Total syntheses of schizandriside, saracoside and (±)-isolariciresinol with antioxidant activities

Article abstract of DOI:10.1007/s11418-018-1198-6

Lignans are widely distributed in plants and exhibit significant pharmacological effects, including anti-tumor and antioxidative activities. Here, we describe the total synthesis of schizandriside (1), a compound we previously isolated from Saraca asoca b

Full text of DOI:10.1007/s11418-018-1198-6

Journal of Natural Medicines
https://doi.org/10.1007/s11418-018-1198-6
ORIGINAL PAPER
Total syntheses of schizandriside, saracoside and ( )‑isolariciresinol
with antioxidant activities
Mana Sampei1 · Midori A. Arai1 · Masami Ishibashi1
Received: 7 February 2018 / Accepted: 27 February 2018
© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018
Abstract
Lignans are widely distributed in plants and exhibit signifcant pharmacological efects, including anti-tumor and antioxida-
tive activities. Here, we describe the total synthesis of schizandriside (1), a compound we previously isolated from Saraca
asoca by monitoring antioxidative activity using the 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Starting from a
tandem Michael-aldol reaction, the lignan skeleton was synthesized in 6 steps, including a cyclization step. To determine the
stereochemistry of 1, we synthesized the natural product ( )-isolariciresinol (18) from alcohol 17. Comparison of the spectral
data showed good agreement. Glycosylation was investigated using four diferent glycosyl donors. Only the Koenigs–Knorr
condition using silver trifuoromethanesulfonate with 1,1,3,3-tetramethylurea provided the glycosylated product. Deprotection
and purifcation using reverse-phase high-performance liquid chromatography gave schizandriside (1) and its diastereomer
saracoside (2). Synthesized 1, 2 and 18 showed antioxidant activity with IC50 =34.4, 28.8, 53.0 μM, respectively.
Keywords Lignan glycoside · Antioxidant activity · Total synthesis · Natural product
Introduction
reaction and the Michael-aldol reaction. However, the syn-
thesis of schizandriside (1) or lignan glycosides substituted
on C9 has not been reported to date despite schizandriside
(1) being frst isolated in 1979 [4]. Although lignan gly-
cosides can be isolated in adequate amounts for biological
assays, a synthetic approach is required for evaluating bio-
activity systematically. Here, we report the total synthesis
of schizandriside (1) and saracoside (2) and the evaluation
of their antioxidant activities.
Lignans are widely distributed in plants, and new related
compounds continue to be isolated [1]. Although the bio-
logical functions of lignans remain unclear, some signifcant
pharmacological efects have been revealed, including anti-
tumor and antioxidative activities. We previously isolated
schizandriside (1) from Saraca asoca by monitoring anti-
oxidative activity determined by the 1,1-diphenyl-2-picryl-
hydrazyl (DPPH) radical scavenging assay [2].
The attractive biological activities of aryltetralin lignan
lactones have long resulted in signifcant eforts towards
their synthesis. Two major approaches can be used to syn-
thesize the aryltetralin lactone skeleton [3]—the Diels–Alder
Results and discussion
Our retrosynthetic analysis is based on the Michael-aldol
reaction, which is the most common approach for such syn-
theses (Scheme 1). We planned to perform the glycosylation
reaction last to facilitate the synthesis of derivatives on C9.
Glycoside precursor 4 was synthesized from alcohol 5 via
a cyclization step.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11418-018-1198-6) contains
supplementary material, which is available to authorized users.
Starting from known compounds lactone 9, dithiane 10
[5], and aldehyde 11 [6], the Michael-aldol reaction gave
alcohol 12 in 65% yield (dr = 1.8:1, determined by NMR,
Scheme 2). We performed the next reaction using a dias-
tereomeric mixture. Reaction using NaBH4 and NiBr2 [7,
8] reductively cleaved the dithiane substituent successfully
* Midori A. Arai
midori_arai@chiba-u.jp
* Masami Ishibashi
mish@chiba-u.jp
1
Graduate School of Pharmaceutical Sciences, Chiba
University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
Vol.:(0123456789)
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Journal of Natural Medicines
C8 but were unable to establish successful reaction condi-
tions. Methanolysis with triethylamine (Et3N) followed by
tert-butyldimethylsilyl (TBS) protection gave 15. Partial
lactonization occurred during the protection step to give
16. However, lactone 16, as well as diol lactone 14, can
be converted to 15 by following the same synthesis steps.
Reduction by LiAlH4 caused removal of the TBS group and
thus diisobutylaluminium hydride was used to obtain alcohol
17. To determine the stereochemistry, we removed the TBS
groups from alcohol 17 to give aglycon 18, which is the
1
natural product ( )-isolariciresinol. The H and 13C NMR
spectra of aglycon 18 showed good agreement with reported
values [9], indicating that the stereochemistry of the synthe-
sized compound is correct.
For the glycosyl donor, we initially planned to use ace-
tate to protect the hydroxy groups of d-(+)-xylose 19 but
the acetyl group migrated to alcohol 17. Therefore, the
protective group was changed to the benzoyl group (Bz,
Scheme 3). After protection with benzoyl chloride, 20 was
converted to bromide 21 and thioglycoside 22. Alcohol 23
was synthesized from bromide 21. Reactions to give trichlo-
roacetimidate 24 and fuoride 25 resulted in moderate yields.
We investigated glycosylation conditions using four dif-
ferent glycosyl donors. Trials without molecular sieves 4A
gave complex mixtures. Use of the boron trifuoride die-
thyl ether complex or trimethylsilyl trifuoromethanesul-
fonate as an activator for glycosyl donors 22, 24, and 25
caused removal of the TBS groups (Scheme 4). Only the
Scheme 1 Retrosynthetic analysis of schizandriside (1)
Scheme 2 Synthesis of alcohol 17 and ( )-isolariciresinol 18. DIBAL
diisobutylaluminium hydride, TBAF tetra-n-butylammonium fuoride
and removed a benzyl group. Cyclization under acidic con-
ditions gave 13 as a single diastereomer, with diol 14 as a
byproduct. Next, we attempted acid-catalyzed methanoly-
sis of the lactone unit while preventing isomerization at
Scheme 3 Synthesis of glycosyl donors. DBU 1,8-diazabicy-
clo[5.4.0]undec-7-ene
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Journal of Natural Medicines
Scheme 4 Attempted glycosylation with glycosyl donor 22, 24 and
25
Fig. 1 Evaluation of antioxidant activity using the DPPH radical
Koenigs–Knorr condition using silver trifuoromethanesul-
fonate with 1,1,3,3-tetramethylurea resulted in glycosylation
(Scheme 5). We could not separate the four possible dias-
tereomers at this point. The coupling constant indicated that
two of the major diastereomers have β glycoside linkages.
Unfortunately, the hydrolysis of benzoates 26 and 27
under basic conditions was unsuccessful. Notably, depro-
tection of the C2″ hydroxy group was difcult, probably due
to steric hindrance. Only the use of zinc acetate [10] as a
catalyst gave the desired result (Scheme 5). Since we could
not isolate the diastereomers at this step, we moved on to the
last step. After removal of the TBS groups with Et3N·3HF,
purifcation using high-performance liquid chromatography
gave schizandriside (1) and the diastereomer saracoside (2)
in 3 and 4% yield, respectively, after these three steps. The
α glycoside yields were very low, and we could not iso-
late the compounds after deprotection. All spectral data of
synthesized 1 and 2 showed good agreement with data of
the corresponding natural compound schizandriside [2] and
saracoside [11], respectively.
scavenging assay
indicating that the presence of xylose is not related to the
antioxidant activity of lignans.
In conclusion, we synthesized schizandriside (1) and two
other natural products, saracoside (2) and ( )-isolaricires-
inol (18). Synthesized 1, 2 and 18 showed antioxidant activ-
ity with IC50 =34.4, 28.8, 53.0 μM, respectively. We are cur-
rently synthesizing other derivatives.
Antioxidant assay
The antioxidant activity was evaluated according to a pre-
vious report [12]. Using a 96-well clear microplate, 10 μL
of sample-DMSO solution was placed in each microwell.
Quercetin (25 μM) was used as a positive control. DPPH-
MeOH solution (190 μL, final concentration of DPPH:
200 μM) was added to each microwell and the microplate
was then shaken for 30 min at room temperature using a
microplate mixer. The absorbance was determined at 492 nm
using a microplate reader (Thermo Scientifc Multiskan FC).
Each sample was measured in triplicate and the mean result
was taken. The antioxidant activity was expressed in terms
of IC50 (μM).
We performed DPPH radical scavenging assays using 1,
2, and aglycon 18 (Fig. 1). Synthesized 1 showed higher
activity compared to the natural product, probably due to its
purity (IC50 =34.4 and 83.3 μM, respectively). Compound
2 showed activity (IC50 =28.8 μM) that was similar to that
of 1. Aglycon 18 also showed activity (IC50 = 53.0 μM),
Scheme 5 Total synthesis of schizandriside (1). TMU 1,1,3,3-tetramethylurea, THF tetrahydrofuran
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Journal of Natural Medicines
6. Zuo SJ, Li S, Yu RH, Zheng GX, Cao YX, Zhang SQ (2014)
Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent
vasodilative agents. Bioorg Med Chem Lett 24:5597–5601
7. Brown CA (1970) Catalytic hydrogenation. V. The reaction of
sodium borohydride with aqueous nickel salts. P-1 nickel bromide,
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Acknowledgements This study was supported by KAKENHI Grant
numbers 17H03992 and 15H04650, Suzuken Memorial Foundation,
Takeda Science Foundation, Astellas Foundation for Research on Meta-
bolic Disorders, the Naito Foundation, Strategic Priority Research Pro-
motion Program, Chiba University, ‘Phytochemical Plant Molecular
Sciences’, JSPS A3 Foresight Program, and a Workshop on Chirality at
Chiba University (WCCU). This work was inspired by the international
and interdisciplinary environment of the JSPS Core-to-Core Program
‘Asian Chemical Biology Initiative’.
8. Brown CA, Ahuja VK (1973) Catalytic hydrogenation. VI. The
reaction of sodium borohydride with nickel salts in ethanol solu-
tion. P-2 nickel, a highly convenient, new, selective hydrogenation
catalyst with great sensitivity to substrate structure. J Org Chem
38:2226–2230
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