Synthesis of Highly Substituted Benzofuran–containing Natural Products via Rh–catalyzed Carbonylative Benzannulation

Article abstract of DOI:10.1002/adsc.201600992

We recently developed a novel Rh-catalyzed carbonylative benzannulation for the synthesis of indoles, benzofurans, and many related heterocycles. In this update, we demonstrated the utility of this method for the synthesis of several highly substituted be

Full text of DOI:10.1002/adsc.201600992

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DOI: 10.1002/adsc.201600992
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Synthesis of Highly Substituted Benzofuran–containing Natural
Products via Rh–catalyzed Carbonylative Benzannulation
a, b
a, c
a
a
Ji-tian Liu, Christopher J. Simmons, Haibo Xie, Fan Yang, Xian-
a, d,
b, e,
a, c,
liang Zhao, * Yu Tang, * and Weiping Tang *
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a
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
Phone: (608) 890-1846
Fax: (608) 262-5345; e-mail: wtang@pharmacy.wisc.edu
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072 P. R. China
b
E-mail: tangyu114@gmail.com
Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706 USA
School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, P. R.
c
d
China
E-mail: xlzhao@iccas.ac.cn
e
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of
China, Qingdao, 266003, P. R. China.
Received: September 7, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600992
[
8]
like reaction induced mice, and the permethylated
Abstract: We recently developed a novel Rh-cata-
lyzed carbonylative benzannulation for the syn-
thesis of indoles, benzofurans, and many related
heterocycles. In this update, we demonstrated the
utility of this method for the synthesis of several
highly substituted benzofuran-containing natural
products. The scope and limitation of the Rh-
catalyzed carbonylative benzannulation was inves-
tigated in the context of natural product synthesis
for the first time. This study also revealed the site-
selectivity for Pd-catalyzed cross-coupling of sub-
stituted benzofurans. Two one-pot sequential cross-
couplings were realized based on the observed site-
selectivity. The strategy of preparing bicyclic het-
erocycles such as benzofurans by de novo synthesis
of the benzene ring will find applications in many
other related bioactive heterocycles.
anigopreissin A (PAA) 7 showed inhibitory activity
[
9]
for human hepatoma cell proliferation.
The benzofuran core of these natural products and
their derivatives were generally constructed by annu-
lation of the five-membered ring starting from poly-
substituted benzene derivatives in previous syntheses
[
10]
(Scheme 1).
For example, natural product 1 was
synthesized by Kraus using phosphazene base-medi-
ated intramolecular condensation of 2-acylphenol
ether to afford permethylated precursor 2 followed by
[
11]
demethylation. An earlier approach to malibatol A
4 by Kraus utilized an intramolecular condensation of
aryllithium with ketone to form the benzofuran
[
12]
moiety. Kim’s approach for compounds 1, 4, and 5
employed a Bi(OTf) -catalyzed cyclodehydration of
3
trisubstituted benzene derivatives for the formation of
[
13]
furan ring in benzofurans. A modified version of the
cyclodehydration strategy was applied to the total
Keywords: Carbonylation; rhodium; annulation;
benzofuran; propargylic ester
[
14]
synthesis of diptoindonesin G.
This strategy was
also adopted by other groups for the synthesis of
[
15]
benzofuran-containing natural products.
group prepared the benzofuran core of intermediate 2
Benzofuran is a common structural motif in numerous by adopting Kraus’s approach and converted it to
Chen’s
[16]
natural products, such as amurensin H (or viniferifur- natural products malibatol A 4 and shoreaphenol 5.
[
1]
[2]
[3]
an) 1, gnetuhainin B 3, malibatol A 4, shoreaphe-
Constructing the benzene portion of benzofuran
[
4]
[5]
nol (or hopeafuran) 5, anigopreissin A 6, and via benzannulation of furan derivatives would com-
fuliginosin A 8 (Figure 1). These highly substituted prise a completely new strategy for the synthesis of
[
6]
benzofurans and their derivatives possess broad range benzofuran-containing natural products as shown in
[
3,7]
of pharmacological activities.
Among them, com- Scheme 1. This strategy will provide new derivatives
pound 1 showed anti-inflammatory effect on asthma- that cannot be easily accessed using previous ap-
Adv. Synth. Catal. 2016, 358, 1–6
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 2. Rh-catalyzed Carbonylative Benzannulation.
applications. In addition, our study uncovered the site-
selectivity for Pd-catalyzed cross-coupling of polysub-
stituted benzofurans.
Based on the Rh-catalyzed carbonylative benzan-
nulation method outlined in Scheme 2, we proposed
that various highly substituted benzofuran-containing
natural products such as those in Figure 1 could be
Figure 1. Representative Benzofuran-containing Natural derived from simple furyl propargylic ester 18 via
Products.
intermediates 16 and 17 as shown in Scheme 3.
Scheme 1. Two Distinct Approaches for Benzofuran-contain-
ing Natural Products.
proaches for structure activity relationship studies. We
recently developed such a catalytic benzannulation
method using propargylic ester 9 as the starting
material and rhodium(I) complex as the catalyst
Scheme 3. A divergent Strategy for the Synthesis of Highly
Substituted Benzofurans.
[17]
(Scheme 2).
This represents a novel and unified
Starting from commercially available 2,3-dibromo-
approach for various heterocycles under very mild furan 19, we first prepared diaryl furan 21 by
conditions. DFT calculations indicated that the formal sequential cross-coupling reactions (Scheme 4). For-
[5+1] carbonylative benzannulation was initiated by a mylation followed by addition of ethynyl Grignard
metal-mediated 1,2-migration of propargylic ester, reagent and esterification yielded substrate 23 via
followed by the formation of a zwitterion intermediate aldehyde 22. Under previously established conditions,
12, metallacycle 13, and ketene intermediate 14, and we were not able to convert this furyl propargylic2
completed by a 6p-electrocyclization and aromatiza- ester to benzofuran 24. We suspected that the Ar
tion to afford product 10.
substituent might prevent the cyclization event to
In this update, we demonstrated the utility of our occur in the 6p-electrocyclization step. This is still
newly developed Rh-catalyzed carbonylative benzan- somewhat surprising to us as alkyl substituents on the
nulation method to the synthesis of highly substituted same position could be tolerated during the develop-
[
17]
benzofuran-containing natural products, including the ment of the methodology.
first total synthesis of fuliginosin A 8. We also Next, we introduced only one aryl substituent to
revealed the scope and limitation of the carbonylative substrate 27 by starting from either dibromofuran 19
benzannulation method in the context of these or dibromofurfural 25 (Scheme 5). We were pleased to
Adv. Synth. Catal. 2016, 358, 1–6
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Scheme 4. Initial Attempt for the Synthesis of Benzofurans
from 2,3-Diarylfurans via Rh-catalyzed Benzannulation.
find that the key benzannulation reaction worked
smoothly for substrate 27, which bears a smaller
bromine substituent. With the highly substituted
benzofuran core 28 in hand, we tried to directly couple
2
it with Ar B(OH) . It failed to give us any desired
2
product. Instead of protecting the phenolic OH, we
next prepared triflate 29 and explored the site-
selectivity for the cross-coupling reaction. Product 30
2
was obtained when 29 was reacted with Ar B(OH) ,
2
suggesting that the C-4 triflate is more reactive. We
then switched the order and coupled 29 with vinyl-
boronic acid first to afford intermediates 31, which
was then converted to 32 after the second cross-
coupling reaction. The pivalate groups was hydrolysed
Scheme 5. Formal Synthesis of Benzofuran-containing Natu-
ral Products via Rh-catalyzed Benzannulation.
during this step. Methylation of 32 yielded compound PAA 7 and natural product fuliginosin A 8 in two and
2, which has been converted to natural products 1, 4 four steps, respectively, through standard functional
[
11,16]
and 5 in literature.
The overall yields for 2 are group transformations. The low yield for the removal
of the methyl groups in compound 35 may be
35.7% or 41.6% from 19 or 25, respectively.
Starting from intermediate 28 (Scheme 6), methyl- attributed to the sensitivity of 35 or 8 to strong acidic
2
ation followed by cross-coupling with Ar B(OH) and conditions. This represents the first total synthesis of
2
removal of pivalate provided benzofuran 34, which natural product fuliginosin A, whose structure is now
could be converted to anti-proliferation compound confirmed by synthesis. The overall yields for 7 and 8
are 24.3% and 3.6%, respectively, form 25.
We also prepared dibromobenzofurans 37 and 38
by the Rh-catalyzed benzannulation of dibromofuran-
yl propargylic ester 36 derived from dibromofurfural
25 (Scheme 7). Diarylbenzofuran 34 could be more
efficiently synthesized by an one-pot sequential cou-
[
18]
pling
process from 38. PAA 7 could also be
prepared by the one-pot sequential cross-coupling
with 39, which was derived from intermediate 33 by
hydrolysis and formation of triflate. Our results
uncovered the order of reactivity for 2-, 3-, and 6-
positions of benzofurans towards Pd-catalyzed cross-
coupling reactions.
In summary, we developed a divergent synthesis of
several highly substituted benzofuran-containing natu-
ral products from simple furan derivatives. We demon-
strated the utility of our Rh-catalyzed carbonylative
benzannulation reaction in natural product synthesis
Scheme 6. Synthesis of PPA and Fuliginosin A via Rh-
catalyzed Benzannulation.
Adv. Synth. Catal. 2016, 358, 1–6
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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(97 mg, 0.25 mmol, 85% yield) as light yellow solid. m.p.=
1
1
9
59-1618C. H NMR (400 MHz, CDCl , TMS): d 1.37 (s,
3
H), 6.27 (d, J=1.8 Hz, 1H), 6.55 (brs, 1H), 6.76 (d, J=1.8
13
Hz, 1H); C NMR (100 MHz, CDCl ): d 27.3, 39.5, 96.4,
3
9
2
8.2, 105.1, 113.8, 127.6, 149.4, 149.5, 155.8, 178.5; IR: n 3380,
À1
958, 2360, 1738, 1127, 739 cm . HRMS (ESI) for C H Br
13
12
2
NaO (M+Na), (Calc.) 414.8975, found 414.8969.
4
Acknowledgements
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We thank NSF (CHE-1464754) and University of Wisconsin-
Madison for financial support. J.-t. Liu and X.-l. Zhao thank
Chinese Scholarship Council for financial supports. F. Yang
thanks the Undergraduate Education Office of the University
of Science and Technology of China for financial support.
This study made use of the Medicinal Chemistry Center at
UW-Madison instrumentation, funded by the Wisconsin
Alumni Research Foundation (WARF) and the UW School of
Pharmacy.
Scheme 7. Pd-catalyzed One-pot Sequential Cross-Couplings.
for the first time and investigated the scope and
limitation of this novel catalytic transformation in the
context of formal synthesis of amurensin H (or References
viniferifuran) 1, malibatol A 4 and shoreaphenol (or
hopeafuran) 5, and total synthesis of PPA 7 and
fuliginosin A 8. This unique approach of de novo
synthesis of the benzene ring should find applications
in many other highly substituted benzofurans and
related heterocycles.
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carbonylative benzannulation:
To an oven-dried flask was added pivalate 27 (105 mg,
0
.27 mmol), anhydrous DCM (20 mL) and [Rh(CO) Cl]
2 2
(
5 mg, 5 mol%). The flask was degassed and attached with a
CO balloon (1 atm). The reaction was stirred at room
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completed, the solvent was evaporated. The residue was
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8, 1600.
(
=
90 mg, 0.22 mmol, 82% yield) as light yellow solid. m.p.
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3
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9H), 3.86 (s, 3H), 6.37 (d, J=1.8 Hz, 1H), 6.56 (brs, 1H), 6.83
(
d, J=1.8 Hz, 1H), 6.95 (d, J=9.1 Hz, 2H), 7.91 (d, J=9.1
1
3
Hz, 2H); C NMR (100 MHz, CDCl ): d 27.4, 39.4, 55.6,
3
8
1
7
8.2, 98.2, 104.5, 114.2, 114.3, 121.9, 128.4, 149.6, 150.2, 150.3,
54.1, 160.3, 177.9; IR: n 3382, 2970, 2360, 1738, 1265,
2
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À1
38 cm . HRMS (ESI) for C H BrNaO (M+Na), 441.0308
2
0
19
5
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Calc.), found 441.0302.
Procedure for the preparation of phenol 37 by Rh-catalyzed
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To an oven-dried flask was added pivalate 36 (108 mg,
0.29 mmol), anhydrous DCM (20 mL) and [Rh(CO)
Cl]
2
2
(
5 mg, 5 mol%). The flask was degassed and attached with a
CO balloon (1 atm). The reaction was stirred at room
temperature and monitored by TLC. After the reaction was
completed, the solvent was evaporated. The residue was
purified by flash column chromatography to give phenol 37
[
[
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UPDATES
Synthesis of Highly Substituted Benzofuran–containing
Natural Products via Rh–catalyzed Carbonylative Ben-
zannulation
Adv. Synth. Catal. 2016, 358, 1–6
J.-t. Liu, C. J. Simmons, H. Xie, F. Yang, X.-l. Zhao*, Y.
Tang*, W. Tang*
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