Synthesis and anti-HCMV activity of novel acyclic nucleosides

Article abstract of DOI:10.1081/NCN-120015727

A series of novel acyclic nucleosides 10, 11, 21, and 22 were synthesized efficiently starting from D-lactose. The condensation of the mesylate 5 and 16 with an adenine and cytosine base under standard nucleophilic substitution conditions (K₂CO

Full text of DOI:10.1081/NCN-120015727

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SYNTHESIS AND ANTI-HCMV ACTIVITY OF NOVEL
ACYCLIC NUCLEOSIDES
Jae Young Lee a , Chang Hyun Oh b , Ok Hyun Ko a & Joon Hee Hong a
a College of Pharmacy , Chosun University , Kwangju, 501-759, South Korea
b Medicinal Chemistry Research Center , Korea Institute of Science and Technology , Seoul,
130-650, South Korea
Published online: 17 Aug 2006.
To cite this article: Jae Young Lee , Chang Hyun Oh , Ok Hyun Ko & Joon Hee Hong (2002) SYNTHESIS AND ANTI-HCMV
ACTIVITY OF NOVEL ACYCLIC NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 21:10, 709-721, DOI: 10.1081/
NCN-120015727
To link to this article: http://dx.doi.org/10.1081/NCN-120015727
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 21, No. 10, pp. 709±721, 2002
SYNTHESIS AND ANTI-HCMV ACTIVITY
OF NOVEL ACYCLIC NUCLEOSIDES
Jae Young Lee,1 Chang Hyun Oh,2 Ok Hyun Ko,1 and
Joon Hee Hong1,*
1College of Pharmacy, Chosun University,
Kwangju 501-759, South Korea
2Medicinal Chemistry Research Center, Korea Institute of Science
and Technology, Seoul 130-650, South Korea
ABSTRACT
A series of novel acyclic nucleosides 10, 11, 21, and 22 were synthesized
eciently starting from D-lactose. The condensation of the mesylate 5
and 16 with an adenine and cytosine base under standard nucleophilic
substitution conditions 0K2CO3, 18-Crown-6, DMF) a€orded a series of
acyclic novel nucleosides. Compound 21 displayed moderate anti-HCMV
activity in the AD-169 cells 0EC50 ˆ 18.5 mg=mL) without exhibiting any
cytotoxicity up to 100 mM.
INTRODUCTION
The discovery of acyclovir[1] as an antiherpes agent ignited the search
for new antiviral nucleosides with a disconnected chain resulting from the
omission of bonds from the pentose or cyclopentane rings. During the past
twenty years, many new synthetic schemes for various acyclic nucleoside[2]
analogues have been discovered and many of these molecules have shown
*Corresponding author. E-mail: hongjh@mail.chosun.ac.kr
709
DOI: 10.1081=NCN-120015727
Copyright # 2002 by Marcel Dekker, Inc.
1525-7770 0Print); 1532-2335 0Online)
www.dekker.com

710
LEE ET AL.
promising antiviral activities.[3] Among them, deciclovir,[4] ganciclovir,[5]
penciclovir,[6] famciclovir[7] have exhibited potent antiviral activity against
HBV, HIV, and the herpes virus. It may be assumed that the potent antiviral
activity originates from the ¯exible acyclic sugar mimicking moiety.
Nevertheless, the utility of these drugs is limited due to their toxicity and
side e€ects, as well as the emergence of drug resistant viral strains. Therefore,
it is essential to search for less toxic and more e€ective antiviral agents, which
do not have a cross-resistance with the existing drugs. To the best of the
authors' knowledge, no attempts to synthesize and screen novel acyclic
nucleosides containing both a tertiary hydroxyl group and a two-bond dis-
connection have yet been made.
In view of the stimulating results of acyclic nucleosides and as part of
our ongoing drug discovery e€orts, this study aimed to synthesize novel
acyclic nucleosides. This paper reports their synthetic routes from very cheap
and commercially available D-lactose and their biological activities.
RESULTS AND DISCUSSIONS
Most methods used to synthesize acyclic nucleosides involve the alky-
lation of the acyclic chain by a suitable alkyl halide or a similar good leaving
group. Thus, the requisite acyclic chain was prepared by starting with an acid
derivative 1, which was prepared from D-lactose in 5 steps using the pro-
cedure reported by Monneret et al.[8] Compound 1 was reduced to alcohol 2
by LiAlH4 in an anhydrous THF solution, which was protected with benzyl
bromide 0BnBr) to give 3 in a 68.6% yield for the two steps 0Sch. 1). Ole®n 3
was hydroborated by stirring overnight with a BH3=DMScomplex in THF at
room temperature. It was then oxidized by 30% H2O2 to provide the primary
alcohol 4 in a 63% yield. The hydroxyl group of 4 was mesylated by treating
it with methanesulfonyl chloride 0MsCl) in an anhydrous CH2Cl2 solvent to
give the key intermediate 5, which was coupled with the nucleobases 0adenine
and cytosine) under well-known standard conditions 0K2CO3, 18-C-6,
DMF)[9] to give adenine and cytosine derivative 6 and 7 in 48±56% yield for
the two steps. Removing the benzyl protecting groups of 6 and 7 was
accomplished by the conditions[10] of 10% Pd0OH)2 in methanol and a
cyclohexene mixture system to furnish 8 and 9 in a 55±64% yield. The iso-
propylidene groups of nucleoside 8 and 9 could be readily removed by an
acidic hydrolysis condition 080% AcOH, 80ꢀC) to give 10 and 11 in 55±64%
yield.
In order to synthesize the other type of diseco-nucleosides 0two bond
disconnection), the key intermediate 16 was made starting from 2 0Sch. 2).
The choice of the hydroxyl protecting groups must be made to avoid the
diculties encountered with removing the benzyl groups during the sub-
sequent step. Based on this consideration, the hydroxyl functional group of

NOVEL ACYCLIC NUCLEOSIDES
711
Scheme 1. Reagents: i) LiAIH4, THF, re¯ux, overnight, 88%; ii) BnBr, NaH, THF, rt,
overnight, 78%; iii) BH3=DMS, THF, NaOH=H2O2, 63%; iv) MsCl, TEA, 0ꢀC, 1 h, 90%; v)
adenine and cytosine, DMF, K2CO3, 18-C-6, 80ꢀC, overnight, 48±56%; vi) Pd0OH)2, MeOH,
cyclohexene, re¯ux, overnight, 77±89%; vii) 80% AcOH, 80ꢀC, overnight, 55±64%.
2 was temporarily protected with t-butyldimethylsilyl chloride 0TBDMSCl)
to give 12 in a 95% yield. Ole®n 12 was sequentially hydroborated with
BH3=DMSand oxidized by H O2 to give 13 in a 56% yield. This time, the
2
resulting hydroxyl group was protected by BnBr to give 14 in an 80%
yield. The TBDMSprotecting group of 14 was removed by a treatment
with tetrabutyl-ammonium ¯uoride 0TBAF) to furnish 15 in an 85% yield,
which was mesylated with MsCl to give 16 in a 69% yield for the two
steps.
The condensation of 16 with the nucleobases 0adenine and cytosine)
gave 17 and 18 in a 45±50% yield. A separate treatment of 17 and 18 with
Pd0OH)2 in the cyclohexene and methanol cosolvent system gave debenzy-
lated nucleosides 19 and 20, respectively. Removing the isopropylidene

712
LEE ET AL.
Scheme 2. Reagents: i) TBDMSCl, imidazole, CH2Cl2, 0ꢀC, 4 h, 95%; ii) BH3=DMS, THF,
H2O2, NaOH, 56%; iii) BnBr, NaH, THF, rt, overnight, 80%; iv) TBAF, THF, rt, 3 h, 85%;
v) MsCl, TEA, CH2Cl2, 0ꢀC, 87%; vi) adenine and cytosine, DMF, K2CO3, 18-C-6, 80ꢀC,
overnight, 45±60%; vii) Pd0OH)2, MeOH, cyclohexene, re¯ux, overnight, 90±95%; viii) 80%
AcOH, 80ꢀC, overnight, 45±60%.
protecting group of 19 and 20 was readily made in an 80% AcOH solution at
80ꢀC to a€ord 21 and 22, respectively. The antiviral assays of the synthesized
®nal nucleosides 10, 11, 20 and 21 against the human immunode®ciency virus
1 0HIV-1), the herpes simplex virus 1,2 0HSV-1, 2) and the human cytome-
galovirus 0HCMV) were performed. The compounds did not show any
antiviral activity except for the adenine derivative 21, which exhibited
moderate anti-HCMV activity in AD-169 cells 0EC50 ˆ 18.5 mg=mL) without
any cytotoxicity up to 100 mM.

NOVEL ACYCLIC NUCLEOSIDES
713
CONCLUSION
Novel acyclic nucleosides were successfully synthesized starting from D-
lactose. The present synthetic method is highly ecient and convenient, and
has the ¯exibility for further applications to the synthesis of geminally sub-
stituted novel acyclic nucleosides. Although the tested compounds did not
display excellent antiviral activity, the adenine derivative 21 exhibited mod-
erate anti-HCMV activity in AD-169 cells 0EC50 ˆ 18.5 mg=mL). This result
strongly suggests that this structure for the novel nucleosides 0diseco-
nucleoside) might be candidate for a new lead compound for developing new
antiviral agents.
EXPERIMENTAL SECTION
The melting points were determined on a Mel-tem II laboratory device
and were uncorrected. The NMR spectra were recorded on a Bruker 300
Fourier transform spectrometer. The chemical shifts are reported in parts per
million 0d) and the signals are quoted as s 0singlet), d 0doublet), t 0triplet), q
0quartet), m 0multiplet) and dd 0doublet of doublets). The UV spectra were
obtained on a Beckman DU-7 spectrophotometer. The optical rotations were
measured on an Autopol-IV digital polarimeter. The elemental analyses
were performed in the Korea Basic Science Institute, Kwangju, Korea. TLC
was performed on Uniplates 0silica gel) purchased from Analtech Co. All
reactions were carried out under N2 unless otherwise speci®ed. Dry
dichloromethane, benzene and pyridine were obtained by distillation from
CaH2. Dry THF was obtained by distillation from Na and benzophenone
immediately prior to use.
)2R)-2-Hydroxy-2-)hydroxymethyl)-2,20-O-isopropylidene-pent-4-en-1-ol
)2): To a solution of 1 05 g, 26.8 mmol) in THF 020 mL), LiAlH4 01.6 g,
42.9 mmol) was added portionwise at 0ꢀC. The mixture was stirred overnight
under re¯ux, and then cooled to room temperature. To the mixture, water
01.48 mL), 15% NaOH solution 01.48 mL), and water 04.4 mL) sequentially
added. The mixture was stirred at room temperature for 2 h, and the resulting
solid was ®ltered through a Celeste pad. The ®ltrate was concentrated under
vacuum and the residue was puri®ed by silica gel column chromatography
0EtOAc=hexane, 2:1) to give alcohol 2 04.06 g, 88%) as a colorless oil: [a]2D5
À2.9ꢀ 0c 3.0, MeOH); 1H NMR 0CDCl3, 300 MHz) d 5.86±5.72 0m, 1H, H-4),
5.16 0d, J ˆ 3.6 Hz, 2H, H-5a), 5.11 0s, 1H, H-5b), 3.90 0d, J ˆ 8.7 Hz, 1H, H-
20a), 3.84 0d, J ˆ 8.7 Hz, 1H, H-20b), 3.55 0d, J ˆ 12.3 Hz, 2H, H-1), 2.41 0t,
J ˆ 6.3 Hz, 2H, H-3), 1.91 0s, 1H, OH), 1.42 0d, J ˆ 2.1 Hz, 6H, 2CH3); 13C
NMR 0CDCl3) d 132.98, 118.70, 109.78, 82.98, 69.26, 65.22, 39.95, 27.09,
26.91; Anal. Calc. for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.68; H, 9.47.

714
LEE ET AL.
)4R)-5-Benzyloxy-4-hydroxy-4-)hydroxymethyl)-4,40-O-isopropylidene-
pent-1-ene )3): To a stirred suspension of NaH 02 g, 50 mmol, 60%) in THF
0100 mL), a solution of 2 08.7 g, 33.3 mmol) in THF was slowly added at 0ꢀC,
and stirred at room temperature for 1 h. The mixture was cooled to 0ꢀC, and
benzyl bromide 06.8 g, 39.9 mmol) was then slowly added. The mixture was
stirred overnight at room temperature, and quenched by adding a saturated
ammonium chloride solution 010 mL). The mixture was extracted with
EtOAc 0200 mL) and water 0200 mL), and the organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and ®ltered. The ®ltrate was
concentrated under reduced pressure, and the residue was puri®ed by silica
gel column chromatography 0EtOAc=hexane, 1:10) to give 3 06.8 g, 78%) as a
1
colorless oil: [a]2D5 À22.49ꢀ 0c 1.52, MeOH); H NMR 0CDCl3, 300 MHz) d
7.37±7.25 0m, 5H, Ar), 5.89±5.75 0m, 1H, H-2), 5.13 0dd, J ˆ 13.5, 1.8 Hz, 2H,
H-1), 4.54 0s, 2H, CH2-Ar), 3.95 0d, J ˆ 8.3 Hz, 1H, H-40a), 3.79 0d,
J ˆ 8.3 Hz, 1H, H-40b), 3.40 0d, J ˆ 4.8 Hz, 2H, H-5), 2.45 0d, J ˆ 7.5 Hz, 2H,
H-3), 1.40 0d, J ˆ 3.6 Hz, 6H, 2CH3); Anal. Calc. for C16H22O3: C, 73.25; H,
8.45. Found: C, 73.38; H, 8.49.
)4R)-5-Benzyloxy-4-hydroxy-4-)hydroxymethyl)-4,40-O-isopropylidene-
pentan-1-ol )4): To a solution of ole®n 3 02.5 g, 9.5 mmol) in dry THF
010 mL), 1.0 M BH3=DMS0in tetrahydrofuran, 11.4 mL) was added drop-
wise with a syringe at 0ꢀC. The mixture was stirred overnight at room
temperature, and then cooled to 0ꢀC. A 2 N NaOH solution 010 mL,
20 mmol) was added followed by the careful addition of a 30% hydrogen
peroxide solution 06.0 mL, 51.3 mmol). The reaction mixture was stirred at
room temperature for 2 h. The mixture was then diluted with brine 010 mL)
and extracted with ethyl acetate 050 mL63). The combined organic layers
were dried over anhydrous magnesium sulfate, ®ltered, and concentrated
under vacuum. The residue was puri®ed by silica gel column chromato-
graphy 0EtOAc=hexane, 1:1) to give 4 01.67 g, 63%) as a colorless oil: [a]2D5
À10.81ꢀ 0c 1.22, MeOH); 1H NMR 0CDCl3, 300 MHz) d 7.37±7.26 0m, 5H,
Ar), 4.53 0s, 2H, CH2-Ar), 4.03 0d, J ˆ 8.4 Hz, 1H, H-40a), 3.76 0d,
J ˆ 8.4 Hz, 1H, H-40b), 3.67 0m, 2H, H-5), 3.45 0dd, J ˆ 13.8, 9.3 Hz, 2H, H-
1), 2.04±1.58 0m, 4H, H-2 and 3), 1.38 0s, 6H, 2CH3); Anal. Calc. for
C16H24O4: C, 68.54; H, 8.63. Found: C, 68.50; H, 8.51.
)4R)-1-O-Mesyl-5-benzyloxy-4-hydroxy-4-)hydroxymethyl)-4,40-O-iso-
propylidene-pentane )5): To a solution of alcohol 4 03.6 g, 12.8 mmol) in
anhydrous CH2Cl2, anhydrous triethyl amine 01 mL) and MsCl 01.76 g,
15.4 mmol) was added at 0ꢀC. The mixture was stirred at the same tem-
perature for 1 h, and quenched by cold water 02 mL). The mixture was
extracted with methylene chloride 0100 mL) and water 050 mL). The organic
layer was dried over anhydrous magnesium sulfate, and ®ltered. The ®ltrate
was concentrated under vacuum, and the residue was puri®ed by silica gel

NOVEL ACYCLIC NUCLEOSIDES
715
column chromatography 0EtOAc=hexane, 1:1.5) to give 5 04.13 g, 90%) as a
1
colorless oil: [a]2D5 ‡1.65ꢀ 0c 1.16, MeOH); H NMR 0CDCl3, 300 MHz) d
7.37±7.26 0m, 5H, Ar), 4.53 0d, J ˆ 3.0 Hz, 2H, CH2-Ar), 4.23 0t, J ˆ 5.7 Hz,
2H, H-1), 4.12 0d, J ˆ 7.2 Hz, 1H, H-40a), 4.00 0d, J ˆ 7.2 Hz, 1H, H-40b), 3.38
0s, 2H, H-5), 2.97 0s, 3H, CH3S), 1.84±1.63 0m, 4H, H-2 and 3), 1.37 0s, 6H,
2CH3); Anal. Calc. for C17H26O6S: C, 56.96; H, 7.31. Found: C, 56.88;
H, 7.33.
)40R)-9-[5-Benzyloxy-4-hydroxy-4-)hydroxymethyl)-4,40-O-iso-
propylidene-pentan-1-yl] adenine )6): A solution of mesylate 5 056.4 mg,
0.157 mmol), K2CO3 043.39 mg, 0.314 mmol), 18±crown-6 062.66 mg,
0.24 mmol), adenine 042.43 mg, 0.314 mmol) in dry DMF 01.5 mL) was stirred
overnight at 80ꢀC. The mixture was cooled to room temperature and con-
centrated under vacuum. The residue was diluted with brine 010 mL) and
extracted with CH2Cl2 010 mL64). The combined organic layer was dried
over anhydrous MgSO4, ®ltered, and concentrated under reduced pressure.
The residue was puri®ed by silica gel column chromatography
0MeOH=CH2Cl2, 1:10) to give 6 041.3 mg, 48%) as a white solid: mp 178±
1
182ꢀC; UV 0MeOH) lmax 262 nm; [a]2D5 ‡1.26ꢀ 0c 2.05, MeOH); H NMR
0CDCl3, 300 MHz) d 8.36 0s, 1H, H-8), 7.77 0s, 1H, H-2), 7.35±7.24 0m, 5H,
Ar), 6.26 0s, 2H, D2O exchangeable, -NH2), 4.50 0d, J ˆ 4.8 Hz, 2H, CH2-Ar),
4.23 0dd, J ˆ 11.4, 7.2 Hz, 2H, H-50), 3.97 0d, J ˆ 9.0 Hz, 1H, H-400a), 3.69 0d,
J ˆ 9.0 Hz, 1H, H-400b), 3.37 0dd, J ˆ 10.5, 9.6 Hz, 2H, H-10), 1.97±1.54 0m,
4H, H-20 and 30), 1.36 0s, 3H, CH3), 1.4 0s, 3H, CH3); Anal. Calc. for
C21H27N5O3: C, 63.46; H, 6.85; N, 17.62. Found: C, 63.38; H, 6.88; N, 17.54.
)40R)-1-[5-Benzyloxy-4-hydroxy-4-)hydroxymethyl)-4,40-O-iso-
propylidene-pentan-1-yl] cytosine )7): Compound
according to the conditions used for synthesizing. Yield: 56%; mp 182±
7
was synthesized
1
184ꢀC; UV 0MeOH) lmax 272 nm; [a]2D5 À12.5ꢀ 0c 0.3, MeOH); H NMR
0DMSO-d6, 300 MHz) d 7.55 0d, J ˆ 7.5 Hz, 1H, H-6), 7.37±7.24 0m, 5H, Ar),
6.96 0br d, 2H, D2O exchangeable, -NH2), 5.61 0dd, J ˆ 7.2, 1.5 Hz, 1H, H-5),
4.47 0s, 2H, CH2-Ar), 3.83 0d, J ˆ 7.5 Hz, 1H, H-400a), 3.66 0d, J ˆ 7.5 Hz, 1H,
H-400b), 3.61 0m, 4H, H-10 and 50), 1.65±1.51 0m, 4H, H-20 and 30), 1.25 0s, 6H,
2CH3); Anal. Calc. for C20H27N3O4: C, 64.34; H, 7.29; N, 11.25. Found: C,
64.27; H, 7.39; N, 11.41.
)40R)-9-[4,5-Dihydroxy-4-)hydroxymethyl)-4,40-O-isopropylidene-pentan-
1-yl] adenine )8): To a solution of 6 0100 mg, 0.25 mmol), 10% Pd0OH)2
0120 mg) in methanol 017 mL), anhydrous cyclohexene 06 mL) was added.
The mixture was stirred overnight and cooled to room temperature, and
®ltered through a Celite pad. The ®ltrate was concentrated in vacuum,
and the residue was puri®ed by silica gel column chromatography
0MeOH=CH2Cl2, 1:8) to give 8 059 mg, 77%) as a white solid: mp 185±188ꢀC;

716
LEE ET AL.
UV 0MeOH) lmax 262.5 nm; [a]2D5 ‡10.5ꢀ 0c 0.19, MeOH); 1H NMR 0DMSO-
d6, 300 MHz) d 8.34 0s, 1H, H-8), 7.73 0s, 1H, H-2), 6.23 0s, 2H, D2O
exchangeable, -NH2), 4.23 0dd, J ˆ 11.4, 7.2 Hz, 2H, H-10), 3.91 0d,
J ˆ 9.7 Hz, 1H, H-40a), 3.69 0d, J ˆ 9.0 Hz, 1H, H-40b), 3.31 0dd, J ˆ 10.5,
9.6 Hz, 2H, H-50), 1.97±1.54 0m, 4H, H-20 and 30), 1.36 0s, 3H, CH3), 1.4 0s,
3H, CH3); Anal. Calc. for C14H21N5O3: C, 54.71; H, 6.89; N, 22.79. Found:
C, 54.55; H, 6.79; N, 22.75.
)40R)-1-[4,5-Dihydroxy-4-)hydroxymethyl)-4,40-O-isopropylidene-pentan-
1-yl] cytosine )9): Compound 9 was synthesized according to the conditions
used to synthesize 8. Yield: 89%; mp 190±192ꢀC; UV 0MeOH) lmax
1
273.5 nm; [a]2D5 À6.34ꢀ 0c 1.04, MeOH); H NMR 0DMSO-d6, 300 MHz) d
7.65 0d, J ˆ 6.9 Hz, 1H, H-6), 7.14 0br d, 2H, D2O exchangeable, -NH2), 5.71
0d, J ˆ 6.9 Hz, 1H, H-5), 4.91 0t, J ˆ 5.6 Hz, 1H, D2O exchangeable, -OH),
3.90 0d, J ˆ 8.4 Hz, 1H, H-1a0), 3.67 0m, 3H, H-1b0 and 50), 1.68±1.51 0m, 4H,
H-20 and 30), 1.33 0d, J ˆ 2.7 Hz, 6H, 2CH3); Anal. Calc. for C13H21N3O4: C,
55.11; H, 7.47; N, 14.83. Found: C, 55.25; H, 7.49; N, 14.75.
9-[4,5-Dihydroxy-4-)hydroxymethyl)-pentan-1-yl] adenine )10):
A
solution of 8 097 mg, 0.31 mmol) in 80% acetic acid solution was stirred
for 5 h at 80ꢀC. The reaction mixture was cooled to room temperature,
and concentrated under reduced pressure. The residue was coevaporated
with toluene 010 mL) twice, and puri®ed by silica gel column chromato-
graphy 0MeOH=CH2Cl2, 1:9) to give 10 063 mg, 77%) as a white solid: mp
1
180±182ꢀC; UV 0H2O) lmax 261 nm; H NMR 0DMSO-d6, 300 MHz) d
8.11 0s, 2H, H-8 and 2), 7.16 0br s, 2H, D2O exchangeable, -NH2), 4.38 0br
s, 2H, -OH), 4.09 0t, J ˆ 6.9 Hz, 2H, H-10), 4.01 0s, 1H, -OH), 3.14 0m, 4H,
H-50 and H-400), 1.88±1.78 0m, 2H, H-20), 1.33±1.28 0m, 2H, H-30); Anal.
Calc. for C11H17N5O3: C, 49.43; H, 6.41; N, 26.20. Found: C, 49.51; H,
6.50; N, 26.25.
1-[4,5-Dihydroxy-4-)hydroxymethyl)-pentan-1-yl] cytosine )11): Similar
reaction conditions at those used for 10 was used to synthesize 11. Yield:
89%; mp 190±192ꢀC; UV 0H2O) lmax 262 nm; 1H NMR 0DMSO-d6,
300 MHz) d 7.54 0d, J ˆ 6.9 Hz, 1H, H-6), 6.98 0br d, 2H, D2O exchangeable,
-NH2), 5.62 0d, J ˆ 6.9 Hz, 1H, H-5), 4.66 0br s, 1H, D2O exchangeable,
-OH), 4.49 0br s, 1H, D2O exchangeable, -OH), 3.92 0br s, 1H, D2O
exchangeable, -OH), 3.90 0d, J ˆ 13.8 Hz, 1H, H-10), 3.80 0d, J ˆ 13.8 Hz, 1H,
H-10), 3.57 0m, J ˆ 6.9 Hz, 4H, H-50 and 400), 1.57 0m, 2H, H-20), 1.32 0m, 2H,
H-30); Anal. Calc. for C10H17N3O4: C, 49.37; H, 7.04; N, 17.27. Found: C,
49.46; H, 7.19; N, 17.35.
)4S)-5-)t-Butyldimethylsilyloxy)-4-hydroxy-4-)hydroxymethyl)-4,40-O-
isopropylidene-pent-1-ene )12): To a solution of 2 010 g, 58 mmol) and

NOVEL ACYCLIC NUCLEOSIDES
717
imidazole 03.9 g, 0.116 M) in anhydrous CH2Cl2 0300 mL) t-butyldi-
methylsilyl chloride 010.5 g, 69.6 mmol) was added at 0ꢀC. The mixture was
stirred for 2 h at room temperature, and quenched by water 010 mL). The
mixture was extracted with CH2Cl2 0300 mL) and water 0200 mL), and the
organic layer was dried over anhydrous MgSO4, and ®ltered. The ®ltrate was
concentrated under reduced pressure, and the residue was puri®ed by silica
gel column chromatography 0EtOAc=hexane, 1:20) to give 12 016.7 g, 95%)
as a colorless oil: [a]2D5 À18.2ꢀ 0c 1.42, MeOH); 1H NMR 0CDCl3, 300 MHz)
d 5.55 0m, 1H, H-2), 5.08 0s, 1H, H-1a), 5.04 0d, J ˆ 7.5 Hz, 1H, H-1b), 3.93
0d, J ˆ 10.2 Hz, 1H, H-40a), 3.68 0d, J ˆ 8.7 Hz, 1H, H-40b), 3.43 0d,
J ˆ 1.2 Hz, 2H, H-5), 2.32 0t, J ˆ 6.6 Hz, 2H, H-3), 1.33 0s, 6H, 2CH3), 0.84 0s,
9H, t-Bu), À 0.02 0s, 6H, 2SiCH3); Anal. Calc. for C15H30O3Si: C, 62.89; H,
10.55; O, 16.75. Found: C, 62.81; H, 10.61; O, 16.71.
)4S)-5-)t-Butyldimethylsilyloxy)-4-hydroxy-4-)hydroxymethyl)-4,40-O-
isopropylidene-pentan-1-ol )13): To a solution of ole®n 12 03 g, 10.47 mmol)
and dry THF 015 mL) 1.0 M BH3=DMS0in tetrahydrofuran, 12.5 mL) was
added dropwise with a syringe at 0ꢀC. The mixture was stirred overnight at
room temperature, and cooled to 0ꢀC. A 2 N NaOH solution 011 mL,
22 mmol) was added, which was followed by the careful addition of 30%
hydrogen peroxide 07.3 mL, 62.3 mmol). The reaction mixture was stirred at
room temperature for 2 h, and brine was then added. The mixture was
extracted with ethyl acetate 0100 mL63). The combined organic layers were
dried over anhydrous magnesium sulfate, ®ltered, and concentrated under
vacuum. The residue was puri®ed by silica gel column chromatography
0EtOAc=hexane, 1:4) to give 13 01.78 g, 56%) as a colorless oil: [a]2D5 À7.7ꢀ 0c
1
2.2, MeOH); H NMR 0CDCl3, 300 MHz) d 3.98 0d, J ˆ 8.4 Hz, 1H, H-40a),
3.6 0m, J ˆ 7.5 Hz, 3H, H-40b and H-1), 3.45 0m, 2H, H-5), 2.11 0br s, 1H,
-OH), 1.75±1.51 0m, 4H, H-2 and 3), 1.33 0s, 6H, 2CH3), 0.82 0s, 9H, t-Bu),
À 0.02 0s, 6H, 2SiCH3); Anal. Calc. for C15H32N4Si: C, 59.17; H, 10.59; O,
21.02. Found: C, 59.30; H, 10.63; O, 21.13.
)4S)-1-Benzyloxy-5-)t-butyldimethylsilyloxy)-4-hydroxy-4-)hydro-
xymethyl)-4,40-O-isopropylidene pentane )14): To a stirred suspension of
NaH 01.5 g, 37 mmol, 60%) in THF 070 mL) a solution of 13 07.6 g,
24.9 mmol) in THF was slowly added at 0ꢀC, and stirred at room tempera-
ture for 1 h. The mixture was cooled to 0ꢀC, and benzyl bromide 05.1 g,
29.8 mmol) was added slowly. The mixture was stirred overnight at room
temperature, and quenched by adding a saturated ammonium chloride
solution 010 mL). The mixture was extracted with EtOAc 0150 mL) and water
0150 mL), and organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and ®ltered. The ®ltrate was concentrated under reduced
pressure, and the residue was puri®ed by silica gel column chromatography
0EtOAc=hexane, 1:15) to give 14 07.86 g, 80%) as a colorless oil: [a]2D5 À12.44ꢀ

718
LEE ET AL.
1
0c 3.51, MeOH); H NMR 0CDCl3, 300 MHz) d 7.32±7.22 0m, 5H, Ar), 4.45
0s, 2H, CH2-Ar), 3.95 0d, J ˆ 8.4 Hz, 1H, H-40a), 3.63 0d, J ˆ 8.1 Hz, 1H, H-
40b), 3.43 0m, 4H, H-1 and 5), 1.61 0m, 4H, H-2 and 3), 3.33 0d, J ˆ 2.7 Hz,
6H, 2CH3), 0.84 0s, 9H, t-Bu), À0.03 0s, 6H, 2SiCH3); Anal. Calc. for
C22H38O4Si: C, 66.96; H, 9.71; O, 16.22. Found: C, 66.79; H, 9.80; O, 16.34.
)2R)-5-Benzyloxy-2±hydroxy-2-)hydroxymethyl)-2,20-O-isopropylidene
pentan-1-ol )15): To a solution of 14 03.6 g, 9.1 mmol) in THF 013 mL),
tetrabutylammonium ¯uoride 010.9 mL, 1 M in THF solution) was added at
0ꢀC. The mixture was stirred for 3 h at room temperature and concentrated
under reduced pressure. The resulting residue was puri®ed by silica gel col-
umn chromatography 0EtOAc=hexane, 1:3) to give 15 02.16 g, 85%) as a
colorless oil: [a]2D5 À2.4ꢀ 0c 2.5, MeOH); 1H NMR 0CDCl3, 300 MHz) d 7.37±
7.28 0m, 5H, Ar), 4.40 0s, 2H, CH2-Ar), 3.92 0d, J ˆ 8.7 Hz, 1H, H-20a), 3.79
0d, J ˆ 8.7 Hz, 1H, H-20b), 3.59±3.46 0m, 4H, H-1 and 5), 1.74±1.61 0m, 4H,
H-3 and 4), 1.41 0d, J ˆ 1.5 Hz, 6H, 2CH3); Anal. Calc. for C16H24O4: C,
68.54; H, 8.63; O, 22.83. Found: C, 68.50; H, 8.68; O, 22.74.
)2R)-1-O-Mesyl-5-benzyloxy-2-hydroxy-2-)hydroxymethyl)-2,20-O-iso-
propylidene pentane )16): To a solution of 15 05.0 g, 17.8 mmol) in anhy-
drous CH2Cl2 050 mL), anhydrous triethyamine 03 mL) and methane sulfonyl
chloride 02.4 g, 21.4 mmol) was added at 0ꢀC. At the same temperature, the
mixture was stirred for 1 h, and quenched by water 05 mL). The mixture was
extracted with CH2Cl2 0100 mL) and water 0100 mL). The organic layer was
dried over anhydrous MgSO4, ®ltered, and concentrated under vacuum. The
residue was puri®ed by silica gel column chromatography 0EtOAc=hexane,
1:4) to give 16 05.5 g, 87%) as a colorless oil: [a]2D5 À2.85ꢀ 0c 1.05, MeOH); 1H
NMR 0CDCl3, 300 MHz) d 7.42±7.28 0m, 5H, Ar), 4.50 0s, 2H, CH2-Ar), 4.11
0s, 2H, H-1), 3.98 0d, J ˆ 9.3 Hz, 1H, H-40a), 3.81 0d, J ˆ 9.3 Hz, 1H, H-40b),
3.49 0t, J ˆ 6.0 Hz, 2H, H-5), 3.04 0s, 3H, CH3S), 1.74 0m, 4H, H-3 and 4),
1.42 0d, J ˆ 12.6 Hz, 6H, 2CH3); Anal. Calc. for C17H26O6S: C, 56.96; H,
7.31; O, 26.78. Found: C, 56.88; H, 7.37; O, 26.75.
)20R)-9-[5-Benzyloxy-2-hydroxy-2-)hydroxymethyl)-2,20-O-iso-
propylidene-pentan-1-yl] adenine )17): A solution of mesylate 16 0222 mg,
0.61 mmol), K2CO3 0171 mg, 1.23 mmol), 18-crown-6 0247 mg, 0.93 mmol),
adenine 0167 mg, 1.24 mmol) in dry DMF 03 mL) was stirred overnight at
80ꢀC. The mixture was cooled to room temperature and concentrated under
vacuum. The residue was diluted with brine 020 mL) and extracted with
CH2Cl2 030 mL64). The combined organic layer was dried over anhydrous
MgSO4, ®ltered, and concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography 0MeOH=CH2Cl2, 1:10) to give
17 0109 mg, 45%) as a white solid: mp 188±192ꢀC; UV 0MeOH) lmax
1
261.5 nm; [a]2D5 À7.26ꢀ 0c 1.07, MeOH); H NMR 0DMSO-d6, 300 MHz) d

NOVEL ACYCLIC NUCLEOSIDES
719
8.12 0s, 1H, H-8), 8.03 0s, 1H, H-2), 7.36±7.23 0m, 5H, Ar), 4.12 0s, 2H, CH2-
Ar), 3.92 0d, J ˆ 13.8 Hz, 1H, H-200a), 3.82 0dd, J ˆ 17.1, 9.0 Hz, 2H, H-10),
3.71 0d, J ˆ 13.8 Hz, 1H, H-200b), 3.39 0t, J ˆ 5.1 Hz, 2H, H-50), 1.56 0m, 4H,
H-30 and 40), 1.28 0s, 3H, CH3), 1.19 0s, 3H, CH3); Anal. Calc. for
C21H27N5O3: C, 63.46; H, 6.85; N, 17.62. Found: C, 63.49; H, 6.80; N, 17.66.
)20R)-1-[5-Benzyloxy-4-hydroxy-2-)hydroxymethyl)-2,20-O-isopropylidene-
pentan-1-yl] cytosine )18): Compound 18 was synthesized according to the
conditions used for 17; Yield: 50%; UV 0MeOH) lmax 273 nm; [a]2D5 À78.5ꢀ
1
0c 0.25, MeOH); H NMR 0DMSO-d6, 300 MHz) d 7.43 0d, J ˆ 6.9 Hz, 1H,
H-6), 7.36±7.23 0m, 5H, Ar), 7.06 0br d, 2H, D2O exchangeable, -NH2), 5.63
0d, J ˆ 7.2 Hz, 1H, H-5), 4.09 0s, 2H, CH2-Ar), 3.92±3.69 0m, 6H, H-10, 50, 200a,
and 200b), 1.68±1.53 0m, 4H, H-30 and 40), 1.28 0s, 3H, CH3), 1.15 0s, 3H, CH3);
Anal. Calc. for C20H27N3O4: C, 64.32; H, 7.29; N, 11.25. Found: C, 64.40; H,
7.38; N, 11.36.
)20R)-9-[2,5-Dihydroxy-2-)hydroxymethyl)-2,20-O-isopropylidene-pentan-
1-yl] adenine )19): To a solution of 17 0165.6 mg, 0.42 mmol), Pd0OH)2
0197.7 mg) in methanol 029.6 mL), anhydrous cyclohexene 09.88 mL) was
added. The mixture was stirred overnight and cooled to room temperature,
and ®ltered through a Celite pad. The ®ltrate was concentrated under
vacuum, and the residue was puri®ed by silica gel column chromatography
0MeOH=CH2Cl2, 1:8) to give 19 0116 mg, 90%) as a white solid: mp 185±
1
187ꢀC; UV 0MeOH) lmax 261 nm; [a]2D5 ‡12.56ꢀ 0c 1.37, MeOH); H NMR
0DMSO-d6, 300 MHz) d 8.13 0s, 1H, H-8), 8.00 0s, 1H, H-2), 7.24 0br s, 2H,
D2O exchangeable, -NH2), 4.31 0d, J ˆ 14.7 Hz, 1H, H-100a), 4.21 0d,
J ˆ 14.7 Hz, H-10b), 4.00 0d, J ˆ 9.0 Hz, 1H, H-200a), 3.79 0d, J ˆ 9.0 Hz, 1H,
H-200b), 3.45 0s, 2H, H-50), 1.51 0m, 4H, H-30 and 40), 1.27 0s, 3H), 1.08 0s,3H);
Anal. Calc. for C14H21N5O3: C, 54.71; H, 6.89; N, 22.79. Found: C, 54.76; H,
6.80; N, 22.78.
)20R)-1-[2,5-Dihydroxy-2-)hydroxymethyl)-2,20-O-isopropylidene-pentan-
1-yl] cytosine )20): Compound 20 was synthesized using similar reaction
conditions as used for to 19; Yield: 95%; UV 0MeOH) lmax 274 nm; [a]2D5
À100.9ꢀ 0c 0.25, MeOH); 1H NMR 0DMSO-d6, 300 MHz) d 7.44 0d,
J ˆ 7.5 Hz, 1H, H-6), 7.11 0br d, 2H, D2O exchangeable, -NH2), 5.65 0d,
J ˆ 6.9 Hz, 1H, H-5), 4.40 0t, J ˆ 6.4 Hz, 1H), D2O exchangeable, OH), 3.94
0d, J ˆ 13.8 Hz, 2H, H-10), 3.81 0d, J ˆ 9.0 Hz, 1H, H-200a), 3.72 0d, J ˆ 3.9 Hz,
1H, H-200b), 3.67 0s, 2H, H-50), 1.48 0m, 4H, H-30 and 40), 1.28 0s, 3H, CH3),
1.14 0s, 3H, CH3); Anal. Calc. for C13H21N3O4: C, 55.11; H, 7.47; N, 14.83.
Found: C, 55.29; H, 7.50; N, 14.86.
)20R)-9-[2,5-Dihydroxy-2-)hydroxymethyl)-pentan-1-yl] adenine )21):
solution of 19 096 mg, 0.31 mmol) in 80% aqueous acetic acid solution 05 mL)
A

720
LEE ET AL.
was stirred for 3 h at 80ꢀC. The solution was concentrated under reduced
pressure, and coevaporated with toluene three times. The residue was puri®ed
by silica gel column chromatography 0MeOH=CH2Cl2, 1:5) to give 21
058 mg, 70%) as a white solid: mp 198±200ꢀC; UV 0MeOH) lmax 261.5 nm;
1
[a]2D5 À17.2ꢀ 0c 0.45, MeOH); H NMR 0DMSO-d6, 300 MHz) d 8.13 0s, 1H,
H-8), 8.02 0s, 1H, H-2), 7.35 0br s, 2H, D2O exchangeable, -NH2), 4.18 0d,
J ˆ 14.4 Hz, 1H, H-10a), 4.11 0d, J ˆ 14.4 Hz, 1H, H-10b), 3.29 0br s, 2H, H-
50), 3.20 0d, J ˆ 11.1 Hz, 1H, H-200a), 3.09 0d, J ˆ 11.1 Hz, 1H, H-200b), 1.48±
1.17 0m, 4H, H-30 and 40); Anal. Calc. for C11H17N5O3: C, 49.43; H, 6.41; N,
26.20. Found: C, 49.49; H, 6.55; N, 26.15.
)20R)-1-[2,5-Dihydroxy-2-)hydroxymethyl)-pentan-1-yl] cytosine )22):
Similar reaction condition as used for 21 was used to synthesize 22. Yield:
1
60%; UV 0MeOH) lmax 273.5 nm; [a]2D5 À23.66ꢀ 0c 0.24, MeOH); H NMR
0DMSO-d6, 300 MHz) d 7.48 0d, J ˆ 6.9 Hz, 1H, H-6), 7.20 0br d, 2H, D2O
exchangeable, -NH2), 5.70 0d, J ˆ 7.2 Hz, 1H, H-5), 4.12 0d, J ˆ 12.4 Hz, 2H,
H-10), 3.85 0d, J ˆ 13.8 Hz, 1H, H-200a), 3.54 0d, J ˆ 13.8 Hz, 1H, H-200b),
3.06±2.96 0m, 2H, H-50), 1.68±1.53 0m, 4H, H-30 and 40); Anal. Calc. for
C10H17N3O4: C, 49.37; H, 7.04; N, 17.27. Found: C, 49.40; H, 7.12; N, 17.6.
ACKNOWLEDGMENTS
This study was supported by intramural research fund from Chosun
University, 2001. We also thank Dr. C.-K. Lee 0KRICT) for antiviral eva-
luations.
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Received June 4, 2002
Accepted July 8, 2002