Symmetry-based approach to oligostilbenoids: Rapid entry to viniferifuran, shoreaphenol, malibatol A, and diptoindonesin G

Article abstract of DOI:10.3762/bjoc.12.266

The recognition of the local symmetric image within benzofuran-based natural oligostilbenoids guided us to design a modular synthetic approach to these molecules by utilizing a three-step sequence consisting of Sonogashira coupling, iodocyclization, and S

Full text of DOI:10.3762/bjoc.12.266

Symmetry-based approach to oligostilbenoids: Rapid entry to
viniferifuran, shoreaphenol, malibatol A, and diptoindonesin G
Youngeun Jung‡, Dileep Kumar Singh‡ and Ikyon Kim*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2689–2693.
College of Pharmacy and Yonsei Institute of Pharmaceutical
Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu,
Incheon 21983, Republic of Korea
doi:10.3762/bjoc.12.266
Received: 30 September 2016
Accepted: 25 November 2016
Published: 12 December 2016
Email:
Ikyon Kim* - ikyonkim@yonsei.ac.kr
Associate Editor: J. Aubé
* Corresponding author ‡ Equal contributors
§ Tel.: +82 32 749 4515; fax: +82 32 749 4105
© 2016 Jung et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
anticancer agent; iodocyclization; natural product; oligostilbenoids;
Pd-catalyzed coupling
Abstract
The recognition of the local symmetric image within benzofuran-based natural oligostilbenoids guided us to design a modular syn-
thetic approach to these molecules by utilizing a three-step sequence consisting of Sonogashira coupling, iodocyclization, and
Suzuki coupling. During our synthesis, the relative reactivities of ester, aldehyde, and alkoxy groups on the same aryl ring toward
the neighboring alkyne in the iodine-mediated cyclization reactions were explored. Starting from the symmetrical 3,5-dimethoxy-
benzyl alcohol, this route allowed rapid access to 2,3-diarylbenzofuran, a key intermediate to several oligostilbenoid natural prod-
ucts, in good overall yields.
Introduction
Oligostilbenoids constitute a family of natural products with furan-containing natural products for the last several years [13-
various biological functions (Figure 1). Monomeric stilbene 15]. For example, we have reported a concise total synthesis of
units are interconnected in a number of ways to lead to com- diptoindonesin G, a potent cytotoxic and immunosuppressant
plex structures [1-3]. Despite a long history of isolation and bio- agent [16,17], by using a highly efficient domino cyclodehydra-
logical studies of these natural products, relatively little atten- tion/intramolecular Friedel–Crafts acylation/regioselective
tion has been paid by the synthetic community to chemical syn- demethylation sequence as a key transformation. Very recently,
thesis of polyphenolic oligostilbenoids. Most synthetic works a dual functional role of diptoindonesin G in modulating α and
on these unique natural products have recently appeared in the β estrogen receptors (ER) has been discovered, thereby
literature [4-10].
suggesting it as a promising drug lead for the treatment of
breast cancer [18]. Our continuing interest in this area led us to
In connection with our research on benzofurans [11,12], our design an alternative approach to oligostilbenoids. As shown in
laboratory has been involved in the synthesis of these benzo- Scheme 1, our idea stemmed from recognition of the symmetry
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relative reactivity of these functional groups toward alkyne
during electrophilic cyclization has been reported [31], the
study with the substrates having these nucleophiles on the same
aromatic ring has not been disclosed, to the best of our know-
ledge. Here we wish to describe our results.
Results and Discussion
By following the known procedures, monoiodination of the
commercially available methyl 3,5-dimethoxybenzoate, 3,5-
dimethoxybenzaldehyde, and 3,5-dimethoxybenzyl alcohol
under the influence of either I2/silver trifluoroacetate or
N-iodosuccinimide afforded 1 [32-34], 2 [35], and 7 [36,37], re-
spectively (Scheme 2). The hydroxy group of 7 was protected
as an acetate, providing 3 in 96% yield. Sonogashira coupling
of the resulting iodides 1, 2, and 3 with alkynylanisole
proceeded without any event to give the corresponding alkynes,
4, 5, and 6, setting the stage for iodocyclization.
When 4 was exposed to I2 and NaHCO3 in CH2Cl2, two
isolable products were obtained (Scheme 3). Surprisingly, 8 was
isolated in 32% yield presumably as a consequence of
Figure 1: Natural oligostilbenoids.
element [19] of the target molecules. We expected that the key HI-promoted cyclization even in the presence of excess base.
intermediate (inset box of Scheme 1) could be constructed from The structure of 8 was confirmed by X-ray crystallographic
the monoiodo compounds 1, 2, or 3 through a sequence involv- analysis (Figure 2) [38]. The other major product 9, less polar
ing Sonogashira coupling, iodocyclization [20-26], and Suzuki than 8, resulted from 6-endo-dig iodocyclization. Obviously, the
coupling. As the starting materials (1, 2, and 3) were readily ester moiety in 4 was competitively involved in the iodine-
available from the corresponding C2 symmetric precursors via mediated electrophilic cyclization. Only a trace amount of 10
monoiodination, we decided to evaluate this route. In particular, was isolated upon subjection of 5 to the same reaction condi-
we wondered what functional group as a G moiety would be tions. We suspected that the aldehyde in 5 also acted as a
appropriate for the successful iodine-mediated cyclization. nucleophile to furnish unstable oxocarbenium species (inset box
Ester, aldehyde, and alkoxy groups have been used as nucleo- of Scheme 3) as a major product which decomposed eventually.
philes of iodocyclization for the syntheses of a number of On the other hand, 6 was successfully converted to the desired
heterocycles, respectively [27-30]. Although Larock’s work on 3-iodobenzofuran 11 in good yield. These results led us con-
Scheme 1: Synthetic plan.
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Scheme 2: Synthesis of 4, 5, and 6.
Scheme 3: Iodocyclization.
clude that either ester or aldehyde groups perform as better our delight, the subsequent Suzuki cross-coupling of 13 with
nucleophiles than an alkoxy group in the iodocyclization.
3,5-dimethoxyphenylboronic acid under the reaction conditions
analogous as described before [26] proceeded well and
furnished 14 in 88% yield. This intermediate was used for our
previous syntheses of permethylated analogues of viniferifuran,
malibatiol A, and shoreaphenol [13]. Under similar reaction
conditions, several other arylboronic acids reacted with 13 to
give the corresponding products in good yields, demonstrating
Having secured gram quantities of 3-iodobenzofuran 11 in
hand, our next task was to elaborate the conversion of 11 to 2,3-
diarylbenzofurans (Scheme 4). To this end, 11 was first trans-
formed to aldehyde 13 via 12 through a two-step sequence
consisting of deacetylation and Dess–Martin oxidation [39]. To
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Beilstein J. Org. Chem. 2016, 12, 2689–2693.
Scheme 4: Synthesis of 14.
neighboring alkyne in the course of iodocyclization was investi-
gated, revealing that neither ester nor aldehyde was compatible
under these conditions to reach the desired product. The versa-
tile key intermediates for the syntheses of several oligostil-
benoids such as viniferifuran, shoreaphenol, malibatol A, and
diptoindonesin G were rapidly accessed in a highly efficient
manner, allowing for large-scale preparations of the target
natural products as well as unnatural analogues.
Supporting Information
Figure 2: Crystal structure of 8.
Supporting Information File 1
Experimental procedures, compound characterization data,
and 1H and 13C NMR spectra of synthesized compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-266-S1.pdf]
the general usefulness of this route for the synthesis of a range
of structural analogues at a late stage.
The direct Friedel–Crafts type intramolecular cyclization of 14
induced by BCl3 was attempted but a complex mixture was ob-
served. Thus, oxidation of the aldehyde in 14 to carboxylic acid
was carried out. Pinnick oxidation [40-42] of 14 went smoothly
to give 18, an intermediate previously employed for the synthe-
sis of diptoindonesin G (Scheme 5) [43,44].
Supporting Information File 2
Chemical information file of compound 8.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-266-S2.cif]
Conclusion
Acknowledgements
In summary, we have established a highly scalable and flexible This work was supported by the National Research Foundation
synthetic route to several benzofuran-containing oligostil- of Korea (NRF) grant funded by the Korea government (MSIP)
benoid natural products by relying on a symmetry-breaking (2014R1A2A1A11050491). This work was also supported in
strategy from 3,5-dimethoxybenzyl alcohol. The relative reac- part by the Yonsei Research Fund of 2015 (project no.: 2015-
tivity of ester, aldehyde, and methoxy moieties toward the 12-0215).
Scheme 5: Synthesis of 18.
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29.Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292.
doi:10.1021/jo051299c
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