Synthesis of (±)-9-[c-4, t-5-bis(hydroxymethyl)cyclopent-2-en-r-1-yl]-9H-adenine (BCA) derivatives branched at the 4′-position based on intramolecular SH2′ cyclization

Article abstract of DOI:10.1016/j.tet.2007.11.038

Synthesis of 4′-branched BCA analogues (5) was carried out. Stereospecific construction of the cis-disposed 4′-carbon-substituents and 5′-hydroxymethyl group was secured by employing the bicyclo[3.3.0]lactone 16 as a key intermediate, which was prepared by radical-mediated intramolecular S_H2′ cyclization of the phenylselenomethyl ester 15. After manipulation of the double bond of 16, bis(Boc)adenine was introduced based on the Mitsunobu reaction of the allyl alcohol 24. Transformation of the lactone function of 27 allowed preparation of the 4′-hydroxymethyl (31), the 4′-vinyl (32), the 4′-cyano (34), and the 4′-ethynyl (35) derivatives. Anti-HIV and anti-HCV activities of the free nucleosides 36-38 were also examined.

Full text of DOI:10.1016/j.tet.2007.11.038

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1494e1505
www.elsevier.com/locate/tet
Synthesis of (ꢀ)-9-[c-4, t-5-bis(hydroxymethyl)cyclopent-2-en-r-
1-yl]-9H-adenine (BCA) derivatives branched at the 40-position
based on intramolecular SH20 cyclization
a
a
a
Hiroki Kumamoto a, , Nonoko Takahashi , Tomomi Shimamura , Hiromichi Tanaka ,
Kazuo T. Nakamura a, Takayuki Hamasaki b, Masanori Baba b, Hiroshi Abe c,
Masahiko Yano d, Nobuyuki Kato d
*
a School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
b Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences,
Kagoshima University, Kagoshima 890-8544, Japan
c Nanomedical Engineering Laboratory, Discovery Research Institute, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
d Department of Molecular Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences,
2-5-1 Shikata-cho, Okayama 700-8558, Japan
Received 11 October 2007; received in revised form 12 November 2007; accepted 13 November 2007
Available online 17 November 2007
Abstract
Synthesis of 40-branched BCA analogues (5) was carried out. Stereospecific construction of the cis-disposed 40-carbon-substituents and
50-hydroxymethyl group was secured by employing the bicyclo[3.3.0]lactone 16 as a key intermediate, which was prepared by radical-mediated
intramolecular SH20 cyclization of the phenylselenomethyl ester 15. After manipulation of the double bond of 16, bis(Boc)adenine was intro-
duced based on the Mitsunobu reaction of the allyl alcohol 24. Transformation of the lactone function of 27 allowed preparation of the
40-hydroxymethyl (31), the 40-vinyl (32), the 40-cyano (34), and the 40-ethynyl (35) derivatives. Anti-HIV and anti-HCV activities of the free
nucleosides 36e38 were also examined.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Carbocyclic nucleoside; Radical cyclization; Mitsunobu reaction
1. Introduction
anti-HIV activity of 40-cyanothymidine (6) and 40-ethynyl-20-
deoxycytidine (7).6 Also, in our recent study, the 40-ethynyl
analogue 9 (40-Ed4T)7 of anti-HIV agent stavudine (8, d4T)8
was found to show a higher activity against HIV than the par-
ent compound 8. Based on these facts, we were interested in
synthesizing 40-branched (ꢀ)-BCA derivatives (5) that can
be regarded as a hybrid of 4 and 40-carbon-substituted nucleo-
sides (6, 7, and 9).
Since the discovery of carbovir (1)1 and its prodrug abaca-
vir (2)2 as anti-HIV agents, carbocyclic nucleosides have been
recognized as a source of new antiviral agents. An anti-HIV
active compound (ꢀ)-9-[c-4, tert-5-bis(hydroxymethyl)cyclo-
pent-2-en-r-1-yl]-9H-adenine [(ꢀ)-BCA (4)] synthesized by
Katagiri et al.3 was designed as a hybrid of 1 and COXT
(3),4 which is a carbocyclic analogue of antibiotic oxetanocin.5
On the other hand, nucleosides having a 40-carbon-substit-
uent have attracted much attention due to the reported potent
2. Result and discussion
A synthetic plan for the title compounds is depicted in
Scheme 1 as a retrosynthetic analysis. Manipulation of the
lactone function of I ensures cis-disposition between the
* 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 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.038

H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
1495
NH2
R
addition of PhSH. Its conversion to the allyl sulfide 12 was
performed by initial reduction of the ketone followed by tri-
fluoromethanesulfonylation of the resulting secondary alcohol,
and then by b-elimination of the triflate with DBN. The allyl
sulfone 13 was also prepared by m-CPBA oxidation of 12. Af-
ter saponification of 12 and 13, the radical precursors 14 and
15 were prepared in 68 and 81% yields, respectively, by treat-
ment with PhSeCH2Cl11 in the presence of i-Pr2NEt and NaI.
N
N
N
N
HO
N
HO
N
N
N
NH2
1: R = OH (carbovir)
OH
3: COXT
2: R = NHC3H5 (abacavir)
HO
Base
O
NH2
4'
R
N
OTBDPS
SPh
N
HO
6: Base = Thy, R = CN
7: Base = Cyt, R = ethynyl
3' 2'
N
1'
HO
b, c, d
N
a
4'
10
MeO2C
R
5'
O
11
OH
4: R = H (BCA)
5: R = carbon-substituents
HO
Thy
O
TBDPSO
S(O)nPh
TBDPSO
O
S(O)nPh
SePh
R
8: R = H (d4T)
f, g
9: R = ethynyl (4'-Ed4T)
MeO2C
e
O
50-hydroxymethyl group and a variety of 40-carbon-substituents
(R in 5). Compound I can be prepared by condensation of ad-
enine base with the allyl alcohol II, which would be obtained
from III by a series of reactions: epoxidation, ring opening
with a selenide anion, and selenoxide elimination.
14 n = 0
15 n = 2
12 n = 0
13 n = 2
Scheme 2. Reagents and conditions: (a) PhSH, Et3N, CH2Cl2; (b) NaBH4,
MeOH; (c) Tf2O, pyridine, CH2Cl2; (d) DBN, MeCN (87% from 10); (e)
m-CPBA, CH2Cl2 (96%); (f), KOH, MeOH, H2O; (g) PhSeCH2Cl, NaI,
i-Pr2NEt, DME (68% for 14, 81% for 15).
NH2
Radical-mediated cyclization of 14 was first carried out by
adding a mixture of Bu3SnH and AIBN over 5 h to a refluxing
toluene solution of 14 containing i-Pr2NEt (Scheme 3). Al-
though the lactone 16 was obtained as a major product in
61% yield, this reaction also gave the saturated lactone 17
(5%) and the non-cyclized doubly reduced product 18
(18%). In contrast to this, the reaction of 15 under the same
reaction conditions gave 16 in a much higher yield of 94%.
N
conversion of the
N
PgO
lactone function
N
5
N
O
O
I
PgO
O
PgO
O
14 or 15
OH
O
O
Bu3SnH, AIBN
i-Pr2NEt
toluene, reflux
II
III
radical 5-exo-trig
cyclization
OTBDPS
OTBDPS
OTBDPS
PgO
OTBDPS
S(O)nPh
SePh
O
O
+
+
O
MeO2C
MeO2C
O
O
O
O
10
16
17
18
IV
Scheme 3. Radical reactions of 14 and 15.
Scheme 1. Retrosynthesis of 5.
Although the observed different outcome between the sul-
fide 14 and the sulfone 15 in this cyclization reaction could
be, in part, due to the lower electrophilicity of the p bond
of the former as compared with that of the latter,12 at least
two factors are likely to be involved in the formation of the
byproducts (17 and 18) from 14.
The bicyclic system of III could be constructed by radical-
mediated 5-exo-trig cyclization of the phenylselenomethyl es-
ter IV, which would take place through an SH20 process with
elimination of S(O)nPh (n¼0 or 2) radical.9 We anticipated
that the enone 1010 can be employed for the preparation of IV.
One is susceptibility of the phenylthio group in the allylic
position to the attack of a tin radical. When 12, lacking the
phenylseleno group, was reacted under the same reaction con-
ditions, a 15% yield of 18 was obtained, apparently via radical
reduction of the phenylthio group with Bu3SnH (Scheme 4). In
contrast, the corresponding sulfone derivative 13 completely
2.1. Radical-mediated 5-exo-trig cyclization of 14 and 15
Preparation of the substrates (14 and 15) for the radical cy-
clization was performed as shown in Scheme 2. The enone
1010 was transformed to the phenylthio derivative 11 by 1,4-

1496
H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
survived in these reaction conditions. It has been reported that
PhSH serves as an excellent hydrogen donor in the reaction
with carbon-centered radicals, whereas benzenesulfinic acid
does not.13 The other factor is an efficient reducing character
of the generated PhSH to radical intermediates. In fact, when
cyclization reaction of the allyl sulfone 15 was carried out in
the presence of PhSH (0.5 equiv), the methyl ester 13 was
formed in 30% yield.
regioselectivity forming the selenide 20 (30%) as well as the
undesired 21 (57%), the reaction of the exo-19 compound
gave 22 exclusively in 86% yield.
As shown in Scheme 5 by method B, the exo-epoxide 19
can be obtained as the major isomer upon reacting 16 with
NIS/AcOH followed by NaOMe. The resulting mixture of
the two epoxides, when reacted with (PhSe)2/NaBH4, fur-
nished the desired selenide 22 in 83% yield from 16 after chro-
matographic purification.
It is interesting that both m-CPBA and NIS favor an ap-
proach from the more hindered concave face of 16. Although
there have been several precedents on the similar curious ob-
servation regarding electrophilic reaction in bicyclo[3.3.0]
systems,14,15 we have no clear explanation for the observed
stereochemical outcome at the present time.
After oxidation of the selenide 22 with m-CPBA, selenox-
ide syn-elimination was effected in refluxing CH2Cl2 in the
presence of Et3N. This gave the allyl alcohol 23 in 90% yield
in two steps (Scheme 6). For the introduction of the adenine
base, we initially considered that the Pd-catalyzed glycosyla-
tion reported by Trost16 could be employed. However, neither
the acetate nor the carbonate derived from 23 gave I upon
reacting with N6-benzoyladenine/NaH in the presence of
Pd(PPh3)4 in DMF. We then selected the Mitsunobu reaction.
Requisite inversion of the hydroxyl group of 23 was also
carried out by this reaction (DEAD/PPh3/AcOH). Subse-
quent methanolysis gave the inverted allyl alcohol 24 in
98% yield.
As a precursor of the adenine base, 6-chloropurine was ini-
tially used in the Mitsunobu reaction of 24 (DIAD/PPh3/THF).
In this step, as shown in Scheme 6, the desired 25 was accom-
panied by the N7-glycoside 26 (9%). Also, ammonolysis of the
crude 25 by heating in a sealed tube gave the amide 28 (5%) as
a byproduct (the yield of 27: 68% from 24). These observa-
tions led us to examine the use of bis(Boc)adenine (29)17
instead of 6-chloropurine.
The reaction between 24 and 29 under the Mitsunobu con-
ditions was followed by removal of the Boc-protecting group
with 50% aqueous HCO2H. Compound 27 was obtained in
83% overall yield from 24. Formation of N7-glycosylated
product was not detected in this reaction. Since 29 is more sol-
uble in THF than 6-chloropurine, and since use of a sealed
tube can be avoided, we feel this method is suitable for the
preparation of carbocyclic adenine nucleosides in general. Ste-
reochemistry of 27 was confirmed by X-ray crystallographic
analysis as shown in Figure 2.
Bu3SnH, AIBN
i-Pr2NEt
18 (15%)
12
toluene, reflux
Bu3SnH, AIBN
i-Pr2NEt, PhSH
16 (70%)
+
13 (30%)
15
toluene, reflux
Scheme 4. Radical reactions of 12 and 15.
2.2. Synthesis of adenine nucleoside I
When m-CPBA oxidation of 16 was carried out as the first
step to prepare the allylic alcohol (II in Scheme 1), the epox-
ide 19 was formed as a mixture of two diastereomers (2.6:1) in
69% yield (Scheme 5, method A). NOE experiments (Fig. 1)
of both products showed that the major isomer is the endo-
19 compound (NOE: H-5/H-6, 8.6%; H-5/H-8b, 0.5%;
H-8b/H-7, 13.0%; H-8a/H-7, 1.0%), and the minor one is the
exo-19 compound (NOE: H-4/H-6, 3.4%; H-7/H-8a, 5.0%;
H-10/H-8b, 3.2%; H-5/H-4b, 6.3%; H-4a/H-6, 3.2%). While
ring opening of the endo-19 compound with phenylselenide
anion generated from (PhSe)2/NaBH4 resulted in poor
OTBDPS
OTBDPS
O
a
O
16
+
O
O
O
O
endo-19
exo-19
b
b
OTBDPS
OTBDPS
OTBDPS
SePh
OH
SePh
21 (57%)
SePh
OH
+
O
O
O
OH
O
O
O
20 (30%)
22 (86%)
Scheme 5. Reagents and conditions: (a) method A: m-CPBA, CH2Cl2 (69%,
endo/exo¼2.6:1), method B: NIS, AcOH, CH2Cl2 then NaOMe, MeOH
(90%, endo/exo¼1:7); (b) (PhSe)2, NaBH4, EtOH, rt.
2.3. Conversion of the lactone nucleoside 27 to
40-branched BCA derivatives
H8α H8β
8β H8α H7
O
H7
O
H6
To prepare BCA derivatives with a variety of carbon-func-
tionalities at the 40-position, the lactone nucleoside 27 was first
converted to the cyclic hemiacetal 30 (98%) by reacting with
DIBALH. Reduction of 30 with NaBH4 gave the 40-hydroxy-
methyl derivative 31 in 86% yield. The Wittig reaction of 30
with PPh3]CH2 proceeded well at low temperature in THF
to give the vinyl derivative 32 in 96% yield. The reaction
H1'
H
O
TBDPSO
O
TBDPSO
O
H6
H4α
H5
H5
endo-19
Figure 1. NOE experiments of the endo- and exo-19.
O
H4β
exo-19

H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
1497
Cl
N
OTBDPS
R1
R2
N
N
N
TBDPSO
O
TBDPSO
O
a
d
N
N
22
N
+
O
N
Cl
O
23: R1 = OH, R2 = H
24: R1 = H, R2 = OH
O
O
b, c
25
26
e
NH2
N
NH2
N
N
N(Boc)2
N
TBDPSO
O
TBDPSO
O
N
f, g
N
N
+
N
N
N
N
H
N
29
NH2
O
OH
28
27
Scheme 6. Reagents and conditions: (a) m-CPBA, CH2Cl2 then Et3N, CH2Cl2, reflux (90%); (b) AcOH, DEAD, Ph3P, THF, 0 ꢁC; (c) K2CO3, MeOH, rt (98% from
23); (d) 6-chloropurine, DIAD, Ph3P, THF, ꢂ40 ꢁC to rt; (e) NH3/MeOH, 120 ꢁC in a sealed tube, 27 (68% from 24) and 28 (5% from 24); (f) 29, DIAD, Ph3P,
THF, ꢂ40 ꢁC to rt; (g) aq 50% HCO2H, THF, 50 ꢁC, 27 (83% from 24).
with a stable ylide such as PPh3]CHCO2Me, on the other
hand, was very sluggish and required refluxing in xylene. Fur-
thermore, the product formed in this reaction was not the ex-
pected one but the bicyclic nucleoside 33 (72% as a single
stereoisomer, the stereochemistry of the 8-position was not de-
termined), which apparently resulted from intramolecular 1,4-
addition of the 50-hydroxymethyl group to the initially formed
Wittig product.
The 40-cyano derivative (34) was prepared from 30 in 84%
yield by the following sequence of reactions: oxime formation,
O-acetylation, and finally elimination of AcOH at 100 ꢁC in
the presence of NaOAc. Several attempts to synthesize the
40-ethynyl derivative (35) from 30 met with failure:
Ph3PþCH2BrBrꢂ/tert-BuOK,18 Ph3PþCH2ClClꢂ/LHMDS,19
and P(O)(OMe)2C(N2)COMe/K2CO3.20 Compound 35 was
formed only when 30 was reacted with TMSCHN2/LDA,21
albeit in a low yield (31%) (Scheme 7).
OPg
OPg
OPg
Ade
Ade
Ade
MeO2C
HO
O
OH
OH
31
32
33
c
d
b
OPg
Ade
h
a
HO
27
O
30
e, f, g
OPg
OPg
Ade
Ade
NC
OH
OAc
35
34
Ade = adenin-9-yl, Pg = TBDPS
Scheme 7. Reagents and conditions: (a) i-Bu2AlH, CH2Cl2, ꢂ78 ꢁC (98%); (b)
NaBH4, MeOH (86%); (c) Ph3PCH3Br, BuLi, THF, ꢂ78 ꢁC to rt (96%);
(d) Ph3P]CHCO2Me, xylene, reflux (72%); (e) NH2OH$HCl, pyridine;
(f) Ac2O, i-Pr2NEt, MeCN; (g) NaOAc, AcOH, 100 ꢁC (84% from 30); (h)
TMSCHN2, LDA, THF, ꢂ78 ꢁC to rt (31%).
Removal of the silyl group in 31, 32, and 35 was performed
by treatment with Bu4NF in THF to give the corresponding free
carbocyclic nucleosides 36e38 (Fig. 3). Deprotection of the cy-
ano derivative (34) with Bu4NF/THF followed by NH3/MeOH
gave the bicyclic iminoether 39 as a result of nucleophilic
addition of the 50-hydroxylmethyl group to the 40-cyano group.
The 40-carbon-substituted BCA analogues 36e38 did not
show any activity against HIV-1 (HTLV-IIIB strain) replication
at their non-toxic concentrations to the host cell (data not
shown). We also examined their effects on genome-length
HCV RNA replication using the OR6 cell-based assay sys-
tem.22,23 However, at 10 mM concentration, these compounds
exerted no effects on HCV RNA replication without concom-
itant cytotoxicity.
Figure 2. ORTEP drawing of compound 27.

1498
H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
OH
O
0.49 mmol) at room temperature. After stirring for 12 h, the
reaction mixture was partitioned between 1 M HCl and
CH2Cl2. After evaporation, the resulting 11 (6.13 g) was
used for the next reaction without further purification. To
a MeOH (160 mL) solution of the crude 11 (6.13 g) was added
NaBH4 (923 mg, 24.4 mmol) at ꢂ40 ꢁC. The reaction mixture
was stirred for 2 h. Quenching the reaction by adding acetone
(40 mL)/AcOH (1.4 mL) was followed by partition between
saturated aqueous NaHCO3 and CH2Cl2. The organic layer
was evaporated and the residue was dissolved in CH2Cl2
(65 mL). To this solution were added pyridine (1.97 mL,
24.4 mmol) and Tf2O (3.08 mL, 18.3 mmol) at ꢂ40 ꢁC. After
being stirred for 0.5 h at room temperature, the reaction mix-
ture was partitioned between saturated aqueous NaHCO3 and
CH2Cl2. The organic layer was evaporated and the residue
was dissolved to MeCN (65 mL). To this solution was added
DBN (3.02 mL, 24.4 mmol) at 0 ꢁC and the mixture was
stirred for 0.5 h at room temperature. The mixture was parti-
tioned between saturated aqueous NaHCO3 and CH2Cl2. Silica
gel column chromatography (hexane/AcOEt¼50:1) of the or-
ganic layer gave 12 (5.31 g, 87% from 10, isomeric mixture
ca. 2:1) as an oil. The two isomers were separated by HPLC
(hexane/AcOEt¼10:1, tR 9.2 min for the minor isomer; tR
10.9 min for the major isomer) for their NMR measurement.
OH
Ade
Ade
HN
R
36: R = CH2OH
37: R = CH=CH2
38: R = C CH
OH
39
Figure 3. Structures of 36e39.
3. Conclusion
The synthesis of novel 40-branched BCA analogues was
carried out using a radical-mediated 5-exo-trig cyclization as
a key step, which takes place through a SH20 process. The allyl
sulfone 15 was found to give a higher yield of the cyclized
product (16) than the allyl sulfide 14. Several experiments
were carried out to see why 15 acts as a better substrate in
this cyclization reaction. Transformation of 16 to the allyl al-
cohol 23 was effected by a series of reactions: stereoselective
epoxide formation, regioselective ring opening with phenylse-
lenide anion, and selenoxide elimination. For glycosylation
under Mitsunobu conditions, the inverted allyl alcohol 24 pre-
pared from 23 was reacted with bis(Boc)adenine (29). Mani-
pulation of the lactone function of the resulting 27 allowed
preparation of the 40-hydroxymethyl (31), the 40-vinyl (32),
the 40-cyano (34), and the 40-ethynyl (35) derivatives, which
were deprotected to give the corresponding free nucleosides
(36e38). Deprotection of the 40-cyano derivative (34) led to
the formation of the bicyclic iminoether (39).
4.2.1. NMR spectra of the major isomer
1H NMR (CDCl3) d 1.01 (9H, s, SiBu-tert), 2.04 (1H, dd,
J¼14.4 and 4.4 Hz, H-5), 2.94 (1H, dd, J¼14.4 and 8.4 Hz,
H-5), 3.68 (3H, s, OMe), 3.73 (1H, d, J¼9.3 Hz, CH2OSi),
3.85 (1H, d, J¼9.3 Hz, CH2OSi), 4.33e4.37 (1H, m, H-4), 5.86
(1H, dd, J¼5.6 and 1.5 Hz, H-2), 5.89 (1H, dd, J¼5.6 and
2.0 Hz, H-3), 7.16e7.63 (15H, m, Ph); 13C NMR (CDCl3)
d 19.3, 26.7, 37.6, 51.5, 52.1, 63.2, 69.3, 126.7, 127.6, 128.9,
129.6, 129.7, 131.1, 133.1, 133.2, 133.3, 134.3, 135.4, 135.6,
135.7, 178.5; FABMS m/z 503 (MþþH).
Compounds 36e38 were tested for their potential to inhibit
replication of HIV-1 and HCV in cell culture, but no signifi-
cant inhibition was observed.
4. Experimental
4.1. General
Melting points were determined on a Yanaco micro melting
1
point apparatus, and are uncorrected. H NMR and 13C NMR
4.2.2. NMR spectra of the minor isomer
1H NMR (CDCl3) d 1.02 (9H, s, SiBu-tert), 2.41e2.43 (2H,
m, H-5), 3.66 (3H, s, OMe), 3.70 (1H, d, J¼9.3 Hz, CH2OSi),
3.75 (1H, d, J¼9.3 Hz, CH2OSi), 4.18e4.22 (1H, m, H-4),
5.88 (1H, dd, J¼5.6 and 2.0 Hz, H-3), 5.94 (1H, dd, J¼5.6
and 1.7 Hz, H-2), 7.20e7.63 (15H, m, Ph); 13C NMR (CDCl3)
d 19.3, 26.7, 37.8, 51.5, 52.0, 62.6, 69.1, 126.8, 127.7, 128.8,
129.7, 131.5, 133.1, 133.2, 133.3, 134.0, 135.2, 135.5, 135.8,
174.5; FABMS m/z 503 (MþþH). Anal. Calcd for
C30H34O3SSi: C, 71.67; H, 6.82. Found: C, 71.38; H, 6.86.
were measured on a JEOL JNM-GX 400 (400 MHz). Chemi-
cal shifts are reported relative to Me4Si. Mass spectra (MS)
were taken in FAB mode with m-nitrobenzyl alcohol as a ma-
trix on a JEOL JMS-700. Infrared spectra (IR) were recorded
on a JASCO FT/IR-410 spectrophotometer. Column chroma-
tography was carried out on silica gel (Micro Bead Silica
Gel PSQ 100B, Fuji Silysia Chemical Ltd). Thin layer chro-
matography (TLC) was performed on silica gel (precoated sil-
ica gel plate F254, Merck). Where necessary, analytical
samples were purified by high-performance liquid chromato-
graphy (HPLC). HPLC was carried out on a Shimadzu LC-6AD
with a Shim-pack PREP-SIL (H)ꢃ KIT column (2ꢄ25 cm).
THF was distilled from benzophenone ketyl.
4.3. Benzenesulfonyl-1-(tert-butyldiphenylsilyloxy)-
methyl-2-cyclopentenecarboxylic acid methyl ester (13)
To a CH2Cl2 (30 mL) solution of 12 (865 mg, 1.72 mmol)
was added m-CPBA (>65%, 1.0 g, 3.78 mmol). The reaction
mixture was stirred for 3 h at room temperature, treated with
Et3N (527 mL, 3.78 mmol), and then partitioned between satu-
rated aqueous NaHCO3 and CH2Cl2. Silica gel column chro-
matography (hexane/AcOEt¼5:1) of the organic layer gave
4.2. 1-(tert-Butyldiphenylsilyloxy)methyl-4-phenylthio-
2-cyclopentenecarboxylic acid methyl ester (12)
To a mixture of 1010 (5.0 g, 12.2 mmol) and PhSH (1.5 mL,
14.6 mmol) in CH2Cl2 (60 mL) was added Et3N (68 mL,

H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
1499
13 (879 mg, 96%, inseparable mixture of two isomers ca. 2:1)
as an oil.
133.2, 133.3, 134.5, 134.9, 135.3, 135.6, 135.7, 173.2, 173.3;
FABMS m/z 697 (MþþH).
4.3.1. NMR spectra of the major isomer
4.5. 4-Benzenesulfonyl-1-(tert-butyldiphenylsilyloxy)-
methyl-2-cyclopentenecarboxylic acid (phenyl-
seleno)methyl ester (15)
1H NMR (CDCl3) d 1.02 (9H, s, SiBu-tert), 2.26 (1H, dd,
J¼15.0 and 5.2 Hz, H-5), 2.82 (1H, dd, J¼15.0 and 9.5 Hz,
H-5), 3.62 (1H, d, J¼9.5 Hz, CH2OSi), 3.65 (3H, s, OMe), 3.77
(1H, d, J¼9.5 Hz, CH2OSi), 4.41e4.44 (1H, m, H-4), 5.83
(1H, dd, J¼5.7 and 1.7 Hz, H-3), 6.06 (1H, dd, J¼5.7 and
2.3 Hz, H-2), 7.37e7.47 (8H, m, Ph), 7.54e7.62 (5H, m,
Ph), 7.80e7.82 (2H, m, Ph); 13C NMR (CDCl3) d 19.3, 26.6,
30.5, 52.3, 63.7, 69.1, 71.6, 126.6, 127.6, 127.7, 128.9, 129.1,
129.7, 129.8, 133.1, 133.8, 135.5, 135.6, 137.3, 138.6, 173.6.
Compound 13 (9.95 g, 18.6 mmol) was treated by the pro-
cedure described for the preparation of 14. This gave 15
(10.4 g, 81% from 13, a mixture of two isomers ca. 10:7) as
an oil. Compound 15 was used for the radical reaction without
further purification due to its instability to silica gel. 1H NMR
(CDCl3) d 0.98 (9H, s, SiBu-tert), 1.00 (6.3H, s, SiBu-tert),
2.21e2.27 (1.7H, m, H-5ꢄ2), 2.67 (1H, dd, J¼15.0 and
5.4 Hz, H-5), 2.75 (0.7H, dd, J¼15.0 and 9.3 Hz, H-5), 3.62e
3.80 (3.4H, m, CH2OSiꢄ4), 5.38e5.59 (3.4H, m, CH2Seꢄ4),
5.82 (0.7H, dd, J¼5.6 and 2.2 Hz, H-2 or H-3), 5.86 (1H, dd,
J¼5.6 and 2.2 Hz, H-2 or H-3), 6.00 (0.7H, dd, J¼5.6 and
2.2 Hz, H-2 or H-3), 6.06 (1H, dd, J¼5.6 and 2.2 Hz, H-2 or
H-3), 7.22e7.85 (34H, m, Ph); 13C NMR (CDCl3) d 19.3,
19.4, 26.7, 30.2, 30.4, 62.7, 62.8, 63.0, 63.8, 68.4, 68.7, 71.3,
71.5, 126.8, 127.2, 127.7, 127.8, 128.9, 129.0, 129.1, 129.2,
129.3, 129.7, 129.8, 129.9, 132.6, 132.7, 133.0, 133.1, 133.2,
133.8, 133.9, 135.5, 135.6, 135.7, 137.3, 138.1, 138.8, 171.7,
172.4; FABMS m/z 729 (MþþK).
4.3.2. NMR spectra of the minor isomer
1H NMR (CDCl3) d 0.99 (9H, s, SiBu-tert), 2.22 (1H, dd,
J¼15.0 and 9.2 Hz, H-5), 2.69 (1H, dd, J¼15.0 and 5.2 Hz,
H-5), 3.56 (3H, s, OMe), 3.62 (1H, d, J¼9.2 Hz, CH2OSi),
3.68 (1H, d, J¼9.2 Hz, CH2OSi), 4.27e4.29 (1H, m, H-4), 5.85
(1H, dd, J¼5.7 and 2.3 Hz, H-3), 6.15 (1H, dd, J¼5.7 and
2.3 Hz, H-2), 7.34e7.37 (4H, m, Ph), 7.40e7.43 (2H, m,
Ph), 7.54e7.57 (6H, m, Ph), 7.63e7.66 (1H, m, Ph), 7.85e
7.87 (2H, m, Ph); 13C NMR (CDCl3) d 19.2, 26.6, 30.4, 52.2,
62.9, 69.0, 71.2, 126.1, 127.7, 129.0, 129.3, 129.8, 132.7,
132.8, 133.7, 135.4, 135.5, 136.7, 139.5, 173.1; FABMS m/z
535 (MþþH). Anal. Calcd for C30H34O5SSi: C, 67.38; H,
6.41. Found: C, 67.39; H, 6.54.
4.6. Radical reaction of 14
4.4. 1-(tert-Butyldiphenylsilyloxy)methyl-4-phenylthio-
2-cyclopentenecarboxylic acid (phenylseleno)methyl
ester (14)
To a refluxing toluene (190 mL) solution of 14 (4.99 g,
7.58 mmol) and i-Pr2NEt (2.18 mL, 12.5 mmol) was added
dropwise a toluene (20 mL) solution of Bu3SnH (4.77 mL,
1.77 mmol) and AIBN (245 mg, 1.52 mmol) over 5 h under
positive pressure of dry Ar. After evaporation of the solvent,
the reaction mixture was purified by silica gel chromatography
(hexane/AcOEt¼30:1). This gave 16 (1.96 g, 61% as a solid),
17 (150 mg, 5% as an oil), and 18 (538 mg, 18% as an oil).
To a mixture of 12 (4.01 g, 7.98 mmol), THF (60 mL), and
MeOH (90 mL) was added aqueous KOH [KOH (2.24 g,
39.9 mmol)/H2O (30 mL)]. After being stirred at room tem-
perature for 2 days, the reaction mixture was partition between
1 M HCl and CH2Cl2. The organic layer was evaporated and
the residue was dissolved in DME (26 mL), to which
PhSeCH2Cl (1.9 g, 9.24 mmol), NaI (1.39 g, 9.24 mmol),
and i-Pr2NEt (1.6 mL, 9.24 mmol) were added. The whole
mixture was refluxed for 24 h and partitioned between
NaHCO3 and Et2O. Flash silica gel column chromatography
(hexane/AcOEt¼80:1) of the organic layer gave 14 (3.57 g,
68% from 12, a mixture of two isomers ca. 10:4) as an oil.
Compound 14 was used for the radical reaction without further
purification due to its instability to silica gel. 1H NMR
(CDCl3) d 1.01 (12.6H, s, SiBu-tert), 2.01 (1H, dd, J¼14.4
and 4.6 Hz, H-5), 2.40e2.42 (0.8H, m, H-5ꢄ2), 2.89 (1H,
dd, J¼14.4 and 8.3 Hz, H-5), 3.71 (0.4H, d, J¼9.5 Hz,
CH2OSi), 3.75 (1H, d, J¼9.5 Hz, CH2OSi), 3.76 (0.4H, d,
J¼9.5 Hz, CH2OSi), 3.86 (1H, d, J¼9.5 Hz, CH2OSi),
4.18e4.23 (0.4H, m, H-4), 4.29e4.33 (1H, m, H-4), 5.49e
5.61 (2.8H, m, CH2Seꢄ4), 5.81 (1H, dd, J¼5.4 and 1.7 Hz,
H-2), 5.88e5.90 (1.8H, m, H-2 and H-3), 7.16e7.63 (20H,
m, Ph); 13C NMR (CDCl3) d 19.3, 26.7, 37.5, 37.7, 51.5,
62.5, 62.6, 62.7, 63.3, 68.6, 68.9, 126.8, 127.6, 127.7, 128.9,
129.2, 129.7, 129.8, 131.1, 131.4, 132.5, 132.8, 133.0, 133.1,
4.6.1. Physical data for 16
Mp 77e78 ꢁC; 1H NMR (CDCl3) d 1.05 (9H, s, SiBu-tert),
2.20e2.26 (1H, m, CH2CH]CH), 2.65e2.71 (1H, m,
CH2CH]CH), 3.57e3.60 (1H, m, H-5), 3.66 (1H, d,
J¼9.6 Hz, CH2OSi), 4.11(1H, d, J¼9.6 Hz, CH2OSi), 4.19
(1H, dd, J¼8.7 and 1.7 Hz, CH2OCO), 4.56 (1H, dd, J¼8.7
and 7.6 Hz, CH2OCO), 5.63e5.65 and 5.72e5.75 (2H, each
as m, CH]CH ), 7.36e7.47 (6H, m, Ph), 7.62e7.73 (4H,
m, Ph); 13C NMR (CDCl3) d 19.2, 26.7, 39.3, 50.3, 56.7,
67.3, 71.8, 127.9, 129.9, 130.0, 131.0, 132.2, 133.1, 135.5
135.7, 181.9; FABMS m/z 431 (MþþK). Anal. Calcd for
C24H28O3Si: C, 73.43; H, 7.19. Found: C, 73.39; H, 7.29.
4.6.2. Physical data for 17
1H NMR (CDCl3) d 1.04 (9H, s, SiBu-tert), 1.40e1.48 (1H,
m, eCH2CH2e), 1.56e1.70 (3H, m, eCH2CH2e), 1.89e2.00
(2H, m, eCH2CH2e), 2.91e2.93 (1H, m, H-5), 3.50 (1H, d,
J¼9.5 Hz, CH2OSi), 3.99 (1H, dd, J¼9.0 and 3.2 Hz,
CH2OCO), 4.05 (1H, d, J¼9.5 Hz, CH2OSi), 4.54 (1H, t,
J¼9.0 Hz, CH2OCO), 7.37e7.47 (6H, m, Ph), 7.63e7.65

1500
H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
(4H, m, Ph); 13C NMR (CDCl3) d 19.2, 25.5, 26.7, 33.7, 34.4,
42.7, 58.5, 67.5, 73.3, 127.8, 129.8, 129.9, 132.5, 133.2, 135.5,
135.7, 181.8; FABMS m/z 395 (MþþH). Anal. Calcd for
C24H30O3Si: C, 73.05; H, 7.66. Found: C, 72.78; H, 7.68.
7.1 Hz, H-4), 4.53 (1H, dd, J¼9.0 and 1.7 Hz, H-4), 7.37e
7.48 (6H, m, Ph), 7.59e7.63 (4H, m, Ph); 13C NMR (CDCl3)
d 19.2, 26.7, 34.3, 44.3, 54.9, 58.3, 60.4, 66.6, 68.4, 127.9,
130.0, 130.1, 135.4, 135.7, 180.0; FABMS m/z 409 (MþþH).
Anal. Calcd for C24H28O4Si: C, 70.55; H, 6.91. Found: C,
70.22; H, 6.89.
4.6.3. Physical data for 18
1H NMR (CDCl3) d 1.05 (9H, s, SiBu-tert), 1.89e1.95 (1H,
m, eCH2CH2e), 2.31e2.43 (3H, m, eCH2CH2e), 3.69 (3H,
s, OCH3), 3.72 (1H, d, J¼9.3 Hz, CH2OSi), 3.81 (1H, d, J¼
9.3 Hz, CH2OSi), 5.74e5.76 and 5.86e5.88 (2H, each as m,
eCH]CHe), 7.36e7.44 (6H, m, Ph), 7.62e7.65 (4H, m,
Ph); 13C NMR (CDCl3) d 18.9, 26.3, 29.6, 31.2, 51.5, 62.6,
68.6, 127.2, 129.2, 130.7, 133.1, 133.5, 135.2, 135.3, 175.2;
FABMS m/z 395 (MþþH). Anal. Calcd for C24H30O3Si: C,
73.05; H, 7.66. Found: C, 72.99; H, 7.87.
4.10.1.2. Physical data for exo-19. 1H NMR (CDCl3) d 1.02
(9H, s, SiBu-tert), 1.82 (1H, d, J¼15.0 Hz, H-8), 2.16 (1H,
dd, J¼15.0 and 2.2 Hz, H-8), 3.45 (1H, dd, J¼9.5 and
5.6 Hz, H-5), 3.51 (1H, d, J¼9.3 Hz, CH2OSi), 3.52 (1H, d,
J¼2.2 Hz, H-6), 3.56 (1H, t, J¼2.2 Hz, H-7), 3.96 (1H, d,
J¼9.3 Hz, CH2OSi), 4.15 (1H, dd, J¼9.5 and 5.6 Hz, H-4),
4.40 (1H, t, J¼9.5 Hz, H-4), 7.37e7.46 (6H, m, Ph), 7.61e
7.64 (4H, m, Ph); 13C NMR (CDCl3) d 18.7, 26.2, 34.1, 43.9,
57.3, 57.6, 61.4, 66.3, 67.2, 127.3, 127.4, 129.4, 131.9, 132.5,
135.0, 135.2, 179.7; FABMS m/z 409 (MþþH). Anal. Calcd
for C24H28O4Si: C, 70.55; H, 6.91. Found: C, 70.40; H, 6.93.
4.7. Radical reaction of 15
Compound 15 (4.50 g, 6.52 mmol) was treated by the pro-
cedure described for the reaction of 14. This gave 16 (2.40 g,
94%).
4.10.2. Method B
To a mixture of 16 (837 mg, 2.13 mmol) and AcOH
(1.23 mL, 21.3 mmol) in CH2Cl2 (20 mL) wad added NIS
(1.92 g, 8.52 mmol). The resulting mixture was stirred for
87 h at room temperature in the dark. After addition of satu-
rated aqueous Na2S2O3 (50 mL), the reaction mixture was par-
titioned between saturated aqueous NaHCO3 and CH2Cl2. The
organic layer was evaporated and treated with NaOMe
(345 mg, 6.39 mmol) in MeOH (18 mL) for 30 min at room
temperature. The reaction mixture was partitioned between
0.5 M HCl and CH2Cl2. Silica gel column chromatography
(hexane/AcOEt¼4:1) of the organic layer gave 19 (785 mg,
90%, exo/endo¼7:1, calculated by integrating CH2OSi). Com-
pound 19 was used for the next ring opening reaction without
separation.
4.8. Radical reaction of 12 (depicted in Scheme 4)
Compound 12 (99 mg, 0.917 mmol) was treated by the pro-
cedure described for the reaction of 14. After evaporation of
1
the solvent, the reaction mixture was analyzed by H NMR
(12/18¼85:15, calculated by integrating OMe).
4.9. Radical reaction of 15 (depicted in Scheme 4)
To a refluxing toluene (5 mL) solution of 15 (138 mg,
0.20 mmol), i-Pr2NEt (105 mL, 0.60 mmol), and PhSH
(10.3 mL, 0.10 mmol) was added dropwise a toluene (1 mL)
solution of Bu3SnH (108 mL, 0.40 mmol) and AIBN (6.6 mg,
0.04 mmol) over 5 h under positive pressure of dry Ar. After
evaporation of the solvent, the reaction mixture was analyzed
by 1H NMR (16/13¼70:30, calculated by integrating
CH2OSi).
4.11. Epoxide ring cleavage of endo-19 by
phenylselenide anion
The phenylselenide anion was prepared from (PhSe)2
(131 mg, 0.41 mmol)/EtOH (10 mL) and NaBH4 (31 mg,
0.83 mmol) with stirring for 10 min at room temperature. To
this solution, an EtOH (3 mL) solution of endo-19 (215 mg,
0.52 mmol) was added. After being stirred for 5 h at room
temperature, the reaction mixture was partitioned between
0.5 M HCl and CH2Cl2. Preparative TLC (hexane/AcOEt¼
2:1) of the organic layer gave 20 (87 mg, 30%, foam) and
21 (169 mg, 57%, solid).
4.10. Preparation of the epoxide 19
4.10.1. Method A
To a CH2Cl2 (5 mL) solution of 16 (341 mg, 0.87 mmol)
was added m-CPBA (>65%, 242 mg, 0.91 mmol) and the
mixture was stirred for 17 h at room temperature. The reaction
mixture was treated with Et3N (0.127 mL, 0.91 mmol) and
then partitioned between saturated aqueous NaHCO3 and
CH2Cl2. Preparative TLC (hexane/AcOEt¼2:1) of the organic
layer gave endo-19 (176 mg, 50%, foam) and exo-19 (69 mg,
19%, foam).
4.11.1. Physical data for 20
1H NMR (CDCl3) d 1.02 (9H, s, SiBu-tert), 1.60 (1H, dd,
J¼13.6 and 10.9 Hz, H-8), 2.31 (1H, br, OH), 2.38 (1H, dd,
J¼13.6 and 6.6 Hz, H-8), 3.14e3.18 (1H, m, H-5), 3.22e
3.27 (1H, m, H-7), 3.52 (1H, d, J¼9.7 Hz, CH2OSi), 3.93
(1H, d, J¼9.7 Hz, CH2OSi), 4.05 (1H, t, J¼8.0 Hz, H-6), 4.31
(1H, t, J¼9.7 Hz, H-4), 4.62 (1H, dd, J¼9.7 and 3.4 Hz, H-4),
7.24e7.32 (3H, m, Ph), 7.37e7.46 (6H, m, Ph), 7.50e7.52
(2H, m, Ph), 7.59e7.63 (4H, m, Ph); 13C NMR (CDCl3)
4.10.1.1. Physical data for endo-19. 1H NMR (CDCl3) d 1.04
(9H, s, SiBu-tert), 1.70 (1H, dd, J¼14.6 and 2.2 Hz, H-8), 2.45
(1H, d, J¼14.6 Hz, H-8), 2.81e2.84 (1H, m, H-5), 3.54e3.57
(2H, m, CH2OSi and H-6), 3.65 (1H, t, J¼2.2 Hz, H-7), 3.91
(1H, d, J¼9.8 Hz, CH2OSi), 4.48 (1H, dd, J¼9.0 and

H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
1501
d 19.2, 26.7, 36.6, 44.6, 46.5, 55.8, 65.8, 67.0, 77.5, 126.6,
127.8, 128.4, 129.4, 129.9, 132.2, 132.9, 135.3, 135.5,
135.6, 180.8; FABMS m/z 605 (MþþK). Anal. Calcd for
C30H34O4SeSi: C, 63.70; H, 6.06. Found: C, 63.33; H, 6.04.
6.12 (1H, dd, J¼5.2 and 2.3 Hz, H-7), 7.38e7.47 (6H, m,
Ph), 7.61e7.64 (4H, m, Ph); 13C NMR (CDCl3) d 19.2, 26.8,
51.5, 63.5, 65.1, 69.6, 81.3, 127.9, 130.1, 131.9, 132.0, 132.1,
135.6, 136.3, 175.8; FABMS m/z 409 (MþþH). Anal.
Calcd for C24H28O4Si: C, 70.55; H, 6.91. Found: C, 70.41;
H, 6.95.
4.11.2. Physical data for 21
1
Mp 127e128 ꢁC; H NMR (CDCl3) d 1.02 (9H, s, SiBu-
tert), 1.99e2.09 (2H, m, H-8), 2.27 (1H, br, OH), 2.90e2.93
(1H, m, H-5), 3.45e3.47 (2H, m, H-6 and CH2OSi), 4.00
(1H, d, J¼9.2 Hz, CH2OSi), 4.12e4.15 (1H, m, H-7), 4.27
(1H, dd, J¼9.2 and 2.9 Hz, H-4), 4.50 (1H, t, J¼9.2 Hz,
H-4), 7.25e7.32 (3H, m, Ph), 7.35e7.53 (6H, m, Ph), 7.58e7.59
(2H, m, Ph), 7.60e7.62 (4H, m, Ph); 13C NMR (CDCl3)
d 19.2, 26.7, 39.3, 47.8, 54.5, 56.3, 68.0, 72.7, 77.3, 127.8,
127.9, 128.3, 129.4, 129.9, 132.2, 132.8, 134.7, 135.5,
136.6, 181.5; FABMS m/z 567 (MþþH). Anal. Calcd for
C30H34O4SeSi: C, 63.70; H, 6.06. Found: C, 63.44; H, 6.08.
4.14. (ꢀ)-t-1-(tert-Butyldiphenylsilyloxy)methyl-
4-hydroxy-7-oxabicyclo-[3.3.0]oct-2-en-8-one (24)
To a stirred THF (2 mL) solution containing 23 (105 mg,
0.257 mmol), PPh3 (202 mg, 0.771 mmol), and AcOH
(73.6 mL, 1.29 mmol) was added DEAD (2.2 M in toluene,
352 mL, 0.771 mmol) at 0 ꢁC. After stirring for 15 min, the re-
action mixture was partitioned between saturated aqueous
NaHCO3 and CH2Cl2. The organic layer was evaporated and
the resulting residue was dissolved in MeOH (4 mL) contain-
ing K2CO3 (80 mg, 0.514 mmol). After being stirred for
15 min at 0 ꢁC, the reaction mixture was partitioned between
0.5 M HCl and CH2Cl2. Silica gel column chromatography
(hexane/AcOEt¼3:1) of the organic layer gave 24 (103 mg,
4.12. Epoxide ring cleavage of exo-19 by phenylselenide
anion: formation of the allyl alcohol 22
1
Compound 22 was prepared from exo-19 (110 mg,
0.22 mmol) by the procedure described for the reaction of
endo-19. Silica gel column chromatography (CH2Cl2) gave
22 (131 mg, 86%) as a foam.
Compound 22 was also obtained in 83% yield from 16
through method B in Scheme 5 without isolating exo-19.
98%, solid). Mp 139e140 ꢁC; H NMR (CDCl3) d 1.05 (9H,
s, SiBu-tert), 1.68 (1H, d, J¼7.3 Hz, OH), 3.21e3.26 (1H, m,
H-5), 3.55 (1H, d, J¼9.8 Hz, CH2OSi), 4.12 (1H, d, J¼9.8 Hz,
CH2OSi), 4.40 (1H, t, J¼9.0 Hz, H-4), 4.64 (1H, dd, J¼9.0
and 4.9 Hz, H-4), 5.00e5.04 (1H, m H-6), 5.67 (1H, dd,
J¼5.6 and 1.5 Hz, H-8), 5.94 (1H, dd, J¼5.6 and 2.0 Hz,
H-7), 7.37e7.47 (6H, m, Ph), 7.62e7.66 (4H, m, Ph); 13C NMR
(CDCl3) d 19.0, 26.5, 44.6, 64.0, 65.6, 65.8, 76.9, 127.6, 129.7,
130.8, 132.1, 132.7, 135.3, 135.4, 136.9, 177.5; FABMS
m/z 409 (MþþH). Anal. Calcd for C24H28O4Si: C, 70.55; H,
6.91. Found: C, 70.45; H, 6.98.
4.12.1. Physical data for 22
1H NMR (CDCl3) d 1.02 (9H, s, SiBu-tert), 1.93 (1H, dd,
J¼14.4 and 10.2 Hz, H-8), 2.08 (1H, dd, J¼14.4 and 8.1 Hz,
H-8), 2.33 (1H, d, J¼3.2 Hz, OH), 2.78e2.82 (1H, m, H-5),
3.22e3.29 (1H, m, H-7), 3.57 (1H, d, J¼9.5 Hz, CH2OSi),
3.80e3.85 (1H, m, H-6), 3.94 (1H, d, J¼9.5 Hz, CH2OSi),
4.33 (1H, dd, J¼9.3 and 1.9 Hz, H-4), 4.50 (1H, dd, J¼9.3
and 7.3 Hz, H-4), 7.26e7.63 (15H, m, Ph); 13C NMR
(CDCl3) d 18.9, 26.4, 35.7, 47.7, 49.9, 53.5, 67.7, 70.2, 81.7,
127.6, 127.7, 128.3, 129.2, 129.8, 131.7, 132.4, 135.2, 135.3,
135.4, 180.4; FABMS m/z 605 (MþþK). Anal. Calcd for
C30H34O4SeSi: C, 63.70; H, 6.06. Found: C, 63.54; H, 6.14.
4.15. Mitsunobu reaction between 24 and
6-chloropurine, and subsequent ammonolysis
To a stirred THF (100 mL) solution containing 24 (2.0 g,
4.90 mmol), PPh3 (3.91 g, 12.2 mmol), and 6-chloropurine
(1.13 g, 7.34 mmol) was added dropwise DIAD (6.42 mL,
12.2 mmol) at 0 ꢁC. After being stirred for 1 h at 0 ꢁC, the re-
action mixture was partitioned between saturated aqueous
NaHCO3 and CH2Cl2. The organic layer was purified by silica
gel column chromatography. Elution with hexane/AcOEt¼3:1
gave a mixture of 25 and triphenylphosphine oxide. Elution
with hexane/AcOEt¼1:1 gave 26 (240 mg, 9%, foam). The
crude 25 dissolved in THF (10 mL) was transferred in a sealed
tube containing NH3/MeOH (200 mL) and the whole mixture
was heated at 120 ꢁC for 6 h. After evaporation, the reaction
mixture was purified by silica gel column chromatography.
Elution with CHCl3/MeOH¼80:1 gave 27 (1.75 g, 68% from
24, solid), which was recrystallized from MeOH/CH2Cl2.
Elution with CHCl3/MeOH¼30:1 gave 28 (120 mg, 5% from
24, solid).
4.13. (ꢀ)-c-1-(tert-Butyldiphenylsilyloxy)methyl-4-
hydroxy-7-oxabicyclo-[3.3.0]oct-2-en-8-one (23)
To a CH2Cl2 (50 mL) solution of 22 (1.9 g, 3.36 mmol) was
added m-CPBA (>65%, 1.07 g, 4.03 mmol) and the mixture
was stirred for 0.5 h at room temperature. After addition of
Et3N (2.34 mL, 16.8 mmol), the reaction mixture was refluxed
for 1 h and then partitioned between saturated aqueous
NaHCO3 and CH2Cl2. Silica gel column chromatography
(hexane/AcOEt¼1:2) of the organic layer gave 23 (1.23 g,
1
90%, solid). Mp 120e121 ꢁC; H NMR (CDCl3) d 1.06 (9H,
s, SiBu-tert), 2.43 (1H, d, J¼10.3 Hz, OH), 3.04 (1H, dd,
J¼9.5 and 6.9 Hz, H-5), 3.82 (1H, d, J¼10.3 Hz, CH2OSi),
3.89 (1H, dd, J¼9.5 and 6.9 Hz, H-4), 3.91 (1H, d, J¼
10.3 Hz, CH2OSi), 4.54 (1H, dd, J¼10.3 and 2.3 Hz, H-6),
4.61 (1H, t, J¼9.5 Hz, H-4), 5.73 (1H, d, J¼5.2 Hz, H-8),
4.15.1. Physical data for 26
1H NMR (CDCl3) d 0.97 (9H, s, SiBu-tert), 3.02e3.03 (1H,
m H-50), 3.48 (1H, d, J¼10.0 Hz, CH2OSi), 4.38 (1H, d,

1502
H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
J¼10.0 Hz, CH2OSi), 4.41 (1H, dd, J¼10.0 and 5.2 Hz, H-40),
4.76 (1H, t, J¼10.0 Hz, H-40), 5.92e5.93 (1H, m, H-60), 6.11
(1H, dd, J¼5.2 and 2.3 Hz, H-80), 6.23 (1H, dd, J¼5.2 and
1.7 Hz, H-70), 7.12e7.20 (3H, m, Ph), 7.28e7.31 (2H, m,
Ph), 7.34e7.38 (3H, m, Ph), 7.49e7.51 (2H, m, Ph), 7.80
(1H, s, H-8), 8.95 (1H, s, H-2); 13C NMR (CDCl3) d 19.0,
26.6, 49.8, 65.5, 68.8, 70.2, 121.8, 127.7, 127.8, 129.5,
129.9, 130.0, 131.8, 132.2, 135.0, 135.4, 137.2, 142.5,
145.6, 152.6, 162.3, 174.6; FABMS m/z 545 (MþþH). Anal.
Calcd for C29H29ClN4O3Si: C, 63.90; H, 5.36; N, 10.28.
Found: C, 63.62; H, 5.32; N, 10.21.
then evaporated to dryness. Silica gel column chromatography
(CHCl3/MeOH¼11:1) of the residue gave 27 (3.09 g, 83%).
4.17. (ꢀ)-c-4-(Adenine-9-yl)-1-(tert-butyldiphenyl-
silyloxy)methyl-7-oxabicyclo-[3.3.0]oct-2-en-8-ol:
the cyclic hemiacetal 30
To a CH2Cl2 (10 mL) solution of 27 (200 mg, 0.49 mmol)
was added i-Bu2AlH (1.01 M in toluene, 1.46 mL, 1.47 mmol)
at ꢂ70 ꢁC. The resulting mixture was stirred for 15 min at
ꢂ70 ꢁC and the reaction was quenched by adding saturated
aqueous NH4Cl. The reaction mixture was partitioned between
0.5 M HCl and CH2Cl2. Silica gel column chromatography
(CHCl3/MeOH¼10:1) of the organic layer gave 30 (194 mg,
97%, a mixture of two isomers ca. 4:1) as a foam.
4.15.2. Physical data for 27
1
Mp 229e231 ꢁC; H NMR (CDCl3) d 0.99 (9H, s, SiBu-
tert), 3.13e3.15 (1H, m, H-50), 3.72 (1H, d, J¼10.0 Hz,
CH2OSi), 4.32 (1H, d, J¼10.0 Hz, CH2OSi), 4.58 (1H, dd,
J¼9.7 and 3.4 Hz, H-40), 4.70 (1H, t, J¼9.7 Hz, H-40), 5.89
(2H, br, NH2), 6.02 (1H, dd, J¼5.4 and 2.0 Hz, H-80), 6.05
(1H, dd, J¼5.4 and 2.0 Hz, H-70), 6.59e6.60 (1H, m, H-60),
7.25e7.58 (10H, m, Ph), 7.59 (1H, s, H-8), 8.33 (1H, s,
H-2); 13C NMR (CDCl3) d 19.1, 26.7, 50.3, 65.2, 65.9,
67.1, 71.7, 120.1, 127.8, 127.9, 129.9, 130.0, 130.7, 131.9,
132.5, 135.0, 135.3, 135.6, 137.0, 149.7, 153.2, 155.5, 175.9;
FABMS m/z 526 (MþþH). Anal. Calcd for C29H31N5O3Si:
C, 66.26; H, 5.94; N, 13.32. Found: C, 66.06; H, 5.85;
N, 13.44.
4.17.1. Physical data for 30
1H NMR (DMSO-d6) d 0.96 and 0.97 (11.25H, each as s,
SiBu-tert), 2.60e2.64 (1H, m, H-50), 3.68 (1H, d, J¼10.0 Hz,
CH2OSi), 3.74e3.75 (0.5H, m, CH2OSi), 3.93e4.02 (2.5H,
m, CH2OSi and H-40), 5.19 (1H, d, J¼4.4 Hz, OCHOH),
5.24 (0.25H, d, J¼5.0 Hz, OCHOH), 5.35e5.37 (1.25H, m,
H-60), 5.97 (0.25H, dd, J¼5.6 and 2.0 Hz, CH]CH), 6.01
(0.25H, dd, J¼5.6 and 1.7 Hz, CH]CH), 6.11 (1H, dd,
J¼5.6 and 2.2 Hz, CH]CH), 6.30 (1H, dd, J¼5.6 and
1.7 Hz, CH]CH), 6.33 (1H, d, J¼4.4 Hz, OH), 6.50 (0.25H,
d, J¼5.0 Hz, OH), 7.20 (2.5H, br, NH2), 7.33e7.64 (12.5H,
m, Ph), 7.75 (1H, s, H-8), 7.82 (0.25H, s, H-8), 8.07 (0.25H,
s, H-2), 8.10 (1H, s, H-2); 13C NMR (DMSO-d6) d 18.9,
26.6, 26.7, 51.7, 52.5, 64.8, 66.0, 66.3, 67.9, 68.0, 68.4, 70.5,
99.1, 99.5, 118.8, 118.9, 127.9, 128.9, 129.1, 129.8, 129.9,
130.0, 132.6, 132.7, 132.8, 139.5, 140.0, 141.3, 148.3, 148.4,
148.6, 153.0; FABMS m/z 528 (MþþH). Anal. Calcd for
C29H33N5O3Si: C, 66.01; H, 6.30; N, 13.27. Found: C, 65.99;
H, 6.18; N, 13.27.
4.15.3. Physical data for 28
Mp 200e202 ꢁC; 1H NMR (DMSO-d6) d 1.00 (9H, s, SiBu-
tert), 2.64 (1H, dd, J¼14.5 and 7.2 Hz, H-50), 3.53e3.59 (1H,
m, CH2OH), 3.68e3.74 (1H, m, CH2OH), 3.90 (1H, d,
J¼9.7 Hz, CH2OSi), 4.11 (1H, d, J¼9.7 Hz, CH2OSi), 4.54
(1H, dd, J¼5.7 and 4.5 Hz, OH), 5.52e5.55 (1H, m, H-10),
6.10 (1H, dd, J¼5.7 and 1.8 Hz, CH]CH), 6.22 (1H, dd,
J¼5.7 and 2.0 Hz, CH]CH), 6.98 (1H, br, NH2), 7.22 (2H,
br, NH2), 7.34 (1H, br, NH2), 7.40e7.48 (6H, m, Ph), 7.64e
7.68 (4H, m, Ph), 7.94 (1H, s, H-8), 8.06 (1H, s, H-2); 13C
NMR (DMSO-d6) d 19.0, 26.6, 52.4, 60.7, 62.7, 63.2, 67.4,
79.2, 119.0, 127.8, 127.9, 129.8, 132.8, 132.9, 135.1, 135.2,
136.5, 138.9, 149.4, 152.2, 156.0, 173.0; FABMS m/z 543
(MþþH). Anal. Calcd for C29H34N6O3Si$H2O: C, 62.12; H,
6.47; N, 14.99. Found: C, 62.39; H, 6.12; N, 14.91.
4.18. (ꢀ)-9-[c-4-(tert-Butyldiphenylsilyloxy)methyl-
t-4,t-5-bis(hydroxymethyl)-cyclopent-2-en-r-1-yl]-9H-
adenine (31)
To a MeOH (40 mL) solution of 30 (200 mg, 0.38 mmol)
was added NaBH4 (43 mg, 1.14 mmol) at 0 ꢁC. After stirring
for 1 h at room temperature, the reaction mixture was parti-
tioned between 0.5 M HCl and CHCl3. Silica gel column chro-
matography (CHCl3/MeOH¼20:1) of the organic layer gave
31 (173 mg, 86%) as an oil.
4.16. Mitsunobu reaction between 24 and bis(Boc)-
adenine (29), and subsequent hydrolysis
To aTHF(50 mL)solutioncontaining24(2.89 g, 7.07 mmol),
Ph3P (2.36 g, 8.98 mmol), and bis(Boc)adenine (29)18 (3.01 g,
8.98 mmol) was added dropwise DIAD (1.77 mL, 8.98 mmol)
at ꢂ40 ꢁC. The resulting mixture was stirred for 18 h at
ꢂ40 ꢁC. After evaporation of the solvent, the reaction mixture
was purified by flash silica gel column chromatography (hex-
ane/AcOEt¼1:1). The crude product obtained was dissolved
in THF (25 mL) containing 50% aqueous HCO2H (50 mL)
and the whole mixture was heated at 50 ꢁC for 9 h. After evap-
oration, the residue was treated with 26% NH4OH (2 mL) and
1H NMR (CDCl3) d 1.00 (9H, s, SiBu-tert), 2.56e2.62
(1H, m, H-50), 3.57e3.83 (6H, m, CH2OSi and CH2OH),
4.58 (1H, t, J¼4.8 Hz, OH), 4.70 (1H, t, J¼5.0 Hz, OH),
5.42e5.45 (1H, m, H-10), 5.92 (1H, dd, J¼5.7 and 1.5 Hz,
H-20 or H-30), 6.00 (1H, dd, J¼5.7 and 2.1 Hz, H-20 or H-30),
7.20 (2H, br, NH2), 7.39e7.48 (6H, m, Ph), 7.61e7.64 (4H,
m, Ph), 7.94 (1H, s, H-8), 8.09 (1H, s, H-2); 13C NMR
(CDCl3) d 18.7, 26.4, 52.5, 57.6, 59.0, 61.6, 62.1, 66.8,
118.6, 127.6, 127.7, 129.6, 130.2, 130.7, 132.7, 134.9, 138.4,
138.8, 149.3, 152.1, 155.7; FABMS m/z 530 (MþþH). Anal.

H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
1503
Calcd for C29H35N5O3Si$1/5H2O: C, 65.31; H, 6.69; N, 13.13.
Found: C, 65.02; H, 6.70; N, 12.90.
4.21. (ꢀ)-9-[t-5-Acetoxymethyl-c-4-(tert-butyl-
diphenylsilyloxy)methyl-t-4-cyanocyclopent-2-en-r-
1-yl]-9H-adenine (34)
4.19. (ꢀ)-9-[c-4-(tert-Butyldiphenylsilyloxy)methyl-t-5-
hydroxymethyl-t-4-vinylcyclopent-2-en-r-1-yl]-9H-
adenine (32)
A mixture of 30 (197 mg, 0.37 mmol) and NH2OH$HCl
(520 mg, 7.48 mmol) in pyridine (5 mL) was stirred at room
temperature for 3 h. The reaction mixture was partitioned be-
tween saturated aqueous NaHCO3 and CHCl3. The organic
layer was evaporated to leave the crude oxime. The crude ox-
ime was dissolved in MeCN (12 mL) and reacted with Ac2O
(106 mL, 1.12 mmol) in the presence of i-Pr2NEt (195 mL,
1.12 mmol) and DMAP (137 mg, 1.12 mmol) for 1 h. The re-
action mixture was partitioned between 0.5 M HCl and CHCl3.
After evaporation of the organic layer, the residue was dis-
solved in AcOH (6 mL) containing NaOAc (27 mg,
0.33 mmol) and the whole mixture was heated at 100 ꢁC for
3 h. The reaction mixture was evaporated, and then partitioned
between saturated aqueous NaHCO3 and CHCl3. Silica gel
column chromatography (CHCl3/MeOH¼60:1) of the organic
layer gave 34 (178 mg, 84% from 30) as a foam. IR (neat)
To a suspension of methyltriphenylphosphonium bromide
(1.04 g, 2.91 mmol) in THF (30 mL) was added dropwise
BuLi (1.67 M in hexane, 1.57 mL, 2.62 mmol) at ꢂ78 ꢁC. The
resulting suspension was allowed to warm to 0 ꢁC and stirred
for 1 h. To this, a THF (4 mL) solution of 30 (154 mg,
0.29 mmol) was added at ꢂ78 ꢁC. The reaction mixture was
stirred at room temperature for 12 h, and then partitioned be-
tween saturated aqueous NH4Cl and Et2O. Silica gel column
chromatography (CHCl3/MeOH¼80:1) of the organic layer
gave 32 (146 mg, 96%) as a foam.
1H NMR (CDCl3) d 1.00 (9H, s, SiBu-tert), 2.68e2.73
(1H, m H-50), 3.50e3.54 (1H, m, CH2OH), 3.60e3.65
(1H, m, CH2OH), 3.82 (1H, d, J¼9.7 Hz, CH2OSi), 3.84 (1H,
d, J¼9.7 Hz, CH2OSi), 4.56 (1H, t, J¼4.6 Hz, OH), 5.01 (1H,
dd, J¼17.8 and 1.7 Hz, CH]CH2), 5.19 (1H, dd, J¼10.6 and
1.7 Hz, CH]CH2), 5.23 (1H, d, J¼8.0 Hz, H-10), 5.98 (1H,
dd, J¼17.8 and 10.6 Hz, CH]CH2), 6.02e6.04 (2H, m, H-20
and H-30), 7.24 (2H, br, NH2), 7.40e7.48 (6H, m, Ph), 7.61e
7.64 (4H, m, Ph), 7.97 (1H, s, H-8), 8.08 (1H, s, H-2); 13C
NMR (CDCl3) d 19.0, 26.6, 53.4, 58.8, 60.5, 61.7, 68.8,
115.9, 118.9, 127.9, 129.8, 129.9, 130.6, 132.9, 135.2, 138.4,
138.6, 138.8, 149.4, 152.3, 156.0; FABMS m/z 526 (MþþH).
Anal. Calcd for C30H35N5O2Si$1/10H2O: C, 68.31; H, 6.73;
N, 13.28. Found: C, 68.04; H, 6.72; N, 13.11.
1
2236 cmꢂ1 (C^N); H NMR (CDCl3) d 1.10 (9H, s, SiBu-
tert), 1.83 (3H, s, Ac), 2.94 (1H, dd, J¼14.3 and 7.4 Hz,
H-50), 3.93 (1H, d, J¼9.7 Hz, CH2OSi), 4.01 (1H, d, J¼9.7 Hz,
CH2OSi), 4.49e4.58 (2H, m, CH2OAc), 5.67e5.69 (1H, m,
H-10), 6.02 (2H, br, NH2), 6.10 (1H, dd, J¼5.7 and 1.7 Hz,
CH]CH), 6.14 (1H, dd, J¼5.7 and 2.3 Hz, CH]CH),
7.27e7.49 (6H, m, Ph), 7.65e7.70 (5H, m, Ph and H-8),
8.26 (1H, s, H-2); 13C NMR (CDCl3) d 19.3, 20.4, 26.7, 49.1,
53.3, 62.3, 63.4, 67.2, 117.8, 119.8, 127.9, 130.2, 132.0, 132.1,
133.2, 133.5, 135.5, 135.6, 138.4, 149.8, 153.1, 155.6, 170.2;
FABMS m/z 567 (MþþH). Anal. Calcd for C31H34N6O3Si$
3/10H2O: C, 65.08; H, 6.10; N, 14.69. Found: C, 64.86; H,
5.93; N, 14.54.
4.20. (ꢀ)-c-4-(Adenine-9-yl)-1-(tert-butyldiphenyl-
silyloxy)methyl-7-oxabicyclo-[3.3.0]oct-2-en-8-ylacetic
acid methyl ester (33)
4.22. (ꢀ)-9-[c-4-(tert-Butyldiphenylsilyloxy)methyl-t-4-
ethynyl-t-5-hydroxymethylcyclopent-2-en-r-1-yl]-9H-
adenine (35)
A mixture of 30 (38 mg, 0.07 mmol) and Ph3P]
CHCO2Me (60 mg, 0.18 mmol) in xylene (8 mL) was refluxed
for 24 h. The reaction mixture was partitioned between H2O
and CHCl3. Silica gel column chromatography (CHCl3/
MeOH¼50:1) of the organic layer gave 33 (30 mg, 72%, a sin-
gle isomer, stereochemistry not known) as a foam.
1H NMR (CDCl3) d 1.06 (9H, s, SiBu-tert), 2.45e2.47 (2H,
m, H-50 and CHCH2CO2Me), 2.68 (1H, dd, J¼15.2 and
4.0 Hz, CHCH2CO2Me), 3.71 (3H, s, OMe), 3.78e3.84 (3H,
m, CH2OSi and CH2Oe), 4.21 (1H, dd, J¼9.7 and 4.0 Hz,
CHCH2CO2Me), 4.29 (1H, d, J¼9.7 Hz, CH2Oe), 5.49e5.51
(1H, m, H-10), 5.76 (2H, br, NH2), 5.95 (1H, dd, J¼5.7 and
2.2 Hz, CH]CH), 6.03 (1H, dd, J¼5.7 and 2.2 Hz, CH]CH),
7.34e7.47 (6H, m, Ph), 7.59e7.63 (5H, m, Ph and H-8), 8.30
(1H, s, H-2); 13C NMR (CDCl3) d 19.2, 26.9, 37.1, 51.9, 55.6,
66.6, 67.1, 67.5, 72.8, 80.2, 120.0, 127.8, 130.0, 130.8, 132.6,
135.5, 135.6, 137.3, 138.1, 149.8, 153.0, 153.7, 155.3, 171.5;
FABMS m/z 584 (MþþH). Anal. Calcd for C32H37N5O4Si:
C, 65.84; H, 6.39; N, 12.00. Found: C, 65.85; H, 6.39; N,
12.12.
To a LDA solution in THF (30 mL), prepared from diiso-
propylamine (626 mL, 4.47 mmol) and BuLi (1.66 M in hex-
ane, 2.53 mL, 4.2 mmol) at 0 ꢁC, TMSCHN2 (0.6 M in
hexane, 7.45 mL, 4.47 mmol) was added at ꢂ78 ꢁC. The mix-
ture was stirred at ꢂ78 ꢁC for 0.5 h. Compound 30 (295 mg,
0.56 mmol) in THF (30 mL) was added to the mixture at
ꢂ78 ꢁC. The whole mixture was stirred for 0.5 h at ꢂ78 ꢁC
and then for 3 h at room temperature. The reaction was
quenched by adding saturated aqueous NH4Cl. Extraction
with CHCl3 followed by preparative TLC (CHCl3/MeOH¼
20:1) gave 35 (92 mg, 31%) as a foam. IR (neat) 2220 cmꢂ1
1
(C^C); H NMR (CDCl3) d 1.05 (9H, s, SiBu-tert), 2.38
(1H, s, C^CH), 2.57e2.62 (1H, m, H-50), 3.76 (1H, d,
J¼10.0 Hz, CH2OSi), 3.79 (1H, d, J¼10.0 Hz, CH2OSi),
3.80 (1H, br, OH), 3.97e4.07 (2H, m, CH2OH), 5.62e5.64
(1H, m, H-10), 5.68 (2H, br, NH2), 5.96 (1H, dd, J¼5.6 and
2.0 Hz, H-20), 6.04 (1H, dd, J¼5.6 and 2.0 Hz, H-30), 7.34e
7.45 (6H, m, Ph), 7.60e7.65 (4H, m, Ph), 7.75 (1H, s, H-8),
8.35 (1H, s, H-2); 13C NMR (CDCl3) d 19.3, 26.9, 52.6,

1504
H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
53.8, 62.6, 62.9, 68.9, 74.1, 81.8, 119.9, 127.8, 129.2, 129.9,
132.7, 135.5, 135.6, 138.3, 138.9, 149.7, 152.9, 155.6;
FABMS m/z 524 (MþþH). Anal. Calcd for C30H33N5O2Si:
C, 68.80; H, 6.35; N, 13.37. Found: C, 68.54; H, 6.40; N,
13.35.
H-30), 5.97 (1H, dd, J¼5.2 and 2.3 Hz, H-20 or H-30), 7.19
(2H, br, NH2), 8.05 (1H, s, H-8), 8.11 (1H, s, H-2); 13C
NMR (DMSO-d6) d 52.2, 52.4, 61.4, 62.3, 66.8, 75.7, 82.9,
118.8, 130.4, 137.3, 139.1, 149.2, 152.2, 155.9; FABMS m/z
286 (MþþH). Anal. Calcd for C14H15N5O2$3/4H2O: C, 56.11;
H, 5.58; N, 23.37. Found: C, 56.30; H, 5.35; N, 23.29.
4.23. (ꢀ)-9-[c-4,t-4,t-5-Tris(hydroxymethyl)-
cyclopent-2-en-r-1-yl]-9H-adenine (36)
4.26. (ꢀ)-c-4-(Adenine-9-yl)-1-hydroxymethyl-7-
oxabicyclo-[3.3.0]oct-2-en-8-ylideneamine (39)
To a THF (8 mL) solution of 31 (154 mg, 0.291 mmol) was
added Bu4NF (1 M solution in THF, 320 mL, 0.32 mmol). Af-
ter being stirred for 0.5 h, the reaction mixture containing the
free nucleoside was reacted with Ac2O (110 mL, 1.16 mmol)
in the presence of i-Pr2NEt (210 mL, 0.32 mmol) and DMAP
(143 mg, 1.16 mmol) for 1 h. The reaction mixture was parti-
tioned between saturated aqueous NaHCO3 and CHCl3. Silica
gel column chromatography (CH2Cl2/MeOH¼100:1) of the
organic layer gave the triacetate (99 mg). The triacetate was
treated with NH3/MeOH (5 mL) at 5 ꢁC for 24 h. After evap-
oration, the residue was purified by silica gel column chroma-
tography (CHCl3/MeOH¼40:1). This gave 36 (48 mg, 74%)
as a foam.
1H NMR (CD3OD) d 2.54e2.60 (1H, m, H-50), 3.61e3.96
(6H, m, CH2OH), 5.58e5.61 (1H, m H-10), 5.95 (1H, dd,
J¼5.6 and 1.7 Hz, H-20 or H-30), 6.00 (1H, dd, J¼5.6 and
2.1 Hz, H-20 or H-30), 8.17 and 8.18 (2H, each as s, H-8 and
H-2); 13C NMR (DMSO-d6) d 53.8, 57.9, 59.1, 61.9, 62.3,
65.3, 118.9, 130.2, 139.1, 139.2, 149.5, 152.2, 155.9; FABMS
m/z 292 (MþþH). Anal. Calcd for C13H17N5O3$1/5H2O: C,
52.95; H, 5.95; N, 23.75. Found: C, 53.18; H, 6.03; N, 23.51.
To a THF (8 mL) solution of 34 (135 mg, 0.238 mmol) was
added Bu4NF (1 M solution in THF, 262 mL, 0.262 mmol). Af-
ter being stirred for 1 h, the reaction mixture containing the
free nucleoside was reacted with Ac2O (34 mL, 0.36 mmol)
in the presence of i-Pr2NEt (104 mL, 0.59 mmol) and DMAP
(44 mg, 0.36 mmol) for 1 h. The reaction mixture was parti-
tioned between saturated aqueous NaHCO3 and CHCl3. Silica
gel column chromatography (CH2Cl2/MeOH¼40:1) of the or-
ganic layer gave the diacetate (87 mg). The acetate was treated
with NH3/MeOH (5 mL) at 5 ꢁC for 18 h. During evaporation
of the solvent, precipitation occurred. The precipitate was
washed with hot benzene (50 mL) to give an analytically
pure 39 (38 mg, 79%, solid, mixture of two isomers ca. 6:4).
Mp 237 ꢁC; 1H NMR (DMSO-d6) d 3.06e3.11 (1H, m,
H-50), 3.66e3.76 (2H, m, CH2OH), 4.24e4.29 (1H, m, CH2O),
4.41e4.47 (1H, m, CH2O), 5.01e5.02 (0.6H, m, OH),
5.14e5.16 (0.4H, m, OH), 5.49e5.51 (1H, m, H-10), 5.99e
6.02 (1.6H, m, CH]CH), 6.09e6.11 (0.4H, m, CH]CH),
7.25 (2H, br, NH2), 7.63 (0.6H, s, NH), 7.93 (0.4H, s, NH),
8.01 (0.4H, s, H-8), 8.03 (0.6H, s, H-8), 8.15 (1H, s, H-2);
13C NMR (DMSO-d6) d 50.6, 50.7, 63.9, 64.4, 64.5, 65.5,
66.1, 71.5, 72.1, 119.0, 119.1, 129.2, 129.4, 136.8, 137.9, 138.7,
138.8, 149.1, 152.4, 156.0, 169.9, 174.6; FABMS m/z 287
(MþþH). Anal. Calcd for C13H14N6O2$1/10H2O: C, 54.20;
H, 4.97; N, 29.17. Found: C, 54.13; H, 4.89; N, 29.11.
4.24. (ꢀ)-9-[c-4,t-5-Bis(hydroxymethyl)-t-4-
vinylcyclopent-2-en-r-1-yl]-9H-adenine (37)
Compound 37 (42 mg, 69%) was obtained as a foam from
32 (113 mg, 0.214 mmol) by the procedure described for the
1
preparation of 36. H NMR (CD3OD) d 2.65e2.70 (1H, m,
4.27. Anti-HIV-1 assay
H-50), 3.63e3.81 (4H, m, CH2OH), 5.12 (1H, dd, J¼17.6
and, 1.5 Hz, CH]CH2), 5.25 (1H, dd, J¼10.7 and 1.5 Hz,
CH]CH2), 5.39 (1H, d, J¼7.6 Hz, H-10), 5.96e6.03 (3H, m,
H-20, H-30 and CH]CH2), 8.18 (1H, s, H-8), 8.20 (1H, s, H-
2); 13C NMR (DMSO-d6) d 55.7, 60.5, 62.3, 64.1, 68.7, 117.0,
120.1, 131.3, 138.8, 140.7, 141.2, 150.6, 153.6, 157.3; FABMS
m/z 288 (MþþH). Anal. Calcd for C14H17N5O2$1/10H2O: C,
58.16; H, 6.00; N, 24.22. Found: C, 58.08; H, 5.94; N, 24.48.
MT-4 cells (1ꢄ105 cells/mL) were infected with HIV-1
(HTLV-IIIB strain) at a multiplicity of infection (MOI) of
0.02 and were cultured in the presence of various concentra-
tions of the test compounds. After a 4-day incubation at 37 ꢁC,
the number of viable cells was monitored by the 3-(4,5-di-
methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method.
The cytotoxicity of the compounds was evaluated in parallel
with their antiviral activity, based on the viability of mock-
infected cells.
4.25. (ꢀ)-9-[t-4-Ethynyl-c-4,t-5-bis(hydroxymethyl)-
cyclopent-2-en-r-1-yl]-9H-adenine (38)
4.28. Anti-HCV assay
Compound 38 (44 mg, 70%, solid) was obtained from 35
(116 mg, 0.22 mmol) by the procedure described for the prep-
aration of 36. Mp 113e115 ꢁC; IR (KBr) 2100 cmꢂ1 (C^C);
1H NMR (DMSO-d6) d 2.60 (1H, q, J¼7.5 Hz, H-50), 3.16
(1H, s, ethynyl), 3.56e3.59 (1H, m, CH2OH), 3.62e3.67
(2H, m, CH2OH), 3.82e3.87 (1H, m, CH2OH), 4.61e4.63
(1H, m, OH), 5.21e5.24 (1H, m, OH), 5.37 (1H, dt, J¼7.5
and 2.3 Hz, H-10), 5.88 (1H, dd, J¼5.2 and 2.3 Hz, H-20 or
OR6 cells, a cell line cloned from ORN/C-5B/KE cells22)
that supports genome-length HCV RNA (strain O of genotype
1b) encoding Renilla luciferase reporter gene, were cultured in
Dulbecco’s modified Eagle’s medium supplemented with 10%
fetal bovine serum in the presence of G418 (300 mg/mL:
Geneticin; Invitrogen, Carlsbad, CA). To monitor the anti-
HCV effects of the compounds, OR6 cells were plated onto

H. Kumamoto et al. / Tetrahedron 64 (2008) 1494e1505
1505
24-well plates in triplicate (1.5ꢄ104 cells per well) and cul-
tured for 24 h. Then, the cells were treated with the com-
pounds (10 mM each) for 72 h. After treatment, the cells
were harvested with Renilla luciferase lysis reagent (Promega,
Madison, WI) and subjected to the Renilla luciferase assay
according to the manufacturer’s protocol.
7. (a) Haraguchi, K.; Takeda, S.; Tanaka, H.; Nitanda, T.; Baba, M.;
Dutschman, G. E.; Cheng, Y.-C. Bioorg. Med. Chem. Lett. 2003, 13,
3775; (b) Dutschman, G. E.; Grill, S. P.; Gullen, E. A.; Haraguchi, K.;
Takeda, S.; Tanaka, H.; Baba, M.; Cheng, Y.-C. Antimicrob. Agents
Chemother. 2004, 48, 1640; (c) Nitanda, T.; Wang, X.; Kumamoto, H.;
Haraguchi, K.; Tanaka, H.; Cheng, Y.-C.; Baba, M. Antimicrob. Agents
Chemother. 2005, 49, 3355; (d) Tanaka, H.; Haraguchi, K.; Kumamoto,
H.; Baba, M.; Cheng, Y.-C. Antiviral Chem. Chemother. 2005, 16, 217.
8. Mansuri, M. M.; Hitchcock, M. J. M.; Broker, R. A.; Bregman, C. L.;
Ghazzouli, L.; Desiderio, J. V.; Starrett, J. E.; Sterzyski, R. Z.; Martin,
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Acknowledgements
9. For examples of radical-mediated 5-exo-trig cyclization of phenylseleno-
methyl esters: (a) Beckwith, A. L. J.; Pigou, P. E. J. Chem. Soc., Chem.
Commun. 1986, 85; (b) Singh, R.; Singh, G. C.; Ghosh, S. K. Tetrahedron
Lett. 2005, 46, 4719.
Financial support from the Japan Society for the Promotion
of Science (KAKENHI, Grant no. 18790090 to H.K.) is grate-
fully acknowledged. The authors are also grateful to Ms. K.
Shiobara and Ms. Y. Odanaka (Center for Instrumental Anal-
ysis, Showa University) for technical assistance with NMR,
MS, and elemental analysis. T.H. is a Research Resident of
the Japanese Foundation for AIDS Prevention.
10. Kumamoto, H.; Haraguchi, K.; Tanaka, H.; Nitanda, T.; Baba, M.;
Dutschman, G. E.; Cheng, Y.-C.; Kato, K. Nucleosides Nucleotides
Nucleic Acids 2005, 24, 73.
11. Beckwith, A. L. J.; Pigou, P. E. Aust. J. Chem. 1986, 39, 77.
12. A brief calculation was carried out in which A and B are model substrates.
Natural bond orbital (NBO) theory was used for analyzing the energy
level of molecular orbitals. Our calculations by B3LYP/6-31G* showed
that the p* of B (0.05644 eV) was located at an energy level slightly
lower than that of A (0.06188 eV). This result is suggestive of the lower
p* level of 15 compared with that of 14, and may also contribute for
a higher yield production of 16 from 14. (a) Giese, B. Angew. Chem.,
Int. Ed. Engl. 1983, 22, 753; (b) Fleming, I. Frontier Orbitals and Organic
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