A divergent synthesis of D- and L-carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides as potential antiviral agents

Article abstract of DOI:10.1016/S0957-4166(00)00482-1

D- and L-Carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides have been synthesized from 2, which can be conveniently prepared from 1,2:5,6-di-O-isopropylidene-D-mannitol 1 in eight steps. Ruthenium-catalyzed ring-closing metathesis has been employed in the syn

Full text of DOI:10.1016/S0957-4166(00)00482-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4853–4875
A divergent synthesis of
D
- and -carbocyclic
L
4%-fluoro-2%,3%-dideoxynucleosides as potential antiviral agents
Youhoon Chong, Giuseppe Gumina and Chung K. Chu*
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens,
GA 30602, USA
Received 29 September 2000; accepted 16 November 2000
Abstract
D
- and
conveniently prepared from 1,2:5,6-di-O-isopropylidene-
ring-closing metathesis has been employed in the synthesis of
L
-Carbocyclic 4%-fluoro-2%,3%-dideoxynucleosides have been synthesized from 2, which can be
-mannitol 1 in eight steps. Ruthenium-catalyzed
-nucleosides, whereas the -series have
D
D
L
been obtained through an intramolecular nucleophilic substitution reaction. The Mitsunobu condensation
was used as a general tool for the synthesis of both purine and pyrimidine nucleosides. © 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Nucleoside analogues display a wide range of biological activities and have attracted
particular attention as antitumor and antiviral agents.1 In spite of the initial success obtained
with several nucleosides, the instability of the glycosidic bond of the classical 4%-oxonucleosides
under physiological conditions2 as well as undesirable side effects and toxicities of certain
nucleosides have prompted the search for other antiviral or antitumor agents with improved
biological and chemical properties. Consequently, extensive modifications have been made to
both the heterocyclic base as well as the sugar moiety,3 and the latter has been extensively
substituted by acyclic4 and carbocyclic moieties.5 Among several approaches to modify the
structure of nucleosides, carbocyclic nucleosides have attracted great interest because the
replacement of the furanose ring oxygen offers greater metabolic stability to the endogenous
phosphorylases which cleave the glycosidic linkage.6 Another interesting feature of carbocyclic
nucleosides is that a number of carbocyclic adenosine analogues are assumed to exert their
antiviral action through the inhibition of S-adenosylhomocysteine hydrolase, and this mecha-
nism might be exploited in a combination therapy in association with nucleosides acting with
* Corresponding author. Tel: (706)-542-5379; fax: (706)-542-5381; e-mail: dchu@rx.uga.edu
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00482-1

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
different mechanisms.7 The recent approval of abacavir (Fig. 1) by the Food and Drug
Administration for the treatment of HIV shows the therapeutic significance of carbocyclic
nucleosides.8
Figure 1.
However, since the conformation of the five-membered ring is believed to play a critical role
in modulation of biological activity, the structural change following the removal of the oxygen
is significant and generally results in decreased biological activity. Introduction of a small and
highly electronegative fluoride atom to a nucleoside structure has been employed to confer
biologically active conformations to the carbocyclic nucleosides.9 The isosteric relationship
between oxygen and a fluoromethylene group10 has prompted various syntheses of fluoro-substi-
tuted carbocyclic nucleosides. Several fluoride-containing carbocyclic nucleosides at 2%, 3%, and 6%
positions have been reported.11 Thus, 2%-ara-fluoro and 6%-a-fluoro substituent have been shown
to confer potent antiherpes activity to some purine analogues12 (Fig. 1). In contrast, substitution
at the 4%-position of carbocyclic nucleosides has been largely ignored despite the presence of a
4%-fluoro substituent in the naturally occurring furanose antibiotic nucleocidin (Fig. 1). To our
knowledge, carbocyclic 4%-fluoro-2%-deoxyguanosine from aristeromycin,13 and carbocyclic 4%-a-
fluoro-2%-ara-fluoro guanosine14 (Fig. 1), which showed potent anti HSV-1 and anti HSV-2
activity, are the only examples of 4%-fluoro-substituted carbocyclic nucleosides. The importance
of carbocyclic nucleosides as antiviral agents, as well as the potential importance of fluorine
substitution, prompted us to combine these two features into novel carbocyclic 4%-fluoro-2%,3%-
dideoxy nucleosides.15,16
Previously, we have reported preliminary synthetic results of 4%-substituted carbocyclic
nucleosides as a communication.16b Herein we report an efficient and general approach to the
asymmetric synthesis of
D
- and
L
-carbocyclic 4%-fluoro-2%,3%-dideoxy nucleosides by using the
common intermediate 2 (Scheme 1)17 obtained by [3,3]-sigmatropic rearrangement of a fluoro
allylic alcohol. Starting from this common intermediate, we developed a divergent synthetic
pathway leading to both
by way of classical five-membered ring cyclization method, whereas a more convenient ring-clos-
ing metathesis route was employed for the synthesis of the -isomer. In both cases, the
Mitsunobu condensation between an a-cyclopentanol and heterocyclic bases was generally used.
D
- and
L
-nucleosides. The synthesis of the
L
-isomer was accomplished
D

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4855
Scheme 1. Synthesis of (1%R,4%R)-9-[4-fluoro-4-(hydroxymethyl)cyclopentan-1-yl]adenine (15). Reagents and condi-
tions: (a) LAH, THF, −40 to −35°C; (b) NaH, BnBr, THF; (c) O3, MeOH, −78°C, then DMS; (d)
(EtO)2P(O)CH2CO2Et, NaHMDS, THF, −78°C; (e) H2, Pd/C, cyclohexane; (f) MsCl, pyridine, CH2Cl2, 0°C; (g)
NaH, THF, reflux; (h) NaOH/H2O, EtOH, rt; (i) Pb(OAc)4, CCl4, hw, reflux, 15 min; I2, CCl4, hw, reflux, 2 h; (j)
NaHCO3, 15% (v/v) water/HMPA, 100°C; (k) 6-chloropurine, DEAD, PPh3, THF; (l) NH3, MeOH, 100°C, steel
bomb; (m) TBAF, THF, rt
2. Results and discussion
Even though the critical intermediate 2 was easily obtained, the cyclopentanol derivative 12
could not be prepared straightforwardly because the tertiary fluoride group was very susceptible
for b-elimination under basic conditions. Several classical methods such as the Dieckmann
condensation18 of diesters and the intramolecular Horner–Emmons reaction of a b-
ketophosphonate19 were tried, but failed because the highly acidic a proton of the ester 2 was
easily abstracted to result in the formation of a diene.20 As reported previously,16b the
susceptibility of the protected ester 2 toward elimination made the synthesis of the
L
-isomer
more difficult than expected (Scheme 1). In order to synthesize -nucleosides, ester 2 was
L
reduced to alcohol 3 in 95% yield by treatment with a solution of lithium aluminum hydride in
THF at −40°C followed by an anhydrous work-up. At temperatures higher than −20°C, the
eliminated by-product was obtained as an inseparable mixture with 3. Alcohol 3 was benzylated
to a fully protected triol 4, which was treated with ozone in methanol at −78°C, followed by
decomposition of the ozonide by dimethyl sulfide to give the aldehyde 5. The Horner–Emmons
reaction was performed by the treatment of 5 with the sodium salt of triethyl phosphonoacetate
in THF. E-Alkene 6, obtained in 80% yield, was quantitatively converted to the intermediate 8
by catalytic hydrogenolysis followed by mesylation of the resulting alcohol 7. Treatment of 8

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
with sodium hydride in THF under reflux generated the enolate that cyclized through an
intramolecular nucleophilic substitution reaction to produce epimeric esters 9 in 75% yield. The
esters 9 were hydrolyzed to acids 10 by treatment with a solution of sodium hydroxide in 1:1
water/ethanol, followed by careful acidification. Oxidative iododecarboxylation of 10 could be
achieved by the method reported by Barton et al.21 to afford epimeric iodides 11, which were
smoothly hydrolyzed by heating at 100°C in a solution of sodium bicarbonate in 15%
water/HMPA. Surprisingly, only the a-alcohol could be isolated from the hydrolysis of the
mixture 11 (epimeric ratio:1:1). Under the reaction conditions, the a-iodide was not hydrolyzed
and only longer reaction times or higher temperatures caused its decomposition. A solution of
the alcohol 12 was added to a mixture containing 6-chloropurine and the preformed
triphenylphosphine/DEAD complex in THF, and the reaction was performed at room tempera-
ture in the dark for 6 h. Removal of the solvent and flash chromatography gave 13 in 80% yield.
The 6-chloropurine derivative 13 was converted to a protected adenosine analogue 14 by
treatment with a saturated solution of ammonia in methanol in a steel bomb at 100°C for 2.5
h. Desilylation of the primary alcohol by treatment with tetrabutylammonium fluoride (TBAF)
in THF resulted in the final
Due to the difficulties and low yield encountered in the synthesis of the
to develop a more efficient method of synthesis for -isomers, in which the ring-closing
metathesis reaction22 of the 1,6-diene allowed a more facile synthesis of the
-enantiomer
L
-carbocyclic 4%-fluoro-2%,3%-dideoxyadenosine 15 in 98% yield.
L
-isomer we decided
D
D
(Scheme 2). The common intermediate, alcohol 3, was oxidized by PCC, and the resulting
aldehyde 16 was subjected to carbonyl addition by vinylmagnesium bromide to result in the 1:1
diastereomeric mixture of 1,6-dienes 17. Due to the instability of intermediates 3 and 16, the best
yield was achieved when they were reacted immediately after filtration without any further
purification. Under these conditions, compound 17 was obtained in 40% yield from 3. A
ring-closing metathesis reaction, catalyzed by Grubbs catalyst23 [benzylidene-bis(tricyclo-
hexylphosphine)-dichlororuthenium], afforded cyclopentenols 18 as a diastereomeric mixture,
whose a/b ratio (1:1) was consistent with the diastereomeric ratio of 17. Even though this
reaction proceeded very smoothly and in high (90%) yield, the instability of the cyclopentenols
Scheme 2. Synthesis of (1R,4S)-4-tert-butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-ol (20). Reagents and con-
,
ditions: (a) PCC, 4 A MS, CH2Cl2; (b) vinylmagnesium bromide, THF, −78°C; (c) Grubbs catalyst, CH2Cl2; (d) H2,
Pd/C, cyclohexane; (e) DEAD, PPh3, PhCOOH, THF; (f) LAH, THF, −40 to −35°C

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4857
18 made it difficult to fully characterize their structures. Therefore, the structure could be
confirmed only after saturation of the double bond. Reduction of the double bond in 18 was
accomplished by catalytic hydrogenation on 10% Pd/C in cyclohexane to result in two easily
separable isomers, 19 and 20, in 88% yield. The b-alcohol 19, however, could be converted into
the a-epimer 20 by Mitsunobu reaction followed by LAH reduction in 86% overall yield
(Scheme 2). The absolute configuration of a-alcohol 20 was confirmed by comparing the
spectroscopic data (1H and 13C spectra) as well as optical rotation values with those of its
enantiomer (12, Scheme 1).16b The a-cyclopentanol 20 was condensed with various protected
purine and pyrimidine bases under Mitsunobu conditions. The success of Mitsunobu reactions
in the syntheses of nucleoside analogues is known to depend on the conditions employed.24
Therefore, appropriate choice of solvent system, temperature, and procedures are critical for the
regioselectivity as well as the yield. In purine synthesis (Scheme 3), THF and a 2:1 mixture of
dioxane and DMF were used as solvents for the coupling of the alcohol 20 with 6-chloropurine
and N2-acetylamino-6-chloropurine, respectively. The use of a dioxane–DMF mixture allowed
better solubility of the heterocyclic bases and better yields. Slow addition of DEAD to a mixture
of alcohol 20, triphenylphosphine, and the corresponding purine base in anhydrous solvent gave
a yellow solution which was stirred for 6–12 hours at room temperature to give protected purine
analogues (21 and 24) in 65–80% yield. Because of the interference of the reduced form of
Scheme 3. Synthesis of purine nucleosides. Reagents and conditions: (a) DEAD, PPh3, N2-acetylamino-6-chloro-
purine, THF; (b) TBAF, THF; (c) HCO2H, 90°C, then NH3, MeOH, rt; (d) DEAD, PPh3, 6-chloropurine, THF; (e)
NH3, MeOH, 100°C, steel bomb; (f) thiourea, EtOH, reflux

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
DEAD, 1,2-dicarbethoxyhydrazine, the structure of 21 could not be characterized until it was
desilylated to give 22. The guanosine analogue 23 was prepared from 22 after treating it with
formic acid24a followed by methanolic ammonia. The 6-chloropurine derivative 24 was converted
into three different nucleosides by using conventional nucleoside chemistry. Thus, the adenosine
analogue 26 was prepared by amination of the 6-chloropurine analogue 24 followed by
desilylation, while treatment of the desilylated 6-chloropurine analogue 27 with either formic
acid24a or thiourea gave the inosine 28 and the 6-mercaptopurine 29 analogues, respectively
(Scheme 4).
Scheme 4. Synthesis of pyrimidine nucleosides. Reagents and conditions: (a) DEAD, PPh3, N3-benzoylpyrimidine,
DMF–dioxane (2:1), 0°C; (b) NH3, MeOH, 0°C; (c) TBAF, THF, rt; (d) 1,2,4-triazole, 4-chlorophenyldichlorophos-
phate, pyridine, 0°C, then NH3, MeOH, 100°C, steel bomb
On the other hand, the syntheses of pyrimidine nucleosides were more complex than the
purine case due to the formation of O2-alkylated by-products (33, 34 and 35). The formation of
O2-alkylated compounds was inevitable in the reaction conditions tested, but the ratio of N- to
O-alkylation was dramatically improved by changing the solvent from THF to 2:1 mixture of
dioxane–DMF; the ratio of 30:33 changed from 1.3:1 in THF to 3.6:1 in dioxane–DMF. The
1
structures of O2-alkylated compounds (33 and 34) were confirmed by H and 13C NMR after
removing the N3-benzoyl groups because debenzoylated compounds (39 and 40) allowed direct
1
comparison with H and 13C spectra reported for other O2-alkylated pyrimidine nucleosides;24c,d
the H-2% chemical shifts of 39 and 40 (l 5.51, 5.46, respectively) were appreciably downfield from
those of the N1 Mitsunobu products 36 and 37 (l 5.02, 5.00, respectively). Furthermore, the C-1%
chemical shifts of 39 and 40 (l 80.14, 79.84, respectively) were also shifted downfield from those

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4859
of the N1 Mitsunobu products 36 and 37 (l 59.87, 57.76, respectively). Unfortunately, the
O2-alkylated product of 5-fluorouridine analogue 35 could not be isolated because it easily
decomposed during column chromatography on silica gel. The products of the Mitsunobu
reaction 30, 31 and 32 were converted into nucleoside analogues 41, 42 and 43 via successive
treatment with methanolic ammonia and tetrabutylammonium fluoride. The cytidine analogue
45 was synthesized by amination of uridine analogue 36 because it is known that the
O-alkylation is the predominant pathway24c in the Mitsunobu reaction of protected cytosine
with cyclopentanol. The well-known two-step conversion of uridine to cytidine25 was adopted to
give the protected cytidine analogue 44 in 62% yield. The final cytidine analogue 45 was
obtained by desilylation.
Anti-HIV activity and cytotoxicity evaluations on the synthesized nucleosides 15, 23, 26, 28,
29, 41, 42, 43 and 45 were performed in human peripheral blood mononuclear cells (PBMC).
The adenine analogue 26 and guanine analogue 23 exhibited weak activity against HIV with
EC50 values of 27.6 and 32.3 mM, respectively, while no other synthesized nucleosides showed
significant anti-HIV activity. The toxicities of these nucleosides were also assessed, and these
compounds did not exhibit any significant toxicities at concentration up to 100 mM in CEM,
PBM and Vero cells.
In summary, we have developed a synthetic method for stereoselectively introducing a tertiary
fluoride group and a de novo synthesis of the key a- and b-cyclopentanol intermediates 12 and
20. Condensation of these intermediates with protected purine and pyrimidine bases, followed
by ammonolysis and deprotection, readily provided optically pure
D
- and
L
-carbocyclic 4%-
fluoro-2%,3%-dideoxynucleosides. The convenience of our approach lies in the possibility of
obtaining a number of different analogues by the reaction of a single intermediate with several
heterocyclic bases.
3. Experimental
Melting points were determined on a Mel-temp II apparatus and are uncorrected. Nuclear
magnetic resonance spectra were recorded on a Bruker 400 AMX spectrometer at 400 MHz for
1H NMR and 100 MHz for 13C NMR with tetramethylsilane as the internal standard. Chemical
shifts (l) are reported as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br s
(broad singlet). UV spectra were recorded on a Beckman DU-650 spectrophotometer. Optical
rotations were measured on a Jasco DIP-370 digital polarimeter. Mass spectra were recorded on
a Micromass Autospec high-resolution mass spectrometer. TLC was performed on Uniplates
(silica gel) purchased from Analtech Co. Flash column chromatography was performed using
silica gel G (TLC grade, >440 mesh). Elemental analyses were performed by Atlantic Microlab
Inc., Norcross, GA.
3.1. (−)-(3R)-3-tert-Butyldimethylsilyloxymethyl-6-tert-butyldimethylsilyloxy-3-fluorohex-4-
enoic acid ethylester 2
This compound was prepared from 1,2:5,6-di-O-isopropylidene- -mannitol in eight steps. The
D
reaction conditions are described in detail in supplementary material: [h]2D4 −1.3 (c 1.63, CHCl3);
1H NMR (CDCl3) l 5.83 (m, 2H), 4.14 (br m, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.71 (m, 2H), 2.82

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
(dd, J=18.4, 15.2 Hz, 1H), 2.71 (dd, J=15.2, 15.0 Hz, 1H), 1.18 (t, J=7.1 Hz, 3H), 0.84 (s, 9H),
0.83 (s, 9H), 0.00 (s, 6H), −0.01 (s, 6H); 13C NMR (CDCl3) l 169.88 (d, J=10.9 Hz), 131.24 (d,
J=9.6 Hz), 127.38 (d, J=19.2 Hz), 95.64 (d, J=179.3 Hz), 67.30 (d, J=26.5 Hz), 63.22, 60.84,
40.48 (d, J=26.0 Hz), 26.29, 26.18, 18.76, 18.65, 14.57, −5.05, −5.17. Anal. calcd for
C21H43FO4Si2: C, 58.02; H, 9.97. Found: C, 58.30; H, 9.98.
3.2. (+)-(3R)-3-tert-Butyldimethylsilyloxymethyl-6-tert-butyldimethylsilyloxy-3-fluorohex-4-
en-1-ol 3
To a stirred solution of 300 mg (0.69 mmol) of 2 in 50 ml of dry diethylether, 1.04 ml (1.04
mmol) of 1.0 M solution of lithium aluminum hydride was added at −50°C. The reaction
mixture was stirred at between −40 and −35°C for 1.5 h, and then quenched with 5 ml of
EtOAc. After 30 minutes the reaction mixture was diluted with 50 ml of hexane and allowed to
slowly warm to rt. It was filtered through a short TLC grade silica gel pad washing with a 4:1
mixture of hexane and ethyl acetate. Evaporation of the solvents under the reduced pressure
gave 270 mg (0.69 mmol) of 3 as a light yellow oil which was used for the next step without
1
further purification: [h]2D5 +7.7 (c 0.92, CHCl3); H NMR (CDCl3) l 5.89 (dt, J=15.6, 4.0 Hz,
1H), 5.77 (ddt, J=21.6, 15.6, 1.6 Hz, 1H), 4.21 (dt, J=4.0 Hz, 1.6 Hz, 2H), 3.81 (m, 1H), 3.73
(m, 1H), 3.69 (dd, J=13.2, 11.1 Hz, 1H), 3.63 (dd, J=22.7, 11.1 Hz, 1H), 2.35 (br s, 1H), 2.12
(dddd, J=17.3, 14.8, 7.3, 4.9 Hz, 1H), 1.98 (dddd, J=25.3, 14.8, 6.7, 4.8 Hz, 1H), 0.91 (s, 9H),
0.90 (s, 9H), 0.08 (s, 6H), 0.07 (s, 6H); 13C NMR (CDCl3) l 130.4 (d, J=10.1 Hz), 127.95 (d,
J=19.8 Hz), 97.21 (d, J=175.3 Hz), 68.00 (d, J=28.4 Hz), 62.72, 58.18 (d, J=5.2 Hz), 38.63
(d, J=21.4 Hz), 25.89, 25.76, 18.36, 18.27, −5.44, −5.55; FABMS (m/z) 393 (M+H)+. Anal.
calcd for C19H43FO4Si2: C, 58.11; H, 10.52. Found: C, 58.07; H, 10.51.
3.3. (+)-(4R)-6-Benzyloxy-1-tert-butyldimethylsilyloxy-4-tert-butyldimethylsilyloxymethyl-4-
fluorohex-2-ene 4
To a stirred, ice cooled suspension of sodium hydride (0.60 g of 60% dispersion in mineral oil,
15.0 mmol) in anhydrous THF (20 ml), was added a solution of 3 (2.37 g, 6.0 mmol) in
anhydrous THF (20 ml). The mixture was stirred at rt for 1 h, then tetrabutylammonium iodide
(TBAI, 0.22 g, 0.6 mmol) was added and, upon recooling at 0°C, benzyl bromide (1.1 ml, 9.2
mmol) was added. The reaction mixture was stirred at rt overnight, then cooled to 0°C,
quenched with water (20 ml), and extracted with ethyl acetate (3×50 ml) to give a crude product
which was purified by flash chromatography (49:1 hexanes/ethyl acetate) to yield 2.17 g (4.49
1
mmol, 74%) of 4 as a colorless oil: [h]D26 +1.1 (c 1.42, CHCl3); H NMR (CDCl3) l 7.32 (m, 5H),
5.86 (dt, J=28.8, 4.0 Hz, 1H), 5.79 (m, 1H), 4.58 (dd, J=16.2, 12.2 Hz, 1H), 4.48 (s, 1H), 4.20
(m, 2H), 3.77–3.50 (m, 2H), 2.27–1.88 (m, 2H), 0.91 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H), 0.06 (s,
6H); 13C NMR (CDCl3) l 138.06, 130.27 (d, J=10.0 Hz), 128.34, 127.98 (d, J=20.3 Hz),
127.65, 127.61, 96.58 (d, J=176.4 Hz), 73.01, 68.00 (d, J=28.0 Hz), 65.78 (d, J=5.3 Hz), 62.91,
38.73 (d, J=22.0 Hz), 25.91, 25.82, 18.37, 18.27, −5.29, −5.42, −5.54.
3.4. (−)-(4S)-4-O-Benzyloxy-2-tert-butyldimethylsilyloxymethyl-2-fluorohexanal 5
A solution of 4 (5.80 g, 12.0 mmol) in methanol (150 ml) was treated with ozone at −78°C,
until a slight blue color persisted (30–45 min). The solution was then degassed with argon,

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4861
allowed to warm to rt and methyl sulfide (2.7 ml, 36.8 mmol) was added. The mixture was
stirred at 0°C for 2 h, then methanol was removed under reduced pressure and the residue was
treated with water (10 ml), and methylene chloride (3×50 ml) was used to extract the product.
The combined organic layers were washed with brine, dried over MgSO4, filtered and concen-
trated. The crude product was purified by flash chromatography (19:1 hexanes/ethyl acetate) to
1
yield 2.36 g (6.93 mmol, 58%) of 5 as a colorless oil: [h]2D8 −15.1 (c 2.38, CHCl3); H NMR
(CDCl3) l 9.70 (dd, J=6.2, 0.6 Hz, 1H), 7.36–7.25 (m, 5H), 4.45 (s, 2H), 3.92 (dd, J=25.8, 11.6
Hz, 1H), 3.80 (dd, J=19.8, 11.6 Hz, 1H), 3.65 (td, J=10.0, 3.8 Hz, 1H), 3.58–3.52 (m, 1H),
2.27–2.11 (m, 1H), 2.05–1.96 (m, 1H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3)
l 200.87 (d, J=40.1 Hz), 137.78, 128.37, 127.62, 127.53, 99.81 (d, J=185.3 Hz), 72.91, 66.15 (d,
J=22.2 Hz), 63.95 (d, J=5.7 Hz), 33.03 (d, J=21.4 Hz), 25.67, 18.22, −5.61; FABMS (m/z) 341
(M+H)+. Anal. calcd for C18H29FO3Si·0.24CH2Cl2: C, 60.70; H, 8.23. Found: C, 60.38; H, 8.48.
3.5. (+)-(4R)-Ethyl (E)-6-O-benzyloxy-4-tert-butyldimethylsilyloxymethyl-4-fluoro-2-enoate 6
To a solution of triethyl phosphonoacetate (1.33 ml, 6.7 mmol) in anhydrous THF (20 ml),
was added a 1.0 M solution of NaHMDS in THF (6.7 ml, 6.7 mmol) at −78°C. After the
addition the mixture was stirred at −78°C for 1 h. A solution of 5 (2.30 g, 6.75 mmol) in
anhydrous THF was added. Stirring was continued at −78°C for 1 h, after which the reaction
was quenched with saturated ammonium chloride solution (2 ml), allowed to warm to rt, and
extracted with ethyl ether (3×10 ml). The combined organic layer was washed with brine, dried
over MgSO4, filtered and concentrated. The crude product was purified by flash chromatogra-
phy (9:1 hexanes/ethyl acetate) to yield 2.22 g (5.41 mmol, 80%) of 6 as a colorless oil: [h]D27
1
+2.90 (c 3.56, CHCl3); H NMR (CDCl3) l 7.38–7.25 (m, 5H), 6.94 (dd, J=22.4, 15.8 Hz, 1H),
6.08 (d, J=15.8 Hz, 1H), 4.48 (d, J=13.9 Hz, 1H), 4.45 (d, J=13.9 Hz, 1H), 4.20 (q, J=7.1 Hz,
1H), 4.19 (q, J=7.1 Hz, 1H), 3.70–3.65 (m, 2H), 3.64–3.51 (m, 2H), 2.26–2.01 (m, 2H), 1.28 (t,
J=7.1 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) l 165.95, 146.01 (d, J=20.0 Hz),
138.07, 128.33, 127.62, 127.57, 120.88 (d, J=10.2 Hz), 96.54 (d, J=181.0 Hz), 73.06, 67.31 (d,
J=27.6 Hz), 65.17 (d, J=5.1 Hz), 60.49, 34.89 (d, J=22.1 Hz), 25.73, 18.22, −5.50, −5.58;
FABMS (m/z) 411 (M+H)+. Anal. calcd for C22H35FO4Si: C, 64.35; H, 8.59. Found: C, 64.45;
H, 8.70.
3.6. (+)-(4S)-Ethyl 4-tert-butyldimethylsilyloxymethyl-4-fluoro-6-hydroxyhexanoate 7
To a solution of 6 (2.56 g, 6.2 mmol) in cyclohexane (100 ml), Pd/C (10%, 1.33 g, 1.2 mmol)
was added. The mixture was thoroughly deoxygenated, then saturated with hydrogen and stirred
for 24 h. The charcoal was, then, removed by filtration through a short Celite pad, which was
thoroughly washed with hexanes. Evaporation of the solvent gave a crude product which was
purified by flash chromatography to yield 1.91 g (5.92 mmol, 95%) of 7 as a colorless oil: [h]D29
+2.2 (c 2.85, CHCl3); 1H NMR (CDCl3) l 4.14 (q, J=7.1, 2H), 3.84–3.73 (m, 2H), 3.71–3.61 (m,
2H), 2.49 (bs, 1H), 2.45–2.40 (m, 2H), 1.26 (t, J=7.1, 3H), 0.90 (s, 9H), 0.09 (s, 6H); 13C NMR
(CDCl3) l 173.18, 97.19 (d, J=172.7 Hz), 66.32 (d, J=30.7 Hz), 60.57, 57.96 (d, J=7.4 Hz),
38.05 (d, J=21.5 Hz), 30.40 (d, J=21.8 Hz), 28.13 (d, J=5.8 Hz), 25.71, 18.17, 14.16, −5.55,
−5.60; FABMS (m/z) 323 (M+H)+. Anal. calcd for C15H31FO4Si: C, 55.87; H, 9.69. Found: C,
56.11; H, 9.73.

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3.7. (−)-(4S)-Ethyl 4-tert-butyldimethylsilyloxymethyl-4-fluoro-6-hydroxy-6-methanesulfonyl-
oxyhexanoate 8
To a solution of 7 (200 mg, 0.62 mmol) and pyridine (0.18 ml, 2.23 mmol) in anhydrous
methylene chloride (5 ml), mesyl chloride (0.15 ml, 1.94 mmol) was added dropwise at 0°C. The
reaction mixture was stirred at rt for 24 h, then quenched with methanol (0.3 ml), concentrated
under reduced pressure, and purified by flash chromatography (9:1 hexanes/ethyl acetate) to
1
yield 210 mg (0.52 mmol, 85%) of 8 as a colorless oil: [h]2D7 −0.3 (c 2.04, CHCl3); H NMR
(CDCl3) l 4.39 (t, J=7.1 Hz, 2H), 4.14 (q, J=7.1, 2H), 3.64 (dd, J=12.2, 10.9 Hz, 1H), 3.60
(dd, J=14.3, 10.9 Hz, 1H), 3.02 (s, 3H), 2.45–2.39 (m, 2H), 2.18 (td, J=7.1, 3.9 Hz, 1H), 2.13
(td, J=7.1, 2.3 Hz, 1H), 2.08–1.98 (m, 2H), 1.26 (t, J=7.1, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C
NMR (CDCl3) l 172.89, 95.98 (d, J=175.0 Hz), 65.75 (d, J=30.3 Hz), 65.26 (d, J=7.8 Hz),
60.63, 37.48, 34.22 (d, J=22.5 Hz), 30.23 (d, J=22.2 Hz), 28.10 (d, J=5.9 Hz), 25.72, 18.13,
14.15, −5.57, −5.61; FABMS (m/z) 401 (M+H)+.
3.8. Ethyl (1R, 3R)-3-tert-butyldimethylsilyloxymethyl-3-fluorocyclopentancarboxylate 9 and
ethyl (1S,3R)-3-tert-butyldimethylsilyloxymethyl-3-fluorocyclopent-1-yl carboxylate 9
To a suspension of sodium hydride (175 mg of 60% dispersion in mineral oil, 4.37 mmol) in
anhydrous THF (20 ml), a solution of 8 (350 mg, 0.87 mmol) in anhydrous THF (20 ml) was
added. The reaction was refluxed overnight, then cooled to 0°C and quenched with saturated
ammonium chloride solution (20 ml). Water (5 ml) was added to dissolve precipitated salt, and
the mixture was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed
with brine (10 ml), dried over MgSO4 and concentrated under reduced pressure to give a crude
product which was purified by flash chromatography (49:1 hexanes/ethyl acetate) to yield h- and
b-9 as colorless oil (combined yield: 200 mg, 0.66 mmol, 75%): For major isomer, [h]2D7 −1.2 (c
1
1.81, CHCl3); H NMR (CDCl3) l 4.13 (q, J=7.1, 2H), 3.74 (dd, J=14.5, 11.0 Hz, 1H), 3.70
(dd, J=15.2, 11.0 Hz, 1H), 3.11–3.02 (m, 1H), 2.21–1.82 (m, 6H), 1.26 (t, J=7.1, 3H), 0.90 (s,
9H), 0.07 (s, 6H); 13C NMR (CDCl3) l 175.65, 106.24 (d, J=176.1 Hz), 66.24 (d, J=29.5 Hz),
60.50, 42.28, 38.14 (d, J=23.6 Hz), 33.82 (d, J=23.2 Hz), 28.08, 25.81, 18.28, 14.20 −5.45;
FABMS (m/z) 305 (M+H)+. Anal. calcd for C15H29FO3Si: C, 59.17; H, 9.60. Found: C, 59.46;
1
H, 9.59. For minor isomer, [h]2D7 +5.7 (c 1.33, CHCl3); H NMR (CDCl3) l 4.15 (q, J=7.1, 2H),
3.67 (d, J=15.0 Hz, 2H), 2.83–2.74 (m, 1H), 2.20 (dd, J=26.3, 8.6 Hz, 1H), 2.14–2.06 (m, 1H),
2.03–1.91 (m, 2H), 1.85–1.69 (m, 2H), 1.26 (t, J=7.1, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR
(CDCl3) l 174.88, 105.18 (d, J=178.0 Hz), 66.09 (d, J=32.5 Hz), 60.54, 43.26, 37.63 (d, J=24.4
Hz), 34.61 (d, J=24.0 Hz), 28.13, 25.81, 18.25, 14.21 −5.47; FABMS (m/z) 305 (M+H)+. Anal.
calcd for C15H29FO3Si: C, 59.17; H, 9.60. Found: C, 59.35; H, 9.53.
3.9. (4R)-3-tert-Butyldimethylsilyloxymethyl-3-fluorocyclopentancarboxylic acid 10
To a solution of 9 (0.90 g, 2.95 mmol) in ethanol (50 ml), a solution of sodium hydroxide
(0.41 g in 50 ml, 10.25 mmol) was added. The mixture was stirred at rt for 5 h, then
concentrated under reduced pressure to about 50 ml, cooled to 0°C, quenched with glacial acetic
acid (1.2 ml, 20.96 mmol), and rapidly extracted with ethyl acetate (3×200 ml). The combined
extracts were washed with water (20 ml) and brine (20 ml), then dried over MgSO4 and
concentrated in vacuo. The crude product thus obtained was rapidly purified by flash chro-

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4863
matography (1:1 hexanes/ethyl acetate) to yield 0.66 g (2.39 mmol, 81%) of the epimeric mixture
1
10 as a colorless oil: H NMR (CDCl3) l 10.52 (bs, 1H), 3.78–3.63 (m, 4H), 3.16–3.08 (m, 1H),
2.91–2.82 (m, 1H), 2.27–1.83 (m, 12H), 0.90 (s, 18H), 0.07 (s, 12H); 13C NMR (CDCl3) l (major
isomer) 181.59, 106.12 (d, J=176.3 Hz), 66.06 (d, J=30.0 Hz), 42.08, 38.04 (d, J=23.7 Hz),
33.81 (d, J=23.1 Hz), 27.96, 25.79, 18.25, −5.47; l (minor isomer) 180.93, 105.19 (d, J=177.0
Hz), 65.91 (d, J=32.7 Hz), 42.87, 37.43 (d, J=24.4 Hz), 34.16 (d, J=24.0 Hz), 28.00, 25.79,
18.26, −5.47; HR-FABMS (m/z) obsd 277.1603, calcd for C13H26FO3Si 277.1635 (M+H)+. Anal.
calcd for C13H25FO3Si·0.11C6H14: C, 56.82; H, 9.21. Found: C, 57.17; H, 9.22.
3.10. (4R)-1-tert-Butyldimethylsilyloxymethyl-1-fluoro-3-iodopentane 11
A mixture of 10 (0.66 g, 2.39 mmol) and lead tetraacetate (3.18 g, 7.17 mmol) in carbon
tetrachloride (20 ml) was stirred under reflux while illuminated with a 250 W tungsten lamp for
15 min. Then, while maintaining the same conditions of reflux and illumination, a solution of
iodine (1.83 g, 7.20 mmol) in carbon tetrachloride (60 ml) was added in small portions until no
more discoloration was observed. The reaction was continued for one more hour, then allowed
to cool to rt. The lead salts were filtered off and the filtrate was decolorized by shaking with a
2% solution of sodium thiosulfate. The organic phase was separated, dried over MgSO4, and
concentrated in vacuo to a crude product which was purified by flash chromatography (hexanes)
1
to yield 0.70 g (1.95 mmol, 82%) of the epimeric mixture 11 as a colorless oil: H NMR (CDCl3)
l 4.44–4.36 (m, 1H), 4.10–4.02 (m, 1H), 3.75 (dd, J=14.3, 10.9 Hz, 1H), 3.71 (dd, J=15.2, 10.9
Hz, 1H), 3.63 (d, J=14.0 Hz, 2H), 2.67–1.72 (m, 12H), 0.91 (s, 9H), 0.89 (s, 9H), 0.08 (s, 6H)
0.06 (s, 6H); 13C NMR (CDCl3) l 105.44 (d, J=178.0 Hz), 104.24 (d, J=179.9 Hz), 66.53 (d,
J=31.8 Hz), 66.19 (d, J=35.0 Hz), 48.56 (d, J=23.9 Hz), 47.79 (d, J=24.4 Hz), 38.81, 38.42,
35.11 (d, J=24.4 Hz), 34.35 (d, J=24.0 Hz), 25.82, 25.78, 21.74, 19.39, 18.29, 18.21, −5.43,
−5.49; FABMS (m/z) 359 (M+H)+. Anal. calcd for C12H24FIOSi.0.02C6H14: C, 40.43; H, 6.80.
Found: C, 40.76; H, 6.87.
3.11. (+)-(1S,3R)-3-tert-Butyldimethylsilyloxymethyl-3-fluorocyclopentan-1-ol 12
A mixture of 11 (690 mg, 1.93 mmol) and sodium bicarbonate (0.33 g, 3.93 mmol) in 15%
(v/v) water/HMPA was heated at 100°C overnight. The mixture was then cooled to 0°C, diluted
with water (20 ml), and extracted with ether (3×40 ml). The combined organic phases were
washed with brine (10 ml), dried over MgSO4, and concentrated under reduced pressure to a
crude product which was purified by flash chromatography (6:1 hexanes/ethyl acetate) to yield
190 mg (0.76 mmol, 40%) of the only diastereomer 12 as a colorless oil: [h]2D7 +2.2 (c 3.13,
1
CHCl3); H NMR (CDCl3) l 4.33 (m, 1H), 3.69 (dd, 1H, J=15.6, 10.7 Hz), 3.65 (dd, 1H,
J=16.4, 10.7 Hz), 2.14–1.74 (m, 6H), 0.89 (s, 9H), 0.07 (s, 6H). 13C NMR (CDCl3): l 106.17 (d,
J=175.0 Hz), 73.28, 66.19 (d, J=32.0 Hz), 43.68 (d, J=21.5 Hz), 34.51, 32.66 (d, J=24.1 Hz),
25.78, 18.23, −5.48. HR-FABMS (m/z) obsd 249.1699, calcd for C12H26FO2Si 249.1686 (M+H)+.
Anal. calcd for C12H25FO2Si: C, 58.02; H, 10.14. Found: C, 57.80; H, 9.96.
3.12. (−)-9-[(1R,4R)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentyl]-6-chloropurine 13
A suspension of triphenylphosphine (590 mg, 2.25 mmol) and 6-chloropurine (348 mg, 2.25
mmol) in anhydrous THF (10 ml) was treated with DEAD (355 ml, 2.25 mmol) at rt in the dark

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
for 1 h. A solution of 12 (140 mg, 0.56 mmol) in anhydrous THF was, then, added and the
mixture was stirred in the dark at rt for 6 h. Evaporation of solvent gave a crude product which
was purified by flash chromatography (4:1 hexanes/ethyl acetate) to yield 149 mg (0.39 mmol,
69%) of 13 as a white solid: mp 74–76°C; [h]2D8 −12.8 (c 1.17, CHCl3); UV (CHCl3) umax 265.5
1
nm; H NMR (CDCl3) l 8.73 (s, 1H), 8.18 (s, 1H), 5.28–5.20 (m, 1H), 3.83 (dd, J=17.4, 10.6
Hz, 1H), 3.80 (dd, J=19.2, 10.6 Hz, 1H), 2.67–2.52 (m, 3H), 2.47–2.32 (m, 1H), 2.26–2.17 (m,
1H), 2.13–1.99 (m, 1H), 0.92 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3) l 151.64,
151.62, 151.16, 143.91, 132.25, 104.32 (d, J=176.4 Hz), 65.58 (d, J=32.7 Hz), 55.68, 40.41 (d,
J=23.7 Hz), 32.88 (d, J=23.4 Hz), 30.86, 25.79, 18.27, −5.45; FABMS (m/z) 385 (M+H)+.
Anal. calcd for C17H26ClFN4OSi: C, 53.04; H, 6.81; N, 14.55; Cl, 9.21. Found: C, 53.28; H, 6.79;
N, 14.35; Cl, 9.35.
3.13. (−)-9-[(1R,4R)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentyl]adenine 14
Compound 13 (140 mg, 0.36 mmol) was dissolved in 15 ml of a stock solution of ammonia
in methanol, and then stirred at 100°C in a steel bomb for 2.5 h. Evaporation under reduced
pressure afforded an off-white solid, which was purified by flash chromatography (49:1
chloroform/methanol) to yield 96 mg (0.26 mmol, 72%) of 14 as a white solid: mp 152–154°C;
1
[h]2D6 −17.9 (c 2.17, CHCl3); UV (CHCl3) umax 261.5 nm; H NMR (CDCl3) l 8.34 (s, 1H), 7.86
(s, 1H), 5.70 (br s, 2H), 5.21–5.12 (m, 1H), 3.83 (dd, J=17.6, 10.6 Hz, 1H), 3.69 (dd, J=19.2,
10.6 Hz, 1H), 2.66–1.96 (m, 6H), 0.92 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3) l
155.45, 152.64, 150.02, 139.02, 120.19, 104.46 (d, J=176.6 Hz), 65.79 (d, J=32.4 Hz), 54.85,
40.57 (d, J=23.7 Hz), 32.92 (d, J=23.4 Hz), 31.06, 25.80, 18.28, −5.45; FABMS (m/z) 366
(M+H)+. Anal. calcd for C17H28FN5OSi: C, 55.86; H, 7.72; N, 19.16. Found: C, 55.68; H, 7.65;
N, 19.07.
3.14. (−)-9-[(1R,4R)-4-Fluoro-4-hydroxymethylcyclopentyl]adenine 15
A 1.0 M solution of TBAF in THF (1 ml) was stirred with 14 (78.0 mg, 0.21 mmol) at rt for
30 min. Evaporation of the solvent under reduced pressure gave an oil that was purified by flash
chromatography (1:19 methanol/chloroform) to yield 52.6 mg (0.197 mmol, 92%) of 15 as a
white solid: mp 167–168°C; [h]2D9 −12.7 (c 0.37, MeOH); UV (MeOH) umax 260.0 (m 20 890, pH
1
2), 261.5 (m 19 800, pH 7), 261.5 (m 17 980, pH 11); H NMR (CD3OD): l 8.12 (s, 1H), 8.08 (s,
1H), 5.08 (m, 1H), 3.69 (dd, 1H, J=16.2, 12.1 Hz), 3.65 (dd, 1H, J=17.4, 12.1 Hz), 2.43–2.34
(m, 3H,), 2.33–2.15 (m, 1H,), 2.13–2.04 (m, 1H,), 2.00–1.86 (m, 1H,). 13C NMR (CD3OD): l
157.3, 153.5, 150.7, 141.2, 120.5, 105.9 (d, J=176.6 Hz), 66.7 (d, J=27.4 Hz), 56.1, 41.6 (d,
J=24.1 Hz), 33.7 (d, J=23.8 Hz), 31.5. HR-FABMS, (m/z) obsd 252.1268; Calcd for
C11H15FON5, m/z 252.1261 (MH+). Anal. calcd for C11H14FON5: C, 52.58; H, 5.62; N, 27.87.
Found: C, 52.74; H, 5.73; N, 27.72.
3.15. (3R)-3-tert-Butyldimethylsilyloxymethyl-6-tert-butyldimethylsilyloxy-3-fluorohex-4-en-1-al
16
The primary alcohol (270 mg, 0.69 mmol) 3 obtained above was dissolved in dry methylene
chloride (50 ml). To this colorless solution was added pyridinium chlorochromate (223 mg, 1.03
,
mmol) and 223 mg of 4 A molecular sieves. The resulting dark brown mixture was vigorously
stirred at rt for 2 h and then filtered through a short TLC grade silica gel pad washing with

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4865
methylene chloride. Evaporation under the reduced pressure gave 270 mg (0.69 mmol) of the
crude aldehyde 16 as a pale yellow oil which was used for the next step without further
purification: 1H NMR (C6D6) l 9.63 (q, J=2.3 Hz, 1H), 5.85 (m, 2H), 3.94 (br, s, 2H), 3.60 (dd,
J=14.4, 11.2 Hz, 1H), 3.49 (dd, J=25.8, 11.2 Hz, 1H), 2.60 (ddd, J=16.8, 16.2, 2.3 Hz, 1H),
2.50 (ddd, J=21.9, 16.2, 2.3 Hz, 1H), 0.94 (s, 9H), 0.89 (s, 9H), −0.02 (s, 3H), −0.04 (s, 3H); 13C
NMR (C6D6) l 196.56 (d, J=7.3 Hz), 130.41 (d, J=9.7 Hz), 125.69 (d, J=19.7 Hz), 94.52 (d,
J=177.2 Hz), 66.65 (d, J=26.1 Hz), 61.25, 47.59 (d, J=21.5 Hz), 24.67, 24.54, 17.11, 17.04,
−6.82, −6.94.
3.16. (5R,3R)/(5R,3S)-5-tert-Butyldimethylsilyloxymethyl-8-tert-butyldimethylsilyloxy-5-fluoro-
3-hydroxyocta-1,6-diene 17
To a stirred solution of the aldehyde 16 (270 mg, 0.69 mmol) in dry THF at −78°C, was
slowly added a 1.0 M solution of vinylmagnesium bromide solution in THF (0.95 ml, 0.95
mmol). After 1.5 h, water (5 ml) was added, and the reaction mixture was slowly warmed to rt.
The aqueous phase was extracted with diethyl ether (3×10 ml), and the combined organic layer
was dried over MgSO4, filtered, and evaporated to give a yellow crude product which was
purified by column chromatography on silica gel (15:1 hexane/diethyl ether) to give 115 mg
1
(0.275 mmol, 40% yield from compound 3) of the desired 1,6-diene 17: H NMR (CDCl3) l
5.83–5.66 (m, 6H), 5.10 (dt, J=17.2, 1.5 Hz, 2H), 4.95 (dtt, J=10.4, 3.8, 1.5 Hz, 2H), 4.22–4.17
(m, 2H), 4.15–4.13 (br m, 4H), 3.65 (dd, J=21.0, 11.1 Hz, 1H), 3.62 (dd, J=15.3, 10.8 Hz, 1H),
3.59 (dd, J=16.8, 11.1 Hz, 1H), 3.54 (dd, J=19.5, 10.8 Hz, 1H), 1.94–1.78 (m, 4H), 0.84 (s, 9H),
0.83 (s, 9H), 0.82 (s, 9H), 0.81 (s, 9H), 0.004 (s, 6H), −0.0053 (s, 6H), −0.0106 (s, 6H), −0.0151
(s, 6H); 13C NMR (CDCl3) l 143.41, 143.37, 131.47 (d, J=10.2 Hz), 131.37 (d, J=10.2 Hz),
130.58 (d, J=19.9 Hz), 130.19 (d, J=20.0 Hz), 114.67, 114.40, 99.12 (d, J=177.1 Hz), 98.02 (d,
J=176.9 Hz), 70.18, 70.12, 69.84 (d, J=28.3 Hz), 69.36 (d, J=27.4 Hz), 64.49, 64.42, 44.37,
44.16, 26.86, 26.79, 19.64, 19.60, −4.79, −4.85; HR-FABMS (m/z) obsd 419.2793, calcd for
C21H44FO3Si2 419.2813 (M+H)+. Anal. calcd for C21H43FO3Si2: C, 60.24; H, 10.35. Found: C,
60.38; H, 10.37.
3.17. (1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopent-3-en-1-ol 18
Grubbs catalyst (20 mg, 0.024 mmol) dissolved in dry methylene chloride (35 ml) in a dry
two-necked flask equipped with an N2 inlet. To this solution a solution of 100 mg (0.24 mmol)
of the 1,6-diene 17 in dry methylene chloride (15 ml) was slowly added over 10 minutes under
an N2 atmosphere. The wine-red solution was stirred for 30 more minutes, and the resulting
dark brown solution was evaporated and purified by column chromatography on silica gel
(6:1:0.01 hexane/diethyl ether/triethyl amine) to give 53 mg (0.215 mmol, 90% yield) of the
cyclopentenol 18 as a 1:1 mixture of diastereomers, which was immediately used in the next step.
Due to the instability of this compound, the structure of this compound was characterized only
1
by NMR spectra: H NMR (CD3OD) l 6.04 (dt, J=5.7, 2.2 Hz, 1H), 5.99 (dt, J=5.7, 1.9 Hz,
1H), 5.86 (dt, J=5.7, 1.5 Hz, 1H), 5.82 (dt, J=5.5, 1.6 Hz, 1H), 4.83 (br s, 1H), 4.53 (br m, 1H),
3.74 (dd, J=18.0, 11.4 Hz, 1H), 3.71 (dd, J=19.8, 11.4 Hz, 1H), 3.63 (dd, J=14.4, 10.9 Hz,
1H), 3.55 (dd, J=17.8, 10.9 Hz, 1H), 2.52 (dt, J=14.0, 7.4 Hz, 1H), 2.26 (ddd, J=21.7, 14.7,
6.8 Hz, 1H), 1.75 (ddd, J=20.6, 14.7, 3.7 Hz, 1H), 1.69 (ddd, J=25.7, 14.0, 4.6 Hz, 1H), 0.83
(s, 9H), 0.81 (s, 9H), 0.00 (s, 6H), 0.00 (s, 6H), −0.019 (s, 3H), −0.027 (s, 3H); 13C NMR (CDCl3)
l 142.81 (d, J=8.8 Hz), 141.39 (d, J=9.2 Hz), 134.29 (d, J=23.4 Hz), 133.98 (d, J=18.3 Hz),

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
108.25 (d, J=174.4 Hz), 106.17 (d, J=180.0 Hz), 76.22, 75.32, 69.14 (d, J=30.8 Hz), 68.57 (d,
J=34.6 Hz), 44.35 (d, J=18.7 Hz), 43.72 (d, J=25.2 Hz), 26.73, 26.67, 19.64, 19.54, −4.87,
−4.90, −4.93, −4.99.
3.18. For the 1:1 mixture of diastereomers (−)-(1S,3S)-3-tert-butyldimethylsilyloxymethyl-3-
fluorocyclopentan-1-ol 19 and (+)-(1R,3S)-3-tert-butyldimethylsilyloxymethyl-3-fluoro-
cyclopentan-1-ol 20
A solution of 18 (1.35 g, 5.48 mmol) in cyclohexane (50 ml) was treated with Pd/C (135 mg,
10% w/w). The mixture was thoroughly deoxygenated, and then saturated with hydrogen. After
stirring for 2 h at rt the reaction mixture was filtered through a Celite pad and evaporated to
give a 1:1 mixture of diastereomeric cyclopentanols which was separated by column chromatog-
raphy on silica gel (10:1 hexanes/ethyl acetate). 621 mg (2.50 mmol, 46% yield) of b-alcohol 19
and 570 mg (2.30 mmol, 42% yield) of a-alcohol 20 were obtained as colorless oil: For 19, [h]D25
1
−0.95 (c 0.97, CHCl3); H NMR (CDCl3) l 4.44 (br d, 1H, H-1), 3.69 (d, J=12.7 Hz, 2H, H-6),
2.55–1.66 (m, 6H, H-2, H-4, H-5), 0.91 (s, 9H, Si-C(CH3)3), 0.09 (s, 6H, Si-CH3); 13C NMR
(CDCl3) l 104.9 (d, J=80.5 Hz), 73.18, 67.20 (d, J=34.8 Hz), 45.53 (d, J=22.5 Hz), 34.75,
32.61 (d, J=23.9 Hz), 26.15, 18.72, −5.09; FABMS (m/z) obsd 249. Anal. calcd for
C12H25FO2Si: C, 58.02; H, 10.14. Found: C, 58.20; H, 9.98. For 20, [h]2D4 −2.3 (c 0.90, CHCl3);
1H NMR (CDCl3) l 4.33 (br s, 1H, H-1), 3.68 (dd, J=15.4, 10.2 Hz, 1H, H-6), 3.66 (dd,
J=16.2, 10.2 Hz, 1H, H-6), 2.14–1.79 (m, 6H, H-2, H-4, H-5), 0.89 (s, 9H, Si-C(CH3)3), 0.06 (s,
6H, Si-CH3); 13C NMR (CDCl3) l 106.12 (d, J=175.1 Hz), 73.23, 66.18 (d, J=32.3 Hz), 43.66
(d, J=21.6 Hz), 34.48, 32.65 (d, J=23.6 Hz), 25.77, 18.22, −5.50; FABMS (m/z) obsd 249.
Anal. calcd for C12H25FO2Si: C, 58.02; H, 10.14. Found: C, 58.28; H, 10.12.
3.19. (−)-(1R,3S)-1-Benzoyloxy-3-tert-butyldimethylsilyloxymethyl-3-fluorocyclopentane 21
To a stirred solution of b isomer 19 (37 mg, 0.149 mmol), triphenyl phosphine (195 mg, 0.743
mmol), and benzoic acid (91 mg, 0.745 mmol) in dry THF (10 ml), a solution of DEAD (0.117
ml, 0.743 mmol) in THF (5 ml) was slowly added. The resulting yellow solution was stirred at
rt for 6 h. Solvent was removed under reduced pressure and the resulting residue was purified
by column chromatography on silica gel (40:1 hexanes/diethyl ether) to give 48 mg (0.136 mmol,
1
91% yield) of the benzoyloxycyclopentanol 21 as a colorless oil: [h]2D5 −15.7 (c 1.49, CHCl3); H
NMR (CD3OD) l 7.98–7.96 (m, 2H), 7.49–7.45 (m, 1H), 7.37–7.33 (m, 2H), 5.33 (m, 1H), 3.62
(dd, J=14.4, 1.60 Hz, 2H), 2.32–1.79 (m, 6H), 0.82 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3) l
166.37, 132.87, 130.48, 129.64, 128.31, 104.41 (d, J=179.0 Hz), 75.74, 66.28 (d, J=32.9 Hz),
40.94 (d, J=23.5 Hz), 33.03 (d, J=23.7 Hz), 31.44, 25.82, 18.27, −5.45; FABMS (m/z) obsd 353,
for C19H30FO3Si. Anal. calcd for C19H29FO3Si: C, 64.74; H, 8.29. Found: C, 64.85; H, 8.23.
3.20. 9-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]-N2-acetylamino-
6-chloropurine 21 and (+)-9-[(1S,4S)-4-fluoro-4-hydroxymethylcyclopentan-1-yl]-N2-
acetylamino-6-chloropurine 22
To a suspension of triphenylphosphine (108 mg, 0.41 mmol), N2-acetylamino-6-chloropurine
(106 mg, 0.50 mmol), and 20 (85 mg, 0.342 mmol) in anhydrous dioxane (6 ml) and DMF (3
ml), was added DEAD (0.08 ml, 0.51 mmol) over 30 minutes at 0°C. The yellow mixture was

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stirred for 6 h at room temperature. Solvent was removed under reduced pressure and the
residue was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to give
97 mg of an inseparable mixture of the desired compound 21 and reduced DEAD. This mixture
was used directly in the next step. The mixture obtained above was dissolved in anhydrous THF
(10 ml) and treated with 1.0 M TBAF in THF (0.22 ml, 0.22 mmol). The solution was stirred
for 30 minutes at room temperature and evaporated to give a colorless residue which was
purified by column chromatography on silica gel (30:1 CH2Cl2/MeOH) to give 70 mg (0.214
mmol, 63% yield from 20) of 22 as a white solid: mp 208–210°C; [h]2D5 −127.8 (c 0.54, MeOH);
1
UV (MeOH) umax 288.0 nm; H NMR (CD3OD) l 8.71 (s, 1H), 5.50 (quintet, J=8.3 Hz, 1H),
4.03 (dd, J=18.4, 12.2 Hz, 1H), 4.00 (dd, J=19.8, 12.2 Hz, 1H), 2.81–2.19 (m, 6H), 2.53 (s, 3H);
13C NMR (CD3OD) l 154.11, 153.63, 151.82, 146.79, 129.68, 106.54 (d, J=176.1 Hz), 67.01 (d,
J=27.4 Hz), 57.23, 41.62 (d, J=23.8 Hz), 34.25 (d, J=23.4 Hz), 31.69, 25.09; HR-FABMS
(m/z) obsd 328.0995, calcd for C13H16ClFN5O2 328.0992 (M+H)+. Anal. calcd for
C13H15ClFN5O2: C, 47.64; H, 4.61; N, 21.37. Found: C, 47.76; H, 4.68; N, 21.19.
3.21. (+)-9-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]guanine 23
Compound 22 (64 mg, 0.196 mmol) was dissolved in 85% formic acid (15 ml) and the resulting
colorless solution was stirred at 80°C for 6 h. After evaporation, the remaining oil was treated
with methanolic ammonia (15 ml), and the solution was stirred overnight. Solvent was removed
in vacuo, and the residue was purified by column chromatography on silica gel (6:1 CH2Cl2/
MeOH) to give 40 mg (0.15 mmol, 76% yield) of 23 as a white solid: mp 220°C, dec.; [h]2D4 +6.4
(c 0.54, MeOH); UV (H2O) umax 253.5 nm (m 8 080, pH 2), 252.5 nm (m 8 263, pH 7), 266.5 nm
1
(m 7 123, pH 11); H NMR (CD3OD) l 8.09 (s, 1H, H-8), 5.26 (quintet, J=8.4 Hz, 1H, H-1%),
4.02–3.97 (m, 2H, H-5%), 2.71–2.20 (m, 6H, H-2%, H-3%, H-6%); 13C NMR (CD3OD) l 198.77,
159.87, 155.36, 138.59, 118.43, 106.34 (d, J=175.9 Hz), 67.06 (d, J=27.5 Hz), 56.03, 41.95 (d,
J=23.7 Hz), 34.13 (d, J=23.8 Hz), 31.77; HR-FABMS (m/z) obsd 268.1204, calcd for
C11H15FN5O2 268.1209 (M+H)+. Anal. calcd for C11H14FN5O2·0.9CHCl3: C, 38.15; H, 4.01; N,
18.69. Found: C, 38.18; H, 4.56; N, 18.78.
3.22. (+)-9-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]-6-chloropurine
24
To a suspension of triphenylphosphine (602 mg, 2.30 mmol) and 6-chloropurine (372 mg, 2.41
mmol) in anhydrous THF (5 ml), a solution of DEAD (0.36 ml, 2.29 mmol) in THF was added
over 30 min at rt. After 1 h, 20 (285 mg, 1.15 mmol) in THF (10 ml) was added to the yellow
mixture, and then the resulting mixture was stirred for 6 h at room temperature. Solvent was
removed under reduced pressure and the resulting residue was purified by column chromatogra-
phy on silica gel (10:1 hexanes/diethyl ether) to give 355 mg (0.922 mmol, 80% yield) of the
desired compound 24 as a white solid: mp 80–82°C; [h]2D6 +13.4 (c 3.80 CHCl3); UV (MeOH)
umax 266.0 nm; 1H NMR (CDCl3) l 8.70 (s, 1H), 8.17 (s, 1H), 5.22 (quintet, J=7.9 Hz, 1H), 3.82
(dd, J=12.3, 10.5 Hz, 1H), 3.78 (dd, J=14.2, 10.5 Hz, 1H), 2.65–1.97 (m, 6H), 0.90 (s, 9H), 0.08
(s, 6H); 13C NMR (CDCl3) l 151.65, 151.62, 151.14, 143.95, 132.26, 104.34 (d, J=176.7 Hz),
65.56 (d, J=32.6 Hz), 55.70, 40.42 (d, J=23.7 Hz), 32.89 (d, J=23.3 Hz), 30.86, 25.80, 18.28,
−5.44; HR-FABMS (m/z) obsd 385.1642, calcd for C17H27ClFN4OSi 385.1626 (M+H)+. Anal.
calcd for C17H26ClFN4OSi: C, 53.04; H, 6.81; N, 14.55. Found: C, 53.56; H, 6.90; N, 14.44.

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3.23. (+)-9-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]adenine 25
Compound 24 (140 mg, 0.36 mmol) was treated with methanolic ammonia and heated to
110°C in a steel bomb for 6 h. Solvent was removed under reduced pressure and the remaining
residue was purified by column chromatography on silica gel (50:1 CH2Cl2/MeOH) to give 110
mg (0.30 mmol, 83% yield) of the aminated compound 25 as a white solid: mp 150–152°C; [h]D26
1
+18.05 (c 0.62, CHCl3); UV (MeOH) umax 266.0 nm; H NMR (CDCl3) l 8.24 (s, 1H), 7.77 (s,
1H), 5.65 (br s, 2H), 5.07 (quintet, J=7.9 Hz, 1H), 3.73 (dd, J=13.1, 10.6 Hz, 1H), 3.69 (dd,
J=14.7, 10.6 Hz, 1H), 2.52–1.87 (m, 6H), 0.82 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3) l 154.36,
151.62, 149.03, 138.06, 119.20, 103.42 (d, J=176.3 Hz), 64.79 (d, J=32.4 Hz), 53.85, 39.57 (d,
J=23.7 Hz), 31.92 (d, J=23.4 Hz), 30.06, 24.80, 17.28, −6.46; HR-FABMS (m/z) obsd
366.2114, calcd for C17H29FN5OSi 366.2125 (M+H)+. Anal. calcd for C17H28FN5OSi: C, 55.86;
H, 7.72; N, 19.16. Found: C, 55.79; H, 7.69; N, 19.16.
3.24. General procedure for the desilylation reaction of tert-butyldimethylsilyl ether by using
TBAF. This is representative of the preparation of adenine analogue 26 from 25
3.24.1. (+)-9-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]adenine 26
To a stirred solution of 100 mg (0.274 mmol) of 25 in anhydrous THF (5 ml), was added a
1.0 M solution of TBAF in THF (0.27 ml, 0.27 mmol). After 1 h, solvent was removed under
reduced pressure and the remaining residue was purified by column chromatography on silica
gel (10:1 CH2Cl2/MeOH) to give 65 mg (0.259 mmol, 95% yield) of 26 as a white solid: mp
170–172°C; [h]2D7 +10.5 (c 0.67, MeOH); UV (H2O) umax 260.0 nm (m 20 858, pH 2), 261.0 nm (m
1
14 624, pH 7), 261.0 nm (m 12 639, pH 11); H NMR (CD3OD) l 8.39 (s, 1H, H-8), 8.35 (s, 1H,
H-2), 5.34 (ddd, J=17.6, 10.0, 8.0 Hz, 1H, H-1%), 3.93 (dd, J=17.3, 12.4 Hz, 1H, H-5%), 3.90 (dd,
J=19.6, 17.3 Hz, 1H, H-5%), 2.70–2.18 (m, 6H, H-2%, H-3%, H-6%); 13C NMR (CDCl3) l 158.78,
154.96, 152.17, 142.76, 122.03, 107.36 (d, J=176.1 Hz), 68.16 (d, J=27.5 Hz), 57.61, 43.10 (d,
J=23.7 Hz), 35.23 (d, J=23.9 Hz), 32.96; HR-FABMS (m/z) obsd 252.1244, calcd for
C11H15FN5O 252.1260 (M+H)+. Anal. calcd for C11H14FN5O·0.2MeOH: C, 52.21; H, 5.79; N,
27.18. Found: C, 52.06; H, 5.61; N, 27.03.
3.24.2. (+)-9-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]-6-chloropurine 27
See the general procedure for deprotection of TBDMS group using TBAF. Mp 142–144°C;
1
[h]2D4 +5.5 (c 0.80, MeOH); UV (MeOH) umax 266.0 nm; H NMR (CD3OD) l 8.99 (s, 1H), 8.91
(s, 1H), 5.57 (ddd, J=17.6, 9.7, 7.9 Hz, 1H), 4.04 (dd, J=17.4, 12.1 Hz, 1H), 4.01 (dd, J=18.7,
12.1 Hz, 1H), 2.86–2.27 (m, 6H); 13C NMR (CD3OD) l 194.17, 193.68, 192.26, 188.30, 173.87,
146.94 (d, J=176.5 Hz), 107.58 (d, J=27.4 Hz), 98.06, 82.39 (d, J=23.9 Hz), 74.78 (d, J=23.7
Hz), 72.22; HR-FABMS (m/z) obsd 271.0759, calcd for C11H13ClFN4O 271.0761 (M+H)+. Anal.
calcd for C11H12ClFN4O·0.6CH3COCH3: C, 50.32; H, 5.15; N, 18.34. Found: C, 50.23; H, 4.92;
N, 18.31.
3.25. (+)-9-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]hypoxanthine 28
Compound 27 (48 mg, 0.177 mmol) was dissolved in 85% formic acid (10 ml) and the resulting
colorless solution was stirred for 2.5 h at 70°C. After evaporating the formic acid under reduced
pressure, the remaining residue was treated with methanolic ammonia. The resulting solution

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4869
was stirred overnight at room temperature. After solvent evaporation, the remaining residue
was purified by column chromatography on silica gel (20:1 CH2Cl2/MeOH) to give 40 mg
(0.159 mmol, 90% yield) of 28 as a white solid: mp 220°C, dec.; [h]2D3 +22.0 (c 0.60, MeOH);
UV (H2O) umax 250.0 nm (m 16 612, pH 2), 251.0 nm (m 16 913, pH 7), 252.0 nm (m 17 930, pH
1
11); H NMR (CD3OD) l 8.33 (s, 1H, H-8), 8.19 (s, 1H, H-2), 5.35 (ddd, J=17.7, 9.9, 7.9 Hz,
1H, H-1%), 3.92 (dd, J=17.3, 12.2 Hz, 1H, H-5%), 3.89 (dd, J=18.5, 12.2 Hz, 1H, H-5%),
2.74–2.16 (m, 6H, H-2%, H-3%, H-6%); 13C NMR (CD3OD) l 159.43, 150.55, 146.64, 141.14,
126.16, 106.30 (d, J=176.1 Hz), 67.00 (d, J=27.5 Hz), 56.81, 42.22 (d, J=23.8 Hz), 34.12 (d,
J=23.6 Hz), 32.03; HR-FABMS (m/z) obsd 253.1102, calcd for C11H14FN4O2 253.1100
(M+H)+. Anal. calcd for C11H13FN4O2·0.2MeOH: C, 52.01; H, 5.38; N, 21.66. Found: C,
51.80; H, 5.18; N, 21.40.
3.26. (+)-9-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]-6-mercaptopurine 29
A solution containing 27 (50 mg, 0.185 mmol) and thiourea (21 mg, 0.276 mmol) in ethanol
(4 ml) was refluxed for 1.5 h. After evaporation under reduced pressure, the remaining
off-white solid was purified by fractional recrystallization in ethyl alcohol to give 29 (40 mg,
0.149 mmol, 81% yield) as a white solid: mp 268–270°C; [h]2D4 +16.5 (c 0.17, MeOH); UV (H2O)
1
umax 322.5 nm (m 24 531, pH 2), 320.5 nm (m 24 374, pH 7), 310.5 nm (m 22 724, pH 11); H
NMR (DMSO) l 14.00 (br s, 1H, N-H), 8.65 (s, 1H, H-8), 8.44 (s, 1H, H-2), 5.43 (t, J=5.8
Hz, 1H, 5%-OH), 5.31 (dt, J=17.7, 8.0 Hz, 1H, H-1%), 3.87–3.80 (m, 2H, H-5%), 2.66–2.07 (m,
6H, H-2%, H-3%, H-6%); 13C NMR (DMSO) l 176.20, 145.04, 144.33, 142.00, 135.79, 105.58 (d,
J=175.7 Hz), 64.93 (d, J=27.2 Hz), 54.44, 40.84 (d, J=23.1 Hz), 32.70 (d, J=23.5 Hz), 30.42;
HR-FABMS (m/z) obsd 269.0885, calcd for C11H14FN4OS 269.0892 (M+H)+. Anal. calcd for
C11H13FN4O2·0.3MeOH: C, 48.83; H, 5.15; N, 20.16. Found: C, 48.74; H, 5.02; N, 20.38.
3.27. (+)-1-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]-N3-
benzoyluracil 30
To a solution of triphenylphosphine (647 mg, 2.47 mmol), N3-benzoyluracil (533 mg, 2.47
mmol), and 20 (245 mg, 0.986 mmol) in anhydrous dioxane (6 ml) and DMF (3 ml), was added
DEAD (0.4 ml, 2.54 mmol) over 30 min at 0°C. The resulting homogeneous yellow solution was
stirred for 3 h at room temperature. Solvent was removed under reduced pressure and the
resulting residue was purified by column chromatography on silica gel (1:1 hexanes/ethyl
acetate) to give 240 mg (0.537 mmol, 54% yield) of the desired N1-alkylated product 30 as a
colorless oil, and 64 mg (0.143 mmol, 15% yield) of an inseparable mixture of the O2-alkylated
product 33 and reduced DEAD as a pale yellow oil, respectively: For 30, [h]2D5 +1.65 (c 1.30,
1
CHCl3); UV (MeOH) umax 253.0 nm; H NMR (CDCl3) l 7.85 (d, J=7.4 Hz, 2H), 7.57 (t,
J=7.4 Hz, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.26 (d, J=8.1 Hz, 1H), 5.74 (d, J=8.1 Hz, 1H), 4.98
(quintet, J=8.2 Hz, 1H), 3.67 (dd, J=11.8, 10.5 Hz, 1H), 3.63 (dd, J=13.8, 10.5 Hz, 1H),
2.35–2.24 (m, 2H), 2.16–2.00 (m, 2H), 1.92–1.76 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H); 13C NMR
(CDCl3) l 168.81, 161.97, 149.69, 141.33, 131.40, 130.46, 129.16, 104.13 (d, J=176.7 Hz),
102.48, 65.67 (d, J=33.0 Hz), 57.25, 39.16 (d, J=23.7 Hz), 32.94 (d, J=23.2 Hz), 29.81, 25.80,
18.26; HR-FABMS (m/z) obsd 447.2104, calcd for C23H32FN2O4Si 447.2115 (M+H)+. Anal.
calcd for C23H31FN2O4Si: C, 61.86; H, 7.00; N, 6.27. Found: C, 61.78; H, 7.00; N, 6.05.

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3.28. (−)-1-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]-N3-
benzoylthymine 31
To a solution of triphenylphosphine (186 mg, 0.709 mmol), N3-benzoylthymine (171 mg, 0.743
mmol), and 20 (88 mg, 0.354 mmol) in anhydrous dioxane (2 ml) and DMF (1 ml), was added
DEAD (0.11 ml, 0.699 mmol) over 30 min at 0°C. The resulting homogeneous yellow solution
was stirred for 3 h at room temperature. Solvent was removed under reduced pressure and the
resulting residue was purified by column chromatography on silica gel (1:1 hexanes/ethyl
acetate) to give 73 mg (0.16 mmol, 45% yield) of the desired N1-alkylated product 31 as a
colorless oil, and 37 mg (0.081 mmol, 23% yield) of an inseparable mixture of the O2-alkylated
product 34 and reduced DEAD as a pale yellow oil, respectively: [h]2D4 −8.1 (c 2.20, CHCl3); UV
1
(MeOH) umax 254.0 nm; H NMR (CDCl3) l 7.84 (d, J=8.1 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H),
7.41 (t, J=7.9 Hz, 2H), 7.01 (br d, J=1.2 Hz, 1H), 4.98 (quintet, J=8.6 Hz, 1H), 3.66 (dd,
J=12.5, 10.6 Hz, 1H), 3.62 (dd, J=14.6, 10.6 Hz, 1H), 2.30–1.97 (m, 4H), 1.92–1.75 (m, 2H),
1.87 (br d, J=1.2 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3) l 169.53, 163.10,
150.15, 137.58, 135.41, 132.01, 130.86, 129.55, 111.58, 104.56 (d, J=176.9 Hz), 66.21 (d, J=32.3
Hz), 57.21, 39.47 (d, J=23.4 Hz), 33.43 (d, J=23.0 Hz), 29.90, 26.23, 18.66, 13.06, −5.02;. Anal.
calcd for C24H33FN2O4Si: C, 62.58; H, 7.22; N, 6.08. Found: C, 62.75; H, 7.22; N, 5.89.
3.29. (−)-1-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]-N3-benzoyl-
5-fluorouracil 32
To a solution of triphenylphosphine (154 mg, 0.587 mmol), N3-benzoyl-5-fluorouracil (167
mg, 0.713 mmol), and 20 (71 mg, 0.286 mmol) in anhydrous dioxane (2 ml) and DMF (1 ml),
was added DEAD (0.113 ml, 0.718 mmol) over 30 min at 0°C. The resulting homogeneous
yellow solution was stirred for 3 h at room temperature. Solvent was removed under reduced
pressure and the resulting residue was purified by column chromatography on silica gel (4:1
hexanes/ethyl acetate) to give 75 mg (0.161 mmol, 56% yield) of the desired N1-alkylated product
1
32 as a colorless oil: [h]2D4 −0.64 (c 4.80, CHCl3); UV (MeOH) umax 265.0 nm; H NMR
(CD3OD) l 7.92 (d, J=7.4 Hz, 2H), 7.68 (t, J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 2H), 7.46 (d,
J=6.0 Hz, 1H), 5.10 (quintet, J=8.2 Hz, 1H), 3.76 (dd, J=11.3, 10.5 Hz, 1H), 3.72 (dd,
J=13.3, 10.5 Hz, 1H), 2.41–1.85 (m, 6H), 0.92 (s, 9H), 0.10 (s, 6H); 13C NMR (CD3OD) l
167.75, 156.26 (d, J=27.2 Hz), 148.69, 140.53 (d, J=240.0 Hz), 135.87, 131.41, 130.97, 129.69,
104.25 (d, J=177.1 Hz), 66.15 (d, J=33.6 Hz), 57.50, 39.55 (d, J=23.9 Hz), 33.36 (d, J=23.3
Hz), 30.26, 26.23, 18.72, −5.05; HR-FABMS (m/z) obsd 465.2029, calcd for C23H31F2N2O4Si
465.2021 (M+H)+. Anal. calcd for C23H30F2N2O4Si·0.2C6H14: C, 60.33; H, 6.86; N, 5.81. Found:
C, 60.66; H, 6.89; N, 5.77.
3.30. General procedure for N3-debenzoylation. This is representative of the synthesis of uridine
analogue 36 from compound 30
3.30.1. (+)-1-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]uracil 36
The N3-benzoylated uridine analogue 30 (240 mg, 0.537 mmol) was treated with methanolic
ammonia (10 ml) for 3 h at 0°C. After evaporation, the residue was purified by column
chromatography on silica gel (1:1 hexanes/ethyl acetate) to give 181 mg (0.528 mmol, 98% yield)
of 36 as a white solid: [h]D28 +2.5 (c 1.10, CHCl3); UV (MeOH) umax 266.0 nm; 1H NMR (CDCl3)

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4871
l 9.55 (br s, 1H), 7.16 (d, J=8.0 Hz, 1H), 5.65 (d, J=8.0 Hz, 1H), 5.02 (quintet, J=8.3 Hz,
1H), 3.67 (dd, J=10.5, 8.8 Hz, 1H), 3.63 (dd, J=13.8, 10.5 Hz, 1H), 2.31–1.69 (m, 6H), 0.82 (s,
9H), 0.00 (s, 6H); 13C NMR (CDCl3) l 163.88, 151.31, 141.84, 104.49 (d, J=176.5 Hz), 103.02,
66.15 (d, J=33.31 Hz), 56.87, 39.59 (d, J=23.5 Hz), 33.36 (d, J=23.3 Hz), 30.24, 26.22, 18.68,
−5.04; HR-FABMS (m/z) obsd 343.1840, calcd for C16H28FN2O3Si 343.1853 (M+H)+. Anal.
calcd for C16H27FN2O3Si·0.11C6H14: C, 56.85; H, 8.17; N, 7.96. Found: C, 56.98; H, 8.03; N,
7.76.
3.30.2. (−)-1-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]thymine 37
See the general procedure for deprotection of benzoyl group using methanolic ammonia. [h]D24
1
−4.75 (c 0.50, CHCl3); UV (MeOH) umax 271.0 nm; H NMR (CDCl3) l 8.29 (s, 1H), 6.90 (s,
1H), 5.00 (tt, J=8.3, 8.2 Hz, 1H), 3.66 (dd, J=11.9, 10.6 Hz, 1H), 3.62 (dd, J=14.0, 10.6 Hz,
1H), 2.28–1.68 (m, 6H), 1.83 (s, 3H), 0.82 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3) l 163.78,
150.99, 137.52, 111.53, 104.41 (d, J=176.5 Hz), 66.17 (d, J=32.9 Hz), 56.41, 39.50 (d, J=23.4
Hz), 33.43 (d, J=23.3 Hz), 30.04 (d, J=13.8 Hz), 26.22, 18.65, 12.99, −5.03; HR-FABMS (m/z)
obsd 357.2008, calcd for C17H30FN2O3Si 357.2009 (M+H)+. Anal. calcd for
C17H29FN2O3Si·0.2C6H14: C,58.49; H, 8.58; N, 7.50. Found: C, 58.23; H, 8.41; N, 7.15.
3.30.3. (+)-1-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]-5-
fluorouracil 38
See the general procedure for deprotection of benzoyl group using methanolic ammonia. [h]D24
1
+1.9 (c 4.00, CHCl3); UV (MeOH) umax 273.5 nm; H NMR (CDCl3) l 9.76 (br s, 1H), 7.24 (d,
J=5.9 Hz, 1H), 5.06 (quintet, J=8.3 Hz, 1H), 3.66 (dd, J=10.5, 10.5 Hz, 1H), 3.62 (dd,
J=12.6, 10.5 Hz, 1H), 2.32–2.22 (m, 2H), 2.15–1.79 (m, 3H), 1.73–1.64 (m, 1H), 0.81 (s, 9H),
0.00 (s, 6H); 13C NMR (CD3OD) l 156.80 (d, J=26.4 Hz), 149.57, 140.63 (d, J=238.4 Hz),
125.38 (d, J=32.6 Hz), 103.72 (d, J=177.0 Hz), 65.71 (d, J=33.9 Hz), 56.31, 39.13 (d, J=23.7
Hz), 32.95 (d, J=23.4 Hz), 29.90, 25.78, 18.27, −5.51. Anal. calcd for C16H26F2N2O3Si·0.1C6H14:
C, 54.02; H, 7.48; N, 7.59. Found: C, 54.09; H, 7.22; N, 7.63.
3.30.4. (+)-O2-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]uracil 39
See the general procedure for deprotection of benzoyl group using methanolic ammonia. [h]D23
+27.4 (c 4.46, CHCl3); UV (MeOH) umax 267.5 nm; 1H NMR (CDCl3) l 7.69 (d, J=6.6 Hz, 1H),
6.03 (d, J=6.6 Hz, 1H), 5.51–5.48 (m, 1H), 3.67 (d, J=17.9 Hz, 2H), 2.40–1.83 (m, 6H), 0.82
(s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3) l 166.12, 157.38, 155.69, 109.15, 105.38 (d, J=177.0
Hz), 80.14, 66.97 (d, J=29.3 Hz), 41.80 (d, J=24.0 Hz), 32.77 (d, J=23.5 Hz), 31.12, 26.22,
18.70, −5.03; FABMS (m/z) obsd 343. Anal. calcd for C16H27FN2O3Si: C, 56.11; H, 7.95; N,
8.18. Found: C, 56.26; H, 7.99; N, 7.95.
3.30.5. (+)-O2-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]thymine 40
See the general procedure for deprotection of benzoyl group using methanolic ammonia. [h]D23
+23.4 (c 1.07, CHCl3); UV (MeOH) umax 271.0 nm; 1H NMR (CDCl3) l 7.53 (br s, 1H), 5.46 (br
s, 1H), 3.67 (d, J=17.1 Hz, 2H), 2.43–1.81 (m, 6H), 1.93 (s, 3H), 0.82 (s, 9H), 0.00 (s, 6H); 13C
NMR (CDCl3) l 175.15, 155.32, 151.68, 118.52, 105.41 (d, J=176.8 Hz), 79.84, 66.92 (d,
J=29.7 Hz), 41.90 (d, J=23.8 Hz), 32.88 (d, J=23.7 Hz), 31.30, 26.21, 18.68, 12.82, −5.00;
FABMS (m/z) obsd 357. Anal. calcd for C17H29FN2O3Si·0.2C6H14: C, 58.49; H, 8.58; N, 7.50.
Found: C, 58.75; H, 8.45; N, 7.16.

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
3.31. (−)-1-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]uracil 41
See the general procedure for deprotection of TBDMS group using TBAF. Mp 75°C; [h]D25
−2.9 (c 1.31, MeOH); UV (H2O) umax 271.5 nm (m 1 602, pH 2), 271.0 nm (m 1 308, pH 7), 270.0
1
nm (m 1 238, pH 11); H NMR (CDCl3) l 7.74 (d, J=8.0 Hz, 1H, H-6), 5.75 (d, J=8.0 Hz, 1H,
H-5), 5.10 (ddd, J=16.0, 10.6, 8.2 Hz, 1H, H-1%), 3.78 (dd, J=15.1, 12.1 Hz, 1H, H-5%), 3.73 (dd,
J=19.4, 12.1 Hz, 1H, H-5%), 2.39–1.96 (m, 6H, H-2%, H-3%, H-6%); 13C NMR (CDCl3) l 166.71,
153.15, 144.82, 106.14 (d, J=175.9 Hz), 103.00, 67.03 (d, J=27.2 Hz), 58.21, 40.38 (d, J=23.4
Hz), 33.90 (d, J=23.7 Hz), 30.04; HR-FABMS (m/z) obsd 229.0989, calcd for C10H14FN2O3
229.0988 (M+H)+. Anal. calcd for C10H14FN2O3·0.2H2O: C, 51.81; H, 5.83; N, 12.08. Found: C,
51.74; H, 5.93; N, 11.70.
3.32. (+)-1-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]thymine 42
See the general procedure for deprotection of TBDMS group using TBAF. Mp 156–158°C;
[h]2D2 +4.6 (c 1.32, MeOH); UV (H2O) umax 267.0 nm (m 21 659, pH 2), 267.0 nm (m 21 233, pH
1
7), 265.0 nm (m 16 569, pH 11); H NMR (CD3OD) l 7.68 (d, J=1.1 Hz, 1H, H-6), 5.22 (ddd,
J=18.9, 10.8, 8.1 Hz, 1H, H-1%), 3.88 (dd, J=18.4, 12.1 Hz, 1H, H-5%), 3.86 (dd, J=19.4, 12.1
Hz, 1H, H-5%), 2.46–2.05 (m, 6H, H-2%, H-3%, H-6%), 2.05 (d, J=1.1 Hz, 3H, CH3); 13C NMR
(CD3OD) l 166.83, 153.31, 140.45, 112.00, 106.16 (d, J=175.9 Hz), 67.07 (d, J=27.4 Hz),
57.76, 40.32 (d, J=23.4 Hz), 33.89 (d, J=23.4 Hz), 29.98, 12.74; HR-FABMS (m/z) obsd
243.1154, calcd for C11H16FN2O3 243.1144 (M+H)+. Anal. calcd for C11H15FN2O3: C, 54.54; H,
6.24; N, 11.56. Found: C, 54.24; H, 6.20; N, 11.34.
3.33. (−)-1-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]-5-fluorouracil 43
See the general procedure for deprotection of TBDMS group using TBAF. Mp 142–144°C;
[h]2D5 −4.2 (c 1.21, MeOH); UV (H2O) umax 273.0 nm (m 8 758, pH 2), umax 273.5 nm (m 8 217, pH
1
7), umax 271.5 nm (m 6 839, pH 11); H NMR (CD3OD) l 7.97, (d, J=6.9 Hz, 1H, H-6), 5.09 (dt,
J=18.4, 8.0 Hz, 1H, H-1%), 3.75 (dd, J=21.0, 12.1 Hz, 1H, H-5%), 3.72 (dd, J=19.6, 12.1 Hz,
1H, H-5%), 2.36–1.87 (m, 6H, H-2%, H-3%, H-6%); 13C NMR (CD3OD) l 159.83 (d, J=25.7 Hz),
151.84, 142.26 (d, J=232.4 Hz), 128.68 (d, J=33.7 Hz), 106.04 (d, J=176.0 Hz), 67.05 (d,
J=27.3 Hz), 58.19, 40.20 (d, J=23.5 Hz), 33.79 (d, J=23.5 Hz), 29.91; HR-FABMS (m/z) obsd
247.0888,
calcd
for
C10H13F2N2O3
247.0889
(M+H)+.
Anal.
calcd
for
C10H12F2N2O3·0.1CH3CH2OCH2OCH3: C, 49.25; H, 5.17; N, 11.05. Found: C, 49.39; H, 5.23;
N, 10.81.
3.34. (+)-O2-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]uracil 46
See the general procedure for deprotection of TBDMS group using TBAF. [h]2D2 +20.9 (c 0.91,
1
MeOH); UV (MeOH) umax 267.5 nm; H NMR (CD3OD) l 7.72 (d, J=6.7 Hz, 1H, H-6), 6.01
(d, J=6.7 Hz, 1H, H-5), 5.56 (m, 1H, H-1%), 3.66 (d, J=19.7 Hz, 2H, H-5%), 2.46–1.91 (m, 6H,
H-2%, H-3%, H-6%); HR-FABMS (m/z) obsd 229.0988, calcd for C10H14FN2O3 229.0983 (M+H)+.
Anal. calcd for C10H13FN2O3: C, 52.63; H, 5.74; N, 12.27. Found: C, 52.91; H, 5.96; N, 12.00.

Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
4873
3.35. (+)-O2-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]thymine 47
See the general procedure for deprotection of TBDMS group using TBAF. [h]2D3 +31.7 (c 0.19,
1
MeOH); UV (MeOH) umax 270.0 nm; H NMR (CD3OD) l 7.57 (d, J=1.0 Hz, 1H, H-6), 5.51
(m, 1H, H-1%), 3.66 (d, J=19.8 Hz, 2H, H-5%), 2.44–1.92 (m, 6H, H-2%, H-3%, H-6%), 1.92 (d,
J=1.0 Hz, 3H, CH3); HR-FABMS (m/z) obsd 243.1145, calcd for C11H16FN2O3 243.1158
(M+H)+.
3.36. (+)-1-[(1S,4S)-4-tert-Butyldimethylsilyloxymethyl-4-fluorocyclopentan-1-yl]cytosine 44
To a solution of 36 (73 mg, 0.213 mmol) and 1,2,4-triazole (97 mg, 1.40 mmol) in anhydrous
pyridine (10 ml), 4-chlorophenyldichlorophosphate (0.111 ml, 0.682 mmol) was slowly added at
0°C. The resulting solution was stirred for 24 h at rt, and then evaporated to dryness in vacuo.
The residue was dissolved in CHCl3, and the solution was washed with water (2×5 ml) and
saturated aq. NaHCO3 solution. After drying over MgSO4, the remaining residue was carefully
dried and used for the next step without further purification. The crude product obtained above
was treated with methanolic ammonia and heated to 100°C for 6 h in a steel bomb. After
evaporation of the solvent, the crude product was purified by column chromatography on silica
gel (2:1 hexanes/acetone) to give 45 mg (0.132 mmol, 62% yield) of the aminated product 44 as
1
a pale yellow syrup: [h]2D5 +6.2 (c 1.59, CHCl3); UV (MeOH) umax 276.0 nm; H NMR (CDCl3)
l 7.25 (d, J=7.3 Hz, 1H), 5.74 (d, J=7.3 Hz, 1H), 5.04 (quintet, J=8.3 Hz, 1H), 3.68 (dd,
J=13.0, 10.5 Hz, 1H), 3.64 (dd, J=14.7, 10.5 Hz, 1H), 2.30–1.70 (m, 6H), 0.82 (s, 9H), 0.00 (s,
6H); 13C NMR (CDCl3) l 165.11, 156.42, 143.23, 104.76 (d, J=176.7 Hz), 94.90, 66.44 (d,
J=32.5 Hz), 57.88, 39.79 (d, J=23.3 Hz), 33.42 (d, J=23.2 Hz), 30.35, 26.25, 18.70, −5.02;
HR-FABMS (m/z) obsd 342.2018, calcd for C16H29FN3O2Si 342.2013 (M+H)+. Anal. calcd for
C16H28FN3O2Si·0.4CH3COCH3: C, 56.64; H, 8.40; N, 11.52. Found: C, 56.62; H, 8.33; N, 11.23.
3.37. (−)-1-[(1S,4S)-4-Fluoro-4-hydroxymethylcyclopentan-1-yl]cytosine 45
See the general procedure for deprotection of TBDMS group using TBAF. [h]2D5 −2.1 (c 1.37,
MeOH); UV (H2O) umax 283.0 nm (m 7 718, pH 2), umax 274.0 nm (m 5 321, pH 7), umax 274.0 nm
1
(m 5 223, pH 11); H NMR (CD3OD) l 7.77 (d, J=7.4 Hz, 1H, H-6), 5.99 (d, J=7.4 Hz, 1H,
H-5), 5.17 (ddd, J=18.5, 10.5, 8.0 Hz, 1H, H-1%), 3.80 (dd, J=18.5, 12.1 Hz, 1H, H-5%), 3.77 (dd,
J=19.5, 12.1 Hz, 1H, H-5%), 2.41–1.92 (m, 6H, H-2%, H-3%, H-6%); 13C NMR (CD3OD) l 167.60,
159.24, 144.94, 106.26 (d, J=175.9 Hz), 96.55, 67.14 (d, J=27.4 Hz), 59.01, 40.72 (d, J=23.4
Hz), 34.04 (d, J=23.8 Hz), 30.46; HR-FABMS (m/z) obsd 228.1155, calcd for C10H15FN3O2
228.1148 (M+H)+. Anal. calcd for C10H14FN3O2·0.39CH2Cl2: C, 47.93; H, 5.72; N, 16.14.
Found: C, 48.09; H, 6.04; N, 15.96.
Acknowledgements
This research was supported by the US Public Health Service Research Grant AI 32351 from
the National Institute of Allergy and Infectious Diseases, NIH. We thank Dr. Michael Bartlett
of the College of Pharmacy, The University of Georgia, for performing the high-resolution mass
spectra and Dr. Raymond F. Schinazi of Emory University and veterans affairs medical center
for anti-HIV evaluations.

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Y. Chong et al. / Tetrahedron: Asymmetry 11 (2000) 4853–4875
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