Radical-mediated stannylation of vinyl sulfones: access to novel 4′-modified neplanocin A analogues

Article abstract of DOI:10.1016/j.tet.2009.07.039

Synthesis of 4′-substituted (halogeno, phenyl, ethynyl, and cyano) neplanocin A analogues was carried out. A cyclopentenol derivative having a vinylstannane structure was designed as key-intermediate in this study, which was prepared based on radical-mediated sulfur-extrusive stannylation. The resulting stannylated cyclopentenol 15 was successfully condensed with 6-chloropurine through the Mitsunobu reaction, leading to the carbocyclic nucleoside 20. Compound 20 was converted to its adenine counterpart 21 by treatment with NH₃/MeOH, during which the 4′-stannyl group remained intact. The title compounds were prepared by using 21 or the 4′-iodo derivative (22) mostly through the Stille reaction.

Full text of DOI:10.1016/j.tet.2009.07.039

Tetrahedron 65 (2009) 8007–8013
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical-mediated stannylation of vinyl sulfones: access to novel 40-modified
neplanocin A analogues
,
a
a
a
a
Hiroki Kumamoto a , Kazuki Deguchi , Tadashi Wagata , Yuu Furuya , Yuki Odanaka ,
*
Yukio Kitade b, Hiromichi Tanaka a
a School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
b Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Synthesis of 40-substituted (halogeno, phenyl, ethynyl, and cyano) neplanocin A analogues was carried
out. A cyclopentenol derivative having a vinylstannane structure was designed as key-intermediate in
this study, which was prepared based on radical-mediated sulfur-extrusive stannylation. The resulting
stannylated cyclopentenol 15 was successfully condensed with 6-chloropurine through the Mitsunobu
reaction, leading to the carbocyclic nucleoside 20. Compound 20 was converted to its adenine coun-
terpart 21 by treatment with NH3/MeOH, during which the 40-stannyl group remained intact. The title
compounds were prepared by using 21 or the 40-iodo derivative (22) mostly through the Stille reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 2 July 2009
Received in revised form 18 July 2009
Accepted 20 July 2009
Available online 23 July 2009
Keywords:
Carbocyclic nucleoside
Neplanocin A
Vinylstannane
Radical reaction
Sulfur-extrusive stannylation
1. Introduction
a rational approach to avoid metabolic transformation to the cor-
responding nucleotide. In this context, the 60-deoxy analogues like
Neplanocin A (NepA, 1 in Fig. 1) is an antibiotic isolated from
Ampullariella regularis.1 This compound has a wide range of anti-
viral activities2 as well as antimalarial activity,3 which are known to
2–5 have already been synthesized either from NepA itself6 or from
carbohydrate precursors.7 However, it has been reported that only
27 retains the inhibitory activity against SAH hydrolase.5,8
To further evaluate the NepA analogues lacking the 60-hydroxyl
group as SAH hydrolase inhibitors, we planned to develop a new
synthetic approach, which allows the introduction of several car-
bon-functionalities into the 40-position of 2. Herein we report the
synthesis of the 40-halogeno, 40-phenyl, 40-ethynyl, and 40-cyano
analogues of 2 from a common vinylstannane intermediate, the
preparation of which is based on radical-mediated stannylation of
a vinyl sulfone.
be associated with its inhibition of S-adenosyl-L-homocysteine
hydrolase (SAH hydrolase).4 On the other hand, because of its
structural similarity to adenosine, NepA acts as a substrate for
adenosine kinase and hence it shows cytotoxic effects.5 In order for
NepA to serve solely as an inhibitor against SAH hydrolase without
showing cytotoxicity, removal of its 60-hydroxyl group is certainly
NH2
N
NH2
N
N
N
N
N
2. Results and discussion
2.1. Synthetic plan
2 R = H
3 R = CH3
N
N
5'
HO
4'
3'
1'
R
6'
2'
4 R = CH2F
Our synthetic plan for the target compounds A is shown in
Scheme 1. Compound A can be prepared from a common in-
termediate B by employing the Stille reaction.9 A conventional SN2
displacement of C will lead to B by the use of adenine or its syn-
thetic equivalent as a nucleophile. Transformation of the vinyl
sulfide or the vinyl sulfone D to the vinylstannane C is certainly
a key-step in this synthetic scheme, and we expected that radical-
mediated sulfur-extrusive stannylation would be applicable.10,11
OH
HO
HO
OH
5 R = CH=CH2
1
Figure 1. Structures of compounds 1–5.
* Corresponding author. Tel.: þ81 3 3784 8187; fax: þ81 3 3784 8252.
E-mail address: kumamoto@pharm.showa-u.ac.jp (H. Kumamoto).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.039

8008
H. Kumamoto et al. / Tetrahedron 65 (2009) 8007–8013
The preparation of D can be carried out starting with the known
optically active cyclopentene E by following a sequence of re-
actions: 1,4-addition of benzenethiol, oxidation to regenerate an
enone system, and selective 1,2-reduction.
under the Luche conditions17 gave the desired sulfide 13. The sul-
fone 14 was prepared simply by oxidation of 13 with m-CPBA.
2.3. Radical-mediated stannylation of 13 and 14
NH2
N
NH2
N
Reaction of the sulfur functionalities in 13 and 14 with tribu-
tyltin radical was next examined (Scheme 3). These reactions were
uniformly carried out in the presence of i-Pr2NEt to prevent de-
composition of the product as reported previously.10e,11f When the
sulfide 13 was reacted with Bu3SnH (3 equiv) in the presence of
AIBN (0.5 equiv) and i-Pr2NEt (3 equiv) in refluxing benzene for 4 h,
only a trace amount of the stannylated product (15) was formed
(Table 1, entry 1). The sulfone 14, on the other hand, gave a higher
yield of 52% (entry 2). Several attempts were made by increasing
the amount of Bu3SnH, prolonging the reaction time, and carrying
out the reaction at higher temperature, but no significant im-
provement was seen in the yield of 15 from 14.
N
N
N
N
N
N
R
Bu3Sn
PgO
OH
OPg
HO
A
B
R = phenyl, ethynyl, cyano
Bu3Sn
PgO
Pg = protecting group
OH
OPg
C
O
OPg
PhS(O)n
OH
OPg
n = 0 or 2
PgO
PgO
Bu3Sn
PhOnS
O
E
D
Bu3SnH (3 equiv)
AIBN (0.5 equiv)
Scheme 1. Synthetic plan.
OR
OR
i-Pr2NEt (3 equiv)
benzene, reflux
4h
O
O
2.2. Synthesis of the sulfur substrates (13 and 14) for
radical-mediated stannylation
O
13 n = 0, R = H
14 n = 2, R = H
16 n = 2, R = TBDMS
18 n = 2, R = Bz
15 R = H
17 R = TBDMS
19 R = Bz
We selected the cyclopentenone 67,12 for the preparation of D in
Scheme 1. Compound 6 was prepared from 7 by the reported method
with a slight modification. As shown in Scheme 2, commercially
Scheme 3. Sulfur-extrusive stannylation of 13–18.
available methyl a-D-mannopyranoside 7 was converted tothe iodide
and then protected as an acetonide to yield 8.13 Treatment of 8 with
Zn-powder in refluxing EtOH/H2O gave the hemiacetal 914 in quan-
titative yield. The Wittig reaction of 9 by using Ph3P]CH2 readily
proceeded to give the diene 10.15 The requisite cyclopentenone 6 was
obtained by ring closing metathesis of 1012a–d and subsequent PDC
oxidation of the resulting allyl alcohol in a one-pot manner.
Table 1
Radical-mediated stannylation of 13–18
Entry
Substrate
Yield (%) of the product
Recovery (%)
1
2
3
4
13
14
16
18
4 (15)
94 (13)
32 (14)
21 (16)a
6 (18)a
52 (15)
79 (17)a
94 (19)a
I
OH
HO
O
Calculated by 1H NMR spectroscopy.
a
MeO
HO
MeO
O
O
O
O
a, b
c
It was found that the silyl protected vinyl sulfone 16 gave
a higher yield of the stannylated product 17 (entry 3). When the
benzoyl protected vinyl sulfone 18 was employed as a substrate, the
highest yield of the product (19) was realized (entry 4). Practically,
the requisite 15 can be obtained in 90% yield simply by evaporating
the reaction mixture containing 19 and then treating the residue
with NaOMe/MeOH.
Direct introduction of adenine base to 15 through the Mitsu-
nobu reaction (DEAD/Ph3P/THF)18 was found to be discouraging,
due to the difficulty to separate the resulting carbocyclic adenine-
nucleoside 21 from diethyl 1,2-hydrazinedicarboxylate and Ph3PO.
The use of 6-chloropurine allowed the isolation of 20 in 80% yield
after column chromatography (Scheme 4). The depicted N9-
substituted regiochemistry of 20 was confirmed by HMBC spec-
trum (correlation between H-10 and C-4). Treatment of 20 with
NH3/MeOH in a sealed tube at 120 ꢀC for 47 h gave the 40-tribu-
tylstannyl derivatives (21) in 87% yield. Since we have experienced
OH
OH
O
O
HO
7
8
9
d
PhS
g
e, f
O
O
O
O
OH
O
O
O
O
10
11
6
h
PhO2S
O
PhS
O
PhS
O
i
j
OH
OH
O
O
O
O
14
12
13
Scheme 2. Reagents and conditions: (a) I2, Ph3P, imidazole, THF, reflux; (b) 2,2-di-
methoxypropane, TsOH, acetone, rt, (93% from 7); (c) Zn-powder, EtOH, H2O, 100 ꢀC,
(93%); (d) Ph3PCH3Br, NaH, DMSO, THF, reflux; (e) Grubbs first generation catalyst,
CH2Cl2, rt; (f) PDC, CH2Cl2, (72% from 9); (g) PhSH, Et3N, CH2Cl2, rt, (81%); (h) NCS,
CH2Cl2, rt, (94%); (i) NaBH4, CeCl3$7H2O, MeOH, ꢁ40 ꢀC, (99%); (j) m-CPBA, CH2Cl2, rt,
(100%).
X
N
6-chloropurine
DIAD, PPh3
N
N
N
Bu3Sn
15
THF
O
O
The sulfide (13) and sulfone (14) to be used for radical stanny-
lation were prepared as follows. Compound 6 was subjected to 1,4-
addition of PhSH to give 11. Treatment of 11 with NCS allowed
regeneration of the double bond through the Pummerer type
oxidation.16 Stereoselective 1,2-reduction of the resulting enone 12
20 X = Cl (80%)
21 X = NH2 (87%)
NH3/MeOH
Scheme 4. Mitsunobu reaction of 15 and further conversion of the product (20) to 21.

H. Kumamoto et al. / Tetrahedron 65 (2009) 8007–8013
8009
that a tributylstannyl group attached to an sp2-hybridized carbon
3. Experimental section
3.1. General
underwent protonolysis upon reacting with NH3/MeOH,19 the ob-
served successful conversion from 20 to 21 under the above con-
siderably forced reaction conditions was surprising.
Preparation of the 40-halogeno, 40-phenyl, 40-ethynyl analogues
was carried out by employing either 21 or the 40-iodo derivative 22
(Table 2 and Fig. 2), the latter was readily obtained in quantitative
yield by reacting 21 with iodine in THF (entry 1 in Table 2). Bromi-
nation and chlorination of 21 wereperformed by using NBS or NCSto
give the respective 40-halogeno derivative (23, 67%; 24, 49%) (entries
2 and 3). The 40-phenyl analogue 25 was prepared in a moderate
yield through the Stille reaction between 21 and iodobenzene in
DMF (entry 4). For the preparation of the ethynyl analogues (26 and
27), the cross-coupling reaction between the 40-iodo derivative 22
and the respective organotin reagents was successfully applied
(entries 5 and 6).
1H and 13C NMR spectra were recorded either at 400 MHz or at
500 MHz. Chemical sifts are reported relative to Me4Si. Mass
spectra (MS) were taken in FAB mode with m-nitrobenzyl alcohol
as a matrix. Column chromatography was carried out on silica gel.
Thin-layer chromatography (TLC) was performed on precoated
silica gel plate F254. When necessary, analytical samples were
purified by high performance liquid chromatography (HPLC). THF
was distilled from benzophenone ketyl.
3.2. Methyl 6-deoxy-6-iodo-2,3-O-isopropylidene-a-D-
mannopyranoside (8)
This compound was prepared by the reported method17 with
a slight modification. To a suspension of methyl -mannopyr-
Table 2
a-D
Conversion of the 40-tributylstannyl group of 21
anoside 7 (30.0 g, 155 mmol), imidazole (21.0 g, 309 mmol), and
Ph3P (60.9 g, 232 mmol) in THF (400 mL) was added I2 (58.9 g,
232 mmol) in several portions. The resulting mixture was refluxed
for 2 h, and then all the volatiles were evaporated. The residue was
dissolved in a mixture of acetone (900 mL) and 2,2-dimethoxy-
propane (100 mL). To this was added TsOH$H2O (17.6 g, 92.7 mmol)
at 0 ꢀC. After stirring for 5 min, the reaction mixture was allowed to
warm to rt and stirred further 1 h. After addition of Et3N (100 mL),
approximately two-thirds of volatiles were evaporated. The re-
action mixture was partitioned between CH2Cl2 and saturated
aqueous NaHCO3. Column chromatography (hexane/EtOAc¼4/1) of
the organic layer gave 813 (49.4 g, 93%) as a solid.
Entry Substrate Condition
Products (% yield by
isolation)
1
2
3
4
21
21
21
21
22
22
22
22
22
I2/THF, rt
NBS/THF, rt
NCS/THF, rt
PhI, (PPh3)2PdCl2, CuI/DMF, 120 ꢀ
22 (100)
23 (67)
24 (49)
25 (51)
26 (83)
27 (100)
28 (9), 21 (11)
28 (25), 21 (20)
28 (73)
C
5
Bu3SnC, CH^Pd(PPh3)4, CuI/THF, rt
Bu3SnC, CMe^Pd(PPh3)4, CuI/THF, rt
6
7a
8
Bu3SnCN, Pd(PPh3)4, CuI/DMF, 120 ꢀ
C
Bu3SnCN, Pd(PPh3)4/dioxane, 90 ꢀ
Bu3SnCN, (PPh3)2PdCl2, CuI/DMF, 120 ꢀ
C
9b
C
a
The reaction was carried out in the presence of 0.2 equiv of CuI.
CuI (1.0 equiv) was used.
b
3.3. 5,6-Dideoxy-2,3-O-isopropylidene-a-D-lyxo-hex-5-
enofuranose (9)
NH2
N
21 R = SnBu3
22 R = I
N
23 R = Br
N
A mixture of 8 (47.4 g, 138 mmol), Zn-powder (46.5 g), H2O
(80 mL), and EtOH (160 mL) was refluxed for 3 h. The mixture was
filtered through a Celite pad and washed with EtOH. The filtrate was
evaporated, and then partitioned between CH2Cl2 and saturated
aqueous NaHCO3. Column chromatography (hexane/EtOAc¼4/1) of
the organic layer gave 914,15 (23.8 g, 93%) as an oil.
N
24 R = Cl
25 R = Ph
26 R = C CH
27 R = C CMe
28 R = CN
R
O
O
Figure 2. Structures of compounds 21–28.
3.4. (1R,40S,50R)-1-(20,20-Dimethyl-50-vinyl[10,30]dioxol-40-
Introduction of a cyano group was also carried out. Compound 22
was reacted with Bu3SnCN in the presence of a catalytic amount of
Pd(PPh3)4 and CuI in DMF according to the reported method (entry
7).20a This reaction, however, gave the desired 40-cyano analogue 34
onlyin9%yield.Anadditionalproductfromthisreactionwas21 (11%),
apparently formed as a consequence of transfer of SnBu3 group from
the reagent. A similar trend was also observed when the reaction was
carried out in the absence of CuI in refluxing dioxane (entry 8).20b
Successful result was obtained by employing stoichiometric amount
of CuI in combination with PdCl2(PPh3)2 in DMF (entry 9).10e
Finally, the above synthesized compounds (22–28) were treated
with 50% aqueous HCO2H to give the respective free 40-substituted
Nep A analogues (29–35, Fig. 3) uniformly in high yields. Evaluation
of antiviral and antimalarial activities of these compounds is
a subject of our future studies.
yl)prop-2-en-1-ol (10)
To a stirred suspension of NaH (60% oil-dispersion, 9.60 g,
255 mmol) in THF (500 mL) was added DMSO (26.6 mL, 375 mmol)
at 0 ꢀC. After stirring for 5 min, the mixture was allowed to warm to
rt and stirred for 1 h, and then reacted with Ph3PCH3Br (91.0 g,
255 mmol) by adding at 0 ꢀC and stirring for 1.5 h at rt. A THF
(200 mL) solution of 9 (27.1 g, 150 mmol) was added to the above
mixture at 0 ꢀC and the resulting solution was refluxed for 4 h. After
cooling the reaction mixture, approximately two-thirds of volatiles
were evaporated. The reaction mixture was partitioned between
Et2O and saturated aqueous NH4Cl. Column chromatography
(hexane/EtOAc¼4/1) of the organic layer gave 1012a 15 (22.2 g, 80%)
,
as an oil.
NH2
29 R = I
3.5. (3aR,6aR)-2,2-Dimethyl-3a,6a-dihydrocyclopenta[1,3]-
N
30 R = Br
dioxol-4-one (6)
N
31 R = Cl
32 R = Ph
N
N
A mixture of 10 (9.70 g, 52.7 mmol) and Grubbs first generation
catalyst (430 mg, 0.530 mmol) in CH2Cl2 (200 mL) was stirred at rt
under positive pressure of dry Ar for 2 days. The reaction mixture
was treated with PDC (39.7 g, 106 mmol) by stirrring at rt for fur-
ther 2 days. After adding AcOEt (ca. 50 mL), the reaction mixture
was filtered through a silica gel pad. The resulting filtrate was
R
33 R = C CH
34 R =C CMe
35 R = CN
HO OH
Figure 3. Compounds 29–35.

8010
H. Kumamoto et al. / Tetrahedron 65 (2009) 8007–8013
25
evaporated and purified by column chromatography (hexane/
a solid: mp 176–178 ꢀC; [
(CDCl3)
a]
þ129.1 (c 1.580, CHCl3), 1H NMR
D
25
EtOAc¼2/1). This gave 67,12(7.20 g, 89%) as a solid: [
a
]
D
ꢁ69.3 (c
d
0.89 and 1.29 (6H, each as s, CMe2), 2.80 (1H, d, J¼10.0 Hz,
25
1.80, CHCl3), [lit12e
[
a]
ꢁ70.8 (c 0.92, CHCl3)].
OH), 4.67 (1H, ddd, J¼10.0, 5.5 and 1.8 Hz, H-1), 4.84 (1H, td, J¼5.5
and 0.7 Hz, H-2), 5.26 (1H, d, J¼5.5 Hz, H-3), 6.77 (1H, t, J¼0.9 Hz,
H-5), 7.53–7.57 (2H, m, Ph), 7.63–7.64 (1H, m, Ph), 7.97–8.00 (2H, m,
D
3.6. (2R,3S,4S)-2,3-Isopropylidenedioxy-4-
(phenylthio)cyclopentan-1-one (11)
Ph); 13C NMR (CDCl3)
d 26.46, 26.53, 72.45, 78.37, 81.17, 113.55,
128.86, 128.97, 133.75, 139.94, 144.76, 145.98; FABMS m/z 297
(MþþH). Anal. Calcd for C14H16O5S: C, 56.74; H, 5.44. Found: C,
56.81; H, 5.37.
A
mixture of 11 (376 mg, 2.44 mmol), PhSH (0.250 mL,
2.44 mmol), and Et3N (14.0 mL, 0.100 mmol) in CH2Cl2 (4 mL) was
stirred at 0 ꢀC for 0.5 h, and then at rt for 2 h under positive pres-
sure of dry Ar. The reaction mixture was partitioned between CHCl3
and saturated aqueous NaHCO3. Column chromatography (hexane/
3.10. Radical reaction of 13 (entry 1 in Table 1)
EtOAc¼20/1) of the organic layer gave 11 (520 mg, 81%) as a solid:
A benzene (2 mL) solution of 13 (50.0 mg, 0.190 mmol), i-Pr2NEt
24
mp 105–107 ꢀC; [
a]
ꢁ214.7 (c 1.13, CHCl3); 1H NMR (CDCl3)
d
1.31
(100
(16.0 mg, 100
m
L, 0.570 mmol), Bu3SnH (150
mL, 0.570 mmol), and AIBN
D
and 1.43 (6H, each as s, CMe2), 2.30 (1H, dq, J¼18.8 and 1.3 Hz, H-5),
3.09 (1H, ddd, J¼18.8, 7.6 and 0.7 Hz, H-5), 3.97 (1H, d, J¼7.6 Hz, H-
4), 4.36 (1H, d, J¼5.1 Hz, H-2), 4.69 (1H, d, J¼5.1 Hz, H-3), 7.28–7.42
m
mol) was heated at 80 ꢀC for 4 h with stirring.
Evaporation of the solvent followed by column chromatography
(hexane/EtOAc¼10/1) gave 15 (3.00 mg, 4%, oil) and 13 (47.0 mg,
24
(5H, m, Ph); 13C NMR (CDCl3)
d
24.93, 26.72, 39.43, 42.47, 77.94,
94% recovery). Physical data of 15: [
a]
þ29.9 (c 0.650, CHCl3); 1H
D
80.79, 113.05, 127.86, 129.43, 131.51, 132.47, 210.96; FABMS m/z 265
(MþþH). Anal. Calcd for C14H16O3S: C, 63.61; H, 6.10. Found: C,
63.63; H, 6.04.
NMR (CDCl3)
d
0.89 (9H, t, J¼7.3 Hz, Sn(CH2)3CH3), 0.95–0.99 (6H,
m, Sn(CH2)3), 1.25–1.32 (6H, m, Sn(CH2)3), 1.36 and 1.38 (6H, each as
s, CMe2), 1.48–1.55 (6H, m, Sn(CH2)3), 2.62 (1H, d, J¼10.3 Hz, OH),
4.57 (1H, ddd, J¼10.3, 5.4 and 1.3 Hz, H-1), 4.69 (1H, t, J¼5.4 Hz, H-
2), 5.03 (1H, d, J¼5.4 Hz, H-3), 5.89 (1H, t, J¼15.4 Hz, H-5); 13C NMR
3.7. (2R,3R)-2,3-Isopropylidenedioxy-4-phenylthio-4-
cyclopenten-1-one (12)
(CDCl3) d 9.4, 13.7, 27.0, 27.3, 27.9, 29.0, 76.8, 89.7, 111.9, 144.9, 147.7;
FABMS m/z 485 (MþþK). Anal. Calcd for C20H38O3Sn: C, 53.95; H,
A mixture of 11 (200 mg, 0.760 mmol) and NCS (111 mg,
0.830 mmol) in CH2Cl2 (5 mL) was stirred at rt for 1 h under
positive pressure of dry Ar. The reaction mixture was partitioned
between CHCl3 and saturated aqueous NaHCO3. Column chromato-
8.60. Found: C, 54.25; H, 8.78.
3.11. Radical reaction of 14 (entry 2 in Table 1)
graphy (hexane/EtOAc¼10/1) of the organic layer gave 12 (187 mg,
A mixture of 14 (967 mg, 3.26 mmol), i-Pr2NEt (1.70 mL,
24
94%) as a solid: mp 144–146 ꢀC; [
a]
ꢁ161.5 (c 0.805, CHCl3); 1H
9.79 mmol), Bu3SnH (2.63 mL, 9.79 mmol), and AIBN (268 mg,
1.63 mmol) in benzene (19 mL) was stirred at 80 ꢀC for 4 h under
positive pressure of dry Ar. Column chromatography (hexane/
EtOAc¼10/1) of the reaction mixture gave 15 (758 mg, 52%, oil) and
14 (329 mg, 32% recovery).
D
NMR (CDCl3)
d 1.45 and 1.48 (6H, each as s, CMe2), 4.57 (1H, d,
J¼5.6 Hz, H-2), 5.20 (1H, d, J¼5.6 Hz, H-3), 5.46 (1H, s, H-5), 7.43–
7.51 (3H, m, Ph), 7.54–7.56 (2H, m, Ph); 13C NMR (CDCl3)
d
26.45,
27.46, 78.96, 79.42, 115.58, 124.11, 128.04, 130.07, 130.47, 134.50,
178.95, 198.03; FABMS m/z 263 (MþþH). Anal. Calcd for C14H14O3S:
C, 64.10; H, 5.38. Found: C, 64.01; H, 5.27.
3.12. (1S,2S,3S)-4-Benzenesulfonyl-1-tert-
butyldimethylsilyloxy-2,3-isopropylidenedioxy-4-
cyclopentene (16)
3.8. (1S,2S,3S)-2,3-Isopropylidenedioxy-4-phenylthio-4-
cyclopenten-1-ol (13)
A mixture of 14 (300 mg, 1.01 mmol), imidazole (206 mg,
3.03 mmol), DMAP (124 mg, 1.01 mmol), and TBDMSCl (305 mg,
2.02 mmol) in MeCN (10 mL) was stirred at rt for 24 h. The reaction
mixture was partitioned between CH2Cl2 and saturated aqueous
To a solution of 12 (336 mg, 1.28 mmol) and CeCl3$7H2O
(477 mg, 1.28 mmol) in MeOH (33 mL) was added NaBH4 (58.0 mg,
1.54 mmol) at 40 ꢀC in several portions. The reaction mixture was
stirred for 1.5 h, quenched by adding AcOH (88.0
and diluted with acetone. Evaporation of the solvents was followed
by partition of the residue between CHCl3 and H2O. The organic
m
L, 1.54 mmol),
NaHCO3. Column chromatography (hexane/EtOAc¼2/1) of the or-
23
ganic layer gave 16 (237 mg, 57%) as a solid: mp 126–129 ꢀC; [
a]
D
þ108.0 (c 0.685, CHCl3); 1H NMR (CDCl3)
d 0.09 (3H, s, SiMe), 0.13
layer was dried (Na2SO4) and evaporated to give 13 (335 mg, 99%)
(3H, s, SiMe), 0.79 (3H, s, Me), 0.90 (9H, s, SiBu-t), 1.23 (3H, s, Me),
4.70–4.72 (2H, m, H-2 and H-3), 5.16–5.18 (1H, m, H-1), 6.73–6.74
(1H, m, H-5), 7.50–7.64 (2H, m, Ph), 7.57–7.63 (1H, m, Ph), 7.98–8.00
25
as an oil: [
a]
ꢁ98.4 (c 1.115, CHCl3); 1H NMR (CDCl3)
d 1.42 and
D
1.53 (6H, each as s, CMe2), 2.67 (1H, d, J¼10.0 Hz, OH), 4.53 (1H,
ddd, J¼10.0, 5.6 and 2.0 Hz, H-1), 4.78 (1H, td, J¼5.6 and 0.7 Hz, H-
2), 4.96 (1H, d, J¼5.6 Hz, H-3), 5.24 (1H, t, J¼1.0 Hz, H-5), 7.35–7.39
(2H, m, Ph); 13C NMR (CDCl3)
d
ꢁ4.8, ꢁ4.6, 18.4, 25.8, 26.3, 26.6,
73.8, 79.7, 80.9, 113.0, 128.9, 133.6, 140.1, 145.0, 145.7; FABMS m/z
411(MþþH). Anal. Calcd for C20H30O5SSi: C, 58.50; H, 7.36. Found: C,
58.85; H, 7.51.
(3H, m, Ph), 7.51–7.53 (2H, m, Ph); 13C NMR (CDCl3)
d 26.85, 27.71,
73.16, 78.19, 84.17, 113.19, 128.02, 128.83, 129.43, 130.82, 134.25,
143.33; FABMS m/z 303 (MþþK). Anal. Calcd for C14H16O3S: C,
63.61; H, 6.10. Found: C, 63.38; H, 6.05.
3.13. (1S,2S,3S)-4-Benzenesulfonyl-1-benzoyloxy-2,3-
isopropylidenedioxy-4-cyclopentene (18)
3.9. (1S,2S,3S)-4-Benzenesulfonyl-2,3-isopropylidenedioxy-
4-cyclopenten-1-ol (14)
To a mixture of 14 (5.50 g, 18.6 mmol), DMAP (2.74 g,
22.3 mmol), and i-Pr2NEt (6.48 mL, 37.2 mmol) in CH2Cl2 (100 m L)
was added BzCl (2.83 mL, 24.2 mmol) at 0 ꢀC. The resulting mixture
was stirred at rt for 3 h. The reaction mixture was partitioned be-
tween CH2Cl2 and saturated aqueous NaHCO3. Column chroma-
To a solution of 13 (101 mg, 0.38 mmol) in CH2Cl2 (10 mL) was
added m-CPBA (purity 65%, 203 mg, 0.760 mmol) at 0 ꢀC in several
portions. The reaction mixture was stirred at rt for 8 h, quenched by
adding saturated aqueous Na2S2O3, and then partitioned between
CH2Cl2 and saturated aqueous NaHCO3. Column chromatography
(hexane/EtOAc¼1/1) of the organic layer gave 14 (116 mg, 100%) as
tography (hexane/EtOAc¼1/4) of the organic layer gave 18 (6.10 g,
25
82%) as a solid: mp 212–215 ꢀC; [
a
]
D
þ159.2 (c 0.990, CHCl3); 1H
NMR (CDCl3)
d
0.07 (3H, s, Me),1.23 (3H, s, Me), 5.12 (1H, t, J¼5.6 Hz,

H. Kumamoto et al. / Tetrahedron 65 (2009) 8007–8013
8011
H-2), 5.31 (1H, d, J¼5.6 Hz, H-3), 5.68–5.69 (1H, m, H-1), 6.90–6.91
3.18. 9-[(1R,2S,3S)-4-Iodo-2,3-isopropylidenedioxy-4-
cyclopenten-1-yl]adenine (22)
(1H, m, H-5), 7.42–7.47 (2H, m, Ph), 7.56–7.59 (2H, m, Ph), 7.64–7.68
(1H, m, Ph); High resolution FABMS (m/z) calcd for C21H21O6S:
401.1059, found: 401.1090 (MþþH).
A mixture of 21 (1.35 g, 2.40 mmol) and iodine (1.22 g, 4.80 mmol
as I2) in THF (40 mL) was stirred at rt for 7 h. The reaction mixture
was quenched by adding saturated aqueous Na2S2O3 and extracted
3.14. Radical reaction of 16 to yield 17 (entry 3 in Table 1)
with CH2Cl2. Column chromatography (CH2Cl2/MeOH¼20/1) of the
25
A benzene (5 mL) solution of 16 (200 mg, 0.490 mmol), i-Pr2NEt
extract gave 22 (957 mg, 100%) as a solid: mp 223–226 ꢀC; [
a]
D
(260
mL, 1.47 mmol), Bu3SnH (0.380 mL, 1.47 mmol), and AIBN
ꢁ31.2 (c 0.510, CHCl3); 1H NMR (CDCl3)
d 1.40 and 1.52 (6H, each as s,
(40.0 mg, 0.250 mmol) was heated at 80 ꢀC for 4 h with stirring. The
yield of 17 was calculated based on 1H NMR spectroscopy by
integrating H-5.
CMe2), 4.70 (1H, d, J¼5.5 Hz, H-20), 5.46 (1H, dt, J¼5.5 and 1.2 Hz, H-
30), 5.49 (1H, t, J¼2.0 Hz, H-10), 5.78 (2H, br, NH2), 6.29–6.30 (1H, m,
H-50), 7.69 (1H, s, H-8), 8.38 (1H, s, H-2); 13C NMR (CDCl3)
d 26.26,
27.40, 65.83, 83.31, 89.71, 106.95, 113.02, 120.03, 135.89, 138.32,
149.62, 153.37, 155.57; High resolution FABMS (m/z) calcd for
C13H15IN5O2: 400.0251, found: 400.0271 (MþþH).
3.15. Radical reaction of 18 to yield 19 (entry 4 in Table 1)
and subsequent conversion to 15
A
mixture of 18 (260 mg, 0.650 mmol), i-Pr2NEt (340
mL,
3.19. 9-[(1R,2S,3S)-4-Bromo-2,3-isopropylidenedioxy-4-
1.95 mmol), Bu3SnH (525 L, 1.95 mmol), and AIBN (54.0 mg,
m
cyclopenten-1-yl]adenine (23)
0.330 mmol) in benzene (4 mL) was stirred at 80 ꢀC for 4 h under
positive pressure of dry Ar. The reaction mixture was evaporated. The
yield of 19 was calculated based on 1H NMR spectroscopy by in-
tegrating H-5. The residue was dissolved in MeOH (15 mL), to which
NaOMe (176 mg, 3.25 mmol) was added at 0 ꢀC. The mixture was
stirred at rt for 2 h and partitioned between CH2Cl2 and saturated
aqueous NH4Cl. Column chromatography (hexane/EtOAc¼10/1) of
the organic layer gave 15 (260 mg, 90%) as an oil.
A mixture of 21 (50 mg, 0.09 mmol) and NBS (23 mg, 0.13 mmol)
in THF (2 mL) was stirred at rt for 1 h. The reaction mixture was
partitioned between CH2Cl2 and saturated aqueous NaHCO3. Col-
umn chromatography (CH2Cl2/MeOH¼40/1) of the organic layer
24
gave 23 (21.0 mg, 67%) as a solid: mp 199–202 ꢀC; [
a]
ꢁ67.7 (c
D
0.830, CHCl3); 1H NMR (CDCl3)
d 1.40 and 1.53 (6H, each as s, CMe2),
4.77 (1H, dt, J¼5.6 and 0.5 Hz, H-20), 5.44 (1H, ddd, J¼5.6, 1.7 and
1.0 Hz, H-30), 5.49 (1H, t, J¼2.1 Hz, H-10), 5.66 (2H, br, NH2), 6.07
(1H, dd, J¼2.1 and 1.0 Hz, H-50), 7.71 (1H, s, H-8), 8.38 (1H, s, H-2);
3.16. 6-Chloro-9-[(1R,2S,3S)-2,3-isopropylidenedioxy-4-
tributylstannyl-4-cyclopenten-1-yl]purine (20)
13C NMR (CDCl3)
d 26.1, 27.3, 64.4, 83.5, 86.8, 113.4, 119.7, 128.2,
131.6, 138.4, 149.6, 152.3, 155.6; FABMS m/z 352 and 354 (MþþH).
Anal. Calcd for C13H14BrN5O2$1/10H2O: C, 44.11; H, 4.04; N, 19.78.
Found: C, 44.39; H, 3.86; N, 19.52.
To a THF (40 mL) solution of PPh3 (1.60 g, 6.10 mmol) was added
DEAD (40% toluene solution, 2.65 mL, 6.10 mmol) dropwise at 0 ꢀC
under positive pressure of dry Ar. The resulting solution was stirred
for 15 min, and then was added to a mixture of 15 (1.06 g,
2.44 mmol) and 6-chloropurine (0.570 g, 3.66 mmol) in THF
(20 mL). After being stirred for 0.5 h, the reaction mixture was
partitioned between CH2Cl2 and saturated aqueous NaHCO3. Col-
3.20. 9-[(1R,2S,3S)-4-Chloro-2,3-isopropylidenedioxy-4-
cyclopenten-1-yl]adenine (24)
A mixture of 21 (60.0 mg, 0.110 mmol) and NCS (28.0 mg,
0.210 mmol) in THF (2 mL) was stirred at rt for 48 h. The reaction
mixture was partitioned between CH2Cl2 and saturated aqueous
umn chromatography (hexane/EtOAc¼8/1) of the organic layer
24
gave 20 (1.14 g, 80%) as an oil: [
a]
ꢁ16.0 (c 0.775, CHCl3); 1H NMR
D
(CDCl3)
d
0.91 (9H, t, J¼7.3 Hz, Sn(CH2)3CH3), 0.97–1.15 (6H, m,
NaHCO3. Column chromatography (CH2Cl2/MeOH¼40/1) of the
21
Sn(CH2)3), 1.30–1.39 (6H, m, Sn(CH2)3), 1.36 and 1.44 (6H, each as s,
CMe2),1.48–1.64 (6H, m, Sn(CH2)3), 4.66 (1H, d, J¼5.4 Hz, H-20), 5.56
(1H, dt, J¼5.4 and 1.0 Hz, H-30), 5.72 (1H, s, H-10), 5.89–5.96 (1H, m,
organic layer gave 24 (16.0 mg, 49%) as a foam: [
a
]
ꢁ115.6 (c
D
0.270, CHCl3); 1H NMR (CDCl3)
d 1.40 and 1.54 (6H, each as s, CMe2),
4.79 (1H, d, J¼5.6 Hz, H-20), 5.38–5.40 (1H, m, H-30), 5.54 (1H, t,
H-50), 7.95 (1H, s, H-8), 8.77 (1H, s, H-2); 13C NMR (CDCl3)
d 9.68,
J¼2.1 Hz, H-10), 5.81 (2H, br, NH2), 5.88–5.90 (1H, m, H-50), 7.72 (1H,
13.68, 26.07, 27.25, 27.48, 29.03, 67.52, 83.83, 90.93, 111.99, 132.14,
135.30, 143.28, 151.10, 151.45, 152.09, 158.04; FABMS m/z 583
(MþþH). Anal. Calcd for C25H39ClN4O2Sn: C, 51.61; H, 6.76; N, 9.63.
Found: C, 51.74; H, 6.74; N, 9.52.
s, H-8), 8.38 (1H, s, H-2); 13C NMR (CDCl3)
d 26.08, 27.31, 63.26,
83.49, 85.18, 113.47, 120.06, 123.93, 138.39, 141.70, 149.64, 153.32,
155.58; High resolution FABMS (m/z) calcd for C13H15ClN5O2:
308.0914, found: 308.0932 (MþþH).
3.17. 9-[(1R,2S,3S)-2,3-Isopropylidenedioxy-4-tributylstannyl-
3.21. 9-[(1R,2S,3R)-2,3-Isopropylidenedioxy-4-phenyl-4-
4-cyclopenten-1-yl]-adenine (21)
cyclopenten-1-yl]adenine (25)
A THF (10 mL) solution of 20 (3.20 g, 5.69 mmol) and NH3/MeOH
(saturated at 0 ꢀC, 40 mL) were placed in a sealed tube and the
whole was heated at 120 ꢀC for 2 days. The reaction mixture was
A
mixture of 21 (149 mg, 0.270 mmol) and (Ph3P)2PdCl2
(37.0 mg, 53.0
mol) in DMF (3 mL) was heated at 120 ꢀC for 1 h
under positive pressure of dry Ar. To this solution were added CuI
m
evaporated and purified by column chromatography (hexane/
(50.0 mg, 0.270 mmol) and PhI (61.0 mL, 0.530 mmol). The reaction
23
EtOAc¼1/1). This gave 21 (2.70 g, 87%) as an oil: [
a
]
ꢁ22.6 (c
mixture was heated at 120 ꢀC for 24 h, and then partitioned be-
tween EtOAc and H2O. Column chromatography (CH2Cl2/
D
0.645, CHCl3); 1H NMR (CDCl3)
d
0.91 (9H, t, J¼7.3 Hz, Sn(CH2)3CH3),
0.96–1.15 (6H, m, Sn(CH2)3), 1.30–1.39 (6H, m, Sn(CH2)3), 1.35 and
1.43 (6H, each as s, CMe2), 1.46–1.65 (6H, m, Sn(CH2)3), 4.63 (1H, d,
J¼5.4 Hz, H-20), 5.51 (1H, dt, J¼5.4 and 1.2 Hz, H-30), 5.66 (1H, s, H-
10), 5.87 (2H, br, NH2), 5.90–5.97 (1H, m, H-50), 7.61 (1H, s, H-8), 8.39
MeOH¼50/1) of the organic layer gave 25 (47 mg, 51%) as a foam:
23
[a
]
þ4.4 (c 0.730, CHCl3); 1H NMR (CDCl3)
d 1.43 and 1.47 (6H,
D
each as s, CMe2), 4.84 (1H, d, J¼5.9 Hz, H-20), 5.76 (1H, t, J¼1.2 Hz,
H-30), 5.84 (1H, dd, J¼5.9 and 1.2 Hz, H-10), 5.87 (1H, br, NH2), 6.22
(1H, d, J¼2.7 Hz, H-50), 7.39–7.45 (3H, m, Ph), 7.70–7.73 (2H, m, Ph),
(1H, s, H-2); 13C NMR (CDCl3)
d 9.6, 13.7, 26.1, 27.5, 29.1, 66.7, 84.1,
90.8, 111.8, 120.1, 136.3, 138.4, 149.9, 153.2, 155.4, 156.8; FABMS m/z
564 (MþþH). Anal. Calcd for C25H41N5O2Sn: C, 53.40; H, 7.35; N,
12.45. Found: C, 53.44; H, 7.45; N, 12.38.
7.74 (1H, s, H-8), 8.39 (1H, s, H-2); 13C NMR (CDCl3)
d 25.89, 27.31,
64.96, 84.41, 84.47, 112.77, 119.51, 121.60, 126.99, 128.72, 132.65,
134.50, 139.37, 148.71, 149.69, 153.54, 155.26; High resolution

8012
H. Kumamoto et al. / Tetrahedron 65 (2009) 8007–8013
FABMS (m/z) calcd for C19H19N5O2: 350.1617, found: 350.1634
(MþþH).
evaporated to dryness and the residue was dissolved in aqueous
NH3. Evaporation of the solvent followed by column chromatog-
raphy (CH2Cl2/MeOH¼13/1) of the residue gave 29 (43.0 mg, 96%)
24
3.22. 9-[(1R,2S,3R)-4-Ethynyl-2,3-isopropylidenedioxy-4-
cyclopenten-1-yl]adenine (26)
as a solid: mp 214–216 ꢀC; [
a
]
D
ꢁ85.8 (c 0.825, MeOH); 1H NMR
(DMSO-d6)
d
4.41–4.47 (2H, m, H-20 and H-30), 5.31 (1H, dt, J¼5.1
and 1.8 Hz, H-10), 5.39 (1H, br, OH), 5.48 (1H, br, OH), 6.49 (1H, d,
A mixture of 22 (261 mg, 0.650 mmol), Pd(PPh3)4 (38.0 mg,
J¼1.8 Hz, H-50), 7.23 (2H, br, NH2), 8.11 (1H, s, H-8), 8.12 (1H, s, H-2);
33
mmol), CuI (6.00 mg, 33
mmol), and Bu3SnC^CH (376
mL,
13C NMR (DMSO-d6)
d 59.7, 75.1, 79.5, 95.4, 104.2, 119.1, 139.8, 149.5,
1.30 mmol) in THF (5 mL) was stirred at rt for 1 h under positive
pressure of dry Ar. The reaction mixture was partitioned between
CH2Cl2 and saturated aqueous NaHCO3. Column chromatography
152.4, 156.0; FABMS m/z 360 (MþþH). Anal. Calcd for
C10H10IN5O2$1/7CH2Cl2: C, 32.83; H, 2.79; N, 18.88. Found: C, 33.01;
H, 2.50; N, 18.77.
(CH2Cl2/MeOH¼40/1) of the organic layer gave 26 (162 mg, 83%) as
25
a solid: mp 235 ꢀC (decomp.); IR (neat) 2140 cmꢁ1 (C^CH); [
a
]
3.26. 9-[(1R,2S,3S)-4-Bromo-2,3-dihydroxy-4-cyclopenten-1-
yl]adenine (30)
D
ꢁ57.7 (c 0.170, CHCl3); 1H NMR (CDCl3)
d
1.39 and 1.54 (6H, each as
s, CMe2), 3.30 (1H, s, C^CH), 4.75 (1H, d, J¼5.6 Hz, H-20), 5.48 (1H,
d, J¼5.6 Hz, H-30), 5.64 (1H, s, H-10), 5.70 (2H, br, NH2), 6.17 (1H, t,
J¼1.3 Hz, H-50), 7.68 (1H, s, H-8), 8.39 (1H, s, H-2); 13C NMR (CDCl3)
25
Obtained in 96% yield as a solid: mp 230–232 ꢀC; [
(c 0.460, MeOH); 1H NMR (DMSO-d6)
a
]
ꢁ109.7
D
d
4.46–4.47 (2H, m, H-20
d
25.90, 27.31, 64.70, 77.19, 83.61, 83.72, 86.00, 113.20, 120.09,
and H-30), 5.32–5.35 (1H, m, H-10), 5.37 (1H, d, J¼6.6 Hz, OH),
5.46 (1H, d, J¼6.8 Hz, OH), 6.27 (1H, d, J¼2.0 Hz, H-50), 7.18 (2H,
br, NH2), 8.10 (1H, s, H-8), 8.11 (1H, s, H-2); 13C NMR (DMSO-d6)
132.29, 133.78, 138.46, 149.81, 153.42, 155.40; FABMS m/z 298
(MþþH). Anal. Calcd for C15H15N5O2$1/3H2O: C, 59.41; H, 5.20; N,
23.09. Found: C, 59.39; H, 4.96; N, 22.95.
d
64.3, 75.2, 76.7, 119.1, 127.8, 132.1, 139.8, 149.5, 152.3, 156.0;
FABMS m/z 312 and 314 (MþþH). Anal. Calcd for C10H10BrN5O2$1/
20CH2Cl2: C, 38.15; H, 3.22; N, 22.14. Found: C, 38.13; H, 3.02; N,
21.86.
3.23. 9-[(1R,2S,3R)-2,3-Isopropylidenedioxy-4-
methylethynyl-4-cyclopenten-1-yl]-adenine (27)
A mixture of 22 (100 mg, 0.250 mmol), Pd(PPh3)4 (15.0 mg,
3.27. 9-[(1R,2S,3S)-4-Chloro-2,3-dihydroxy-4-cyclopenten-1-
13
mmol), CuI (3.00 mg, 13
mmol), and Bu3SnC^CMe (165 mg,
yl]adenine (31)
0.500 mmol) in THF (2 mL) was stirred at rt for 1 h under positive
pressure of dry Ar. The reaction mixture was partitioned between
CH2Cl2 and saturated aqueous NaHCO3. Column chromatography
25
Obtained in 97% yield as a solid: mp 232–234 ꢀC; [
0.285, MeOH); 1H NMR (DMSO-d6)
a]
ꢁ139.0 (c
D
d
4.44 (1H, ddd, J¼11.0, 5.9 and
(CH2Cl2/MeOH¼40/1) of the organic layer gave 27 (80.0 mg, 100%)
1.7 Hz, H-20), 4.47 (1H, t, J¼5.9 Hz, H-30), 5.38 (1H, dt, J¼5.1 and
1.7 Hz, H-10), 5.43 (1H, d, J¼6.6 Hz, OH), 5.56 (1H, d, J¼6.3 Hz, OH),
6.10 (1H, d, J¼1.7 Hz, H-50), 7.21 (2H, br, NH2), 8.11 (1H, s, H-8), 8.13
25
as a solid: mp 190–192 ꢀC; IR (neat) 2330 cmꢁ1 (C^CMe); [
a]
D
ꢁ36.0 (c 0.830, CHCl3); 1H NMR (CDCl3)
d 1.38 and 1.54 (6H each as
s, CMe2), 2.07 (3H, s, C^CMe), 4.70 (1H, d, J¼5.6 Hz, H-20), 5.37 (1H,
d, J¼5.4 Hz, H-30), 5.63 (1H, s, H-10), 5.84 (2H, br, NH2), 5.98 (1H, d,
J¼2.7 Hz, H-50), 7.68 (1H, s, H-8), 8.39 (1H, s, H-2); 13C NMR (CDCl3)
(1H, s, H-2); 13C NMR (DMSO-d6)
d 63.64, 75.18, 72.26, 119.16,
127.89, 137.42, 139.86, 149.51, 152.32, 156.00; FABMS m/z 268
(MþþH). Anal. Calcd for C10H10ClN5O2$2/5H2O: C, 43.70; H, 3.96; N,
25.48. Found: C, 43.54; H, 3.74; N, 25.39.
d
4.7, 25.9, 27.3, 64.7, 73.6, 83.8, 86.1, 93.2, 113.0, 120.1, 130.6, 133.7,
138.4, 149.8, 153.4, 155.4; FABMS m/z 312 (MþþH). Anal. Calcd for
C16H17N5O2$1/6CH2Cl2: C, 59.62; H, 5.36; N, 21.50. Found: C, 59.71;
H, 5.18; N, 21.36.
3.28. 9-[(1R,2S,3R)-2,3-Dihydroxy-4-phenyl-4-cyclopenten-1-
yl]adenine (32)
25
3.24. 9-[(1R,2S,3R)-4-Cyano-2,3-isopropylidenedioxy-4-
cyclopenten-1-yl]adenine (28)
Obtained in 72% yield as a solid: mp 228–230 ꢀC; [
a
]
ꢁ22.5 (c
D
0.405, MeOH); 1H NMR (DMSO-d6)
d
4.51 (1H, q, J¼6.1 Hz, H-20),
4.91 (1H, t, J¼6.1 Hz, H-30), 5.18 (1H, J¼6.1 Hz, H-10), 5.33 (1H, d,
J¼7.3 Hz, OH), 5.56 (1H, d, J¼6.6 Hz, OH), 6.43 (1H, d, J¼1.7 Hz, H-
50), 7.20 (2H, br, NH2), 7.32 (1H, t, J¼7.3 Hz, Ph), 7.39 (2H, t,
J¼7.3 Hz, Ph), 7.65 (2H, d, J¼7.3 Hz, Ph), 8.12 (1H, s, H-8), 8.18 (1H,
A mixture of Bu3SnCN (238 mg, 0.750 mmol) and (Ph3P)2PdCl2
(53.0 mg, 75 m
mol) in DMF (4 mL) was heated at 120 ꢀC for 1 h
under positive pressure of dry Ar. To this solution were added 22
(150 mg, 0.380 mmol) and CuI (72.0 mg, 0.380 mmol). The reaction
mixture was heated at 120 ꢀC for 24 h and partitioned between
EtOAc and H2O. Column chromatography (CH2Cl2/MeOH¼40/1) of
s, H-2); 13C NMR (DMSO-d6)
d 64.54, 72.57, 76.78, 119.28, 126.23,
126.32, 128.08, 128.42, 134.16, 139.89, 144.59, 149.77, 152.27,
156.03; FABMS m/z 309 (MþþH). Anal. Calcd for C16H15N5O2$2/
5H2O: C, 60.71; H, 5.03; N, 22.13. Found: C, 61.00; H, 4.88; N,
21.82.
the organic layer gave 28 (83.0 mg, 74%) as a solid: mp 172–175 ꢀC;
25
IR (neat) 2230 cmꢁ1 (C^N); [
a
]
ꢁ128.1 (c 1.650, CHCl3); 1H NMR
D
(CDCl3)
d
1.40 and 1.53 (6H, each as s, CMe2), 4.90 (1H, d, J¼5.5 Hz,
H-20), 5.61 (1H, t, J¼1.8 Hz, H-30), 5.77 (1H, d, J¼5.5 Hz, H-10), 5.96
(2H, br, NH2), 6.59 (1H, d, J¼2.7 Hz, H-50), 7.73 (1H, s, H-8), 8.32 (1H,
3.29. 9-[(1R,2S,3R)-4-Ethynyl-2,3-dihydroxy-4-cyclopenten-1-
yl]adenine (33)
s, H-2); 13C NMR (CDCl3)
d 25.8, 27.2, 65.0, 82.9, 85.2, 113.8, 119.9,
123.2, 138.8, 142.2, 149.5, 153.3, 155.7; FABMS m/z 299 (MþþH).
Anal. Calcd for C14H14N6O2$2/5H2O: C, 55.04; H, 4.88; N, 27.51.
Found: C, 55.22; H, 4.58; N, 27.27.
Obtained in quantitative yield as a solid: mp 233 ꢀC (decomp.);
IR (KBr) 2120 cmꢁ1 (C^CH); [
a]
ꢁ49.0 (c 0.270, MeOH); 1H NMR
25
D
(DMSO-d6)
d
4.20 (1H, s, C^CH), 4.37 (1H, q, J¼6.3 Hz, H-20), 4.44
(1H, t, J¼6.3 Hz, H-30), 5.26 (1H, d, J¼7.0 Hz, OH), 5.32 (1H, d,
J¼6.4 Hz, OH), 5.44 (1H, dd, J¼6.3 and 1.1 Hz, H-10), 6.29 (1H, d,
J¼2.1 Hz, H-50), 7.16 (2H, br, NH2), 8.09 (1H, s, H-8), 8.10 (1H, s, H-2);
3.25. Preparation of 9-[(1R,2S,3S)-2,3-Dihydroxy-4-iodo-4-
cyclopenten-1-yl]adenine (29): general procedure for removal
of the isopropylidene group
13C NMR (DMSO-d6)
d 64.20, 74.94, 75.78, 79.80, 84.65, 119.16,
128.64, 138.31, 140.01, 149.54, 152.32, 155.94; FABMS m/z 258
(MþþH). Anal. Calcd for C12H11N5O2$1/4H2O: C, 55.06; H, 4.43; N,
26.76. Found: C, 54.90; H, 4.16; N, 26.81.
Compound 22 (50.0 mg, 0.125 mmol) in 50% aqueous HCO2H
(6 mL) was stirred at rt for 24 h. The reaction mixture was

H. Kumamoto et al. / Tetrahedron 65 (2009) 8007–8013
8013
2. De Clercq, E. Antimicrob. Agents Chemother. 1985, 28, 84.
3. Whaun, J. M.; Miura, G. A.; Brown, N. D.; Gordon, R. K.; Chiang, P. K. J. Phar-
macol. Exp. Ther. 1986, 236, 277.
3.30. 9-[(1R,2S,3R)-2,3-Dihydroxy-4-methylethynyl-4-
cyclopenten-1-yl]adenine (34)
4. Borchardt, R. T.; Keller, B. T.; Patel-Thombre, U. J. Biol. Chem. 1984, 259, 4353.
5. Hasobe, M.; McKee, J. G.; Borcherding, D. R.; Keller, B. T.; Borchardt, R. T. Mol.
Pharmacol. 1988, 33, 713.
6. Shuto, S.; Obara, T.; Toriya, M.; Hosoya, M.; Snoeck, R.; Andrei, G.; Balzarini, J.;
De Clercq, E. J. Med. Chem. 1992, 35, 324.
7. Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J. Org. Chem. 1987, 52, 5457.
8. Hasobe, M.; McKee, J. G.; Borcherding, D. R.; Borchardt, R. T. Antimicrob. Agents
Chemother. 1987, 31, 1849.
9. For a review concerning the Stille reaction, see: Mitchell, T. N. Synthesis 1992,
803.
10. For the reaction of vinyl sulfides, see: (a) Schmidt, R. R.; Betz, R. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 430; (b) Tanaka, H.; Hayakawa, H.; Obi, K.; Miyasaka, T.
Tetrahedron Lett. 1985, 26, 6229; (c) White, J. D.; Pallenberg, A. J. Tetrahedron
Lett. 1986, 27, 5591; (d) Hollingsworth, G. J.; Perkins, G.; Sweenyy, J. J. Chem. Soc.,
Perkin Trans. 1 1996, 1913; (e) Kumamoto, H.; Onuma, S.; Tanaka, H. J. Org. Chem.
2004, 69, 72.
11. For the reaction of vinyl sulfones, see: (a) Watanabe, Y.; Ueno, Y.; Araki, T.; Endo,
T.; Okawara, M. Tetrahedron Lett. 1986, 27, 215; (b) Dubois, E.; Bwau, J.-M. Tet-
rahedron Lett. 1990, 31, 5165; (c) McCarthy, J. R.; Matthews, D. P.; Stemerick, D.
M.; Huber, E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J. Am. Chem.
Soc. 1991, 113, 7439; (d) Wnuk, S. F.; Robins, M. J. Can. J. Chem. 1993, 71, 192;
(e) McCarthy, J. R.; Huber, E. W.; Le, T.-B.; Laskovics, F. M.; Matthews, D. P.
Tetrahedron 1996, 52, 45; (f) Onuma, S.; Kumamoto, H.; Kawato, K.; Tanaka, H.
Tetrahedron 2002, 58, 2497.
12. (a) Choi, W. J.; Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon, H. R.; Chun, M. W.; Jung,
Y. H.; Jeong, L. S. J. Org. Chem. 2001, 66, 6490; (b) Jin, Y. H.; Chu, C. K. Tetrahedron
Lett. 2002, 43, 4141; (c) Jin, Y. H.; Liu, P.; Wang, J.; Baker, R.; Huggins, J.; Chu,
C. K. J. Org. Chem. 2003, 68, 9012; (d) Yang, M.; Ye, W.; Schneller, S. W. J. Org.
Chem. 2004, 69, 3993; (e) Johonson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1986,
108, 5655.
Obtained in quantitative yield as a solid: mp 225 ꢀC (decomp.);
23
IR (KBr) 2220 cmꢁ1 (C^CMe); [
a
]
D
ꢁ88.4 (c 0.380, MeOH); 1H
NMR (DMSO-d6)
d
2.01 (3H, s, C^CMe), 4.33 (1H, q, J¼6.2 Hz, H-20),
4.39 (1H, t, J¼6.2 Hz, H-30), 5.23 (1H, d, J¼7.1 Hz, OH), 5.26 (1H, d,
J¼6.1 Hz, OH), 5.41 (1H, d, J¼6.2 Hz, H-10), 6.08 (1H, d, J¼2.0 Hz, H-
50), 7.18 (2H, br, NH2), 8.08 (1H, s, H-8), 8.10 (1H, s, H-2); 13 C NMR
(DMSO-d6)
d 4.05, 64.26, 75.16, 75.89, 76.05, 90.57, 119.17, 129.92,
135.14, 139.85, 149.54, 152.26, 155.99; FABMS m/z 272 (MþþH).
Anal. Calcd for C13H13N5O2$3/4MeOH: C, 55.92; H, 5.46; N, 23.72.
Found: C, 55.87; H, 5.48; N, 23.68.
3.31. 9-[(1R,2S,3R)-4-Cyano-2,3-dihydroxy-4-cyclopenten-1-
yl]adenine (35)
26
Obtained in 83% yield as a foam: IR (KBr) 2230 cmꢁ1 (C^N); [
a]
D
þ28.7 (c 0.215, MeOH); 1H NMR (DMSO-d6)
4.41 (1H, t, J¼5.9 Hz, H-
d
20), 4.67 (1H, d, J¼5.9 Hz, H-30), 5.56 (1H, d, J¼6.3 Hz, H-10), 7.14 (1H,
d, J¼1.5 Hz, H-50), 7.25 (2H, br, NH2), 8.11 (1H, s, H-8), 8.13 (1H, s, H-
2); 13C NMR (DMSO-d6)
d 64.14, 73.48, 75.28, 115.87, 119.07, 140.19,
148.70,149.45,152.44,156.05; High resolution FABMS (m/z) calcd for
C11H11N6O2: 259.0943, found: 259.0960 (MþþH).
Acknowledgements
13. Ichikawa, Y.; Matsukawa, Y.; Nishiyama, T.; Isobe, M. Eur. J. Org. Chem. 2004,
586.
14. Berges, D. A.; Fan, J.; Liu, N.; Dalley, N. K. Tetrahedron 2001, 57, 9915.
15. Vonlanthen, D.; Leumann, C. J. Synthesis 2003, 1087.
The authors are grateful to Ms. K. Shiobara and S.S. Matsu-
bayashi (Center for Instrumental Analysis, Showa University) for
technical assistance with NMR, MS, and elemental analyses.
16. Bakuzis, P.; Bakuzis, M. L. F. J. Org. Chem. 1981, 46, 235.
17. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
18. Yoshida, N.; Kamikubo, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4677.
19. Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Shindoh, S.; Shuto, S.;
Miyasaka, T. J. Org. Chem. 1997, 62, 6833.
References and notes
20. (a) Nair, V.; Buenger, G. S. J. Am. Chem. Soc. 1989, 111, 8502; (b) Gudmundsson,
K. S.; Wang, Z.; Daluge, S. M.; Feldman, P. L. Nucleosides Nucleotides Nucleic
Acids 2001, 20, 1823.
1. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani, M. J. Antibiot.
1981, 34, 359.