Total synthesis of penta-Me amurensin H and diptoindonesin G featuring a Rh-catalyzed carboacylation/aromatization cascade enabled by C–C activation

Article abstract of DOI:10.1016/j.tetlet.2019.02.040

Oligostilbenoids represented a family of natural products, which contained one or several multifused benzofuran substructures and displayed promising biological activities towards cancer as well as immunological therapeutic targets. A convergent-divergent

Full text of DOI:10.1016/j.tetlet.2019.02.040

Accepted Manuscript
Total Synthesis of penta-Me Amurensin H and Diptoindonesin G Featuring a
Rh-catalyzed Carboacylation/Aromatization Cascade Enabled by C-C Activa-
tion
Yuting Qin, Jun-Ling Zhan, Tian-tian Shan, Tao Xu
PII:
S0040-4039(19)30185-6
https://doi.org/10.1016/j.tetlet.2019.02.040
TETL 50634
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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11 January 2019
19 February 2019
22 February 2019
Please cite this article as: Qin, Y., Zhan, J-L., Shan, T-t., Xu, T., Total Synthesis of penta-Me Amurensin H and
Diptoindonesin G Featuring a Rh-catalyzed Carboacylation/Aromatization Cascade Enabled by C-C Activation,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.02.040
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Graphical Abstract
Total Synthesis of penta-Me Amurensin H
and Diptoindonesin G Featuring a Rh-
Catalyzed Carboacylation/Aromatization
Cascade Enabled by C-C Activation.
Leave this area blank for abstract info.
Yuting Qin, Jun-Ling Zhan, Tian-tian Shan and Tao Xu*

1
Tetrahedron Letters
Total Synthesis of penta-Me Amurensin H and Diptoindonesin G Featuring a Rh-
catalyzed Carboacylation/Aromatization Cascade Enabled by C-C Activation.
Yuting Qina,†, Jun-Ling Zhana,†, Tian-tian Shana and Tao Xua,b
a Key Laboratory of Marine Drugs, Ministry of Education; School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
b Laboratory for Marine Drugs and Bioproducts and Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine
Science and Technology(Qingdao), 1 Wenhai Road, Qingdao 266237, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Oligostilbenoids represented a family of natural products, which contained one or several
multifused benzofuran substructures and displayed promising biological activities towards
cancer as well as immunological therapeutic targets. A convergent-divergent strategy featuring
Rh-catalyzed carboacylation/aromatization cascade reaction based on C-C activation of
benzocyclbutenones had been conceived. penta-Methyl amurensin H and diptoindolnesin G
were successfully synthesized without any protecting groups, constituting a new entry towards
oligostilbenoids’ natural product synthesis. The synthesis completed within 10 steps for both
natural products, suggesting conciseness and efficacy of the C-C activation in complex natural
product synthesis.
Available online
Keywords:
Dipindolnesin G
Total Synthesis
C-C activation
Carboacylation/aromatization cascade
2009 Elsevier Ltd. All rights reserved.
———
 Corresponding author. Tel.: +86-532-8590-6822; e-mail: xutao@ouc.edu.cn
† These authors contributed equally to this work.

2
Tetrahedron
Oligostilbenoids represented a family of natural products,
which was followed by insertion into C=O and spontaneous
aromatization, furnishing a variety of 2,3 substituted benzofuran
analogues(Eq. 1).[10a] While the field of C−C activation
methodologies based on benzocyclobutenones has seen limited
use in complex natural product synthesis, there remains great
potential in its application into total synthesis oligostilbenoids
natural products.
which contained one or several multifused benzofuran
substructures and displayed promising biological activities
towards cancer as well as immunological therapeutic targets.[1]
As a representative member, diptoindonesin G (DipG) was
isolated from Hopea mengarawan in Indonesia by Syah group in
2009 and at roughly the same time by Tan group from a Chinese
stem bark as well.[2] DipG featured a rather rigid tetracyclic
polyfused benzofuran skeleton and four phenolic OH groups,
which might be the structural basis for its unique biological
activities. It showed potent growth-inhibitory effect towards P-
388 cell line. Recently, it was reported that diptoindonesin G
displayed regulatory effects towards nuclear receptor family
namely, estrogen receptor α/β, which are validated target proteins
for breast cancer therapy.[3] Diptoindonesin G also showed anti-
proliferation ability by inducing G2/M phase arrest and cell
differentiation in acute myeloid leukemia(AML) cell lines and
primary AML cells, making it a potential new candidate for
AML differentiation therapy.[4] On the other hand, amurensin H
also known as viniferifuran, malibatol A and shoreaphenol all
belonged to oligostilbenoids family containing multisubstituted
benzofuran skeleton. These natural products also exhibited a
wide variety of pharmacological activities including anti-
inflammatory, antioxidant, antifungal, antibacterial, anti-HIV,
and anticarcinogenic activities[5].(Figure 1) Outstanding total
synthesis of these molecules had been achieved by Krause[6],
Kim[7], Tang[8] and Chen[9] using different Lewis acid
promoted cyclization and/or gold-catalysis. A recent report from
Kim’s group, displayed skeletal rearrangement strategy towards
Dip G[7d]. We are particularly intrigued by utilization of the C-
The core structural features as well as their important biological
activities of amuresin H and diptoindonesin G prompted us to
embark on the total synthesis of these multi-substituted
benzofuran-containing
retrosynthetic analysis is based on a convergent-divergent design.
We hypothesized that penta-Me amuresin (1) and
diptoindonesin (2) could be accessed through Wittig
olefination and Friedel-Crafts cyclization, respectively from a
common intermediate 5. The benzofuran compound 5 could be
reached
oligostilbenoids.(Figure
2)
Our
H
G
by
the
key
transformation:
Rh-catalyzed
carboacylation/aromatization cascade via intermediate I, from the
coupling product 7. The starting material 7 can be readily
synthesized from benzocyclobutenone 8 and the known ketone
9.[10a] This design join the two fragments together and
diversified at later stage of the synthesis, which allowed
introduction of different aromatic rings in each part that could
ultimately serve as a key plat-form for further SAR studies in
medicinal research.
C
bond activation strategy into the total synthesis of
oligostilbenoids.[10]
Our forward synthesis commenced with synthesizing
benzocyclobutenone 9. (Figure 3) We started from commercially
available 1-bromo-3,5-dimethoxybenzene (10) by performing a
[2+2] cycloaddition between an in situ generated benzyn (from
LiTMP and purchased arylbromide 10) and the freshly made
Figure 1. Representative oligostibenoids containing multi-
substituted benzofuran skeleton.
Transition metal-catalyzed formal [4+2] cycloadditions between
four-membered cyclic ketones and a 2π component through C−C
σ-bond activation has established as an attractive approach for
preparing complex ring systems.[11] These methods generally
operated at near pH and redox neutral conditions in an atom-
economical fashion. Carbon-Carbon bond activation has emerged
as a unique booming area in modern transition metal catalysis
although tandem design and application in natural product
synthesis are still rare. To the best of our knowledge, only two
examples of application in natural product synthesis utilizing
metal-catalyzed carboacylation of olefins through C–C bond
cleavage of four-membered ketones have been reported,[10,12]
in which simple non-polar olefins were employed as coupling
partners. This approach allows converting one relatively inert C–
C bond into two reactive M–C bonds, providing unusual
strategies to access 2,3-disubstituted benzofuran skeletons in a
single step.
Figure 2. A convergent-divergent strategy featuring Rh-catalyzed
carboacylation/aromatization cascade towards amuresin H and
pentaMe diptoindonesin G.
Recently, our group had developed a cascade transformation
initiated by regioselective activation of benzocyclobutenone,

3
liuthium-enolate (11), following a modified procedure of Dong
and coworkers.[13] The resulting benzocyclobutenol (12) was -
oxidized with DMP under basic condition to afford methylated
benzocyclobutenone 13 in an 85% yield. The selective
demethylation was carried out with extensive optimization, only
obtaining regioisomers 9 and 9’ as mixtures in a ratio of 1:1 with
50% combined yield. The isomer mixture was alkylated with
literature known α–chloro ketone 8[10] and yielded compound 7
as inseperable mixtures, too. They were nevertheless subjected to
the previously reported[10b] reaction condition employing 10
mol% [Rh(cod)(MeCN)2]BF4 and 12 mol% DPPF in THF for the
Elimination with tBuOK followed by dihydroxylation and diol
cleavage afforded the common intermediate 5 in a total of 75%
yield over two steps. The aldehyde 5 was advanced to penta-Me
amuresin H (1) through Wittig olefination in a satisfactory 75%
yield. The spectra of synthesized penta-Me amuresin H (1)
matched very well with the previously reported data.[5a] As for
penta-Me diptoindonesin G, the aldehyde 5 was first oxidized
with unusual KMnO4 in acetone and water to carboxylic acid,
which was activated by trifluoroacetic anhydride (TFAA) to
induce a Fredel-Crafts cyclization to afford the desired tetracyclic
core of diptoindonesin G in a combined 75% yield over two steps.
The spectra of penta-Me diptoindonesin G (2) was in well
accordance with the reported data[7].
carboacylation/aromatization
Gratifyingly, the only isolated product was the desired 2,3-
substituted benzofuran in a 76% yield based on the
cascade
transformation.
6
In summary, a new entry towards two oligostilbenoids’ natural
benzocyclobutenone C3 regioisomer 9. The robustness and
efficacy of this key step paved way for following synthesis of the
target molecules. One carbon abstraction was realized using a
three-step sequence. Benzofuran 6 was reduced by LiAlH4 and
converted to meslate 15 in an 80% yield over two steps.
product namely, penta-Me amuresin
H
and penta-Me
diptoindonesin G had been conceived and total synthesis realized.
Rh-catalyzed carboacylation/aromatization cascade initiated by
C-C activation of benzocyclobutenone was employed as the key
step. Total synthesis of penta-Me amurensin H and penta-Me
diptoindonesin G were completed without using any protecting
groups. We believe that this convergent-divergent strategy
featuring C-C activation will find further application in complex
natural product synthesis.
Acknowledgments
We thank "1000 Talents Plan for Young Professionals" and
OUC for a startup fund, NSFC (No.81502913, No.U1606403 &
No. U1706213), the pilot QNLMST (No.2015ASTP-ES14 & No.
2018SDKJ0403) and National Science and Technology Major
Project of China (No. 2017ZX09305-004) for research grants.
The project was partially funded by the Engineering Research
Center for Marine Bioresources Comprehensive Utilization, SOA
(MBRCU201802). T.X. is a Taishan Youth Scholar Qingdao
municipal government is especially acknowledged for a grant in
“Leading Innovative Talents” program.
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4
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Graphical Abstract
Total Synthesis of penta-Me Amurensin H
and Diptoindonesin G Featuring a Rh-
Catalyzed Carboacylation/Aromatization
Cascade Enabled by C-C Activation.
Leave this area blank for abstract info.
Yuting Qin, Jun-Ling Zhan, Tian-tian Shan and Tao Xu*