An effective and convenient synthesis of cordycepin from adenosine

Article abstract of DOI:10.1007/s11696-017-0266-9

Cordycepin is a purine nucleoside analog with potent and diverse biological activities. Herein, we designed two methods to synthesize cordycepin. One method mainly converted the 3′-OH group into an iodide group and further dehalogenation to yield the final product. Although this method presented a short synthetic procedure, the synthesis had a low overall yield, resulting in only 13.5% overall yield. To improve the overall yield of cordycepin, another synthetic route was studied, which consisted of four individual steps: (1) 5′-OH protection (2) esterification (3) -O-tosyl (-OTs) group removal (4) deprotection. The key step in the synthetic method involved the conversion of 5′-O-triphenylmethyladenosine to 3′-O-tosyl-5′-O-triphenylmethyladenosine, using LiAlH₄ as reducing agent. The main advantages of this route were an acceptable total product yield and the commercial availability of all starting materials. The optimal reaction conditions for each step of the route were identified. The overall yield of cordycepin obtained from adenosine as the starting material was 36%.

Full text of DOI:10.1007/s11696-017-0266-9

Chem. Pap.
DOI 10.1007/s11696-017-0266-9
ORIGINAL PAPER
An effective and convenient synthesis of cordycepin
from adenosine
1
1
1
1
1
•
Shen Huang
Jiangfeng Xu
•
Hui Liu
Yuwei Hu
•
Yanhua Sun
1
•
Jian Chen
Zhiwei Deng
•
Xiufang Li
1
1
1
1
•
•
Yuqing Li
•
•
Shian Zhong
Received: 18 May 2017 / Accepted: 3 August 2017
Ó Institute of Chemistry, Slovak Academy of Sciences 2017
Abstract Cordycepin is a purine nucleoside analog with
potent and diverse biological activities. Herein, we
designed two methods to synthesize cordycepin. One
Introduction
A large number of medicinal fungi are currently being used
in various health care applications as well as in disease
prevention and treatment. The Chinese fungus Dong-
Chong-Xia-Cao, which translates to the Latin technical
term Cordyceps sinensis, is an entomogenous fungus that
grows on the larvae or pupae of insects. The medicinal
Cordyceps species exhibits various clinical health effects.
In traditional Chinese medicine, the alcoholic extracts of
Cordyceps species have been used for thousands of years as
a tonic to reach longevity and vitality (Zhou et al. 2008).
As early as 1950, a nucleoside substance, namely cordy-
cepin, was isolated from the original liquid of Cordyceps
militaris by Cunningham et al. (1950). Shortly thereafter,
cordycepin has been shown to be the main component of
Cordyceps sinensis (Bentley et al. 1951).
0
method mainly converted the 3 -OH group into an iodide
group and further dehalogenation to yield the final product.
Although this method presented a short synthetic proce-
dure, the synthesis had a low overall yield, resulting in only
1
3.5% overall yield. To improve the overall yield of
cordycepin, another synthetic route was studied, which
0
consisted of four individual steps: (1) 5 -OH protection (2)
esterification (3) -O-tosyl (-OTs) group removal (4)
deprotection. The key step in the synthetic method
0
involved the conversion of 5 -O-triphenylmethyladenosine
0
0
to 3 -O-tosyl-5 -O-triphenylmethyladenosine, using LiAlH
4
as reducing agent. The main advantages of this route were
an acceptable total product yield and the commercial
availability of all starting materials. The optimal reaction
conditions for each step of the route were identified. The
overall yield of cordycepin obtained from adenosine as the
starting material was 36%.
Cordycepin (compound 1, Fig. 1), with the systematic
0
IUPAC name 3 -deoxyadenosine or 9-(3-deoxy-b-D-ribo-
furanosyl)adenine, represents a nucleoside analogue that
proves to be structurally similar to adenosine, except for
0
Keywords Adenosine Á Deoxyadenosine Á Cordycepin Á
the lack of a 3 -hydroxyl group. Therefore, it has been
Synthesis
shown to competitively inhibit the processes of synthesis
and metabolism of DNA and RNA (Holbein et al. 2009;
Tuli et al. 2013) and may further interfere with the activity
of adenosine deaminase (Vodnala et al. 2013) (ADA) and
the mTOR signaling pathway (Wong et al. 2010). There-
fore, cordycepin exhibits a variety of pharmacological
activities including immunological (Zhou et al. 2002),
anticancer (Hunter et al. 2008; Noh et al. 2010), antioxi-
dant, anti-inflammatory (Rao et al. 2010), anti-microbial
Shen Huang and Hui Liu contributed equally to this work.
Electronic supplementary material The online version of this
article (doi:10.1007/s11696-017-0266-9) contains supplementary
material, which is available to authorized users.
&
Shian Zhong
zhongshian@aliyun.com
(
Sugar and Mccaffrey 1998; Ahn et al. 2000), antiviral
M u¨ ller et al. 1991), hypolipidemic (Guo et al. 2010) and
(
1
hypoglycemic properties (Ma et al. 2015). Furthermore,
School of Chemistry and Chemical Engineering, Central
South University, Changsha 410083, China
some research groups have also shown that Cordyceps
123

Chem. Pap.
synthetic pathway of cordycepin was first reported by Todd
and Ulbricht (Todd and Ulbricht 1960) in 1960. In this
method (Scheme 1), 3 was used as a starting material. The
0
0
3
-hydroxyl group (3 -OH) was first esterified by p-ni-
trobenzenesulfonyl chloride and the obtained ester was
then reacted with sodium iodide to yield 4. Finally,
cordycepin 1 was obtained by deiodination and deprotec-
tion reactions. All materials were commercially available
at the time and the synthetic procedure was short, however,
the overall yield in the last reaction step is reported to be
only 17%, resulting in a low overall yield.
Fig. 1 Chemical structures of cordycepin (1) and adenosine (2)
McDonald and Gleason (1996) reported a route for the
0
militaris seems to be suitable for the treatment of influenza
A viral infections (Ohta et al. 2011).
synthesis of cordycepin starting from 5 to obtain the 3 -
deoxyribose derivative 6 (Scheme 2). This method repre-
sents the first total synthesis of cordycepin. However, 5
Due to the large amount of applications and over-ex-
ploitation, natural Cordyceps and cordycepin are becoming
more sparse. As a consequence, in the last 10 years the
market price of cordycepin has increased almost 20-fold,
(
synthesized from allyl alcohol, 21% yield) and TMSOTf
were not commercially available at the time, and a low
overall yield (14% total yield) was obtained.
-
1
approximately $12,000 kg in 2006 (Ni et al. 2009), with
gram quantities now sold by some suppliers at a price of
more than $2200. Therefore, artificial synthetic methods
are now being developed to produce cordycepin. In tradi-
tional procedures, cordycepin is mainly obtained by
extraction from Cordyceps militaris. However, this
extraction process is not suitable to satisfy market needs
due to the low amount of cordycepin in Cordyceps militaris
of only 2–3 mg/kg. So far, chemical synthesis has gradu-
ally replaced Cordyceps militaris extractions as a way to
produce cordycepin.
Aman et al. (2000) developed another method to pro-
duce cordycepin 1 with adenosine 2 as starting material
0
(
Scheme 3). The 3 -OH group in adenosine was first con-
0
verted into a 3 -bromo intermediate 7 by selectively pro-
and
tecting
other
hydroxyl
groups
using
2
-acetoxyisobutyryl bromide as a reagent. The target
compound cordycepin was synthesized by debromination
and deprotection reactions. In this process, cordycepin was
obtained as the main product. However, two features limit
the overall applicability of this route to cordycepin: (1)
2
-acetoxyisobutyryl bromide is no longer available from
Several semisynthetic and total synthetic methods have
been reported for the preparation of cordycepin. A
commercial sources and (2) the purification process is
complicated.
Scheme 1 Synthetic route of cordycepin reported by Todd and Ulbricht
Scheme 2 Synthetic route of cordycepin designed by McDonald
1
23

Chem. Pap.
Scheme 3 Synthetic route of
cordycepin designed by Aman
Scheme 4 Synthetic route of
cordycepin designed by
Christelle Moreau
Scheme 5 Total synthesis of
cordycepin from D-glucose 8
and D-xylose 9 designed by Li
et al. (2013)
Moreau et al. (2013) reported another method for the
0
this method, 9 and 10 were used as starting materials. The
key step in the process involved was to remove 3-hydroxyl
synthesis of cordycepin (Scheme 4). In this method, the 2 -
0
0
OH and 3 -OH group in adenosine were cyclized by tri-
group via Barton–McCombie reaction to obtain the 3 -
methyl orthoacetate. Then, the intermediate was bromi-
nated with acetyl bromide to yield 8. Finally, cordycepin
was obtained by debromination and deprotection reactions.
The overall procedure included only three steps and all
materials were commercially available. However, the yield
of the bromination step was only 29%, resulting in a low
overall yield of approximately 20%. In any case, to date
this synthetic route represents the most common synthetic
pathway used to produce cordycepin (Katayama et al.
deoxyribose derivative 11, followed by a total of eight and
seven steps, respectively, with an overall yield of 37–40%.
If further optimized, this method may be used for the large-
scale production of cordycepin.
Experimental
General information
2
006; Shiragami et al. 1992; Takamatsu et al. 2006).
Meanwhile, Li et al. (2013) have developed a total
All starting materials, reagents and solvents were of ana-
lytical reagent (AR) grade, from commercial sources, and
synthesis for the preparation of cordycepin (Scheme 5). In
123

Chem. Pap.
were used without further purification, except for
dimethylsulfoxide (DMSO). Calcium hydride (CaH2) was
added to DMSO to remove water. The mixture was stirred
at room temperature for 48 h, and anhydrous DMSO was
obtained by reduced pressure distillation. Analytical sam-
ples were obtained by column chromatographic purifica-
tion on silica gel (200–300 mesh). Nuclear magnetic
J = 5.9, 4.8 Hz, 1H), 4.42 (dd, J = 11.8, 3.8 Hz, 1H),
4.38–4.34 (m, 1H), 4.24 (dd, J = 11.8, 5.5 Hz, 1H), 2.12
1
(s, 3H), 2.05 (s, 3H), 2.02 (s, 3H). C NMR (126 MHz,
3
CDCl ) d 170.36 (–CONH–)169.60 (–COO–), 169.40 (–
3
COO–), 155.57 (6-C), 153.36 (2-C), 149.77 (4-C), 138.80
0
0
0
(8-C), 120.12 (5-C), 86.21 (4 -C), 80.25 (1 -C),77.28 (2 -C)
0
0
70.65 (5 -C), 63.13 (3 -C), 20.78 (–CH ), 20.56 (–CH ),
3
3
1
13
resonance (NMR, H NMR and C NMR) spectra were
recorded on an Avance III 500 M using tetramethylsilane
20.43 (–CH3).
0 0
Synthesis of 2 , 3 -O-isopropylideneadenosine (14)
(
TMS) as an internal standard. DMSO-d or CDCl were
6
3
used as the NMR solvents and in the case of benzotriflu-
oride as the internal standards. All reactions were moni-
tored by thin-layer chromatography and the compounds
were analyzed on TLC using UV-light for visualization.
In a 250 mL, three-neck round-bottom flask were placed
adenosine 2 (4.01 g, 15 mmol) and acetone (40 mL). Tri-
methyl orthoacetate (6 mL) was added to the reaction
Adenosine 2 was used as a starting material with a purity of
mixture upon stirring and thionyl chloride (SOCl , 3.3 mL)
2
1
9
8
1
5%. H NMR (400 MHz, DMSO-d ) d 8.36 (s, 1H, 2-H),
.14 (s, 1H, 8-H), 7.38 (s, 2H, –NH ), 5.88 (d, J = 6.2 Hz,
2
was added dropwise to the solution for acidification. After
addition of thionyl chloride, the mixture was stirred at
room temperature for another 6 h. After reaction comple-
tion, the mixture was filtered and the residue was added
into saturated sodium bicarbonate solution to adjust the pH
value to 7 or 8. After 30 min of standing, the crude product
was obtained by filtration and was dried at 50 °C in a
vacuum drying oven. Recrystallization from water afforded
6
0
0
0
H, 1 -H), 5.45 (d, J = 6.4 Hz, 1H, 2 -OH ? 5 -OH), 5.20
0
0
0
(
s, 1H, 3 -OH), 4.63–4.59 (m, 1H, 2 -H), 4.14 (s, 1H, 3 -H),
0
3
5
.98–3.95 (m, 1H, 4 -H), 3.67 (dd, J = 12.1, 3.7 Hz, 1H,
0
0
13
-H), 3.57–3.54 (m, 1H, 5 -H). C NMR (101 MHz,
DMSO) d 156.61 (6-C), 152.84 (2-C), 149.49 (4-C), 140.41
0 0 0
(
8-C), 119.81 (5-C), 88.36 (4 -C), 86.36 (1 -C), 73.88 (2 -
0
0
C), 71.14 (3 -C), 62.14 (5 -C).
pure 14 as a light yellow solid (3.23 g, 70.1%) with the
1
purity of 98.7% (HPLC). H NMR (500 MHz, DMSO-d )
6
0
0
0
0
Synthesis of N-acetyl-2 ,5 -O-diacetyl-3 -iodo-3 -
deoxyadenosine (12)
d 8.35 (s, 1H, 2-H), 8.16 (s, 1H, 8-H), 7.40 (s, 2H, –NH ),
2
0
6.13 (d, J = 3.1 Hz, 1H, 1 -H), 5.35 (dd, J = 6.2, 3.1 Hz,
0 0
1
H, 2 -H), 5.25 (s, 1H, 5 -OH), 4.97 (dd, J = 6.2, 2.5 Hz,
0 0 0
Under nitrogen atmosphere, TsOHÁH O (1.0 g) was added
1H, 3 -H), 4.23–4.21 (m, 1H, 4 -H), 3.58–3.51 (m, 2H, 5 -
1
H), 1.55 (s, 3H, –CH ), 1.33 (s, 3H, –CH ). C NMR
3 3
2
3
to a solution of adenosine 2 (2.67 g, 10 mmol) and tri-
methyl orthoacetate (4.0 mL, 30 mmol) in anhydrous
DMSO (30 mL). The reaction mixture was stirred at room
temperature for 12 h. Then, the mixture was neutralized
with a 1 M methanolic MeONa solution. Chloroform was
added to dissolve the crude product and the solution was
washed with brine until no adenosine 2 could be detected in
the organic layer as judged by TLC. The organic layer was
dried with anhydrous sodium sulfate, filtered, and con-
centrated in vacuo.
(101 MHz, DMSO) d 156.60 (6-C), 153.10 (2-C), 149.25
(4-C), 140.17 (8-C), 119.56 (5-C), 113.49 (quaternary
0
0
0
0
carbon), 90.09 (1 -C), 86.80 (4 -C), 83.67 (2 -C), 81.82 (3 -
0
C), 62.05 (5 -C), 27.54 (–CH ), 25.64 (–CH ).
3
3
0
Synthesis of 2 -O-p-toluenesulfonyladenosine (16)
Adenosine 2 (2.67 g, 10 mmol) and dibutyltin oxide
(2.99 g, 12 mmol) were added to methanol (50 mL) in a
100 mL round-bottom flask. The mixture was heated under
reflux for 2 h and was then concentrated in vacuo. Then, p-
toluenesulfonyl chloride (p-TsCl, 2.86 g, 15 mmol), 1,4-
dioxane (50 mL) and triethylamine (2 mL) were added to
the mixture. The solution was stirred at room temperature
for 24 h. After reaction completion, the mixture was
dropped slowly into methanol (25 mL) and the resulting
solid was filtered off. The solid was washed with methanol
for a total of three times and the precipitate was dried at
60 °C in a vacuum drying oven to obtain pure 16 (3.43 g,
The crude product, sodium iodide (2.25 g, 15 mmol),
and acetic acid (40 mL) were placed in a 100 mL round-
bottom flask. The reaction mixture was stirred at 50 °C for
8
h, and was then concentrated in vacuo. The crude product
was neutralized with sodium bicarbonate solution, extrac-
ted with dichloromethane (3 9 20 mL), and the organic
phases were combined, dried with anhydrous sodium sul-
fate, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel using
dichloromethane/methanol (20:1) as eluents to afford neat
compound 12 (2.17 g, 43.1%) as an orange liquid with the
1
purity of 98.6% (HPLC). H NMR (500 MHz, DMSO-d )
81.4%) as a white solid with the purity of 98.3% (HPLC).
1
H NMR (500 MHz, DMSO-d ) d 8.15 (s, 1H, 8-H), 7.97
6
6
d 8.36 (s, 1H), 8.17 (s, 1H), 7.39 (s, 1H), 6.21 (d,
J = 5.5 Hz, 1H), 6.04 (t, J = 5.7 Hz, 1H), 5.63 (dd,
(s, 1H, 2-H), 7.41 (s, 2H, Ph-H), 7.38–7.34 (m, 2H, –NH2),
0
6.98 (d, J = 8.0 Hz, 2H, Ph-H), 6.09–6.05 (m, 2H, 1 -
1
23

Chem. Pap.
0
0
0 0
(m, 1H, 2 -H), 4.34–4.30 (m, 1H, 3 -H), 4.09–4.05 (m, 1H,
H ? 5 -OH), 5.79 (dd, J = 8.6, 3.9 Hz, 1H, 3 -OH), 5.45
0
0
0
0
13
(
dd, J = 7.4, 4.9 Hz, 1H, 2 -H), 4.36–4.32 (m, 1H, 3 -H),
4 -H), 3.27–3.18 (m, 2H, 5 -H). C NMR (126 MHz,
DMSO) d 156.54 (6-C), 153.06 (2-C), 149.76 (4-C), 144.09
(Ph), 140.07 (8-C), 128.71 (Ph), 128.31 (Ph), 127.47
0 0
13
4
3
.07–4.04 (m, 1H, 4 -H), 3.67–3.62 (m, 1H, 5 -H),
0
.58–3.51 (m, 1H, 5 -H), 2.26 (s, 3H, –CH ). C NMR
3
0 0 0
0 0
73.42 (Ph C-), 70.73 (3 -C), 64.36 (5 -C).
3
(
(
(
(
126 MHz, DMSO) d 156.53 (6-C), 152.36 (2-C), 148.28
(Ph),119.66 (5-C), 88.43 (4 -C), 86.51 (1 -C), 83.33 (2 -C),
4-C), 145.42 (Ph-C), 140.28 (8-C), 131.68 (Ph-C), 129.79
0
Ph-C), 127.12 (Ph-C), 119.97 (5-C), 87.79 (4 -C), 85.33
0
0
0
0
0
0
1 -C), 79.37 (2 -C), 70.27 (3 -C), 62.03 (5 -C), 21.54 (–
Synthesis of 3 -O-tosyl-5 -O-
triphenylmethyladenosine (19)
CH3).
0
0
Synthesis of 2 -deoxyadenosine (17)
5 -O-triphenylmethyladenosine 18 (2.55 g, 5 mmol) and
anhydrous DMF (30 mL) were placed in a 100 mL round-
bottom flask. Triethylamine (10 mL) and p-toluenesulfonyl
chloride (1.91 g, 10 mmol) were added to the reaction
mixture while stirring. The reaction mixture was stirred at
30 °C for 24 h, which was sampled and showed no or very
0
Under nitrogen atmosphere, 2 -O-p-toluenesulfony-
ladenosine 16 (2.11 g, 5 mmol) and anhydrous tetrahy-
drofuran (THF, 35 mL) were placed in a 100 mL round-
bottom flask. Lithium aluminum hydride in anhydrous THF
0
(
LiAlH /THF, 1 M, 25 mL) was slowly dropped to the
4
low amounts of 5 -O-triphenylmethyladenosine 18 being
solution and the resulting mixture was stirred at 0–5 °C for
detected by TLC, and it showed two new points on the
thin-layer. Then, ethyl acetate (50 mL) was added to the
reaction mixture to dissolve the crude product and the
solution was washed with saturated salt water for three
times. The organic layer was dried with anhydrous sodium
sulfate, concentrated in vacuo to afford the crude product
19 as a yellow liquid. The crude product was purified by
flash chromatography on silica gel using dichloromethane/
methanol (40:1) as eluents to afford pure 19 (2.35 g,
4
h and was then continued to stir at room temperature for
6
h. After reaction completion, the mixture was carefully
quenched with 10 mL of methanol, concentrated in vacuo,
and recrystallization from ethanol to afford pure 17
(
(
1.06 g, 84.6%) as a white powder with the purity of 98.3%
1
HPLC). H NMR (400 MHz, DMSO-d ) d 8.34 (s, 1H,
6
8
-H), 8.13 (s, 1H, 2-H), 7.32 (s, 2H, –NH ), 6.35 (dd,
2
0
J = 7.9, 6.1 Hz, 1H, 1 -H), 5.31 (dd, J = 4.0, 1.3 Hz, 1H,
0
0
3
-OH), 5.25 (dd, J = 6.6, 4.8 Hz, 1H, 5 -OH), 4.43–4.39
0
70.7%) as a white powder with the purity of 97.5%
1
0
(
m, 1H, 3 -H), 3.90–3.87 (m, 1H, 4 -H), 3.65–3.60 (m, 1H,
(HPLC). H NMR (400 MHz, DMSO-d ) d 8.13 (s, 1H,
6
0
0
0
5
2
1
1
6
-H), 3.55–3.49 (m, 1H, 5 -H), 2.77–2.70 (m, 1H, 2 -H),
0
8-H), 7.86 (s, 1H, 2-H), 7.47 (d, J = 8.4 Hz, 2H, Ts-H),
13
.28–2.23 (m, 1H, 2 -H). C NMR (126 MHz, DMSO) d
56.56 (6-C), 152.84 (2-C), 149.34 (4-C), 140.03 (8-C),
7.39–7.35 (m, 7H, Tr-H ? –NH ), 7.32–7.25 (m, 10H, Tr-
2
H), 7.06 (d, J = 8.1 Hz, 2H, Ts-H), 6.11 (d, J = 6.0 Hz,
0 0
0
0
0
19.72 (5-C), 88.46 (4 -C), 84.42 (1 -C), 71.45 (3 -C),
0
1H, 1 -H), 6.06 (d, J = 5.9 Hz, 1H, 2 -OH), 5.75 (d,
0 0
J = 6.2 Hz, 1H, 2 -H), 4.55–4.51 (m, 1H, 3 -H), 4.15–4.11
0
2.37 (5 -C), 39.44 (2 -C).
0
0
(
m, 1H, 4 -H), 3.33 (dd, J = 10.4, 4.3 Hz, 1H, 5 -H), 3.17
0
0
13
(dd, J = 10.5, 5.0 Hz, 1H, 5 -H), 2.28 (s, 3H, –CH ). C
Synthesis of 5 -O-triphenylmethyladenosine (18)
3
NMR (101 MHz, DMSO) d 156.36 (6-C), 152.66 (2-C),
148.90 (4-C), 145.48 (Ph), 143.93 (Ph), 140.36 (8-C),
132.11 (Ph), 129.89 (Ph), 128.68 (Ph), 128.35 (Ph), 127.54
In a 100 mL round-bottom flask, adenosine 2 (1.34 g,
mmol) and anhydrous N,N-dimethylformamide (30 mL)
5
0
0
was placed. Triphenylmethyl chloride (4.20 g, 15 mmol)
and triethylamine (10 mL) were added to the reaction
mixture while upon stirring at 45 °C for 24 h. Ethyl acetate
(Ph), 127.36 (Ph), 119.64 (5-C), 86.62 (4 -C), 85.32 (1 -C),
0
0
0
84.19 (Ph C-), 79.11 (2 -C), 69.30 (3 -C), 63.35 (5 -C),
3
21.55 (–CH3).
(
50 mL) was added to the reaction mixture to dissolve the
0
0
crude product and washed with saturated salt water. The
organic layer was dried with anhydrous sodium sulfate and
concentrated in vacuo to afford the crude product 18 as an
orange liquid. The crude product was purified by flash
chromatography on silica gel using dichloromethane/
methanol (30:1) as eluents to afford pure 18 (2.16 g,
Synthesis of 5 -O-triphenylmethyl-3 -deoxyadenosine
(20)
0
0
3 -O-tosyl-5 -O-triphenylmethyladenosine 19 (3.32 g,
5 mmol) and THF (30 mL) were placed in a 100 mL
round-bottom flask. Lithium aluminum hydride in anhy-
7
5.0%) as a light yellow solid with the purity of 97.9%
1
drous THF (LiAlH /THF, 1 M, 25 mL) was slowly drop-
4
(
HPLC). H NMR (400 MHz, DMSO-d ) d 8.26 (s, 1H,
ped to the solution and the resulting mixture was stirred at
0–5 °C for 4 h. After reaction completion, the reaction
mixture was kept standing until the temperature reached
room temperature. Then, the mixture was carefully
6
2
-H), 8.10 (s, 1H, 8-H), 7.38–7.26 (m, 17H, Ph-H ? –
0
NH ), 5.93 (d, J = 4.5 Hz, 1H, 1 -H), 5.56 (d, J = 5.7 Hz,
2
0
0
1
H, 2 -OH), 5.23 (d, J = 5.9 Hz, 1H, 3 -OH), 4.72–4.68
123

Chem. Pap.
quenched with 10 mL methanol. Ethyl acetate (50 mL)
was added to the reaction mixture to dissolve the crude
product and the solution was washed with brine for three
times. The organic layer was dried with anhydrous sodium
sulfate, and was concentrated in vacuo to afford the crude
product 20 as a light yellow liquid with the purity of 94.6%
Compound 13 (56 mg, 4.8%) was obtained as a white
1
solid. H NMR (500 MHz, DMSO-d ) d 8.35 (s, 1H, 8-H),
6
8.13 (s, 1H, 2-H), 7.25 (s, 2H, –NH ), 6.22 (dd, J = 5.9,
2
0
4.7 Hz, 1H, 1 -H), 5.06 (t, J = 5.6 Hz, 1H, OH), 4.14–4.09
0
0
(m, 1H, 4 -H), 3.66–3.61 (m, 1H, 5 -H), 3.53–3.49 (m, 1H,
0
0
0
5 -H), 2.43–2.39 (m, 2H, 3 -H), 2.09–2.02 (m, 2H, 2 -
1
3
(
HPLC). The crude product was purified by flash chro-
matography on silica gel using dichloromethane/methanol
60:1) as eluents to afford pure 20 (1.98 g, 75.3%) as a
H). C NMR (126 MHz, DMSO) d 156.46 (6-C), 152.83
0
(2-C), 149.27 (4-C), 139.46 (8-C), 119.56 (5-C), 84.88 (1 -
0
0
0
0
(
C), 82.12 (4 -C), 63.41 (5 -C), 32.18 (3 -C), 26.18 (2 -C).
1
lightly yellow powder. H NMR (500 MHz, DMSO-d ) d
6
8
.24 (s, 1H, 8-H), 8.07 (s, 1H, 2-H), 7.36–7.32 (m, 6H, Tr-
Method B
H ? –NH ), 7.30–7.22 (m, 11H, Tr-H), 6.38–6.34 (m, 1H,
2
0
0
0
0
1
4
-H), 5.38 (d, J = 4.5 Hz, 1H, 2 -OH), 4.48 (dd, J = 6.1,
0
5 -O-triphenylmethyl-3 -deoxyadenosine
20
(2.47 g,
0
.3 Hz, 1H2 -H), 4.00–3.97 (m, 1H, 4 -H), 3.18 (d,
0
5 mmol) was dissolved in a mixture of dichloromethane
(30 mL) and methanol (20 mL), and the pH of the reaction
mixture was adjusted to *4 using acetic acid. After stir-
ring the reaction mixture at room temperature for 4 h, the
pH of the reaction mixture was adjusted to 7–8 by addition
0
J = 5.1 Hz, 2H, 5 -H), 2.90–2.85 (m, 1H, 3 -H), 2.40–2.25
0
13
(
m, 1H, 3 -H). C NMR (126 MHz, DMSO) d 156.50 (6-
C), 152.94 (2-C), 149.53 (4-C), 144.11 (Ph), 139.91(8-C),
28.68 (Ph), 128.27 (Ph), 127.43 (Ph), 119.72 (5-C), 86.44
1
0
0
0
0
0
(
1 -C), 86.10 (4 -C), 83.77 (2 -C), 71.08 (5 -C), 64.67 (3 -
of a 1 M methanolic CH ONa solution. After removal of
3
C).
all solvents in vacuo, the residue was purified by column
chromatography on silica gel using a gradient of dichlor-
omethane/methanol (15:1–8:1) as eluents to afford the
target product 1 (1.13 g, 90.0%, 35.9% overall yield) as a
white solid with the purity of 99.1% (HPLC).
Synthesis of cordycepin (1)
Method A
0
0
0
0
N-acetyl-2 ,5 -O-diacetyl-3 -iodo-3 -deoxyadenosine 12
2.52 g, 5 mmol), toluene (40 mL) and 2,2-azobisisobuty-
(
Results and discussion
ronitrile (AIBN, 0.1 g, 0.6 mmol) were placed in a 100 mL
round-bottom flask. Lithium aluminum hydride in anhy-
Considering the structural similarity between cordycepin
and adenosine, and considering the fact that adenosine
represents a cheap and commercially readily available
material, adenosine was selected as the starting material in
drous THF (LiAlH /THF, 1 M, 20 mL) was slowly drop-
4
ped to the solution. The stirred reaction mixtures were then
heated to reflux for 12 h. After reaction completion, the
reaction mixture was cooled to room temperature and was
then poured into petroleum ether. The resulting precipitate
was collected by filtration and further washed with petro-
leum ether. The residue was used directly in the next step.
The residue was added into a 1 M methanolic MeONa
solution (25 mL) and the mixture was stirred for 6 h at
0
the synthesis of cordycepin. Only the removal of the 3 -OH
group in adenosine to afford cordycepin needs to be con-
sidered for this synthesis. Initially, reactions involving the
0
3 -OH group were considered to be most feasible, thought
to improve the synthetic route originally designed by
Christelle Moreau et al. To conduct the dehalogenation
reaction in a convenient fashion, the formation of an iodine
group was carried out in the second step (Scheme 6).
6
0 °C. After reaction completion, the reaction mixture was
cooled to room temperature and concentrated in vacuo. The
crude product was purified by flash chromatography on
silica gel using dichloromethane/methanol (10:1) as eluents
to afford pure 1 (0.39 g, 31.3%, 13.5% overall yield) as a
0
0
According to a literature procedure, the 2 -OH and 3 -OH
groups in adenosine were cyclized by trimethyl orthoac-
etate and were reacted with sodium iodide in acetic acid to
yield 12. Finally, cordycepin 1 was obtained by deiodina-
tion and deprotection reactions as follows:
1
white solid with the purity of 99.1% (HPLC). H NMR
(
500 MHz, DMSO-d ) d 8.37 (s, 1H, 8-H), 8.15 (s, 1H,
-H), 7.32 (s, 2H, –NH ), 5.87 (d, J = 2.4 Hz, 1H, 1 -H),
2
6
0
2
5
4
3
2
Our study first focused on optimizing the synthesis of 12
via reaction of 2 with trimethyl orthoacetate and NaI. The
results are shown in Table 1. However, only a miniscule
amount of 12 was obtained. This poor result can be mostly
attributed to the fact that NaI does not completely dissolve in
the reaction mixture, leading to a less than ideal heteroge-
nous solid–liquid system. However, hydrolysis was found to
occur when NaI dissolved in water was added to the reaction
0
0
.67 (d, J = 4.3 Hz, 1H, 2 -OH), 5.17 (s, 1H, 5 -OH),
0
0
.59–4.57 (m, 1H, 2 -H), 4.37–4.34 (m, 1H, 4 -H),
0
0
.71–3.68 (m, 1H, 5 -H), 3.52 (d, J = 12.1 Hz, 1H, 5 -H),
13
0
0
.28–2.23 (m, 1H, 3 -H), 1.94–1.90 (m, 1H, 3 -H).
C
NMR (101 MHz, DMSO) d 156.49 (6-C), 152.88 (2-C),
0
1
49.29 (4-C), 139.52 (8-C), 119.52 (5-C), 91.24 (1 -C),
0
0
0
0
8
1.14 (4 -C), 75.05 (2 -C), 63.06 (5 -C), 34.50 (3 -C).
1
23

Chem. Pap.
Scheme 6 Improved synthetic route based on the route of Christelle Moreau
Table 1 Reaction of adenosine with trimethyl orthoacetate and sodium iodide
c
a
b
Yield of 12 (%)
Entry
Solvent 1
Solvent 2
Temp (°C)
1
2
3
4
5
DMSO
Acetic acid
25
25
25
25
40
50
25
40.1
32.6
24.8
28.8
42.3
43.1
38.5
DMSO
CH
Acetic acid
CH CN
3
CN
Acetic acid
Acetic acid
DMSO
3
Acetic acid
Acetic acid
Acetic acid
d
6
DMSO
e
7
DMSO
a
3 3 3
Temperature in the reaction between 2 and CH C(OCH )
b
c
Isolated yield after column chromatography
Standard conditions: 2 (10 mmol), trimethyl orthoacetate (30 mmol), solvent 1 (30 mL), r.t., 12 h, sodium iodide (15 mmol), solvent 2
40 mL), 50 °C, 8 h
(
d
The optimum condition
e
Sodium iodide was increased to 20 mmol
mixture. Unfortunately, a large amount of unreacted ade-
nosine was found to be present in the reaction mixture as
detected by TLC, leading to a low overall yield of 12.
Some polar impurities like adenosine were found to be
present as detected by TLC and these impurities could not
be removed easily, negatively affecting the purity of 12.
To improve this synthetic route (Table 1), the intermediate
synthesized by 2 with CH C(OCH ) was replaced by 14
C H ) SnH or lithium aluminum hydride (LAH) was
4 9 3
attempted. In addition, different conditions were screened
for this reaction, e.g., different solvents and reaction times,
and the influence of the deprotection reaction in different
bases was tested. The corresponding results are shown in
Table 2.
The produced amount of 1 was found to be reduced by
replacing LiAlH4 with (n-C H ) SnH (entry 4) and by
3
3 3
4 9 3
obtained by reacting adenosine 2 with acetone (Townsend
et al. 2009). However, we found that the formation of com-
pound 14 did not take place upon addition of NaI into the
reaction mixture. The corresponding process is shown in
Scheme 7.
replacing toluene with DCM or THF (entries 1-3). Fur-
thermore, the obtained results show that the produced
amount of 1 was reduced and 13 was increased by
increasing the molar ratio of the reducing agent (entries 1
and 4–7). To assess the effect of LiAlH , we monitored the
4
With 12 in hand, the selection of a suitable reducing
agent was considered for removal of the iodine group. To
be specific, reaction of 12 with tributyltin hydride (n-
reaction time from 4 to 12 h. When the reaction was
continued for at least 6 h, compound 13 could be detected
by TLC analysis.
123

Chem. Pap.
Table 2 Synthesis of cordycepin via deiodination and deprotection reaction
b
a
Yield of 1 (%)
a
Yield of 13 (%)
Entry
Solvent
Reducing agent
Time (h)
Base
d
c
1
Toluene
DCM
LiAlH
LiAlH
LiAlH
4
4
4
4
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
ONa–CH
ONa–CH
ONa–CH
ONa–CH
ONa–CH
ONa–CH
ONa–CH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
30.2
28.1
23.2
25.6
27.7
30.6
31.3
25.8
0
2
3
4
5
6
7
8
a
4
7.4
2.3
THF
4
c
Toluene
Toluene
Toluene
Toluene
Toluene
(n-C
4
H
9
)
3
SnH
4
0
LiAlH
LiAlH
LiAlH
LiAlH
4
6
2.5
3.8
4.8
8.5
4
4
4
8
12
12
2
NaOH–H O
Isolated yield after column chromatography
b
c
d
Standard conditions: 12 (5 mmol), solvent (40 mL), AIBN (0.6 mmol), reducing agent (20 mmol), 12 h, reflux, base (1 M, 25 mL) 6 h, 60 °C
Compound 13 was observed by TLC
The optimum condition
Adenosine was used and directly reacted with p-TsCl.
This process exhibited unsuitable selectivity characteristics
0
0
as judged by TLC. Most likely, the reactivity of all 2 -OH, 3 -
0
OH and 5 -OH groups when exposed to p-TsCl is fairly
similar, resulting in the production of various compounds
that prove to be difficult to be separated from each other.
However, upon using (n-C H ) SnO, 16 has been shown to
4
9 2
be the main product (Wagner et al. 1974) (Scheme 9). Upon
Scheme 7 Attempted synthesis of 12 from 2 via intermediate 14
removal of the –OTs group from 16, a product structurally
0
similar to cordycepin(2 -deoxyadenosine) 17 was obtained.
In an effort to reduce the amount of byproducts formed,
As –OTs represents a good leaving group and given the fact
that tosylates of secondary alcohols in particular may undergo
0
the 5 -OH group in adenosine was protected by triphenyl-
0
0
elimination reaction, the reaction between 3 -OH group of
methyl chloride (TrCl) before the reaction of the 3 -OH
0
adenosine and p-toluenesulfonyl chloride (p-TsCl) was also
considered to furnish 15 (Grouiller et al. 1987). Then, a
reducing agent can be used to remove the –OTs group to pro-
duce cordycepin 1. This process is shown in Scheme 8 below.
group with p-TsCl. Then, the 3 -OH group was reacted
with p-TsCl to reduce 19 (Morio and Masakatsu 1967) and
a reducing agent could be used to remove the –OTs group
to obtain 20. Finally, acetic acid and dichloromethane
Scheme 8 Synthesis of cordycepin via 15
1
23

Chem. Pap.
Scheme 9 Synthesis of 17 from
adenosine 2
Scheme 10 Improved synthesis
of cordycepin
Table 3 Reaction of adenosine 2 with TrCl and triethylamine
b
a
Yield of 18 (%)
Entry
Solvent
DMF
Temperature (°C)
Reaction time (h)
1
2
3
4
5
6
7
30
30
30
45
60
30
30
45
24
24
24
24
24
36
48
24
71.6
65.4
69.8
73.5
73.8
72.0
73.1
75.0
2 2
CH Cl
Pyridine
DMF
DMF
DMF
DMF
DMF
c
8
a
Isolated yields after column chromatography
b
c
Standard conditions: 2 (5 mmol), TrCl (10 mmol), Et
3
N (10 mL)
The optimum condition where TrCl was increased to 15 mmol
solution were used to remove the triphenylmethyl pro-
tecting group to obtain cordycepin 1 (Scheme 10).
The synthetic pathway first focused on the synthesis of
Several solvents, temperature ranges and reaction times
were investigated in an effort to obtain a higher product
yield (Table 4). As listed in Table 4, the reaction temper-
ature did not have a significant effect on the product yield
of 19 (entries 1 and 4–5). The same proved to be the case
for modifications in reaction time (entries 1 and 6–7) and
molar ratio of 18 and p-TsCl. Thus, the temperature was set
at 30 °C and the molar ratio of the reactants was 1:2, using
triethylamine as acid neutralizing agent, DMF as solvent
and continuous stirring for 24 h were chosen as reaction
1
8 from 2 using triethylamine as base. In an effort to
achieve an improved yield, several other solvents and
temperatures were screened as shown in Table 3.
As shown in Table 3, The reaction for 18 can get a best
c
overall yield of 75.0% with an optimized reaction tem-
c
perature of 45 °C, an optimum ratio of reactants (2 and
TrCl) at 1: 3, using triethylamine as acid neutralizing
agent, DMF as solvent and continuous stirring for 24 h.
Similarly, reaction conditions for the transformation of
intermediate 18–19 were also screened for optimization.
c
conditions.
Furthermore, we evaluated the synthetic progress of 20
under several experimental conditions as shown in Table 5.
123

Chem. Pap.
Table 4 Reaction of 18 with p-toluenesulfonyl chloride and triethylamine
b
a
Yield of 19 (%)
Entry
Solvent
DMF
Temperature (°C)
Reaction time (h)
c
1
30
30
30
45
60
30
30
30
24
24
24
24
24
36
48
24
70.7
62.9
66.3
71.1
71.8
71.5
72.0
71.4
2
3
4
5
6
7
2 2
CH Cl
Pyridine
DMF
DMF
DMF
DMF
DMF
d
8
a
Isolated yield from column chromatography
b
c
d
Standard conditions: 18 (5 mmol), p-TsCl (10 mmol), solvent (30 mL), triethylamine (10 mL)
The optimum condition
p-TsCl was increased to 15 mmol
Table 5 Reaction of 19 with lithium aluminum hydride
b
a
Yield of 20 (%)
Entry
Solvent
Reducing agent
Reaction time (h)
1
2
DMSO
DMF
THF
LiAlH
LiAlH
LiAlH
LiAlH
4
4
4
4
4
76.3
75.1
75.3
62.8
65.4
73.4
75.9
76.5
70.9
4
c
3
4
4
5
6
7
8
CH
Cl
2 2
4
THF
THF
THF
THF
THF
LiBH(CH
Bu SnH
2
CH
3
)
3
4
3
4
LiAlH
LiAlH
LiAlH
4
4
4
8
12
4
d
9
a
Isolated yield from chromatography
b
c
d
Standard conditions: 19 (5 mmol), Reducing agent(1 M), solvent (30 mL), temperature at 0–5 °C
The optimum condition
4
LiAlH /THF was increased to 1 M, 25 mL
1
23

Chem. Pap.
When the reaction was considered complete as judged by
TLC analysis, product 20 could be purified by column
chromatography. As shown in Table 5, the choice of
reducing agent was explored, considering the toxicity and
cumbersome post-treatment of Bu SnH, we prefer LiAlH
transfer conditions. Synthesis 1987:1121–1122. doi:10.1055/s-
987-28193
Guo P, Kai Q, Gao J, Lian ZQ, Wu CM, Wu CA, Zhu HB (2010)
Cordycepin prevents hyperlipidemia in hamsters fed a high-fat
diet via activation of AMP-activated protein kinase. J Pharmacol
Sci 113:395–403. doi:10.1254/jphs.10041FP
1
3
4
Holbein S, Wengi A, Decourty L, Freimoser FM, Jacquier A, Dichtl B
0
as the reducing agent. The reaction using an incremental
amount of LiAlH4 provided a lower yield (entry 9).
Meanwhile, the influences of the reaction time were
explored. However, increasing the yield of 20 was not
obvious (entries 1 and 7–8) upon increasing the reaction
time. The isolated yield reached an optimum value upon
(
2009) Cordycepin interferes with 3 end formation in yeast
independently of its potential to terminate RNA chain elonga-
tion. RNA 15:837–849. doi:10.1261/rna.1458909
Hunter KW, Crawford NP, Alsarraj J (2008) Mechanisms of
metastasis. Breast Cancer Res 10:135–166. doi:10.1186/bcr1988
Katayama S, Takamatsu S, Naito M, Tanji S, Ineyama T, Izawa K
0 0 0
(
2006) A synthesis of 3 -a-fluoro-2 ,3 -dideoxyadenosine via a
treatment of 19 with 5 equivalents of LiAlH at room
4
bromine rearrangement during fluorination with MOST reagent.
Cheminform 127:524–528. doi:10.1002/chin.200638182
Li Q, Yang R, Ruan Z, Hu T, Ding H, Xiao Q (2013) Total synthesis
of cordycepin. Chin J Organ Chem 33:1340–1344. doi:10.6023/
cjoc201303009
Ma L, Zhang S, Du M (2015) Cordycepin from Cordyceps militaris
prevents hyperglycemia in alloxan-induced diabetic mice. Nutr
Res 35:431–439. doi:10.1016/j.nutres.2015.04.011
temperature, with an adopted reaction time of 4 h.
Finally, 20 was converted into the final product,
cordycepin 1 in acetic acid and dichloromethane solution
via deprotection reaction.
McDonald FE, Gleason MM (1996) Asymmetric synthesis of
nucleosides via molybdenum-catalyzed alkynol cycloisomeriza-
tion coupled with stereoselective glycosylations of deoxyfura-
nose glycals and 3-amidofuranose glycals. J Am Chem Soc
Conclusions
We designed two independent methods for the synthesis of
cordycepin. One method we developed for the production
of cordycepin proves to be shorter, however, suffers from a
relatively low yield of 13.5%. The other synthetic method
we developed proves to be more suitable for the production
of cordycepin, and leads to the production of cordycepin
both in higher product quality and yield. This synthetic
route consists of four steps with a total product yield of
1
18:6648–6659. doi:10.1021/ja960581l
Moreau C, Kirchberger T, Swarbrick JM, Bartlett SJ, Fliegert R,
Yorgan T, Bauche A, Harneit A, Guse AH, Potter BV (2013)
0
Structure-activity relationship of adenosine 5 -diphosphoribose
at the transient receptor potential melastatin2 (TRPM2) channel:
rational design of antagonists. J Med Chem 56:10079–10102.
doi:10.1021/jm401497a
Morio I, Masakatsu K (1967) Synthesis of purine cyclonucleoside
0
having 8,3 -O-anhydro linkage. Chem Pharm Bull
15:1261–1262. doi:10.1248/cpb.15.1261
3
5.9%. The key step in the synthetic process is the con-
M u¨ ller WE, Weiler BE, Charubala R, Pfleiderer W, Leserman L,
Sobol RW, Suhadolnik RJ, Schr o¨ der HC (1991) Cordycepin
version from 18 to 19. Since all starting materials are
commercially available and produce cordycepin in a high
overall yield, this synthetic method proves to be superior
over other pathways reported in the literature.
0
0
analogues of 2 ,5 -oligoadenylate inhibit human immunodefi-
ciency virus infection via inhibition of reverse transcriptase.
Biochemistry 30:2027–2033. doi:10.1021/bi00222a004
Ni H, Zhou XH, Li HH, Huang WF (2009) Column chromatographic
extraction and preparation of cordycepin from Cordyceps militaris
waster medium. J Chromatogr, B: Anal Technol Biomed Life Sci
Acknowledgements This work was financially supported by the
National Science Foundation of China (No. 21576295).
8
77:2135–2141. doi:10.1016/j.jchromb.2009.06.009
Noh EM, Youn HJ, Jung SH, Han JH, Jeong YJ, Chung EY, Jung JY,
Kim BS, Lee SH, Lee YR (2010) Cordycepin inhibits TPA-
induced matrix metalloproteinase-9 expression by suppressing
the MAPK/AP-1 pathway in MCF-7 human breast cancer cells.
Int J Mol Med 25:255–260. doi:10.3892/ijmm_00000338
Ohta Y, Lee JB, Hayashi K, Fujita A, Park DK, Hayashi T (2011)
In vivo anti-influenza virus activity of an immunomodulatory
acidic polysaccharide isolated from Cordyceps militaris grown
on germinated soybeans. J Agric Food Chem 55:10194–10199.
doi:10.1021/jf0721287
References
Ahn Y, Park S, Lee S, Shin S, Choi DH (2000) Cordycepin: selective
Growth Inhibitor Derived from Liquid Culture of Cordyceps
militaris against Clostridium spp.
8:2744–2748. doi:10.1021/jf990862n
Aman S, Anderson DJ, Connolly TJ, Crittall AJ, Ji G (2000) From
J Agric Food Chem
4
0
adenosine to 3 -deoxyadenosine: development and scale up. Org
Process Res Dev 4:601–605. doi:10.1021/op000209x
Bentley HR, Cunningham KG, Spring FS (1951) 509. Cordycepin, a
metabolic product from cultures of Cordyceps militaris (Linn.)
link. Part II. The structure of cordycepin. J Chem Soc. doi:10.
Rao YK, Fang SH, Wu WS, Yewmin T (2010) Constituents isolated
from Cordyceps militaris suppress enhanced inflammatory
mediator’s production and human cancer cell proliferation.
J Ethnopharmacol 131:363–367. doi:10.1016/j.jep.2010.07.020
Shiragami H, Tanaka Y, Uchida Y, Iwagami H, Izawa K, Yukawa T
(1992) A novel method for the synthesis of ddA and F-ddA via
1
039/JR9510002301
Cunningham KG, Manson W, Spring FS, Hutchinson SA (1950)
Cordycepin, a metabolic product isolated from cultures of Cordy-
ceps militaris (Linn.) Link. Nature 166:949. doi:10.1038/166949a0
Grouiller A, Essadiq H, Najib B, Moliere P (1987) Regioselective O-
p-toluenesulfonylation of nucleosides under solid/liquid phase-
0
regioselective 2 -O-deacetylation of 9-(2,5-DI-O-Acetyl-3-
bromo-3-deoxy-b-D-xylofuranosyl)adenine. Nucleosides
Nucleotides 11:391–400. doi:10.1080/07328319208021713
123

Chem. Pap.
0
Sugar AM, Mccaffrey RP (1998) Antifungal activity of 3 -
deoxyadenosine (Cordycepin). Antimicrob Agents Chemother
synthetic cordycepin analogues as experimental therapeutics for
African trypanosomiasis. J Med Chem 56:9861–9873. doi:10.
1021/jm401530a
4
Takamatsu S, Katayama S, Naito M, Yamashita K, Ineyama T, Izawa
2:1424–1427
Wagner D, Verheyden JPH, Moffatt JG (1974) Preparation and
synthetic utility of some organotin derivatives of nucleosides.
J Org Chem 5:24–30. doi:10.1021/jo00915a005
0
0
0
K (2006) A facile synthetic method for 3 -a-fluoro-2 ,3 -
dideoxyadenosine. Nucleosides, Nucleotides Nucleic Acids
3
5:711–713. doi:10.1002/chin.200403214
Todd A, Ulbricht TLV (1960) 656 Deoxynucleosides and related
Wong YY, Moon A, Duffin R, Barthet-Barateig A, Meijer HA,
Clemens MJ, de Moor CH (2010) Cordycepin inhibits protein
synthesis and cell adhesion through effects on signal transduc-
0
compounds Part IX A synthesis of 3 -deoxyadenosine. J Chem
Soc. doi:10.1039/JR9600003275
tion. J Biol Chem 285:2610–2621. doi:10.1074/jbc.M109.
071159
Townsend AP, Roth S, Williams HE, Stylianou E, Thomas NR (2009)
New s-adenosyl-L-methionine analogues: synthesis and reactiv-
ity studies. Org Lett 11:2976–2979. doi:10.1021/ol9009859
Tuli HS, Sharma AK, Sandhu SS, Kashyap D (2013) Cordycepin: a
bioactive metabolite with therapeutic potential. Life Sci
Zhou X, Meyer CU, Schmidtke P, Zepp F (2002) Effect of cordycepin
on interleukin-10 production of human peripheral blood
mononuclear cells. Eur J Pharmacol 453:309–317. doi:10.1016/
S0014-2999(02)02359-2
9
3:863–869. doi:10.1016/j.lfs.2013.09.030
Zhou X, Luo L, Dressel W, Shadier G, Krumbiegel D, Schmidtke P,
Zepp F, Meyer CU (2008) Cordycepin is an immunoregulatory
active ingredient of Cordyceps sinensis. Am J Chin Med
36:967–980. doi:10.1142/S0192415X08006387
Vodnala SK, Lundback T, Yeheskieli E, Sjoberg B, Gustavsson AL,
Svensson R, Olivera GC, Eze AA, de Koning HP, Hammarstrom
LG, Rottenberg ME (2013) Structure-activity relationships of
1
23