Improved synthesis of gastrodin, a bioactive component of a traditional chinese medicine

Article abstract of DOI:10.2298/JSC131011026L

Highly practical, four-step synthesis of gastrodin was developed using penta- O-acetyl-β-D-glucopyranose and p-cresol as glycosyl donor and glycosyl acceptor, respectively, in 58.1% overall yield. As the initial step, the penta-O-acetyl-β-D-glucopyranose was treated with p-cresol in the presence of BF₃ ?Et₂O as catalyst to generate 4-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D- -glucopyranoside in 76.3% yield. Further, this product was subjected to radical bromination with N-bromosuccinimide (NBS) to provide 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 91% yield. Subsequently, reaction of 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside with a solution of acetone and saturated aqueous sodium bicarbonate led to 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 93% yield. Finally, global deprotection of 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O- -acetyl-β- D-glucopyranoside under Zemplen conditions furnished gastrodin in 90% yield. Compared to the previously reported methods, this protocol has the advantages of operational simplicity, chromatography-free separation, high overall yield, inexpensive and common reagents as well as less waste pollutants, rendering it an alternative suitable for industrial production.

Full text of DOI:10.2298/JSC131011026L

J. Serb. Chem. Soc. 79 (10) 1205–1212 (2014)
JSCS–4658
UDC 577.175.73+547.918+547.563.13’023+
542.913+66.094.414+66.095.12:61(510)
Original scientific paper
Improved synthesis of gastrodin, a bioactive component of a
traditional Chinese medicine
1
2
*
YU-WEN LI and CUI-LI MA
1School of Chemistry and Pharmacy, Qingdao Agricultural University, Qingdao 266109,
China and 2Affiliated Hospital, Qingdao Agricultural University, Qingdao 266109, China
(Received 11 October 2013, revised 23 March, accepted 24 March 2014)
Abstract: Highly practical, four-step synthesis of gastrodin was developed
using penta-O-acetyl-β-D-glucopyranose and p-cresol as glycosyl donor and
glycosyl acceptor, respectively, in 58.1 % overall yield. As the initial step, the
penta-O-acetyl-β-D-glucopyranose was treated with p-cresol in the presence of
BF3·Et2O as catalyst to generate 4-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-
-glucopyranoside in 76.3 % yield. Further, this product was subjected to radical
bromination with N-bromosuccinimide (NBS) to provide 4-(bromomethyl)phe-
nyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 91 % yield. Subsequently,
reaction of 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside
with a solution of acetone and saturated aqueous sodium bicarbonate led to
4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 93 %
yield. Finally, global deprotection of 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O-
-acetyl-β-D-glucopyranoside under Zemplen conditions furnished gastrodin in
90 % yield. Compared to the previously reported methods, this protocol has the
advantages of operational simplicity, chromatography-free separation, high
overall yield, inexpensive and common reagents as well as less waste pol-
lutants, rendering it an alternative suitable for industrial production.
Keyword: gastrodin; glycosylation; penta-O-acetyl-β-D-glucopyranose; radical
bromination.
INTRODUCTION
Chemically known as 4-(hydroxymethyl)phenyl β-D-glucopyranoside, gas-
trodin is believed to be an important bioactive component of the famous Chinese
herb Gastrodia elata B1, a well-known natural calcium channel blocker. Thera-
peutically, it has long been extensively used in China for the treatment of cardio-
vascular and cerebrovascular diseases, such as hypertension, stroke, migraine,
1,2
dementia and hemiplegia. In addition to its therapeutic functions in cardiovas-
cular and cerebrovascular diseases, gastrodin has comprehensive pharmaco-
*Corresponding author. E-mail: ywli@qau.edu.cn
doi: 10.2298/JSC131011026L
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1206
LI and MA
logical profiles, including hypoxia tolerance, neuroprotective and anticonvulsant
3–5
6
effect,
antioxidant and radical scavenger, protection against cardiac hyper-
7
8
trophy and fibrosis as well as an anti-myocardial ischemia effect in MI rabbits.
Recent studies have linked gastrodin with suppressing the inflammatory response
9
in septic cardiac dysfunction and stimulating anticancer immune response as
10
well as repressing transplanted H22 hepatic ascetic tumour cell growth.
11–13
Conventionally, gastrodin was extracted from G. elata flower,
which is
a time-consuming and expensive process. In addition, this preparation procedure
was challenged by the extremely low content (0.025 %) in the rhizome as well as
the ever-increasing shortage of G. elata flower due to over exploitation. To cir-
cumvent these problems associated with the extraction of gastrodin from G. elata
14
flower, a chemical synthesis of gastrodin was developed (Scheme 1), in which
2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 3 was employed as a glycosyl
donor. As shown in Scheme 1, this preparation of3 involves the employment of
bromine and red phosphorus in the presence of perchloric acid as catalyst,
thereby generating a large volume of highly toxic and harmful bromine and phos-
phorus-containing waste pollutants that are detrimental to the environment and
human health, and therefore raising additional safety concerns especially when
handling on the industrial scale.
OH
O
OAc
O
OAc
O
Ac2O/HClO4
Br2/P
p-HO-C6H5CHO
HO
HO
O
AcO
AcO
AcO
AcO
OH
CH3COCH3/NaOH
OH
AcO
OAc
Br
CHO
2
3
4
OH
O
OAc
1.H2/Raney Ni
2.NaBH4 or KBH4
NaOMe
MeOH
O
O
HO
HO
O
AcO
AcO
OH
OAc
CH2OH
CH2OH
1
5
Scheme 1. Reported synthesis of gastrodin (1).
Although many new convenient and efficient alternatives for the synthesis of
15
3 in the absence of bromine and red phosphorus are available nowadays, the
moisture and heat-labile 3 led to the subsequent glycosylation in poor yield under
the aqueous conditions. Moreover, conversion of 4-formylphenyl 2,3,4,6-tetra-O-
-acetyl-β-D-glucopyranoside 4 to 4-hydroxyphenyl 2,3,4,6-tetra-O-acetyl-β-D-
-glucopyranoside 5 by either catalytic hydrogenation over Raney Ni at high pres-
sure or chemical reduction with potassium (sodium) borohydride in methanol
confers limited value for the large scale production of gastrodin due to the use of
relatively expensive catalysts and reagents.
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HIGHLY PRACTICAL SYNTHESIS OF GASTRODIN
1207
Recently, a laboratory-scale preparation of gastrodin was realized via bio-
16–18
transformation.
Unfortunately, preparation was seriously impaired by seve-
ral drawbacks such as difficult strain development and cultivation, frequentstrain
variation, i.e., large volumes of fermentation broth, a longer reaction time and
extremely low yield, suggesting that it is still far removed from its commercial
production via the biotransformation strategy.
In this context, the development of a chemical synthesis of gastrodin super-
ior to the existing procedures is highly desired. Herein, a novel and efficient stra-
tegy for the chemical synthesis of gastrodin 1 using penta-O-acetyl-β-D-gluco-
pyranose 6 and p-cresol 12 as a glycosyl donor and glycosyl acceptor, respect-
ively, thereby avoiding many disadvantages inevitable in the previously reported
procedures, is presented. The operational simplicity, cost-effectiveness and high
overall yield of the procedure would make this new strategy suitable for the
industrial production of gastrodin.
RESULTS AND DISCUSSION
Initially, the synthesis of 1 according to Scheme 2 was attempted. Disap-
19
pointedly, treatment of 6 with 4-hydroxybenzyl acetate 10 in the presence of
BF ·Et O as catalyst led to the undesired compound 11 as a pink precipitate
3
2
instead of the desired compound 9. The suggested mechanism underlying the
formation of compound 11 is depicted in Scheme 3.
OAc
O
O
AcO
AcO
OAc
O
OAc
CH2OAc
BF3.Et2O
AcO
AcO
OAc
+
9
HO
CH2OAc
OAc
10
6
O
11
Scheme 2. Unsuccessful synthesis of gastrodin (1).
Frustrated with chemical synthesis of gastrodin 1 according to Scheme 2,
another synthetic route was attempted, as shown in Scheme 4. As the first step, 6
was treated with 12 in the presence of BF ·Et O as catalyst to generate 4-methyl-
3
2
phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 7 using a similar method as
20
that described in the literature, with some modifications, i.e., the glycosylation
was performed using BF ·Et O alone as catalyst instead of the BF ·Et O–Et N
3
2
3
2
3
combination and the time for the glycosylation was much shorter than in the
reference. Additionally, product 7 was purified by crystallization from ethanol in
76.3 % yield and confirmed to be the β anomer by the coupling constant (J
=
1,2
1
= 7.2 Hz) calculated from the H-NMR spectrum of 7 (Supplementary material to
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1208
LI and MA
this paper). Subsequently, radical bromination of 7 was accomplished through
reaction with N-bromosuccinimide (NBS) at 67 °C in the presence of azodiiso-
butyronitrile (AIBN) or benzoyl peroxide (BPO, dibenzoyl peroxide) as initiator.
At first, CCl was selected as the reaction solvent for the radical bromination of
4
7, but the reaction did not proceed at all irrespective of whether AIBN or BPO
was used as the initiator. This indicates that the choice of the reaction solvent is of
crucial importance for the successful synthesis of 4-(bromomethyl)phenyl 2,3,4,6-
-tetra-O-acetyl-β-D-glucopyranoside 8.
Scheme 3. Plausible mechanism for the formation of 11.
OAc
OAc
BF3.Et2O
CH2Cl2
O
NBS/AIBN
PhCl
AcO
AcO
O
O
AcO
AcO
OAc
+
HO
CH3
OAc
OAc
CH3
7
6
12
OAc
OAc
O
O
AcO
AcO
NaOMe
MeOH
O
H2O/CH3COCH3
NaHCO3
AcO
AcO
O
OAc
OAc
CH2Br
8
CH2OH
5
OH
O
HO
HO
O
OH
CH2OH
1
Scheme 4. Practical synthesis of gastrodin (1).
To this end, a solvent screening was conducted among solvents commonly
used in the radical bromination reaction, including CCl , n-hexane, cyclohexane,
4
benzene, CHCl and chlorobenzene, to determine the best solvent with respect to
3
reaction yield. As a result, chlorobenzene was found to be the optimal one. Addi-
tionally, to test if the mole ratio of NBS to 7 and manner of NBS addition could
affect the yield of 8, a mole ratio titration was conducted and it was found that a
molar ratio of NBS to 7 of 1.2:1 and the portion-wise addition of NBS gave the
highest yield, presumably because it could significantly prevent the formation of
the dibrominated side-product. Under these circumstances, 8 was obtained by
reaction of 7 with NBS in 91% yield (the highest). Theoretically, the formation
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HIGHLY PRACTICAL SYNTHESIS OF GASTRODIN
1209
of gastrodin 1 is achievable via direct hydrolysis of 8 under strong basic condi-
tions, but separation of gastrodin 1 by extraction from aqueous mixture is diffi-
cult practice due to its strong hydrophilicity and insolubility in water-immiscible
organic solvents. Consequently, a selective hydrolysis of 8 into 5 is advisable.
Therefore, interaction of 8 with a mixture of acetone and saturated aqueous
sodium bicarbonate solution at 50 °C gave rise to product 5. Of special note is
that the volume ratio of acetone to saturated aqueous sodium bicarbonate affects
the reaction rate and yield. To determine the optimal ratio, a titration was per-
formed and the results showed that a volume ratio of 4:1 of acetone to saturated
aqueous sodium bicarbonate solution gave the best yield (93 %) after the usual
aqueous work-up. Finally, global deprotection of 5 under Zemplen conditions
(NaOMe/MeOH system) followed by recrystallization from methanol–chloro-
form (1:8, V/V) furnished gastrodin (1) as white crystals in 90 % yield.
EXPERIMENTAL
Materials and methods
Penta-O-acetyl-β-D-glucopyranose, p-cresol, BF3·Et2O, NBS and AIBN were obtained
from Sigma–Aldrich. Sodium methoxide was obtained from the Qingdao Justness Reagent
Co. (China). All solvents were of reagent grade and used without further purification unless
otherwise stated and deionised water was used. CH2Cl2 was dried with CaH2 under reflux and
freshly distilled prior to use.
Instrumentation
1
All the synthesized compounds were confirmed by spectral methods, H-NMR and 13C-
-NMR spectroscopy and HRMS (ESI). The 1H-NMR and 13C-NMR spectra were acquired on
a Bruker Avance III400 spectrometer, operating at 400 MHz for protons and 100 MHz for
1
carbons. 2D NMR techniques (1H–1H COSY, H–13C HSQC) were used for full assignment
of the spectra. Thin layer chromatography was performed on silica gel plates (GF254, Qing-
dao Haiyang Chemical Plant, China), and detection was effected by UV irradiation and sub-
sequent charring with 10 % sulphuric acid in ethanol followed by heating. The melting points
were determined with a digital melting point apparatus (WRS-1B) without correction. The
optical rotations were measured with JASCO P1030 polarimeter.
Physical, analytic and spectral data are given in the Supplementary material to this paper.
Synthesis of 4-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7). To a stirred
solution of p-cresol (12, 27.0 g, 0.25 mol) and penta-O-acetyl-β-D-glucopyranose (6, 65.0 g,
0.16 mol) in 200 mL dry CH2Cl2 was added dropwise a solution of BF3·Et2O (0.25 mol, 29.8
mL) in 30 mL dry CH2Cl2 at 0 °C within 1 h. The reaction mixture was then stirred for 2 h at
room temperature, neutralized with saturated aqueous sodium bicarbonate (200 mL) and
extracted with CH2Cl2 (2×100 mL). The combined organic layer was washed with saturated
aqueous NaCl and dried over anhydrous sodium sulphate. Then, the filtrate was concentrated
under reduced pressure to give yellowish solid crude product that was recrystallized from 95 %
ethanol to afford the desired compound 7 as white crystals. Yield: 76.3 %.
Synthesis of 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (8). A
suspension of 4-methylphenyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7) (43.8 g, 0.1
moL) in 300 mL chlorobenzene was heated to 67 °C to obtain a clear solution followed by the
addition of AIBN (0.42 g, 0.0024 mol). To the obtained clear solution, a small portion of a
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1210
LI and MA
suspension containing NBS (21.4 g, 0.12 mol) in 100 mL of chlorobenzene was added. The
initiation of the reaction was easily indicated by orange colour and a 2 °C temperature inc-
rease in the reaction mixture. Subsequently, the remaining NBS suspension in chlorobenzene
was added portionwise within 1 h while maintaining the temperature at 64–69 °C. The reac-
tion mixture was stirred for another 1 h at 67 °C before cooling to 40 °C. The succinimide
formed in the reaction was removed by filtration and washed twice with chlorobenzene and
the chlorobenzene washings were combined with the filtrate. The combined filtrate was eva-
porated to dryness under vacuum to give the crude glucopyranoside (8), which was recryst-
allised from absolute ethanol to furnish 52.5 g of compound 8 as white needle-like crystals.
Yield: 91 %.
Synthesis of 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (5).
To a stirred solution of 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside
(8) (22.70 g, 0.05 mol) in 200 mL acetone was added 50 mL of a saturated aqueous sodium
bicarbonate solution, and then heated to 50 °C for 10 h. The reaction mixture was evaporated
under vacuum to recover the acetone solvent and the remaining aqueous solution was ext-
racted with CH2Cl2 (2×120 mL). The combined CH2Cl2 layers were washed with saturated
aqueous NaCl (100 mL) and dried over anhydrous sodium sulphate and filtered. The filtrate
was concentrated under reduced pressure to give a white solid crude product that on recryst-
allization from absolute ethanol afforded 21.12 g of the desired compound 5 as white crystals.
Yield: 93 %.
Synthesis of 4-(hydroxymethyl)phenyl β-D-glucopyranoside (1). Sodium methoxide (200
μL, 1 M in MeOH) was added to a solution of 5 (9.92 g, 0.020 mol) in 100 mL dry methanol
under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 h
followed by neutralization with Amberlite IR 120(H+). Then the reaction mixture was filtered,
and the resulting filtrate was evaporated to dryness under vacuum. Finally, recrystallization of
the crude product from methanol–chloroform (1:8, V/V) yielded 5.21 g of the desired com-
pound 1 as white crystals. Yield: 90 %
CONCLUSIONS
In summary, a novel efficient, and practical protocol for gastrodin synthesis
in four sequential chemical steps was developed, in which penta-O-acetyl-β-D-
-glucopyranose was used as the glycosyl donor instead of 2,3,4,6-tetra-O-acetyl-
-α-D-glucopyranosyl bromide, in an overall yield of 58.1 %. Moreover, the pre-
sented protocol has the advantages over previous ones in terms of operational
simplicity, commercially available and inexpensive reagents, easy separation and
purification procedure dispensing with tedious and laborious chromatography,
which render this protocol possibly suitable for the commercial production of
gastrodin.
SUPPLEMENTARY MATERIAL
Physical, analytic and spectral data are available electronically from http://
//www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgments. This work was supported by a grant from the Natural Science Found-
ation of Shandong Province (No. ZR2011BL003) and a grant from the Start-up Foundation of
high talents in Qingdao Agricultural University, Qingdao, P. R.China (No. 630708).
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HIGHLY PRACTICAL SYNTHESIS OF GASTRODIN
1211
И З В О Д
УНАПРЕЂЕНА СИНТЕЗА ГАСТРОДИНА, БИОЛОШКИ АКТИВНЕ СУПСТАНЦЕ ИЗ
ТРАДИЦИОНАЛНЕ КИНЕСКЕ МЕДИЦИНЕ
YU-WEN LI1 и CU-LI MA2
1
2
School of Chemistry and Pharmacy, Qingdao Agricultural University, Qingdao 266109, China и Affiliated
Hospital, Qingdao Agricultural University, Qingdao 266109, China
Развијен је практичан поступак синтезе гастродина, употребом пента-O-ацетил-β-
-D-глукопиранозе и p-крезола као гликозил донора и акцептора, редом, у четири реак-
циона корака у укупном приносу од 58 %. Реакцијом између пента-O-ацетил-β-D-глуко-
пиранозе и p-крезола у присуству BF3·Et2O као катализатора добијен је (4-метилфенил)-
-2,3,4,6-тетра-O-ацетил-β-D-глукопиранозид у приносу од 76,3 %. Производ је бромован
помоћу NBS и добијен је [4-(бромметил)фенил]-2,3,4,6-тетра-O-ацетил-β-D-глукопира-
нозид (принос 91 %) који је помоћу засићеног воденог раствора натријум-бикарбоната,
реакцијом у ацетону, преведен у [4-(хидроксиметил)фенил]-2,3,4,6-тетра-O-ацетил-β-D-
-глукопиранозид (принос 93 %). Даљом реакцијом под Земпленовим условима добијен
је гастродин (принос 90 %). У поређењу са раније описаним поступцима, нов протокол
је једноставнији, омогућава лакше пречишћавање компоненти хроматографијом, висок
укупан принос, употребу приступачних реагенаса, даје мање опасних отпадних компо-
ненти и погодан је за индустријску производњу.
(Примљено 11. октобра 2013, ревидирано 23. марта, прихваћено 24. марта 2014)
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