Synthesis of 2′,3′-dideoxy-6′-fluorocarbocyclic nucleosides via Reformatskii-Claisen rearrangement

Article abstract of DOI:10.1016/j.tet.2011.03.054

2′,3′-Dideoxy-6′-fluorocarbocyclic nucleosides, analogues of highly bioactive carbovir and abacavir were synthesized. The notable steps were the incorporation of fluoromethylene group by way of silicon-induced Reformatskii-Claisen rearrangement of allyl b

Full text of DOI:10.1016/j.tet.2011.03.054

Tetrahedron 67 (2011) 3388e3394
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Synthesis of 20,30-dideoxy-60-fluorocarbocyclic nucleosides via
ReformatskiieClaisen rearrangement
,b,
Yi Yang a, Feng Zheng a, Feng-Ling Qing a
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
20,30-Dideoxy-60-fluorocarbocyclic nucleosides, analogues of highly bioactive carbovir and abacavir were
synthesized. The notable steps were the incorporation of fluoromethylene group by way of silicon-in-
duced ReformatskiieClaisen rearrangement of allyl bromofluoroacetate, the construction of the carbo-
cyclic ring via ring-closing metathesis (RCM) and the introduction of base by Mitsunobu reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 26 January 2011
Received in revised form 8 March 2011
Accepted 17 March 2011
Available online 25 March 2011
Keywords:
Fluorinated carbocyclic nucleosides
ReformatskiieClaisen rearrangement
Ring-closing metathesis
Mitsunobu reaction
1. Introduction
stereoselective synthesis of 20,30-dideoxy-60-fluorocarbocyclic nu-
cleosides 1 (Fig. 1). The design of 20,30-dideoxy-60-fluorocarbocyclic
Carbocyclic nucleosides (CNAs),1 in which the oxygen in the
sugar portion of the nucleoside was replaced with a methylene
(CH2) unit, are highly resistant to the phosphorylases that cleave
the N-glycosidic linkage in conventional nucleosides. In recent
years, structural modification of carbocyclic nucleosides has
attracted much attention in order to find more effective antiviral
and antitumor agents. Carbovir2 and Abacavir3 are the most rep-
resentative carbocyclic nucleosides because of their potent and
selective inhibition of human immunodeficiency virus (HIV). Fur-
thermore, the position C-60 at carbocyclic framework may provide
a platform for structural elaboration, that is, not available in the
common ribofuranosyl based nucleosides. It is well-known that
fluorine is often used to replace hydrogen in medicinal chemistry
due to its small size and high compactness. Several synthetically
derived C-60 fluorinated carbocyclic nucleosides have been stud-
ied.4 Among these C-60 fluorinated carbocyclic nucleosides, 60-flu-
oroaristeromycin exhibited moderate activity against herpes
simplex virus type 1 (HSV-1) and type 2 (HSV-2) and served as
potent inhibitors of AdoHcy hydrolase in vitro.4l During our ongo-
ing search for new antiviral and antitumor agents, we are interested
in stereoselective introduction of a fluorine atom at position C-60 of
carbocyclic nucleosides. Herein, we describe rational design and
nucleosides is based on the fact that 20,30-dideoxynucleoside
(ddNs) is a kind of effective therapeutic agents against HIV and
hepatitis B virus (HBV), such as 20,30-didehydro-20,30-dideox-
ythymidine (d4T),5 an anti-HIV drug. In addition, nucleosides 1 are
analogues of the highly bioactive Carbovir and Abacavir in which
the methylene (CH2) unite of C-60 site in sugar moiety was replaced
* Corresponding author. Fax: þ86 21 64166128; e-mail address: flq@mail.sioc.
ac.cn (F.-L. Qing).
Fig. 1. Rational design of the target molecule 1.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.054

Y. Yang et al. / Tetrahedron 67 (2011) 3388e3394
3389
with a fluoromethylene (CHF) group, which may provide us
a chance to further study the fluorine effects in the bioactivities of
these carbocyclic nucleosides.
afforded ester 7 in 90% yield (Scheme 4). Then the silicon-induced
ReformatskiieClaisen reaction of compound 7 ( a mixture of 7,
2.0 equiv of TMSCl and 10.0 equiv of fresh activated zinc was
stirred in dry acetonitrile at 100 ꢀC for 12 h), followed by esteri-
fication with SOCl2/MeOH provided the monofluorinated esters in
70% overall yield with four diastereoisomers (8.7:3.4:1.8:1, de-
termined by 19F NMR). Fortunately, the major diastereoisomer 8
could be separated by flash chromatography in 45% yield
(Scheme 4).
2. Results and discussion
The synthetic strategy was based on that the target molecule 1
could be derived from the precursor 2 by introduction of a base
moiety via palladium-catalyzed allylic substitution6,11b or Mitsu-
nobu reaction7 (Scheme 1). The ring-closing metathesis8 of diene 3
would provide carbocyclic sugar 2. Compound 3 could be easily
prepared from the key intermediate 4, which can be prepared via
With the key ester 8 in hand, we then turned our attention to
establish the carbocyclic sugar (Scheme 5). Ester 8 was transformed
to Weinreb amide 9 in 87% yield. Allylation of 9 with allylmagne-
sium chloride at ꢁ78 ꢀC, followed by triethylamine-induced double
the ReformatskiieClaisen reaction of allyl
Although Welch and co-workers had reported the stereoselective
rearrangement of allyl -fluoro-acetates via -fluoro silyl ketene
acetal (Scheme 2),9 the starting material fluoroacetic acid
a-bromofluoroacetate 5.
bond isomerization gave the
a,b-unsaturated ketone 10 in 94%
yield. Ring-closing metathesis of electron-deficient diene 10 with
Grubbs-II catalyst (5 mol %) in toluene at 100 ꢀC proceeded
smoothly, providing the desired product 11 in 95% yield. Luche
reduction of compound 11 afforded alcohols 12 and 13 in a ratio of
3.2:1, which were converted to allyl carbonate 14 and 15, re-
spectively. Unfortunately, attempts to install a base moiety into
carbonate 14 and 15 via palladium-catalyzed allylic substitution
reaction11b failed to give any desired product (Scheme 6).
a
a
(FCH2CO2H) for preparation of allyl
a-fluoroacetates is very tox-
ic.10a,b Inspired by our recent work relating the silicon-induced
stereoselective ReformatskiieClaisen rearrangement of secondary
allyl chlorodifluoroacetate (Scheme 3),11 we expected that the
construction of 4 from the much less poisonous bromofluoroacetic
acid10c,d would be feasible and safe.
Scheme 1. Retrosynthesis of compound 1.
Alternatively, the Mitsunobo reaction was investigated for in-
troduction of bases (Scheme 7). To our delight, the coupling of al-
cohol 12 with 6-chloropurine in the presence of DEAD and PPh3
afforded compound 16 in moderate yield. Amination of compound
16 with NH3/CH3OH at 80 ꢀC afforded compound 18 in good yield.
Deprotection of benzyl group with BCl3, followed by oxidation of
the resulting vicinal diol 20 with NaIO4 and subsequent reduction
Scheme 2.
of aldehyde with NaBH4 successfully afforded
a-nucleoside 22.
Using same strategy, fluorinated
from alcohol 13.
b-nucleoside 23 was also obtained
Encouraged by the successful access to nucleosides 22 and 23, a-
uridine 28 and a-thymidine 29 were also obtained in a similar way
Scheme 3.
(Scheme 8).
Accordingly, the synthesis of target molecules began by prep-
aration of allyl bromofluoroacetate 7. Treatment of allylic alcohol
611b with bromofluoroacetyl chloride in the presence of pyridine
The stereochemistry assignments of final products were estab-
lished by 2D NMR NOESY experiment of compound 12 and the X-
ray crystal analysis12 of compound 18 (Fig. 2).
Scheme 4. ReformatskiieClaisen rearrangement of compound 7.

3390
Y. Yang et al. / Tetrahedron 67 (2011) 3388e3394
Scheme 5.
highlighted the preparation of chiral fluorinated building block 8
via silicon-induced ReformatskiieClaisen rearrangement of allyl
bromofluoroacetate, construction of the carbocyclic ring through
RCM, and installation of the base moiety by Mitsunobu reaction.
Scheme 6.
Scheme 7.
4. Experimental section
4.1. General
All reagents were used as received from commercial sources,
unless specified otherwise, or prepared as described in the litera-
ture. THF was distilled from sodium and benzophenone.
Dichloromethane was distilled from calcium hydride. Petroleum
ether refers to the fraction of light petroleum ether with bp
60e90 ꢀC 1H NMR and 13C NMR spectra were recorded on Bruker
AM-300, Bruker AM-400 or Varian Mercury-300 spectrometers. 19F
NMR was recorded on a Bruker AM-300 spectrometer (FCCl3 as
Scheme 8.
outside standard and low field is positive). Chemical shifts (d) are
reported in parts per million, and coupling constants (J) are in hertz.
Optical rotations were measured using a PerkineElmer 241 or 341
polarimeter. Crystallographic data were analyzed with Rigaku FCR
Diffractimer.
4.2. Synthesis and characterization
4.2.1. (S,E)-4,5-Bis(benzyloxy)pent-2-enyl 2-bromo-2-fluoroacetate
(7). To a solution of compound 6 (150 mg, 0.50 mmol) in anhydrous
dichloromethane (3 mL) was added pyridine (48
dropwise at 0 ꢀC. After the reaction mixture was stirred for 5 min at
ꢀC, bromofluoroacetyl chloride (81
L, 0.60 mmol) was added
mL, 0.60 mmol)
Fig. 2. NOESY correlation of compound 12 and X-ray structure of compound 18.
0
m
dropwise. After stirring for 1 h at 0 ꢀC, the reaction mixture was
then warmed to ambient temperature and stirred for 12 h.
Dichloromethane (5 mL) was added to the reaction system and the
resultant organic phase was washed with saturated copper sulfate
solution (5 mLꢂ3) and water (5 mL), dried over anhydrous Na2SO4,
3. Conclusion
We described herein the design and synthesis of 20,30-dideoxy-
60-fluorocarbocyclic nucleosides 22, 23, 28, and 29. Our synthesis

Y. Yang et al. / Tetrahedron 67 (2011) 3388e3394
3391
filtered, and concentrated. The residue was purified by flash chro-
matography (petroleum ether/ethyl acetate¼15:1) to give com-
1.7 M solution in THF) at ꢁ78 ꢀC. After being stirred for 60 min at
ꢁ78 ꢀC, the reaction was quenched with 1 M HCl (10 mL). The
aqueous layer was extracted with ether (5 mLꢂ2). The combined
organic layer was washed with water and brine, dried over Na2SO4.
The solvent was removed in vacuo and the residue was dissolved in
THF (5 mL). The resulting solution was then treated with Et3N
(0.2 mL) and stirred overnight. The solvent was removed under
reduced pressure and then the residue was purified by flash chro-
matography (petroleum ether/ethyl acetate¼20:1) on silica gel to
pound 7 as a clear oil (196 mg, 90% yield): [
a
]
15.4ꢀ (c 4.80,
D25
CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.33e7.21 (m, 10H), 6.56 (d,
J¼50.1 Hz, 1H), 5.86 (m, 2H), 4.77 (d, J¼4.2 Hz, 2H), 4.65e4.46 (m,
4H), 4.08 (dd, J¼4.8, 5.2 Hz, 1H), 3.62e3.49 (m, 2H); 13C NMR
(100.7 MHz, CDCl3)
d
164.5 (d, J¼26.1 Hz), 138.5, 138.4, 134.2, 134.1,
128.7, 128.0, 127.9, 127.9, 126.0, 82.3, 79.7, 78.1, 73.7, 72.9, 71.2, 66.6;
19F NMR (282 MHz, CDCl3)
d
ꢁ150.17 (d, J¼50.5 Hz,1F); IR (KBr) nmax
3063, 3030, 2862, 1766, 1091 cmꢁ1; MS (ESI) m/z 454 (MþNH4)þ;
give 10 as a yellow oil (180 mg, 94% yield): [
a
ꢁ15.7ꢀ (c 3.10,
D25
]
HRMS calcd for C21H22FBrO4: 436.0685; found: 436.0687.
CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.37e7.23 (m, 10H), 7.04e6.92
(m, 1H), 6.46e6.41 (m, 1H), 5.75e5.66 (td, J¼6.1, 7.5 Hz, 1H),
5.17e5.00 (m, 3H), 4.88e4.45 (m, 4H), 4.62 (td, J¼3.0, 4.5 Hz, 1H),
3.65e3.47 (m, 2H), 2.83 (ddd, J¼2.1, 9.3, 12.6 Hz, 1H), 1.89 (d,
4.2.2. (2S,3S)-Methyl 3-((S)-1,2-bis(benzyloxy)ethyl)-2-fluoropent-
4-enoate(8). A mixture of compound 7 (211 mg, 0.48 mmol), chlor-
otrimethyl silane (0.18 mL,1.04 mmol) and freshlyactivated zinc dust
(420 mg, 6.45 mmol) in dry acetonitrile (3 mL) was heated to 100 ꢀC
over a period of 20 min and stirred for 10 h at the same temperature.
After the reaction mixture cooled to room temperature, the mixture
was filtered and the residue was washed by MeOH (1.5 mLꢂ2). To the
combined organic solution, SOCl2 (0.3 mL, 4.14 mmol) was added
slowlyandthen stirred for 3 h. Water (5 mL) was added to quench the
reaction and the solvent was partially removed in vacuo. The re-
sultant mixture was extracted with Et2O (5 mLꢂ3). The combined
organic layer was washed with brine, and dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by silica
gel chromatography (petroleum ether/ethyl acetate¼25:1) to give
J¼6.9 Hz, 3H); 13C NMR (100.7 MHz, CDCl3)
d
195.5 (d, J¼22.5 Hz),
145.5, 145.5, 138.3, 138.0, 131.0, 130.9, 128.3, 128.2, 127.6, 127.5,
127.5, 126.3, 120.4, 93.6 (d, J¼188.9 Hz), 76.6, 75.8, 75.7, 73.2, 73.1,
71.0, 49.0 (d, J¼20.2 Hz), 18.5; 19F NMR (282 MHz, CDCl3)
d
ꢁ191.9
(dd, J¼11.8, 49.6 Hz, 1F); IR (KBr) nmax 3064, 3030, 2912, 2864, 1699,
1629, 1099 cmꢁ1; MS (ESI) m/z 383 (MþH)þ; HRMS calcd for
C24H27FO3Na: 405.1842; found: 405.1836.
4.2.5. (4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluorocyclopent-2-
enone (11). A solution of Grubbs-II catalyst (10 mg) in toluene (5 mL)
was added slowly to a solution of compound 10 (150 mg, 0.39 mmol) in
toluene (10 ml) at 100 ꢀC and the reaction mixture was heated for 16 h
at 100 ꢀC. After removing the solvent in vacuo, the residue was purified
by flashchromatography (petroleum ether/ethyl acetate¼8:1) on silica
compound 8 as a colorless oil (70 mg, 45% yield) : [
a]
10.6ꢀ (c 2.85,
D25
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.32e7.22 (m, 10H), 5.81e5.69
D25
(m, 1H), 5.19e5.05 (m, 2H), 4.91e4.44 (m, 5H), 4.00(s, 1H), 3.61 (s,
2H), 3.63e3.49 (m, 2H), 2.87 (dd, J¼11.7, 12.0 Hz, 1H); 13C NMR
gel to give 11 as a yellow oil (120 mg, 95%): [
a]
ꢁ140.3ꢀ (c 0.15,
CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.66 (m, 1H), 7.39e7.25 (m, 10H),
(100.7 MHz, CDCl3)
d
169.5 (d, J¼24.0 Hz), 138.4, 138.1, 130.8, 130.7,
6.21 (d, J¼5.7 Hz 1H), 4.90e4.51 (m, 5 H), 3.84e3.66(m, 3H), 3.31e3.22
128.4, 127.7, 127.6, 127.6, 120.6, 88.8 (d, J¼187.4 Hz), 76.7, 75.7, 73.4,
(m,1H);13CNMR(100.7MHz, CDCl3)
136.6, 136.5, 131.3, 127.6, 127.5, 127.5, 127.4, 127.4, 127.1, 126.9, 126.9,
d
201.0 (d, J¼15.8Hz),160.4,160.3,
73.3, 71.1, 51.9, 49.7, 49.5; 19F NMR (282 MHz, CDCl3)
d
ꢁ191.6 (dd,
J¼34.4, 13.5 Hz 1F); IR (KBr) nmax 3030, 2951, 2862, 1758, 1102,
696 cmꢁ1; MS (ESI) m/z 373 (MþH)þ, 390 (MþNH4)þ; HRMS calcd for
C22H25FO4Na: 395.1635; found: 395.1629.
126.8, 126.7, 89.8 (d, J¼191.9 Hz), 75.8, 75.3, 72.6, 71.3, 69.0, 48.5 (d,
J¼30.3 Hz); 19F NMR (282 MHz, CDCl3)
ꢁ198.3 (dd, J¼51.3, 20.0 Hz,
d
1F); IR (KBr) nmax 3063, 3030, 2866,1726,1583,1454,1090,1028 cmꢁ1
;
MS (ESI) m/z 341 (MþH)þ; 358 (MþNH4)þ; HRMS calcd for
4.2.3. (2S,3S)-3-((S)-1,2-Bis(benzyloxy)ethyl)-2-fluoro-N-methoxy-
N-methylpent-4-enamide(9). To a stirred suspension of N,O-dime-
thylhydroxylamine hydrochloride (300 mg, 3.08 mmol,) in CH2Cl2
(10 mL) at 0 ꢀC was slowly added AlMe3 (2.0 M solution in toluene,
1.54 mL, 3.08 mmol). After stirring for 60 min, compound 8
(380 mg, 1.03 mmol) in CH2Cl2 (5 mL) was added dropwise at 0 ꢀC.
Then the reaction mixture was warmed to room temperature and
stirred for 24 h. Saturated NH4Cl solution (40 mL) was added slowly
to quench the reaction (caution: methane will bulb outside). Then
HCl solution (0.5 M, 10 mL) was added to dissolve some precipitate.
The aqueous phase was extracted with ethyl acetate, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by silica gel chromatography (petroleum ether/ethyl
acetate¼5:1) to give compound 9 as a clear oil (360 mg, 87% yield) :
C21H21FO3Na: 363.1372; found: 363.1367.
4.2.6. (1S,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluorocyclopent-
2-enol(12) and (1R,4S,5S)-4-((S)-1,2-bis(benzyloxy)ethyl)-5-fluo-
rocyclopent-2-enol(13). A solution of 11 (204 mg, 0.603 mmol) and
CeCl3$7H2O (1.3 g, 3.49 mmol) in methanol (10 mL) was cooled to
0
ꢀC, and NaBH4 (76 mg, 2 mmol) was added in portions. The so-
lution was remained at 0 ꢀC for 1 h and quenched with aqueous
ammonium chloride (20 mL). The mixture was extracted with ethyl
acetate (15 mLꢂ3), dried over Na2SO4, and the solvent was removed
under reduced pressure. The residue was purified by flash chro-
matography (petroleum ether/ethyl acetate¼5:1) on silica gel to
give 12 (144 mg, 70%) and 13 as a clear oil (45 mg, 22%).
D25
Data for compound 12: [
a
]
ꢁ45.2ꢀ (c 0.65, CHCl3); 1H NMR
D25
[
a]
32.4ꢀ (c 3.06, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.35e7.25
(300 MHz, CDCl3) d 7.43e7.32 (m, 10H), 5.94e5.87 (m, 2H), 4.84 (d,
(m, 10H), 5.82e5.73 (m, 1H), 5.41 (dd, J¼9.9, 49.8 Hz, 1H), 5.16e5.11
(m, 2H), 4.86(d, J¼11.4 Hz, 1H), 4.62 (d, J¼11.4 Hz, 1H), 4.53 (d,
J¼12.6 Hz, 1H), 4.49 (d, J¼12.6 Hz, 1H), 4.09 (t, J¼5.1 Hz, 1H), 3.63 (s,
3H), 3.60e3.46 (m, 2H), 3.14 (s, 3H), 2.98 (dd, J¼19.2, 9.6 Hz); 13C
J¼51.1 Hz, 1H), 4.80e4.57 (m, 5H), 3.89e3.96 (m, 1H), 3.71 (dd,
J¼5.3,10.2 Hz,1H), 3.65 (dd, J¼5.3,10.2 Hz,1H), 3.10 (ddd, J¼2.0, 4.1,
6.1 Hz), 2.73 (d, J¼9.8 Hz, 1H); 13C NMR (100.7 MHz, CDCl3)
d 138.0,
137.4,134.0,133.9,131.8,128.9, 128.8,128.7,128.5, 128.2,128.0,101.6
NMR (100.7 MHz, CDCl3)
d
168.0 (d, J¼23.9 Hz), 137.9, 137.2, 129.6,
(d, J¼182.0 Hz), 80.4, 80.1, 73.8, 72.9, 70.9, 53.5 (d, J¼24.2 Hz); 19F
129.5, 127.4, 127.3, 126.6, 126.5, 126.5, 120.0, 84.8 (d, J¼180.3 Hz),
NMR (282 MHz, CDCl3)
d
ꢁ179.1 (m, 1F); IR (KBr) nmax 3422, 3030,
76.4, 76.0, 75.7, 74.7, 72.7, 72.3, 71.0, 60.6, 48.4, 48.2, 31.1; 19F NMR
2862, 1496, 1453,1246, 1095 cmꢁ1; MS(ESI) m/z 360 (MþNH4)þ;
(282 MHz, CDCl3)
d
ꢁ190.9 (dd, J¼9.6, 49.6 Hz, 1F); IR (KBr) nmax
HRMS calcd for C21H23FO3Na: 365.1529; found: 365.1523.
3064, 2916, 1686, 1677, 1452, 1106, 698 cmꢁ1; MS(ESI) m/z 402
Data for compound 13: [
a
]
ꢁ139.3ꢀ (c 1.00, CHCl3); 1H NMR
D25
(MþH)þ; HRMS calcd for C22H29FO7: 424.1897; found: 424.1892.
(300 MHz, CDCl3)
d
7.65e7.56 (m, 10H), 6.20 (s, 2H), 5.13 (d,
J¼60.3 Hz, 1H), 5.03e4.81 (m, 5H), 4.08 (d, J¼4.8 Hz, 1H), 3.91e3.88
4.2.4. (5S,6S,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluoroocta-2,7-
dien-4-one(10). To a stirred solution of 9 (200 mg, 0.5 mmol) in THF
(5 mL) was added allylmagnesium chloride (1.2 mL, 2.04 mmol,
(m, 2H), 3.52 (d, J¼22.5 Hz, 1H), 2.45 (br, 1H); 13C NMR (100.7 MHz,
CDCl3)
d 138.0, 137.9, 133.5, 131.7, 131.6, 128.4, 128.3, 127.8, 127.7,
127.6, 94.0 (d, J¼184.1 Hz), 77.4, 75.4 (d, J¼17.1 Hz), 73.4, 72.4, 71.0,

3392
Y. Yang et al. / Tetrahedron 67 (2011) 3388e3394
52.8 (d, J¼21.7 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢁ179.1 (ddd,
13C NMR (75.5 MHz, CDCl3)
d
152.1, 151.3 (d, J¼44.3 Hz), 143.9, 137.6,
J¼32.1, 22.0,10.4 Hz,1F); IR (KBr) nmax 3440, 3030, 2863,1496,1454,
1209, 1072 cmꢁ1; MS (ESI) m/z 360 (MþNH4)þ; HRMS calcd for
C21H23FO3Na: 365.1529; found: 365.1523.
137.1, 136.7, 128.5, 128.3, 128.2, 127.9, 126.1, 100.5 (d, J¼190.0 Hz),
73.6, 72.3, 70.1, 65.7 (d, J¼31.9 Hz), 54.4 (d, J¼23.8 Hz); 19F NMR
(282 MHz, CDCl3)
d
ꢁ176.6 (ddd, J¼50.5, 27.4, 22.6 Hz, 1F); IR (KBr)
nmax 2921, 2855, 1748, 1733,1590, 1561, 1336, 1196, 1122, 1095 cmꢁ1
;
4.2.7. (1S,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluorocyclopent-
2-enyl methyl carbonate(14). To a stirred solution of 12 (62 mg,
MS (ESI) m/z 479 (MþH)þ, 501 (MþNa)þ; HRMS calcd for
C26H24N4O2FClNa: 501.1470; found: 501.1464.
0.183 mmol) and pyridine (59
added methyl chloroformate (57
m
L, 0.732 mmol) in CH2Cl2 (2 mL) was
m
L, 0.732 mmol) dropwise at 0 ꢀC.
4.2.11. 9-((1R,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluo-
rocyclopent-2-enyl)-9H-purin-6-amine(18). Compound 16 (50 mg,
0.105 mmol) was dissolved in NH3/MeOH (2 mL) in a sealed tube and
heated at 80 ꢀC for 12 h. The solvent was then removed in vacuo, and
the residue was purified by flash chromatography (CH2Cl2/
MeOH¼20:1) on silica gel to give compound 18 as a white solid
The reaction mixture was then stirred at 0 ꢀC for 60 min. The solvent
was removed in vacuo, and the residue was purified by flash chro-
matography (petroleum ether/ethyl acetate¼8:1) on silica gel to give
ꢁ20.5ꢀ (c 1.85,
D25
carbonate 14 (68 mg, 93% yield) as a clear oil: [
a
]
CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.33e7.23 (m, 10H), 6.02 (d,
D25
J¼6.3 Hz, 1H), 5.79 (d, J¼6.3 Hz, 1H), 5.66 (d, J¼20.7 Hz, 1H), 5.03 (dt,
(41 mg, 86% yield): mp 193 ꢀC; [
(300 MHz, CDCl3)
a
]
ꢁ25.49ꢀ (c 1.60, CHCl3); 1H NMR
J¼51.6, 3.6 Hz,1H), 4.75e4.54 (m, 4H), 3.79 (s, 3H), 3.67e3.62 (m, 3H),
d
8.39 (s, 1H), 7.74 (s, 1H), 7.39e7.35 (m, 10H), 6.19
3.1 (d, J¼25.2 Hz); 13C NMR (100.7 MHz, CDCl3)
d
155.2, 138.1, 138.0,
(d, J¼5.1 Hz, 1H), 5.97e5.92 (m, 2H), 5.78 (s, 2H), 5.07 (dd, J¼54.0,
5.7 Hz, 1H), 4.76e4.52 (m, 4H), 3.85(dd, J¼10.2, 5.1 Hz, 1H),
3.67e3.59 (m, 2H), 3.36 (d, J¼24.0 Hz); 13C NMR (100.7 MHz, CDCl3)
135.2,135.2,128.5,128.4127.9,127.7,127.7, 99.1(d, J¼185.8 Hz), 86.5 (d,
J¼29.5 Hz), 77.7, 73.5, 72.6, 70.8, 55.0, 52.5 (d, J¼22.5 Hz); 19F NMR
(282MHz,CDCl3)
d
ꢁ186.4(ddd,J¼45.7, 25.7, 21.2Hz,1F);IR(KBr) nmax
d 152.1151.9,150.9,144.9,137.7,137.6,135.2,131.5,128.7,128.6,128.3,
3064, 3030, 2955, 2863, 1752, 1442, 1269, 697 cmꢁ1; MS(ESI) m/z 418
(MþNH4)þ; HRMS calcd for C23H25FO5Na: 423.1584; found: 423.1578.
128.2, 128.0, 127.8, 93.3 (d, J¼190.5 Hz), 73.7, 72.4, 70.2, 60.8 (d,
J¼16.9 Hz), 54.6 (d, J¼21.9 Hz); 19F NMR (282 MHz, CDCl3)
ꢁ188.3
d
(ddd, J¼44.0, 25.4, 18.0 Hz, 1F); IR (KBr) nmax 3311, 2922, 2851, 1647,
1597,1473,1096, 698 cmꢁ1;MS (ESI) m/z 479 (MþH)þ, 501 (MþNa)þ;
HRMS calcd for C26H27N5O2F: 460.2143; found: 460.2133.
4.2.8. (1R,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluorocyclopent-
2-enyl methyl carbonate(15). Using the same conditions as de-
scribed for compound 14, compound 15 (115 mg, 96%) was prepared
as a clear oil from compound 13 (103 mg, 0.30 mmol): [
a
]
ꢁ48.6ꢀ
4.2.12. 9-((1S,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluo-
rocyclopent-2-enyl)-9H-purin-6-amine(19). Using the same condi-
tions as described for compound 18, compound 19 (58 mg, 80%)
was prepared as a white solid from compound 17 (72 mg,
D25
(c 1.95, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.35e7.25 (m,10H), 6.08
(s, 1H), 5.87 (s, 1H), 5.02 (d, J¼53.1 Hz, 1H), 4.76e4.53 (m, 4H), 3.79
(s,3H), 3.78 (m, 1H), 3.63 (d, J¼3.3 Hz, 2H), 3.27 (d, J¼20.7 Hz); 13C
NMR (100.7 MHz, CDCl3)
d
155.3, 138.0, 137.9, 135.8, 135.7, 128.2,
0.15 mmol): mp 201 ꢀC; [
(300 MHz, CDCl3) d 8.40 (s,1H), 7.74 (s,1H), 7.40e7.07 (m, 10H), 6.31
a
]
ꢁ13.2ꢀ(c 0.60, CHCl3); 1H NMR
D25
128.0, 127.9, 127.8, 127.7, 91.6 (d, J¼194.0 Hz), 79.0 (d, J¼14.9 Hz),
73.5, 72.5, 71.0, 54.9, 52.4 (d, J¼21.2 Hz); 19F NMR (282 MHz, CDCl3)
(s, 2H), 6.22 (d, J¼5.7 Hz, 1H), 5.84 (d, J¼5.1 Hz, 1H), 5.74 (d,
J¼23.1 Hz, 1H), 4.98 (d, J¼51.6 Hz, 1H), 4.67e4.44 (m, 4H),
3.80e3.77 (m, 1H), 3.68 (s, 2H), 3.27 (d, J¼27.0 Hz, 1H); 13C NMR
d
ꢁ199.6 (ddd, J¼26.5, 21.1, 5.4 Hz, 1F); IR (KBr) nmax 3063, 3031,
2955, 2863,1746,1441,1262, 696 cmꢁ1; MS (ESI) m/z 418 (MþNH4)þ;
HRMS calcd for C23H25FO5Na: 423.1584; found: 423.1578.
(100.7 MHz, CDCl3) d 155.6, 152.9, 149.8, 138.9, 137.7, 137.3, 135.5,
128.4, 128.4, 128.2, 128.0, 127.8, 127.7, 127.6, 126.8, 119.6, 100.8 (d,
4.2.9. 9-((1R,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluo-
rocyclopent-2-enyl)-6-chloro-9H-purine(16). To a mixture of com-
pound 12 (69 mg, 0.204 mmol), 6-chloropurine (64 mg, 0.416 mmol),
and PPh3 (142 mg, 0.541 mmol) in dry THF (2 mL) was added DEAD
(95 mg, 0.546 mmol) slowly at 0 ꢀC. Then the reaction mixture was
warmed to room temperature and stirred overnight. The solvent was
removed in vacuo, and the residue was purified by flash chroma-
tography (petroleum ether/ethyl acetate¼3:1) on silica gel to give
J¼86.7 Hz), 73.5, 72.2, 70.3, 65.0 (d, J¼30.7 Hz), 54.1 (d, J¼23.2 Hz),
29.6; 19F NMR (282 MHz, CDCl3)
d
ꢁ177.8 (ddd, J¼50.5, 27.1, 22.0 Hz,
1F); IR (KBr) nmax 3311, 3171, 2922, 2851, 1647, 1597, 1473, 1328,
1096, 698 cmꢁ1; MS (ESI) m/z 460 (MþH)þ, 482 (MþNa)þ; HRMS
calcd for C26H27N5O2F: 460.2149; found: 460.2143.
4.2.13. (S)-1-((1S,4R,5S)-4-(6-Amino-9H-purin-9-yl)-5-fluo-
rocyclopent-2-enyl)ethane-1,2-diol(20). To a solution of compound
18 (34 mg, 0.074 mmol) in anhydrous CH2Cl2 (3 mL) was added BCl3
(1 M in CH2Cl2, 0.75 mL, 0.75 mmol) at ꢁ30 ꢀC. After the reaction
mixture was stirred for 2 h, the mixture was quenched with MeOH
(2 mL), and the solvent was removed in vacuo. The residue was
purified by silica gel column (CH2Cl2/MeOH¼12:1) to give com-
D25
a]
compound 16 as a pale yellow oil (47 mg, 48% yield): [
ꢁ42.4ꢀ (c
0.90, CHCl3); 1H NMR (300 MHz, CDCl3)
d
8.79 (s, 1H), 8.05 (d,
J¼2.4 Hz, 1H), 7.40e7.31 (m, 10H), 6.22 (d, J¼5.7 Hz, 1H), 6.02 (d,
J¼17.7 Hz), 5.95 (d, J¼5.7 Hz, 1H), 5.07 (dd, J¼52.8, 5.4 Hz, 1H),
4.78e4.54 (m, 4H), 3.91 (dd, J¼9.6, 4.5 Hz, 1H), 3.69e3.58 (m, 2H),
3.40 (d, J¼27.3 Hz, 1H); 13C NMR (100.7 MHz, CDCl3)
d
152.1, 151.9,
pound20 as a foam (19 mg, 90% yield):[
a
]
ꢁ101.2ꢀ(c0.36, CH3OH);
D25
150.9, 144.9, 137.7, 137.6, 135.2, 131.5, 128.7, 128.6, 128.3, 128.2, 128.0,
1H NMR (300 MHz, CD3OD)
d 8.45 (s, 1H), 8.25 (s, 1H), 6.37 (d,
127.8, 93.3 (d, J¼190.5 Hz), 73.7, 72.4, 70.2, 60.8 (d, J¼16.9 Hz), 54.6 (d,
J¼4.5 Hz, 1H), 6.11(d, J¼6.0 Hz,1H), 5.99 (d, J¼16.8 Hz, 1H), 5.36 (dd,
J¼53.1, 4.2 Hz,1H), 3.96 (dd, J¼10.5, 5.1 Hz,1H), 3.61 (d, J¼5.7 Hz, 2H),
J¼21.9 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢁ188.3 (ddd, J¼44.0, 25.4,
18.0 Hz, 1F); IR (KBr) nmax 3064, 2864, 1776, 1699, 1591, 1561, 1402,
1336, 1200, 1102 cmꢁ1; MS (ESI) m/z 479(MþH)þ, 501(MþNa)þ;
HRMS calcd for C26H25N4O2FCl: 479.1650; found: 479.1645.
3.35 (d, J¼11.7 Hz, 1H); 13C NMR (75.5 MHz, CD3OD)
d 156.6, 151.7,
147.6, 142.4, 141.9, 133.9, 125.7, 116.9, 91.9 (d, J¼194.3 Hz), 70.0 (d,
J¼6.3 Hz), 62.4, 59.6, 53.0 (d, J¼21.2 Hz); 19F NMR (282 MHz, CD3OD)
d
ꢁ191.6 (ddd, J¼40.6, 25.9, 14.7 Hz, 1F); IR (KBr) nmax 3422, 1686,
4.2.10. 9-((1S,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluo-
rocyclopent-2-enyl)-6-chloro-9H-purine(17). Using the same con-
ditions as described for compound 16, compound 17 (66 mg, 55%)
was prepared as a pale yellow oil from compound 13 (86 mg,
1497,1416,1228,1095 cmꢁ1; MS (ESI) m/z 280 (MþH)þ; HRMS calcd
for C12H15FN5O2: 280.1210; found: 280.1204.
4.2.14. (S)-1-((1S,4S,5S)-4-(6-Amino-9H-purin-9-yl)-5-fluo-
rocyclopent-2-enyl)ethane-1,2-diol(21). Using the same conditions
as described for compound 20, compound 21 (31 mg, 94%) was
0.25 mmol): [
a
]
ꢁ18.0ꢀ(c 1.05, CHCl3); 1H NMR (300 MHz, CDCl3)
D25
d
8.77 (s, 1H), 8.05 (s, 1H), 7.39e7.00 (m, 10H), 6.27 (d, J¼4.8 Hz, 1H),
5.86 (d, J¼6.0 Hz, 1H), 5.66 (d, J¼22.2 Hz, 1H), 4.93 (d, J¼51.9 Hz,
1H), 4.61e4.40 (m, 4H), 3.82e3.34 (m, 2H), 3.29 (d, J¼30.0 Hz, 1H);
prepared as a foam from compound 19 (57 mg, 0.12 mmol): [
a]
D25
4.5ꢀ (c 1.50, CH3OH); 1H NMR (300 MHz, CD3OD)
d
8.77 (s, 1H), 8.68

Y. Yang et al. / Tetrahedron 67 (2011) 3388e3394
3393
(s, 1H), 6.65 (d, J¼5.1 Hz, 1H), 6.30 (d, J¼5.7 Hz, 1H), 6.16 (d,
J¼22.5 Hz, 1H), 5.58 (d, J¼51.9 Hz, 1H), 4.16 (dd, J¼10.5, 5.7 Hz, 1H),
3.95 (d, J¼6.0 Hz, 2H), 3.52 (d, J¼27.9 Hz, 1H); 13C NMR (100.7 MHz,
25.9, 18.3 Hz, 1F); IR (KBr) nmax 3381, 3185, 1645, 1576, 1385, 1107,
698 cmꢁ1
;
MS (ESI) m/z 437 (MþH)þ; HRMS calcd for
C25H25FN2O4Na: 459.1696; found: 459.1691.
CD3OD)
d 150.3, 148.8, 143.7, 142.8, 135.7, 126.5, 118.6, 100.8 (d,
J¼186.9 Hz), 71.5, 66.0 (d, J¼31.7 Hz), 63.9, 54.3 (d, J¼22.4 Hz); 19F
4.2.18. 1-((1R,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluo-
rocyclopent-2-enyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(25). Using the same conditions as described for compound 24,
compound 25 (33 mg, 37%) was prepared as a yellow oil from
NMR (282 MHz, CD3OD)
d
ꢁ178.8 (m, 1F); IR (KBr) nmax 3415, 1712,
1608, 1557, 1379, 1143, 1095, 600 cmꢁ1; MS(ESI) m/z 280 (MþH)þ;
HRMS calcd for C12H15FN5O2: 280.1210; found: 280.1204.
compound 12 (68 mg, 0.2 mmol): [
a
]
18.5ꢀ(c 0.35,CHCl3); 1H
D25
4.2.15. ((1S,4R,5S)-4-(6-Amino-9H-purin-9-yl)-5-fluorocyclopent-2-
enyl)methanol(22). Compound 20 was dissolved in methanol
(1 mL), followed by treatment with a solution of saturated NaIO4
(0.2 mL) at room temperature with stirring. After the reaction
mixture was stirred for 15 min, NaBH4 (22 mg, 0.585 mmol) was
added in portions at 0 ꢀC, and the mixture was stirred at 0 ꢀC for 1 h.
Then the reaction was quenched by aqueous NH4Cl, extracted with
EtOAc, dried by Na2SO4. The solvent was then removed under re-
duced pressure, and the residue was purified by flash chromatog-
raphy (CH2Cl2/MeOH¼15:1) on silica gel to give 22 as a white solid
NMR (300 MHz, CDCl3) 9.21 (s, 1H), 7.37e7.31 (m, 10H), 6.93 (s,
d
1H), 6.12 (d, J¼5.4 Hz, 1H), 5.77 (d, J¼20.7 Hz, 1H), 5.75 (d, J¼5.4 Hz,
1H), 5.02 (dd, J¼53.1, 5.4 Hz, 1H), 4.71e4.49 (m, 4H), 3.83 (dd,
J¼10.2, 5.4 Hz), 3.59 (ddd, J¼15.0, 10.2, 4.8 Hz, 1H), 3.27 (d,
J¼27.6 Hz, 1H), 1.89(s, 3H); 13C NMR (100.7 MHz, CDCl3)
d 164.2,
151.3, 138.4, 138.4, 137.7, 137.5, 134.7, 128.7, 128.6, 128.5, 128.3, 128.1,
127.9, 127.8, 109.6, 93.7 (d, J¼188.2 Hz), 73.6, 72.5, 70.3, 62.0 (d,
J¼16.2 Hz), 54.7 (J¼22.1 Hz), 12.5; 19F NMR (282 MHz, CDCl3)
d
ꢁ189.7 (ddd, J¼45.7, 27.1, 18.0 Hz, 1F); IR (KBr) nmax 3186, 3032,
2925, 2863, 1689, 1454, 1261, 1101, 746, 699 cmꢁ1; MS (ESI) m/z 451
(MþH)þ; HRMS calcd for C26H27FN2O4Na: 473.1853; found:
473.1847.
(11 mg, 75% yield): mp 190 ꢀC; [
NMR (300 MHz, CD3OD)
a
]
ꢁ28.9ꢀ(c 0.85, CH3OH); 1H
D25
d
8.24 (s,1H), 8.02 (s, 1H), 6.24 (s, 1H), 6.06
(d, J¼3.9 Hz, 1H), 5.87 (d, J¼15.3 Hz, 1H), 5.26 (dd, J¼53.1, 4.2 Hz,
1H), 3.82e3.62 (m, 2H), 3.22 (d, J¼24.6 Hz, 1H); 13C NMR
4.2.19. 1-((1R,4S,5S)-4-((S)-1,2-Dihydroxyethyl)-5-fluorocyclopent-
2-enyl)pyrimidine-2,4(1H,3H)-dione (26). Using the same condi-
tions as described for compound 20, compound 26 (27 mg, 95%)
(100.7 MHz, CD3OD)
d 155.8, 152.2, 149.5, 140.5, 136.1, 127.4, 118.4,
92.6 (d, J¼189.6 Hz), 60.6 (d, J¼36.8 Hz), 54.5 (d, J¼20.6 Hz); 19F
NMR (282 MHz, CD3OD)
d
ꢁ193.0 (ddd, J¼39.8, 25.1, 15.8 Hz, 1F); IR
was prepared as
0.11 mmol): [
CD3OD)
a yellow oil from compound 24 (48 mg,
(KBr) nmax 3410, 3185, 2925, 1648, 1602, 1477, 1068 cmꢁ1; MS (ESI)
m/z 250 (MþH)þ; HRMS calcd for C11H13FN5O: 250.1104; found:
250.1099.
a
]
D25
ꢁ21.0ꢀ (c 0.65, MeOH); 1H NMR (300 MHz,
d
7.29 (d, J¼6.9 Hz, 1H), 6.14 (d, J¼3.3 Hz, 1H), 5.78 (d,
J¼6.3 Hz, 1H), 5.71 (d, J¼17.1 Hz, 1H), 5.65 (d, J¼7.5 Hz, 1H), 5.40 (s,
1H), 5.11 (dd, J¼53.1, 5.4 Hz, 1H), 3.78 (dd, J¼10.5, 4.5 Hz, 1H), 3.45
(d, J¼5.7 Hz, 1H), 3.20 (d, J¼28.2 Hz, 1H); 13C NMR (100.7 MHz,
4.2.16. ((1S,4S,5S)-4-(6-Amino-9H-purin-9-yl)-5-fluorocyclopent-2-
enyl)methanol(23). Using the same conditions as described for
compound 22, compound 23 (17 mg, 79%) was prepared as a white
CD3OD)
d
165.3,151.8,143.6,134.8, 128.2, 100.3, 93.9 (d, J¼187.4 Hz),
71.9 (d, J¼8.3 Hz), 64.2, 62.6 (d, J¼16.2 Hz), 55.1 (d, J¼21.2 Hz), 53.6;
solid from compound 21 (25 mg, 0.09 mmol): mp 188 ꢀC; [
a
]
19F NMR (282 MHz, CD3OD)
d
ꢁ190.9 (ddd, J¼44.0, 27.9, 16.4 Hz,
D25
32.6ꢀ(c 0.80, CH3OH); 1H NMR (300 MHz, CD3OD)
d
8.63 (s, 1H),
1F); IR (KBr) nmax 3428, 2995, 1688, 1664, 1466, 1412, 1260,
8.52 (s, 1H), 6.59 (d, J¼5.4 Hz, 1H), 6.35 (d, J¼5.4 Hz, 1H), 5.60 (d,
1047 cmꢁ1
;
MS (ESI) m/z 257 (MþH)þ; HRMS calcd for
J¼52.2 Hz, 1H), 4.22e4.11 (m,2H), 3.52 (d, J¼27.3 Hz, 1H); 13C NMR
C11H13FN2O4Na: 279.0757; found: 279.0752.
(100.7 MHz, CD3OD)
d 157.7, 154.1, 150.9, 141.3, 138.2, 128.6, 120.6,
101.9 (d, J¼186.1 Hz), 67.5 (d, J¼30.7 Hz), 62.9 (d, J¼4.7 Hz), 56.0 (d,
4.2.20. 1-((1R,4S,5S)-4-((S)-1,2-Dihydroxyethyl)-5-fluorocyclopent-
2-enyl)-5-methylpyrimidine-2,4(1H,3H)-dione (27). Using the same
conditions as described for compound 20, compound 27 (23 mg,
92%) was prepared as a foam from compound 25 (48 mg,
J¼22.3 Hz); 19F NMR (282 MHz, CD3OD)
d
ꢁ179.1 (m, 1F); IR (KBr)
nmax 3436,1679,1606,1470,1414,1296, 1094 cmꢁ1; MS(ESI) m/z 250
(MþH)þ; HRMS calcd for C11H13FN5O: 250.1104; found: 250.1099.
0.11 mmol): [
CD3OD)
a
]
ꢁ43.0ꢀ(c 0.90, CH3OH); 1H NMR (300 MHz,
D25
4.2.17. 1-((1R,4S,5S)-4-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluo-
rocyclopent-2-enyl)pyrimidine-2,4(1H,3H)-dione (24). To a mixture
of compound 13 (69 mg, 0.204 mmol), 3-benzoyl uracil (64 mg,
0.416 mmol), and PPh3 (142 mg, 0.541 mmol) in dry THF (2 mL) was
added DEAD (95 mg, 0.546 mmol) slowly at 0 ꢀC. Then the reaction
mixture was warmed to room temperature and stirred overnight.
The solvent was then removed in vacuo, and the residue was pu-
rified by flash chromatography (petroleum ether/ethyl
acetate¼3:1) on silica gel to give the crude product. To a solution of
the crude product in MeOH (3 mL) was added NH3/MeOH (3 mL)
and the reaction mixture was stirred at room temperature for 2 h.
Then The solvent was removed under reduced pressure, and the
residue was purified by flash chromatography (CH2Cl2/
MeOH¼20:1) on silica gel to give 24 as a yellow oil (36 mg, 40%
d
7.08 (s, 1H), 6.12 (d, J¼5.4 Hz, 1H), 5.78 (d, J¼6.0 Hz, 1H),
5.57 (d, J¼13.8 Hz, 1H), 5.09 (dd, J¼53.4, 5.4 Hz, 1H), 3.79 (dd,
J¼10.5, 6.0 Hz), 3.45e3.21 (m, 4H), 3.13 (s, 1H), 3.04 (s, 1H), 1.75 (s,
3H); 13C NMR (100.7 MHz, CD3OD)
d 165.2, 151.7, 139.1, 134.4, 128.2,
108.8, 93.7 (d, J¼187.4 Hz), 71.7 (d, J¼8.0 Hz), 64.0, 62.2 (d,
J¼15.4 Hz), 54.9 (d, J¼21.0 Hz), 10.9; 19F NMR (282 MHz, CD3OD)
d
ꢁ191.0 (ddd, J¼44.0, 27.9, 16.6 Hz, 1F); IR (KBr) nmax 3413, 1686,
1655, 1461, 1383, 1257, 999 cmꢁ1; MS (ESI) m/z 271 (MþH)þ; HRMS
calcd for C12H15FN2O4Na: 293.0932; found: 293.0908.
4.2.21. 1-((1R,4S,5S)-5-Fluoro-4-(hydroxymethyl)cyclopent-2-enyl)
pyrimidine-2,4(1H,3H)-dione (28). Using the same conditions as
described for compound 22, compound 28 (16 mg, 80%) was pre-
pared as a sticky oil from compound 26(23 mg, 0.09 mmol): [
a]
D25
yield for two steps): [
CDCl3)
a
]
ꢁ36.4ꢀ (c 1.65, CHCl3); 1H NMR (300 MHz,
0.9ꢀ (c 0.65, MeOH); 1H NMR (300 MHz, CD3OD)
d
7.28 (d, J¼6.3 Hz,
D25
d
9.65 (s, 1H), 7.84 (d, J¼7.5 Hz, 1H), 7.82e7.26 (m, 10H), 7.10
1H), 6.06 (t, J¼3.0 Hz, 1H), 5.75 (d, J¼6.0 Hz, 1H), 5.58 (d, J¼18.0 Hz,
1H), 5.54 (d, J¼8.1 Hz, 1H), 5.05 (dd, J¼52.8, 5.1 Hz, 1H), 3.63 (dd,
J¼11.1, 4.8 Hz, 1H), 3.45 (dd, J¼11.1, 6.0 Hz, 1H), 3.00 (d, J¼26.4 Hz,
(d, J¼7.5 Hz, 1H), 6.28 (s, 1H), 6.11 (s, 1H), 5.74e5.65 (m, 2H), 5.02
(dd, J¼52.8, 5.1 Hz, 1H), 4.71e4.49 (m, 1H), 4.21 (dd, J¼8.4, 3.6 Hz),
3.96 (ddd, J¼14.7, 10.2, 4.8 Hz, 2H), 3.26 (d, J¼28.2 Hz, 1H); 13C NMR
1H); 13C NMR (100.7 MHz, CD3OD)
31.5 Hz), 132.7, 131.8, 129.6, 128.5, 128.3, 127.9, 127.7, 126.5, 126.2,
d
170.6, 159.7 (dd, J¼63.4,
(100.7 MHz, CDCl3)
d
169.8, 163.9, 151.2, 142.6, 137.7, 137.5, 135.0,
133.4, 132.0, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8, 127.4,
126.2, 125.6, 125.1, 124.7, 123.7, 118.5 (d, J¼299.8 Hz),35.3 (d,
101.2, 93.6 (d, J¼188.6 Hz), 73.6, 72.4, 70.2, 62.3 (d, J¼16.2 Hz), 54.7
J¼224.9 Hz); 19F NMR (282 MHz, CD3OD)
d
ꢁ192.2 (ddd, J¼43.4,
(d, J¼22.0 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢁ188.2 (ddd, J¼45.4,
25.9, 17.5 Hz, 1F); IR (KBr) nmax 3428, 1713, 1665, 1284, 1221, 1070,

3394
Y. Yang et al. / Tetrahedron 67 (2011) 3388e3394
958 cmꢁ1; MS (ESI) m/z 227 (MþH)þ; HRMS calcd for C10H12FN2O3:
Boone, L.; Tisdale, M.; Parry, N.; Reardon, J.; Dornsife, R.; Averett, D.; Krenitsky,
T. Antimicrob. Agents Chemother. 1997, 41, 1082.
227.0832; found: 227.0827.
4. (a) Yin, X.-Q.; Schneller, S. W. Tetrahedron Lett. 2005, 46, 7535; (b) Moon, H. R.;
Lee, H. J.; Kim, K. R.; Lee, K. M.; Lee, S. K.; Kim, H. O.; Chun, M. W.; Jeong, L. S.
Bioorg. Med. Chem. Lett. 2004, 14, 5641; (c) Kim, H. O.; Yoo, S. J.; Ahn, H. S.; Choi,
W. J.; Moon, H. R.; Lee, K. M.; Chun, M. W.; Jeong, L. S. Bioorg. Med. Chem. Lett.
2004, 14, 2091; (d) Jeong, L. S.; Yoo, S. J.; Lee, K. M.; Koo, M. J.; Choi, W. J.; Kim,
H. O.; Moon, H. R.; Lee, M. Y.; Park, J. G.; Lee, S. K.; Chun, M. W. J. Med. Chem.
2003, 46, 201; (e) Wachtmeister, J.; Classon, B.; Samuelsson, B. Tetrahedron
1997, 53, 1861; (f) Payne, A. N.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1992,
2633; (g) Highcock, R. M.; Hilpert, H.; Myers, P. L.; Roberts, S. M.; Storer, R. J.
Chem. Soc., Perkin Trans. 1 1991, 1127; (h) Coe, D. M.; Parry, D. M.; Roberts, S. M.;
Storer, R. J. Chem. Soc., Perkin Trans. 1 1991, 2373; (i) Coe, D. M.; Myers, P. L.;
Parry, D. M.; Roberts, S. M.; Storerb, R. J. Chem. Soc., Chem. Commun. 1990, 151;
(j) Borthwick, A. D.; Evans, D. N.; Kirk, B. E.; Biggadike, K.; Exall, A. M.; Youds, P.;
Roberts, S. M.; Knight, D. J.; Coates, J. A. V. J. Med. Chem. 1990, 33, 179; (k)
Fletcher, C. A.; Hilpert, H.; Myers, P. L.; Roberts, S. M.; Storer, R. J. Chem. Soc.,
Chem. Commun. 1989, 1707; (l) Madhavan, G. V. B.; McGee, D. P. C.; Rydzewski,
R. M.; Boehme, R.; Martin, J. C.; Prisbe, E. J. J. Med. Chem. 1988, 31, 1798; (m)
Biggadike, K.; Borthwick, A. D.; Exall, A. M.; Kirk, B. E. K.; Roberts, S. M.; Youds,
P.; Slawin, A. M. Z.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1987, 255.
5. Hamamoto, Y.; Nakashima, H.; Matsui, T.; Matsuda, A.; Ueda, T.; Yamamoto, N.
Antimicrob. Agents Chemother. 1987, 31, 907.
4.2.22. 1-((1R,4S,5S)-5-Fluoro-4-(hydroxymethyl)cyclopent-2-enyl)-
5-methylpyrimidine-2,4(1H,3H)-dione (29). Using the same condi-
tions as described for compound 22, compound 29 (16 mg, 82%)
was prepared a sticky oil from compound 27 (22 mg, 0.08 mmol):
[
a]
ꢁ12.9ꢀ(c 0.65, CH3OH); 1H NMR (300 MHz, CD3OD)
d 7.13 (s,
D25
1H), 6.12 (d, J¼6.3 Hz, 1H), 5.81 (d, J¼5.7 Hz, 1H), 5.61 (d, J¼18.6 Hz,
1H), 5.09 (dd, J¼52.5, 4.8 Hz, 1H), 3.68 (dd, J¼11.1, 4.5 Hz, 1H), 3.50
(dd, J¼11.1, 6.3 Hz, 1H), 3.06 (d, J¼26.7 Hz,1H), 1.81 (s, 3H); 13C NMR
(100.7 MHz, CD3OD) d 165.2, 151.7, 139.1, 135.8, 127.6, 108.8, 92.8 (d,
J¼187.9 Hz), 62.3 (d, J¼16.3 Hz), 60.8 (d, J¼9.3 Hz), 54.8 (d,
J¼21.0 Hz), 10.8; 19F NMR (282 MHz, CD3OD)
ꢁ192.1 (ddd, J¼44.3,
d
26.5, 18.0 Hz, 1F); IR (KBr) nmax 3448, 2926, 1691, 1469, 1388,
1258 cmꢁ1
C11H13FN2O3Na: 263.0808; found: 263.0802.
;
MS (ESI) m/z 241 (MþH)þ; HRMS calcd for
6. (a) Trost, B. M.; Madsen, R.; Guile, S. D. Tetrahedron Lett. 1997, 38, 1707; (b) Trost,
B. M.; Madsen, R.; Guile, S. G.; Elia, A. E. H. Angew. Chem., Int. Ed. 1996, 35, 1569.
7. For review, see: Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P.
Chem. Rev. 2009, 109, 2551.
8. For review about metathesis in nucleoside chemistry, see: Amblard, F.; Nolan,
S. P.; Agrofoglio, L. A. Tetrahedron 2005, 61, 7067.
9. (a) Araki, K.; Welch, J. T. Tetrahedron Lett. 1993, 34, 2251; (b) Welch, J. T.;
Plummer, J. S.; Chou, T. S. J. Org. Chem. 1991, 56, 353; (c) Welch, J. T.; Samartino,
J. S. J. Org. Chem. 1985, 50, 3663.
Acknowledgements
We thank National Natural Science Foundation of China
(21072028, 20832008) for funding this work.
References and notes
10. (a) Marais, J. S. C. Onderstepoort J. Vet. Sci. Anim. Ind. 1944, 20, 67; (b) Marais, J. S.
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Yang, Y.-Y.; Meng, W.-D.; Qing, F.-L. Org. Lett. 2004, 6, 4257.
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12. Crystal data have been deposited at the Cambridge Crystallographic Data
Center with reference number: CCDC 805686.
3. (a) Weller, S.; Radomski, K. M.; Lou, Y.; Stein, D. S. Antimicrob. Agents Chemother.
2000, 44, 2052; (b) Daluge, S.; Good, S.; Faletto, M.; Miller, W.; St. Clair, M.;