Development of a kilogram-scale synthesis of salidroside and its analogs

Article abstract of DOI:10.1080/00397911.2010.515332

An efficient, safe, and viable process has been developed for large-scale preparation of salidroside, a natural product. The process consists of two chemical steps, which produce the salidroside on a multikilogram scale with 72% overall yield and >98% purity.A series of novel salidroside analogs were prepared according to the same method. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515332

This article was downloaded by: [University of Guelph]
On: 14 May 2012, At: 05:21
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Development of a Kilogram-Scale
Synthesis of Salidroside and Its Analogs
Tianyao Shi a , Hui Chen a , Linlin Jing a , Xueying Liu b , Xiaoli Sun a
& Ru Jiang b
a Department of Chemistry, School of Pharmacy, Fourth Military
Medical University, Xi'an, China
b Department of Medicinal Chemistry and Pharmaceutical Analysis,
School of Pharmacy, Fourth Military Medical University, Xi'an, China
Available online: 29 Jun 2011
To cite this article: Tianyao Shi, Hui Chen, Linlin Jing, Xueying Liu, Xiaoli Sun & Ru Jiang (2011):
Development of a Kilogram-Scale Synthesis of Salidroside and Its Analogs, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:17, 2594-2600
To link to this article: http://dx.doi.org/10.1080/00397911.2010.515332
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 41: 2594–2600, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515332
DEVELOPMENT OF A KILOGRAM-SCALE SYNTHESIS
OF SALIDROSIDE AND ITS ANALOGS
Tianyao Shi,1 Hui Chen,1 Linlin Jing,1 Xueying Liu,2
Xiaoli Sun,1 and Ru Jiang2
1Department of Chemistry, School of Pharmacy, Fourth Military Medical
University, Xi’an, China
2Department of Medicinal Chemistry and Pharmaceutical Analysis, School of
Pharmacy, Fourth Military Medical University, Xi’an, China
GRAPHICAL ABSTRACT
Abstract An efficient, safe, and viable process has been developed for large-scale prep-
aration of salidroside, a natural product. The process consists of two chemical steps, which
produce the salidroside on a multikilogram scale with 72% overall yield and >98% purity.
A series of novel salidroside analogs were prepared according to the same method.
Keywords Kilogramscale; salidroside; synthesis; tyrosol glycoside
INTRODUCTION
Rhodiola sachalinensis, which belongs to the family Crassulaceae and the genus
Rhodiola,[1] is a wild plant that can grow at the altitude of 1700–2500 m in the tundra
zone in adverse circumstances and extreme weather conditions. It has been used as
an adaptogen by Russian researchers because of its activity in increasing resistance
to a variety of chemical, biological, and physical stressors.[2] In recent years, Rho-
diola sachalinensis extract was supplied to astronauts, athletes, military personnel,
and tourists in high-altitude areas to enhance their ability to survive in adverse
Received February 25, 2010.
Address correspondence to Dr. Ru Jiang, Department of Medicinal Chemistry and Pharmaceutical
Analysis, School of Pharmacy, Fourth Military Medical University, No. 17, Changle West Road, Xi’an,
Shaanxi, 710032, China. E-mail: jiangru@fmmu.edu.cn
2594

SYNTHESIS OF SALIDROSIDE AND ITS ANALOGS
2595
Figure 1. Structure of salidroside (1).
environments. Salidroside (1) has been identified as the most potent ingredient in
Rhodiola sachalinensis (Fig. 1), and further studies have shown that 1 has many
pharmacological functions including anticancer, antiaging, anti-inflammatory,
oxygen-uptake enhancement, fatigue elimination, neuroprotective, hepatoprotective,
and antioxidative effects.[3–6] Recently, more attention has been focused on the study
of 1. Our ultimate goal was to develop 1 as a new clinical drug.
The most significant problem presented to us was the large-scale preparation of
1. Because the content of 1 in Rhodiola sachalinensis is very low (<1.99%), and wild
Rhodiola sachalinensis is on the edge of exhaustion because of overexploitation, a
chemical synthetic route amenable to large-scale preparation is necessary to address
initial pharmacological and toxicological requirements and fully develop the clinical
applications of 1. We report an efficient and safe preparation of 1 and its analogs on
a multikilogram scale.
Compound 1 is (4-hydroxyphenethyl)-b-D-glucopyranoside, which can be
synthesized by reaction of tyrosol (2) with 2,3,4,6-O-tetraacetyl-a-D-glucopyranosyl
bromide (3) in the presence of Ag2CO3, followed by successive deacetylation
(Scheme 1).[7] Unfortunately, the yield is very poor because of the competing reac-
tion of the phenolic hydroxyl group of 2. In 2004, Shi et al. improved the procedure
by using nonproton solvent methylene chloride, which was still unfavorable because
of the use of a chlorinated reaction solvent.[8] To improve the selectivity, several
research groups tried to protect the phenolic hydroxyl group using benzyl or allylic
Scheme 1. Reported synthetic scheme of 1.

2596
T. SHI ET AL.
Scheme 2. Scalable preparation of 1.
groups and managed to obtain the desired product in good yield.[9,10] However, these
methods were deemed undesirable for scale-up owing to the multistep protecting and
deprotecting reactions, high cost, and dangerous reagents (e.g., LiAlH4, Grignard
reagent, and ethylene oxide). Currently, there is no report of scalable synthesis of 1.
Having already used an acetyl group as the protecting group for the hydroxyl
group of 3, we attempted to selectively protect the phenolic hydroxyl group of 2 with
an acetyl group, which could then be removed together with the acetyl group of 3.
With this improvement, the preparation of 1 was condensed to a two-step synthesis.
The route is shown in Scheme 2.
The first step was the selective acetylation of 2, which already had been
reported in some literature studies.[11–13] In our initial studies, we performed the
acetylation reaction according to the literature.[11] Acetic anhydride was gradually
added to the isopropanol solution of 2 containing saturated aqueous NaOH for
1 h with the pH maintained at 7–8. The phenol hydroxyl group could be ionized
in the weak alkali reaction medium, but the alcohol hydroxyl could not. Hence,
the 2-(4-acetoxyphenyl)ethanol (5) was obtained in 78% yield. However, the exother-
mic nature of this step presented a significant challenge to scale-up preparation. To
avoid a sudden exotherm during the reaction, the addition rate of acetic anhydride
was controlled, and the reaction temperature was lowered to 0 ꢀC by a cooling bath.
In practice, with the reaction proceeding, the solution has been observed to sponta-
neously form a thick slurry, making agitation difficult and resulting in an uncon-
trolled exotherm and formation of large amounts of tyrosol diacetate. We
speculated that the formation of thick slurry was due to the NaOAc generated lar-
gely in the reaction. This problem could be solved by increasing the volume of water
in the reaction system. Taking the exothermic effect into consideration, it was better
to add ice instead of water. In fact, with the addition of ice, there was no thick slurry
during the reaction, and the reaction temperature was well controlled. After further
optimization, the reaction could proceed well in NaOH aqueous solution without
isopropanol, which meant that the reaction was carried out in aqueous media. After
completion of the reaction, the product was extracted into EtOAc. With the solvents
evaporated, the desired product 5 was obtained as a colorless oil (3.24 kg, 90% yield)
pure enough for the next step. The purity was determined by high-performance
liquid chromatography (HPLC) area (>90%).
The coupling of 5 with 3 on a pilot scale was carried out under typical reaction
conditions. Reaction of 5 and 3 occurred in the presence of Ag2CO3 and molecular
sieve powder (4A) in CH2Cl2 for 16 h at ambient temperature. After filtration and

SYNTHESIS OF SALIDROSIDE AND ITS ANALOGS
2597
Figure 2. The X-ray crystal structure of 1.
concentration, a syrupy residue was obtained. n-Hexane was slowly added to the syr-
upy residue under vigorous stirring. The precipitate obtained was collected by fil-
tration and dried in vacuo, which was deprotected directly in the MeONa=MeOH.
With extractive workup and recrystallization, 1 was isolated in 80% yield. The pro-
duct was characterized by NMR, mass spectrometry (MS), and x-ray structure
analysis (Fig. 2, Table 1), and the purity was determined by HPLC area (>98%).
Tyrosol was the main by-product.
Table 1. Crystallographic data and refinement of 1
Parameter
Value
Formula
Mr
T [K]
C
14H20O7
300.30
296(2)
˚
Wavelength [A]
Crystal system
Space group
0.71073
Orthorhombic
P 212121
a ¼ 6.0436(7), b ¼ 7.7916(8), c ¼ 30.070(3)
˚
Unit-cell dimensions [A]
V (A3)
1416.0(3)
Z
4
1.409
0.113
Density (calc.) (Mg=m3)
Absorption coefficient (mmꢁ1
F(000)
)
640
0.33 ꢂ 0.25 ꢂ 0.14
2.70–25.10
Crystal sie (mm)
h Range (ꢀ) for data collection
Reflections collected
7093
2514
Independent reflections
Data=restraints=parameters
Goodness of fit on F2
2514=0=195
1.055
Final R indices [I > 2 r(I)]
Final R indices (all data)
R1 ¼ 0.0304, wR2 ¼ 0.0732
R1 ¼ 0.0370, wR2 ¼ 0.0757

2598
T. SHI ET AL.
Figure 3. Structure of tyrosol galactoside (6).
Next, a series of novel salidroside analogs were synthesized according to the
same method. It was found that tyrosol galactoside (6) exhibited obvious antihy-
poxia, antifatigue, and antiradiation effects (Fig. 3). In particular, 6 showed excellent
protective effect against liver injury. Compound 6 has been prepared on a multikilo-
gram scale in our pilot plant according to a similar operation (70% of overall yield).
Further study on 6 is currently in progress.
In summary, an efficient and safe large-scale preparation of tyrosol glycoside
was developed. This procedure consisted of a two-step reaction starting from cheap
and readily available starting materials. In addition, neither unsafe reagents nor
complicated purification was required, and good yields were obtained. The
preparations of 1 and 6 were scaled up successfully and reliably on a multikilogram
scale in a pilot-plant facility. Good overall yields (70–72%) and purities (>98%)
were obtained.
EXPERIMENTAL
All solvents and reagents were obtained from commercial suppliers and were
1
used without further purification. H NMR and 13C NMR spectra were recorded
on a Bruker AV-300 spectrometer. HPLC analyses were performed on an Agilent
1100 liquid chromatograph equipped with an ultraviolet (UV) detector.
Preparation of 2-(4-Acetoxyphenyl)ethanol 5
Ice (15 kg) was added to a stirred solution of 2 (2.76 kg, 20 mol) in 6 M NaOH
aqueous solution (5 L). After the temperature was decreased to 0 ꢀC, acetic anhy-
dride (2.45 kg, 24 mol) was added slowly over 40 min under vigorous stirring with
the pH maintained at 7–8. The addition was exothermic, and the temperature was
no more than 10 ꢀC. The reaction mixture was stirred at this temperature for 1 h until
thin-layer chromatography (TLC), n-hexane=EtOAc 3:1) indicated that 2 had disap-
peared. The solution was extracted three times with EtOAc (3 ꢂ 20 L), and the com-
bined organic solutions were washed with brine (5 L), dried over Na2SO4, and then
concentrated in vacuo to give a colorless oil 3.24 kg at 90% yield, which is pure
1
enough for the next step. H NMR (300 MHz, CDCl3): d 2.24 (s, 3H), 2.75 (t,
J ¼ 6.6 Hz, 2H), 2.83 (s, 1H), 3.69 (t, J ¼ 6.6 Hz, 2H), 6.98 (d, J ¼ 8.1 Hz, 2H), 7.15
(d, J ¼ 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 21.0, 38.5, 63.3, 121.5, 130.0,
136.5, 149.1, 169.8.

SYNTHESIS OF SALIDROSIDE AND ITS ANALOGS
2599
Preparation of Salidroside 1
Ag2CO3 (4.11 kg, 15 mol) and molecular sieve powder (4A) (2.50 kg) were
added to a stirred solution of 5 (2.70 kg, 15 mol) in CH2Cl2 (18 L). The resulting mix-
ture was stirred for 15 min at ambient temperature, and a solution of 2,3,4,6-O-tetra-
acetyl-a -D-glucopyranosyl bromide 3 (6.60 kg, 15 mol) in CH2Cl2 (22 L) was added
slowly over 40 min under vigorous stirring. The mixture was stirred for 16 h at room
temperature. The reaction mixture was filtered, and the filtrate was washed with
saturated NaHCO3 (5 L) and brine (5 L), dried over Na2SO4, and then concentrated
to afford a syrup. n-Hexane (3.5 L) was slowly added to the syrupy residue under vig-
orous stirring. The precipitate formed was collected by filtration and dried in vacuo.
The solid was dissolved in MeOH (30 L), and MeONa (1.23 kg, 22.5 mol) was added.
The mixture was stirred at ambient temperature for about 24 h until TLC (n-hexane=
MeOH 3=1) indicated that the material had disappeared. Concentrated HCl was
added slowly to adjust the pH to 6–7. The organic layer was separated, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was recrystallized twice
from n-hexane=MeOH (5=1), giving 3.83 kg of white powder 1 (80% yield). The
purity was determined by HPLC area (>98%) (column, Inertsil ODS-3
150 ꢂ 4.6 mm, 5 mm; mobile phase, CH3CN=H2O 10=90; flow rate, 1.0 mL minꢁ1
;
1
detection, UV 275 nm). Mp 158–159 ꢀC; H NMR (300 MHz, MeOD): d 2.85(m,
2H), 3.19–3.38 (m, 4H), 3.72 (d, J ¼ 5.4 Hz, 2H), 3.87 (d, J ¼ 11 Hz, 1H), 4.06 (d,
J ¼ 7.5 Hz, 1H), 4.32 (d, J ¼ 6.1 Hz, 1H), 4.85 (s, 5H), 6.73 (d, J ¼ 6.5 Hz, 2H),
7.08 (d, J ¼ 6.5 Hz, 2H); 13C NMR (75 MHz, MeOD): d 35.0, 61.4, 70.3, 70.7,
73.7, 76.5, 76.7, 103.0, 114.8, 129.4, 129.6, 155.4; MS (ESI) m=z 323.1098 [M þ Na]þ.
Preparation of Tyrosol Galactoside 6
Compound 6 was synthesized according to the preparation of 1, using 2,3,4,6-
O-tetraacetyl-a -galactopyranosyl bromide 7 in place of 3. The desired compound
was obtained as a white powder at 3.60 kg at 78% yield. The purity was determined
by HPLC area (>98%) (column, Inertsil ODS-3 150 ꢂ 4.6 mm, 5 mm; mobile phase,
CH3CN=H2O 7=93; flow rate, 1.2 mL minꢁ1; detection, UV 275 nm). Mp 161–
1
162 ꢀC; H NMR (300 MHz, MeOD): d 2.76 (m, 2H), 3.10–3.33 (m, 4H), 3.55 (m,
1H), 3.75 (d, J ¼ 12.0 Hz, 2H), 3.96 (d, J ¼ 7.2 Hz, 1H), 4.30 (d, J ¼ 6.1 Hz, 1H),
6.72 (d, J ¼ 6.6 Hz, 2H), 7.09 (d, J ¼ 6.6 Hz, 2H); 13C NMR (75 MHz, MeOD):
35.0, 61.1, 70.7, 71.2, 73.6, 75.1, 75.2, 103.3, 114.9, 129.5, 129.6, 155.3.
ACKNOWLEDGMENT
This work was financially supported by the National Natural Science
Foundation of China (Nos. 20972189, 30901883, and 20802091).
REFERENCES
1. Jun, F. K.; Ohba, H. Rhodiola sachalinensis. Flora China. 2001, 8, 202.
2. Kelly, G. S. Rhodiola rosea: A possible plant adaptogen. Altern Med. Rev. 2001, 6, 29.

2600
T. SHI ET AL.
3. Linh, P. T.; Kim, Y. H.; Hong, S. P.; Jian, J. J.; Kang, J. S. Quantitative determination of
salidroside and tyrosol from the underground part of Rhodiola rosea by high-performance
liquid chromatography. Arch. Pharm. Res. 2000, 23, 349.
4. Lee, M. W. Y.; Lee, A.; Park, H. M.; Toh, S. H.; Lee, E. J.; Jang, H. D. Antioxidative
phenolic compounds from the roots of Rhodiola sachalinensis A. Bor. Arch. Pharm.
Res. 2000, 23, 455.
5. Darbinyan, V.; Kteyan, A.; Panossian, A.; Gabrielian, E.; Wikman, G.; Wagner, H.
Rhodiola rosea in stress-induced fatigue—A double blind cross-over study of a standar-
dized extract SHR-5 with a repeated lowdose regimen on the mental performance of
healthy physicians during night duty. Phytomedicine 2000, 7, 365.
6. Agnieszka, M.; Hoser, G.; Furmanowa, M.; Urbanska, N.; Pietrosiuk, A.; Zobel, A.;
Mieczyslaw, K. Antiproliferative and antimitotic effect, S phase accumulation and induc-
tion of apoptosis and necrosis after treatment of extract from Rhodiola rosea rhizomes on
HL-60 cells. J. Ethnopharmacol. 2006, 103, 43.
7. Troshchenko, J. Synthesis of glycoside of 2-(p-hydroxy–phenyl)-ethanol(tyrosol). Khim.
Prir. Soedin 1969, 5, 256.
8. Shi, L. F.; Cai, Z.; Yao, B. Preparation of salidroside derivatives as antioxidants. Faming
Zhuanli Shenqing Gongkai Shuomingshu. 2004; CN Patent 1475492 A 20040218.
9. Li, G. Q.; Li, C. Synthesis of 2-(N-arylaminomethyl)-5-(E) pentylidene cyclopentanoe
derivatives and studies on their anti-inflammatory activity. Chin. J. Med. Chem. 1996,
2, 136.
10. Zhang, S. Q.; Shang, G. W.; Li, Z. J.; Wang, A. B.; Cai, M. S. A new approach to
synthesis of solidroside. Chin. J. Med. Chem. 1997, 4, 256.
11. Srivastava, V.; Tandon, A.; Ray, S. Convenient and selective acetylations of phenols,
amines, and alcohols. Synth. Commun. 1992, 18, 2703.
12. Paradisi, M. P.; Zecchini, G. P.; Torrini, I. Selective acylations of aminophenols and
hydroxyalkylphenols with 1-acetyl-v-triazolo=_4,-5-b=pyridine. Tetrahedron Lett. 1986,
27(41), 5029–5032.
13. Zhao, X. G.; Cammidge, A. N.; Horwell, D. C. Dendroid peptide structural mimetics
of x-conotoxin MVIIA based on a 2(1H)-quinolinone core. Tetrahedron 2000, 56,
5169–5175.