Convergent synthesis of diptoindonesin G

Article abstract of DOI:10.1016/j.tetlet.2018.12.036

A convergent and scalable synthetic route to a tetracyclic oligostilbenoid natural product, diptoindonesin G, is described where Suzuki-Miyaura cross-coupling and intramolecular Friedel-Crafts acylation were employed to construct the central C ring of dip

Full text of DOI:10.1016/j.tetlet.2018.12.036

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Convergent Synthesis of Diptoindonesin G
Dileep Kumar Singh, Ikyon Kim
PII:
S0040-4039(18)31478-3
https://doi.org/10.1016/j.tetlet.2018.12.036
TETL 50499
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Reference:
Tetrahedron Letters
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29 October 2018
14 December 2018
16 December 2018
Please cite this article as: Singh, D.K., Kim, I., Convergent Synthesis of Diptoindonesin G, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.036
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Convergent Synthesis of Diptoindonesin G
Dileep Kumar Singh and Ikyon Kim
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1
Tetrahedron Letters
Convergent Synthesis of Diptoindonesin G
Dileep Kumar Singh and Ikyon Kim
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convergent and scalable synthetic route to a tetracyclic oligostilbenoid natural product,
diptoindonesin G, is described where Suzuki-Miyaura cross-coupling and intramolecular
Friedel-Crafts acylation were employed to construct the central C ring of diptoindonesin G. Two
fragments for cross-coupling reaction were readily synthesized with similar efficiency.
Available online
.
Keywords:
Diptoindonesin G
Oligostilbenoids
Natural product
Suzuki-Miyaura coupling
Intramolecular reaction
Friedel-Crafts acylation
Biologically active natural products have been a source of a
number of inspirations and creativities on total synthesis over the
last decades.1 Diptoindonesin G, a tetracyclic oligostilbenoid
natural product first isolated from the tree bark of Hopea
mengarawan in 2009,2 has been such a case in our laboratory.
Although it is relatively small, its intriguing biological activity3
as well as our interest on benzofurans4 guided us to pursue
several synthetic approaches to diptoindonesin G from three
different starting materials, 1-3 (Scheme 1).5,6
Notably, all these approaches took advantage of
intramolecular Friedel-Crafts type acylation7 as a means to form
the C ring as noted in blue line due to high reactivity of the
electron-rich D ring toward the neighboring acid moiety attached
to the A ring. Disconnection of the central C ring in a distinctive
way (indicated in red line) provided us an opportunity to devise a
new convergent route to this natural product as retrosynthetically
analyzed in Scheme 1. Thus, we envisioned that construction of
the target skeleton would be achieved via intramolecular Friedel-
Crafts acylation of 4, which in turn could be assembled by
Suzuki-Miyaura cross-coupling reaction of 5 and 6.
Scheme 1. Our Synthetic Plans to Diptoindonesin G
1,3-dimethoxybenzene in the presence of iodine and
(diacetoxyiodo)benzene11 took place to give 8 which was coupled
with 4-ethynylanisole under Sonogashira cross-coupling
conditions to furnish 9 in 95% yield.Subsequent iodine-mediated
cyclization12,13 of 9 led to 3-iodobenzofuran 6.Suzuki-Miyaura
coupling14 of 5 and 6 proceeded smoothly to afford 10 in good
yield (Scheme 4). Aldehyde 10 was oxidized to acid 4 under
Lindgren-Kraus-Pinnick conditions.15 Intramolecular Friedel-
Crafts type cyclization of 4 occurred upon exposure to
trifluoroacetic anhydride to give tetramethyl ether of
diptoindonesin G (11), a known intermediate, whose spectral data
were in good agreement with those from the literature.5a
With this idea in mind, we began the synthesis by making two
fragments, 5 and 6, respectively. Boronate 5 was prepared from
commercially available starting material in two steps (Scheme
2).8
Vilsmeier-Haack
dimethoxybenzene afforded aldehyde 7 which was transformed
to boronate
under Miyaura borylation conditions.10 3-
Iodobenzofuran was easily synthesized from 1,3-
formylation9
of
1-bromo-3,5-
5
6
dimethoxybenzene as shown in Scheme 3. Mono-iodination of
———
 Corresponding author. Tel.: +82-32-749-4515; fax: +82-32-749-4105; e-mail: ikyonkim@yonsei.ac.kr

2
Tetrahedron
Gao, J.; Fan, M.; Xiang, G.; Wang, J.; Zhang, X.; Guo, W.; Wu,
X.; Sun, Y.; Gu, Y.; Ge, H.; Tan, R.; Qiu, H.; Shen, Y.; Xu, Q.
Cell Death Dis. 2017, 8, 2765.
Conversion of 11 to diptoindonesin G by excess BBr3 treatment
was known in the literature.5a
4. (a) Kim, I.; Lee, S.-H.; Lee, S. Tetrahedron Lett. 2008, 49, 6579.
(b) Kim, I.; Choi, J. Org. Biomol. Chem. 2009. 7, 2788. (c) Kim,
I.; Kim, K.; Choi, J. J. Org. Chem. 2009, 74, 8492. (d) Lee, J. H.;
Kim, M.; Kim, I. J. Org. Chem. 2014, 79, 6153. (e) Nayak, M.;
Jung, Y.; Kim, I. Org. Biomol. Chem. 2016, 14, 8074. (f) Nayak,
M.; Singh, D. K.; Kim, I. Tetrahedron 2017, 73, 1831.
5. (a) Kim, K.; Kim, I. Org. Lett. 2010, 12, 5314. (b) Jung, Y.;
Singh, D. K.; Kim, I. Beilstein J. Org. Chem. 2016, 12, 2689. (c)
Singh, D. K.; Kim, I. J. Org. Chem. 2018, 83, 1667.
Scheme 2. Synthesis of 5
6. For synthesis of diptoindonesin G by others, see: (a) Liu, J.-t.; Do,
T. J.; Simmons, C. J.; Lynch, J. C.; Gu, W.; Ma, Z.-X. Xu, W.;
Tang, W. Org. Biomol. Chem. 2016, 14, 8927. (b) Xu, W.; Tang,
W.; Liu, J.; Kolesar, J. US 20180065945 A1 20180308. (c)
(synthesis of C13-dehydroxydiptoindonesin G) Sun, T.; Zhang,
Y.; Qiu, B.; Wang, Y.; Qin, Y.; Dong, G.; Xu, T. Angew. Chem.,
Int. Ed. 2018, 57, 2859.
7. For recent examples, see: (a) Fillion, E.; Fishlock, D. Tetrahedron
2009, 65, 6682. (b) Motiwala, H. F.; Vekariya, R. H.; Aube, J.
Org. Lett. 2015, 17, 5484. (c) Sun, D.; Li, B.; Lan, J.; Huang, Q.;
You, J. Chem. Commun. 2016, 52, 3635. (d) Jousselin-Oba, T.;
Sbargoud, K.; Vaccaro, G.; Meinardi, F.; Yassar, A.; Frigoli, M.
Chem. Eur. J. 2017, 23, 16184. (e) Wang, S.; Kraus, G. A.
Tetrahedron Lett. 2018, 59, 1968. (f) Goswami, S.; Harada, K.;
El-Mansy, M. F.; Lingampally, R.; Carter, R. G. Angew. Chem.,
Int. Ed. 2018, 57, 9117.
Scheme 3. Synthesis of 6
8. See the Supplementary Material for experimental details.
9. (a) Jones, G.; Stanforth, S. P. Org. React. (Hoboken, NJ, US),
1997, 49, 1. (b) Koch, K.; Podlech, J.; Pfeiffer, E.; Metzler, M. J.
Org. Chem. 2005, 70, 3275. (c) Snyder, S. A.; Sherwood, T. C.;
Ross, A. G. Angew. Chem., Int. Ed. 2010, 49, 5146.
10. (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Fan-Chiang, T.-T.; Wang, H.-K.; Hsieh, J.-C.
Tetrahedron 2016, 72, 5640.
11. Karade, N. N.; Tiwari, G. B.; Huple, D. B.; Siddiqui, T. A. J. J.
Chem. Res. 2006, 366. Although synthesis of 1-iodo-3,5-
dimethoxybenzene was reported from the reaction of 1,3-
dimethoxybenzene with I2 and (diacetoxyiodo)benzene in this
paper, 1-iodo-2,4-dimethoxybenzene was obtained instead in our
hands.
12. (a) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70,
10292. (b) Chiummiento, L.; Funicello, M.; Lopardo, M. T.;
Lupattelli, P.; Choppin, S.; Colobert, F. Eur. J. Org. Chem. 2012,
188. (c) He, Y.; Liu, S.; Menon, A.; Stanford, S.; Oppong, E.;
Gunawan, A. M.; Wu, L.; Wu, D. J.; Barrios, A. M.; Bottini, N.;
Cato, A. C. B.; Zhang, Z.-Y. J. Med. Chem. 2013, 56, 4990.
13. For our work in heterocycle synthesis by way of iodocyclization,
see: (a) Jung, Y.; Kim, I. Asian J. Org. Chem. 2016, 5, 147 and
references therein. (b) Jung, Y.; Kim, I. Org. Biomol. Chem. 2016,
14, 10454. (c) Nayak, M.; Singh, D. K.; Kim, I. Synthesis 2017,
49, 2063.
Scheme 4. Assembly of 5 and 6
In conclusion, we have established a new convergent synthetic
approach to biologically active diptoindonesin G by relying on
Suzuki-Miyaura coupling and intramolecular Friedel-Crafts
cyclization to construct the central C ring. Ease of synthetic
manipulations, flexibility, and high overall yields of this route
should be useful for large-scale synthesis of diptoindonesin G
and its derivatives for further biological evaluation.
Acknowledgments
We thank the National Research Foundation of Korea (NRF-
2017R1A2A2A05069364 and NRF-2018R1A6A1A03023718)
for generous financial support.
14. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Taheri
Kal Koshvandi, A., Heravi, M. M.; Momeni, T. Appl. Organomet.
Chem. 2018, 32, 4210.
15. (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(c) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091.
References
1. (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
John Wiley: New York, 1989. (b) Nicolaou, K. C.; Vourloumis,
D.; Winssinger, N.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39,
44.
2. Juliawaty, L. D.; Sahidin; Hakim, E. H.; Achmad, S. A.; Syah, Y.
M.; Latip, J.; Said, I. M. Nat. Prod. Commun. 2009, 4, 947.
3. For biological studies of diptoindonesin G, see: (a) Ge, H. M.;
Yang, W. H.; Shen, Y.; Jiang, N.; Guo, Z. K.; Luo, Q.; Xu, Q.;
Ma, J.; Tan, R. X. Chem. Eur. J. 2010, 16, 6338. (b) Zhao, J.;
Wang, L.; James, T.; Jung, Y.; Kim, I.; Tan, R.; Hoffmann, M.;
Xu, W. Chem. Biol. 2015, 22, 1608. (c) Bumroong, B.;
Thanakijcharoenpath, W. Thai J. Pharm. Sci. 2016, 40, 185. (d)
Supplementary Material
Experimental procedures, compound characterization data,
1
and H and 13C NMR spectra of synthesized compounds can be
found, in the online version at…
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Highlights
- A convergent and scalable synthetic
approach to diptoindonesin G is decribed.
- Suzuki-Miyaura coupling and
intramolecular Friedel-Crafts acylation as
key steps
- This route should be useful for synthesis of
diptoindonesin G and its derivatives.