Synthesis of Indole-, Benzo[ b]thiophene-, and Benzo[ b]selenophene-Based Analogues of the Resveratrol Dimers Viniferifuran and (±)-Dehydroampelopsin B

Article abstract of DOI:10.1021/acs.orglett.8b02638

A convenient synthetic strategy to obtain viniferifuran and (±)-dehydroampelopsin B analogues based on the heterocyclic cores of indole, benzo[b]thiophene, and benzo[b]selenophene is presented. The key transformations utilized in the described syntheses include Sonogashira couplings, Cacchi and alkyne electrophilic cyclizations, Horner-Wadsworth-Emmons (HWE) reaction, chemoselective Suzuki-Miyaura couplings, and acid-promoted intramolecular cyclization to form the seven-membered ring of (±)-dehydroampelopsin B.

Full text of DOI:10.1021/acs.orglett.8b02638

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Indole‑, Benzo[b]thiophene‑, and
Benzo[b]selenophene-Based Analogues of the Resveratrol Dimers
Viniferifuran and ( )-Dehydroampelopsin B
Adrian Krzyzanowski,† Michael Saleeb, and Mikael Elofsson*
Department of Chemistry, Umeå University, Umeå 90187, Sweden
S
* Supporting Information
ABSTRACT: A convenient synthetic strategy to obtain viniferifuran and ( )-dehydroampelopsin B analogues based on the
heterocyclic cores of indole, benzo[b]thiophene, and benzo[b]selenophene is presented. The key transformations utilized in the
described syntheses include Sonogashira couplings, Cacchi and alkyne electrophilic cyclizations, Horner−Wadsworth−Emmons
(HWE) reaction, chemoselective Suzuki−Miyaura couplings, and acid-promoted intramolecular cyclization to form the seven-
membered ring of ( )-dehydroampelopsin B.
atural products have been an indispensible source of
positive bacteria.5 Therefore, 1 was considered to be an
interesting starting point for the development of novel
antivirulence agents.
1
Nnovel therapeutics,
and stilbenoids, hydroxylated
derivatives of stilbene, have been increasingly gaining popular-
ity in the scientific community because of their wide spectrum
of diverse biological activities and intriguing molecular
structures.2 Over the past decade, numerous synthetic methods
employing both biomimetic and de novo strategies have been
developed. Biomimetic methods typically utilize enzyme- or
metal-based oxidative dimerization reactions of stilbenoid
monomers,3 but as they do not allow for easy modifications
of the structures, a multitude of de novo syntheses have
emerged.4 The de novo synthesis of resveratrol dimers was
pioneered by Snyder and colleagues in 2007, followed by a
number of syntheses of complex stilbenoids by various research
groups.4
Viniferifuran (3a) and ( )-dehydroampelopsin B (4a),
resveratrol dimers structurally related to 2, were recently
synthesized in our laboratory (Figure 1),7 and we have
continued to explore the chemistry of resveratrol-based
compounds by the design and synthesis of diversity-oriented
libraries of compounds with benzofuran and 2,3-dihydroben-
zofuran scaffolds,8 leading to the identification of inhibitors of
Chlamydia trachomatis.8b Methyl groups are generally preferred
for protection of phenolic alcohols because of the availability of
suitable starting materials, ease of introduction, and robustness
toward various types of chemistries. During our synthetic work
on viniferifuran and analogues as well as other resveratrol
dimers, we have frequently experienced that final demethyla-
tions are sluggish and often result in decomposition and low
yields.7a,b In addition, viniferifuran (3a) readily underwent
acid-catalyzed cyclization to form ( )-dehydroampelopsin B
(4a), and we found that the cyclization is highly dependent on
the substitution pattern of the aromatic rings.7a To further
explore the chemistry and biology of resveratrol dimers, we
focused on the synthesis of viniferifuran and ( )-dehydroam-
pelopsin B analogues based on alternative heterocyclic cores of
indole (3b,c and 4b,c), benzo[b]thiophene (3d and 4d), and
We recently showed that (−)-hopeaphenol (1), a tetramer
of resveratrol (2) (Figure 1), exhibits micromolar antivirulence
activity against the Gram-negative pathogens Pseudomonas
aeruginosa and Yersinia pseudotuberculosis in cell-based assays
by acting on the type-III secretion system (T3SS).5 The T3SS
is a conserved syringelike protein complex that is indispensable
for the pathogen to be able to establish an infection by
injecting virulence effectors into the host cell cytosol, thereby
causing disruption of crucial cellular processes, including cell-
cycle progression, gene expression, programmed cell death, or
vesicular trafficking.6
Moreover, compound 1 showed no significant effect on the
growth of the assessed panel of Gram-negative and Gram-
Received: August 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02638
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Letter
Cacchi-type cyclization,9 whereas structures based on benzo-
[b]thiophene and benzo[b]selenophene should be reached
through alkyne electrophilic cyclization10 followed by Pd-
catalyzed coupling at C-3 starting from Sonogashira coupling
product 6. The retrosynthesis was designed in a modular
fashion to allow future structural modifications and thus the
facile synthesis of a compound library and a number of
analogues of related stilbenoids.
The synthetic scheme toward the indole-based polyphenols
3b,c and 4b,c (Scheme 2) commenced from commercially
Scheme 2. Preparation of the Permethylated Indole-Based
Analogues of Viniferifuran (15a and 15b)
Figure 1. Structures of (−)-hopeaphenol (1), resveratrol (2),
viniferifuran (3a), ( )-dehydroampelopsin B (4a), and the target
stilbenoid structures based on different heterocyclic cores (3b−e and
4b−e).
benzo[b]selenophene (3e and 4e). Thus, in this study, we
present a successful synthetic strategy to obtain stilbenoid
structures based on various heterocyclic cores. To the best of
our knowledge, the structures presented in this study are the
very first examples of resveratrol oligomers built on hetero-
cycles different than benzo[b]furan.
As depicted in Scheme 1, we envisaged that all of the desired
analogues of viniferifuran (3b−e) and ( )-dehydroampelopsin
Scheme 1. General Overview of the Synthetic Strategy To
Obtain the Analogues of Viniferifuran and
( )-Dehydroampelopsin B
available 7, which gave compound 9 when treated with Tf2O
and TEA in DCM. Molecule 9 was prepared as a substrate for
Pd-catalyzed Sonogashira cross-coupling. A number of
coupling conditions were screened, and the best result was
achieved using 4-ethynylanisole, Pd(PPh3)4, CuI, and 2,6-
lutidine in 1,4-dioxane at 60 °C. This result was in agreement
with the observations of Dakin et al.,11 who found that
utilization of 2,6-lutidine as the base and 1,4-dioxane as the
solvent, in comparison with alternative coupling conditions,
significantly diminished the decomposition of the unstable
triflate-containing reagent and consequently greatly increased
the reaction yield. The Sonogashira product 10 was obtained
in 64% yield over two steps.
Various protocols were tested to achieve selective reduction
of the nitro group in the presence of the triple bond and the
aldehyde group. Methods involving reduction with SnCl2, Zn,
In, and Na2S2O4 were screened, and the best result was
obtained using Fe with HCl in a mixture of EtOH, THF, and
H2O at 80−90 °C. The selective reduction was followed by
protection/activation of the amino group with a trifluoroacetyl
group. Application of TFAA with TEA in THF gave 6a in good
49% yield over two steps. The trifluoroacetyl group had been
B (4b−e) could be conveniently obtained through the
application of the same disconnections. We anticipated that
the seven-membered ring in compounds 4b−e would be
reached through acid-promoted cyclization of viniferifuran
analogues.7a,b Compounds 3b−e should be obtained through
Horner−Wadsworth−Emmons (HWE) reaction or Pd-cata-
lyzed Suzuki−Miyaura coupling from 5. The framework of 5,
based on the indole core, could be potentially achieved with
B
DOI: 10.1021/acs.orglett.8b02638
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Organic Letters
Letter
introduced in preparation for the Cacchi cyclization, where the
appropriate pKa of the NH moiety appears to be crucial for the
transformation.14 Cyclization to the key molecule 5a was
achieved cleanly in 94% yield without premature formation of
the unsubstituted indole byproduct. For this reaction we used
iodide 12, Pd(PPh3)4, and Cs2CO3 in anhydrous MeCN under
microwave irradiation (MWI) at 100 °C. It was also noted that
the Cacchi cyclization did not occur unless the reagents were
of satisfactorily high purity. Synthesis of the final permethy-
lated scaffold 15a was attempted via a HWE reaction using 5a
and phosphonate 14. However, the tested conditions gave only
complex reaction mixtures. Thus, we decided to introduce a
protective group onto the indole nitrogen.
Scheme 4. Preparation of Permethylated
Benzo[b]thiophene- and Benzo[b]selenophene-Based
Analogues of Viniferifuran (15c and 15d)
Boc-protected 5b was prepared in quantitative yield with
Boc2O and DMAP in MeCN. The HWE reaction was
attempted again, and to our delight, the Boc-protected
permethylated indole-based analogue of viniferifuran was
successfully obtained as the main product using phosphonate
14 and NaH in THF under MWI at 70 °C. Curiously, during
the reaction we observed partial Boc cleavage, resulting in an
approximately 2:1 mixture of Boc-protected and deprotected
products. It was then determined that the Boc group, present
on both the HWE substrate 5b and the reaction product, was
thermally stable, and as expected, it could not be cleaved by
NaH alone, despite relatively long reaction times. In order to
eliminate any potential side reactions caused by impurities in
the reaction mixture, the synthesized phosphonate 14 was
further purified by distillation under reduced pressure. We
observed that the Boc cleavage occurred only when the HWE
reaction was in progress and stopped immediately when the
HWE reaction was finished. Moreover, alternative protective
groups, such as a Cbz or allyl group, were tested and gave
comparable results. Thus, we hypothesized that the cleavage of
the protective group present on the indole nitrogen occurred
during the elimination of the phosphate byproduct (Scheme
3). Ironically, deliberate attempts at Boc cleavage from the
was reached in 70% yield in a sterically challenged Sonogashira
reaction using standard coupling reagents in TEA at reflux.
Compounds 6b and 6c were obtained in quantitative yield by
selective lithiation of one of the bromo positions of 17 with 1
equiv of n-BuLi at −78 °C, followed by treatment with Me2S2
or Me2Se2. However, we could not induce cyclization to 18
using standard alkyne electrophilic cyclization protocols with I2
at rt.10 Instead, we found that extensive heating was necessary,
and the cyclization products could be obtained in excellent
yields after stirring for at least 1 h at 80 °C in a microwave
reactor.
Chemoselective Suzuki−Miyaura coupling between 18 and
3,5-dimethoxyphenylboronic acid proved to be very challeng-
ing because of prevalent deiodination of 18 and unwanted
double coupling at both the iodo and bromo positions.
Extensive screening of reaction conditions was performed,
testing various combinations of numerous catalysts, bases,
solvent mixtures, temperatures, and concentrations under
conventional as well as microwave heating. As a result of our
efforts, we managed to successfully synthesize and isolate
Suzuki products 5d and 5e, both in satisfactory yields of 49%.
The optimal protocol was highly reproducible and involved
using Pd(dppf)Cl2·DCM complex, K3PO4, and 1,4-dioxane/
H2O in a 6:1 ratio and heating in a microwave reactor. Finally,
the permethylated viniferifuran analogues 15c and 15d were
obtained in a second Suzuki−Miyaura reaction catalyzed by
Pd2(dba)3·CHCl3 complex aided by SPhos in the presence of
K3PO4. The volume ratio of 1,4-dioxane/H2O used in the
reaction had a significant impact on the reaction efficiency, and
the ratio of 6:1 was found to give satisfactory results. The
permethylated analogues 15c and 15d were synthesized in five
steps from 8 in overall yields of 27% and 28%, respectively.
Demethylation of compounds 15a−d was performed with
BBr3 in DCM.7a,b Indole-based molecules 3b and 3c were
obtained in 39% and 56% yield, respectively (entries 1 and 2,
Table 1). When the same reaction conditions were applied to
15c and 15d, products 3d and 3e were obtained in 26% and
28% yield, respectively (entries 3 and 5, Table 1). In all of the
Scheme 3. Proposed Mechanism of the Indole Deprotection
Occurring during the HWE Reaction with 5b
HWE product with aqueous TFA at 120 °C under MWI or
with TIPSCl and phenol in DCM were completely ineffective.
Interestingly, however, direct addition of TBAF hydrate to a
quenched HWE reaction mixture followed by heating to 120
°C under MWI, according to the modified procedure by Rutier
et al.,15 worked efficiently, affording the target permethylated
analogue 15a in 81% yield.
The synthesis of indole 15b was achieved readily through
quantitative methylation of 5a with MeI and NaH followed by
the HWE reaction. Thus, the milestone permethylated
viniferifuran analogues 15a and 15b were obtained in seven
steps in overall yields of 24% and 23%, respectively.
The synthesis of the benzo[b]thiophene- and benzo[b]-
selenophene-based analogues (3d,e and 4d,e) commenced by
obtaining the known molecule 8 (Scheme 4).16 Compound 17
C
DOI: 10.1021/acs.orglett.8b02638
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Organic Letters
Letter
Table 1. Demethylation and Cyclization of Compounds 15a−e to Viniferifuran (3) and ( )-Dehydroampelopsin B (4)
Analogues
yield (%)
entry
X
equiv of BBr3 used
temp (°C)
aq HBr added?
time
24 h
24 h
24 h
3 days
24 h
3 days
3
4
Aim: Demethylation
−78 to rt
−78 to rt
−78 to rt
−78 to −30
−78 to rt
1
2
3
4
5
6
NH
NMe
S
6
6
6
6
6
6
no
no
no
no
no
no
39
56
26
28
28
34
5
9
23
16
20
14
S
Se
Se
−78 to −30
Aim: Demethylation and Cyclization
a
7
8
9
10
11
NH
NH
NMe
S
15 + 15
0 to rt
−78 to rt
0 to rt
0 to rt
0 to rt
yes
yes
yes
yes
yes
3 days
decomposition
b
15
15
15
15
1.5 days
overnight
overnight
overnight
10
10
1
19
14
49
45
Se
1
a
b
The reaction was started with 15 equiv of BBr3, and after 1.5 days another 15 equiv was added. Aqueous HBr was added after the demethylation
was complete.
tested reactions, the deprotection always occurred with partial
concomitant cyclization to 4, but the cyclization seemed to
occur more extensively with benzo[b]thiophene- and benzo-
[b]selenophene-based molecules. Decreasing the temperature
range and stirring at a maximum temperature of −30 °C
resulted in slight increases in the yields of 3d (28%) and 3e
(34%) and decreases in cyclization (entries 4 and 6, Table 1).
This tentatively suggested that formation of the internal seven-
membered ring in the benzo[b]thiophene- and benzo[b]-
selenophene-based molecules could be controlled kinetically to
some extent.
The intramolecular cyclization was promoted in the
presence of acid. Addition of aqueous HBr to BBr3 significantly
increased the cyclization yield, and although indoles 4b and 4c
were obtained in rather modest yields, ( )-dehydroampelop-
sin B analogues 4d and 4e were formed as the main products
in reasonable yields of 49% and 45%, respectively (entries 10
and 11, Table 1).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02638.
■
S
Full experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*Address: Department of Chemistry, Umeå University,
̈
Linnaeus Vagen, Umeå 90187, Sweden. E-mail: mikael.
elofsson@umu.se.
ORCID
Mikael Elofsson: 0000-0002-3219-4669
Present Address
†A.K.: Department of Chemical Biology, Max-Planck-Institute
of Molecular Physiology, 44227 Dortmund, Germany.
In conclusion, a successful strategy for the synthesis of a
number of analogues (3b−e, 4b−e) of viniferifuran (3a) and
( )-dehydroampelopsin B (4a) have been reported. The
indole-based analogues (3b,c and 4b,c) were synthesized in
eight steps from commercially available 7. The benzo[b]-
thiophene- and benzo[b]selenophene-based analogues (3d,e
and 4d,e) were obtained in six steps from known compound 8.
Because of the modular design of the synthetic pathways,
modifications to the structures could be readily applied, thus
allowing a library of related molecules to be created. The
presented strategy could be applied for the synthesis of a
variety of other stilbenoid-inspired structures and natural
product analogues.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Swedish Metabolomics Centre, Umeå, Sweden (www.
swedishmetabolomicscentre.se), is acknowledged for the
HRMS analysis. The authors thank the Swedish Research
Council for financial support (Grant 621-2014-4670).
REFERENCES
■
(1) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629−661.
(2) Reviews of stilbenoid biology and chemistry: (a) Xiao, K.;
Zhang, H. J.; Xuan, L. J.; Zhang, J.; Xu, Y. M.; Bai, D. L. Stud. Nat.
D
DOI: 10.1021/acs.orglett.8b02638
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Organic Letters
Letter
Prod. Chem. 2008, 34, 453−646. (b) Shen, T.; Wang, X. N.; Lou, H.
̀
X. Nat. Prod. Rep. 2009, 26, 916−935. (c) Riviere, C.; Pawlus, A. D.;
́
Merillon, J. M. Nat. Prod. Rep. 2012, 29, 1317−1333. (d) Keylor, M.
H.; Matsuura, B. S.; Stephenson, C. R. Chem. Rev. 2015, 115, 8976−
9027.
(3) Selected examples of biomimetic stilbenoid syntheses: (a) Velu,
S. S.; Thomas, N. F.; Weber, J.-F. F. Curr. Org. Chem. 2012, 16, 605−
662. (b) Li, W.; Li, H.; Li, Y.; Hou, Z. Angew. Chem. 2006, 118,
7771−7773. (c) Matsuura, B. S.; Keylor, M. H.; Li, B.; Lin, Y.;
Allison, S.; Pratt, D. A.; Stephenson, C. R. Angew. Chem., Int. Ed.
2015, 54, 3754−3757.
(4) Selected examples of de novo stilbenoid total syntheses:
(a) Snyder, S. A.; Zografos, A. L.; Lin, Y. Angew. Chem., Int. Ed.
2007, 46, 8186−8191. (b) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.;
Lin, Y.; Zografos, A. L. J. Am. Chem. Soc. 2009, 131, 1753−1765.
(c) Snyder, S. A.; Wright, N. E.; Pflueger, J. J.; Breazzano, S. P. Angew.
Chem., Int. Ed. 2011, 50, 8629−8633. (d) Snyder, S. A.; Gollner, A.;
Chiriac, M. I. Nature 2011, 474, 461−466. (e) Wright, N. E.; Snyder,
S. A. Angew. Chem. 2014, 126, 3477−3481. (f) Jepsen, T. H.;
Thomas, S. B.; Lin, Y.; Stathakis, C. I.; de Miguel, I.; Snyder, S. A.
Angew. Chem., Int. Ed. 2014, 53, 6747−6751. (g) Nicolaou, K. C.;
Kang, Q.; Wu, T. R.; Lim, C. S.; Chen, D. Y. K. J. Am. Chem. Soc.
2010, 132, 7540−7548. (h) Lee, B. H.; Choi, Y. L.; Shin, S.; Heo, J.
N. J. Org. Chem. 2011, 76, 6611−6618. (i) Klotter, F.; Studer, A.
Angew. Chem., Int. Ed. 2014, 53, 2473−2476. (j) Sudhakar, G.; Satish,
K. Chem. - Eur. J. 2015, 21, 6475−6480. (k) Chen, D. Y. K.; Kang, Q.;
Wu, T. R. Molecules 2010, 15, 5909−5927. (l) Nicolaou, K. E.; Wu, T.
R.; Kang, Q.; Chen, D. Y. K. Angew. Chem. 2009, 121, 3492−3495.
̈
(5) Zetterstrom, C. E.; Hasselgren, J.; Salin, O.; Davis, R. A.; Quinn,
R. J.; Sundin, C.; Elofsson, M. PLoS One 2013, 8, e81969.
́
(6) Galan, J. E.; Wolf-Watz, H. Nature 2006, 444, 567−573.
(7) (a) Vo, D. D.; Elofsson, M. Adv. Synth. Catal. 2016, 358, 4085−
̈
4092. (b) Lindgren, A. E.; Oberg, C. T.; Hillgren, J. M.; Elofsson, M.
Eur. J. Org. Chem. 2016, 2016, 426−429. (c) Vo, D. D.; Elofsson, M.
ChemistrySelect 2017, 2, 6245−6248.
(8) (a) Qin, L.; Vo, D. D.; Nakhai, A.; Andersson, C. D.; Elofsson,
M. ACS Comb. Sci. 2017, 19, 370−376. (b) Saleeb, M.; Mojica, S.;
Eriksson, A. U.; Andersson, C. D.; Gylfe, Å.; Elofsson, M. Eur. J. Med.
Chem. 2018, 143, 1077−1089.
(9) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33,
3915−3918.
(10) (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905−1909.
(b) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006,
71, 2307−2312.
(11) Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67,
6812−6815.
(12) Csuk, R.; Albert, S. Z. Naturforsch., B: J. Chem. Sci. 2011, 66,
311−316.
(13) Chen, G.; Shan, W.; Wu, Y.; Ren, L.; Dong, J.; Ji, Z. Chem.
Pharm. Bull. 2005, 53, 1587−1590.
(14) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002,
2002, 2671−2681.
́
́
(15) Routier, S.; Sauge, L.; Ayerbe, N.; Coudert, G.; Merour, J. Y.
Tetrahedron Lett. 2002, 43, 589−591.
(16) (a) Aggarwal, A. V.; Jester, S. S.; Taheri, S. M.; Foerster, S.;
Hoeger, S. Chem. - Eur. J. 2013, 19, 4480−4495. (b) Tahara, K.;
Okuhata, S.; Adisoejoso, J.; Lei, S.; Fujita, T.; Feyter, S. D.; Tobe, Y. J.
Am. Chem. Soc. 2009, 131, 17583−17590.
(17) Bismuto, A.; Thomas, S. P.; Cowley, M. J. Angew. Chem., Int.
Ed. 2016, 55, 15356−15359.
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