Total Synthesis of Casuarinin

Article abstract of DOI:10.1021/acs.orglett.0c00876

This study involves the total synthesis of casuarinin, a naturally occurring ellagitannin, in which an open-chain glucose is esterified with two (S)-hexahydroxydiphenoyl (HHDP) groups. One HHDP group incorporates a C-glycosidic bond between its benzene ring and the glucose moiety, which was constructed with complete stereoselectivity using a benzyl oxime group that opened the glucopyranose ring and acted as a scaffold for C-glycoside production. This total synthesis enables future structure-activity relationship studies of this compound.

Full text of DOI:10.1021/acs.orglett.0c00876

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Total Synthesis of Casuarinin
Shinnosuke Wakamori,* Shintaro Matsumoto, Reina Kusuki, Kazutada Ikeuchi, and Hidetoshi Yamada*
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ABSTRACT: This study involves the total synthesis of casuarinin,
a naturally occurring ellagitannin, in which an open-chain glucose is
esterified with two (S)-hexahydroxydiphenoyl (HHDP) groups.
One HHDP group incorporates a C-glycosidic bond between its
benzene ring and the glucose moiety, which was constructed with
complete stereoselectivity using a benzyl oxime group that opened
the glucopyranose ring and acted as a scaffold for C-glycoside
production. This total synthesis enables future structure−activity
relationship studies of this compound.
asuarinin [(1R)-1] is an ellagitannin originally isolated in
C
1981 by Okuda and co-workers from the leaves of the
1
drooping she-oak, Casuarina stricta. The ubiquitous avail-
ability of (1R)-1 has allowed for a variety of investigations to
test its biological activities. This compound is typically found
2
to show anti-herpes virus type 2 (HSV-2) activity and
3
,4
antioxidant activity;
progression in the G /G phase in human breast cancer cells
it affects apoptosis and cell cycle
0
1
5
,6
(
MCF-7) and lung cancer cells (A549) and blocks NF-κB
activation of HaCaT cells.
7
,8
However, the relationships
between the various bioactivities reported and the structural
features of (1R)-1 have been poorly studied.
Casuarinin [(1R)-1] and its 1-OH epimer, stachyurin [(1S)-
9
1
], consist of an open-chain form of a D-glucose unit with two
(
S)-hexahydroxydiphenoyl (HHDP) groups: one between
oxygens 2 and 3 (O-2 and O-3, respectively) and the other
between O-4 and O-6 of glucose (Figure 1). The difference
between these two HHDP groups is that a benzene ring of the
2
,3-O-HHDP group notably links to C-1 of the glucose moiety
through a C-glycosidic bond, as opposed to the usual acyl
linkage of the 4,6-O-HHDP group. In addition, the benzylic C-
Figure 1. Structures of casuarinin [(1R)-1], stachyurin [(1S)-1], and
compounds utilized to determine the axial chiralities of (1R)-1 and
1
is a reactive site that allows for the formation of a
(1S)-1.
carbocation, which can generate its analogues, such as
10−12
oligomers and complexes with a flavan-3-ol unit.
group, and the presently accepted structures are the (1R)-
Okuda and co-workers proposed the configuration of C-1 to
14
isomer for (1R)-1 and the (1S)-isomer for stachyurin (1S)-1.
be S in (1R)-1 and R in (1S)-1 on the basis of the dihedral
1
Quideau and co-workers proposed a biosynthetic pathway
for the C-glycosidic ellagitannins and their analogues (Scheme
angles between H-1 and H-2 in the corresponding H NMR
1
,9
spectra. The axial chirality of the 4,6-O-HHDP group in
1R)-1 was determined to be S via the release of (S)-2 as a
(
fragment from its pentadecamethylated derivative. In contrast,
the (S)-axial chirality of another fragment 3 from the same
derivative was determined, as well as structures of other
ellagitannins, by comparison of the CD and optical rotatory
Received: March 9, 2020
1
3
dispersion data. A 1990 study by Nishioka and co-workers
contradicted the configuration at C-1 assigned by Okuda’s
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00876
A
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1
5
1
). Starting from β-pentagalloylglucose (4), the galloyl
Scheme 2. Previous Methods and Our Strategy for the
Construction of the C-Glycosidic Bond
groups between O-4 and O-6, followed by those between O-
Scheme 1. Biosynthesis of C-Glycosidic Ellagitannins
Proposed by Quideau and Co-workers
2
and O-3, oxidatively couple to form the two HHDP groups.
Successively, the galloyl group at O-1 is hydrolyzed to produce
pedunculagin (5).
1
6,17
Subsequently, the pyranose ring of 5
opens and the newly formed hydroxy group at O-5 is
galloylated to generate liquidambin (6). Then, C-glycosylation
takes place between C-1 and the 2,3-O-HHDP group to
provide (1R)-1 and (1S)-1. As a result, it is believed that the
(S)-axial chirality of the 2,3-O-HHDP group of both (1R)-1
and (1S)-1 preserves that of 6.
For the construction of the characteristic C-glycosidic bond,
two kinds of approaches have been developed. Tanaka and co-
workers reported the biomimetic direct transformation from
pedunculagin (5) to casuariin (7) and 5-O-desgalloylstachyur-
in (8), where the C-glycosidic bond was formed by the
treatment of 5 with pH 7.5 phosphate buffer (Scheme 2a, eq
1
). Under the same reaction conditions, platycaryanin B (9)
was transformed into platycariin (10) and its 1-epimer 11
18
(Scheme 2a, eq 2). Deffieux, Quideau, and co-workers
applied this direct transformation to chemically synthesized 12
19
to provide C-glycoside 13 (Scheme 2a, eq 3). This method
was also employed for the transformation of 14 to 15 (Scheme
2
a, eq 4), in which the hydroxy groups of the HHDP moiety
were partially protected. Although these direct transformations
yielded C-glycosidic products, the generation of two secondary
hydroxy groups might limit the site-selective introduction of
the desired galloyl group at O-5. Thus, Quideau and co-
workers reported that the fully protected aldehyde 16 was
transformed into C-glycosides 17 and 18 in 81% total yield
when using tetrabutylammonium fluoride with acetic acid in
2
0
tetrahydrofuran (Scheme 2b).
Although their study
from glucopyranose 19 required four chemical conversion
improved the yield of C-glycosylation, the preparation of 16
steps.
B
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Scheme 3. Total Synthesis of Casuarinin [(1R)-1]
We herein describe the total synthesis of casuarinin [(1R)-1]
toward the synthesis of a series of its analogues. In this work,
an oxime was successfully used for both opening the
successfully formed the (S)-HHDP group between the O-4
and O-6 galloyl groups and provided the desired compound 24
(optimization of this solvent system is described in the next
paragraph). Protection of the hydroxyl groups of 24 with
benzyl groups, followed by removal of the allyl groups,
produced tetraol 25. Oxidation of 25 in the same solvent
system formed the 2,3-O-(S)-HHDP group. The assignment of
(S)-axial chirality of both the 4,6-O- and 2,3-O-HHDP groups
21−23
glucopyranose ring
and forming the C-glycosidic bond
as an electrophile (Scheme 2c). This method led to the
efficient synthesis of (1R)-1 along with complete control of the
configuration at C-1 to provide the desired (1R)-isomer as a
single diastereomer.
The key intermediate 28 was synthesized from a known diol
was reliable on the basis of the results previously obtained by
24
19,27−31
2
0 (Scheme 3). Acylation of 20 with a gallic acid derivative
three different groups.
After MOM protection of the
25
protected by allyl and benzyl groups yielded 21. Removal of
the benzylidene acetal from 21, followed by the introduction of
two gallic acid derivatives protected with benzyl and
remaining hydroxyl groups, 26 was obtained in 85% yield. N-
Bromosuccinimide (NBS) oxidation of the ethylthio group in
26 generated the corresponding sulfoxides as a mixture of
diastereomers, which were hydrolyzed using trifluoromethane-
sulfonic (triflic) anhydride in the presence of 2,6-lutidine,
26
methoxymethyl (MOM) groups, furnished 22. Removal of
the MOM groups from 22 gave 23. The oxidation of 23 with a
26
32
complex derived from copper(II) chloride and butylamine in
a 1/1 (v/v) mixture of methanol and dichloromethane
transforming the sulfoxides to pyranose 27. Treatment of 27
with O-benzylhydroxylamine hydrochloride in the presence of
C
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pyridine opened the pyranose ring to furnish the correspond-
ing benzyloxime. Subsequently, galloylation of the resulting
hydroxy group at C-5 afforded the desired key intermediate 28
as a 92/8 mixture of geometrical isomers.
In the intramolecular oxidative coupling of the galloyl motifs
in 23 (Scheme 3), the use of a mixture of methanol and
dichloromethane (1/1, v/v) as the solvent system was essential
to obtain 24 in satisfactory yield. The reaction employing the
mixed solvent system provided 24 in 80% yield when using 23
on a 4.06 g scale. The yield of the reaction was retained when
the amount of 23 was increased to 11.3 and 20.8 g (89% and
temperature, concentration, and amount of water contami-
nation. Therefore, all of the phenolic hydroxy groups of the
synthesized (1R)-1 were methylated to obtain pentadecameth-
yl ether 30 (Scheme 3), which eliminated the chemical shift
1
variability, and gave a H NMR spectrum that was identical to
that reported for 30 derived from natural casuarinin [(1R)-1]
(details in SI-02). Thus, we achieved the total synthesis of
(1R)-1.
In summary, the total synthesis of casuarinin [(1R)-1] was
demonstrated in this study. The novel method presented here
utilizing the benzyloxime group was sufficiently effective for
the construction of the C-glycosidic bond involving pyranose
ring opening and Friedel−Crafts-type C-glycosylation. The
complete stereoselectivity of 1-OH in the C-glycosylation step
is another significant feature of this synthesis. The proposed
synthetic route would enable the preparation of various
analogues of (1R)-1, which can contribute to detailed
structure−activity relationship studies.
7
8% yields, respectively), demonstrating stable reproducibility.
In contrast, under the standard reaction conditions using
26
methanol as the solvent, the yield of 24 was 29% and 23 was
recovered in 22% yield (details in SI-09). The use of the mixed
solvent system was also necessary for the oxidation of 25 due
to the low solubility of 25 in methanol alone.
The low reactivity at the anomeric position of 26 was
unusual (Scheme 3). Treatment of ethylthio glycoside with
NBS in the presence of water commonly results in hydrolysis
ASSOCIATED CONTENT
sı Supporting Information
■
33−35
to provide the corresponding hemiacetal.
Treatment of 26
*
with NBS and water, however, gave the corresponding
sulfoxides (dr = 50/50). A deactivation process, named the
disarming effect, from the four electron-withdrawing acyl
bonds at O-2, O-3, O-4, and O-6 may be the cause of the
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00876.
Additional supporting data (PDF)
36
irregularly low reactivity. The use of m-chloroperoxybenzoic
acid also produced the corresponding sulfoxide; however, the
yield was lower than that obtained when using NBS, due to
overoxidation to sulfone. An attempt to oxidize the ethylthio
group with a combination of N-iodosuccinimide and triflic acid
resulted in decomposition, and no reaction occurred with
silver(I) nitrate.
AUTHOR INFORMATION
Corresponding Author
■
Shinnosuke Wakamori − School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan;
orcid.org/0000-0002-0544-9486;
The final stage of the total synthesis was C-glycosylation.
The formation of the desired intramolecular carbon−carbon
bond between C-1 and the 2,3-O-HHDP group was
investigated, and the total synthesis of casuarinin [(1R)-1]
was achieved (Scheme 3). For the conversion of 28 to C-
glucoside 29, stirring 28 with 3 M hydrochloric acid in
tetrahydrofuran under reflux was optimal to obtain 29 in 76%
yield as a single diastereomer. This treatment provided a one-
pot process for the removal of the MOM groups, the release of
benzyloxyamine, and the Friedel−Crafts-type C-glycosylation.
Because the generated 1-OH was at a benzylic position, its
configuration was considered to easily epimerize via the
formation of the corresponding carbocation under such highly
acidic conditions. Thus, the stereoselectivity of the C-
glycosylation might arise under thermodynamic control,
though the reaction mechanism has not yet been elucidated
in detail. Workup procedures, however, impacted the yield of
Email: shinnosuke1010@kwansei.ac.jp
Authors
Shintaro Matsumoto − School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
Reina Kusuki − School of Science and Technology, Kwansei
Gakuin University, Sanda, Hyogo 669-1337, Japan
Kazutada Ikeuchi − School of Science and Technology, Kwansei
Gakuin University, Sanda, Hyogo 669-1337, Japan;
orcid.org/0000-0001-5343-3502
Hidetoshi Yamada − School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan;
orcid.org/0000-0003-2272-319X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00876
Notes
2
9. Direct extraction using ethyl acetate without neutralization
The authors declare no competing financial interest.
of the reaction mixture was important for the reproducible
formation of product 29. When saturated aqueous sodium
hydrogen carbonate was used to neutralize the reaction
mixture, the yield of 29 was approximately 36−50% (details
in SI-17). Finally, (1R)-1 was synthesized by hydrogenolytic
debenzylation.
ACKNOWLEDGMENTS
■
The authors are grateful to Emeritus Prof. Shigeo Katsumura
(Kwansei Gakuin University) for his help in writing the
manuscript. The authors also express thanks to The Ministry of
Education, Culture, Sports Science and Technology of Japan
for supporting the program for the Strategic Research
Foundation at Private Universities (S1311046) and JSPS
KAKENHI (Grant JP16H01163 in Middle Molecular Strat-
egy), which partly supported this work. The authors also thank
Osaka Synthetic Chemical Laboratories, Inc., for their
provision of EDCI·HCl.
To identify the synthesized (1R)-1 with the natural product,
full methylation of the phenolic hydroxy groups was required.
1
13
The H and C NMR spectra of the synthesized (1R)-1 were
37
not identical with those reported previously (details in SI-
1). Such a trend is frequently observed in ellagitannins
0
because the NMR chemical shifts are sensitive to the
measurement conditions and often vary depending on the
D
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DEDICATION
■
†
Deceased on November 23, 2019. This paper is dedicated to
the memory of Prof. Dr. Hidetoshi Yamada.
1
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