Synthesis of 4′-benzoyloxycordycepin from adenosine

Article abstract of DOI:10.1016/j.tet.2008.01.018

With an aim to synthesize 4′-substituted cordycepins, the 4′-benzoyloxy precursor (9) was prepared from adenosine through an electrophilic addition (iodo-benzoyloxylation) to the 4′,5′-unsaturated derivative (5) and subsequent radical-mediated removal of

Full text of DOI:10.1016/j.tet.2008.01.018

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2391e2396
www.elsevier.com/locate/tet
Synthesis of 40-benzoyloxycordycepin from adenosine
Yutaka Kubota, Mayumi Kunikata, Nobuhide Ishizaki, Kazuhiro Haraguchi,
*
Yuki Odanaka, Hiromichi Tanaka
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Received 14 December 2007; received in revised form 25 December 2007; accepted 2 January 2008
Available online 6 January 2008
Abstract
With an aim to synthesize 40-substituted cordycepins, the 40-benzoyloxy precursor (9) was prepared from adenosine through an electrophilic
addition (iodo-benzoyloxylation) to the 40,50-unsaturated derivative (5) and subsequent radical-mediated removal of the 30-iodine atom of the
resulting adducts (6). Usefulness of 9 was briefly verified by synthesizing the 40-allyl (12) and 40-cyano (13) analogues of cordycepin.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cordycepin; 40-Substituted nucleoside; Stereochemistry; Organosilicon reagent
1. Introduction
attention as promising anti-HIV agents, which can be exempli-
fied by the 20-deoxyadenosine analogues having 40-cyano (2,
EC50 0.051 mM) and 40-ethynyl (3, EC50 0.0098 mM) substitu-
ents.13 In this context, we were interested in synthesizing
40-carbon-substituted cordycepin derivatives. Although there
have been several methods available to synthesize 40-
substituted nucleosides,12 we intended to employ nucleophilic
displacement at the 40-position of cordycepin, as have been
reported from our laboratory in the synthesis of 10- and 40-
branched nucleosides.14,15 To do so, introduction of a leaving
group to the 40-position of cordycepin was necessary.
In this paper, we describe the preparation of 40-benzoyloxy-
cordycepin from adenosine through halo-acyloxylation to the
30,40-unsaturated derivative and subsequent radical-mediated
dehalogenation. Also, usefulness of 40-benzoyloxycordycepin
is very briefly demonstrated by the synthesis of the 40-allyl
and 40-cyano analogues of cordycepin.
Cordycepin was the first nucleoside antibiotic identified as
a metabolite of the mold Cordycep militaris in 1951.1 A wrong
structure was initially assigned for it,2 but later in 1964, 30-de-
oxyadenosine (1) isolated from Aspergillus nidulans was
shown to be identical to cordycepin.3,4 The reported biological
effects of cordycepin on RNA biosynthesis,5 methyltransfer-
ase,6 and purine biosynthesis7 have stimulated the synthesis
of its analogues with an aim to discover chemotherapeutically
viable compounds,8e10 but reported modification at its sugar
moiety has been quite limited.11
NH2
NH2
N
N
N
N
N
N
N
N
HO
HO
O
O
R
OH
HO
2 R = CN
1
3 R = ethynyl
2. Results and discussion
As reviewed recently by Hayakawa et al.,12 nucleosides an-
alogues substituted at the 40-position have attracted much
2.1. Halo-acyloxylation of the 30,40-unsaturated derivative (5)
Adenosine was converted to the 30,40-unsaturated deriv-
ative 4 according to the method reported by Moffatt et al.16
The 20- and 50-hydroxyl groups of 4 were protected with
* Corresponding author.
E-mail address: hirotnk@pharm.showa-u.ac.jp (H. Tanaka).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.018

2392
Y. Kubota et al. / Tetrahedron 64 (2008) 2391e2396
Table 1
Iodo-benzoyloxylation of 5 by changing the solventa
Ade
Ade
RO
+
RO
O
O
NIS
5
Entry
Solvent
Time (h)
Combined yield
(%) of 6aþ6b
Ratio of 6a/6bb
+
I
I
OR
OR
B
A
1
2
3
4
5
a
CH2Cl2
THF
3
82
1:1.6
1:5.0
2.5
3
45c
51c
32
PhCO2H
or
PhCO2
PhCO2H
CHCl3
Pyridine
1:1.2
Only 6b
Only 6b
−
3
3.5
d
CH2Cl2
64
6b
6a
6b
+
All reactions were carried out by using NIS (3.0 equiv) and PhCO2H
(R = TBDMS, Ade = adenin-9-yl)
(3.0 equiv) at rt in the solvent indicated (concentration of 5, 42 mM).
b
The ratio was determined by integrating the respective H-10.
Several unknown byproducts were also formed.
DMAP (3.0 equiv) was added as an additive. Compound 5 was recovered
Scheme 2.
c
d
in 23% yield.
Table 2
Iodo-benzoyloxylation by varying concentration of 5 in CH2Cl2
a
Entry
Concentration
(mM) of 5
Time (h)
Combined yield
(%) of 6aþ6b
Ratio of 6a/6bb
tert-butyldimethylsilyl (TBDMS) to give 5 as reported previ-
ously.17 Halo-acyloxylation of 5 was first carried out by using
NBS/PhCO2H in CH2Cl2, but this reaction gave an intractable
mixture of products.18 The use of NIS/PhCO2H, on the other
hand, allowed 5 to undergo the iodo-benzoyloxylation to
give a mixture of the syn-(6a) and anti-(6b) adducts in 82%
yield with a slight preponderance of the latter as shown in en-
try 1 of Table 1. The depicted stereochemistry of these adducts
was assumed based on their NOE experiments (Scheme 1).19
Concomitant formation of the syn-adduct (6a) suggested that
the incipient 30,40-iodonium A was followed by the formation
of a carboxonium intermediate B (Scheme 2). The observed
stereochemistry of the iodonium formation was quite unex-
pected, since epoxidation of 5 with dimethyldioxirane took
place exclusively at its b-face in our previous study.17 At the
moment, we have no explanation for the reversed stereochem-
istry of these electrophilic reactions.
Use of THF or CHCl3 as a solvent also gave a mixture of
6a and 6b with a lower combined yield (entries 2 and 3). In
contrast to these cases, the reaction conducted in pyridine
gave only the anti-adduct (6b), albeit in a low yield (entry
4). We assumed that the pyridine worked as a base to dissoci-
ate PhCO2H. Under such circumstances, higher nucleophilic-
ity of the resulting benzoate ion would allow its reaction with
the initially formed 30,40-iodonium intermediate (A). In fact,
when DMAP was used as an additive and the reaction was
carried out in CH2Cl2, only 6b was formed in 64% yield
(entry 5).
1
2
3
4
5
6
7
8
a
84
42
5.5
3.5
3.0
3.0
3.0
3.0
3.0
3.0
83
82
81
80
71
77
67
58
1:2.0
1:1.6
1:1.2
1.2:1
1.5:1
1.8:1
1.1:1
1:1.8
21
11
5.3
2.1
0.7
0.4
All reactions were carried out by using NIS (3.0 equiv) and PhCO2H
(3.0 equiv) in CH2Cl2 at rt.
b
The ratio was determined by integrating the respective H-10.
can be seen a trend, within entries 1e3, that formation of
the anti-adduct (6b) was favored at higher concentration. At
comparatively lower concentration shown in entries 4e6, re-
verse stereoselectivity was observed. One explanation for
these results could possibly be made again based on Scheme
2: at higher concentration where nucleophilic attack of
PhCO2H is statistically favored, A reacts as soon as it is
formed, while at lower concentration, A has enough time be-
fore reacting with PhCO2H to form B, which undergoes pref-
erential attack from its a-face due to the presence of adenine
base. However, this explanation would be too simple and does
not give the answer to entries 7 and 8 where formation of the
syn-adduct (6a) became less favored again.
Carboxylic acids other than PhCO2H also work in this iodo-
acyloxylation as exemplified by the formation of 7 (82%, 7a/
7b¼1:1.9) and 8 (64%, 8a/8b¼1:4).20 These adducts were
prepared by reacting 5 with the respective acids under the con-
ditions of entry 2 in Table 2.
We also examined the above iodo-benzoyloxylation by
varying concentration of 5 in CH2Cl2 (Table 2). Although no
dramatic change was observed in the ratio of 6a/6b, there
NH2
NH2
N
NH2
N
N
N
N
N
N
N
N
N
TBDMSO
BzO
NIS
N
BzO
N
RO
O
O
O
PhCO2H
+
TBDMSO
solvent, rt
OR
4 R = H
5 R = TBDMS
OTBDMS
OTBDMS
I
I
6a
6b
Scheme 1.

Y. Kubota et al. / Tetrahedron 64 (2008) 2391e2396
2393
the 40-pivaloyloxy group as well as its anti-disposition caused
the elimination pathway as shown in Scheme 4.
NH2
N
NH2
N
N
N
N
O
C
N
TBDMSO
N
O
N
R
NH2
N
O
O
TBDMSO
O
C
N
O
O
C
R
N
OTBDMS
I
OTBDMS
I
O
N
Bu3Sn.
O
11b
5
7a R = Me
8a R = CMe3
7b R = Me
8b R = CMe3
RO
OR
(R = TBDMS)
2.2. Radical-mediated deiodination of the adducts (6e8)
Scheme 4.
Removal of the iodine atom at the 30-position of 6e8 was car-
ried out. Upon hydrogenolysis of 6 in the presence of 5% Pd/C
and an acid acceptor Et3N in MeOH, the major reaction pathway
was elimination to yield 5 (75%), the desired product 9 being
isolated only in 22% yield. An apparent alternative, radical-me-
diated deiodination, was next examined, although one concern
of this operation was well known 1,2-acyloxy migration.21
When the deiodination was carried out by reacting 6 (6a/
6b¼1:2) with Bu3SnH/AIBN in refluxing benzene for 3 h
(Scheme 3), 9 was obtained in 94% yield (9a/9b¼1:2.2).
Each diastereomer was isolated by HPLC separation
(CHCl3/MeOH¼80:1).22 Although a trace amount of the elim-
ination product 5 was detected in this reaction, no product
resulting from 1,2-acyloxy migration was formed.
2.3. Reaction of 40-benzoyloxycordycepin (9) with
organosilicon reagents: synthesis of the 40-allyl and 40-cyano
analogues
Finally, we intended to briefly demonstrate that the cordy-
cepin derivative having a 40-acyloxy group is a useful substrate
for the synthesis of 40-branched analogues. By using the 40-
benzoyloxy derivative (9), the reaction with organosilicon re-
agents in the presence of SnCl4 was examined (Scheme 5).
NH2
N
NH2
N
N
N
N
N
RO
N
N
RO
O
O
Me3SiX/SnCl4
CH2Cl2
NH2
N
NH2
N
X
BzO
N
N
N
N
(X = CH2CH=CH2 or CN)
OR
OR
9
N
X
N
X
12 X = CH2CH=CH2
13 X = CN
O
O
Bu3SnH/AIBN
benzene, reflux
Y
Y
(R = TBDMS)
OR
I
OR
Scheme 5.
6a X = CH2OR, Y = OBz
6b X = OBz, Y = CH2OR
9a X = CH2OR, Y = OBz
9b X = OBz, Y = CH2OR
Compound
9
(9a/9b¼1:2) was reacted with Me3-
(R = TBDMS)
SiCH2CH]CH2 (5 equiv) in the presence of SnCl4 (5 equiv)
in CH2Cl2 for 2 h. Two products isolated from the reaction mix-
ture were the b-D-isomer of 40-allylcordycepin (12, 44%)24 and
the elimination product (5, 9%). Neither the starting material nor
the a-L-isomer was isolated. To see if the 40-stereochemistry of 9
has any influence on the reactivity, 9a and 9b were reacted sep-
arately with Me3SiCH2CH]CH2/SnCl4, but no significant dif-
ference was observed: 12 (47%) and 5 (8%) from 9a; 12 (43%)
and 5 (9%) from 9b. When Me3SiCN was reacted with 9 (9a/
9b¼1:2) under similar reaction conditions to the above, the b-
D-isomer of 40-cyanocordycepin (13, 58%)25 was again the
sole 40-substituted product with the elimination product (5) be-
ing isolated in 19% yield. At the present time, it is not known
why the above reactions gave exclusively the b-D-isomer.
Scheme 3.
The deiodination was also examined by using the 40-ace-
toxy (7) and the 40-pivaloyloxy (8) derivatives. While 7 (7a/
7b¼1:2.7) gave the expected product 10 in 87% yield (10a/
10b¼1:2.7) without forming the elimination product (5), the
reaction of 8 (8a/8b¼1:4) gave a considerable amount of 5
(11%) together with 11 (77%, 11a/11b¼1:3.6). By carrying
out the reaction of 8a and 8b separately, it became apparent
that the formation of 5 took place solely from 8b: 5 (19%)
and 11b (74%). Although the stereoelectronic preference for
an anti-coplanar arrangement is known to be much less dom-
inant in radical-mediated b-elimination,23 the result of 8b sug-
gests that the favorable generation of tert-butyl radical from
NH2
N
3. Experimental section
N
10a X = CH2OR, Y = OAc
3.1. General
N
10b X = OAc, Y = CH2OR
N
X
O
11a X = CH2OR, Y = OCOCMe3
11b X = OCOCMe3, Y = CH2OR
NMR spectra were recorded either at 400 MHz (JNM-GX
400) or at 500 MHz (JNM-LA 500). Chemical sifts are
Y
R = TBDMS
OR

2394
Y. Kubota et al. / Tetrahedron 64 (2008) 2391e2396
reported relative to Me4Si. Mass spectra (MS) were taken in
FAB mode with m-nitrobenzyl alcohol as a matrix on a JNS-
SX 102A. UV spectra were measured on a JASCO Ubest-55
spectrophotometer. Column chromatography was carried out
on silica gel (Micro Bead Silica Gel PSQ 100B, Fuji Silysia
Chemical Ltd.). Thin layer chromatography (TLC) was per-
formed on silica gel (precoated silica gel plate F254, Merck).
High performance liquid chromatography (HPLC) was carried
out on a Shimadzu LC-6AD with a Shim-pack PREP-SIL (H)
KIT column (2ꢀ25 cm). THF was distilled from benzophe-
none ketyl.
(tert-butyldimethylsilyl)-3-deoxy-3-iodo-a-L-
lyxofuranosyl]adenine (7b)
Column chromatography (hexane/EtOAc¼1:2) of the reac-
tion mixture gave 7 (82%, 7a/7b¼1:1.9). HPLC separation
(CHCl3/MeOH¼50:1) gave analytically pure 7a (tR¼4.1 min,
foam) and 7b (tR¼5.7 min, foam).
Physical data for 7a: UV (MeOH) lmax 259 nm (3 13,600),
lmin 228 nm (3 1700); 1H NMR (CDCl3) d 0.12, 0.13, and 0.18
(12H, each as s), 0.92 and 0.96 (18H, each as s), 2.10 (3H, s),
3.99 (1H, d, J¼10.8 Hz), 4.57 (1H, dd, J¼1.7 and 5.4 Hz),
4.64 (1H, d, J¼10.8 Hz), 5.07 (1H, d, J¼5.4 Hz), 5.92 (2H,
br), 6.24 (1H, d, J¼1.7 Hz), 8.17 (1H, s), 8.32 (1H, s); 13C
NMR (CDCl3) d ꢁ5.49, ꢁ5.28, ꢁ4.79, ꢁ4.39, 18.07, 18.36,
22.01, 25.81, 25.88, 27.79, 61.82, 76.35, 91.15, 110.68,
119.91, 138.84, 149.32, 153.07, 155.44, 168.94; FABMS
(m/z) 664 (MþþH). Anal. Calcd for C24H42IN5O5Si2: C,
43.43; H, 6.38; N, 10.55. Found: C, 43.24; H, 6.30; N, 10.36.
Physical data for 7b: UV (MeOH) lmax 259 nm (3 14,100),
lmin 226 nm (3 2000); 1H NMR (CDCl3) d ꢁ0.34, ꢁ0.02, 0.06,
and 0.10 (12H, each as s), 0.79 and 0.91 (18H, each as s), 2.19
(3H, s), 4.29 (1H, d, J¼11.0 Hz), 4.65 (1H, d, J¼11.0 Hz),
4.82 (1H, d, J¼5.1 Hz), 5.08 (1H, dd, J¼5.1 and 6.8 Hz),
5.99 (1H, d, J¼6.8 Hz), 6.08 (2H, br), 7.86 (1H, s), 8.33
(1H, s); 13C NMR (CDCl3) d ꢁ5.51, ꢁ5.43, ꢁ5.22, ꢁ4.97,
17.83, 18.16, 22.11, 25.46, 25.71, 39.01, 65.69, 71.52,
90.62, 110.29, 120.53, 140.71, 149.82, 152.90, 155.72,
168.91; FABMS (m/z) 664 (MþþH). Anal. Calcd for C24H42-
IN5O5Si2: C, 43.43; H, 6.38; N, 10.55. Found: C, 43.55; H,
6.23; N, 10.45.
3.1.1. 40-Benzoyloxy-20,50-bis-O-(tert-butyldimethylsilyl)-30-
deoxy-30-iodoadenosine (6a) and 9-[4-benzoyloxy-2,4-bis-
O-(tert-butyldimethylsilyl)-3-deoxy-3-iodo-a-L-
lyxofuranosyl]adenine (6b)
A mixture of 5 (1.0 g, 2.09 mmol), benzoic acid (0.77 g,
6.28 mmol), and NIS (1.4 g, 6.28 mmol) in CH2Cl2 (25 mL)
was stirred at rt for 5.5 h under positive pressure of dry Ar.
The reaction mixture was partitioned between EtOAc and sat-
urated aqueous Na2S2O3. The organic layer was further
washed with saturated aqueous NaHCO3. Column chromatog-
raphy (hexane/EtOAc¼1:1) of the organic layer gave a mixture
of 6a and 6b as a pale yellow foam (1.26 g, 83%: 6a/6b¼ca.
1:2). HPLC separation (CHCl3/MeOH¼80:1) gave analyti-
cally pure 6a (tR¼13.5 min, foam) and 6b (tR¼15.5 min,
foam).
Physical data for 6a: UV (MeOH) lmax 235 nm (3 16,500)
and 259 nm (3 17,200), lmin 223 nm (3 11,700) and 246 nm (3
1
13,800); H NMR (CDCl3) d 0.07, 0.08, 0.12, and 0.22 (12H,
each as s), 0.87 and 0.90 (18H, each as s), 4.07 (1H, d,
J¼11.0 Hz), 4.78 (1H, dd, J¼1.2 and 5.7 Hz), 4.85 (1H, d,
J¼11.0 Hz), 5.33 (1H, d, J¼5.7 Hz), 5.81 (2H, br), 6.22
(1H, d, J¼1.2 Hz), 7.42e7.46, 7.56e7.61, and 8.16e8.19
(5H, each as m), 8.12 (1H, s), 8.31 (1H, s); 13C NMR
(CDCl3) d ꢁ5.52, ꢁ5.28, ꢁ4.59, ꢁ4.50, 18.18, 18.33, 25.82,
27.55, 61.72, 76.35, 91.84, 111.28, 120.01, 128.29, 130.02,
133.42, 139.24, 149.34, 153.15, 155.47, 164.32; FABMS
(m/z) 726 (MþþH). Anal. Calcd for C29H44IN5O5Si2: C,
47.99; H, 6.11; N, 9.65. Found: C, 48.03; H, 6.04; N, 9.52.
Physical data for 6b: UV (MeOH): lmax 234 nm (3 16,500)
and 259 nm (3 15,300), lmin 222 nm (3 12,000) and 247 nm (3
3.1.3. 20,50-Bis-O-(tert-butyldimethylsilyl)-30-deoxy-30-iodo-
40-pivaloyloxyadenosine (8a) and 9-[2,5-bis-O-(tert-
butyldimethylsilyl)-3-deoxy-3-iodo-4-pivaloyloxy-a-L-
lyxofuranosyl]adenine (8b)
Column chromatography (hexane/EtOAc¼1:2) of the reac-
tion mixture gave 8 (64%, 8a/8b¼1:4). HPLC separation
(CHCl3/MeOH¼50:1) gave analytically pure 8a (tR¼
10.7 min, foam) and 8b (tR¼11.3 min, foam).
Physical data for 8a: UV (MeOH) lmax 260 nm (3 16,100),
lmin 227 nm (3 3200); 1H NMR (CDCl3) d 0.06, 0.10, and 0.17
(12H, each as s), 0.90 and 0.92 (18H, each as s), 1.27 (9H, s),
3.94 (1H, d, J¼10.8 Hz), 4.64 (1H, d, J¼10.8 Hz), 4.73 (1H,
dd, J¼2.0 and 6.1 Hz), 5.28 (1H, d, J¼6.1 Hz), 5.64 (2H,
br), 6.18 (1H, d, J¼2.0 Hz), 8.05 (1H, s), 8.32 (1H, s); 13C
NMR (CDCl3) d ꢁ5.53, ꢁ5.33, ꢁ4.63, ꢁ4.38, 18.33, 18.35,
25.88, 25.92, 27.03, 28.42, 39.87, 61.85, 76.37, 91.61,
110.42, 119.99, 139.40, 149.41, 153.19, 155.35, 176.61;
FABMS (m/z) 706 (MþþH). Anal. Calcd for C27H48IN5O5Si2:
C, 45.95; H, 6.86; N, 9.92. Found: C, 45.63; H, 6.81; N, 9.71.
Physical data for 8b: UV (MeOH) lmax 259 nm (3 15,400),
lmin 227 nm (3 3000); 1H NMR (CDCl3) d ꢁ0.30, ꢁ0.03, 0.05,
and 0.09 (12H, each as s), 0.78 and 0.90 (18H, each as s), 1.29
(9H, s), 4.33 (1H, d, J¼11.0 Hz), 4.51 (1H, d, J¼11.0 Hz),
4.76 (1H, dd, J¼5.1 and 6.8 Hz), 4.85 (1H, d, J¼5.1 Hz),
5.62 (2H, br), 6.11 (1H, d, J¼6.8 Hz), 7.96 (1H, s), 8.35
(1H, s); 13C NMR (CDCl3) d ꢁ5.45, ꢁ5.30, ꢁ5.24, ꢁ5.07,
17.90, 18.34, 25.46, 25.88, 27.17, 30.91, 37.19, 39.37,
1
12,700); H NMR (CDCl3) d ꢁ0.35, ꢁ0.05, ꢁ0.03, and 0.02
(12H, each as s), 0.78 and 0.79 (18H, each as s), 4.41 (1H,
d, J¼11.0 Hz), 4.76 (1H, d, J¼11.0 Hz), 5.05 (1H, d,
J¼5.4 Hz), 5.12 (1H, dd, J¼5.4 and 6.9 Hz), 5.67 (2H, br),
6.07 (1H, d, J¼6.9 Hz), 7.46e7.50, 7.59e7.61, and 8.03e
8.06 (5H, each as m), 7.62 (1H, s), 7.88 (1H, s); 13C NMR
(CDCl3) d ꢁ5.54, ꢁ5.52, ꢁ5.22, ꢁ5.02, 17.86, 18.08, 25.47,
25.63, 38.63, 66.05, 71.88, 90.42, 110.99, 120.24, 128.34,
129.76, 130.65, 133.06, 140.40, 149.84, 152.86, 155.47,
164.37; FABMS (m/z) 726 (MþþH). Anal. Calcd for C29H44I-
N5O5Si2: C, 47.99; H, 6.11; N, 9.65. Found: C, 48.10; H, 6.09;
N, 9.65.
3.1.2. 40-Acetoxy-20,50-bis-O-(tert-butyldimethylsilyl)-30-
deoxy-30-iodoadenosine (7a) and 9-[4-acetoxy-2,5-bis-O-

Y. Kubota et al. / Tetrahedron 64 (2008) 2391e2396
2395
66.40, 73.02, 89.54, 109.92, 120.18, 139.78, 150.13, 153.15,
155.54, 176.13; FABMS (m/z) 706 (MþþH). Anal. Calcd for
C27H48IN5O5Si2: C, 45.95; H, 6.86; N, 9.92. Found: C,
45.91; H, 6.88; N, 9.95.
gave analytically pure 10a (tR¼6.4 min, foam) and 10b
(tR¼8.1 min, foam).
Physical data for 10a: UV (MeOH): lmax 259 nm (3
1
14,600), lmin 227 nm (3 2200); H NMR (CDCl3) d ꢁ0.13,
ꢁ0.07, 0.12, and 0.13 (12H, each as s), 0.80 and 0.95 (18H,
each as s), 2.08 (3H, s), 2.64 (1H, dd, J¼5.6 and 13.9 Hz),
2.85 (1H, dd, J¼7.2 and 13.9 Hz), 3.92 (1H, d, J¼10.3 Hz),
4.01 (1H, d, J¼10.3 Hz), 4.76 (1H, ddd, J¼4.6, 5.6, and
7.2 Hz), 5.74 (2H, br), 6.34 (1H, d, J¼4.6 Hz), 8.11 (1H, s),
8.35 (1H, s); 13C NMR (CDCl3) d ꢁ5.43, ꢁ5.34, ꢁ5.20,
ꢁ5.15, 17.83, 18.40, 21.99, 25.51, 25.92, 33.40, 39.29,
64.60, 76.09, 90.92, 111.22, 119.79, 138.89, 149.98, 153.19,
155.28, 169.58; FABMS (m/z) 538 (MþþH). Anal. Calcd for
C24H43N5O5Si2: C, 53.60; H, 8.06; N, 13.02. Found: C,
53.74; H, 8.22; N, 13.02.
3.1.4. 40-Benzoyloxy-20,50-bis-O-(tert-butyldimethyl-
silyl)cordycepin (9a) and 9-[4-benzoyloxy-2,5-
bis-O-(tert-butyldimethylsilyl)-3-deoxy-a-L-arabino-
furanosyl]adenine (9b)
To a benzene (12 mL) solution of 6 (6a/6b¼1:2, 1.0 g,
1.38 mmol) and AIBN (0.34 g, 2.07 mmol) was added
Bu3SnH (1.11 mL, 4.14 mmol). The resulting solution was re-
fluxed for 3 h. Column chromatography (hexane/EtOAc¼1:1)
of the reaction mixture gave 9 (9a/9b¼1:2.2, 0.77 g, 94%) as
a foam. HPLC separation (CHCl3/MeOH¼80:1) gave analyti-
cally pure 9a (tR¼13.0 min, foam) and 9b (tR¼14.1 min,
foam).
Physical data for 10b: UV (MeOH): lmax 259 nm (3
1
14,300), lmin 227 nm (3 2000); H NMR (CDCl3) d ꢁ0.17,
Physical data for 9a: UV (MeOH) lmax 233 nm (3 16,900)
and 259 nm (3 16,000), lmin 223 nm (3 12,900) and 246 nm (3
ꢁ0.05, 0.10, and 0.12 (12H, each as s), 0.80 and 0.95 (18H,
each as s), 2.09 (3H, s), 2.56 (1H, dd, J¼6.8 and 14.0 Hz),
2.68 (1H, dd, J¼7.2 and 14.0 Hz), 3.89 (1H, d, J¼10.5 Hz),
3.96 (1H, d, J¼10.5 Hz), 5.23 (1H, ddd, J¼5.0, 6.8, and
7.2 Hz), 5.73 (2H, br), 6.07 (1H, d, J¼5.0 Hz), 8.14 (1H, s),
8.34 (1H, s); 13C NMR (CDCl3) d ꢁ5.45, ꢁ5.34, ꢁ5.19,
ꢁ5.15, 17.77, 18.26, 21.98, 25.50, 25.83, 40.61, 65.67,
74.83, 91.37, 110.35, 119.74, 139.40, 150.25, 153.15,
155.33, 169.38; FABMS (m/z) 538 (MþþH). Anal. Calcd for
C24H43N5O5Si2: C, 53.60; H, 8.06; N, 13.02. Found: C,
53.77; H, 8.22; N, 12.98.
1
12,300); H NMR (CDCl3) d ꢁ0.16, ꢁ0.12, 0.14, and 0.15
(12H, each as s), 0.70 and 0.96 (18H, each as s), 2.79 (1H,
dd, J¼5.4 and 14.1 Hz), 2.98 (1H, dd, J¼7.1 and 14.1 Hz),
4.06 (1H, d, J¼10.4 Hz), 4.22 (1H, d, J¼10.4 Hz), 4.78 (1H,
ddd, J¼4.4, 5.4, and 7.1 Hz), 5.76 (2H, br), 6.43 (1H, d,
J¼4.4 Hz), 7.42e7.46, 7.55e7.59, and 8.04e8.06 (5H, each
as m), 8.16 (1H, s), 8.36 (1H, s); 13C NMR (CDCl3)
d ꢁ5.43, ꢁ5.33, ꢁ5.29, ꢁ5.18, 17.77, 18.39, 25.40, 25.92,
39.36, 64.54, 76.42, 91.15, 112.10, 119.73, 128.31, 129.84,
130.22, 133.25, 138.73, 149.92, 153.19, 155.42, 165.20;
FABMS (m/z) 600 (MþþH). Anal. Calcd for C29H45N5O5Si2:
C, 58.06; H, 7.56; N, 11.67. Found: C, 58.45; H, 7.72; N,
11.87.
3.1.6. 20,50-Bis-O-(tert-butyldimethylsilyl)-4-
pivaloyloxycordycepin (11a) and 9-[2,5-bis-O-(tert-
butyldimethylsilyl)-3-deoxy-4-pivaloyloxy-a-L-
lyxofuranosyl]adenine (11b)
Physical data for 9b: UV (MeOH): lmax 234 nm (3 16,900)
and 259 nm (3 15,200), lmin 223 nm (3 12,900) and 247 nm (3
These compounds (11a/11b¼1:3.6) were obtained in 77%
yield from 8 (8a/8b¼1:4.0, 147.5 mg, 0.209 mmol) by the pro-
cedure described for the preparation of 9: Bu3SnH (0.17 mL,
0.627 mmol), AIBN (52 mg, 0.314 mmol). The reaction was
continued for 3 h. HPLC separation (CHCl3/MeOH¼70:1)
gave analytically pure 11a (tR¼7.6 min, foam) and 11b
(tR¼8.1 min, foam).
1
12,200); H NMR (CDCl3) d ꢁ0.15, ꢁ0.03, 0.09, and 0.13
(12H, each as s), 0.82 and 0.93 (18H, each as s), 2.69 (1H,
dd, J¼7.1 and 14.1 Hz), 2.87 (1H, dd, J¼7.6 and 14.1 Hz),
4.06 (1H, d, J¼10.5 Hz), 4.13 (1H, d, J¼10.5 Hz), 5.34 (1H,
ddd, J¼5.1, 7.1, and 7.6 Hz), 5.82 (2H, br), 6.14 (1H, d,
J¼5.1 Hz), 7.43e7.47, 7.56e7.61, and 8.00e8.03 (5H, each
as m), 8.18 (1H, s), 8.19 (1H, s); 13C NMR (CDCl3)
d ꢁ5.43, ꢁ5.32, ꢁ5.15, ꢁ5.12, 17.79, 18.24, 25.52, 25.82,
40.64, 65.55, 74.92, 91.57, 111.19, 119.74, 128.42, 129.73,
130.27, 133.33, 139.47, 150.21, 153.11, 155.33, 164.73;
FABMS (m/z) 600 (MþþH). Anal. Calcd for C29H45N5O5Si2:
C, 58.06; H, 7.56; N, 11.67. Found: C, 58.12; H, 7.63; N,
11.57.
1
Physical data for 11a: H NMR (CDCl3) d ꢁ0.20, ꢁ0.12,
0.13, and 0.14 (12H, each as s), 0.77 and 0.96 (18H, each as
s), 1.23 (9H, s), 2.54 (1H, dd, J¼6.8 and 13.8 Hz), 2.90
(1H, dd, J¼7.4 and 13.8 Hz), 3.91 (1H, d, J¼10.1 Hz), 3.97
(1H, d, J¼10.1 Hz), 4.76 (1H, ddd, J¼5.4, 6.8, and 7.4 Hz),
5.65 (2H, br), 6.32 (1H, d, J¼5.4 Hz), 8.10 (1H, s), 8.35
(1H, s); 13C NMR (CDCl3) d ꢁ5.43, ꢁ5.36, ꢁ5.20, 17.94,
18.37, 25.54, 25.92, 27.00, 39.32, 40.27, 64.91, 76.38,
90.51, 110.49, 119.71, 138.95, 150.05, 153.19, 155.30,
177.03; FABMS (m/z) 580 (MþþH). FAB-high resolution
MS (m/z) calcd for C27H50N5O5Si2: 580.3351, found:
580.3339 (MþþH).
3.1.5. 40-Acetoxy-20,50-bis-O-(tert-butyldimethylsilyl)-
cordycepin (10a) and 9-[4-acetoxy-2,5-bis-O-(tert-
butyldimethylsilyl)-3-deoxy-a-L-lyxofuranosyl]-
adenine (10b)
These compounds (10a/10b¼1:2.7) were obtained in 87%
yield from 7 (7a/7b¼1:2.7, 227.4 mg, 0.343 mmol) by the pro-
cedure described for the preparation of 9: Bu3SnH (0.28 mL,
1.028 mmol), AIBN (84.5 mg, 0.515 mmol). The reaction was
continued for 1 h. HPLC separation (CHCl3/MeOH¼60:1)
Physical data for 11b: UV (MeOH): lmax 259 nm (3
1
14,400), lmin 228 nm (3 2500); H NMR (CDCl3) d ꢁ0.13,
ꢁ0.03, 0.10, and 0.12 (12H, each as s), 0.81 and 0.95 (18H,
each as s), 1.21 (9H, s), 2.55 (1H, dd, J¼6.3 and 14.4 Hz),
2.61 (1H, dd, J¼7.1 and 14.4 Hz), 3.89 (1H, d, J¼10.5 Hz),

2396
Y. Kubota et al. / Tetrahedron 64 (2008) 2391e2396
3.98 (1H, d, J¼10.5 Hz), 5.15 (1H, ddd, J¼4.6, 6.3, and
7.1 Hz), 5.62 (2H, br), 6.10 (1H, d, J¼4.6 Hz), 8.19 (1H, s),
8.34 (1H, s); 13C NMR (CDCl3) d ꢁ5.42, ꢁ5.39, ꢁ5.16,
ꢁ5.14, 17.77, 18.25, 25.52, 25.83, 27.01, 39.31, 40.52,
65.70, 75.21, 91.27, 110.51, 119.65, 139.17, 150.19, 153.14,
155.32, 176.80; FABMS (m/z) 580 (MþþH). Anal. Calcd for
C27H43N5O5Si2: C, 55.92; H, 8.52; N, 12.08. Found: C,
55.95; H, 8.48; N, 12.38.
Acknowledgements
Financial support from Showa University Research Grant
for Young Researchers (Y.K.) is gratefully acknowledged.
References and notes
1. Cunningham, K. G.; Hutchinson, S. A.; Manson, W.; Spring, F. S.
J. Chem. Soc. 1951, 2299.
3.1.7. 40-Allyl-20,50-bis-O-(tert-butyldimethyl-
silyl)cordycepin (12)
2. Bentley, H. R.; Cunningham, K. G.; Spring, F. S. J. Chem. Soc. 1951, 2301.
3. Kaczka, E. A.; Dulaney, E. L.; Gitterman, C. O.; Woodruff, H. B.; Folkers,
K. Biochem. Biophys. Res. Commun. 1964, 14, 452.
To a CH2Cl2 (5.0 mL) solution of 9 (9a/9b¼1:2, 50 mg,
0.083 mmol) were added Me3SiCH2CH]CH2 (0.07 mL,
0.417 mmol) and then SnCl4 (1.0 M in CH2Cl2, 0.42 mL,
0.417 mmol) at 0 ꢂC under positive pressure of dry Ar. The re-
action mixture was stirred at rt for 2 h. After being quenched
with saturated aqueous NaHCO3, the reaction mixture was fil-
tered through a Celite pad. The filtrate was extracted with
CH2Cl2. Column chromatography (hexane/EtOAc¼1:2) gave
12 (19 mg, 44%) as a syrup.
UV (MeOH): lmax 260 nm (3 14,800), lmin 229 nm (3
2200); 1H NMR (CDCl3) d ꢁ0.18, ꢁ0.11, 0.12, and 0.14
(12H, each as s), 0.79 and 0.96 (18H, each as s), 2.00 (1H,
dd, J¼7.1 and 12.9 Hz), 2.39 (1H, dd, J¼7.3 and 12.9 Hz),
2.46 (2H, d, J¼7.1 Hz), 3.56 (1H, d, J¼10.5 Hz), 3.76 (1H,
d, J¼10.5 Hz), 4.82 (1H, ddd, J¼5.1, 7.1, and 7.3 Hz),
5.14e5.19 (2H, m), 5.84e5.91 (3H, m), 5.99 (1H, d,
J¼5.1 Hz), 8.22 (1H, s), 8.35 (1H, s); 13C NMR (CDCl3)
d ꢁ5.42, ꢁ5.37, ꢁ5.23, ꢁ5.20, 17.81, 18.44, 25.52, 26.01,
38.88, 42.27, 68.38, 77.27, 86.74, 90.05, 119.07, 119.68,
132.90, 139.15, 150.00, 152.89, 155.33; FABMS (m/z) 520
(MþþH). Anal. Calcd for C25H45N5O3Si2: C, 57.76; H,
8.73; N, 13.47. Found: C, 57.87; H, 8.91; N, 13.25.
4. Kaczka, E. A.; Trenner, N. R.; Arison, B.; Walker, R. W.; Folkers, K.
Biochem. Biophys. Res. Commun. 1964, 14, 456.
5. Shigeura, H. T.; Gordon, C. N. J. Biol. Chem. 1965, 240, 806.
6. Glazer, R. I.; Peale, A. L. Biochem. Biophys. Res. Commun. 1978, 81, 521.
7. Hunting, D.; Henderson, J. F. Biochem. Pharmacol. 1978, 27, 2163.
8. Walton, E.; Holly, F. W.; Boxer, G. E.; Nutt, R. F.; Jenkins, S. R. J. Med.
Chem. 1965, 8, 659.
9. Hayakawa, H.; Tanaka, H.; Sasaki, K.; Haraguchi, K.; Saitoh, T.; Takai, F.;
Miyasaka, T. J. Heterocycl. Chem. 1989, 26, 189.
10. Ikejiri, M.; Ohshima, T.; Kato, K.; Toyama, M.; Murata, T.; Shimotohno,
K.; Maruyama, T. Bioorg. Med. Chem. 2007, 15, 6882.
11. (a) Koole, L. H.; Buck, H. M.; Bazin, H.; Chattopadhyaya, J. Tetrahedron
1987, 43, 2989; (b) Bazin, H.; Chattopadhyaya, J. Chem. Scr. 1986, 26, 13.
12. Hayakawa, H.; Kohgo, S.; Kitano, K.; Ashida, N.; Kodama, E.; Mitsuya,
H.; Ohrui, H. Antiviral Chem. Chemother. 2004, 15, 169.
13. The EC50 values of these compounds were taken from Ref. 7.
14. Itoh, Y.; Haraguchi, K.; Tanaka, H.; Gen, E.; Miyasaka, T. J. Org. Chem.
1995, 60, 656.
15. Haraguchi, K.; Sumino, M.; Tanaka, H. J. Org. Chem. 2006, 71, 4433.
16. Jain, T. C.; Jenkins, I. D.; Russell, A. F.; Verheyden, J. P. H.; Moffatt, J. G.
J. Org. Chem. 1974, 39, 30.
17. Kubota, Y.; Haraguchi, K.; Kunikata, M.; Hayashi, M.; Ohkawa, M.;
Tanaka, H. J. Org. Chem. 2006, 71, 1099.
18. Compound 5, upon reacting with NBS/MeOH by using CH2Cl2 as a sol-
vent, gave the corresponding addition product in high yield, which
contrasts to this particular reaction with NBS/PhCO2H.
19. NOE data for the syn-adduct (6a): H-50b/H-8 (0.5%); H-50b/H-30 (1.1%).
NOE data for the anti-adduct (6b): H-50b/H-10 (0.5%); H-8/H-30 (0.2%).
Of the two protons at the 50-position, the one that appears at a higher field
is designated as H-50a, and the other as H-50b. This applies to notes 20, 22,
24 and 25.
20. NOE data for 7a: H-30/H-8 (4.3%); H-8/H-50b (0.4%); H-50b/H-8(0.5%); H-
50b/H-30 (1.1%); H-50a/H-30 (2.3%); acetoxy/H-10 (0.5%). NOE data for 7b:
H-50a/H-10 (0.7%); acetoxy/H-2 (1.0%); acetoxy/H-8 (0.2%); acetoxy/H-20
(0.3%);acetoxy/H-30 (0.1%). NOE data for 8a: H-8/H-30 (2.1%);H-50a/H-30
(1.7%). NOE data for 8b: H-50a/H-10 (0.6%); pivaloyloxy/H-2 (3.7%); piv-
aloyloxy/H-8 (3.7%); pivaloyloxy/H-20 (2.3%); pivaloyloxy/H-30 (0.9%).
21. For radical-mediated 1,2-acyoxy migration: Itoh, Y.; Haraguchi, K.;
Tanaka, H.; Matsumoto, K.; Nakamura, K. T.; Miyasaka, T. Tetrahedron
Lett. 1995, 36, 3867 and references cited therein.
3.1.8. 20,50-Bis-O-(tert-butyldimethylsilyl)-40-
cyanocordycepin (13)
This compound was obtained in 58% yield from 9 (9a/
9b¼1:2, 50 mg, 0.083 mmol) by the procedure described for
the preparation of 12: Me3SiCN (0.053 mL, 0.42 mmol),
SnCl4 (1.0 M in CH2Cl2, 0.42 mL, 0.42 mmol). The reaction
mixture was stirred at rt for 3 h.
UV (MeOH): lmax 259 nm (3 15,100), lmin 228 nm (3
1
2900); IR (neat) 2240 cmꢁ1 (CN); H NMR (CDCl3) d 0.10
and 0.11 (12H, each as s), 0.91 and 0.93 (18H, each as s),
2.34 (1H, dd, J¼2.2 and 13.7 Hz), 2.90 (1H, dd, J¼5.4 and
13.7 Hz), 3.92 (1H, d, J¼10.8 Hz), 4.11 (1H, d, J¼10.8 Hz),
5.00 (1H, ddd, J¼2.0, 2.2, and 5.4 Hz), 5.72 (2H, br), 6.11
(1H, d, J¼2.0 Hz), 8.02 (1H, s), 8.33 (1H, s); 13C NMR
(CDCl3) d ꢁ5.50, ꢁ5.44, ꢁ5.09, ꢁ4.86, 17.83, 18.41, 25.51,
25.80, 39.89, 66.15, 75.86, 80.82, 93.53, 118.94, 120.17,
139.14, 149.34, 153.07, 155.40; FABMS (m/z) 505 (MþþH).
Anal. Calcd for C23H40N6O3Si2: C, 54.73; H, 7.99; N,
16.65. Found: C, 54.78; H, 8.09; N, 16.39.
22. NOE data for 9a: H-50a/H-8 (0.7%); H-50b/H-30b (1.1%); H-8/H-30b
(0.7%). NOE data for 9b: H-10/H-30a (1.0%); H-50b/H-10 (0.5%); H-50b/
H-30a (1.4%); H-50a/H-10 (0.9%); H-50a/H-30a (2.0%).
23. Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic
Synthesis; Academic: London, UK, 1992.
24. NOE data for 12: H-20/H-50b (0.3%); H-50b/H-8 (0.8%); H-50b/H-20
(0.9%); H-30a/H-8 (0.8%); H-30a/H-20 (11.1%); H-30a/H-50a (2.4%).
25. NOE data for 13: H-50a/H-8 (0.3%); H-50a/H-30b (1.7%); H-50b/H-8
(0.4%); H-50b/H-30b (1.1%); H-8/H-30b (0.8%); H-8/H-50b (0.3%).