Stereocontrolled synthesis of novel 6′(α)-hydroxy carbovir analogues

Article abstract of DOI:10.1016/S0040-4020(03)00986-4

This paper describes the racemic and stereoselective synthetic route for a novel 6′(α)-hydroxy-carbovir from a simple acyclic precursor, Solketal. The relative stereochemistry of the target nucleosides was successfully controlled by a sequential stereoselective glycolate Claisen rearrangement followed by a ring-closing metathesis (RCM). Adenine and cytosine were coupled using a Pd(0) catalyzed allylic alkylation strategy in a high regio- and stereoselective manner.

Full text of DOI:10.1016/S0040-4020(03)00986-4

Tetrahedron 59 (2003) 6103–6108
Stereocontrolled synthesis of novel 60(a)-hydroxy
carbovir analogues
b
b
Joon Hee Hong,a Chang-Hyun Oh and Jung-Hyuck Cho
,
*
aCollege of Pharmacy, Chosun University, Kwangju 501-759, South Korea
bMedicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, South Korea
Received 16 May 2003; accepted 16 June 2003
Abstract—This paper describes the racemic and stereoselective synthetic route for a novel 60(a)-hydroxy-carbovir from a simple acyclic
precursor, Solketal. The relative stereochemistry of the target nucleosides was successfully controlled by a sequential stereoselective
glycolate Claisen rearrangement followed by a ring-closing metathesis (RCM). Adenine and cytosine were coupled using a Pd(0) catalyzed
allylic alkylation strategy in a high regio- and stereoselective manner.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Claisen rearrangement and a ring-closing metathesis (RCM)
as the key reactions.
Many natural and synthetic carbocyclic nucleosides have
been reported. Carbocyclic nucleosides possess greater
metabolic stability against nucleoside phosphorylas,1 and
show interesting antiviral activity against the herpes virus,2
the human cytomegalovirus,3 the hepatitis B virus,4 and the
human immunodeficiency virus owing to their structural
characteristics.5 Another interesting feature of carbocyclic
nucleosides is that a number of carbocyclic adenosine
analogues appear to exert their antiviral action by inhibiting
S-adenosylhomocysteine hydrolase.6 Therefore, this mech-
anism might be exploited in a combination therapy with a
nucleoside acting by a different mechanism.7
2. Results and discussion
It was envisaged that cyclopentenol 11(b) might be
constructed using a RCM of 10. In addition, it was
suggested that an acyclic precursor 10 might be prepared
from a simple Solketal using a stereoselective a-chelation
controlled Claisen rearrangement of compound 7 and an a-
chelation controlled nucleophilic addition on carbonyl 9
(Scheme 1).
Cheap and commercially available Solketal was oxidized
and converted to the a,b-unsaturated methyl ester 2 using a
well-known procedure in a 53% two step yield.11 The a,b-
unsaturated methyl ester 2 was reduced by DIBALH at
2788C in CH2Cl2 to give the allylic alcohol 3 in a 92%
yield. This was protected by benzyl bromide (BnBr) to give
compound 4 (90%). The isopropylidene protecting group of
compound 4 was removed by acid hydrolysis to give the diol
5 (95%). The selective mono-silylation of the diol 5 with t-
butyldimethylsilyl chloride (TBDMSCl) (1.1 equiv.) and
imidazole in CH2Cl2 at 08C for 5 h furnished compound 6,
which was then converted to the benzyloxymethyl-protected
allylic glycolate ester 7 under DCC and DMAP conditions
in a 76% two-step yield.12
Since the 60-hydroxymethyl substituted carbovir8 was
reported to exhibit good biological activity as a potent
anti-HIV agent, many medicinal chemists have begun to
examine the 60-modified carbocyclic nucleosides including
the 60(b)-hydroxy carbovir analogue, which was reported by
Katagirietal.9 Moreover, the recentFDA approvalofabacavir
asananti-HIVagent has promptedfurther studies onthe use of
carbocyclic nucleosides as chemotherapeutic agents.10
In this study novel 60(a)-hydroxy carbovir analogues were
synthesized based on the interesting findings from the 60-
modified carbovir analogues as part of our ongoing drug
discovery program. This paper reports their synthetic
procedures with use of a chelation controlled glycolate
A sigmatropic rearrangement process was used to convert
the allylic glycolate 7 to a g,d-unsaturated methyl ester 8
with the correct stereochemistry at C-2 and C-3. The
concept of an acyclic steroeselection has attracted sub-
stantial interest with impressive results.13 Therefore, a
Keywords: carbocyclic nucleosides; glycolate Claisen rearrangement;
RCM.
*
Corresponding author: Tel.: þ82-62-230-6378; fax: þ82-62-222-5414;
e-mail: hongjh@mail.chosun.ac.kr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00986-4

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J. H. Hong et al. / Tetrahedron 59 (2003) 6103–6108
Scheme 1. Reagents: (i) PCC, CH2Cl2, 4 MS, rt, 5 h, 80%; (ii) (MeO)2POCH2CO2Me, NaH, DME, rt, 2 h, 79%; (iii) DIBALH, CH2Cl2, 2788C, 2 h, 92%; (iv)
BnBr, NaH, THF, overnight, rt, 90%; (v) 2N HCl, rt, 2 h, 95%; (vi) TBDMSCl, imidazole, CH2Cl2, 08C, 5 h, 92%; (vii) BnOCH2CO2H, DCC, DMAP, CH2Cl2,
rt, 4 h, 83%; (viii) (a) LHMDS, TMSCl/TEA, THF, 2788C, 1 h, then rt, 3 h, (b) CH3I, Triton-B, MeOH, overnight, rt, 82% in two steps; (ix) DIBALH, CH2Cl2,
2788C, 2 h, 96%; (x) vinylMgBr, THF, 2788C, 1 h, 63%; (xi) Cl2(Cy3P)2RuCHC6H5, benzene, reflux, 1 h, 82%; (xii) ClCO2Et, pyridine, DMAP, rt,
overnight, 86%.
chelation-controlled modification of Ireland’s ester enolate
Claisen rearrangement (LHMDS, TMSCl/TEA) was used to
convert the allylic glycolate ester 7 to a g,d-unsaturated
glycolate,14 possibly via a chelation-controlled chair-like
transition state, to give the crude acid (Fig. 1). The crude
acid, which was not purified because of its high polarity,
was treated directly with CH3I, in the presence of Triton-B,
which produced the desired product 8 in a highly
stereoselective fashion in an 82% two step yield. With the
enolate geometry fixed, the selective entry into either of the
diastereomeric series would depend only on the geometry of
the olefinic linkage. As a result, a notable increase in the
diastereoselectivity resulted from the introduction of an a-
substituent in the allylic system. A single diastereomer
could be obtained in a majority of a-benzyloxy substrates.
vinyl magnesium bromide to provide a 2.1:1 mixture of
divinyl 10, as determined by 1H NMR. The exact
stereochemical assignment was performed in the subsequent
reaction, because the mixture was difficult to separate at this
stage.
The diastereomeric mixture 10 was subjected to the standard
RCM15 conditions using [benzylidene-bis(tricyclohexyl-
phosphine)-dichlororuthenium] to afford the separable
cyclopentenols 11(b) and 11(a) in a 56 and 26% yield,
respectively. A thorough NOE study on the cyclized
product, together with the mechanistic rationale for the
[3,3]-sigmatropic rearrangement, strongly suggested that
the stereochemical assignment of the cyclopentenol 11(b)
1
and 11(a) was correct. Indeed, according to the H NMR
data, the integral ratio of the crude reaction mixture of
compound 10 was almost identical to the ratio of the
separated 11(b) and the more polar 11(a) isomers (2.1/1).
The slow addition of DIBALH to a solution of ester 8 in
CH2Cl2 at 2788C furnished the desired aldehyde 9 in a 96%
yield. The aldehyde 9 underwent a carbonyl addition by
The stereochemical outcomes could be readily explained in
terms of an a-chelation controlled carbonyl addition
model.16 The facile conversion of the hydroxyl group of
compound 11(b) to the palladium substrate 12 was
accomplished using ethyl chloroformate in pyridine in an
86% yield.
Palladium catalyzed allylic alkylations17 are the corner
stone in synthetic organic chemistry owing to their highly
reliable regio- and stereoselectivity. This methodology was
successfully adopted for synthesizing the desired nucleo-
sides (Scheme 2). The adenine and cytosine anion, which
was generated by NaH/DMSO in THF/DMSO at 608C, was
successfully condensed with compound 12 using a tris(di-
benzylideneacetone)-dipalladium(0)-chloroform adduct as
the coupling catalyst to give compounds 13 and 14 in a 46
Figure 1. a-chelation controlled transition state.

J. H. Hong et al. / Tetrahedron 59 (2003) 6103–6108
6105
HV-3). The NMR spectra were obtained on a bruker 300
Fourier transform spectrometer.
3.1.1. (6)-2,3-(O-Isopropylidene)-glyceraldehyde (1). To
a cooled (08C) solution of Solketal 1 (2 g, 15.1 mmol) in dry
˚
methylene chloride (50 mL), a 4 A molecular sieve (7.5 g)
and pyridinium chlorochromate (6.5 g, 30.3 mmol) was
added with constant stirring. The reaction mixture was
stirred for 5 h at room temperature and diluted with diethyl
ether. The resulting suspension was filtered through a
Florisil pad and washed repeatedly with diethyl ether. The
combined extracts were concentrated in vacuo to give
compound 1 (1.6 g, 80%) as a liquid, which was used for the
subsequent reaction without further purification.
Scheme 2. Reagents: (i) adenine and cytosine Pd2(dba)3·CHCl3, P(O-i-Pr)3,
NaH, THF/DMSO, reflux, overnight; (ii) Na, NH3/THF, 2788C, 10 min.
3.1.2. (6)-(40E)-Methyl 3-(2,2-dimethyl-1,3-dioxolan-4-
yl) acrylate (2). To a suspension of sodium hydride (60% in
mineral oil, 307 mg, 7.68 mmol) in distilled DME at 08C,
trimethyl phosphonoacetate (1.24 mL, 7.68 mmol) was
added drop wise and with constant stirring for 30 min.
The aldehyde 1 (1.0 g, 7.68 mmol) was added to this
mixture and stirred for 2 h at room temperature. The
solution was neutralized with a saturated ammonium
chloride solution, and extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous MgSO4,
filtered and finally evaporated. The residue was chromato-
graphed on a silica gel column (EtOAc/hexane, 1:10) to give
and 42% yield, respectively. Although a small amount of the
N7-isomer18 (6%) of the adenine base was present, it could
be readily differentiated [UV(MeOH) lmax 279 nm].
BCl3 or BBr3 were used in various reaction conditions to
obtain the deprotected 20,30-olefinic nucleosides. However,
none of the desired products could be obtained under these
conditions. Therfore, the Birch-type reaction was used to
overcome these problems. Treating compounds 13 and 14
with sodium metal in liquid ammonia at 2788C gave the
targeted adenine and cytosine nucleosides 15 and 16 in a 57
and 49% yield, respectively.
1
2 (1.13 g, 79%) as a colorless syrup: H NMR (CDCl3,
300 MHz) d 6.92 (dd, J¼15.0, 6.0 Hz, 1H), 6.04 (dd,
J¼15.0, 1.5 Hz, 1H), 4.68 (m, 1H), 4.18 (m, 1H), 3.75 (s,
3H), 3.63 (m, 1H), 1.48 (s, 3H), 1.45 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 166.42, 144.98, 121.89, 110.18, 74.86,
68.74, 51.68, 26.39, 25.68.
The stereochemistry of compound 15 was unambiguously
assigned based on the NOE correlations between the proximal
hydrogens (H-50, H-60vs. H-8) and (H-50 vs. H-60), and the
structure of compound 16 was also similarly determined.
3.1.3. (E)-4,5-(O-Isopropylidene)-pent-2-en-1-ol (3). To a
cooled solution (2788C) of compound
2 (10.0 g,
It should be noted that based on an extensive literature
search, the final nucleosides, 15 and 16, are novel
compounds. The antiviral activities of the synthesized
compounds were evaluated against the HIV-1, HSV-1,
HSV-2, and HCMV, respectively. However, none exhibited
any significant antiviral activity up to 100 mM without
showing any cytotoxicity.
53.7 mmol) in dry CH2Cl2 (150 mL), DIBALH
(112.7 mL, 1 M solution in hexane) was added slowly.
The mixture was stirred for 2 h at the same temperature, and
quenched by the slow addition of methanol (112 mL). The
solution was stirred for 2 h at rt, and the resulting white solid
was filtered through a Celite pad. The filtrate was
concentrated under reduced pressure and the residue was
purified by silica gel column chromatography (EtOAc/
hexane, 1:2) to give the allylic alcohol 3 (7.8 g, 92%) as a
colorless oil: 1H NMR (CDCl3, 300 MHz) d 6.22–5.81 (m,
1H), 5.62 (dd, J¼15.2, 6.0 Hz, 1H), 4.51 (ddd, J¼8, 8, 6 Hz,
1H), 4.24 (m, 2H), 3.52 (t, J¼8.0 Hz, 2H), 1.41 (s, 6H); 13C
NMR (CDCl3, 75 MHz) d 133.7, 129.3, s109.7, 72.2, 69.7,
58.4, 27.0, 26.2; Anal. Calcd for C8H14O3: C, 60.74; H,
8.92. Found: C, 60.58; H, 9.21.
In summary, a de novo synthetic method for novel 60(a)-
hydroxyl-carbocyclic nucleosides from Solketal was devel-
oped. The required relative stereochemistry was success-
fully elaborated using an a-chelation-controlled [3,3]
rearrangement, an a-chelation controlled carbonyl addition
and a RCM. Based on this strategy, the optically active
syntheses of other 60-modified carbocyclic nucleosides
using different bases are currently underway.
3.1.4. (E)-1-Benzyloxy-4,5-(O-isopropylidene)-pent-2-
ene (4). To
a stirred suspension of NaH (2.5 g,
63.5 mmol, 60% oil suspension) in THF (150 mL), a
solution of 3 (6.7 g, 42.3 mmol) in dry THF (50 mL) was
added slowly, and stirred for 1 h at rt. To this mixture,
benzyl bromide (8.68 g, 50.7 mmol) was added, and stirred
overnight at rt. The mixture was quenched using a saturated
ammonium chloride solution (10 mL), and extracted with
EtOAc (200 mL) and water (200 mL). The organic layer
was washed with brine, dried over anhydrous MgSO4, and
filtered. The filtrate was concentrated under reduced
3. Experimental
3.1. General
All chemicals used in this study were of reagent grade and
were used as purchased. All moisture-sensitive reactions
were performed in an inert atmosphere of either N2 or Ar
using distilled dry solvents. The elemental analyses were
performed using an Elemental Analyzer System (Profile

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J. H. Hong et al. / Tetrahedron 59 (2003) 6103–6108
pressure, and the residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:10) to give compound 4
(9.45 g, 90%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) d 7.37 (m, 5H), 5.83 (quintet, J¼5.5 Hz, 1H),
5.64 (t, J¼8.3 Hz, 1H), 4.82 (q, J¼10.0 Hz, 1H), 4.57 (dd,
J¼15.6, 11.8 Hz, 2H), 4.13 (dd, J¼6.3, 1.2 Hz, 2H), 4.07
(dd, J¼8.0, 6.2 Hz, 1H), 3.57 (t, J¼7.9 Hz, 1H), 1.44 (s,
3H), 1.40 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 138.5,
131.3, 130.8, 128.8, 128.2, 128.1, 109.7, 72.6, 72.5, 69.8,
66.0, 27.2, 26.3; Anal. Calcd for C15H20O3: C, 72.55; H,
8.12. Found: C, 72.61; H, 8.19.
chromatography (EtOAc/hexane, 1:10) to give compound 7
(12.8 g, 83%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) d 7.43–7.30 (m, 10H), 5.97 (dt, J¼15.6,
5.2 Hz, 1H), 5.8 (dd, J¼15.6, 6.4 Hz, 1H), 5.55 (dd,
J¼11.5, 5.7 Hz, 1H), 4.68 (s, 2H), 4.55 (s, 2H), 4.16 (s,
2H), 4.07 (d, J¼5.1 Hz, 2H), 3.75 (d, J¼5.6 Hz, 2H), 0.92
(s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 170.0,
138.6, 137.6, 132.7, 128.9, 128.5, 128.4, 128.3, 128.1,
127.5, 73.7, 73.0, 72.0, 67.6, 66.7, 65.0, 26.3, 18.7, 24.9;
Anal. Calcd for C27H38O5Si: C, 68.90; H, 8.14. Found: C,
68.79; H, 8.26.
3.1.5. (6)-1-Benzyloxy-4,5-dihydroxy-pent-2-ene (5). A
solution of compound 4 (10 g, 40.27 mmol) in a 2N aqueous
HCl solution (150 mL) was stirred for 2 h at rt. The mixture
was neutralized by the slow addition of a saturated NaHCO3
solution and diluted with brine (100 mL). The mixture was
extracted with EtOAc (150 mL£3), and the combined
organic layer was dried over anhydrous MgSO4, and
filtered. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (EtOAc/hexane, 3:1) to give the diol 5
(7.96 g, 95%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) d 7.33 (m, 5H), 5.93–5.86 (dt, J¼15.6, 5.5 Hz,
1H), 5.72 (dd, J¼15.6, 5.6 Hz, 1H), 4.52 (s, 1H), 4.23 (t,
J¼7.4 Hz, 2H), 4.04 (d, J¼5.5 Hz, 2H), 3.64 (dd, J¼11.3,
3.4 Hz, 1H), 3.49 (dd, J¼11.3, 7.3 Hz, 1H), 3.10 (br s, 2H);
13C NMR (CDCl3, 75 MHz) d 138.3, 132.5, 129.6, 128.9,
128.3, 128.3, 72.8, 69.2, 66.4, 66.3; Anal. Calcd for
C12H16O3: C, 69.21; H, 7.74. Found: C, 69.41; H, 7.68.
3.1.8. (6)-(2S,3S)-2-Benzyloxy-3-benzyloxymethyl-6-(t-
butyldimethylsilyloxy)-hex-4-enoic acid methyl ester
(8). To a cooled (2788C) solution of 1 M lithium
bis(trimethylaily) amide in THF (46.4 mL, 46.4 mmol), a
solution of compound 7 (5.5 g, 11.68 mmol) and trimethyl-
silyl chloride/triethylamine (1/1 v/v, 30.4 mL) in dry THF
(200 mL) was slowly added. After stirring for 30 min at the
same temperature, the reaction mixture was warmed to rt
and stirred for 2 h, and then quenched with a 1N NaOH
solution (200 mL) in an ice bath. The resulting mixture was
then stirred for 10 min at room temperature, and acidified to
pH 4–5 using a 2N HCl solution. The mixture was extracted
with EtOAc (300 mL) and water (300 mL). The aqueous
layer was extracted twice with EtOAc (200 mL), and the
combined organic layer was dried over anhydrous MgSO4,
filtered, concentrated under vacuum to give a crude acid.
Without further purification, the crude acid was dissolved in
THF (150 mL) and titrated with Triton-B (40% in methanol)
using phenolphthalein as an indicator. After the solution
turned violet, it was stirred at rt for 1 h, and CH3I (2.88 mL,
46.4 mmol) was slowly added. The resulting mixture was
stirred overnight at rt. It was then diluted with hexane
(150 mL), and filtered through a Celite pad. The filtrate was
concentrated under reduced pressure, and purified by silica
gel column chromatography (EtOAc/hexane, 1:15) to give
the methyl ester 8 (4.6 g, 82%) as a colorless oil: 1H NMR
(CDCl3, 300 MHz) d 7.37–7.28 (m, 10H), 5.70 (m, 2H),
4.84 (d, J¼11.5 Hz, 1H), 4.53 (d, J¼11.9 Hz, 1H), 4.47 (d,
J¼11.9 Hz, 1H), 4.39 (m, 2H), 4.16 (s, 2H), 3.74 (s, 3H),
3.65 (t, J¼9.3 Hz, 1H), 3.50 (dd, J¼9.0, 5.1 Hz, 1H), 2.98
(m, 1H), 0.94 (s, 9H), 0.10 (s, 6H); 13C NMR (CDCl3,
75 MHz) d 173.0, 138.7, 138.3, 134.0, 128.7, 128.4, 128.1,
128.0, 125.9, 73.4, 73.3, 70.3, 64.2, 52.1, 46.4, 26.4, 18.8,
24.7; Anal. Calcd for C28H40O5Si: C, 69.38; H, 8.32.
Found: C, 69.01; H, 8.44.
3.1.6. (6)-(E)-1-Benzyloxy-4-hydroxy-5-(t-butyldi-
methylsilyloxy)-pent-2-ene (6). To a solution of the diol
5 (20.0 g, 96.03 mmol) and imidazole (9.8 g, 0.144 mol) in
dry CH2Cl2 (300 mL), TBDMSCl (14.47 g, 105.6 mmol)
dissolved in anhydrous CH2Cl2 (150 mL) was slowly added
at 2108C over 30 min. After 30 min at the same
temperature, the reaction mixture was quenched using a
saturated aqueous NaHCO3 solution (100 mL). The solvent
was extracted with CH2Cl2 (300 mL) and water (200 mL),
and the organic layer was washed with brine, dried over
anhydrous MgSO4, filtered. The filtrate was concentrated
under reduced pressure, and the residue was purified by
silica gel column chromatography (EtOAc/hexane, 1:5) to
1
give compound (28.5 g, 92%) as a colorless oil: H NMR
(CDCl3, 300 MHz) d 7.38–7.31 (m, 5H), 5.81 (dt, J¼6.0,
5.3 Hz 1H), 5.63 (dd, J¼9.6, 8.0 Hz, 1H), 4.54 (s, 2H), 4.22
(m, 1H), 4.07 (d, J¼5.0 Hz, 2H), 3.70 (dd, J¼10.0, 3.6 Hz,
1H), 3.50 (dd, J¼9.5, 8.0 Hz, 1H), 2.6 (br s, 1H), 0.93 (s,
9H), 0.10 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 138.6,
131.5, 129.3, 128.7, 128.1, 128.0, 72.6, 70.5, 67.4, 26.2,
18.7, 24.9; Anal. Calcd for C18H30O3Si: C, 67.03; H, 9.38.
Found: C, 66.89; H, 9.33.
3.1.9. (6)-(2S,3S)-2-Benzyloxy-3-benzyloxymethyl-6-(t-
butyldimethylsilyloxy)-hex-4-enal (9). To a solution of
compound 8 (15.2 g, 31.3 mmol) in anhydrous CH2Cl2
(62 mL), a DIBALH solution (34.5 mL, 1 M solution in
CH2Cl2) was slowly added at 2788C. The reaction mixture
was stirred for 2 h at the same temperature, quenched by the
addition of methanol (34.5 mL), and stirred at rt for 2 h. The
resulting solid was filtered through a Celite pad. The filtrate
was concentrated under vacuum, and the residue was
purified by silica gel column chromatography (EtOAc/
hexane, 1:10) to give the aldehyde 9 (13.6 g, 96%) as a
3.1.7. (6)-(E)-1-Benzyloxy-4-O-(benzyl-glycoloyloxy)-5-
(t-butyldimethylsilyloxy)-pent-2-ene (7). To a solution of
compound 6 (10.6 g, 32.86 mmol) and benzyloxyacetic acid
(6.0 g, 36.1 mmol) in dry CH2Cl2 (200 mL) DCC (6.78 g,
37.7 mmol) and DMAP (401 mg, 3.28 mmol) was added at
08C. The reaction mixture was stirred for 4 h at room
temperature, and the resulting solid was filtered through a
Celite pad. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column
1
colorless oil: H NMR (CDCl3, 300 MHz) d 9.73 (s, 1H),
7.38–7.31 (m, 10H), 5.71 (m, 2H), 4.77 (d, J¼11.7 Hz, 1H),
4.56–4.47 (m, 3H), 4.15–4.10 (m, 3H), 3.62–3.52 (m, 2H),
2.97 (m, 1H), 0.93 (s, 9H), 0.08 (s, 6H); 13C NMR (CDCl3,

J. H. Hong et al. / Tetrahedron 59 (2003) 6103–6108
6107
75 MHz) d 204.21, 138.47, 138.01, 134.21, 128.83, 128.80,
128.34, 128.09, 125.18, 83.57, 73.53, 73.45, 69.93, 63.88,
45.30, 26.36, 18.80, 24.73; Anal. Calcd for C27H38O4Si: C,
71.32; H, 8.42. Found: C, 70.97; H, 8.27.
saturated NaHCO3 solution. The solvent was concentrated
under vacuum, and the residue was extracted with EtOAc
(10 mL) and water (100 mL). The organic layer was washed
with brine, dried over MgSO4, and then filtered. The filtrate
was concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography (EtOAc/
hexane, 1:8) to give the cyclopentene 12 (2.7 g, 86%) as a
colorless oil: 1H NMR (CDCl3, 300 MHz) d 7.31–7.23 (m,
10H), 6.26 (dd, J¼6.0, 2.7 Hz, 1H), 5.92 (dd, J¼6.3, 1.8 Hz,
1H), 4.47 (dd, J¼5.4, 2.4 Hz, 1H), 4.66 (dd, J¼15.0,
12.3 Hz, 2H), 4.48 (s, 2H), 4.16–4.08 (m, 3H), 3.87 (dd,
J¼8.7, 6.0 Hz, 1H), 3.52 (t, J¼8.7 Hz, 1H), 3.02 (m, 1H),
1.25 (t, J¼6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d
154.76, 140.15, 138.37, 138.15, 128.19, 128.15, 127.62,
127.50, 127.41, 127.36, 127.32, 78.19, 77.79, 73.17, 72.64,
71.48, 63.75, 46.65, 14.13; Anal. Calcd for C23H26O5: C,
72.23; H, 6.85. Found: C, 72.14; H, 6.77.
3.1.10. (6)-(3S,4S,5S)-3-Hydroxy-4-benzyloxy-5-benzyl-
oxymethyl-8-(t-butyldimethylsilyloxy)-1,6-octadiene and
(6)-(3R,4S,5S)-3-hydroxy-4-benzyloxy-5-benzyloxy-
methyl-8-(t-butyldimethylsilyloxy)-1,6-octadiene (10).
To a solution of compound 9 (5.4 g, 11.87 mmol) in
anhydrous THF vinyl magnesium bromide (14.2 mL, 1 M
solution in THF) was slowly added at 2788C and stirred for
1 h. The mixture was quenched with a saturated ammonium
chloride solution (10 mL), and elevated to room tempera-
ture. The mixture was extracted with EtOAc (200 mL) and
water (200 mL), washed with brine, dried over anhydrous
MgSO4, and then filtered. The filtrate was concentrated
under reduced pressure, and the residue was purified by
silica gel column chromatography (EtOAc/hexane, 1:7) to
give a diastereomeric mixture of compound 10 (3.6 g, 63%)
as a colorless oil: 1H NMR (CDCl3, 300 MHz) d 7.38–7.31
(m, 10H), 6.02–5.74 (m, 3H), 5.34–5.21 (m, 2H), 4.68–
4.17 (m, 6H), 3.72–3.47 (m, 3H), 2.97–2.85 (m, 1H), 0.93
(s, 9H), 0.09 (s, 6H); Anal. Calcd for C29H42O4Si: C, 72.15;
H, 8.77. Found: C, 72.47; H, 8.60.
3.1.13. (6)-(10S,40S,60S)-9-[4-Benzyloxymethyl-6-benzy-
loxy-cyclopent-2-en-1-yl] adenine (13). To a stirred pure
NaH (17.8 mg, 0.74 mmol) solution in anhydrous DMSO,
adenine (100 mg, 0.74 mmol) was added. The reaction
mixture was stirred for 45 min at 45–558C to prepare the
sodium salt of adenine, and was then cooled to room
temperature. Simultaneously, P(O-i-Pr)3 (0.053 mL,
0.12 mmol) was added to a solution of Pd2(dba)3.CHCl3
(2.53 mg, 1.37 mmol) in anhydrous THF (2.0 mL), which
was stirred for 45 min. To the adenine solution in DMSO, a
catalyst solution of THF and 12 (183.5 mg, 0.48 mmol)
dissolved in anhydrous THF (2 mL) was sequentially added.
The reaction mixture was gently refluxed overnight and
quenched with water (1.5 mL). The reaction solvent was
removed under vacuum. The residue was purified by silica
gel column chromatography (MeOH/CH2Cl2, 1:10) to give
compound 13 (94.3 mg, 46%) as a white solid. mp 186–
1898C; UV (MeOH) lmax 261 nm: 1H NMR (CDCl3,
300 MHz) d 8.36 (s, 1H), 8.00 (s, 1H), 7.34–7.21 (m,
10H), 6.45 (s, 1H), 6.14 (dd, J¼5.4, 2.7 Hz, 1H), 5.79 (d,
J¼7.2 Hz, 1H), 5.50 (s, 1H), 4.66 (dd, J¼15.6, 12.0 Hz,
2H), 4.57 (dd, J¼6.3, 2.4 Hz, 1H), 4.17 (d, J¼11.7 Hz, 1H),
4.09 (d, J¼11.4 Hz, 1H), 3.46 (t, J¼9.0 Hz, 1H), 3.22
(t. J¼7.2 Hz, 1H), 2.96 (q, J¼6.9 Hz, 1H), 2.83 (br s, 4H);
13C NMR (CDCl3, 75 MHz) d 155.40, 152.87, 150.18,
141.21, 138.28, 137.66, 136.98, 133.34, 128.58, 128.50,
128.22, 127.76, 127.67, 127.53, 127.42, 81.196, 73.43,
72.321, 65.82, 57.55, 45.98; Anal. calcd for C25H25N5O2:
C, 70.24; H, 5.89; N, 16.38. Found: C, 70.44; H, 5.79; N,
16.51.
3.1.11. (6)-(1S,4S,6S)-4-Benzyloxymethyl-6-benzyloxy-
cyclopent-2-en-1-ol (11(b)); and (6)-(1R,4S,6S)-4-ben-
zyloxymethyl-6-benzyloxy-cyclopent-2-en-1-ol (11(a).
To a solution of Grubbs catalyst (733 mg, 0.89 mmol) in
anhydrous benzene (5 mL), the starting material 10 (4.3 g,
8.9 mmol) in anhydrous benzene (5 mL) was slowly added.
The mixture was refluxed for 1 h, and cooled to room
temperature. The solvent was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:10) to give the cyclo-
pentenol 11(b) (1.55 g, 56%) and the more polar 11(a)
1
(718 mg, 26%) as colorless oils: 11(b): H NMR (CDCl3,
300 MHz) d 7.38–7.23 (m, 10H), 6.03 (d, J¼6.0 Hz, 1H),
5.83 (dd, J¼6.3, 3.0 Hz, 1H), 4.83 (d, J¼11.7 Hz, 1H), 4.55
(d, J¼11.7 Hz, 1H), 4.52 (s, 2H), 4.46–4.40 (m, 1H), 4.01
(dd, J¼7.5, 2.1 Hz, 1H), 3.66 (dd, J¼9.3, 3.0 Hz, 1H), 3.59
(s, 1H), 3.56 (s, 1H), 3.44 (dd, J¼9.3, 3.3 Hz, 1H); 13C
NMR (CDCl3) d 138.39, 137.30, 133.72, 133.30, 128.21,
128.13, 127.62, 127.52, 127.33, 77.83, 73.24, 71.56, 71.27,
66.27, 46.39; Anal. Calcd for C20H22O3: C, 77.39; H, 7.14.
Found: C, 77.58; H, 7.31. 11(a): 1H NMR (CDCl3,
300 MHz) d 7.33–7.25 (m, 10H), 5.98 (dd, J¼6.0, 4.5 Hz,
1H), 5.80 (m, 1H), 4.85 (br s, 1H), 4.68 (s, 2H), 4.60 (s,
2H), 4.01 (dd, J¼6.9, 4.8 Hz, 1H), 3.75 (dd, J¼14.4, 5.1 Hz,
1H), 3.48 (dd, J¼9.0, 7.5 Hz, 1H), 3.18 (m, 1H), 1.8 (br
s, 1H); 13C NMR (CDCl3, 75 MHz) d 138.46, 138.38,
134.73, 132.70, 128.37, 128.29, 127.59, 127.55, 127.45,
87.82, 81.05, 73.25, 72.41, 70.00, 46.66; Anal. Calcd
for C20H22O3: C, 77.39; H, 7.14. Found: C, 77.59; H,
7.22.
3.1.14. (6)-(10S,40S,60S)-1-[4-Benzyloxymethyl-6-benzy-
loxy-cyclopent-2-en-1-yl] cytosine (14). The cytosine
derivative 14 was synthesized using the same procedure
described for synthesizing compound 13; yield 42%; mp
1
182–1858C; UV (MeOH) lmax 272 nm: H NMR (CDCl3,
300 MHz) d 7.34–7.24 (m, 11H), 7.07 (br s, 2H), 6.46 (d,
J¼6.8 Hz, 1H), 5.98 (m, 1H), 5.73 (d, J¼8.1 Hz 1H), 5.59
(d, J¼7.5 Hz, 1H), 4.67 (d, J¼12.0 Hz, 1H), 4.59 (d,
J¼12.0 Hz, 1H), 4.45 (d, J¼3.9 Hz, 1H), 4.32 (s, 2H),
3.42–3.25 (m, 4H), 2.78 (m, 1H); 13C NMR (CDCl3,
75 MHz) d 166.1, 156.6, 143.7, 139.6, 139.2, 137.5, 134.8,
129.1, 129.0, 128.3, 128.2, 128.1, 128.0, 93.8, 81.7, 73.3,
71.9, 66.2, 59.6, 45.3; Anal. calcd for C24H25N3O3: C,
71.44; H, 6.25; N, 10.41. Found: C, 71.69; H, 6.33; N, 10.51.
3.1.12. (6)-(1S,4S,6S)-1-Ethoxycarbonyloxy-4-benzylox-
ymethyl-6-benzyloxy-cyclopent-2-ene (12). To a solution
of compound 11(b) (2.6 g, 8.37 mmol) and DMAP
(101 mg, 0.83 mmol) in anhydrous pyridine (10 mL), ethyl
chloroformate (1.36 g, 12.5 mmol) was slowly added. The
mixture was stirred overnight at rt, and quenched with a

6108
J. H. Hong et al. / Tetrahedron 59 (2003) 6103–6108
3.1.15. (6)-(10S,40S,60S)-9-[4-Hydroxymethyl-6-hydroxy-
cyclopent-2-en-1-yl] adenine (15). To a solution of
compound 13 (80 mg, 0.187 mmol) in anhydrous THF
(1 mL) at 2788C, anhydrous ammonia gas was bubbled
until the total volume of the solution reached 4 mL. To this
mixture, a small portion of Na metal was added until a blue
color persisted for 5 min. The mixture was quenched using a
few drops of methanol and then warmed to room
temperature. The residue was dissolved in 3 mL of methanol
and neutralized with AcOH. The mixture was concentrated
under vacuum, and the residue was purified by silica gel
column chromatography (MeOH/CH2Cl2, 1:6) to give
compound 15 (26 mg, 57%) as a white solid: mp 189–
1908C; UV (H2O) lmax 260 nm: 1H NMR (DMSO-d6,
300 MHz) d 8.09 (s, 1H), 7.97 (s, 1H), 7.30 (br s, 1H), 6.31
(s, 1H), 6.01 (d, J¼3.0 Hz, 1H), 5.51 (d, J¼8.1 Hz, 1H),
4.62 (d, J¼3.6 Hz, 1H), 3.37 (t, J¼7.5 Hz, 1H), 2.99 (q,
J¼7.8 Hz, 1H), 2.61 (quint, J¼6.9 Hz, 1H); 13C NMR
(DMSO-d6, 75 MHz) d 156.9, 152.7, 150.2, 142.0, 139.9,
132.0, 119.8, 74.1, 59.4, 57.8, 48.6; Anal. Calcd for
C11H13O5N2: C, 53.43; H, 5.30, N, 28.32. Found: C,
53.71; H, 5.21; N, 28.49.
3. Slusarchyk, W. A.; Young, M. G.; Bisacchi, G. S.; Hockstein,
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3.1.16. (6)-(10S,40S,60S)-1-[4-Hydroxymethyl-6-hydroxy-
cyclopent-2-en-1-yl] cytosine (16). The cytosine derivative
16 was synthesized using same reaction condition used for
synthesizing compound 15; yield 49%; mp 168–1718C; UV
(H2O) lmax 271 nm: 1H NMR (MeOH-d4, 300 MHz) d 7.61
(d, J¼7.4 Hz, 1H), 6.38 (dd, J¼2.9, 1.4 Hz, 1H), 5.97 (dd,
J¼5.4, 2.5 H, 1H), 5.85 (d, J¼7.4 Hz, 1H), 5.65 (s, 1H),
4.79 (dd, J¼6.2, 2.3 Hz, 1H), 3.61 (dd, J¼11.4, 3.9 Hz, 1H),
3.47 (dd, J¼11.0, 6.98, 1H), 2.68 (quint, J¼6.9 Hz, 1H); 13C
NMR (MeOH-d4, 75 MHz) d 166.4, 158.6, 144.6, 139.6,
131.9, 94.3, 74.2, 61.6, 57.9; Anal. calcd for C10H13N3O3:
C, 53.80; H, 5.87; N, 18.82. Found: C, 53.69; H, 6.03; N,
18.51.
11. (a) Kappert, M. J. Angew. Chem. Int. Ed. Engl. 1983, 22, 63.
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Acknowledgements
The authors wish to acknowledge Dr C.-K. Lee (Korea
Research Institute of Chemical Technology) for the antiviral
assays.
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