Practical Synthesis of D- and L-2-Cyclopentenone and their Utility for the Synthesis of Carbocyclic Antiviral Nucleosides against Orthopox Viruses (Smallpox, Monkeypox, and Cowpox Virus)

Article abstract of DOI:10.1021/jo034999v

Highly efficient and practical methodology for the syntheses of D- and L-4,5-O-isopropylidene-2-cyclopentenone (9 and 22), versatile intermediates for the synthesis of carbocyclic nucleosides, have been developed via a ring-closing metathesis reaction from D-ribose in eight steps. The utility of D- and L-4,5-O-isopropylidene-2-cyclopentenone is demonstrated by their application for the preparation of D-cyclopentyl-6-azauridine 12 and D-cyclopentenyl-5-halocytosine nucleosides (33-35) using Mitsunobu reaction to introduce pyrimidine bases as potential antiviral agents. Preliminary antiviral activity against orthopox viruses (smallpox, monkeypox, and cowpox virus) of the synthesized nucleosides are described.

Full text of DOI:10.1021/jo034999v

P r a ctica l Syn th esis of D- a n d L-2-Cyclop en ten on e a n d Th eir Utility
for th e Syn th esis of Ca r bocyclic An tivir a l Nu cleosid es a ga in st
Or th op ox Vir u ses (Sm a llp ox, Mon k eyp ox, a n d Cow p ox Vir u s)
Yun H. J in,† Peng Liu,† J ianing Wang,† Robert Baker,‡ J ohn Huggins,‡ and Chung K. Chu*,†
The University of Georgia, College of Pharmacy, Athens, Georgia 30602, and US Army Medical Research
Institute of Infectious Diseases, Frederick, Maryland 21702
dchu@rx.uga.edu
Received J uly 11, 2003
Highly efficient and practical methodology for the syntheses of D- and L-4,5-O-isopropylidene-2-
cyclopentenone (9 and 22), versatile intermediates for the synthesis of carbocyclic nucleosides, have
been developed via a ring-closing metathesis reaction from D-ribose in eight steps. The utility of
D- and L-4,5-O-isopropylidene-2-cyclopentenone is demonstrated by their application for the prep-
aration of D-cyclopentyl-6-azauridine 12 and D-cyclopentenyl-5-halocytosine nucleosides (33-35)
using Mitsunobu reaction to introduce pyrimidine bases as potential antiviral agents. Preliminary
antiviral activity against orthopox viruses (smallpox, monkeypox, and cowpox virus) of the
synthesized nucleosides are described.
In tr od u ction
Previously, the synthesis of enantiomerically pure D-
and L-aristeromycin4 and neplanocin A5 have been de-
veloped in our laboratory.6 However, the overall avail-
ability of optically active carbocyclic nucleosides has been
limited due to the lack of a methodology for a preparative-
scale preparation of the key intermediate such as D-2-
cyclopentenone. D- and L-2-cyclopentenone (9 and 22)
have been previously prepared from D-ribose,7 D-lyxose,8
and D-isoascorbic acid9 with low and inconsistent yields.
Therefore, efficient and practical synthetic methodologies
for optically pure D- and L-2-cyclopentenone are highly
desirable. Recently, we reported preliminary results of
an efficient and practical synthetic methodology of D- and
L-2-cyclopentenone10 as well as antiviral activities of
several cyclopentenyl nucleosides as a communication.3b
Among the synthesized nucleosides, adenine, cytosine,
and 5-fluorocytosine analogues were found to be active
against HIV, West Nile virus, and orthopox viruses
including smallpox virus.3 Additionally, Morrey et al.
reported that 6-azauridine was found to be a potent
antiviral agent against West Nile virus.11 Therefore,
herein we report the full accounts of further improved
Nucleosides have played a major role in the treatment
of viral infectious diseases such as human immunodefi-
ciency virus, hepatitis B virus, and various herpes viruses
infections. Recently, much attention has been focused on
carbocyclic nucleosides, as a synthetic carbocyclic nucleo-
side such as abacavir1 has been approved by the Food
and Drug Administration as an anti-HIV agent. A car-
bocyclic nucleoside with an exocyclic double bond, ente-
cavir,2 is also currently undergoing phase III clinical
trials for the treatment of chronic hepatitis B virus
infection (Figure 1). Furthermore, carbocyclic nucleosides
have recently been reported as antiviral agents against
smallpox and monkeypox virus as well as West Nile
virus,3 which are related to bioterrorism-related organ-
isms, and therapeutic agents against these organisms are
critically needed as part of national biodefense strategies.
In view of these interesting antiviral activities demon-
strated by the carbocyclic nucleosides, an efficient pre-
parative synthetic methodology for key intermediates is
needed for additional exploration of this important class
of compounds.
(4) Kusaka, T.; Yamamoto, H.; Muroi, M.; Kishi, T.; Mizuno, K. J .
Antibiot. 1968, 21, 255.
(5) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hatashi, M.;
Otani, M. J . Antibiot. 1981, 34, 359.
(6) (a) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J .; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J . Med. Chem. 2001, 44, 3958. (b) Wang,
P.; Gullen, B.; Newton, M. G.; Cheng, Y. C.; Schinazi, R. F.; Chu, C.
K. J . Med. Chem. 1999, 42, 3390. (c) Wang, P.; Newton, M. G.; Chu,
C. K. J . Org. Chem. 1999, 64, 4173.
(7) Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J . Org. Chem.
1987, 52, 5457.
(8) Ali, S. M.; Ramesh, K.; Borchardt. R. T. Tetrahedron Lett. 1990,
31, 1509.
(9) Choi, W. J .; Park, J . G.; Yoo, S. J .; Kim, H. O.; Moon, H. R.;
Chun, M. W.; J ung, Y. H.; J eong, L. S. J . Org. Chem. 2001, 61, 6490.
(10) J in, Y. H.; Chu, C. K. Tetrahedron Lett. 2002, 43, 4141-4143.
(11) Morrey, J . D.; Smee, D. F.; Sidwell, R. W.; Tseng, C. Antiviral
Res. 2002, 55, 107.
† The University of Georgia.
‡ US Army Medical Research Institute of Infectious Diseases.
(1) (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St.
Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J . E.;
Dornsife, R. E.; Averett, D. R.; Krenitsky, T. A. Antimicrob. Agents
Chemother. 1997, 41, 1082. (b) Weller, S.; Radomski, K. M.; Lou, Y.;
Stein, D. S. Antimicrob. Agents Chemother. 2000, 44, 2052.
(2) (a) Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.;
Zahler, R.; Colonno, R. J . Antimicrob. Agents Chemother. 1997, 41,
1444. (b) Levine, S.; Hernandez, D.; Yamanaka, G.; Zhang, S.; Rose,
R.; Weinheimer, S.; Colonno, R. J . Antimicrob. Agents Chemother. 2002,
46, 2525-32.
(3) (a) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J .; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J . Med. Chem. 2001, 44, 3958. (b) Chu, C.
K.; J in, Y. H.; Baker, R. O. Huggins. Bioorg. Med. Chem. Lett. 2003,
13, 9.
10.1021/jo034999v CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003
9012
J . Org. Chem. 2003, 68, 9012-9018

Practical Synthesis of D- and L-2-Cyclopentenone
F IGURE 1. Biologically active carbocyclic nucleosides.
SCHEME 1. Syn th esis of d -2-Cyclop en ten on e a n d D-Cyclop en tyl-6-a za u r id in ea
a
Reagents and conditions: (a) 2,2-dimethoxypropane, p-toluenesulfonic acid, acetone, 0 °C to rt, 1 h; (b) TBDMSCl, imidazole, CH2Cl2,
rt, 1 h; (c) vinylmagnesium bromide, anhydrous THF, -78 °C to rt, 1 h; (d) TBAF, THF, rt, 1 h; (e) NaIO4, H2O, rt,1 h; (f) NaH, DMSO,
methyltriphenylphosphonium bromide, THF, 0 °C to reflux, 3 h; (g) Grubbs’ catalyst, anhydrous CH2Cl2, 24 °C, 4 h; (h) pyridinium
dichromate, 4 Å molecular sieves, AcOH, CH2Cl2, rt, 12 h; (i) 6-azauracil, PPh3, DIAD, -78 °C to rt, 3 days; (j) 6 N HCl, MeOH, rt, 12 h.
preparative-scale synthesis for the D- and L-2-cyclopen-
tenone (9 and 22) over the previously reported method3b,10
as well as additional exploration of carbocyclic 5-halocy-
clopentenylpyrimidines and the 6-carbocyclic azauridine
derivative as potential antiviral agents.
with 1 mol % Grubbs’ catalyst for 24 h, the reaction was
completed within 4 h at 25 °C with the same amounts of
catalyst. However, since the ring-closed cyclopentenol 8
was highly volatile, the desired key intermediate D-2-
cyclopentenone 9 was directly obtained by oxidation of
the secondary alcohol under PDC oxidation conditions
without isolation of the cyclopentenol 8 in 54% overall
yield from D-ribose. D-2-Cyclopentenone 9 can also be
obtained from D-ribonolactone using the intramolecular
Horner-Emmons reaction7 as well as from D-isoascorbic
acid using the ring-closing metathesis reaction.9 How-
ever, these synthetic methods are problematic for a large-
scale preparation due to extreme sensitivity to the
reaction conditions as well as difficulties in controlling
stereoselective oxidation and reduction steps, which lower
the overall yields. In our synthetic methodology, most
reaction conditions are mild and give excellent yields for
the D-2-cyclopentenone 9 up to 10 g scale.
An efficient preparative methodology in hand, it was
of interest to synthesize cyclopentyl-6-azauridine, in
which D-2-cyclopentenone 9 was converted to an ad-
ditional product 10 by our previously reported method.6
As observed previously,12 Mitsunobu reaction of pyrim-
idines is more difficult and problematic than that of
purines, both in terms of protecting group strategies as
well as N- vs O-alkylation. However, upon introduction
of the third nitrogen into the pyrimidine ring, the acidity
of its adjacent N1 atom is greatly increased and thus
Resu lts a n d Discu ssion
D-Ribose 1 was converted to the isopropylidene-
protected derivative 2 with 2,2-dimethoxypropane in the
presence of a catalytic amount of p-toluenesulfonic acid
in 90% yield, followed by silylation of primarily the
hydroxyl group using tert-butyldimethylsilyl chloride to
give lactol 3 in 85% yield (Scheme 1). Compound 3 was
reacted with vinylmagnesium bromide to obtain a ring-
opened olefin 4 in quantitative yield as a single stereo-
isomer. The stereoselectivity is probably due to the steric
as well as the electronic effect of the isopropylidene group,
which prevents the coordination of vinylmagnesium
bromide at the R site. To introduce another olefinic
moiety, deprotection of the silyl group was accomplished
by using a 1 M solution of TBAF in THF followed by an
oxidative cleavage of the vicinal diol with sodium perio-
date to give a lactol 6 in 92% yield. The lactol 6 was
subjected to the Wittig reaction using NaH, DMSO, and
methyltriphenylphosphonium bromide to give a diene 7
in 86% yield.9 The ring-closing metathesis reaction was
carried out using Grubbs’ catalyst to obtain D-cyclopen-
tenol 8. It was found that the metathesis reaction was
affected by the reaction temperature. Although the diene
7 was converted to ring-closed cyclopentenol 8 at 17 °C
(12) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
J . Org. Chem, Vol. 68, No. 23, 2003 9013

J in et al.
SCHEME 2. Syn th esis of l-2-Cyclop en ten on e a n d D-Cyclop en ten yl Nu cleosid esa
a
Reagents and conditions: (a) NaH, DMSO, methyltriphenylphosphonium bromide, THF, 0 °C to reflux, 3 h; (b) dicyclohexyl carbodiimide,
DMSO, pyridine, trifluoroacetic acid, toluene, rt, 4 h; (c) vinylmagnesium bromide, anhydrous THF, -78 °C to rt, 1 h; (d) 5% Grubbs’
catalyst, anhydrous CH2Cl2, reflux, 24 h; (e) TBAF, THF, rt, 1 h; (f) NaIO4, H2O, rt, 0.5 h; (g) (i) NaIO4, H2O/CH2Cl2 (1:2), 0 °C to rt, 0.5
h, (ii) NaBH4, CeCl3‚7H2O, MeOH, 0 °C, 0.5 h; (h) Grubbs’ catalyst, anhydrous CH2Cl2, 24 °C, 4 h and then pyridinium dichromate, 4 Å
molecular sieves, AcOH, CH2Cl2, rt, 12 h; (i) PPh3, DEAD, N3-benzoyl-5-chlorouracil (for 28), N3-benzoyl-5-bromouracil (for 29), N3-
benzoyl-5-iodouracil (for 30), rt, 17 h; (j) saturated NH3 in MeOH, 0 °C, 4 h; (k) 2,4,6-triisopropylbenzenesulfonyl chloride, DMAP, Et3N,
MeCN, 0 °C to rt, 24 h then 30% NH4OH, rt, 5 h; (l) CF3CO2H/H2O (2:1), 50 °C, 3 h.
favorable to the regioselective N1-substitution with re-
spect to the N3- or O-alkylation. This allows us to con-
dense 6-azauracil with 10 to obtain the desired nucleoside
12 under the Mitsunobu conditions. The major problem
in direct coupling of the sugar moiety 10 with 6-azauracil
would be to discriminate N1, N3, and O-substituted
products. We found that the best method for distinguish-
ing these structures was 13C NMR spectra. In the 13C
NMR spectrum of the carbocyclic 6-azauridine derivative
12, C-1′ appeared at 57.39 (in MeOH-d4), which was
assigned to be the N-substituted rather than O-substi-
tuted product. It is noteworthy to mention that the
chemical shift of the C-1′ resonance signal in the 13C
NMR spectrum (in DMSO-d6) of 1-(2,3-dihydroxypropyl)-
6-azauracil is at 53.63 ppm,13 and the chemical shift
of C-1′ resonance signal in the 13C NMR (in CDCl3) of
O- alkylated derivatives of uracil and thymine are >67
ppm.14 Evidence for the regioselectivity of N1- instead of
N3-substituted compound was provided by the compari-
son of 13C NMR data of compound 12 with that of
6-azauridine. The heterocyclic base peaks of 12 (157.4,
149.8, and 135.1 ppm) were similar to those of 6-aza-
uridine (158.5, 149.5, and 137.3 ppm),15 clearly indicating
that it was the N1-substituted compound. Furthermore,
the UV spectrum of 12 (257.5 nm in pH 7) was similar
to that of 6-azauridine (253 nm in pH 9).16 The antiviral
activity of synthesized â-D-cyclopentyl-6-azauridine 12
was evaluated against West Nile virus, but it did not
show any significant antiviral activity against this virus.
To develop an efficient preparative synthetic method
for L-2-cyclopentenone 22, the protected D-ribose 3 was
converted to an olefin 13 by the Wittig reaction using
NaH, DMSO, and methyltriphenylphosphonium bromide
in refluxing THF in 91% yield (Scheme 2). The oxidation
of the secondary hydroxyl group of 13 was highly affected
by the oxidation conditions.
Oxidation with pyridinium chlorochromate as an oxi-
dizing agent provided ketone 14 in 53% yield. Although
Swern oxidation with DMSO, oxalyl chloride, and tri-
ethylamine in dichloromethane gave ketone 14 in 70%
yield, the yield was dramatically decreased to 15% in the
large scale (10 g scale). However, a milder oxidation
condition, Moffatt oxidation with dicyclohexyl carbodi-
imide, DMSO, pyridine, and trifluoroacetic acid in tolu-
ene, was successfully carried out to obtain ketone 14 in
(13) Tzeng, C.; Hwang, L.; Chen, C.; Wei, D. Nucleosides Nucleotides
1995, 14, 1425.
(14) Frieden, M.; Giraud, M.; Reese, C. B.; Song, Q. J . Chem. Soc.,
Perkin Trans. 1 1998, 2827.
(15) Harry-O’kuru, R. E.; Smith, J . M.; Wolfe, M. S. J . Org. Chem.
1997, 62, 1754.
(16) Lismane, A.; Muiznieks, I.; Vitols, M.; Cihak, A.; Skoda, J .
Collect. Czech. Chem. Commun. 1977, 42, 2586.
9014 J . Org. Chem., Vol. 68, No. 23, 2003

Practical Synthesis of D- and L-2-Cyclopentenone
virus, anti-smallpox virus, and anti-vaccinia virus activ-
ities. â-D-Cyclopentenyl-5-chlorocytidine 33 exhibited
moderate anti-smallpox virus and anti-cowpox virus
activities. However, â-D-cyclopentenyl-5-bromocytidine 34
did not display any significant antiviral activity against
orthopox viruses.
In summary, we have developed an efficient and
practical synthetic method for D- and L-2-cyclopentenone
(9 and 22) as key intermediates for the synthesis of
various carbocyclic nucleosides in a preparative scale
(>10 g scale). From these intermediates we synthesized
enantimerically pure D-cyclopentyl-6-azauridine and sev-
eral D-cyclopentenyl-5-halo-cytidine nucleosides, which
demonstrated interesting anti-orthopox virus activity.
F IGURE 2. NOE relationships of 16 and 17.
75% yield in a 30 g scale. A Grignard reaction was then
performed on 14 to introduce another olefin with vinyl-
magnesium bromide in anhydrous THF to give an insep-
arable diastereomeric mixture of dienes 15 in 80% yield.
The diene 15 was converted to a cyclopentene moiety by
ring-closing metathesis reaction using 5% Grubbs cata-
lyst at refluxing condition in anhydrous CH2Cl2 as a
separable diastereomeric mixture of R and â cyclopen-
tanol 16 and 17 (16/17 ratio ) 1/10) in 88% yield. The R
and â isomers were assigned by 1H NMR and NOE
spectroscopy (Figure 2). We investigated the reaction
with several other protecting groups to improve the ratio
(16/17) without success.
Exp er im en ta l Section
(4R,5S)-(+)-1-[4-[2-(ter t-Bu t yld im et h ylsilyloxy)-1-h y-
d r oxyeth yl]-2,2-d im eth yl-1,3-d ioxola n -5-yl]-(S)-2-p r op en -
1-ol (4). A solution of 3 (91 g 0.30 mol) in dry tetrahydrofuran
(1000 mL) was cooled to -78 °C, and vinylmagnesium bromide
(1 M solution in tetrahydrofuran, 890 mL, 0.89 mol) was added
dropwise at -60 °C. After addition was completed, the reaction
mixture was allowed to stir at room temperature for 1 h. Upon
recooling the resulting clear brown mixture to -78 °C,
saturated NH4Cl solution (1000 mL) was added dropwise to
quench and the resulting solution was extracted with EtOAc
(1500 mL). The organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (EtOAc/
Removal of the primary hydroxyl protecting group
using 1 M solution of TBAF in THF gave diols 18 and
19. Oxidative cleavage with sodium periodate afforded
the L-2-cylopentenone 22 in 95% yield which served as
the key intermediate for D-cyclopentenyl nucleosides.
However, the ring-closing metathesis reaction for the
synthesis of L-2-cyclopentenone 22 required harsh condi-
tions in comparison to that of D-2-cycloentenone 9, which
might be due to the steric hindrance of the quaternary
carbon adjacent to the vinyl group. An alternative route
was developed to generate a diene alcohol 21 which was
efficiently converted to the L-2-cycloentenone 22. Depro-
tection of the silyl group using TBAF gave diol 20 in 95%
yield. Oxidative cleavage of the vicinal diol using sodium
periodate followed by reduction of ketone using sodium
borohydride and cerium(III) chloride heptahydrate pro-
vided alcohol 21 in 98% yield. The L-2-cyclopentenone 22
was obtained from 21 by the same procedure for D-2-
cyclopentenone 9, giving 34% overall yield from D-ribose.
D-Cyclopentenyl alcohol 23 was synthesized by the pre-
viously reported method from L-2-cycloentenone 22.6a
Coupling of 23 with the appropriate protected 5-halou-
racils was accomplished under the standard Mitsunobu
coupling conditions using N3-benzoyl-5-halouracils, DEAD,
and Ph3P in THF followed by removal of the benzoyl
group using saturated methanolic ammonia. The conver-
sion of uracil analogues to cytosine analogues was carried
out by the treatment of 2,4,6-triisopropylbenzenesulfonyl
chloride, DMAP, and NEt3 in CH3CN to give 30-32 in
65-90% yield. Deprotection of tert-butyl and isopro-
pylidene groups was carried out with CF3COOH/H2O
(2:1,v/v) solution at 50-60 °C to give â-D-cyclopetenyl-
5-halocytosine nucleosides 33-35 in 58-75% yield.
The anti-orthopox virus activities of the synthesized
â-D-cyclopetenyl-5-halocytosine nucleosides were evalu-
ated, and the results are summarized in Table 1. â-D-
Cyclopetenyl cytosine nucleoside 36, which was previ-
ously synthesized in our laboratory, has been shown to
have significant anti-orthopox virus activities.3b
hexane ) 1:20), giving compound 4 (94 g, 96%) as a colorless
1
oil: [R]23 +6.86 (C 0.59, CHCl3); H NMR (400 MHz, CDCl3)
D
δ 6.02 (m, 2H), 5.43 (d, J ) 17.2 Hz, 1H), 5.26 (d, J ) 10.4 Hz,
1H), 4.35 (bs, OH, D2O exchangeable, 1H), 4.31 (bs, 1H), 4.07
(m, 2H), 3.86 (m, 2H), 3.65 (dd, J ) 6.7 and 9.9 Hz, 1H), 3.36
(bs, OH, D2O exchangeable, 1H), 1.39 (s, 3H), 1.32 (s, 3H), 0.91
(s, 9H), 0.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 137.3, 115.9,
108.6, 80.6, 76.5, 69.6, 69.2, 64.1, 27.9, 25.7, 25.3, -5.5. Anal.
Calcd for C16H32O5Si: C, 57.79; H, 9.70. Found: C, 58.13; H,
9.80.
(4R,5S)-(-)-1-[4-(1,2-Dih yd r oxyeth yl)-2,2-d im eth yl-1,3-
d ioxola n -5-yl]-(S)-2-p r op en -1-ol (5). Tetrabutylammonium
fluoride (1 M solution in tetrahydrofuran, 333 mL, 333 mmol)
was added to a solution of 4 (107 g, 322 mmol) in tetrahydro-
furan (1000 mL) and stirred at room temperature for 1 h. The
resulting brown mixture was concentrated in vacuo, and the
residue was purified by column chromatography on a silica
gel (EtOAc/hexane ) 2:1), giving compound 5 (66 g, 95%) as a
white crystal: mp 72.4-73.9 °C; [R]23D -31.33 (c 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 6.03 (m, 1H), 5.40 (dd, J ) 0.8,
17.2 Hz, 1H), 5.31 (dd, J ) 0.8, 10.5 Hz, 1H), 4.34 (t, J ) 8.1
Hz, 1H), 4.16 (dd, J ) 5.4, 9.4 Hz, 1H), 4.06 (dd, J ) 5.4, 9.2
Hz, 1H), 3.95-3.87 (m, 1H D2O exchangeable, 3H), 2.15 (bs,
OH, D2O exchangeable, 1H), 1.40 (s, 3H), 1.34(s, 3H); 13C NMR
(100 MHz, CDCl3) δ 137.6, 117.1, 80.0, 77.8, 69.3, 64.6, 28.0,
25.4. Anal. Calcd for C10H18O5‚0.03 hexane: C, 55.37; H, 8.41.
Found: C, 55.60; H, 8.31.
(1S,2S,3S)-2,2-Dim eth yl-6-vin yltetr a h yd r ofu r o[3,4-d ]-
1,3-d ioxol-4-ol (6). A solution of triol 5 (38.9 g, 178.2 mmol)
in H2O (400 mL) was cooled to 0 °C, and NaIO4 (57.2 g, 26.7
mmol) was added portionwise. After being stirred at room
temperature for 1 h, the reaction mixture was extracted with
EtOAc (500 mL × 3), and the extracts were dried over MgSO4,
filtered, and concentrated to dryness under reduced pressure.
The residue was purified by silica gel column chromatography
(EtOAc/hexane ) 1:10), giving compound 6 (32.4 g, 97%) as a
colorless oil: 1H NMR spectral data were identical to the
literature;9 13C NMR (100 MHz, CDCl3) δ 137.9, 134.4, 117.3,
117.0, 114.3, 112.5, 103.0, 102.9, 96.2, 88.5, 86.6, 84.7, 80.5,
79.0, 26.4, 26.2, 25.0. Anal. Calcd for C9H14O4: C, 58.05 H,
7.58. Found: C, 58.38; H, 7.74.
It was found that â-D-cyclopentenyl-5-iodocytidine 35
showed significant anti-monkeypox virus, anti-cowpox
J . Org. Chem, Vol. 68, No. 23, 2003 9015

J in et al.
TABLE 1. An ti-or th op ox Vir u s Activity of â-D-Cyclop en ten yl-5-h a locytosin e Nu cleosid esa
a
VAR-BSH (variola major strain Bangladesh 1975); VAR-7124 (variola major strain 7124); MPX (monkeypox strain Zaire); CPX (cowpox
strain Brighton); VAC (vaccinia strain Copenhagen). ND: not determined.
(1S,2S,3R)-(-)-1-(2,2-Dim et h yl-5-vin yl-1,3-d ioxola n -4-
yl)-(S)-2-p r op en -1-ol (7). A suspension of NaH (9.9 g, 0.248
mol, 60% dispersion in mineral oil) in tetrahydrofuran (1000
mL) was cooled to 0 °C, and then DMSO (29.3 mL, 0.413 mol)
was added. After being stirred at room temperature for 0.5 h,
the resulting white suspension mixture was cooled to 0 °C and
treated with methyltriphenylphosphonium bromide (88.6 g,
0.248 mol). The reaction mixture was stirred at room temper-
ature for 1 h and then recooled to 0 °C. A solution of lactol 6
(30.8 g, 0.165 mol) in tetrahydrofuran (300 mL) was added to
the resulting reaction mixture at 0 °C. After being heated at
reflux for 3 h, the reaction mixture was cooled to room
temperature. Diethyl ether (1000 mL) was added to the
reaction mixture and washed with H2O (500 mL) and brine
(500 mL). The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by silica
gel column chromatography (EtOAc/hexane ) 1:10), giving
compound 7 (26.2 g, 86%) as a colorless oil. All the spectral
data were identical to the literature.9
mmol) and alcohol 10 (245 mg, 1.0 mmol) were dried in vacuo
for 3 h at 50 °C. Anhydrous THF (10 mL) was added and the
mixture cooled to -78 °C. DIAD (0.5 mL, 2.5 mmol) was added
dropwise to a solution of triphenylphosphine (660 mg, 2.5
mmol) in THF (15 mL) at 0 °C. The DIAD and Ph3P complex
was stirred for 10 min before being added to the mixture of
6-azauracil and cyclopentanol 10 at -78 °C. The reaction
mixture was stirred at the same temperature for 1 h and
allowed to reach room temperature. After being stirred for 3
days at room temperature, the clear amber solution was
concentrated in vacuo and the residue was purified by column
chromatography on a silica gel (EtOAc/hexane ) 1:10), giving
compound 11 which was contaminated by reduced DIAD and
used in the next reaction without further purification. The
crude compound 11 was dissolved in methanol (5 mL) and then
added dropwise by 6 N hydrochloric acid (5 mL). After being
stirred for 12 h at room temperature, the solvent was evapo-
rated under diminished pressure and the residue was purified
by column chromatography on a silica gel (CH2Cl2/MeOH )
20:1-10:1), giving carbocyclic 6-azauridine 12 (128 mg, 54%)
as a white solid: mp 278-279 °C; [R]23D -3.26 (c 0.61, MeOH);
UV (H2O) λmax 257.5 nm (3,459, pH 2), 257.5 nm (4,548, pH
7), 300 nm (3,110, pH 11); 1H NMR (CD3OD, 500 MHz) δ 7.34
(s, 1H), 5.14-5.09 (m, 1H), 4.58 (t, J ) 6.0 Hz, 1H), 4.04 (t, J
) 6.0 Hz, 1H), 3.74-3.71 (m, 1H), 3.76-3.54 (m,1H), 2.15-
2.12 (m,1H), 2.04-1.99 (m,1H), 1.89-1.82 (m, 1H); 13C NMR
(CD3OD, 125 MHz) δ 157.4, 149.8, 135.1, 72.5, 72.1, 63.6, 57.4,
45.9, 25.6; MS (ESI) m/z 242 (M+ - 1), 266 (M+ + Na), 282
(M•+ + K). Anal. Calcd for C9H13N3O5: C, 44.44; H, 5.39; N,
17.28. Found: C, 44.56; H, 5.54; N, 17.18.
(4R,5R)-(-)-4,5-O-Isopr opyliden e-2-cyclopen ten on e (9).
To a 500 mL round-bottom flask filled with the Grubbs’
catalyst (670 mg, 1 mol %, flushed with N2 three times) was
added a solution of the diene 7 (15.1 g, 81.3 mmol) in
anhydrous CH2Cl2 (300 mL). After being stirred at 24 °C for 4
h, 4 Å molecular sieve (30 g), pyridinium dichromate (35.3 g,
162.1 mmol), and acetic acid (0.23 mL, 5 mol %) were added
to the resulting dark brown mixture. The reaction mixture was
stirred at the same temperature for 12 h and filtered over a
silica gel pad (∼15 cm) with EtOAc. The filtrate was concen-
trated in vacuo, and the residue was purified by column
chromatography on a silica gel (EtOAc/hexane ) 1:10), giving
compound 9 (11.4 g, 93%) as a white crystal: mp 68.5-70.3
(4R,5S)-(-)-1-(2,2-Dim eth yl-5-vin yl-1,3-d ioxola n -4-yl)-
2-(ter t-bu tyld im eth ylsilyloxy)-1(R)-eth a n -1-ol (13). Com-
pound 3 (62.1 g, 204 mmol) was converted to compound 13
(56.1 g, 91%) using the same procedure as for compound 7:
°C; [R]23 -69.3 (c 0.60, CHCl3) [lit.9 mp 68.6-70.1 °C; [R]D
D
-70.4 (c 0.92, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.61 (dd,
J ) 2.4, 6.0 Hz, 1H), 6.22 (d, J ) 6.0 Hz, 1H), 5.28 (dd, J )
2.4, 5.6 Hz, 1H), 4.47 (d, J ) 5.6 Hz, 1H), 1.42 (s, 3H), 1.41 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 134.6, 115.4, 78.6,
76.5, 27.4, 26.1. Anal. Calcd for C10 H10O3: C, 62,33; H, 6.54.
Found: C, 62.15; H, 6.52.
[R]23 -9.97 (c 0.39, MeOH); 1H NMR spectral data were
D
identical to the literature;17 13C NMR (100 MHz, CDCl3) δ
134.2, 117.6, 108.7, 78.8, 77.4, 69.6, 64.3, 27.8, 25.4, 18.3, -5.4,
(1′R,2′S,3′R,4′R)-1-[2,3-Dih d r oxy-4-(h yd r oxym eth yl)cy-
clop en t-1-yl]-6-a za u r a cil (12). 6-Azauracil (170 mg, 1.5
(17) RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P. J . J .
Am. Chem. Soc. 1988, 110, 7135.
9016 J . Org. Chem., Vol. 68, No. 23, 2003

Practical Synthesis of D- and L-2-Cyclopentenone
-5.5. Anal. Calcd for C15H29O4Si: C, 59.56; H, 10.00. Found:
as for compound 5. Compound 18: mp 103-104 °C; [R]23
D
1
C, 59.53; H, 10.04.
+104.12 (c 0.28, MeOH); H NMR (400 MHz, CDCl3) δ 5.96
(dd, J ) 1.6, 5.8 Hz, 1H), 5.64 (d, J ) 5.8 Hz, 1H), 5.25 (d, J
) 5.8 Hz, 1H), 4.49 (d, J ) 5.8 Hz, 1H), 3.84 (dd, J ) 4.2, 11.4
Hz, 1H), 3.56 (dd, J ) 8.7, 11.2 Hz, 1H), 2.89 (s, OH, D2O
exchangeable, 1H), 2.32 (dd, J ) 4.7, 8.6 Hz, OH, D2O
exchangeable, 1H), 1.38 (s, 3H), 1.29 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 135.3, 135.1, 112.9, 86.3, 84.4, 65.8, 27.1, 25.4.
Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.06;
H, 7.61. Compound 19: [R]23D +88.18 (C 0.27, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.95 (dd, J ) 1.7, 5.8 Hz, 1H), 5.72 (d, J
) 5.8 Hz, 1H), 5.07 (d, J ) 5.5 Hz, 1H), 4.61 (d, J ) 5.6 Hz,
1H), 3.73 (d, J ) 11.5 Hz, 1H), 3.31 (bs, OH, D2O exchangeable,
1H), 3.26 (d, J ) 11.5 Hz, 1H), 2.13 (bs, OH, D2O exchangeable,
1H), 1.46 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
136.4, 133.6, 112.8, 83.4, 82.6, 79.1, 66.4, 27.7, 26.5. Anal.
Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.10; H, 7.63.
(4R,5S)-(-)-1-(2,2-Dim eth yl-5-vin yl-1,3-d ioxola n -4-yl)-
2-(ter t-bu tyld im eth ylsilyloxy)eth a n -1-on e (14). To a solu-
tion of alcohol 13 (31.0 g, 0.10 mol), dicyclohexylcarbodiimide
(42.0 g, 0.21 mol), DMSO (18.1 mL, 0.25 mol), and pyridine
(17.2 mL, 0.10 mol) in toluene (500 mL) was added trifluoro-
acetic acid (8.3 mL, 0.10 mol) dropwise at 0 °C for 10 min.
After being stirred at room temperature for 10 h, the resulting
suspension mixture was filtered through a Celite pad. The
filtrate was washed with H2O, saturated NaHCO3, and brine,
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on a silica
gel (EtOAc/hexane ) 1:30) to give a crude compound contami-
nated by reduced DCC which was dissolved in hexane. The
precipitate was filtered off, and the filtrate was concentrated
in vacuo. The residue was repurified by column chromatog-
raphy on a silica gel (EtOAc/hexane ) 1:30), giving ketone 14
(4R,5S)-1-(2,2-Dim eth yl-5-vin yl-1,3-dioxolan -4-yl)-1-(h y-
d r oxym eth yl)-2-p r op en -1-ol (20). Compound 15 (28.5 g, 86.7
mol) was converted to diastereomers 20 (17.6 g, 95%) as a
colorless oil using the same procedure as for compound 5: 1H
NMR (500 MHz, CDCl3) δ 6.17-6.10 (m, 2H), 5.86-5.80 (m,
0.3H), 5.47-5.20 (m, 5.2H), 4.70 (t, J ) 6.0 Hz, 1H), 4.62 (t, J
) 5.6 Hz, 0.3H), 4.32 (t, J ) 5.6 Hz, 1H), 3.76 (d, J ) 9.2 Hz,
0.3H), 3.69 (d, J ) 8.8 Hz, 1H), 3.45 (d, J ) 8.4 Hz, 1H), 2.88
(s, OH, D2O exchangeable, 0.2H), 2.59 (s, OH, D2O exchange-
able, 1H), 2.25 (s, OH, D2O exchangeable, 1H), 1.53 (s, 3H),
1.39(s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.2, 137.6, 135.5,
135.1, 119.5, 118.5, 117.1, 116.8, 108.8, 108.7, 81.7, 79.6, 79.4,
76.2, 75.3, 69.2, 67.6, 27.6, 27.3, 25.5, 25.0. Anal. Calcd for
(23.4 g, 75%): [R]23 -20.34 (c 0.70, MeOH); 1H NMR (400
D
MHz, CDCl3) δ 5.74-5.66 (m, 1H), 5.41 (d, J ) 16.6 Hz, 1H),
5.24 (d, J ) 10.5 Hz, 1H), 4.92-4.87 (m, 2H), 4.47 (d, J ) 18.9
Hz, 1H), 4.22 (d, J ) 18.9 Hz, 1H), 1.61 (s, 3H), 1.40 (s, 3H),
0.92 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 132.7,
118.9, 81.9, 78.2, 68.6, 31.4, 27.0, 25.8, 24.9, 22.6, 13.7, -5.5.
Anal. Calcd for C15H28O4Si: C, 59.96; H, 9.39. Found: C, 59.92;
H, 9.17.
(4R,5S)-1-(2,2-Dim eth yl-5-vin yl-1,3-dioxolan -4-yl)-1-(ter t-
bu tyld im eth ylsilyloxym eth yl)-2-p r op en -1-ol (15). Com-
pound 14 (20.1 g 67.1 mmol) was converted to inseparable
diastereomers 15 (17.0 g, 80%) using the same procedure as
for 4: 1H NMR (400 MHz, CDCl3) δ 6.14-5.88 (m, 2H), 5.43-
5.14 (m, 4H), 4.66 (t, J ) 7.1 Hz, 0.9H), 4.54 (t, J ) 6.6 Hz,
0.1H), 4.38 (d, J ) 6.4 Hz, 0.1H), 4.29 (d, J ) 6.9 Hz, 0.9H),
2.77 (s, OH, D2O exchangeable, 0.9H), 2.51 (s, OH, D2O
exchangeable, 0.1H), 1.53 (s, 0.3H), 1.51 (s, 2.7H), 1.38 (s,
0.3H), 1.36 (s, 2.7H), 0.89 (s, 8.1H), 0.87 (s, 0.9H), 0.05 (s,
5.4H), 0.03 (s, 0.6H); 13C NMR (100 MHz, CDCl3) δ 138.1,
138.0, 135.7, 135.3, 117.6, 117.1, 115.8, 115.7, 108.2, 107.9,
79.3, 78.6, 78.3, 75.1, 76.7, 75.1, 74.8, 68.2, 68.0, 27.7, 27.3,
25.8, 25.8, 25.4, 24.9, 18.3, 18.2, -5.4, -5.5. Anal. Calcd for
C
11H18O4: C, 61.66; H, 8.47. Found: C, 61.37; H, 8.67.
(4R,5S)-1-(2,2-Dim eth yl-5-vin yl-1,3-dioxolan -4-yl)-2-pr o-
p en -1-ol (21). To a solution of diol 20 (13.4 g, 63.1 mmol) in
CH2Cl2 (200 mL) and H2O (100 mL) was added NaIO4 (16.2 g,
75.8 mmol) at 0 °C and the mixture stirred at room temper-
ature for 35 min. The organic phase was separated, and the
water phase was extracted with CH2Cl2. The combined organic
phase was dried over MgSO4, filtered, and concentrated in
vacuo. After the residue was dissolved in MeOH (200 mL) and
cooled to 0 °C, CeCl3‚7H2O (19.0 g, 51.0 mmol) was added and
stirred at 0 °C for 10 min. Sodium borohydride (2.38 g, 63.1
mmol) was then added portionwise. The reaction was stirred
at 0 °C for 30 min, and a solution of (EtOAc/hexane ) 1:1)
was added. After filtering off the precipitate, the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography on a silica gel (EtOAc/hexane ) 10:1) to give
alcohol 21 (11.4 g, 98%) as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 6.04-6.00 (m, 1H), 5.88-5.82 (m, 1H), 5.41-5.23 (m,
4H), 4.63-4.60 (m, 1H), 4.14-4.08 (m, 2H), 2.38-2.36 (m, OH,
D2O exchangeable, 1H), 1.55 (s, 3H), 1.40 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 136.9, 134.1, 119.7, 117.3, 109.0, 80.8,
79.2, 70.8, 27.6, 25.2. Anal. Calcd for C10H16O3‚0.15CH2Cl2: C,
61.89; H, 8.34. Found: C, 61.83; H, 8.41.
C
17H32O4Si: C, 62.15; H, 9.82. Found: C, 62.05; H, 9.76.
(1R,4S,5S)-(+)-4,5-O-Isop r op ylid en e-1-(ter t-b u t yld i-
m eth ylsilyloxym eth yl)-2-cyclop en ten -1-ol (16) a n d Its
Ep im er (17). To a 500 mL round-bottom flask filled with
Grubbs’ catalyst (1.25 g, 5 mol %, flushed with N2 three times)
was added a solution of the diene 15 (10.0 g, 30.4 mmol) in
anhydrous CH2Cl2 (300 mL). After being heated at reflux for
24 h, the resulting dark brown mixture was concentrated in
vacuo and the residue was purified by column chromatography
on a silica gel (EtOAc/hexane ) 1:10) to give â-cyclopentenol
16 (7.3 g, 80%) and its R-epimer 17 (729 mg, 8%). Compound
16: [R]23D +55.97 (c 0.37, MeOH); 1H NMR (400 MHz, CDCl3)
δ 5.98 (d, J ) 5.7 Hz, 1H), 5.74 (d, J ) 5.7 Hz, 1H), 5.31 (d, J
) 5.3 Hz, 1H), 4.47 (d, J ) 5.4 Hz, 1H), 3.92 (d, J ) 9.9 Hz,
1H), 3.62 (d, J ) 9.9 Hz, 1H), 3.22 (s, OH, D2O exchangeable,
1H), 1.38 (s, 3H), 1.32 (s, 3H), 0.92 (s, 9H), 0.10 (s, 3H), 0.09
(s, 3H); 13C NMR (100 MHz, CDCl3) 135.2, 135.0, 112.1, 84.8,
84.7, 65.0, 27.5, 26.0, 25.9, 18.4, -5.4. Anal. Calcd for C15H29O4-
Si: C, 59.96; H, 9.39. Found: C, 60.05; H, 9.48. Compound
(4S,5S)-(+)-4,5-O-Isopr opyliden e-2-cyclopen ten on e (22).
Compound 21 (11.4 g, 61.8 mmol) was converted to compound
22 (8.3 g, 88%) using the same procedure as for compound 9:
mp 68.1-69.4 °C; [R]23 +69.1 (c 0.77, CHCl3) [lit.9 mp 68.7-
D
69.8 °C; [R]D +69.1 (c 1.98, CHCl3)]; 1H NMR (400 MHz, CDCl3)
δ 7.57 (dd, J ) 2.0, 5.8 Hz, 1H), 6.17 (d, J ) 5.9 Hz, 1H), 5.23
(dd, J ) 2.3, 5.4 Hz, 1H), 4.42 (d, J ) 5.4 Hz, 1H), 1.37 (s,
3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 134.6,
115.4, 78.6, 76.5, 27.4, 26.1. Anal. Calcd for C10 H10O3: C,
62,33; H, 6.54. Found: C, 62.20; H, 6.48.
17: [R]24 +72.04 (c 0.35, CHCl3); 1H NMR (400 MHz, CDCl3)
D
δ 5.90 (d, J ) 5.7 Hz, 1H), 5.66 (d, J ) 5.7 Hz, 1H), 5.00 (d, J
) 5.3 Hz, 1H), 4.47 (d, J ) 5.2 Hz, 1H), 3.69 (ddd, J ) 1.5,
9.7, 38.7 Hz, 2H), 3.12 (s, OH, D2O exchangeable, 1H), 1.43
(s, 3H), 1.39 (s, 3H), 0.85 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13
C
(1′S,2′R,3′S)-(-)-1-[2,3-(Isop r op ylen ed ioxy)-4-(ter t-bu -
toxym eth yl)-4-cyclop en ten -1-yl]-5-ch lor ou r a cil (27). To
a solution of N3-benzoyl-5-chlorouracil (0.75 g, 3.18 mmol),
Ph3P (1.06 g, 4.22 mmol), and 23 (0.51 g, 2.12 mmol) in
anhydrous THF was added a solution of diethylazodicarboxy-
late (0.73 g, 4.22 mmol) in anhydrous THF at 0 °C under N2
atmosphere. The mixture was stirred for 15 h at room
temperature, and solvent was removed in vacuo. The resulting
residue was purified by column chromatography on silica gel
NMR (100 MHz, CDCl3) δ 136.9, 133.2, 112.4, 84.1, 82.5, 80.8,
67.0, 27.9, 26.8, 25.8, -5.5. Anal. Calcd for C15H29O4Si: C,
59.96; H, 9.39. Found: C, 60.10; H, 9.39.
(1R,4S,5S)-(+)-4,5-O-Isop r op ylid en e-1-h yd r oxym eth yl-
2-cyclop en ten -1-ol (18) a n d Its Ep im er (19). R-Cyclopen-
tenol 16 (5.0 g, 17.2 mmol) and â-cyclopentenol 17 (150 mg,
0.49 mmol) were converted to cyclopentenediol 18 (3.9 g, 99%)
and 19 (90 mg, 97%), respectively, using the same procedure
J . Org. Chem, Vol. 68, No. 23, 2003 9017

J in et al.
(EtOAc/hexane ) 1:4) to give 24 (0.92 g) as a crude white solid
which was used in the next reaction without further purifica-
tion. The crude 24 (0.92 g) was dissolved in saturated metha-
nolic ammonia solution (20 mL) at 5 °C and stirred for 3 h at
room temperature. The solvent was evaporated under vacuum,
and the residue was purified by column chromatography on a
silica gel (EtOAc/hexane ) 1:1), giving compound 27 (397 mg,
13C NMR (100 MHz, CDCl3) δ 162.3, 155.0, 152.0, 142.3, 121.5,
112.3, 87.1, 84.5, 83.3, 73.8, 68.9, 58.9, 29.6, 27.4, 27.2, 25.8;
HRMS-ESI calcd for C17H24BrN3O4 413.0950, found 414.1026
(M + 1). Anal. Calcd for C17H24BrN3O4‚0.4hexane: C, 51.92;
H, 6.65; N, 9.36. Found: C, 52.02; H, 6.45; N, 9.07.
(1′S,2′R,3′S)-(-)-1-[2,3-(Isop r op ylen ed ioxy)-4-(ter t-bu -
toxym eth yl)-4-cyclopen ten -1-yl]-5-iodocytosin e (32). Com-
pound 32 was prepared using the same procedure as for
51%) as a white solid: mp 170-172 °C; [R]24 -55.27 (c 0.57,
D
CHCl3); UV (MeOH) λmax 280 nm; 1H NMR (400 MHz, CDCl3)
δ 9.06 (br s, 1H), 7.44 (s, 1H), 5.78 (s, 1H), 5.62 (s, 1H), 5.38
(d, J ) 5.76 Hz, 1H), 4.74 (d, J ) 5.81 Hz, 1H), 4.32 (dd, J )
7.48 Hz, J ) 15.04 Hz, 2H), 1.57 (s, 3H), 1.50 (s, 3H), 1.44
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.6, 153.0, 149.5,
138.0, 120.9, 112.8, 108.9, 84.4, 83.4, 74.0, 68.0, 58.9, 27.4,
27.2, 25.7; MS m/z 371 (M + 1), 373 (M + 3). Anal. Calcd for
compound 30: yield 65%; mp 200-202 °C; [R]25 -82.24 (c
D
1
0.46, MeOH); UV (MeOH) λmax 296 nm; H NMR (400 MHz,
CDCl3) δ 7.41 (s, 1H), 5.59 (s, 1H), 5.47 (s, 1H), 5.16 (d, J )
5.71 Hz, 1H), 4.54 (d, J ) 5.75 Hz, 1H), 4.13 (dd, J ) 15.17
Hz, J ) 22.50 Hz, 2H), 1.42 (s, 3H), 1.32 (s, 3H), 1.24 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 163.9, 152.5, 148.4, 122.0, 112.8,
85.0, 83.8, 74.3, 69.4, 59.9, 28.9, 27.7, 26.2; MS m/z 462 (M +
1). Anal. Calcd for C17H24IN3O4: C, 44.26; H, 5.24; N, 9.11.
Found: C, 44.35; H, 5.37; N, 8.93.
C
17H23ClN2O5: C, 55.06; H, 6.25; N, 7.55. Found: C, 55.06; H,
6.26; N, 7.51.
(1′S,2′R,3′S)-(-)-1-[2,3-(Isop r op ylen ed ioxy)-4-(ter t-bu -
toxym eth yl)-4-cyclopen ten -1-yl]-5-br om ou r acil (28). Com-
pound 28 was prepared using the same procedure as for
(1′S,2′R,3′S)-(-)-1-(2,3-Dih yd r oxy-4-h yd r oxym eth yl-4-
cyclop en t en -1-yl)-5-ch lor ocyt osin e (33). Compound 30
(0.15 g, 0.42 mmol) was dissolved in 30 mL of CF3COOH/H2O
(2:1, v/v) and heated at 50 °C for 5 h. The solvent was removed
under vacuum, and the residue was coevaporated twice with
ethanol (20 mL) under vacuum. The resulting residue was
purified by column chromatography on silica gel (MeOH/
CH2Cl2 ) 1:5), giving compound 34 (90 mg, 75%) as a white
solid (recrytallized from MeOH and diethyl ether): mp 194-
196 °C; [R]25D -96.40 (c 0.13, MeOH); UV (H2O) λmax 299.5 nm
(ꢀ 12 106, pH 2), 289.0 nm (ꢀ 8143, pH 7.4), 290.0 nm (ꢀ 7504,
pH 11); 1H NMR (400 MHz, MeOH-d4) δ 5.70 (s, 1H), 5.47 (bs,
1H), 4.53 (d, J ) 5.26 Hz, 1H), 4.27 (dd, J ) 15.27, 17.72 Hz,
2H), 4.05 (t, J ) 5.59 Hz, 1H); 13C NMR (100 MHz, MeOH-d4)
δ 163.7, 152.7, 142.4, 125.9, 102.6, 79.0, 74.6, 69.9, 60.7; MS
m/z 274 (M + 1), 276 (M + 3). Anal. Calcd for C10H12ClN3O4:
C, 43.89; H, 4.42; N, 15.35; Found: C, 43.81; H, 4.51; N, 15.18.
compound 27: yield 52%; mp 196-198 °C; [R]23 -54.60 (c
D
1
0.88, CHCl3); UV (MeOH) λmax 282 nm; H NMR (400 MHz,
CDCl3) δ 8.84 (br s, 1H), 7.28 (s, 1H), 5.59 (s, 1H), 5.42 (s,
1H), 5.19 (d, J ) 5.78 Hz, 1H), 4.55 (d, J ) 5.82 Hz, 1H), 4.14
(dd, J ) 16.12 Hz, J ) 21.68 Hz, 2H), 1.43 (s, 3H), 1.34 (s,
3H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 159.3, 153.3,
150.3, 141.0, 121.3, 113.2, 97.0, 84.8, 83.8, 77.1, 74.4, 59.3, 30.7,
27.8, 27.6, 26.2; MS m/z 415 (M + 1), 417 (M + 3). Anal. Calcd
for C17H23BrN2O5: C, 49.17; H, 5.58; N, 6.75. Found: C, 49.59;
H, 5.79; N, 6.52.
(1′S,2′R,3′S)-(-)-1-[2,3-(Isop r op ylen ed ioxy)-4-(ter t-bu -
toxym eth yl)-4-cyclop en ten -1-yl]-5-iod or a cil (29). Com-
pound 29 was prepared using the same procedure as for
compound 27: yield 52%; mp 198-200 °C; [R]23 -86.87 (c
D
1
0.57, MeOH); UV (MeOH) λmax 289 nm; H NMR (400 MHz,
(1′S,2′R,3′S)-(-)-1-(2,3-Dih yd r oxy-4-h yd r oxym eth yl-4-
cyclop en ten -1-yl)-5-br om ocytosin e (34). Compound 34 was
prepared using the same procedure as for compound 33: yield
CDCl3) δ 8.89 (br s, 1H), 7.37 (s, 1H), 5.59 (s, 1H), 5.39 (s,
1H), 5.21 (d, J ) 5.74 Hz, 1H), 4.56 (d, J ) 5.81 Hz, 1H), 4.14
(dd, J ) 15.44 Hz, J ) 21.44 Hz, 2H), 1.41 (s, 3H), 1.35 (s,
3H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.4, 153.2,
150.6, 146.1, 121.4, 113.2, 108.8, 84.4, 83.84, 74.4, 68.5, 59.3,
58%; mp 236-238 °C; [R]28 -116.27 (c 0.49, H2O); UV (H2O)
D
λ
max 303 nm (ꢀ 11 949, pH 2), 291.0 nm (ꢀ 9711, pH 7.4), 291.0
1
nm (ꢀ 9658, pH 11); H NMR (400 MHz, MeOH-d4) δ 7.62 (s,
1H), 5.49 (s, 1H), 5.32 (br s, 1H), 4.31 (d, J ) 5.64 Hz, 1H),
4.03 (dd, J ) 15.20, 17.62 Hz, 2H), 3.89 (t, J ) 5.31 Hz, 1H);
13C NMR (100 MHz, MeOH-d4) δ 162.2, 156.1, 152.1, 143.5,
124.1, 75.3, 72.2, 67.2, 59.0; MS m/z 318 (M + 1), 320 (M + 3).
Anal. Calcd for C10H12BrN3O4: C, 37.75; H, 3.80; N, 13.21;
Found: C, 37.63; H, 3.95; N, 12.97.
27.8, 27.6, 26.2; MS m/z 463 (M + 1). Anal. Calcd for C17H23
-
IN2O5: C, 44.17; H, 5.01; N, 6.06. Found: C, 44.21; H, 5.12;
N, 5.97.
(1′S,2′R,3′S)-(-)-1-[2,3-(Isop r op ylen ed ioxy)-4-(ter t-bu -
toxym eth yl)-4-cyclop en ten -1-yl]-5-ch lor ocytosin e (30). A
mixture of 27 (0.21 g, 5.61 mmol), 2,2-(dimethylamino)pyridine
(0.14 g, 1.12 mmol), triethylamine (0.17 mL, 1.68 mmol), and
2,4,6-triisopropylbenzenesulfonyl chloride (0.51 g, 1.68 mmol)
in anhydrous CH3CN (15 mL) was stirred at room temperature
for 36 h. After an addition of 28% NH4OH (15 mL), the mixture
was stirred at room temperature for 5 h. Solvent was coevapo-
rated with ethanol under reduced pressure. The residue was
purified by column chromatography on silica gel (MeOH/
CH2Cl2 ) 3:100) to give 30 (0.13 g, 65%) as a white solid: mp
(1′S,2′R,3′S)-(-)-1-(2,3-Dih yd r oxy-4-h yd r oxym eth yl-4-
cyclop en ten -1-yl)-5-iod ocytosin e (35). Compound 35 was
prepared using the same procedure as for compound 33: yield
63%; mp 210-212 °C; [R]29 -127.90 (c 0.46, H2O); UV (H2O)
D
λ
max 312.0 nm (ꢀ 14 318, pH 2), 295.5 nm (ꢀ 7576, pH 7.4), 297.0
1
nm (ꢀ 8739, pH 11); H NMR (400 MHz, DMSO-d6 + D2O) δ
7.63 (s, 1H), 5.48 (s, 1H), 5.31 (br s, 1H), 4.30 (d, J ) 5.56 Hz,
1H), 4.04 (dd, J ) 15.27 Hz, J ) 17.72 Hz, 2H), 3.87 (t, J )
5.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6 + D2O) δ 167.8,
159.5, 155.1, 152.8, 128.3, 81.1, 76.5, 71.1, 62.9, 60.6; HRMS-
ESI calcd for C10H11IN3O4 364.9873, found 365.9960 (M + 1).
Anal. Calcd for C10H12IN3O4: C, 32.89; H, 3.31; N, 11.51.
Found: C, 33.14; H, 3.34; N, 11.27.
178-180 °C; [R]23 -38.37 (c 0.54, CHCl3); UV (MeOH) λmax
D
290 nm; 1H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 5.58 (s,
1H), 5.41 (s, 1H), 5.14 (d, J ) 5.69 Hz, 1H), 4.52 (d, J ) 5.78
Hz, 1H), 4.12 (dd, J ) 15.01 Hz, J ) 23.02 Hz, 2H), 1.41 (s,
3H), 1.31 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
161.5, 154.7, 152.2, 139.9, 121.5, 112.4, 99.8, 84.5, 83.4, 73.8,
68.7, 58.9, 27.4, 25.8; HRMS-ESI calcd for C17H24ClN3O4
Ack n ow led gm en t. This research was supported by
grants from the National Institute of Allergy and
Infectious Diseases (U19 AI 56540, UO1 AI 48495).
369.1455, found 370.1538 (M + 1). Anal. Calcd for C17H24
-
ClN3O4‚0.2H2O: C, 54.68; H, 6.59; N, 11.24. Found: C, 54.64;
H, 6.55; N, 10.94.
(1′S,2′R,3′S)-(-)-1-[2,3-(Isop r op ylen ed ioxy)-4-(ter t-bu -
t oxym et h yl)-4-cyclop en t en -1-yl]-5-b r om ocyt osin e (31).
Compound 31 was prepared using the same procedure as for
Su p p or tin g In for m a tion Ava ila ble: Experimental gen-
eral methods, detailed experimental procedures for compounds
2 and 3, and spectroscopic data (1H and 13C NMR) for
compounds 9, 12, 22, and 33-35. This material is available
free of charge via the Internet at http://pubs.acs.org.
compound 30: yield 90%; mp 194-196 °C; [R]22 -62.63 (c
D
1
0.56, MeOH); UV (MeOH) λmax 291 nm; H NMR (400 MHz,
CDCl3) δ 7.33 (s, 1H), 5.59 (s, 1H), 5.43 (s, 1H), 5.16 (d, J )
5.70 Hz, 1H), 4.55 (d, J ) 5.78 Hz, 1H), 4.14 (dd, J ) 15.10
Hz, J ) 23.00 Hz, 2H), 1.42 (s, 3H), 1.31 (s, 3H), 1.25 (s, 9H);
J O034999V
9018 J . Org. Chem., Vol. 68, No. 23, 2003