Total Synthesis of Sophoraflavanone H and Confirmation of Its Absolute Configuration

Article abstract of DOI:10.1021/acs.orglett.0c01063

Sophoraflavanone H (1) is a polyphenol with a hybrid-type structure containing 2,3-diaryl-2,3-dihydrobenzofuran and flavanone ring moieties. This compound and related analogues are promising leads for antimicrobial and antitumor drug development. Here we

Full text of DOI:10.1021/acs.orglett.0c01063

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Letter
Total Synthesis of Sophoraflavanone H and Confirmation of Its
Absolute Configuration
Haruka Murakami,⊥ Tomohiro Asakawa,⊥ Yoshihiro Muramatsu, Ryo Ishikawa, Aiki Hiza,
Yuta Tsukaguchi, Yohei Tokumaru, Masahiro Egi, Makoto Inai, Hitoshi Ouchi, Fumihiko Yoshimura,
Tohru Taniguchi, Yoshinobu Ishikawa, Mitsuru Kondo, and Toshiyuki Kan*
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ABSTRACT: Sophoraflavanone H (1) is a polyphenol with a
hybrid-type structure containing 2,3-diaryl-2,3-dihydrobenzofuran
and flavanone ring moieties. This compound and related analogues
are promising leads for antimicrobial and antitumor drug develop-
ment. Here we describe a total synthesis of 1 and its diastereomer.
The dihydrobenzofuran and flavanone rings were constructed by a
Rh-catalyzed asymmetric C−H insertion reaction and selective oxy-
Michael reaction. The absolute configuration of 1 was established by
X-ray crystallographic analysis and CD spectral investigation of
synthetic derivatives.
ophoraflavanone H (1) (Figure 1), which was isolated
total synthesis of optically active 12 and the determination of
its absolute configuration.
Our synthetic strategy for the heterocyclic rings of 1 is
illustrated in Scheme 1. We considered that a rhodium
carbenoid-mediated C−H insertion reaction3,4 starting from 2
would be suitable for the construction of 3, the 2,3-diaryl-2,3-
dihydrobenzofuran ring of 1. On the basis of our experiences
S
from the root of the plant Sophora moorcroftiana in 1990,1
Scheme 1. Synthetic Strategy for the Construction of the
2,3-Diaryl-2,3-benzofuran and Flavanone Moieties of 1.
Figure 1. Structure of sophoraflavanone H (1).
is a hybrid polyphenol composed of prenyl flavanone and 2,3-
dihydrobenzofuran lignin moieties. The relative stereochemis-
try of 1 was determined by means of detailed NMR analysis,
including NOE experiments. Comparison of the CD spectra of
1 and related monomeric flavanone and 2,3-dihydrobenzofuran
lignan natural products established the absolute configuration
at C-2; however, the absolute configurations at the 7‴ and 8‴
positions have not yet been confirmed by a nonempirical
method. In addition, Shirataki et al. reported that 1 and its
derivatives show antibacterial activity against methicillin-
resistant Staphylococcus aureus (MRSA) and vancomycin-
resistant Enterococcus faecium (VREF) as well as cytotoxicity
toward human oral tumor cell lines (HSC-2 and HSG).2
Attracted by the unusual structure and biological activities of 1,
we began a synthetic investigation. Herein we report the first
Received: March 24, 2020
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© XXXX American Chemical Society
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with the synthesis of natural products containing flavone5 and
flavane rings,6 we planned to employ the oxy-Michael reaction
of 4 to construct 5, the flavanone ring of 1. Because of the
expected difficulties in the direct connection of dihydrobenzo-
furan and flavanone rings, we focused on the stepwise
construction of each ring for the total synthesis.
tion, 13b was obtained with 99% ee. The relative stereo-
chemistry and the absolute configuration of 13b (2S,3R) were
confirmed by X-ray analysis (Figure 2).13
The synthesis of the dihydrobenzofuran moiety was started
with selective protection of the three acidic hydroxyl groups of
5-bromo-2,4-dihydroxybenzoic acid (6), as shown in Scheme
2. Following the conversion of 6 to the methyl ester, the MOM
Scheme 2. Synthesis of Dihydrobenzofuran 13b
Figure 2. ORTEP structure of 13b.
Initially, we attempted to construct the flavanone ring by
reduction of a flavone ring through a β-diketone intermediate.5
Several reduction conditions for the unsaturated double bond
were tested, including hydrogenolysis, one-electron reduction,
and hydride reduction, but none gave satisfactory results. For
example, application of Sajiki’s protocol, which was reported to
give excellent results for the reduction of α,β-unsaturated
bonds,14 to 14 resulted in cleavage of the benzyl O-7‴ bond
position of the dihydrobenzofuran to give 15 (Scheme 3).
Scheme 3. Initial Attempts to Construct the Flavanone Ring
Therefore, we selected the oxy-Michael reaction of chalcone
derivatives for the synthesis of the flavanone ring. Wang and
Hou reported that the Claisen rearrangement of 7-allylflavone
derivatives provided 8-alkylated products regioselectively.15
However, employment of thermal conditions similar to those
used for flavanone 16 gave a 1:1 mixture of 17 and 18, as
shown in Scheme 4. Thus, regioselective prenylation through
ether was incorporated selectively at OH-4, avoiding OH-2,
which formed a hydrogen bond with the ester carbonyl group.
The remaining OH-2 was benzylated by treatment with K2CO3
and 77 to provide 8. Construction of diaryl ketone 10 from 8
was performed by magnesium amide-mediated ester exchange
to the Weinreb amide8 followed by treatment with the
corresponding aryl Grignard reagent 9. Treatment of 10 with
anhydrous hydrazine followed by MnO2 oxidation yielded
diaryl diazomethane 11b.9 Since 11b is labile, the C−H
insertion reaction was performed without purification. Upon
treatment of 11b with Rh2(S-DOSP)410 at −55 °C, the desired
C−H insertion reaction proceeded smoothly to provide cis-
dihydrobenzofuran 13b (97% yield, 79% ee) through
carbenoid intermediate 12. Optimization of the C−H insertion
conditions was performed with methyl ether 11a using several
catalysts (for details, see the Supporting Information11).
Although high enantioselectivity was observed in methyl
ether 11a, subsequent removal of the methyl ether was
troublesome. Therefore, we selected tert-butyl ether 13b as the
dihydrobenzofuran moiety of 1. Hashimoto and co-workers
reported a similar construction of a 2,3-diaryl-2,3-dihydroben-
zofuran ring by Rh carbenoid-mediated C−H insertion,
affording the cis-dihydrobenzofuran ring.12 After recrystalliza-
Scheme 4. Claisen Rearrangement of Flavanone Derivatives
cyclization precursor 19 was expected to give a single isomer
by Claisen rearrangement (Scheme 5). Therefore, we selected
the oxy-Michael reaction of chalcone derivatives for the
synthesis of the flavanone ring.
After conversion of bromide 13b to the benzaldehyde
derivative by halogen−lithium exchange and subsequent
treatment with DMF, aldol condensation with acetophenone
B
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Scheme 5. Construction of the Flavanone Ring by the Oxy-
Michael Reaction
Figure 3. Lowest-energy conformer of 27a. In its ball-and-stick
model, the C, O, and H atoms are represented by the gray, red, and
white spheres, respectively. The gray rods show the bonds between
the atoms.
Scheme 6. Completion of the Total Synthesis of
Sophoraflavanone H (1)
agreement with the reported values. The sign of the optical
rotation and the Cotton effects in the CD spectrum were also
identical to those of the natural product 1.
To confirm the absolute configuration of the 2-position of
the flavanone ring of 1 by a nonempirical method, we next
performed theoretical CD calculations of truncated molecules
(2S)-32 and (2R)-3321 (Figure 4). These model molecules 32
2016 in the presence of KOH and MS4A provided chalcone 21.
The reverse prenylation was performed with Kaiho’s protocol17
by treatment of 21 with 22 in the presence of Pd(PPh3)4.
Upon heating, the desired Claisen rearrangement proceeded to
give 23. Optimization of the oxy-Michael reaction was initially
performed with chalcone 23 using various bases. Although the
cyclization reaction of chalcones 21, 25, and 26 proceeded
with (DHQ)2Pyr catalyst18 in moderate yields (60−80%), no
stereoselectivity was observed in the formation of 28−30 (α:β
= 1:1). Unexpectedly, slight β-stereoselectivity (α:β = 1:2.5)
was witnessed with the prenyl and tert-butyl ether derivative 23
under the same conditions. Conformational analysis19
identified the most stable form of 27a (the α isomer), as
shown in Figure 3. The rotational barrier at C2 and C1′ should
be high because of the prenyl and tert-butyl ether groups, and
this may account for the interesting stereospecificity of 27.
Although the desired 27a was obtained as a minor product,
this reaction is advantageous in that the two isomers of 27
were readily separated by silica gel column chromatography,
which was not the case for 28−30. Separated 27a was treated
with BBr3 for simultaneous removal of the tert-butyl, MOM,
and Bn ethers (Scheme 6). Under these Lewis acidic
conditions, isomerization occurred to form the stable 2,3-
trans-dihydrobenzofuran ring via quinone methide intermedi-
ate 31.4a−c,20 All of the spectral data (1H NMR, 13C NMR, IR,
and HRMS) of 1 synthesized from α-isomer 27a were in full
Figure 4. Simplified models 32 and 33 used for the calculation of CD
spectra.
and 33 were designed to reduce the computational cost while
retaining the major CD characteristics of 27a and 27b above
265 nm. The CD spectrum of 32 calculated at the DFT/
B3LYP/6-31G(d) level of theory using the PCM for
acetonitrile showed good agreement with the observed
spectrum of 27a, i.e., a weak positive Cotton effect at around
350 nm and a strong negative signal at around 300 nm (Figure
5, blue solid and dotted lines). Meanwhile, the predicted CD
spectrum of 33 well-reproduced the observed one for 27b
(Figure 5, red solid and dotted lines). These results suggest
that the absolute configuration at the 2-position of 27a, and
therefore that of 1, is S.
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Authors
Haruka Murakami − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Tomohiro Asakawa − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan;
Department of Fisheries-Food Science, Tokai University,
Shizuoka, Shizuoka 424-8610, Japan
Yoshihiro Muramatsu − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Ryo Ishikawa − School of Pharmaceutical Sciences, University of
Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Aiki Hiza − School of Pharmaceutical Sciences, University of
Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Yuta Tsukaguchi − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Yohei Tokumaru − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Masahiro Egi − School of Pharmaceutical Sciences, University of
Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Makoto Inai − School of Pharmaceutical Sciences, University of
Shizuoka, Shizuoka, Shizuoka 422-8526, Japan; orcid.org/
0000-0001-7074-0520
Hitoshi Ouchi − School of Pharmaceutical Sciences, University
of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Fumihiko Yoshimura − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan;
orcid.org/0000-0002-1187-6062
Tohru Taniguchi − Faculty of Advanced Life Science, Frontier
Research Center for Advanced Material and Life Science,
Hokkaido University, Sapporo, Hokkaido 001-0021, Japan;
orcid.org/0000-0002-4965-7383
Yoshinobu Ishikawa − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
Mitsuru Kondo − Graduate School of Science and Technology,
Shizuoka University, Shizuoka, Shizuoka 422-8529, Japan
Figure 5. Comparison of CD spectra of synthetic isomers 27a (blue
solid line) and 27b (red solid line) and the model compounds 32 (S
form) (blue dashed line) and 33 (R form) (red dashed line).
In conclusion, we have achieved a stereocontrolled total
synthesis of sophoraflavanone H in 14 steps from commercially
available 6. Our synthesis features an asymmetric Rh-mediated
C−H insertion reaction that provides ready access to the
highly substituted dihydrobenzofuran skeleton of 13b. This
method provides both diastereomers, enabling unambiguous
determination of the absolute configuration of 1. Modifications
of the present route to prepare analogues for SAR studies are
in progress.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01063
Author Contributions
⊥H.M. and T.A. contributed equally.
ASSOCIATED CONTENT
* Supporting Information
■
sı
Notes
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01063.
The authors declare no competing financial interest.
Experimental procedures and spectroscopic character-
ization (PDF)
X-ray structure report for 13b (PDF)
ACKNOWLEDGMENTS
■
This work was financially supported by MEXT/JSPS
KAKENHI Grants JP17H03973, JP19K05460, and
JP20K06946, Grants-in-Aid for Scientific Research on Priority
Areas JP16H01160 and JP17H06402 from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
of Japan, and the Platform Project for Supporting Drug
Discovery and Life Science Research [Basis for Supporting
Innovative Drug Discovery and Life Science Research
(BINDS)] from AMED under Grant JP19am0101099.
Accession Codes
CCDC 1968420 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
DEDICATION
■
Toshiyuki Kan − School of Pharmaceutical Sciences, University
of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan;
orcid.org/0000-0002-9709-6365; Email: kant@u-
shizuoka-ken.ac.jp
This work is dedicated to the memory of Centennial Professor
Koji Nakanishi, Columbia University, who passed away on
March 28, 2019.
D
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