Total synthesis of diptoindonesin G via a highly efficient domino cyclodehydration/intramolecular friedel-crafts acylation/regioselective demethylation sequence

Article abstract of DOI:10.1021/ol102322g

A highly efficient total synthesis of diptoindonesin G is described employing a domino dehydrative cyclization/intramolecular Friedel-Crafts acylation/regioselective demethylation reaction of aryloxyketone 7 by the action of BCl₃ wherein the tetracyclic 6H-anthra[1,9-bc]furan-6-one skeleton was constructed via the 3-arylbenzofuran in a one-pot manner. This is the first example of the strategic combination of these three reactions in a cascade fashion. The routes presented here allow for direct access to diptoindonesin G and its analogues.

Full text of DOI:10.1021/ol102322g

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5314-5317
Total Synthesis of Diptoindonesin G via
a Highly Efficient Domino
Cyclodehydration/Intramolecular
Friedel-Crafts Acylation/Regioselective
Demethylation Sequence
Kyungsun Kim and Ikyon Kim*
Medicinal Chemistry Research Center, Korea Research Institute of Chemical
Technology, Daejeon 305-600, Republic of Korea
ikyon@krict.re.kr
Received September 27, 2010
ABSTRACT
A highly efficient total synthesis of diptoindonesin G is described employing a domino dehydrative cyclization/intramolecular Friedel-Crafts
acylation/regioselective demethylation reaction of aryloxyketone 7 by the action of BCl3 wherein the tetracyclic 6H-anthra[1,9-bc]furan-6-one
skeleton was constructed via the 3-arylbenzofuran in a one-pot manner. This is the first example of the strategic combination of these three
reactions in a cascade fashion. The routes presented here allow for direct access to diptoindonesin G and its analogues.
Dipterocarpaceae is known to be a rich source of a variety
of biologically active oligostilbenoids.1 Indeed, a number of
oligomeric stilbenes have been isolated with distinct modes
of connectivity of their basic 1,2-diphenylethylene skeleton.
Not surprisingly, many interesting pharmacological functions
of this family have been also identified including antiin-
flammatory, antibacterial, antifungal, and anticancer activi-
ties.2 Despite their intriguing biological properties as well
as unique molecular structures, only a few chemical ap-
proaches to oligostilbene natural products have been re-
ported.3
Recently, we described a modular approach to benzofuran-
containing oligostilbenoids that led to the syntheses of perm-
ethylated analogues of viniferifuran, malibatol A, and sho-
(2) (a) Samaraweera, U.; Sotheeswaran, S.; Sultanbawa, M. U. S.
Phytochemistry 1982, 21, 2585. (b) Bokel, M.; Diyasena, M. N. C.;
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Kamijou, A.; Matuoka, S.; Nakano, M.; Terao, K.; Ohizumi, Y. Experientia
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(i) Privat, C.; Telo, J. P.; Bernades-Genisson, V.; Vieira, A.; Souchard,
J. P.; Nepveu, F. J. Agric. Food Chem. 2002, 50, 1213. (j) Wang, S.; Ma,
D.; Hu, C. HelV. Chim. Acta 2005, 88, 2315. (k) Yamada, M.; Hayashi,
K.-i.; Hayashi, H.; Tsuji, R.; Kakumoto, K.; Ikeda, S.; Hoshino, T.; Tsutsui,
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Yamada, M.; Hayashi, K.-i.; Ikeda, S.; Tsutsui, K.; Ito, T.; Iinuma, M.;
Nozaki, H. Biol. Pharm. Bull. 2006, 29, 1504.
(1) For recent reviews on natural stilbenes, see: (a) Takaya, Y.; Niwa,
M. Trends Heterocycl. Chem. 2001, 7, 41. (b) Seo, E.-K.; Kinghorn, A. D.
Stud. Nat. Prod. Chem. 2000, 23 (Bioactive Natural Products (Part D)),
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Natural Products (Part M)), 601. (d) Shen, T.; Wang, X.-N.; Lou, H.-X.
Nat. Prod. Rep. 2009, 26, 916.
10.1021/ol102322g  2010 American Chemical Society
Published on Web 10/29/2010

pleased to find that acid obtained by hydrolysis of ester
38 underwent smooth cyclization in the presence of
trifluoroacetic anhydride at room temperature to afford 4
in 77% yield (Scheme 3). Unmasking of four phenolic
Scheme 1
.
Our Previous Synthetic Approach to Oligostilbenoids
Bearing a Benzofuran Unit
Scheme 3. Initial Synthetic Route to Diptoindonesin G
reaphenol (Scheme 1).4 Thus, coupling of 1 and 2, dehydrative
cyclization, and subsequent direct arylation at the C2 position
of the benzofuran moiety provided a key intermedate 3 which,
upon further elaboration, was converted to the pentamethyl
ethers of three natural products.
A few months after this publication, isolation of a novel
oligostilbenoid possessing strong cytotoxic activity, dipto-
indonesin G, from the tree bark of Hopea mengarawan was
reported by Syah and co-workers.5 More recently, this natural
product has been shown to exhibit potent immunosuppressive
activity.6 Alongside these interesting biological activities, the
structural relationship of diptoindonesin G with 3 prompted
us to pursue the total synthesis of diptoindonesin G, which
is the topic of this paper.
hydroxyl groups in 4 occurred upon exposure to BBr3,
delivering diptoindonesin G in 93% yield. Spectral data
of synthetic samples are in good agreement with those of
natural diptoindonesin G.5
At this point, we attempted to synthesize much simpler
analogues which can be derived from synthetic intermediates
for pharmacological evaluation.9 In this respect, 5 was also
exposed to BBr3 to produce the corresponding trihydroxy
compound. Surprisingly, however, tetracyclic compound 6
was isolated as a major product instead of expected methyl
ester shown in the box of Scheme 4. This result certainly
arises from the action of BBr3 to coordinate to the carbonyl
group to promote Friedel-Crafts-type cyclization in addition
to its demethylation ability.10 Similarly, subjection of 3 to
the identical conditions directly provided diptoindonesin G
in 92% yield. Since BCl3-mediated cyclodehydration of
aryloxyketones to benzofurans (for example, 7 to 5) is
plausible, we anticipated that more direct synthesis of 6 might
be realized from 7 by modifying the reported procedure.11
Thus, BBr3 was added to the reaction mixture after formation
of benzofuran was confirmed by TLC upon treatment of 7
with BCl3.12,13 To our delight, 93% of the desired product
was obtained in this case.
It was initially envisaged that diptoindonesin G would
beeasilysynthesizedfrom3byintramolecularFriedel-Crafts
acylation7 followed by global demethylation (Scheme 2).
Scheme 2. Initial Synthetic Plan
(4) Kim, I.; Choi, J. Org. Biomol. Chem. 2009, 7, 2788.
(5) Juliawaty, L. D.; Sahidin; Hakim, E. H.; Achmad, S. A.; Syah, Y. M.;
Latip, J.; Said, I. M. Nat. Prod. Commun. 2009, 4, 947.
(6) Ge, H. M.; Yang, W. H.; Shen, Y.; Jiang, N.; Guo, Z. K.; Luo, Q.;
Xu, Q.; Ma, J.; Tan, R. X. Chem.sEur. J. 2010, 16, 6338.
(7) For recent examples, see: (a) Olah, G. A.; Mathew, T.; Farnia, M.;
Prakash, G. K. S. Synlett 1999, 1067. (b) Fillion, F.; Fishlock, D. J. Am.
Chem. Soc. 2005, 127, 13144. (c) Lan, K.; Shao, F.; Shan, Z. Aust. J. Chem.
2007, 60, 80. (d) Fillion, E.; Fishlock, D. Tetrahedron 2009, 65, 6682. (e)
Yadav, J. S.; Ravindar, A. R. K.; Reddy, B. V. S. Synthesis 2010, 797. (f)
Prinz, H.; Bo¨hm, K. J.; Mu¨ller, K. J. Org. Chem. 2010, 75, 3867. (g) Malik,
H.; Rutjes, F. P. J. T.; Zwanenburg, B. Tetrahedron 2010, 66, 7198.
(8) Direct cyclization of 3 was also attempted with trifluoroacetic acid.
Thus, exposure of 3 to refluxing trifluoroacetic acid resulted in clean
conversion to 4 although long reaction time was required (36 h).
(9) For concepts on diverted total synthesis, see: (a) Wilson, R. M.;
Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329. (b) Kumar, K.; Waldmann,
H. Angew. Chem., Int. Ed. 2009, 48, 3224. (c) Wilson, R. M.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2010, 49, 6032.
With this notion in mind, a large quantity of 3 was
prepared by adopting the reported procedure.4 We were
(3) (a) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191. (b) Yao, C.-S.;
Zhou, L.-X.; Lin, M. Chem. Pharm. Bull. 2004, 52, 238. (c) Takaya, Y.;
Terashima, K.; Ito, J.; He, Y.-H.; Tateoka, M.; Yamaguchi, N.; Niwa, M.
Tetrahedron 2005, 61, 10285. (d) Snyder, S. A.; Zografos, A. L.; Lin, Y.
Angew. Chem., Int. Ed. 2007, 46, 8186. (e) Velu, S. S.; Buniyamin, I.;
Ching, L. K.; Feroz, F.; Noorbatcha, I.; Gee, L. C.; Awang, K.; Abd. Wahab,
I.; Weber, J.-F. F. Chem.sEur. J. 2008, 14, 11376. (f) Snyder, S. A.;
Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. J. Am. Chem. Soc.
2009, 131, 1753. (g) Nicolaou, K. C.; Wu, T. R.; Kang, Q.; Chen, D. Y.-
K. Angew. Chem., Int. Ed. 2009, 48, 3440. (h) Kraus, G. A.; Gupta, V.
Tetrahedon Lett. 2009, 50, 7180. (i) Nicolaou, K. C.; Kang, Q.; Wu, T. R.;
Lim, C. S.; Chen, D. Y.-K. J. Am. Chem. Soc. 2010, 132, 7540.
(10) For a recent report on the use of BBr3 as an activator of imide
carbonyl group to initiate electrophilic cyclization without demethylation,
see: Selvakumar, J.; Makriyannis, A.; Ramanathan, C. R. Org. Biomol.
Chem. 2010, 8, 4056.
(11) Kim, I.; Lee, S.-H.; Lee, S. Tetrahedron Lett. 2008, 49, 6579.
Org. Lett., Vol. 12, No. 22, 2010
5315

Friedel-Crafts acylation process of aryloxyketones such as
7 is unprecedented in the literature.18
Scheme 4. Direct Approaches to Diptoindonesin G by BBr3
At this point, compound 8 was also advanced to diptoin-
donesin G via the route illustrated in Scheme 5. Direct
arylation19 under palladium catalysis was attempted to install
an aryl group at the C2 position of the benzofuran20 unit of
8. Initial reaction of 8 under the conditions employed in our
previous syntheses of oligostilbenoids only furnished 9 in
18-22% yield (entry 1, Table 1).21 Subjection of 8 to
Table 1. Reaction Optimization
entry
X
R
product
yielde
1a
2b
3c
Br
I
Br
I
Br
Br
Br
Br
Br
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-Me
3,4,5-(OMe)3
4-n-Bu
4-t-Bu
9
9
9
9
9
10
11
12
13
18-22
28-31
26
39
83
78
42
44
56
With these exciting results in hand, we further reasoned
that BCl3 alone might also trigger Friedel-Crafts-type ring
closure after the cyclodehydration event on aryloxyketone
7. Indeed, when 7 was treated with 5 equiv of BCl3, 8 was
isolated in excellent yield (Scheme 5).14 Mechanistically,
4d
5d
6d
7d
8d
9d
a A mixture of 8 (0.1 mmol), aryl halide (2 equiv), Pd(OAc)2 (10 mol
%), and KOAc (2 equiv) in DMA (1 mL) was heated at 80 °C for 13 h. b
A
Scheme 5. Concise Route to Diptoindonesin G
mixture of 8 (0.1 mmol), aryl halide (2 equiv), Pd(OAc)2 (10 mol %),
NaHCO3 (2 equiv), and TBAC (1 equiv) in DMF (1 mL) was heated at
100 °C for 13 h. c A mixture of 8 (0.1 mmol), aryl halide (2 equiv), Pd(OAc)2
(10 mol %), PCy3HBF4 (20 mol %), PivOH (30 mol %), and K2CO3 (1.5
equiv) in DMA (1 mL) was heated at 100 °C for 1 h. d A mixture of 8
(0.17 mmol), aryl halide (2 equiv), Pd(OAc)2 (10 mol %), PCy3HBF4 (20
mol %), PivOH (3 equiv), and K2CO3 (1.5 equiv) in DMA (3 mL) was
heated at 100 °C for 1 h. e Isolated yield (%).
Jeffery’s ligandless conditions22 gave a similar yield (entry
2). We were delighted to observe that cross coupling with
(16) For books and reviews on domino or tandem reactions, see: (a)
Ho, T.-L. Tandem Organic Reactions; John Wiley & Sons: New York, 1992.
(b) Tietze, L. F., Brasche, G., Gericke, K. M., Eds.; Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (c) Tietze,
L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32, 131. (d) Tietze, L. F.
Chem. ReV. 1996, 96, 115. (e) Nicolaou, K. C.; Montagnon, T.; Snyder,
S. A. Chem. Commun. 2003, 551. (f) Ramon, D. J.; Yus, M. Angew. Chem.,
Int. Ed. 2005, 44, 1602. (g) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem., Int. Ed. 2006, 45, 7134. (h) Pellissier, H. Tetrahedron 2006,
62, 2143. (i) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1.
successive formation of two rings set the stage for regiose-
lective demethylation by BCl3 as shown in the box of Scheme
5. Notably, construction of 6H-anthra[1,9-bc]furan-6-one15
by use of a domino16,17 cyclodehydration/intramolecular
(17) (a) Kim, I.; Kim, S. G.; Kim, J. Y.; Lee, G. H. Tetrahedron 2008,
64, 664. (b) Kim, I.; Kim, K.; Choi, J. J. Org. Chem. 2009, 74, 8492. (c)
Kim, I.; Kim, K. Org. Lett. 2010, 12, 2500.
(18) Formation of this skeleton under Lewis or Brønsted acid catalysis
in a cascade fashion is currently being investigated.
(19) For reviews, see: (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002,
35, 826. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(c) Godula, K.; Sames, D. Science 2006, 312, 67. (d) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (e) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (f) Li, B.-J.; Yang, S.-D.;
Shi, Z.-J. Synlett 2008, 949. (g) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (h) Ackermann, L.; Vicente,
R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (i) Sun, C.-L.; Li,
B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677.
(12) See the Supporting Information for detailed experimental proce-
dures.
(13) Direct exposure of 7 to excess BBr3 resulted in very low yield of
product.
(14) Gram-scale reaction of 7 also proceeded smoothly.
(15) (a) Mainagashev, I. Y.; Klimenko, L. S. IzV. Akad. Nauk, Ser. Khim.
1996, 2710. (b) Gotzhein, F.; Kirmse, W. Tetrahedron Lett. 1998, 39, 6675.
5316
Org. Lett., Vol. 12, No. 22, 2010

aryl bromide under slightly modified Fagnou’s conditions23
dramatically increased the isolated yield (entries 3-5).24 Several
aryl groups were introduced under these conditions to afford
the corresponding products (entries 6-9). Deprotection of three
methyl groups of 9 by BBr3 produced diptoindonesin G.
In summary, we have accomplished the first total synthesis
of diptoindonsin G via several concise and flexible routes
by which diptoindonesin G analogues should be easily
prepared. In particular, exploitation of a novel BCl3-facilitated
domino cyclodehydration/intramolecular Friedel-Crafts acy-
lation/regioselective demethylation sequence allows for ready
access to the key tetracyclic core in one reaction step with
remarkable efficiency. Subsequent direct arylation at the C2
site of the benzofuran moiety followed by demethylation led
to diptoindonesin G in good overall yield (70%, four linear
steps) from 1 and 2. Extension of this protocol to the
assembly of other carbo- and heterocycles as well as
biological evaluation of diptoindonesin G and its analogues
is currently underway and will be reported in the near future.
(20) Direct C2-arylation of benzofurans is less studied. (a) Ohta, A.;
Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.;
Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951. (b) Aoyagi, Y.; Inoue,
A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Komatsu, J.;
Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma, R.; Akita, Y.; Ohta, A.
Heterocycles 1992, 33, 257. (c) Nandurkar, N. S.; Bhanushali, M. J.; Bhor,
M. D.; Bhanage, B. M. Tetrahedron Lett. 2008, 49, 1045. (d) Yang, S.-D.;
Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed.
2008, 47, 1473. (e) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem.
Soc. 2008, 130, 15185. (f) Matsuda, S.; Takahashi, M.; Monguchi, D.; Mori,
A. Synlett 2009, 1941. For direct C3-arylation of benzofurans, see: (g) Ionita,
M.; Roger, J.; Doucet, H. ChemSusChem 2010, 3, 367.
Acknowledgment. We thank Korea Research Institute of
Chemical Technology for financial support. We are grateful
to Dr. Syah at Institut Teknologi Bandung for providing us
with NMR spectra of diptoindonesin G.
(21) No homodimer was observed in this case as compared with direct
arylation of 5. See ref 4.
Supporting Information Available: Full experimental
details, characterization data, and copies of 1H and 13C NMR
spectra of 4, 6, 8-13, and synthetic diptoindonesin G. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287. (b)
Jeffery, T. Tetrahedron Lett. 1985, 26, 2667. (c) Jeffery, T. Tetrahedron
Lett. 1994, 35, 3051. (d) Jeffery, T. Tetrahedron 1996, 52, 10113.
(23) Lie´gault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J.
Org. Chem. 2009, 74, 1826.
(24) Studies on the reason and reaction scope under these modified
conditions are in progress.
OL102322G
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