Deconstructive Reorganization: De Novo Synthesis of Hydroxylated Benzofuran

Article abstract of DOI:10.1002/anie.201915212

An unprecedented deconstructive reorganization strategy for the de novo synthesis of hydroxylated benzofurans from kojic acid- or maltol-derived alkynes is reported. In this reaction, both the benzene and furan rings were simultaneously constructed, whereas the pyrone moiety of the kojic acid or maltol was deconstructed and then reorganized into the benzene ring as a six-carbon component. Through this strategy, at least one free hydroxyl group was introduced into the benzene ring in a substitution-pattern tunable fashion without protection–deprotection and redox adjustment. With this method, a large number of hydroxylated benzofuran derivatives with different substitution-patterns have been prepared efficiently. This methodology has also been shown as the key step in a collective total synthesis of hydroxylated benzofuran-containing natural products (11 examples).

Full text of DOI:10.1002/anie.201915212

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Accepted Article
Title: Deconstructive Reorganization: De Novo Synthesis of
Hydroxylated Benzofuran
Authors: Shifa Zhu, Ling Zhang, Tongxiang Cao, and Huanfeng Jiang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915212
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10.1002/anie.201915212
Angewandte Chemie International Edition
RESEARCH ARTICLE
Deconstructive Reorganization: De Novo Synthesis of
Hydroxylated Benzofuran
Ling Zhang+, Tongxiang Cao+, Huanfeng Jiang, and Shifa Zhu*
Abstract: An unprecedented deconstructive reorganization strategy
for the de novo synthesis of hydroxylated benzofurans from kojic
acid- or maltol-derived alkynes is reported. In this reaction, both the
benzene and furan rings were simultaneously constructed, whereas
the pyrone moiety of the kojic acid or maltol was deconstructed and
then reorganized into the benzene ring as a six-carbon component.
Through this strategy, at least one free hydroxyl group was
introduced into the benzene ring in a substitution-pattern tunable
fashion without protection-deprotection and redox adjustment. With
this method, a large number of hydroxylated benzofuran derivatives
with different substitution-patterns have been prepared efficiently.
This methodology has also been shown as the key step in a
collective total synthesis of hydroxylated benzofuran-containing
natural products (11 examples).
and has been tested in phase II clinical trials.[5] The great
biological potential of hydroxylated benzofurans stimulates us to
exploit a platform for the practical synthesis of hydroxylated
benzofuran derivatives with different substitution patterns in
order to streamline the drug discovery process.[6]
Scheme 1. Hydroxylated benzofuran-containing natural products and drug
candidates.
Introduction
So far, there are two general strategies to assemble
functionalized benzo-fused five-membered heteroarenes in the
literature. The first strategy is based on transition metal-
catalyzed C-H functionalization, which can directly introduce the
desired functional groups to the heteroarene precursors
(Scheme 2a: C-H functionalization). It has become a powerful
tool to realize the selective functionalization of the challenging
C4-C7 positions of indole, which is assisted by a directing group
in two complementary directions (e.g. DG1 and DG2).[7] However,
this strategy cannot be extended to the substitution-pattern
tunable synthesis of benzofuran, because the oxygen atom of
benzofuran cannot sever as “anchor donor” for directing group
introduction, leaving the remote C6 and C7 sites almost
inaccessible. The second strategy is via annulation, which
capitalizes on individual construction of the benzene or five-
membered heteroarenes (Scheme 2b: annulation). As for the
synthesis of benzofuran, mostly pericyclic reactions[8] and
transition metal-catalyzed cyclizations[9] were applied to forge
the benzene moiety. For comparison, more studies have been
devoted to the construction of the furan moiety by formal [3+2][10]
cycloadditions or intramolecular ring-closure reactions[11] with
prefunctionalized phenols,[10d-p, 11i-m] quinones,[10b, 10c] or phenolic
ethers as starting materials.[11a-g, 11j, 11k, 12] Of all these methods,
the alkyne-based benzofuran synthesis has many benefits such
as easy availability and versatile reaction types, but usually it
needs to sacrifice a phenolic hydroxyl group of the starting
material.[10m-p, 11l, 11m, 13] Although these annulation approaches
could provide a wide spectrum of substituted benzofurans, it is
still challenging to incorporate free hydroxyl group into the
benzene moiety due to the interference of phenolic hydroxyl
groups,[10g, 10h] which usually require protection-deprotection or
redox manipulation. Therefore, it is desirable for a practical and
flexible avenue to free hydroxylated benzofurans with tunable
substitution pattern. We thus surmised that a de novo synthesis
strategy through formation of both benzene and furan rings
could address these challenges, because there might be more
possibilities for the incorporation of functional groups in the ring-
forming process, which could obviate aforementioned
Hydroxylated benzofurans are ubiquitous structural motifs of
various natural products and bioactive molecules.[1] As shown in
Scheme 1, these molecules contain at least one free hydroxyl
group attached to the benzene ring with different substituent
patterns, which have attracted much attention owing to their
wide spectrum of biological activities. For example, as a
phytoestrogen, coumestrol (with one hydroxyl at C6) exhibits
diverse activities against cancers, neurological disorders, and
autoimmune diseases.[2] The marine natural product liphagal
(with two hydroxyl groups at C5 and C6) can modulate human
phosphatidylinositol-3-kinase (PI3K) signalling pathway,[3], which
may have therapeutic potential in treatment of autoimmune
disorders, cardiovascular disease, and cancer.[4] Furthermore,
hydroxylated benzofuran is also a privileged structure in drug
candidates. For instance, BNC 105 (with one methoxyl at C6
and one hydroxyl at C7) is a tubulin polymerization inhibitor with
potent antiproliferative and tumor vascular disrupting properties
[*] L. Zhang,[+] Dr. T. Cao,[+] Prof. Dr. H. Jiang, Prof. Dr. S. Zhu[*]
Key Laboratory of Functional Molecular Engineering of Guangdong
Province
School of Chemistry and Chemical Engineering, South China
University of Technology
510640, Guangzhou (China);
E-mail: zhusf@scut.edu.cn
Prof. Dr. S. Zhu
State Key Laboratory of Elemento-Organic Chemistry
Nankai University
300071, Tianjing (China);
Prof. Dr. S. Zhu
Singfar Laboratories
510670, Guangzhou (China)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.under
http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.201915212
Angewandte Chemie International Edition
RESEARCH ARTICLE
challenges of C-H functionalization and the dependence of
arenes.
was completely depressed with the addition of 4Å molecular
sieve (entry 11). Nevertheless, an external addition of water
didn’t display any beneficial effect on the reaction results (entry
12). These results indicated that the adventitiously introduced
and trace amount of water might be involved in the catalytic
process.
As two kinds of cheap and commercially available pyrone-
containing compounds, kojic acid ($17/kg) and maltol ($14/kg)
have been widely used in food, medicine and daily chemical
industry (Scheme 2c). Furthermore, they have also been utilized
as five-carbon component in oxidopyrylium-based [5+2]
cycloadditions and were showcased as the key steps in the total
synthesis of several complex natural products.[14] Conceptually,
if the pyrone moiety of kojic acid or maltol was broken, releasing
the inherent oxidation state, unlocking the embedded functional
groups, awaking the dormant reactivity, and then harnessing its
behaviour, it might serve as a versatile synthon for numerous
transformations (Scheme 2c). In combination with these
considerations and the inspiration from keto alkyne cyclization,[15]
especially the cascade reaction that was initiated by π-acid
activation,[16] we proposed that a suitable alkynophilic catalyst
could activate the pyrone-based keto alkyne I, trigger the 5-
endo-dig cyclization and then hydrolysis to give a pyrone-free
furan II, which could then engage in an aldol cyclization and
followed by dehydration process to finally deliver benzofuran III
(Scheme 2d). As part of our continuous endeavours to develop
new dearomatic cascade rearrangement of pyrones,[17] we
herein would like to report an unprecedented deconstructive
reorganization strategy for the de novo synthesis of hydroxylated
benzofuran from kojic acid- or maltol-derived alkynes (Scheme
2d). In this reaction, both the benzene and furan rings were
simultaneously established via an arene cycloisomerizaiton
tandem reaction. The pyrone moiety originated from kojic acid or
maltol was deconstructed and finally reorganized into the
benzene ring as a six-carbon component. In this process, at
least one free hydroxyl group was introduced in a substitution-
pattern tunable fashion without protection-deprotection and
redox adjustment.
Table 1. Optimization of the reaction conditions[a,b]
.
Conversion
1a [%]
Yield
2a [%]
Entry
Catalyst
Additive
Solvent
1
2
PPh3AuCl
PPh3AuCl
PPh3AuCl
IPrAuCl
AgBF4
DCE
DCE
DCE
DCE
DCE
THF
THF
THF
THF
THF
THF
THF
100
100
100
100
100
100
100
87
n.d.
n.d.
AgSbF6
3
AgNTf2
n.d.
4
AgNTf2
n.d.
5
SIPrAuCl
Fe(OTf)3
Yb(OTf)3
Sn(OTf)3
Bi(OTf)3
In(OTf)3
In(OTf)3
AgNTf2
n.d.
6
-
trace
trace
32
7
-
8
-
9
-
-
90
45
10
11[d]
12[e]
100
<5
82 (78)[c]
n.r.
4Å MS
H2O
In(OTf)3
95
76%
[a] Reaction conditions: 1a (0.2 mmol) and 10 mmol% catalyst in 2 mL solvent
stirred at 60 ºC for 12 h. [b] Yields were based on 1H NMR analysis with 4-
Nitrotoluene as internal standard. [c] Isolated yield. [d] 120 mg 4 Å molecular
sieves (MS) was added [e] 0.5 eq H2O was added. DCE: 1,2-dichloroethane;
THF: tetrahydrofuran; IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene;
SIPr: 1,3-bis (2,6-diisopropylphenyl)imidazolin-2-ylidene.
With the optimized reaction conditions (Table 1, entry 10) in
hand, the substrate scope was then explored. As shown in
Figure 1, kojic acid-derived substrates 1 with both aryl- and
alkyl-substituted alkynes could be effectively converted into the
desired C5, C6-dihydroxyl benzofurans 2. The reaction was not
strongly affected by the electronic properties of group R1. Both
electron-donating and electron-withdrawing aryl groups were
well-tolerated under the reaction conditions, giving rise to the
products 2a-p in 43-78% yield. The reaction wasn’t noticeably
affected by the position of the substituents on the aryl group R1
either (2j-n). The thiophene-containing substrate could
participate in this reaction to give product 2p in 62% yield. In
addition, the pyrazole- and isoxazole-substituted benzofurans 2q
and 2r were also obtained in 65% and 68% yields, respectively,
under an elevated temperature (100 oC). The alkyl-capped
substrates could be efficiently converted to the desired products
2s-u in 54-72% yield. Finally, the synthesis of dihydroxyl
benzofuran 2v without substituent on furan moiety was also
achievable, albeit in a relative lower yield (36%).
Scheme 2. Challenges and strategies in attaining benzofuran with pattern-
tunable substituents.
Results and Discussion
Initially, the kojic acid-derived alkyne 1a with an unprotected
hydroxyl group was selected as the model substrate for
optimization of the reaction conditions. Firstly, several gold
complexes in combination with different silver salts as the
additives were tested as catalysts, which resulted in
a
Having established the indium-catalyzed reaction as a reliable
and efficient method to assemble dihydroxylated benzofurans,
we then proceeded to evaluate the substituent of R2, with a
desire to vary the substituent-patterns of benzene moiety. When
dehydroxyl kojic acid-derived alkynes 1 (R2 = H) were used as
substrates, the reactions took place smoothly under a modified
complicated system (Table 1, entries 1-5). When utilizing
Fe(OTf)3 and Yb(OTf)3 as the catalysts, a trace amount of the
desired product 2a, bearing two free phenolic hydroxyl groups,
were detected (entries 6-7). Encouraged by these observations,
several other metal triflates were then examined. When Sn(OTf)3
and Bi(OTf)3 were applied, the desire product 2a was furnished
in 32% and 45% yields, respectively (entries 8-9). Gratifyingly,
the product yield increased to 82% by using In(OTf)3 as the
catalyst (entry 10). Control experiment showed that the reaction
o
condition (10 mol% catalyst, 100 C). A variety of C6-hydroxyl
benzofuran 2w-2ah with different aryl and alkyl groups could be
furnished in 56-76% yield.
2
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RESEARCH ARTICLE
To further investigate the generality and robustness of this
methodology, other substituents of R2 were also explored.
Interestingly, when 5.0 equivalents of methanol (using as
reaction reagent) were added to the reaction mixture with the
bromine-substituted starting material (1ai-1aj, R2 = Br), the
methanol incorporated products 2ai and 2aj could be furnished
instead in 53% and 54% yields. Furthermore, the thiol-
substituted hydroxylated benzofuran 2ak and 2al were also
obtained in good yields under the standard conditions. In
addition to the substituent patterns, a series of L-shape
trisubstituted hydroxylated benzofurans (C4-aryl, C5, C6-
dihydroxyl benzofurans) 2am-2ap were also prepared in 52-78%
yield. The structure of the dihydroxylated benzofuran 2am was
confirmed by the X-ray diffraction analysis.
As shown in Figure 2, both alkyl- and aryl-substituted substrates
could take part in this transformation smoothly, affording the
desired C4-hydroxylated benzofurans 4a-t in 36-78% yield. It is
noteworthy that the dimethylamino- and thiophenyl-adorned
substrates were well tolerated to give 4h and 4q in 65% and 56%
yields, respectively. In addition, when ethyl maltol-derived
substrates 3 were applied, the C4, C5-disubstituted (C4-OH, C5-
Me) benzofurans 4u-x were afforded in 65-76% yield.
Figure 2. Substrate scope for the cycloisomerization of maltol-derived
alkynes.[a] [a] General procedure: the reactions were stirred with 3 (0.2 mmol)
and 10 mmol% In(OTf)3 in 2 mL THF at 60 oC for 12 h, then 2 mL 3M HCl
(aqueous) was added and stirred at 60 oC for another 8 h; Isolated yields;
Encouraged by the above achievements, we further advanced
to address the unmet challenges of different substitution-
patterns, especially for those difficult accessible C6, C7-
disubstituted pattern (Figure 3). For this purpose, two new
maltol-derived alkynes 5 and 7 were prepared from maltol
through a three-step transformation (see details in SI). Under the
condition
B
(See Figure 2), the C6, C7-disubstituted
hydroxylated 6a and 6b were obtained in 76% and 53% yields,
respectively, from maltol-derived alkynes 5. Similarly, the C5, C6,
C7-trisubstituted hydroxylated benzofuran 8 could also be
afforded in 72% yield from the ethyl maltol-derived alkyne 7. For
the molecules 6 and 8, there are one free hydroxyl group at C6-
position and one methoxyl group (hidden hydroxyl) at C7-
position, which make it possible to differentiate the C6 and C7
positions for further selective transformations or modifications.
After the realization of C6, C7 substitution-pattern, endeavors
were made to attain C4, C7 substitution-pattern by leveraging
the C4-phenolic hydroxyl group. After the indium-acid mediated
deconstructive ring-isomerization and followed by a salcomine-
catalyzed oxidation, the benzofuran C4, C7-dione 9 was
obtained in 38% yield from 3a. Similarly, C4, C5, C7-
trisubstituted product 11 was also achieved in 60% yield from
ethyl maltol-derived starting material 3u. The desired C4,C7-
diphenols 10 and 12 could be formed in quantitative yields
(disclosed by the NMR spectra of the crude reaction mixture)
from p-quinones 9 and 11 by the NaBH4 reduction, but both
diphenols 10 and 12 are oxygen-sensitive and easily reoxidized
to the corresponding p-quinones 9 and 11 automatically under
Figure 1. Substrate scope for the cycloisomerization of kojic acid-derived
alkynes.[a] [a] General procedure: the reactions were stirred with 1 (0.2 mmol)
and 10 mmol% In(OTf)3 in 2 mL THF at 60 oC for 12 h; Isolated yields. [b] 100
oC. [c] Using 1ah (R2 = Br) as substrate and 5.0 equiv. MeOH was added.
Having realized four kinds of substitution patterns of
hydroxylated benzofuran with kojic acid derivatives, other
substitution patterns by using maltol derivatives 3 as the
substrates were then exploited (Figure 2). Although the
aforementioned conditions were initially found inapplicable for
the maltol derivatives 3, satisfactory results could be obtained
with the addition of methanol and hydrochloric acid, which could
promot the methanolysis process and the subsequent aldol
cyclization, respectively. These modified conditions were also
found to be robust and efficient for one-pot synthesis of C4-
substituted and C4, C5-disubstituted hydroxylated benzofurans.
3
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10.1002/anie.201915212
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RESEARCH ARTICLE
an air atmosphere. After a flash chromatograph process (about
5 min′s elution), C4,C7-diphenols 10 and 12 could be obtained in
75% and 33% yields, respectively. The unsatisfactory yields
could be caused by their high sensitivity to oxygen. It is noted
that the quinone-type dione could serve as
a versatile
intermediate for scaffold diversification,[10b, 10c, 18] and the redox-
shuttle effect between the p-quinone and diphenol might play a
critical role in many bioactive molecule.[19]
Scheme 3. Application in collective total synthesis of hydroxylated
benzofuran-containing natural products.
To further demonstrate the power of this methodology,
Liphagal (Scheme 1), a densely functionalized hydroxylated
benzofuran-containing natural product, was chose as
a
showcase. The interesting [6-5-7-6] tetracyclic architecture
coupled with a human phosphatidylinositol-3-kinase α (PI3Kα)
selective inhibitory activity[3] has attracted much attention from
both pharmaceutical and synthetic community, and accumulated
several elegant synthetic studies.[3, 30] For example, Andersen
and co-workers firstly isolated it and determined its structure
through an elegant biomimetic synthesis (11 linear steps).[3a]
Subsequently, George[30a] and Alvarez-Manzaneda[30b] exploited
another biomimetic synthesis independently (13 steps and 11
steps, respectively), which features a pinacol ring-expansion
rearrangement. In addition, Stoltz and co-worker reported a
catalytic enantioselectivity synthesis (15 steps),[30c] highlighting a
combination of enantioselective α-alkylation,[31] ring expansion,
and an intramolecular aryne cyclization. Lately, Winne and co-
workers have realized a convergent synthesis of 5-epi-Liphagal
(8 steps) by using an acid-catalyzed intermolecular [4+3]
cycloaddition.[30d] Ferreira and co-workers accomplished the
formal synthesis of Liphagal (9 steps) by using a carbenoid
mediate conjugate addition as the key strategy.[30e] Herein, we
would like to report a de novo synthetic route for the synthesis of
Liphagal with the indium-triggered arene cycloisomerization as
the key step. As shown in Scheme 4, the key intermediate
diphenolic benzofuran 24 could be synthesized in 72% yield
from the kojic acid-derived precursor 23 under the indium
catalysis. The precursor 23 was prepared from Geranylacetone
through a sequence of Wittig olefination, hydrolysis, Seyferth-
Gilbert Homologation and Sonogashira coupling in 5 steps. By
using Andersen’s insightful acid-catalyzed cationic polyene
cyclization conditons,[3a] the dimethylation product of 24 was
smoothly evolved to an intricate tetracyclic intermediate, which,
after formylation, could advance to dimethyl-8-epi-Liphagal (25)
in 27% yield over 3 steps. Interestingly, the diastereoselectivity
is very good (dr > 8:1) compared with Andersen’s results (dr =
2.5:1). The stereochemical outcome of 25 indicated that a
cationic-triggered C8 epimerization might be involved during this
cyclization. The spectra of 25 were identical in all respects to the
Figure 3. Avenue for different substitution patterns of hydroxylated benzofuran.
As aforementioned, a myriad of bioactive natural products and
drug candidates shared a hydroxylated benzofuran motif. Herein
we exhibited a collective synthesis of these compounds to
demonstrate the utility of this methodology (Scheme 3). Moracin
family contains
a plethora of pharmacological important
benzofuran, which exhibits a broad scope of biological activity,
including anticancer, antimicrobial, antioxidant, anti-inflammatory
and immunomodulatory.[20] Moracin F (13) could be obtained in
51% yield from 2m through methylation and then hydrogenation.
After the deprotection of 2l and 2aj, the tetraphenolic Alfafuran[21]
(14) and triphenolic Wittifuran X[22] (15) were afforded in 86%
and 54% yields, respectively. Coumestrol (16), a proliferate
inhibitor of ovarian and breast cancer,[2] which could be obtained
in 17% total yield from 2ab via a sequence of formylation,
Pinnick oxidation, demethylation and automatic esterification.
Moracin M[23] (17), a phosphodiesterase-4 inhibitor, was also
accessible from 2ac after simple transformation[24] in 88% yield.
Through esterification with propargylic acid and palladium-
catalyzed cyclization,[25] 2af could advance to anhydromarmesin
(18) in 39% yield. Global or partial demethylation of 4p gave the
corresponding Cuspidan B (19, inhibit HL-60 cells)[26] and
Stemofuran B (20, anti-inflammatory activity)[27] in 93% and 68%
yields, respectively. After protecting group manipulation, 4q was
transferred to Gnetucleistol C[28] (21) in 49% yield. Global
demethylation of 6b could afford Wittifuran E (22, pancreatic
lipase inhibitor)[29] in 88% yield.
4
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10.1002/anie.201915212
Angewandte Chemie International Edition
RESEARCH ARTICLE
30b, 30c]
data reported in the literatures,[3a,
which represents a
furan-fused cyclohexanone F, which might proceed through the
aldehyde Int-3 or oxonium E. A sequential elimination and
aromatization eventually produced the final benzofuran 4.
formal total synthesis of 8-epi-Liphagal (26).
Scheme 4. Formal total synthesis of 8-epi-Liphagal.
To figure out the reaction mechanism, several control
reactions were then performed. As shown in Scheme 5, 3-
furanaldehyde (Int-1) could be isolated in 90% yield when kojic
acid-derived alkyne 1a was subject to a PtCl2 catalysis in the
presence of moisture (eq. 1). With Int-1 as the substrate under
condition A, the reaction afforded the desired hydroxylated
benzofuran 2a in excellent yield (eq. 1), which indicated that Int-
1 might be the reaction intermediate for the kojic acid-based
system. Furthermore, when only 5.0 equivalents of methanol
(without HCl compared with the standard condition B) were
added to the reaction of maltol-derived alkyne 3a, the acetal Int-
2 (95%) and its hydrolyzed aldehyde Int-3 (less than 5 %) were
accumulated (eq. 2). Interestingly, neither Int-2 nor Int-3 was
converted to the desired product 4a under the catalysis of
In(OTf)3, which was different with the kojic acid-based system.
Further reactions showed that the aqueous HCl alone was able
to promote the transformations, with the desired product 4a was
obtained in 76% yield (eqs. 3 and 4). These reactions indicated
that both Int-2 and Int-3 might be the reaction intermediates for
the maltol-based system.
Scheme 6. Proposed deconstructive arene cycloisomerization mechanism.
Conclusion
In summary, we have established
a
deconstructive
reorganization process for pattern-tunable synthesis of
a
hydroxylated benzofuran in an easy handled one-pot manner by
utilizing kojic acid and maltol type pyrone derived alkynes.
Based on this platform, a range of substitution patterns were
achieved and a large number of hydroxylated benzofurans were
prepared in one-step with 100% atom economy, which enabled
a collective total synthesis of different kinds of natural products
(11 examples). It is note-worthy that a C8 epimer of Liphagal,
containing an interesting [6-5-7-6] tetracyclic architecture, could
be assembled in 10 steps from commercially available
Geranylacetone, which makes it to be distinguished from
previous reports. With the above advantages, we believe such a
new deconstructive reorganization strategy for the de novo
synthesis of hydroxylated benzofurans could not only inspire the
chemists to design new synthetic routes for the total synthesis of
benzofuran-containing complex natural products, but also help
streamline the drug discovery process.
Acknowledgements
Scheme 5. Mechanistic investigation.
We are grateful to Ministry of Science and Technology of the
People's Republic of China (2016YFA0602900), the NSFC
(21372086, 21422204, and 21672071), NSF of Guangdong
(2018B030308007, 2018A030310359, 2016A030310433), the
On the basis of the above investigations,
a tentative
mechanism was then proposed (Scheme 6). The carbon-carbon
triple bond of starting material in 1 or 3 was initially activated by
the indium salt to form a π-complex A, which was followed by
the 5-endo-dig cyclization to generate the furanium B and its
resonance structure pyrylium C. Starting from intermediate C,
two different pathways might be expected for kojic acid-based
and maltol-based systems. For the former one, the pyrylium C
was trapped by water to give the 1, 5-dicarbonyl intermediate
Int-1, followed by intramolecular aldol cyclization to give ketol D.
And then selective elimination of C4-OH and aromatization led
to the desired dihydroxylated benzofuran 2. As for the maltol-
based system, the pyrylium C was attacked by methanol to
produce the acetal Int-2. In the presence of aqueous HCl, an
intramolecular (formal) aldol cyclization occurred to deliver the
Science
and
Technology
Program
of
Guangzhou
(201707010316), the China Postdoctoral Science Foundation
(2018M643062, 2019T120723), and the Fundamental Research
Funds for the Central Universities, SCUT. Prof. Li Zhang from
SYSU is specially appreciated for her help in English language
revision.
Conflict of interest
The authors declare no competing financial interests.
5
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[11] a) E. L. Fisher, S. M. Wilkerson-Hill, R. Sarpong, J. Am. Chem. Soc.
2012, 134, 9946-9949; b) M. Yagoubi, A. C. Cruz, P. L. Nichols, R. L.
Elliott, M. C. Willis, Angew. Chem. Int. Ed. 2010, 49, 7958-7962; c) C.
Wang, I. Piel, F. Glorius, J. Am. Chem. Soc. 2009, 131, 4194-4195; d)
A. Varela-Fernández, C. González-Rodríguez, J. A. Varela, L. Castedo,
C. Saá, Org. Lett. 2009, 11, 5350-5353; e) S. W. Youn, J. I. Eom, Org.
Lett. 2005, 7, 3355-3358; f) G. Deng, M. Li, K. Yu, C. Liu, Z. Liu, S.
Duan, W. Chen, X. Yang, H. Zhang, P. J. Walsh, Angew. Chem. Int. Ed.
2019, 58, 2826-2830; g) S. S. Bera, S. Debbarma, S. Jana, M. S. Maji,
Adv. Synth. Catal. 2018, 360, 2204-2210; h) A. Sivaraman, D. S.
Harmalkar, J. Kang, Y. Choi, K. Lee, Org. Biomol. Chem. 2019, 17,
2153-2161; i) M. J. Moure, R. SanMartin, E. Dominguez, Angew. Chem.
Int. Ed. 2012, 51, 3220-3224; j) W. Chen, Y. Zhang, L. Zhang, M. Wang,
L. Wang, Chem. Commun. 2011, 47, 10476-10478; k) L. M. Geary, P.
G. Hultin, Org. Lett. 2009, 11, 5478-5481; l) A. S. K. Hashmi, T. M.
Frost, J. W. Bats, Org. Lett. 2001, 3, 3769-3771; m) A. S. K. Hashmi, E.
Enns, T. M. Frost, S. Schäfer, W. Frey, F. Rominger, Synthesis 2008,
2008, 2707-2718.
Keywords: benzofuran • deconstructive reorganization • arene
cycloisomerization • total synthesis • Liphagal
[1]
a) Z. Xu, S. Zhao, Z. Lv, L. Feng, Y. Wang, F. Zhang, L. Bai, J. Deng,
Eur. J. Med. Chem. 2019, 162, 266-276; b) N. Al-Maharik, Nat Prod
Rep 2019, 36, 1156-1195; c) N. T. T. Thuy, J.-E. Lee, H. M. Yoo, N.
Cho, J. Nat. Prod. 2019.
[2]
[3]
a) W. Lim, W. Jeong, G. Song, J. Endocrinol. 2016, 228, 149-160; b) A.
Zafar, S. Singh, I. Naseem, Food. Chem. Toxicol. 2017, 99, 149-161.
a) F. Marion, D. E. Williams, B. O. Patrick, I. Hollander, R. Mallon, S. C.
Kim, D. M. Roll, L. Feldberg, R. Van Soest, R. J. Andersen, Org. Lett.
2006, 8, 321-324; b) A. R. Pereira, W. K. Strangman, F. Marion, L.
Feldberg, D. Roll, R. Mallon, I. Hollander, R. J. Andersen, J. Med.
Chem. 2010, 53, 8523-8533.
[4]
[5]
[6]
Y. Samuels, Z. Wang, A. Bardelli, N. Silliman, J. Ptak, S. Szabo, H. Yan,
A. Gazdar, S. M. Powell, G. J. Riggins, J. K. V. Willson, S. Markowitz, K.
W. Kinzler, B. Vogelstein, V. E. Velculescu, Science 2004, 304, 554-
554.
[12] H.-X. Zheng, X.-H. Shan, J.-P. Qu, Y.-B. Kang, Org. Lett. 2018, 20,
3310-3313.
B. L. Flynn, G. S. Gill, D. W. Grobelny, J. H. Chaplin, D. Paul, A. F.
Leske, T. C. Lavranos, D. K. Chalmers, S. A. Charman, E. Kostewicz,
D. M. Shackleford, J. Morizzi, E. Hamel, M. K. Jung, G. Kremmidiotis, J.
Med. Chem. 2011, 54, 6014-6027.
[13] F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004, 104, 3079-3160.
[14] a) F. López, L. Castedo, J. L. Mascareñas, Chem. Eur. J. 2002, 8, 884-
899; b) J. R. Rodríguez, A. Rumbo, L. Castedo, J. L. Mascareñas, J.
Org. Chem. 1999, 64, 4560-4563; c) P. A. Wender, C. D. Jesudason, H.
Nakahira, N. Tamura, A. L. Tebbe, Y. Ueno, J. Am. Chem. Soc. 1997,
119, 12976-12977; d) P. A. Wender, H. Y. Lee, R. S. Wilhelm, P. D.
Williams, J. Am. Chem. Soc. 1989, 111, 8954-8957; e) P. A. Wender, F.
E. McDonald, J. Am. Chem. Soc. 1990, 112, 4956-4958; f) P. A.
Wender, N. Buschmann, N. B. Cardin, L. R. Jones, C. Kan, J.-M. Kee, J.
A. Kowalski, K. E. Longcore, Nat. Chem. 2011, 3, 615; g) P. A. Wender,
N. D'Angelo, V. I. Elitzin, M. Ernst, E. E. Jackson-Ugueto, J. A.
Kowalski, S. McKendry, M. Rehfeuter, R. Sun, D. Voigtlaender, Org.
Lett. 2007, 9, 1829-1832.
a) F. X. Talamas, G. Ao-Ieong, K. A. Brameld, E. Chin, J. de Vicente, J.
P. Dunn, M. Ghate, A. M. Giannetti, S. F. Harris, S. S. Labadie, V.
Leveque, J. Li, A. S. T. Lui, K. L. McCaleb, I. Nájera, R. C. Schoenfeld,
B. Wang, A. Wong, J. Med. Chem. 2013, 56, 3115-3119; b) P. J.
Hajduk, J. Med. Chem. 2006, 49, 6972-6976.
[7]
[8]
[9]
a) Y. Yang, P. Gao, Y. Zhao, Z. Shi, Angew. Chem. Int. Ed. 2017, 56,
3966-3971; b) X. Qiu, H. Deng, Y. Zhao, Z. Shi, Sci. Adv. 2018, 4,
eaau6468; c) Y. Yang, Z. Shi, Chem. Commun. 2018, 54, 1676-1685;
d) C. N. Kona, Y. Nishii, M. Miura, Angew. Chem. Int. Ed. 2019, 58,
9856-9860.
a) T. Kudoh, T. Mori, M. Shirahama, M. Yamada, T. Ishikawa, S. Saito,
H. Kobayashi, J. Am. Chem. Soc. 2007, 129, 4939-4947; b) J. Zhang, X.
Zhang, T. Wang, X. Yao, P. Wang, P. Wang, S. Jing, Y. Liang, Z.
Zhang, J. Org. Chem. 2017, 82, 12097-12105; c) H. Zhang, T. Cao, H.
Luo, L. Chen, S. Zhu, Org. Chem. Front. 2019, 6, 1118-1122.
a) A. S. K. Hashmi, M. Wölfle, Tetrahedron 2009, 65, 9021-9029; b) J.-t.
Liu, C. J. Simmons, H. Xie, F. Yang, X.-l. Zhao, Y. Tang, W. Tang, Adv.
Synth. Catal. 2017, 359, 693-697; c) J. Barluenga, A. Gómez, J.
Santamaría, M. Tomás, J. Am. Chem. Soc. 2009, 131, 14628-14629; d)
M. M. Hansmann, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew.
Chem. Int. Ed. 2013, 52, 2593-2598; e) T. Tsuchimoto, H.
Matsubayashi, M. Kaneko, Y. Nagase, T. Miyamura, E. Shirakawa, J.
Am. Chem. Soc. 2008, 130, 15823-15835; f) N. Sun, X. Xie, Y. Liu,
Chem. Eur. J. 2014, 20, 7514-7519.
[15] a) A. V. Gulevich, A. S. Dudnik, N. Chernyak, V. Gevorgyan, Chem.
Rev. 2013, 113, 3084-3213; b) Y. Li, W. Li, J. Zhang, Chem. Eur. J.
2017, 23, 467-512; c) L. Chen, K. Chen, S. Zhu, Chem 2018, 4, 1208-
1262.
[16] a) S. F. Kirsch, J. T. Binder, C. Liébert, H. Menz, Angew. Chem. Int. Ed.
2006, 45, 5878-5880; b) B. Crone, S. F. Kirsch, J. Org. Chem. 2007, 72,
5435-5438; c) K.-D. Umland, A. Palisse, T. T. Haug, S. F. Kirsch,
Angew. Chem. Int. Ed. 2011, 50, 9965-9968; d) G. Li, X. Huang, L.
Zhang, J. Am. Chem. Soc. 2008, 130, 6944-6945; e) D. Qian, J. Zhang,
Chem. Rec. 2014, 14, 280-302.
[17] a) T. Cao, Y. Kong, K. Luo, L. Chen, S. Zhu, Angew. Chem. Int. Ed.
2018, 57, 8702-8707; b) T. Cao, L. Chen, S. Zhu, Org. Lett. 2019, 21,
90-94.
[18] E. Tzouma, I. Mavridis, V. P. Vidali, E. N. Pitsinos, Tetrahedron Lett.
2016, 57, 3643-3647.
[10] a) J. L. Pan, C. Liu, C. Chen, T. Q. Liu, M. Wang, Z. Sun, S. Y. Zhang,
Org. Lett. 2019, 21, 2823-2827; b) F. Wu, R. Bai, Y. Gu, Adv. Synth.
Catal. 2016, 358, 2307-2316; c) S. R. Mothe, D. Susanti, P. W. H. Chan,
Tetrahedron Lett. 2010, 51, 2136-2140; d) H. Zhang, C. Ma, Z. Zheng,
R. Sun, X. Yu, J. Zhao, Chem. Commun. 2018, 54, 4935-4938; e) K.
Yang, A. P. Pulis, G. J. P. Perry, D. J. Procter, Org. Lett. 2018, 20,
7498-7503; f) S. Porcu, S. Demuro, A. Luridiana, A. Cocco, A. Frongia,
D. J. Aitken, F. Charnay-Pouget, R. Guillot, G. Sarais, F. Secci, Org.
Lett. 2018, 20, 7699-7702; g) D. T. Smith, E. Vitaku, J. T. Njardarson,
Org. Lett. 2017, 19, 3508-3511; h) K. Murakami, H. Yorimitsu, A. Osuka,
Angew. Chem. Int. Ed. 2014, 53, 7510-7153; i) D. H. Lee, K. H. Kwon,
C. S. Yi, J. Am. Chem. Soc. 2012, 134, 7325-7328; j) T. Kobatake, D.
Fujino, S. Yoshida, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2010,
132, 11838-11840; k) X. Guo, R. Yu, H. Li, Z. Li, J. Am. Chem. Soc.
2009, 131, 17387-17393; l) J. B. Hendrickson, M. A. Walker, Org. Lett.
2000, 2, 2729-2731; m) W. Zeng, W. Wu, H. Jiang, L. Huang, Y. Sun, Z.
Chen, X. Li, Chem. Commun. 2013, 49, 6611-6613; n) R. Zhu, J. Wei,
Z. Shi, Chem. Sci. 2013, 4, 3706-3711; o) M. R. Kuram, M.
Bhanuchandra, A. K. Sahoo, Angew. Chem. Int. Ed. 2013, 52, 4607-
4612; p) R. C. Larock, E. K. Yum, M. J. Doty, K. K. C. Sham, J. Org.
Chem. 1995, 60, 3270-3271.
[19] J. J. Newsome, M. Hassani, E. Swann, J. M. Bibby, H. D. Beall, C. J.
Moody, Bioorg. Med. Chem. 2013, 21, 2999-3009.
[20] R. Naik, D. S. Harmalkar, X. Xu, K. Jang, K. Lee, Eur. J. Med. Chem.
2015, 90, 379-393.
[21] A. Noguchi, T. Yoshihara, A. Ichihara, S. Sugihara, M. Koshino, M.
Kojima, Y. Masaoka, Biosci. Biotech. Biochem. 1994, 58, 2312-2313.
[22] Y. X. Tan, Y. Yang, T. Zhang, R. Y. Chen, D. Q. Yu, Fitoterapia 2010,
81, 742-746.
[23] Chen, K. Shang, Zhao, Peng, Shao, X. Yong, Li, Zhe, Zhang, Cuixian,
Liu, Peiqing, He, Xixin, Luo, B. Hai, Hu, Xiaopeng, Bioorg. Med. Chem.
Lett. 2012, 22, 3261-3264.
[24] D. Wu, H. Mei, P. Tan, W. Lu, J. Zhu, W. Wang, J. Huang, J. Li,
Tetrahedron Lett. 2015, 56, 4383-4387.
[25] T. Kitamura, K. Otsubo, J. Org. Chem. 2012, 77, 2978-2982.
[26] Y. Shimokawa, Hirasawa, Y., Kaneda, T., Hadi, A. H. A., & Morita, H.,
Chem. Pharm. Bull. 2012, 60, 790-792.
[27] M. Adams, T. Pacher, H. Greger, R. Bauer, J. Nat. Prod. 2005, 68, 83-
85.
[28] C.-S. Yao, M. Lin, X. Liu, Y.-H. Wang, Journal of Asian Natural
Products Research 2005, 7, 131-137.
6
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[29] J. Y. Jeong, Y. H. Jo, S. B. Kim, Q. Liu, J. W. Lee, E. J. Mo, K. Y. Lee,
B. Y. Hwang, M. K. Lee, Bioorg Med Chem Lett 2015, 25, 2269-2274.
[30] a) J. H. George, J. E. Baldwin, R. M. Adlington, Org. Lett. 2010, 12,
2394-2397; b) E. Alvarez-Manzaneda, R. Chahboun, E. Alvarez, M.
José Cano, A. Haidour, R. Alvarez-Manzaneda, Org. Lett. 2010, 12,
4450-4453; c) J. J. Day, R. M. McFadden, S. C. Virgil, H. Kolding, J. L.
Alleva, B. M. Stoltz, Angew. Chem. Int. Ed. 2011, 50, 6814-6818; d) D.
R. Laplace, B. Verbraeken, K. Van Hecke, J. M. Winne, Chem. Eur. J.
2014, 20, 253-262; e) K. Q. Huynh, C. A. Seizert, T. J. Ozumerzifon, P.
A. Allegretti, E. M. Ferreira, Org. Lett. 2017, 19, 294-297; f) J.-L. Wang,
H.-J. Li, Y.-C. Wu, J. Org. Chem. 2018, 83, 8716-8723; g) G. Mehta, N.
S. Likhite, C. S. Ananda Kumar, Tetrahedron Lett. 2009, 50, 5260-
5262; h) T. Kamishima, T. Kikuchi, K. Narita, T. Katoh, Eur. J. Org.
Chem. 2014, 2014, 3443-3450.
[31] D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 15044-
15045.
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Entry for the Table of Contents
Arene Cycloisomerization
Ling Zhang+, Tongxiang Cao+, Huanfeng
Jiang, and Shifa Zhu*
__________ Page – Page
Deconstructive Reorganization:
De Novo Synthesis of Hydroxylated
Benzofuran
An unprecedented de novo synthesis of hydroxylated benzofuran was reported through
a deconstructive arene cycloisomerization process by using kojic acid- or maltol-derived
alkynes, which furnished several types of free hydroxyl group-adorned benezofurans
with different substitution patterns. To showcase the utility of this methodology, a
collective total synthesis of hydroxylated benzofuran-containing natural products (11
examples) was realized efficiently.
8
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