, T.; Kondo, Y. Chem. Commun. 2006, 37,
891.
(12) 2,5-Dibromo-3,6-dimethoxy-1,4-benzoquinone (3) can be prepared
in two steps from cheap and commercially available 2,5-dimethoxy-1,4-
benzoquinone in high yields; see the Supporting Information for details.
(14) Ye, Y. Q.; Koshino, H.; Onose, J.; Yoshikawa, K.; Abe, N.;
Takahashi, S. Org. Lett. 2007, 9, 4131.
590
Org. Lett., Vol. 11, No. 3, 2009

significant (entries 4-8). Clearly, the optimal reaction yield
was achieved in dioxane (entry 4). No reaction occurred
when DMF was used (entry 7) and water dramatically
hindered reaction (entry 8). We found that the substantial
decomposition of the substrate 3 was observed under these
reaction conditions. Survey of bases revealed that K2CO3
was of choice (entries 4, 9, and 10). Finally, the reaction
time was also optimized. It was found that 24 h reaction
time was optimal using PdCl2(dppf) as catalyst and K2CO3
as base in dioxane at 110 °C with obtaining the best yield
(80%) (entries 4, 12, and 13).
with p-benzyloxyphenylboronic acid under the standard
reaction conditions (entry 2). It was found that switching
the base from K2CO3 to Cs2CO3 and lowering reaction
temperature to rt led to a significant improvement of yield
(80%). Longer reaction times did not help in enhancing
reaction yields for boronic acids possessing electron-
withdrawing moieties (entries 9 and 10). In contrast, a
considerable amount (ca. 10%) of monoreduction and
dicoupling reduction phenol products were obtained as
byproducts. Addition of Ag2O did not result in improved
reaction yields but instead suppressed the formation of the
byproduct.15 Probing steric effects indicated that the impact
was limited (entry 5). Finally, the catalytic system worked
smoothly for the heterocylic boronic acid substrate as well
(entry 11).
Having established the optimal reaction conditions of the
Suzuki coupling reaction, we next probed the scope of the
process. As revealed in Table 2, a variety of boronic acids
Having successfully established the protocol for producing
a monocoupling product, we shifted our focus to the second
Suzuki coupling process with the aim of further diversifying
the 2-arylbenzoquinones (5). After extensive exploration of
reaction conditions including catalyst screening and loading,
solvents, and bases using 5a reacting with 4-methoxyphe-
nylboronic acid as a model system, we found that the cross-
coupling process could be accomplished in high yield (84%)
with the same catalyst PdCl2(dppf) (2 mol %) but in toluene
and CsF as base (Table 3, entry 1). It is noteworthy that
higher catalyst loading (e.g., 5 mol %) gave rise to a
pronounced amount of reduction phenol product. As dem-
onstrated, the optimized reaction conditions served as a
general approach to the preparation of the corresponding
unsymmetrical 3,5-diarylbenzoquinones (6). Various boronic
acids with different electronic and steric features could be
tolerated in the process. High to excellent yields were
achieved (entries 1-8, 84-96%). Heterocyclic susbtrate
could also participate in the process despite relatively low
reaction yield (entry 9).
Table 2. Suzuki Monocoupling of
2,5-Dibromo-3,6-dimethoxy-1,4-benzoquinone (3) with Boronic
Acids (4)
To further demonstrate the versatility of the synthetic
strategy, we also investigated a one-step bis-Suzuki
reaction of 2,5-dibromo-3,6-dimethoxy-1,4-benzoquinone
(3) with boronic acids (Scheme 2). During the course of
our study of these Suzuki coupling reactions, we found
that the major side reaction was the reduced phenol of
bromosubstrates. This insight prompted us to add Ag2O
to suppress the formation of reductive products.15 Indeed,
it was shown that one-pot process was successfully
developed for efficient preparation of the symmetrical
disubstituted benzoquinones in good yields (64% and 72%,
respectively).
a Reaction conditions, unless specified, boronic acid (1.4 equiv), 5 mol
% of PdCl2(dppf), K2CO3 (2.0 equiv), dioxane, 110 °C, 24 h. b Isolated
yield. c Recovered starting material. d Boronic acid (1.4 equiv), 5 mol % of
PdCl2(dppf), Cs2CO3 (2.0 equiv), dioxane, rt, 16 h. e Boronic acid (1.4
equiv), 5 mol % of PdCl2(dppf), K2CO3 (2.0 equiv), Ag2O (1.2 equiv),
dioxane, 110 °C, 24 h.
Finally, we demonstrated the synthetic utility of the
powerful strategy for three-step synthesis of natural product
(15) (a) Uenishi, J.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756. (b) Gillmann, T.; Weeber, T. Synlett 1994,
649. (c) Mu, Y.; Gibbs, R. A. Tetrahedron Lett. 1995, 36, 5669. (d) Ruel,
F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1998, 75, 69. (e) Chen, H.;
Deng, M.-Z. J. Chem. Soc., Perkin Trans. 1 2000, 1609. (f) Chen, H.; Deng,
M.-Z. Org. Lett. 2000, 2, 1649. (g) Zhou, S.-M.; Deng, M.-Z. Tetrahedron
Lett. 2000, 41, 3951. (h) Yao, M.-L.; Deng, M.-Z. J. Org. Chem. 2000, 65,
5034. (i) Zou, G.; Reddy, K.; Falck, J. R. Tetrahedron Lett. 2001, 42, 7213.
(j) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2001, 66,
2459. (k) Lopez, L. C.; Strohriegl, P.; Stubinger, T. Macromol. Chem. Phys.
2002, 203, 1926.
bearing electron-donating, neutral, and withdrawing substit-
uents could participate in the process and generally good to
high yields for products 5 were obtained. The relatively
higher yields were achieved with boronic acids containing
electron-donating (entries 1-6) and -neutral groups (entry
7). Interestingly, the reaction proceeded very poorly (28%)
Org. Lett., Vol. 11, No. 3, 2009
591

Table 3. Suzuki Monocoupling of
5-Aryl-2-bromo-3,6-dimethoxy-1,4-benzoquinone (5a) with
Boronic Acids
Scheme 2. Suzuki Dicoupling of
2,5-Dibromo-3,6-dimethoxy-1,4-benzoquinone (2) with
Boronic Acids
Scheme 3. Total Synthesis of Leucomelone (9)
construct the medicinally interesting, structurally diversified
terphenylquinones or terphenylhydroquinones for biological
studies.
a Unless specified, reaction conditions: 1.5 equiv of boronic acid, 2
mol % of PdCl2(dppf), CsF (2.0 equiv), toluene, 70 °C, 10 h. b Isolated
yields. c Conditions: 1.5 equiv of boronic acid, 5 mol % of PdCl2(dppf),
CsF (2.0 equiv), toluene, 70 °C, 10 h.
Acknowledgment. Financial support for this work was
supported by the National Natural Science Foundation of China
(NSFC30572241 and 30772638) and the Chinese National
High-tech R&D Program (2007AA02Z147). We thank Dr.
W. Y. Tai, X. F. Chun, H. Y. Yang, and S. J. Lin (Shanghai
Institute of Materia Medica) for fruitful discussions.
leucomelone (9) in 61% overall yield from readily available
3 (Scheme 3).16
Supporting Information Available: Experimental pro-
cedures; 1H NMR and 13C NMR data and spectra of 5a-k,
6a-i, and 7-9. This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we have developed a new, convergent, and
versatile synthetic strategy for efficient synthesis of 2,5-
disubstituted 3,6-methoxy-1,4-benzoquinones from readily
available molecules. By careful manipulation of the Suzuki
cross-coupling reaction conditions, it is possible to chemose-
lectively introduce aromatic components into dihalogenated
benzoquinone scaffolds. This approach can be used to rapidly
OL802645F
(16) Leucomelone shows potent inhibitory activity against FabK as an
antibacterial agent: Zheng, C.-J.; Sohn, M.-J.; Kim, W.-G. J. Antibiot. 2006,
59, 808.
592
Org. Lett., Vol. 11, No. 3, 2009