Synthesis of cyclopentenyl carbocyclic nucleosides as potential antiviral agents against orthopoxviruses and SARS

Article abstract of DOI:10.1021/jm0509750

A practical and convenient methodology for the synthesis of chiral cyclopentenol derivative (+)-12a has been developed as the key intermediate that was utilized for the synthesis of biologically active carbocyclic nucleosides. The selective protection of

Full text of DOI:10.1021/jm0509750

1140
J. Med. Chem. 2006, 49, 1140-1148
Synthesis of Cyclopentenyl Carbocyclic Nucleosides as Potential Antiviral Agents Against
Orthopoxviruses and SARS
Jong Hyun Cho,† Dale L. Bernard,‡ Robert W. Sidwell,‡ Earl R. Kern,§ and Chung K. Chu*,†
The UniVersity of Georgia College of Pharmacy, Athens, Georgia 30602, Institute for AntiViral Research, Utah State UniVersity,
Logan, Utah 84322, and UniVersity of Alabama School of Medicine, Birmingham, Alabama 35294
ReceiVed September 29, 2005
A practical and convenient methodology for the synthesis of chiral cyclopentenol derivative (+)-12a has
been developed as the key intermediate that was utilized for the synthesis of biologically active carbocyclic
nucleosides. The selective protection of allylic hydroxyl group followed by the ring-closing metathesis (RCM)
reaction with Grubbs catalysts provided (+)-12a on a 10 g scale with 52% overall yield from D-ribose (4).
The key intermediate (+)-12a was utilized for the synthesis of unnatural five-membered ring heterocyclic
carbocyclic nucleosides. The newly synthesized 1,2,3-triazole analogue (17c) exhibited potent antiviral activity
(EC50 0.4 µM) against vaccinia virus and moderate activities (EC50 39 µM) against cowpox virus and severe
acute respiratory syndrome coronavirus (SARSCoV) (EC50 47 µM). The 1,2,4-triazole analogue (17a) also
exhibited moderate antiviral activity (EC50 21 µM) against SARSCoV.
Introduction
Neplanocin A (NPA, 1),1 a carbocyclic nucleoside isolated
from Ampullariella regularis, has received a great deal of
attention as a potential antiviral or antitumor agents.2 NPA
mediated inhibition of S-adenosylhomocysteine hydrolase
(AdoHcy-ase) is responsible for its biological activity, which
is the key enzyme in the regulation of S-adenosyl-L-methionine-
(AdoMet-) dependent methylation reactions during mRNA
replication cycles.3 NPA is also a substrate for adenosine kinase
as well as adenosine deaminase, and it exhibits cellular toxicity.4
On the basis of these interesting biological results, a
significant amount of synthetic efforts have been directed toward
finding more selective analogues.5 As part of these efforts, a
number of 6′-modified analogues, such as (6′R)-6′-C-methyl-
Figure 1. Neplanocin A and its analogues.
neplanocin A (RMNPA, 2a)5e and 6′-homoneplanocin A
(HNPA, 2b),5i have been synthesized (Figure 1). 3-Deazane-
when Schrock’s catalysts were used.11 Herein, we report an
efficient and practical method for the synthesis of cyclopentenol
(+)-12a from D-ribose (4) and its utilization for the synthesis
of novel biologically active five-membered ring heterocyclic
NPA analogues (17a-c) as potential antiviral agents of bio-
defense interest.
planocin A (2c)5d and its analogue (2d)5a also showed potent
antiviral activity against various viruses, including orthopox-
viruses. Our group has reported synthetic methods for NPA and
several NPA analogues as well as their antiviral activities.6
Among the modified NPA analogues, cytosine (3a) and fluoro-
cytosine (3b) analogues were found to be active against human
immunodeficiency virus (HIV), West Nile virus (WNV), and
Results and Discussion
orthopoxviruses.6
The chiral intermediate 7a was synthesized according to
modified published procedures6 as shown in Scheme 1. D-Ribose
(4) was treated with 2,2-dimethoxypropane in the presence of
a catalytic amount of p-toluenesulfonic acid to give isopropyl-
idene derivative 5 in 90% yield, followed by the protection of
the primary alcohol with triphenylmethyl chloride (TrCl) to
provide 6 in 85% yield. The protected lactol 6a was reacted
with vinylmagnesium bromide to quantitatively give a single
diastereomeric diol 7a, which was subsequently protected with
a tert-butyldimethylsilyl group (TBDMS) only at the allylic
hydroxyl position to afford silyldienol 8a in 82% yield, which
was observed as two conformers in the NMR spectrum as
previously observed.12
The syntheses of NPA analogues have utilized a chiral
cyclopentenol as the key intermediate, starting from optically
pure carbohydrates or tartaric acids by various synthetic
methods.7 Recently, the ring-closing metathesis (RCM) reac-
tion,8 one of the most powerful methods for the formation of
small-sized rings via C-C double bonds, has been employed
for the synthesis of disubstituted cyclopentenols.9 Although a
few examples used the RCM reaction as the key synthetic step
for the trisubstituted cyclopentenol derivatives, large amounts
of expensive Grubbs catalysts were necessary to complete the
reaction10 and its reaction conditions were difficult to control
* Corresponding author: tel (706) 542-5379; fax (706) 542-5381; e-mail
DCHU@RX.UGA.EDU.
To incorporate another double bond for the RCM reaction,
the protected secondary alcohol 8a was oxidized to the ketone
9a by Swern oxidation, followed by Wittig reaction with
methyltriphenylphosphonium bromide and butyllithium (n-BuLi)
† The University of Georgia College of Pharmacy.
‡ Utah State University.
§ University of Alabama School of Medicine.
10.1021/jm0509750 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/14/2006

AntiViral Cyclopentenyl Carbocyclic Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1141
Scheme 1a
a Reagents and conditions: (a) 2,2-dimethoxypropane, TsOH‚H2O, acetone, 0 °C f rt, 1 h; (b) (i) TrCl, Et3N, DMAP, DMF, rt, 48 h (6a), (ii) TBDPSCl,
imidazole, CH2Cl2, 0 °C f rt, 24 h (6b); (c) vinylmagnesium bromide, THF, -78 °C f rt, 12 h; (d) TBDMSCl, imidazole, CH2Cl2-DMF (10:1 v/v), 0 °C
f rt, 24 h; (e) (COCl)2, Et3N, CH2Cl2, -60 °C; (f) Ph3PCH3Br, n-BuLi, THF, 0 °C f rt, 12 h; (g) TBAF, THF, rt, 2-6 h; (h) second-generation Grubbs
catalyst, CH2Cl2, rt, 24 h; (i) first/second-generation Grubbs catalysts, CH2Cl2, rt, 24 h; (j) TrCl, Et3N, DMAP, CH2Cl2, rt, 12 h.
in tetrahydrofuran (THF) to provide the diene 10a in quantitative
yield. With the diene 10a in hand, the RCM reaction was
investigated in the presence of 10 or 20 mol % first- or second-
generation Grubbs catalysts without success, providing trace
amounts of the desired trisubstituted diene 13a (Scheme 1). The
literature search indicated that few RCM reactions with hindered
terminal double bonds, as in the case of dienes 10a, b, have
been successful with the Grubbs catalysts, due to the significant
steric hindrance by bulky groups, the major obstacle of the RCM
reaction.13 Therefore, the silyl group from diene 10a was
removed with tetrabutylammonium fluoride (TBAF) to give the
less sterically demanding dienol 11a, which was successfully
converted to cyclopentenol (+)-12a with only 2.0 mol %
second-generation catalyst in 94% yield (procedure A), whereas
a 40.0 mol % first-generation catalyst was required to obtain a
similar yield. Thus, this improved procedure was able to provide
multigram-scale (10 g) cyclopentenol (+)-12a without any major
difficulties.
Alternative approaches for the substrate with unprotected
dihydroxyl moiety (11b) were also investigated to further
minimize the amount of Grubbs catalysts in the RCM reaction
as shown in Scheme 1 (procedure B). Thus, the dienol 11b was
prepared from 5 following the same route: 2′,3′-protected
D-ribose 5 was reacted with tert-butyldiphenylsilyl chloride
(TBDPSCl) in the presence of imidazole in CH2Cl2 to obtain a
silyl lactol 6b in 90% yield. Grignard reaction of the lactol 6b,
followed by subsequent selective protection with TBDMSCl,
Swern oxidation, and Wittig reaction, afforded bis(silyl) diene
10b in 80% overall yield. Two silyl groups of 10b were then
removed with TBAF to obtain dihydroxydiene 11b as the
substrate for the RCM reaction. The diene 11b was then cyclized
to provide the cyclopentenol 14 with 10.0 mol % first-generation
Figure 2. NOE studies of (+)-12a and (+)-12b.
or 5.0 mol % second-generation catalyst in 90% and 92% yield,
respectively. The primary alcohol 14 was reacted with TrCl in
the presence of Et3N in CH2Cl2 to give the monoprotected
cyclopentenol (+)-12a in 92% yield. However, considering the
required amounts of the RCM catalysts as well as the reaction
conditions, we concluded that the procedure A was the preferred
method of synthesis for (+)-12a. Thus, procedure A was mainly
used for the preparation of the key intermediate (+)-12a for
the desired nucleosides. The overall yield of (+)-12a was 70%
from compound 6a (procedure A) and 64% from compound
6b (procedure B).
The stereochemistry of cyclopentenol (+)-12a was deter-
1
mined on the basis of H NMR spectra, nuclear Overhauser
effect (1D-NOE) and [R]D value, which were compared to the
reported values14 for (+)-12a along with the data of its
diastereomer (+)-12b, which was readily converted from (+)-
12a by Mitsunobu reaction.15 Additionally, 1D-NOE was
determined in which a significant interaction between Ha and
Hc in (+)-12a was observed, whereas the NOE between He and
Hc was not observed in (+)-12b as shown in Figure 2.
With the chiral (+)-12a in hand, Mitsunobu reaction16 of (+)-
12a with methyl-1H-1,2,4-triazole-3-carboxylate in the presence
of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine

1142 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3
Cho et al.
Scheme 2a
a Reagents and conditions: (a) (i) DIAD, PPh3, THF, 0 °C f -78 °C and then rt, 24 h, methyl-1H-1,2,4-triazole-3-carboxylate (15a); (ii) DIAD, PPh3,
THF, 0 f -78 °C and then rt, 24 h methyl imidazole-4-carboxylate (15b). (b) (i) NH3, MeOH, rt, 24 h for 16a and 16c; (ii) NH3, MeOH, 100 °C, 24 h for
16b. (c) 1.0 M HCl in ether, MeOH, 0 °C, 2-4 h. (d) (i) MsCl, Et3N, CH2Cl2, 0 °C, 2 h; (ii) NaN3, DMF, 80 °C, 24 h. (e) methyl propiolate, CuI, Et3N,
THF, rt, 12 h.
Table 1. Antiviral Activities of Five-membered Ring Heterocyclic Carbocyclic Analogues against Vaccinia, Cowpox, SARS, West Nile (WNV), Yellow
Fever, and Venezuelan Equine Encephlitis (VEE) Viruses
a Positive control.
(PPh3) was carried out to obtain the triazole nucleoside 15a
(Scheme 2). The ester 15a was transformed to the amide 16a
with saturated methanolic ammonia, followed by deprotection
of trityl and isopropylidene groups by methanolic hydrogen
chloride solution (1.0 M HCl in diethyl ether) to afford the
desired nucleoside 17a in 75% yield in three steps from (+)-
12a. The regioselectivity of 15a was determined by comparing
the UV data (λmax 204 nm in H2O) of 17a with that of ribavirin
(λmax 207 nm in H2O).17 The other five-membered ring
heterocyclic nucleoside 17b was also prepared from the coupling
reactions of (+)-12a with methyl imidazole-4-carboxylate by a
similar method in 72% yield. The structure of 15b was identified
by 1D-NOE (a correlation between C1′-H and C5-H). The final
compound (17b) was also compared to the previous reported
UV data of an imidazole nucleoside derivative (λmax 235 nm at
pH 11).18 The 1,2,3-triazole derivative (17c) was also synthe-
sized by the 1,3-dipolar reaction of methyl propiolate with the
azide derivative (18), prepared from (+)-12a by the reported
method.19 The ester 15c was converted to the amide 16c in
saturated methanolic ammonia, which was treated with metha-
nolic hydrogen chloride to afford 1,2,3-triazole carbocyclic
nucleoside 17c in 80% overall yield from (+)-12a.

AntiViral Cyclopentenyl Carbocyclic Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1143
0.1H), 4.87 (t, J ) 10.0 Hz, 0.1H), 4.66 (dd, J ) 14.0 and 6.0 Hz,
0.1H), 4.59 (dd, J ) 14.0 and 8.0 Hz, 0.1H), 4.35 (m, 0.1H), 4.12
(dd, J ) 10.0 and 6.0 Hz, 0.1H), 3.67 (br s, 0.2H), 1.52 (s, 0.3H),
1.34 (s, 0.3H); 13C NMR (CDCl3, 125 MHz) δ 114.12, 89.01, 81.47,
81.09, 79.42, 63.08, 26.70, 25.48.
Antiviral Activity. The newly synthesized carbocyclic
nucleosides (17a-c) have been evaluated for their antiviral
activity against vaccinia, cowpox, severe acute respiratory
syndrome (SARS), West Nile (WNV), yellow fever, and
Venezuelan equine encephalitis (VEE) viruses, as well as for
their cytotoxicity, as summarized in Table 1. While all three
carbocyclic nucleosides (17a-c) did not show any significant
antiviral activity against WNV, yellow fever, and VEE viruses,
1,2,4-triazole analogue (17a) exhibited moderate antiviral activ-
ity [EC50 21 µM, selectivity index (SI) > 4.8] against SARS
virus. Interestingly, 1,2,3-triazole analogue (17c) exhibited the
most potent antiviral activity among the five-membered ring
carbocyclic nucleosides (17a-c) against vaccinia virus with high
selectivity (EC50 0.4 µM, SI > 750) and moderate activity
against cowpox virus (EC50 39 µM, SI > 7.7) as well as
marginal activity against SARS virus (EC50 47 µM, SI > 2.1).
However, the imidazole analogue (17b) did not show any
significant antiviral activity against any of the viruses evaluated.
These preliminary in vitro antiviral activities for novel carbo-
cyclic nucleosides warrant additional studies of structure-
activity relationships as well as studies of the mode of action,
which are in progress in our laboratories.
2,2-Dimethyl-6-(trityloxymethyl)tetrahydrofuro[3,4-d][1,3]-
dioxol-4-ol (6a). To a solution of compound 5 (15.30 g, 80.46
mmol), a catalytic amount of 4-(dimethylamino)pyridine (DMAP,
0.30 g, 2.41 mmol), and trityl chloride (26.92 g, 96.56 mmol) in
200 mL of anhydrous N,N-dimethylformamide (DMF) was added
Et3N (12.21 g, 0.12 mol) at room temperature under nitrogen
atmosphere. The resulting solution was stirred for 48 h at room
temperature and poured into ice water (100 mL). The organic layer
was extracted with CH2Cl2 (200 mL × 3), washed with saturated
aqueous NH4Cl (100 mL × 2) and water (200 mL), and then dried
over Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by silica gel column chromatography
(hexane/EtOAc ) 10:1 to 2:1 v/v) to give compound 6a as a
mixture of R- and â-isomers (25.0 g, 58.0 mmol) in 85% yield.
â-Form: 1H NMR (CDCl3, 500 MHz) δ 7.41-7.38 (m, 6H), 7.34-
7.24 (m, 12H), 5.33 (d, J ) 8.5 Hz, 0.8H) 4.79 (d, J ) 6.0 Hz,
0.8H), 4.66 (d, J ) 6.0 Hz, 0.8H), 4.35 (t, J ) 4.0 Hz, 0.8H), 3.95
(d, J ) 9.0 Hz, 0.8H), 3.42 (dd, J ) 10.0 and 4.0 Hz, 0.8H), 3.34
(dd, J ) 10.0 and 4.0 Hz, 0.8H), 1.48 (s, 2.4H), 1.34 (s, 2.4H); 13
C
NMR (CDCl3, 125 MHz) δ 142.83, 128.71, 128.15, 127.54, 112.29,
103.57, 88.25, 87.11, 86.10, 81.96, 65.10, 26.56, 25.14. R-Form:
1H NMR (CDCl3, 500 MHz) δ 7.41-7.38 (m, 1.2H), 7.34-7.24
(m, 2.4H), 5.75 (dd, J ) 11.5 and 4.0 Hz, 0.2H), 4.74 (dd, J )
11.5 and 4.0 Hz, 0.2H), 4.58 (d, J ) 6.5 Hz, 0.2H), 4.19 (t, J )
3.0 Hz, 0.2H), 4.01 (d, J ) 11.5 Hz, 0.2H), 3.45 (dd, J ) 10.0 and
3.0 Hz, 0.2H), 3.01 (dd, J ) 10.0 and 3.0 Hz, 0.2H), 1.55 (s, 0.6H),
1.37 (s, 0.6H); 13C NMR (CDCl3, 125 MHz) δ 143.52, 128.62,
128.03, 127.26, 113.01, 98.02, 87.60, 82.23, 80.15, 79.59, 65.51,
26.21, 24.79.
1-[5-(1-Hydroxy-2-trityloxyethyl)-2,2-dimethyl-[1,3]dioxolan-
4-yl]prop-2-en-1-ol (7a). To a solution of compound 6a (23.76 g,
54.94 mmol) in 300 mL of anhydrous THF was added 165 mL of
vinylmagnesium bromide (165.0 mmol, 1.0 M of THF) at -78 °C
under nitrogen atmosphere. After 1 h, the temperature was raised
to room temperature and the reaction mixture was stirred for an
additional 6 h and was treated with saturated NH4Cl solution (100
mL) dropwise at 0 °C, and the resulting solution was poured into
iced ether-saturated aqueous NH4Cl solution (400 mL, 3:1 v/v).
The organic layer was separated and the aqueous layer was washed
with ether (100 mL × 2). The combined organic layer was dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified on a silica gel column (hexane/EtOAc ) 10:
1 to 3:1 v/v) to give compound 7a (25.29 g, 54.90 mmol) in
quantitative yield. [R]D27 +12.32 (c 0.50, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 7.56 (d, J ) 8.0 Hz, 6H), 7.38 (m, 10H), 6.12 (ddd,
J ) 17.0, 10.0, and 5.0 Hz, 1H) 5.52 (d, J ) 17.0 Hz, 1H), 5.34
(d, J ) 10.5 Hz, 1H), 4.41 (s, 2H), 4.22 (dd, J ) 10.0 and 5.0 Hz,
1H), 4.13 (dd, J ) 10.0 and 5. Hz 0, 1H), 4.04 (m, 1H), 3.65 (d,
J ) 3.5 Hz, 2H), 3.61 (dd, J ) 10.0 and 3.5 Hz, 1H), 3.40 (dd, J
) 10.0 and 7.5 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 143.83, 137.61, 128.74, 128.03, 127.28,
116.37, 108.89, 87.15, 80.76, 77.42, 69.96, 69.08, 65.24, 28.07,
25.63; Anal. (C29H32O5) C, H.
In summary, an efficient synthetic methodology for the
cyclopentenol (+)-12a, employing the RCM reaction with the
minimum amount of second-generation Grubbs catalyst, has
been developed for a multigram scale. Coupling reactions of
cyclopentenol (+)-12a with appropriate five-membered ring
heterocycles provided novel antiviral agents of biodefense
interest. 1,2,3-Triazole NPA analogue (17c) exhibited the most
potent activity against vaccinia (EC50 0.4 µM, SI > 750) along
with moderate activities against cowpox (EC50 39 µM, SI >
7.7) and SARSCoV (EC50 47 µM, SI > 2.1).
Experimental Section
NMR spectra were recorded on a 500 MHz Fourier transform
spectrometer; chemical shifts are reported in parts per million (δ),
and signals are quoted as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad), dd (doublet of doublets), ddd
(doublet of doublets of doublets), and dt (doublet of triplets). Optical
rotations were measured by a Jasco DIP-370 digital polarimeter.
High-resolution mass spectra (HRMS) were recorded on a Micro-
mass Autospec high-resolution mass spectrometer with electrospray
ionization (ESI) in positive mode. Infrared spectra were recorded
on an Avatar 360 FT-IR as neat type. Melting points were taken
on Mel-Temp II melting point apparatus and were uncorrected.
Thin-layer chromatography (TLC) was performed on 0.25 mm silica
gel. Purifications were carried out on silica gel (60 Å, 32-63 mm).
The data for elemental analysis were provided by Atlantic Microlab
Inc., Norcross, GA.
6-Hydroxymethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-
4-ol (5). To a solution of d-ribose (50.0 g, 0.34 mol) and a catalytic
amount of p-toluenesulfonic acid monohydrate (TsOH‚H2O, 1.90
g, 1.0 mmol) in 500 mL of acetone was added 2,2-dimethoxy-
propane (38.16 g, 0.37 mol) at 0 °C. The suspension was stirred
for 1 h at room temperature until a clear solution was achieved.
The solution was then treated with NaHCO3 (0.10 g, 1.20 mmol)
and was stirred for an additional 30 min at room temperature. The
solid was filtered and the filtrate was adsorbed on silica gel and
purified by silica gel column chromatography (hexane/EtOAc )
3:1 to 1:1 v/v) to give compound 5 as a mixture of R- and â-isomers
(54.0 g, 0.29 mol) in 90% yield. â-Form: 1H NMR (CDCl3, 500
MHz) δ 5.65 (d, J ) 6.0 Hz, 0.9H), 5.35 (d, J ) 6.0 Hz, 0.9H),
4.75 (d, J ) 6.0 Hz, 0.9H), 4.52 (d, J ) 6.0 Hz, 0.9H), 4.33 (t, J
) 2.5 Hz, 0.9H), 4.30 (br s, 0.9H), 3.65 (t, J ) 12.0 Hz, 1.8H),
1.43 (s, 2.7H), 1.27 (s, 2.7H); 13C NMR (CDCl3, 125 MHz) δ
112.13, 102.65, 87.56, 86.66, 81.60, 63.41, 26.30, 24.66. R-Form:
1H NMR (CDCl3, 500 MHz) δ 5.38 (dd, J ) 12.0 and 8.0 Hz,
1-{5-[1-((tert-Butyldimethylsilanyl)oxyl)allyl]-2,2-dimethyl-
[1,3]dioxolan-4-yl}-2-(trityloxy)ethanol (8a). To a solution of
compound 7a (25.29 g, 54.90 mmol) in 300 mL of anhydrous
CH2Cl2-DMF solution (10:1 v/v) were added imidazole (11.23 g,
16.50 mmol) and TBDMSCl (10.34 g, 68.64 mmol) at 0 °C under
nitrogen atmosphere. The reaction mixture was stirred for 24 h at
room temperature and then poured into 500 mL of ether-water
solution (1:1 v/v). The organic layer was separated and the aqueous
layer was washed with ether (100 mL × 2). The combined organic
layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified on a silica gel column
(hexane/EtOAc ) 30:1 v/v) to give compound 8a as a mixture of
1
two conformers (26.10 g, 45.02 mmol) in 82% yield. H NMR

1144 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3
Cho et al.
(CDCl3, 500 MHz) δ 7.53-7.47 (m, 6H), 7.34-7.23 (m, 9H), 5.93
(m, 1H) 5.35-5.22 (m, 2H), 4.51 (s, 0.8H), 4.34 (m, 0.2H), 4.28
(m, 0.4H), 4.14 (m, 2H), 4.07 (m, 1.6H), 3.74 (s, 0.8H), 3.68 (m,
0.2H), 3.44 (m, 1.2H), 3.25 (m, 0.8H), 1.40 (s, 0.6H), 1.32 (s, 0.6H),
1.29 (s, 2.4H), 1.27 (s, 2.4H), 0.96 (s, 7.2H), 0.86 (s, 1.8H), 0.18
(s, 2.4H), 0.12 (s, 2.4H), 0.11 (s, 0.6H), 0.03 (s, 0.6H); 13C NMR
(CDCl3, 125 MHz) δ 149.24, 148.64, 142.77, 133.81, 133.68,
132.90, 132.82, 132.64, 132.11, 131.77, 122.95, 120.80, 112.93,
112.13, 92.15, 91.30, 84.95, 82.99, 78.56, 76.31, 74.33, 73.89,
70.32, 70.14, 32.98, 32.77, 30.90, 30.70, 23.22, 23.05, 1.08, 0.60,
0.26, 0.00.
127.99, 127.25, 116.13, 113.96, 108.23, 87.55, 80.59, 77.95, 70.34,
65.42, 27.18, 25.19.
2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-ol [(+)-12a]: Method A. To a solution of compound
11a (10 g, 21.90 mmol) in 400 mL of anhydrous CH2Cl2 was added
second-generation Grubbs catalyst (0.40 g, 0.44 mmol) at room
temperature under argon atmosphere. After being stirred for 24 h,
the reaction mixture was adsorbed on silica gel and purified on a
silica gel column (hexane/EtOAc ) 10:1 to 5:1 v/v) to give
23
compound (+)-12a (8.82 g, 1.86 mmol) in 94% yield. [R]D
1
+33.21 (c 1.00, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.46 (m,
1-{5-[1-((tert-Butyldimethylsilanyl)oxyl)allyl]-2,2-dimethyl-
[1,3]dioxolan-4-yl}-2-(trityloxy)ethanone (9a). To a solution of
oxalyl chloride (3.59 g, 41.02 mmol) in 100 mL of anhydrous
CH2Cl2 was added DMSO (5.82 g, 82.05 mmol) at -60 °C under
nitrogen atmosphere, and then the resulting solution was stirred
for 10 min. A solution of compound 8a (19.0 g, 32.82 mmol) in
200 mL of anhydrous CH2Cl2 was added to the reaction mixture
dropwise over 20 min at -60 °C. After 30 min, Et3N (16.60 g,
164.09 mmol) was added dropwise over 20 min to the reaction
mixture at -60 °C. The mixture was stirred for 1 h at -60 °C and
then stirred for 30 min at room temperature. The reaction mixture
was treated with 200 mL of water dropwise at 0 °C. The organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (200 mL × 3). The combined organic layer was washed
with brine (200 mL × 2), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified on
a silica gel column (hexane/EtOAc ) 20:1 to 10:1 v/v) to give
6H), 7.29-7.20 (m, 9H), 5.99 (s, 1H) 5.23 (s, 1H), 4.86 (d, J )
5.0 Hz, 1H), 4.73 (t, J ) 5.0 Hz, 1H), 4.57 (m, 1H), 3.88 (d, J )
15.0 Hz, 1H), 3.67 (d, J ) 15.0 Hz, 1H), 2.76 (d, J ) 10.0 Hz,
1H), 1.36 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
143.95, 143.43, 129.84, 128.63, 127.94, 127.15, 112.52, 87.01,
83.36, 77.93, 73.51, 60.95, 27.83, 26.93.
Method B. To a solution of compound 14 (1.0 g, 5.37 mmol),
a catalytic amount of DMAP (0.07 g, 0.54 mmol), and trityl chloride
(1.90 g, 6.71 mmol) in 20 mL of anhydrous CH2Cl2 was added
Et3N (0.73 g, 6.71 mmol) at room temperature under N2 atmosphere.
After 12 h at room temperature, the reaction mixture was poured
into ice water (20 mL). The product was extracted with CH2Cl2
(20 mL × 3) from the aqueous layer. The combined solution was
washed with saturated aqueous NH4Cl (10 mL × 2), water (20
mL), and brine (10 mL × 2) and then dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/EtOAc ) 20:1 to
4:1 v/v) to give compound (+)-12a (2.21 g, 4.94 mmol) in 92%
23
compound 9a (18.0 g, 31.64 mmol) in 95% yield. [R]D -14.97
1
22
(c 1.00, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.57 (m, 6H),
yield. [R]D +30.57 (c 0.57, CHCl3).
7.39-7.29 (m, 9H), 5.90 (m, 1H) 4.64 (d, J ) 7.5 Hz, 1H), 4.41
(m, 2H), 4.24 (d, J ) 18.0 Hz, 1H), 3.95 (d, J ) 18.0 Hz, 1H),
1.42 (s, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 148.13, 141.87, 133.31, 133.25, 132.49,
131.69, 122.50, 113.95, 91.71, 87.01, 84.01, 77.67, 74.06, 30.78,
30.63, 29.29, 22.95.
2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-ol ((+)-12b). To a solution of Ph3P (0.15 g, 1.26
mmol) and DIAD (0.26 g, 1.26 mmol) in 5.0 mL of anhydrous
THF were added benzoic acid (0.15 g, 1.26 mmol) and a solution
of compound (+)-12a (0.36 g, 0.84 mmol) in 10.0 mL of anhydrous
THF at 0 °C under N2 atmosphere. After the suspension overnight
at room temperature, the reaction mixture was adsorbed on silica
gel and purified on silica gel pad (hexane/EtOAc ) 1:2 v/v) to
give a crude product with a small amount of DIAD. The crude
intermediate was treated with LiOH (0.11 g, 2.52 mmol) in 20 mL
of THF-H2O solution (3:1 v/v) for 12 h at room temperature. The
basic solution was neutralized by addition of 1.0 M HCl solution.
The product was extracted with ethyl acetate (20 mL × 3) from
the aqueous layer. The combined organic layer was washed with
brine (20 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 10:1 to 4:1 v/v) to give
compound (+)-12b (0.30 g, 0.71 mmol) in 84% yield (two steps).
[R]D24 +2.44 (c 0.50, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.46
(m, 6H), 7.29-7.24 (m, 9H), 5.99 (s, 1H) 5.08 (s, 1H), 4.76 (s,
1H), 4.51 (s, 1H), 3.89 (d, J ) 15.0 Hz, 1H), 3.71 (d, J ) 15.0 Hz,
1H), 2.03 (br s, 1H), 1.33 (s, 3H), 1.30 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 147.26, 143.94, 128.61, 127.88, 127.28, 127.08,
111.89, 86.47, 83.80, 80.01, 70.06, 61.34, 27.49, 26.17.
tert-Butyl-{1-[2,2-dimethyl-5-(1-(trityloxymethyl)vinyl)-[1,3]-
dioxolan-4-yl]allyloxy}dimethylsilane (10a). To a suspension of
Ph3PCH3Br (52.63 g, 147.33 mmol) in 100 mL of THF was added
90 mL of n-BuLi (140.0 mmol, 1.6 M in hexane) at 0 °C under N2
atmosphere. After 30 min, a solution of compound 9a (17.0 g, 29.46
mmol) in 200 mL of THF was added to the reaction mixture at 0
°C. The resulting mixture was stirred for 12 h at room temperature,
treated with 50 mL of MeOH and 100 mL of water, and then poured
into 300 mL of ether-water solution (2:1 v/v). The organic layer
was separated and the aqueous layer was extracted with ether (200
mL × 2). The combined organic layer was washed with brine (20
mL × 2), dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified on a silica gel column
(hexane/EtOAc ) 50:1 to 10:1 v/v) to give compound 10a (16.02
g, 27.99 mmol) in 95% yield. 1H NMR (CDCl3, 500 MHz) δ 7.54
(m, 6H), 7.34-7.30 (m, 9H), 5.74 (m, 1H) 5.72 (s, 1H), 5.46 (s,
1H), 5.24 (d, J ) 10.0 Hz, 1H), 5.06 (d, J ) 17.5 Hz, 1H), 4.82
(d, J ) 5.5 Hz, 1H), 3.98 (m, 2H), 3.79 (d, J ) 13.5 Hz, 1H), 3.60
(d, J ) 13.5 Hz, 1H), 1.36 (s, 3H), 1.32 (s, 3H), 0.89 (s, 9H), 0.01
(s, 6H); 13C NMR (CDCl3, 125 MHz) δ 148.25, 146.08, 142.74,
132.73, 131.98, 131.15, 121.04, 117.65, 112.04, 90.88, 84.73, 82.92,
77.29, 68.84, 30.57, 30.22, 29.15, 22.27, 0.71, 0.01.
6-(((tert-Butyldiphenylsilanyl)oxy)methyl)-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (6b). To a solution of
compound 5 (19.0 g, 99.92 mmol) in 200 mL of anhydrous CH2Cl2
were added TBDPSCl (25.60 g, 99.92 mmol) and imidazole (20.21
g, 149.88 mol) at 0 °C under nitrogen atmosphere. The suspension
solution was allowed to stir for 24 h at room temperature. The
reaction mixture was absorbed on silica gel and then purified by
silica gel column chromatography (hexane/EtOAc ) 20:1 v/v) to
1-[2,2-Dimethyl-5-(1-(trityloxymethyl)vinyl)-[1,3]dioxolan-4-
yl]prop-2-en-1-ol (11a). A solution of compound 10a (16.0 g, 27.99
mmol) in 100 mL of THF was treated with 35 mL of TBAF (35.0
mmol, 1.0 M in THF) at room temperature. After being stirred for
2 h, the reaction mixture was adsorbed on silica gel and purified
on a silica gel column (hexane/EtOAc ) 30:1 v/v) to give
1
give compound 6b (40.0 g, 88.20 mmol) in 88% yield. H NMR
(CDCl3, 500 MHz) δ 7.66 (m, 4H), 7.47-7.40 (m, 6H), 5.35 (d, J
) 8.0 Hz, 1H), 4.72 (m, 1H), 4.61 (m, 1H), 4.55 (d, J ) 10.0 Hz,
1H), 4.28 (s, 1H), 3.82 (d, J ) 11.0 Hz, 1H), 3.65 (d, J ) 11.0 Hz,
1H), 1.47 (s, 3H), 1.31 (s, 3H), 1.09 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 135.77, 135.60, 130.43, 130.25, 128.14, 128.08,
127.95, 112.15, 103.41, 87.31, 87.09, 81.74, 65.53, 26.95, 26.91,
26.52, 25.02, 19.18. R-Isomer: δ 7.66 (m, 0.8H), 7.47-7.40 (m,
1.2H), 5.62 (d, J ) 11.0 Hz, 0.2H), 4.78 (m, 0.2H), 4.66 (m, 0.2H),
1
compound 11a (12.52 g, 27.43 mmol) in 98% yield. H NMR
(CDCl3, 500 MHz) δ 7.46 (m, 6H), 7.32-7.22 (m, 9H), 5.94 (m,
1H) 5.61 (s, 1H), 5.51 (s, 1H), 5.27 (dt, J ) 17.0 and 1.5 Hz, 1H),
5.18 (dt, J ) 11.0 and 1.5 Hz, 1H), 4.58 (d, J ) 6.0 Hz, 1H), 3.96
(m, 2H), 3.89 (dd, J ) 8.0 and 6.0 Hz, 1H), 3.74 (dd, J ) 24.0 and
13.0 Hz, 2H), 2.22 (d, J ) 4.0 Hz, 3H), 1.37 (s, 3H), 1.29 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 143.73, 142.22, 137.73, 128.71,

AntiViral Cyclopentenyl Carbocyclic Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1145
4.15 (s, 0.2H), 4.11 (m, 0.4H), 3.98 (d, J ) 11.0 Hz, 0.2H), 3.82
(m, 0.2H), 3.61 (m, 0.2H), 1.55 (s, 0.6H), 1.39 (s, 0.6H), 1.05 (s,
1.8H).
9H), 0.84 (s, 9H), 0.03 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ
210.06, 142.00, 140.10, 140.03, 137.64, 137.31, 134.26, 134.25,
132.19, 132.16, 122.47, 113.74, 86.66, 83.55, 77.95, 73.54, 31.23,
30.89, 30.52, 29.04, 23.77, 22.87, 0.23, 0.00.
1-{5-[2-((tert-Butyldiphenylsilanyl)oxy)-1-hydroxyethyl]-2,2-
dimethyl-[1,3]dioxolan-4-yl}prop-2-en-1-ol (7b). To a solution
of compound 6b (36.0 g, 78.90 mmol) in 400 mL of anhydrous
THF was added 237 mL of vinylmagnesium bromide (237 mmol,
1.0 M of THF) at -78 °C under nitrogen atmosphere. After 1 h,
the temperature was raised to room temperature and the reaction
mixture was stirred for an additional 6 h at room temperature. The
resulting solution was poured into iced ether-saturated aqueous
NH4Cl solution (400 mL, 3:1 v/v). The organic layer was separated
and the aqueous layer was washed with ether (150 mL × 2). The
combined organic layer was dried over MgSO4 and the solvent was
removed under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/EtOAc ) 10:1 to 3:1 v/v) to
give compound 7b (35.64 g, 78.10 mmol) in quantitative yield.
4-[1-(((tert-Butyldimethylsilanyl)oxy)allyl]-5-[1-((tert-butyl-
diphenylsilanyl)oxy)methyl)vinyl]-2,2-dimethyl-[1,3]dioxolane
(10b). To a suspension of Ph3PCH3Br (15.54 g, 43.50 mmol) in
50 mL of THF was added 25 mL of n-BuLi (1.6 M in hexane) at
0 °C under N2 atmosphere. After 30 min, a solution of compound
9b (4.50 g, 7.91 mmol) in 100 mL of THF was added to the reaction
mixture at 0 °C. The resulting solution was allowed to stir for 12
h at room temperature, treated with 20 mL of MeOH and 40 mL
of water, and then poured into ether-water solution (200 mL, 3:1
v/v). The organic layer was separated and the aqueous layer was
washed with ether (100 mL × 2). The collected solution was washed
with brine (50 mL × 2), dried over MgSO4, and purified by silica
gel column chromatography (hexane/EtOAc ) 50:1 to 10:1 v/v)
to give compound 10b (4.17 g, 7.36 mmol) in 93% yield. 1H NMR
(CDCl3, 500 MHz) δ 7.72 (m, 4H), 7.48-7.40 (m, 6H), 5.78 (m,
1H), 5.148 (s, 1H), 5.38 (s, 1H), 5.20 (d, J ) 10.0 Hz, 1H), 5.14
(d, J ) 17.0 Hz, 1H), 4.80 (d, J ) 6.5 Hz, 1H), 4.25 (dd, J ) 14.0
and 17.0 Hz, 1H), 4.05 (t, J ) 7.5 Hz, 1H), 3.98 (d, J ) 6.5 Hz,
1H), 1.39 (s, 3H), 1.35 (s, 3H), 1.12 (s, 9H), 0.85 (s, 9H), 0.02 (s,
3H), 0.00 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 147.28, 142.91,
139.67, 139.63, 137.59, 137.53, 133.84, 133.81, 131.86, 131.84,
131.82, 121.39, 116.30, 111.92, 84.68, 81.82, 77.46, 69.08, 30.98,
30.81, 30.23, 29.24, 23.42, 22.31, 0.73, 0.00.
24
1
[R]D +11.05 (c 1.12, CHCl3); H NMR (CDCl3, 500 MHz) δ
7.68 (m, 4H), 7.48-7.38 (m, 6H), 6.06 (m, 1H), 5.49 (dt, J ) 17.0
and 1.5 Hz, 1H), 5.27 (dt, J ) 10.0 and 1.5 Hz, 1H), 4.36 (m, 1H),
4.25 (d, J ) 3.0 Hz, 1H), 4.12 (dd, J ) 10.0 and 5.5 Hz, 1H), 4.05
(dd, J ) 10.0 and 5.5 Hz, 1H), 3.92 (m, 2H), 3.77 (m, 1H), 3.42
(d, J ) 3.0 Hz, 1H), 1.31 (s, 3H), 1.26 (s, 3H), 1.09 (s, 9H); 13C
NMR (CDCl3, 125 MHz) δ 135.77, 135.60, 130.43, 130.25, 128.14,
128.08, 127.95, 112.15, 103.41, 87.31, 87.09, 81.74, 65.53, 26.95,
26.91, 26.52, 25.02, 19.18.
1-{5-[1-((tert-Butyldimethylsilanyl)oxy)allyl]-2,2-dimethyl-
[1,3]dioxolan-4-yl}-2-((tert-butyldiphenylsilanyl)oxy)ethanol (8b).
To a solution of compound 7b (28.0 g, 61.14 mmol) in 200 mL of
anhydrous CH2Cl2-DMF solution (10:1 v/v) were added imidazole
(12.48 g, 183.45 mmol) and TBDMSCl (10.20 g, 67.50 mmol) at
0 °C under nitrogen atmosphere. The reaction mixture was stirred
for 24 h at room temperature and then poured into 600 mL of ether-
water solution (1:1 v/v). The organic layer was separated and the
aqueous layer was washed with ether (100 mL × 2). The combined
organic layer was washed with brine (150 mL × 2), dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/EtOAc )
20:1 v/v) to give compound 8b (31.42 g, 55.03 mmol) in 90% yield.
1H NMR (CDCl3, 500 MHz) δ 7.72 (m, 4H), 7.42-7.33 (m, 6H),
5.90 (m, 1H), 5.25 (dd, J ) 16.5 and 11.5 Hz, 2H), 5.27 (dt, J )
10.0 and 1.5 Hz, 1H), 4.28 (t, J ) 6.0 Hz, 1H), 4.15 (dd, J ) 10.0
and 5.0 Hz, 1H), 4.06 (t, J ) 5.0 Hz, 1H), 3.92 (m, 2H), 3.80 (dd,
J ) 10.0 and 6.0 Hz, 1H), 3.58 (d, J ) 5.0 Hz, 1H), 1.29 (s, 3H),
1.28 (s, 3H), 1.05 (s, 9H), 0.92 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 143.05, 140.82, 140.75, 138.80,
138.65, 134.59, 134.57, 132.66, 132.60, 123.15, 113.18, 85.07,
81.93, 78.81, 74.76, 70.54, 32.83, 31.90, 31.86, 31.01, 30.74, 24.38,
23.32, 1.32, 0.71.
1-{5-[1-((tert-Butyldimethylsilanyl)oxy)allyl]-2,2-dimethyl-
[1,3]dioxolan-4-yl}-2-((tert-butyldiphenylsilanyl)oxy)ethanone (9b).
To a solution of oxalyl chloride (1.38 g, 10.95 mmol) in 20 mL of
anhydrous CH2Cl2 was added DMSO (1.72 g, 21.98 mmol) at -60
°C under nitrogen atmosphere, and then the resulting solution was
stirred for 10 min. A solution of compound 8b (5.0 g, 8.76 mmol)
in 50 mL of anhydrous CH2Cl2 was added to the reaction mixture
dropwise over 15 min at -60 °C. After another 30 min, Et3N (4.43
g, 43.79 mmol) was added dropwise at -60 °C to the reaction
mixture. The mixture was allowed to stir for 30 min at -60 °C
and then stirring for 30 min, to the reaction mixture was added
100 mL of cold water, and the aqueous layer was separated and
extracted with CH2Cl2 (50 mL × 3). The combined organic layer
was washed with brine (50 mL × 2), dried over MgSO4,
concentrated under reduced pressure, and purified by silica gel
column chromatography (hexane/EtOAc ) 20:1 to 10:1 v/v) to give
compound 9b (4.74 g, 8.32 mmol) in 95% yield. [R]D23 -22.81 (c
1.00, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.62 (m, 4H), 7.40-
7.29 (m, 6H), 5.82 (m, 1H), 5.13 (s, 1H), 5.11 (dd, J ) 17.0 and
10.0 Hz, 1H), 4.56 (d, J ) 7.5 Hz, 1H), 4.51 (d, J ) 18.5 Hz, 1H),
4.38 (d, J ) 18.5 Hz, 1H), 4.32 (dd, J ) 7.5 and 3.5 Hz, 1H), 4.28
(dd, J ) 7.0 and 3.5 Hz, 1H), 1.39 (s, 3H), 1.23 (s, 3H), 1.01 (s,
1-[5-(1-(Hydroxymethyl(vinyl)-2,2-dimethyl-[1,3]dioxolan-4-
yl]prop-2-en-1-ol (11b). To a solution of compound 10b (0.84 g,
1.48 mmol) in 10 mL of THF was added 4.0 mL of TBAF in THF
solution (1.0 M in THF) at room temperature. After being stirred
for 2 h, the reaction mixture was adsorbed on silica gel and then
purified by silica gel column chromatography (hexane/EtOAc )
2:1 to 1:2 v/v) to give compound 11b (0.31 g, 1.42 mmol) in 95%
yield. [R]D24 -161.30 (c 0.50, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 5.97 (m, 1H), 5.40 (s, 1H), 5.27 (d, J ) 17.0 Hz, 1H), 5.25 (s,
1H), 5.19 (d, J ) 10.0 Hz, 1H), 4.77 (d, J ) 6.0 Hz, 1H), 4.46 (br
s, 1H), 4.16 (s, 1H), 3.98 (m, 2H), 3.20 (m, 1H), 1.44 (s, 3H), 1.34
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 143.35, 138.21, 116.27,
113.09, 107.75, 80.28, 77.74, 69.81, 65.44, 27.51, 25.23, 23.94,
19.67, 13.70.
6-Hydroxymethyl-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxo-4-ol (14): Method A. To a solution of compound 11b
(0.14 g, 0.65 mmol) in 50 mL of anhydrous CH2Cl2 was added
0.05 equiv of second-generation Grubbs catalyst (0.028 g, 0.03
mmol) at room temperature under argon atmosphere. After beomg
stirred for 24 h, the reaction mixture was adsorbed on silica gel
and then purified by silica gel column chromatography (hexane/
EtOAc ) 1:1 to 1:2 v/v) to give compound 14 (0.11 g, 0.60 mmol)
in 92% yield. 1H NMR (CDCl3, 500 MHz) δ 5.75 (s, 1H), 4.98 (d,
J ) 5.0 Hz, 1H), 4.79 (dd, J ) 5.0 and 6.0 Hz, 1H), 4.57 (m, 1H),
4.31 (dd, J ) 14.5 and 33.5 Hz, 2H), 2.87 (d, J ) 10.5 Hz, 1H),
2.60 (br s, 1H), 1.45 (s, 3H), 1.41 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 144.86, 129.95, 112.61, 83.08, 77.89, 73.22, 59.47, 27.55,
26.46.
Method B. To a solution of compound 11b (0.040 g, 0.187
mmol) in 10 mL of anhydrous CH2Cl2 was added 0.10 equiv of
first-generation Grubbs catalyst (0.016 g, 0.019 mmol) at room
temperature under argon atmosphere. After being stirred for 24 h,
the reaction mixture was adsorbed on silica gel and then purified
by silica gel column chromatography (hexane/EtOAc ) 1:1 to 1:2
v/v) to give compound 14 (0.032 g, 0.171 mmol) in 90% yield.
1-(2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-yl)-1H-1,2,4-triazole-3-carboxylic Acid Methyl Es-
ter (15a). To a solution of Ph3P (0.60 g, 2.10 mmol) in 2.0 mL of
anhydrous THF was added 0.35 mL of DIAD at 0 °C under N2
atmosphere, and the mixture was stirred for 30 min. A solution of
compound (+)-12a (0.30 g, 0.70 mmol) in 5.0 mL of anhydrous
THF was added to the reaction mixture at -78 °C, and stirring
continued for an additional 30 min. To the suspension was added
methyl 1H-1,2,4-triazole-3-carboxylate (0.15 g, 1.05 mmol) at -78

1146 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3
Cho et al.
°C, and then the reaction mixture was allowed to stir for 24 h at
room temperature. The reaction mixture was adsorbed on silica gel
and then purified by silica gel column chromatography (hexane/
EtOAc ) 2:1 to 1:2 v/v) to give compound 15a (0.38 g, 0.70 mmol)
with a small amount of DIAD. 1H NMR (CDCl3, 500 MHz) δ 7.98
(s, 1H), 7.45 (m, 6H), 7.30-7.21 (m, 9H), 6.45 (s, 1H) 6.03 (t, J
) 2.0 Hz, 1H), 5.27 (d, J ) 5.5 Hz, 1H), 4.84 (t, J ) 5.5 Hz, 1H),
4.05 (s, 3H), 3.98 (dt, J ) 15.5 and 2.0 Hz, 1H), 3.76 (d, J ) 15.5
Hz, 1H), 1.42 (s, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 161.14, 151.22, 143.65, 140.04, 128.55, 128.02, 127.31, 126.39,
121.19, 112.94, 87.39, 84.43, 83.79, 70.42, 61.33, 52.33, 27.45,
26.08.
1-(2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-yl)-1H-1,2,4-triazole-3-carboxylic Acid Amide (16a).
The crude compound 15a (0.38 g, 0.70 mmol) was dissolved in
20.0 mL of saturated methanolic ammonia at 0 °C, and then the
solution was allowed to stir for 12 h at room temperature. The
solvent and ammonia were evaporated under reduced pressure, and
then the residue was purified by silica gel column chromatography
(hexane/EtOAc ) 1:1 v/v) to give compound 16a (0.34 g, 0.65
mmol) in 92% yield from (+)-12a. 1H NMR (CDCl3, 500 MHz) δ
7.87 (s, 1H), 7.45 (m, 6H), 7.38 (s, 1H), 7.29-7.21 (m, 9H), 6.70
(s, 1H), 6.34 (s, 1H), 6.06 (s, 1H), 5.28 (d, J ) 4.5 Hz, 1H), 4.87
(d, J ) 4.5 Hz, 1H), 3.96 (d, J ) 15.5 Hz, 1H), 3.74 (d, J ) 15.5
Hz, 1H), 1.42 (s, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 158.86, 151.11, 148.74, 143.83, 128.60, 127.91, 127.12, 123.35,
112.35, 87.14, 84.65, 84.07, 69.38, 61.46, 27.65, 26.37. Anal.
(C31H30N4O4‚0.1H2O) C, H, N.
MHz) δ 158.81, 150.11, 148.74, 145.55, 143.83, 128.60, 127.90,
127.12, 123.35, 112.35, 87.14, 84.65, 84.07, 69.38, 61.45, 27.64,
26.37.
1-(4,5-Dihydroxy-3-hydroxymethylcyclopenten-2-enyl)-1H-
imidazole-4-carboxylic Acid Amide (17b). The solution of
compound 16b (0.25 g, 0.48 mmol) in 6.0 mL of MeOH was treated
with 25 mL of 1.0 M HCl in ether solution at 0 °C. The acidic
solution was allowed to stir for 3 h at room temperature. The
solvents and hydrogen chloride was evaporated under vacuum and
the residue was treated with water (20 mL), and then the aqueous
layer was washed with EtOAc (10 mL × 5) and concentrated under
reduced pressure. The gum-type product was dissolved in ethanol
(20 mL) and concentrated. The resulting solid was dried in vacuo
for 72 h at room temperature to give compound 17b (0.10 g, 0.42
mmol) as the HCl salt form in 85% yield. mp 161-163 °C; UV
(H2O) λmax 237.0 (ꢀ 2455, pH 11), 204.0, 239 (ꢀ 5132, 4034, pH
7), 198 (ꢀ 7180, pH 2); [R]D25 -15.43 (c 0.50, CH3OH); 1H NMR
(D2O, 500 MHz) δ 7.88 (br s, 1H), 7.61 (br d, J ) 2.5 Hz, 1H),
5.83 (d, J ) 1.5 Hz, 1H), 5.79 (s, 1H), 4.53 (d, J ) 5.5 Hz, 1H),
4.21 (s, 2H), 4.06 (t, J ) 5.5 Hz, 1H); 13C NMR (D2O, 125 MHz)
δ 163.99, 148.76, 131.90, 124.93, 78.71, 72.81, 65.60, 58.56, 48.80;
Anal. (C10H14N3O4‚1.0HCl‚0.30H2O) C, H, N.
4-Azido-2,2-dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-
cyclopenta[1,3]dioxole (18). To a solution of (+)-12a (0.35 g, 0.82
mmol) in 20 mL of anhydrous CH2Cl2 were added MsCl (0.15 mL,
1.64 mmol) and Et3N (0.40 mL, 2.86 mmol) at 0 °C under N2
atmosphere. After the mixture was stirred for 1 h at 0 °C, the
reaction mixture was poured into 50 mL of water-CH2Cl2 (1:5
v/v) solution. The organic layer was separated and washed with
brine (10 mL × 2) and dried over MgSO4. The solution was
concentrated and the residue was purified on a short silica gel pad.
To the crude product (0.42 g, 0.82 mmol) were directly added 15
mL of anhydrous DMF and NaN3 (0.44 g, 6.70 mmol) at room
temperature under N2 atmosphere; then the mixture was stirred for
24 h at 80 °C. The reaction mixture was poured into 100 mL of
iced ether-water (5: 1 v/v) and then the organic layer was separated
and the aqueous layer was washed with ether (25 mL × 2). The
collected organic layer was washed with brine (20 mL × 2), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane/
EtOAc ) 10:1 v/v) to give compound 18 (0.34 g, 0.76 mmol) in
1-(4,5-Dihydroxy-3-hydroxymethylcyclopenten-2-enyl)-1H-
1,2,4-triazole-3-carboxylic Acid Amide (17a). A solution of
compound 16a (0.20 g, 0.38 mmol) in 5.0 mL of MeOH was treated
with 20 mL of 1.0 M HCl in ether solution at 0 °C. The acidic
solution was allowed to stir for 2 h at room temperature. The
solvents and hydrogen chloride were evaporated under reduced
pressure, and then the residue was purified by reverse silica gel
column chromatography (distilled water) to give compound 17a
(0.08 g, 0.35 mmol) in 88% yield: mp 177-179 °C; UV (H2O)
λmax 225.0 (ꢀ 10 203, pH 11), 204.0 (ꢀ 8587, pH 7), 199 (ꢀ 9959,
26
1
pH 2); [R]D -146.93 (c 1.00, CH3OH); H NMR (CD3OD, 500
MHz) δ 8.13 (s, 1H), 6.44 (d, J ) 2.5 Hz, 1H), 5.81 (dd, J ) 8.5
and 2.5 Hz, 1H), 4.64 (d, J ) 5.5 Hz, 1H), 4.46 (dd, J ) 8.5 and
5.5 Hz, 1H), 4.30 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 158.93,
148.98, 148.81, 146.85, 124.70, 77.27, 72.87, 69.69, 58.89. Anal.
(C9H12N4O4‚0.25H2O) C, H, N.
1
92% yield. H NMR (CDCl3, 500 MHz) δ 7.46 (m, 6H), 7.44-
7.22 (m, 9H), 6.01 (d, J ) 1.5 Hz, 1H), 5.04 (d, J ) 5.5 Hz, 1H),
4.58 (d, J ) 5.5 Hz, 1H), 4.42 (s, 1H), 3.87 (td, J ) 1.5 and 15.0
Hz, 1H), 3.74 (d, J ) 15.0 Hz, 1H), 1.33 (s, 3H), 1.30 (s, 3H); 13
C
1-(2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-yl)-1H-imidazole-4-carboxylic Acid Methyl Ester
(15b). Compound 15b (0.39 g, 0.70 mmol) was synthesized in
quantitative yield from (+)-12a (0.30 g, 0.70 mmol) and methyl
imidazole-4-carboxylate (0.15 g, 1.05 mmol) by following the same
NMR (CDCl3, 125 MHz) δ 149.01, 143.84, 128.60, 127.98, 127.21,
122.70, 112.14, 87.21, 84.06, 83.83, 69.99, 61.29, 27.49, 26.22;
IR (neat, cm-1) 3072, 2988, 2097, 1265, 1082, 735, 701.
1-(2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-yl)-1H-1,2,3-triazole-4-carboxylic Acid Methyl Es-
ter (15c). To a solution of compound 18 (0.18 g, 0.40 mmol) in
10 mL of THF were added CuI (0.76 g, 4.0 mmol), methyl
propiolate (0.14 g, 1.60 mmol), and Et3N (1.22 g, 12.0 mmol) at
room temperature under N2 atmosphere, and then the mixture was
stirred for 12 h. The suspension was adsorbed on silica gel and
then purified by silica gel column chromatography (hexane/EtOAc
) 10:1 to 1:2 v/v) to give compound 15c (0.21 g, 0.39 mmol) in
1
procedure as for compound 15a. H NMR (CDCl3, 500 MHz) δ
7.81 (s, 1H), 7.47 (m, 6H), 7.33-7.24 (m, 9H), 6.05 (s, 1H) 5.23
(s, 1H), 5.11 (d, J ) 5.0 Hz, 1H), 4.53 (t, J ) 5.0 Hz, 1H), 4.03
(d, J ) 15.0 Hz, 1H), 3.90 (s, 3H), 3.83 (d, J ) 15.0 Hz, 1H), 1.41
(s, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 160.75,
153.57, 150.51, 143.72, 138.61, 128.55, 127.98, 127.25, 122.02,
112.49, 87.26, 85.33, 83.66, 71.82, 66.29, 61.23, 51.78, 27.60,
26.33.
1
98% yield. H NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.46 (m,
1-(2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-yl)-1H-imidazole-4-carboxylic Acid Amide (16b).
The crude compound 15b (0.39 g, 0.70 mmol) was dissolved in
10.0 mL of saturated methanolic ammonia at 0 °C, and then the
solution was allowed to stir for 24 h at 100 °C. The solvent and
ammonia were evaporated under reduced pressure, and the residue
was purified by silica gel column chromatography (hexane/EtOAc
) 1:1 v/v to EtOAc) to give compound 16b (0.33 g, 0.63 mmol)
6H), 7.33-7.22 (m, 9H), 6.06 (s, 1H) 5.74 (s, 1H), 5.17 (d, J )
6.0 Hz, 1H), 4.71 (d, J ) 6.0 Hz, 1H), 4.03 (d, J ) 16.0 Hz, 1H),
3.98 (s, 3H), 3.83 (d, J ) 16.0 Hz, 1H), 1.42 (s, 3H), 1.31 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 161.14, 151.22, 143.65, 140.04,
128.55, 128.02, 127.31, 126.39, 121.19, 112.94, 87.39, 84.43, 83.79,
70.42, 61.33, 52.33, 27.45, 26.08.
1-(2,2-Dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta-
[1,3]dioxol-4-yl)-1H-1,2,3-triazole-4-carboxylic Acid Amide (16c).
A solution of compound 15c (0.19 g, 0.36 mmol) in 40 mL of
MeOH was bubbled with NH3 gas at 0 °C for 30 min, and then the
solution was allowed to stir for 24 h at room temperature. The
solvent and NH3 were removed under reduced pressure. The solvent
was removed under reduced pressure for 24 h at room temperature
1
in 90% yield from (+)-12a. H NMR (CDCl3, 500 MHz) δ 7.87
(s, 1H), 7.44 (m, 6H), 7.30-7.21 (m, 9H), 6.69 (s, 1H), 6.06 (d, J
) 2.0 Hz, 1H), 5.87 (br s, 2H), 5.27 (d, J ) 5.5 Hz, 1H), 4.87 (d,
J ) 5.5 Hz, 1H), 3.96 (dt, J ) 15.5 and 2.0 Hz, 1H), 3.73 (d, J )
15.5 Hz, 1H), 1.42 (s, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 125

AntiViral Cyclopentenyl Carbocyclic Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1147
cally Active Butenolide. J. Org. Chem. 2000, 65, 4200-4203. (c)
Wolfe, M. S.; Lee, Y.; Bartlett, W. J.; Borcherding, D. R.; Borchardt,
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S.; Minakawa, N.; Niizuma, S.; Kim, H.-S.; Wataya, Y.; Matsuda,
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Antimalarial Effect of (6′R)-6′-C-Methylneplanocin A, a Potent
AdoHcy Hydrolase Inhibitor. J. Med. Chem. 2002, 45, 748-751 and
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S-Adenosylhomocysteine Hydrolase. J. Med. Chem. 2003, 46, 201-
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L-Cyclopentenyl Nucleosides and Their Antiviral Activity Against
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Against Orthopox Viruses (Smallpox, Monkepox and Cowpox)
Bioorg. Med. Chem. Lett. 2003, 13, 9-12.
to give the product 16c in quantitative yield (0.19 g, 0.36 mmol).
1H NMR (CDCl3, 500 MHz) δ 8.06 (s, 1H), 7.45 (m, 6H), 7.32-
7.21 (m, 9H), 7.19 (d, J ) 2.0 Hz, 1H), 6.21 (d, J ) 2.0 Hz, 1H),
6.07 (d, J ) 1.5 Hz, 1H), 5.74 (s, 1H), 5.18 (d, J ) 5.5 Hz, 1H),
4.71 (d, J ) 5.5 Hz, 1H), 4.16 (dt, J ) 16.0 and 1.5 Hz, 1H), 3.81
(d, J ) 16.0 Hz, 1H), 1.41 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 162.15, 151.12, 143.65, 142.83, 128.55, 128.02,
127.30, 124.78, 121.27, 112.89, 87.33, 84.43, 83.84, 70.37, 61.28,
27.46, 26.13.
1-(4,5-Dihydroxy-3-hydroxymethylcyclopenten-2-enyl)-1H-
1,2,3triazole-4-carboxylic Acid Amide (17c). Compound 17c was
prepared in 88% yield (0.08 g, 0.33 mmol) from 16c (0.20 g, 0.38
mmol) following the same procedure as for compound 17a: mp
178-180 °C; UV (H2O) λmax 222.0 (ꢀ 7041, pH 11), 204.0 (ꢀ 6463,
pH 7), 199 (ꢀ 10 503, pH 2); [R]D25 -127.56 (c ) 1.0, MeOH); 1H
NMR (CD3OD, 500 MHz) δ 8.46 (s, 1H), 5.95 (s, 1H), 5.61 (s,
1H), 5.52 (s, 1H), 4.63 (d, J ) 5.5 Hz, 1H), 4.30 (m, 3H); 13C
NMR (CD3OD, 125 MHz) δ 150.63, 125.35, 123.39, 78.24, 73.02,
58.95, 53.86, 48.68; Anal. (C9H12N4O4‚0.3H2O) C, H, N.
Acknowledgment. This research was supported by U.S.
Public Health Service Grants UO19 AI056540 (C.K.C.) and by
Contracts NO1-AI-30048 (R.W.S.) and NO1-AI-30049 (E.R.K.)
from the National Institute of Allergy and Infectious Diseases,
NIH. The orthopoxvirus assays were performed by Kathy Keith,
University of Alabama at Birmingham.
Supporting Information Available: Elemental analysis data
for compounds 7a, 16a, and 17a-c and high-resolution mass
spectral (HRMS-ES) data for compounds 6a-12a, 12b, 6b-11b,
14, 15a-17a, 15b-17b, 15c, and 16c. This material is available
free of charge via the Internet at http://pubs.acs.org.
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