Synthesis of 9-[1-(substituted)-2-(phosphonomethoxy)ethyl]adenine derivatives as possible antiviral agents

Article abstract of DOI:10.1080/15257770500265315

Various C-1′-substituted acyclic N⁹ adenine nucleosides were prepared from 9-[(1-hydroxymethyl)(3-monomethoxytrityloxy)propyl]-N ⁶-monomethoxytrityladenine. The hydroxymethyl was modified to the phosphonomethoxy derivative, and the 3

Full text of DOI:10.1080/15257770500265315

This article was downloaded by: [Florida State University]
On: 25 December 2014, At: 16:29
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
Synthesis of 9-[1-(Substituted)-2-
(Phosphonomethoxy)Ethyl]Adenine Derivatives as
Possible Antiviral Agents
Minwan Wu a , Yahya El-Kattan a , Tsu-Hsing Lin a , Ajit Ghosh a , V. Satish Kumar a , Pravin L.
Kotian a , Xiaogang Cheng a , Shanta Bantia a , Yarlagadda S. Babu a & Pooran Chand a
a BioCryst Pharmaceuticals, Inc. , Birmingham, Alabama, USA
Published online: 16 Aug 2006.
To cite this article: Minwan Wu , Yahya El-Kattan , Tsu-Hsing Lin , Ajit Ghosh , V. Satish Kumar , Pravin L. Kotian ,
Xiaogang Cheng , Shanta Bantia , Yarlagadda S. Babu & Pooran Chand (2005) Synthesis of 9-[1-(Substituted)-2-
(Phosphonomethoxy)Ethyl]Adenine Derivatives as Possible Antiviral Agents, Nucleosides, Nucleotides and Nucleic Acids,
24:10-12, 1569-1585, DOI: 10.1080/15257770500265315
To link to this article: http://dx.doi.org/10.1080/15257770500265315
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Nucleosides, Nucleotides, and Nucleic Acids, 24:1569–1585, 2005
c
Copyright ꢀ Taylor & Francis Group, LLC
ISSN: 1525-7770 print/1532-2335 online
DOI: 10.1080/15257770500265315
SYNTHESIS OF
9-[1-(SUBSTITUTED)-2-(PHOSPHONOMETHOXY)ETHYL]ADENINE
DERIVATIVES AS POSSIBLE ANTIVIRAL AGENTS
Minwan Wu, Yahya El-Kattan, Tsu-Hsing Lin, Ajit Ghosh, V. Satish Kumar,
Pravin L. Kotian, Xiaogang Cheng, Shanta Bantia, Yarlagadda S. Babu, and
ᮀ
Pooran Chand
BioCryst Pharmaceuticals, Inc., Birmingham, Alabama, USA
Various C-1ꢀ-substituted acyclic N9 adenine nucleosides were prepared from 9-[(1-hydroxymeth-
yl)(3-monomethoxytrityloxy)propyl]-N6-monomethoxytrityladenine. The hydroxymethyl was modi-
fied to the phosphonomethoxy derivative, and the 3-monomethoxytrityloxy was converted to hy-
droxyl, methoxy, azido, and amino. Other substituents, such as ethyl and -hydroxyethyl were
also prepared. The resulting phosphonomethoxy derivatives were converted to prodrugs.
ᮀ
Keywords Acyclic nucleosides; Prodrugs; Antiviral
INTRODUCTION
Extensive studies have been done on 9-[2-(phosphonomethoxy)ethyl]-
adenine and guanine derivatives.[1–5] A number of lead compounds (Chart
1), such as PMEA, PMEDAP, PMEG evolved from those studies and adefovir
dipivoxil (1a), the prodrug of PMEA, was approved by FDA for HBV
infections.[6–12] All these compounds are unsubstituted acyclic nucleoside
derivatives. Substituting the C-2ꢁ position by methyl, hydroxymethyl, and
fluoromethyl resulted into some more lead compounds (Chart 1), such as
PMPA, HPMPA, FPMPA, HPMPDAP, PMPG, and HPMPG. One 2ꢁ-methyl
compound, tenofovir disoproxil (1b), the prodrug of PMPA, was approved
by FDA for HIV infections.[6–12] Very little work has been done on the C-1ꢁ-
substituted compounds.[13–16]
Dedicated to the memory of John A. Montgomery.
Received 19 January 2005; accepted 3 May 2005.
The authors thank Drs. Charlie Bugg and Claude Bennett for their encouragement throughout
this work. The authors also express appreciation to Linda Kay First for preparation of this manuscript.
Address correspondence to Pooran Chand, BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake
Drive, Birmingham, AL 35244. Fax: (205)444-4640; E-mail: pchand@biocryst.com
1569

1570
M. Wu et al.
CHART 1
In continuation of our work in the preceding paper, we have now
prepared the compounds to examine the effect of the side chain from
the C-1ꢁ position of acyclic nucleosides, their phosphonomethyl ether
derivatives and corresponding prodrugs on antiviral activity. Based upon the
structure of adefovir and tenofovir, we have synthesized these compounds
keeping the spacer of 4 atoms between the adenine nitrogen and the
phosphorus atom, and the oxygen β- to the phosphorus atom. All the
compounds synthesized here in this report are the substituted compounds
at C-1ꢁ of the acyclic chain.
RESULTS AND DISCUSSION
The synthesized compounds are racemic. The synthesis of the com-
pounds with hydroxyl, methoxy, azido, and amino groups in the C-1ꢁ substi-
tution started from 9-[(1-hydroxymethyl)(3-monomethoxoxytrityloxy)pro-
pyl]-N6-monomethoxytrityladenine (2) reported in the preceding paper. In
this case also, the hydroxyl protecting group was chosen as the monometh-
oxytrityl group to avoid the problem of migration as reported with the tert-
butyldimethylsilyl group.[15]
Compound 2 (Scheme 1) on reaction with diisopropyl p-toluenesulfonyl-
oxymethylphosphonate using sodium hydride as base gave compound 3, a
precursor for the target 25a. Azido derivative 6, precursor for target 25b, was
obtained by selectively deprotecting the primary hydroxyl of compound 3
with 25 mM HCl in acetonitrile to give compound 4 which was converted to
azido 6 through mesylate 5. The precursor 8 for amino target 25c was ob-
tained by reduction of azide 6 to give 7 and protection with monomethoxy-
trityl chloride. Methoxy derivative 9, a precursor for target 25d, was obtained
by alkylation of 4 with methyl iodide and sodium hydride.

Synthesis of Possible Antiviral Agents
1571
SCHEME 1 Reagents: i) NaH, TsO-CH2P(O)(O-ipr)2; ii) HCl, CH3CN; iii) MsCl; iv) NaN3; v) Ph3P,
H2O, THF; vi) MMTrCl; vii) NaH, CH3I.
The preparation of the C-1ꢁ ethyl derivative 25e started from known
10[17] (Scheme 2), which under Mitsunobu reaction conditions with ade-
nine, triphenylphosphine (TPP), and diisopropylazodicarboxylate (DIAD)
in dioxane gave desired compound 11. The amino group of adenine was
protected with MMTr-chloride in pyridine to give 12, which on tetrabutyl-
ammonium fluoride (TBAF) reaction gave compound 13 with the free hy-
droxyl. The hydroxyl of 13 was reacted with diisopropyl p-toluenesulfonyl-
oxymethylphosphonate using sodium hydride as the base to give compound
14, a precursor for the target 25e.
The introduction of 2-hydroxypropyl could not be achieved from the
suitable phosphonomethyl compound 4 because of the complications dur-
ing oxidation of the primary hydroxyl group. Therefore, we chose 9-[(1-
monomethoxytrityloxymethyl)(3-hydroxy)propyl]adenine 15 (Scheme 2)

1572
M. Wu et al.
SCHEME 2 Reagents: i) Adenine, Ph3P, DIAD; ii) MMTr-Cl; iii) Bu4NF, THF; iv) NaH, TsO-CH2-
P(O)(O-iPr)2; v) Dess-Martin; vi) CH3MgBr; vii) HCl; viii) TBDMS-Cl, imidazole.
reported in the preceding paper as our starting material. The oxidation of
the primary hydroxyl with Dess-Martin reagent gave aldehyde 16, which on
reaction with Grignard reagent, CH3MgBr, yielded 2-hydroxypropyl com-
pound 17. In this case, both MMTr protecting groups were removed under
acidic conditions to give 18, and the primary hydroxyl was blocked with the
tert-butyldimethylsilyl (TBDMS) group to give 19. Forcing reaction condi-
tions with MMTr-chloride resulted in the protection of both the amino and

Synthesis of Possible Antiviral Agents
1573
secondary hydroxyl to give 20. The desired free hydroxyl compound 21 was
now obtained by deprotection of the TBDMS group with TBAF and the pre-
cursor 22 for the target 25f was obtained by reaction of 21 with diisopropyl
p-toluenesulfonyloxymethylphosphonate using sodium hydride as base.
The precursors 3, 6, 8, 9, 14, and 22 on reaction with trimethylsilyl iodide
in the presence of triethylamine gave the desired phosphonomethoxy
compounds 23a-23f (Scheme 3). The use of triethylamine was essential
to keep the MMTr protecting group intact, since the further reactions
for the formation of prodrugs were not successful with the free amino
group. The reaction of 23a-23f with an appropriate chloromethyl pivalate
or chloromethyl-2-propylcarbonate in the presence of triethylamine gave
diprotected prodrugs 24a-24f and the removal of the MMTr groups under
mild acidic conditions yielded the desired targets 25a-25f.
BIOLOGICAL ACTIVITY
These compounds showed poor activity against HCV virus in replicon
assay.[18]
EXPERIMENTAL
All reagents and solvents were purchased from Aldrich and used as
1
received. H NMR and 13C NMR were recorded on a Bruker 300 MHz
instrument. Chemical shifts (δ) are reported in parts per million (ppm)
referenced to TMS at 0.00 or respective deuterated solvent peak. Coupling
constants (J) are reported in HERTZ. IR spectra were obtained from
films on NaCl plates for oils or KBr pellets for solids with a scan range
of 4000–500 cm−1 on a FT-IR spectrometer (BioRad FTS-3500GX). Mass
spectra data were acquired on a Waters ZMD mass spectrometer coupled
with a Waters System 2695 for loading of the samples in ES positive or
negative mode. HRMS data were recorded on Bruker Bioapex 4.7E. UV
spectroscopy was carried out on an Agilent 8453 spectrophotometer. The
elemental analysis (C, H, and N) were performed by Atlantic Microlab in
Norcross, Georgia. The TLC solvent system CMA-80 and CMA-50 refers to
chloroform:methanol:conc. NH4OH (80:18:2) and chloroform:methanol:
conc. NH4OH (50:40:10), respectively. Tetraethyl ammonium bicarbonate
is abbreviated as TEAB. The non-UV active compounds were visualized by
charring the TLC plate sprayed with ammonium molybdate/cesium sulfate
spray prepared by dissolving conc. H2SO4 (22.4 mL), CeSO4 (45 mg),
(NH4)6Mo7O24 4 H2O (7 g) in 100 mL water. The olefin compounds were
visualized by using KMnO4 spray. The following conditions were used for
HPLC analysis.

1574
M. Wu et al.
SCHEME 3 Reagents: i) TMSI, Et3N; ii) ClCH2OC(O)C(CH3)3 or ClCH2OC(O)OCH(CH3)2, Et3N;
iii) HCl.

Synthesis of Possible Antiviral Agents
1575
Column: Spherisorb ODS 4.6
solvent B: MeOH.
250 mm. Mobile phase: solvent A: water,
Gradient: time: 0 min., A: 95%, B 5%; time: 20 min, A: 0%, B: 100%; then
isocratic for 5 min.
Time: 25.1 min., A: 95, B: 5% then isocratic for 5 min. Flow rate 1.0 mL/min.
Run time 30 min. Detection UV at 259 nm.
( )-9-[1-[(Diisopropylphosphono)methoxy]methyl][(3-monomethoxy-
trityloxy)-propyl]-N6-monomethoxytrityladenine (3). A solution of 2 (72.45
g, 94.35 mmol) in DMF (810 mL) was treated with sodium hydride (60%,
15.1 g, 377.5 mmol) at room temperature and the mixture was stirred for
1 h. To this solution was added a solution of diisopropyl p-toluenesulfonyl-
oxymethylphosphonate (39.65 g, 113.17 mmol) in DMF (70 mL) and the
mixture was stirred at room temperature for 15 h. The reaction mixture was
diluted with ethyl acetate (3 L), neutralized with acetic acid and washed with
water (2 ) and brine and the organic layer was dried over MgSO4. After
filtration, the filtrate was concentrated and the residue was purified on a
silica gel column using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.1) as
eluent to give 61.2 g (69%) of product as a white solid: 1H NMR (DMSO-d6):
δ 8.20 (s, 1H), 7.87 (s, 1H), 7.32–7.03 (m, 25H), 6.84 (d, J = 8.9 Hz, 2H),
6.78 (d, J = 8.9 Hz, 2H), 5.01–4.90 (m, 1H), 4.45–4.32 (m, 2H), 4.03–3.94
(m, 1H), 3.82–3.63 (m, 3H), 3.71 (s, 3H), 3.69 (s, 3H), 2.93–2.81 (m, 1H),
2.81–2.70 (m, 1H), 2.40–2.20 (m, 1H), 2.20–2.03 (m, 1H), 1.11 (d, J = 6.2
Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 1.01 (d, J =
6.2 Hz, 3H). IR (KBr, cm−1) 3420, 2978, 1605, 1508 and 1250. Anal. Calcd
for C56H60N5O7P 0.5 H2O 0.25 EtOAc: C, 70.06; H, 6.50; N, 7.17. Found:
C, 69.62; H, 6.55; N, 7.21.
(
)-9-[1-[(Diisopropylphosphono)methoxy]methyl][(3-hydroxy)pro-
pyl]-N6-monomethoxytrityladenine (4). A solution of 3 (52.2 g, 55.18 mmol)
in acetonitrile (2 L) was treated with conc. HCl (4 mL) at room tempera-
ture and the mixture was stirred for 24 h. The reaction was neutralized with
2N NaOH and diluted with water (250 mL). It was then concentrated to re-
move most of acetonitrile and treated with ethyl acetate (500 mL) and water
(200 mL). The organic layer was separated and dried over MgSO4. After fil-
tration, the filtrate was concentrated and the residue was purified on a silica
gel column using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.2) as eluent
1
to give 6.18 g (17%) of 4 as a white solid: H NMR (DMSO-d6): δ 8.27 (s,
1H), 7.93 (s, 1H), 7.38–7.20 (m, 13H), 6.89 (d, J = 9.0 Hz, 2H), 4.92–4.80
(m, 1H), 4.64 (t, J = 5.1 Hz, 1H), 4.50–4.36 (m, 2H), 4.14 (t, J = 9.8 Hz,
1H), 3.89–3.65 (m, 3H), 3.76 (s, 3H), 3.42–3.18 (m, 2H), 2.22–1.95 (m, 2H),
1.18–1.11 (m, 6H), 1.06 (d, J = 6.2 Hz, 6H). IR (KBr, cm−1) 3418, 2978,

1576
M. Wu et al.
1605, 1503, and 1250. Anal. Calcd for C36H44N5O6P 0.5 H2O: C, 63.33; H,
6.64; N, 10.26. Found: C, 63.31; H, 6.47; N, 10.19.
( )-9-[1-[(Diisopropylphosphono)methoxy]methyl][(3-azido)propyl]-
N6-monomethoxytrityladenine (6). A solution of 4 (1.00 g, 1.48 mmol)
in pyridine (20 mL) was treated with methanesulphonyl chloride (539
mg, 97%, 3.00 mmol) and the mixture was stirred for 20 h at room
temperature. The reaction mixture was diluted with ethyl acetate (200 mL),
was washed with water (2 ) and brine and the organic layer dried over
MgSO4 followed by filtration and concentration. The residue containing
5 was dissolved in DMF (9 mL), treated with sodium azide (260 mg, 3.96
mmol) and the mixture was stirred for 4 h at 100◦C. The reaction mixture
was diluted with ethyl acetate (300 mL), washed with water (2 ) and brine
and the organic layer was dried over MgSO4. After filtration, the filtrate was
concentrated and the residue was purified on a silica gel column using ethyl
acetate:hexanes:methanol (1:1:0 to 1:1:0.2) as eluent to give 458 mg (44%,
1
two steps) of product as a colorless film: H NMR (CDCl3): δ 8.04 (s, 1H),
7.89 (s, 1H), 7.40–7.18 (m, 13H), 6.79 (d, J = 8.8 Hz, 2H), 4.87–4.76 (m,
1H), 4.73–4.60 (m, 2H), 4.19–3.68 (m, 4H), 3.77 (s, 3H), 3.41–3.32 (m, 1H),
3.22–3.10 (m, 1H), 2.47–2.32 (m, 1H), 2.24–2.12 (m, 1H), 1.29 (d, J = 6.0
Hz, 6H), 1.24 (d, J = 6.7 Hz, 6H). IR (neat, cm−1) 3017, 2103, 1605, and
1216. HRMS Calcd for C36H43N8O5P (M+H)+ 699.3172. Found: 699.3152.
( )-9-[1-[(Diisopropylphosphono)methoxy]methyl][(3-amino)propyl]-
N6-monomethoxytrityladenine (7). A mixture of 6 (805 mg, 1.15 mmol)
in THF (8 mL) and water (1.6 mL) was treated with triphenylphosphine
(640 mg, 2.44 mmol) and was stirred at room temperature for 14 h. The
reaction mixture was concentrated and purified on silica gel column using
chloroform:CMA-80 (1:0 to 1:1) as eluent to give 660 mg (85%) as a white
solid: 1H NMR (DMSO-d6): δ 8.09 (s, 1H), 7.72 (s, 1H), 7.17–7.00 (m, 13H),
6.67 (d, J = 9.0 Hz, 2H), 4.70–4.59 (m, 1H), 4.28–4.16 (m, 2H), 3.95 (t,
J = 9.2 Hz, 1H), 3.68–3.45 (m, 3H), 3.54 (s, 3H), 2.29–2.05 (m, 2H), 1.93–
1.60 (m, 4H), 0.96–0.91 (m, 6H), 0.84 (d, J = 6.1 Hz, 6H). IR (neat, cm−1
)
3414, 3020, 1605, 1511, and 1216. Anal. Calcd for C36H45N6O5P 1.5 H2O:
C, 61.79; H, 6.91; N, 12.01. Found: C, 61.70; H, 6.63; N, 12.07.
( )-9-[1-[(Diisopropylphosphono)methoxy]methyl][(3-monomethoxy-
tritylamino)propyl]-N6-monomethoxytrityladenine (8). A solution of com-
pound 7 (600 mg, 0.89 mmol) in pyridine (5 mL) was treated with mono-
methoxytrityl chloride (561 mg, 1.78 mol) and the reaction mixture was
heated at 70◦C with stirring for 16 h. It was diluted with ethyl acetate (150
mL) and washed with water (2 ) and brine and the organic layer dried
over MgSO4. After filtration, the filtrate was concentrated and the residue

Synthesis of Possible Antiviral Agents
1577
was purified on a silica gel column using ethyl acetate:hexanes:methanol
(1:1:0 to 1:1:0.1) as eluent to give 645 mg (87%) of product as a light yellow
film: 1H NMR (DMSO-d6): δ 7.99 (s, 1H), 7.66 (s, 1H), 7.12–6.79 (m, 25H),
6.61 (d, J = 9.0 Hz, 2H), 6.50 (d, J = 9.1 Hz, 2H), 4.88–4.75 (m, 1H), 4.22–
4.09 (m, 2H), 3.80–3.68 (m, 1H), 3.63–3.40 (m, 3H), 3.48 (s, 3H), 3.45 (s,
3H), 2.37–1.93 (m, 2H), 1.83–1.49 (m, 3H), 0.89–0.84 (m, 6H), 0.80–0.75
(m, 6H). IR (KBr, cm−1) 3418, 2978, 1605, 1503, 1250, and 989. Anal. Calcd
for C56H61N6O6P 0.5 H2O: C, 70.50; H, 6.55; N, 8.81. Found: C, 70.38; H,
6.52; N, 8.72.
( )-9-[1-(tert-Butyldiphenylsilyloxy)methyl]propyladenine (11). To a
mixture of 10 (19 g, 55.5 mol), triphenylphosphine (29 g, 0.11 mol) and
adenine (15 g, 0.11 mol) in anhydrous dioxane (300 mL) was added a so-
lution of DIAD (21.8 mL) in dioxane (30 mL) over a period of 2 h at room
temperature and the mixture was stirred further for 16 h. The reaction mix-
ture was evaporated to dryness and the residue was purified on a column
of silica gel eluting with chloroform:methanol (100:0 to 95:5) to provide 20
1
g (81%) of 11 as a white foam: H NMR (DMSO-d6): 7.99 (s, 1H), 7.85 (s,
1H), 7.4–7.00 (m, 12H), 4.34 (m, 1H), 3.82 (m, 1H), 3.68 (m, 1H), 1.87 (m,
1H), 1.70 (m, 1H), 0.58 (m, 12H). IR (KBr, cm−1) 3147, 2962, 2931, 2857,
1674, 1601, 1472, and 1303.
( )-9-[1-(tert -Butyldiphenylsilyloxy)methyl]propyl-N6 -monomethoxy-
trityladenine (12). A solution of 11 (20 g, 0.044 mol) in pyridine (500
mL) was treated with MMTr-chloride (27.75 g, 0.088 mol) and the reaction
mixture was heated at 70◦C with stirring for 20 h. It was evaporated to
dryness, diluted with ethyl acetate (1.5 L) and was washed with water (2
500 mL) and brine and the organic layer was dried over MgSO4. After
filtration, the filtrate was concentrated and the residue was purified on a
silica gel column using ethyl acetate:hexanes as eluent (0:1 to 1:1) to give
22 g (69%) of product as a yellow solid: 1H NMR (DMSO-d6): δ 8.32 (s, 1H),
7.84 (s, 1H), 7.4–6.8 (m, 24H), 4.55 (m, 1H), 4.00 (m, 1H), 3.88 (m, 1H),
3.70 (s, 3H), 2.09 (m, 1H), 1.92 (m, 1H), 0.77 (m, 12H). IR (KBr, cm−1
2931, 2856, 2361, 1734, 1604, 1467, 1249, and 1111.
)
( )-9-[1-Hydroxymethyl]propyl-N6 -monomethoxytrityladenine (13).
Compound 12 (22 g, 30.0 mmol) was dissolved in THF (200 L) and was
treated with TBAF (1M in THF, 30.68 mL) and the reaction mixture was
stirred at room temperature for 2 h followed by concentration. The residue
was purified on a silica gel column using chloroform:methanol (100:0 to
90:10) as an eluent to give 10 g (70%) of 13 as a white foam, mp 188◦C:
1H NMR (DMSO-d6): δ 8.23 (s, 1H), 7.89 (s, 1H), 7.4–6.9 (m, 14H), 5.01
(bs, 1H), 4.36 (m, 1H), 3.84 (m, 1H), 3.71 (s, 3H), 3.67 (m, 1 H, partially

1578
M. Wu et al.
masked by CH3 peak), 1.90 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H). IR (KBr,
cm−1) 3408, 3313, 2966, 1715, 1605, 1469, and 1249.
( )-9-[1-[(Monomethoxytrityloxy)methyl][3-oxopropyl]-N6-monometh-
oxytrityladenine (16). A solution of 15 (4.16 g, 5.42 mmol) in methylene
chloride (300 mL) was treated with Dess-Martin reagent (4.74 g, 97%,
10.84 mmol) and was stirred at room temperature for 4 h. The reaction
mixture was concentrated and was purified on a silica gel column using
ethyl acetate:hexanes (0:1 to 2:1) as eluent to provide 2.9 g (70%) of 16 as a
white solid: 1H NMR (DMSO-d6): δ 9.58 (s, 1H), 8.44 (s, 1H), 7.80 (s, 1H),
7.43–6.67 (m, 29H), 5.24–5.12 (m, 1H), 4.08–3.89 (m, 1H), 3.70 (s, 6H),
3.65–3.48 (m, 1H), 3.18 (d, J = 10.3 Hz, 2H). MS (ES+) 766.58 (M+H)+.
( )-9-[1-[(tert-Butyldimethylsilyloxy)methyl][(3-hydroxy)butyl]adenine
(19). A solution of 16 (2.8 g, 3.66 mmol) in THF (150 mL) was treated with
3M methyl magnesium bromide (6.1 mL, 18.3 mmol) and the mixture was
stirred for 6 h at room temperature. The reaction mixture was diluted with
ethyl acetate (400 mL) and was washed with water (2 ) and brine and the
organic layer dried over MgSO4. After filtration and concentration, a white
solid (17) was obtained (2.65 g).
A solution of 17 (2.55 g, 3.26 mmol) in acetonitrile (300 mL) and water
(14 mL) was treated with 2M HCl (1.5 mL) at room temperature and the
mixture stirred for 14 h. The reaction mixture was neutralized by adding
0.5N NaOH followed by dilution with water (100 mL) and concentration to
remove most of the organic solvent. The aqueous phase was extracted with
ethyl acetate (2 100 mL) and concentrated to give 830 mg of 18 as light
yellow film.
To a solution of 18 in DMF (8 mL) was added imidazole (375 mg, 5.45
mmol) and TBDMS-chloride (332 mg, 2.18 mmol) and stirred at room
temperature for 31 h. The reaction mixture was diluted with chloroform
(300 mL), washed with water (2 ), and dried over MgSO4. After filtration,
the filtrate was concentrated and the residue was purified on a silica gel
column using chloroform:CMA-80 (1:0 to 1:1) to give 338 mg (49%) of 19
1
as a colorless film: H NMR (a mixture of diastereomers, CDCl3): δ 8.28,
8.275, 8.12, 7.93 (4s, 2H), 5.79, 5.76 (2s, 2H), 4.85–4.75 (m, 1H), 4.01 (d,
J = 3.8 Hz, 2H), 3.88–3.76, 3.28–3.18 (2m, 2H), 2.18–1.98, 1.73–1.62 (2m,
2H), 1.19, 1.10 (2d, J = 6.2 Hz each, 3H), 0.83, 0.78 (2s, 9H), 0.00, 0.11,
0.12 (3s, 6H). HRMS Calcd for C16H29N5O2Si (M+H)+ 352.2168. Found:
352.2177.
( )-9-[1-(Hydroxymethyl)[(3-monomethoxytrityloxy)butyl]-N6 -mono-
methoxytrityladenine (21). A solution of 19 (320 mg, 0.91 mmol) in
pyridine (5 mL) was treated with monomethoxytrityl chloride (1.15 g, 98%,

Synthesis of Possible Antiviral Agents
1579
3.65 mmol) and the reaction mixture heated at 70◦C with stirring for 14
h. It was diluted with ethyl acetate (150 mL) and washed with water (2 )
and brine and the organic layer was dried over MgSO4. After filtration, the
filtrate was concentrated and the residue was purified on a silica gel column
using ethyl acetate:hexanes as eluent (0:1 to 1:3) to give 1.07 g of 20 as a
colorless syrup.
A solution of 20 in THF (9 mL) was treated with TBAF (1M in THF,
0.91 mL) and the reaction mixture was stirred at room temperature for 2 h
followed by concentration. The residue was purified on a silica gel column
using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.1) to give 507 mg (71%,
1
two steps) of 21 as a white solid: H NMR (a mixture of diastereomers,
DMSO-d6): δ 8.11, 7.94, 7.91, 7.85 (4s, 2H), 7.39–7.13 (m, 25H), 6.93–6.75
(m, 4H), 5.02 (t, J = 5.8 Hz, 1H), 4.72–4.64, 4.52–4.44 (2m, 1H), 3.77, 3.76,
3.75, 3.73 (4s, 6H), 3.71–3.51, 3.31–3.11 (2m, 3H), 2.27–2.14, 1.99–1.72 (2m,
2H), 0.81, 0.70 (2d, J = 6.0 Hz each, 3H). IR (KBr, cm−1) 3414, 2931, 1606,
1508, and 1250. Anal. Calcd for C50H47N5O4 0.3 EtOAc: C, 76.07; H, 6.16;
N, 8.66. Found: C, 75.92; H, 6.29; N. 8.59.
( )-9-[1-[(Diisopropylphosphonomethoxy)methyl][(3-monomethoxy-
trityloxy)butyl]-N6-monomethoxytrityladenine (22). This compound was
prepared from 21 by the same procedure as given for 3. The crude product
was purified on a silica gel column using ethyl acetate:hexanes:methanol
(1:1:0 to 1:1:0.1) as eluent to give 22 in 57% yield as a colorless oil: 1H NMR
(a mixture of diastereomers, CDCl3): δ 8.08, 8.02, 8.01, 7.89 (4s, 2H), 7.39–
7.13 (m, 25H), 6.83 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 4.98–4.89
(m, 1H), 4.78–4.63 (m, 2H), 4.19–3.15 (m, 5H), 3.79, 3.78 (2s, 6H), 2.29–
1.70 (m, 2H), 1.35–1.22 (m, 12H), 1.20, 1.14 (2d, J = 6.2 Hz each, 3H).
HRMS Calcd for C57H62N5O7P (M+H)+ 960.4465. Found: 960.4417.
( )-9-[1-[(Phosphonomethoxy)methyl][(3-monomethoxytrityloxy)pro-
pyl]-N6-monomethoxytrityladenine (23a). A solution of 3 (17.7 g, 18.71
mmol) in DMF (170 mL) was treated with triethylamine (15 mL) followed
by trimethylsilyl iodide (25 mL, 174.9 mmol) and the reaction mixture flask
was covered with aluminum foil to protect from light and was stirred for 16
h at room temperature. It was then diluted with TEAB buffer (0.5 L), water
(0.75 L) and chloroform (1.5 L) and was stirred for 1 h. The organic phase
was collected and the aqueous phase was re-extracted with chloroform (3 ).
The combined organic extracts were dried over MgSO4. After filtration,
the filtrate was concentrated and the residue was purified on a silica gel
column using chloroform:methanol (1:0 to 85:15), then CMA-80:CMA-50
1
(1:0 to 0:1) as eluent to give 7.5 g (47%) of 23a as a yellow solid: H NMR
(DMSO-d6): δ 8.29 (s, 1H), 7.86 (s, 1H), 7.34–7.01 (m, 25H), 6.85 (d, J =
9.1 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 4.97–4.86 (m, 1H), 3.94–3.85 (m,

1580
M. Wu et al.
1H), 3.80–3.72 (m, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.37 (d, J = 7.6 Hz, 2H),
2.89–2.72 (m, 2H), 2.42–2.26 (m, 1H), 2.23–2.07 (m, 1H). HRMS Calcd for
C50H48N5O7P (M+H)+ 862.3369. Found: 862.3387.
( )-9-[1-[(Phosphonomethoxy)methyl][(3-monomethoxytritylamino)
propyl]-N6-monomethoxytrityladenine (23c). This compound was pre-
pared from 8 by the same procedure as given for 23a. The crude prod-
uct was purified on a silica gel column using chloroform:methanol (1:0 to
85:15), then CMA-80:CMA-50 (1:0 to 0:1) as eluent to give 45% yield of 23c
as a white solid: 1H NMR (DMSO-d6): δ 8.26 (s, 1H), 7.83 (s, 1H), 7.32–6.99
(m, 25H), 6.82 (d, J = 9.1 Hz, 2H), 6.70 (d, J = 9.1 Hz, 2H), 5.00–4.83 (m,
1H), 3.92–3.79 (m, 1H), 3.76–3.66 (m, 1H), 3.68 (s, 3H), 3.63 (s, 3H), 3.37
(d, J = 7.5 Hz, 2H), 2.28–2.14 (m, 1H), 2.06–1.90 (m, 1H), 1.84–1.62 (m,
2H). HRMS Calcd for C50H49N6O6P (M+H)+ 861.3529. Found: 861.3562.
( )-9-[1-[(Phosphonomethoxy)methyl][(3-methoxy)propyl]-N6-mono-
methoxytrityladenine (23d). A solution of 4 (1.0 g, 1.48 mmol) in DMF
(12 mL) was treated with sodium hydride (60%, 0.24 g, 6.0 mmol) at room
temperature and the mixture was stirred for 1 h. To this solution was then
added a solution of methyl iodide (0.11 mL, 1.77 mmol) in DMF (2 mL)
and the mixture was stirred at room temperature for 12 h. The reaction
mixture was diluted with ethyl acetate (30 mL), neutralized with acetic acid
and chloroform (400 mL) added. The mixture was washed with water (2 )
and brine and the organic layer was dried over MgSO4 followed by filtration
and concentration to give 9 which was converted to 23d following the same
procedure as used for 23a. The product was purified on a silica gel column
using chloroform:methanol (1:0 to 85:15), then CMA-80:CMA-50 (1:0 to
0:1), as eluent to give 296 mg (33%, two steps) of 23d as an off-white film:
1H NMR (DMSO-d6): δ 8.34(s, 1H), 7.89 (s, 1H), 7.36–7.16 (m, 13H), 6.84
(d, J = 9.1 Hz, 2H), 4.80–4.67 (m, 1H), 4.02–3.90 (m, 1H), 3.87–3.77 (m,
1H), 3.71 (s, 3H), 3.36–3.26 (m, 2H), 3.27–3.18 (m, 1H), 3.14–3.03 (m, 1H),
3.10 (s, 3H), 2.24–2.04 (m, 2H). HRMS Calcd for C31H34N5O6P (M+H)+
604.2325. Found: 604.2335.
( )-9-[1-[(Phosphonomethoxy)methyl]propyl]-N6-monomethoxytrityl-
adenine (23e). Compound 13 was converted to 14 in 30% yield with the
same procedure as used for 3 and 14 was converted to 23e by the same
method used for 23a. The crude product was purified on a silica gel column
using chloroform:methanol (1:0 to 85:15), then CMA-80:CMA-50 (1:0 to
1
0:1) as eluent to give 47% of 23e as a yellow solid: H NMR (DMSO-d6): δ
8.36 (s, 1H), 7.87 (s, 1H), 7.4–6.8 (m, 14H), 6.50 (bs, 2H), 4.56 (m, 1H),
3.95 (m, 1H), 3.82 (m, 1H), 3.69 (s, 3H), 3.32 (m, 2H), 1.86 (m, 2H), 0.67
(t, J = 7.1 Hz, 3H). IR (KBr, cm−1) 3408, 3159, 1604, 1469, 1401, and 1249.

Synthesis of Possible Antiviral Agents
1581
( )-9-[1-[(di-tert-Butylcarbonyloxymethylphosphonomethoxy)methyl]
[(3-monomethoxytrityloxy)propyl]-N6-monomethoxytrityladenine (24a). A
solution of 23a (400 mg, 0.46 mmol) in DMF (24 mL) was treated with
triethylamine (24 mL) followed by chloromethyl pivalate (8.9 mL, 97%,
59.9 mmol) and stirred for 3 days at room temperature. It was then diluted
with chloroform (250 mL) and washed with water (2 ). The organic layer
was dried over MgSO4. After filtration, the filtrate was concentrated and the
residue purified on a silica gel column using ethyl acetate:hexanes:methanol
(1:1:0 to 1:1:0.1) as eluent to give 83 mg (17%) of 24a as a colorless film: 1H
NMR (DMSO-d6): δ 8.41 (s, 1H), 8.10 (s, 1H), 7.57–7.25 (m, 25H), 7.08 (d,
J = 8.8 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 5.78 (s, 2H), 5.74 (s, 2H), 5.24–
5.12 (m, 1H), 4.22–4.10 (m, 3H), 4.10–4.00 (m, 1H), 3.95 (s, 3H), 3.92 (s,
3H), 3.15–3.05 (m, 1H), 3.05–2.92 (m, 1H), 2.68–2.50 (m, 1H), 2.43–2.28
(m 1H), 2.23 (s, 18H). IR (KBr, cm−1) 3420, 2972, 1753, 1605, 1511, 1471,
and 1251. Anal. Calcd for C62H68N5O11P 0.75 H2O 0.25 EtOAc: C, 67.22;
H, 6.40; N, 6.22. Found: C, 67.09; H, 6.37; N, 6.01.
( )-9-[1-[(di-Isopropyloxycarbonyloxymethylphosphonomethoxy)meth-
yl][(3-monomethoxytritylamino)propyl]-N6 -monomethoxytrityladenine
(24c). This compound was prepared from 23c with the same procedure as
given for 24a but using chloromethyl-2-propylcarbonate in place of chloro-
methyl pivalate. The time of the reaction was also increased to 7 days. The
crude product was purified on a silica gel column using ethyl acetate:hexanes:
methanol (1:1:0 to 1:1:0.1) as eluent to give 27% yield of product as a color-
less oil: 1H NMR (CDCl3): δ 7.98 (s, 1H), 7.87 (s, 1H), 7.38–7.07 (m, 25H),
6.80 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.9 Hz, 2H), 5.68–5.56 (m, 4H),
5.08–4.95 (m, 1H), 4.95–4.84 (m, 2H), 4.05–3.80 (m, 2H), 3.86 (d, J =
7.4 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 2.37–2.20 (m, 1H), 2.12–1.78 (m,
4H), 1.28 (d, J = 6.2 Hz, 6H), 1.27 (d, J = 6.2 Hz, 6H). HRMS Calcd for
C60H65N6O12P (M+H)+ 1093.4476. Found: 1093.4483.
( )-9-[1-[(di-Isopropyloxycarbonyloxymethylphosphonomethoxy)
methyl][(3-methoxy)propyl]-N6 -monomethoxytrityladenine (24d). This
compound was prepared from 23d by the same procedure as given for
24c. The crude product was purified on a silica gel column using ethyl
acetate:hexanes:methanol (1:1:0 to 1:1:0.1) as eluent to give 35% yield of
1
product as a colorless oil: H NMR (CDCl3): δ 8.03 (s, 1H), 7.87 (s, 1H),
7.38–7.19 (m, 13H), 6.80 (d, J = 9.0 Hz, 2H), 5.68–5.58 (m, 4H), 4.96–4.81
(m, 3H), 4.20–4.12 (m, 1H), 3.95–3.82 (m, 3H), 3.78 (s, 3H), 3.41–3.32 (m,
1H), 3.24 (s, 3H), 3.18–3.08 (m, 1H), 2.38–2.15 (m, 2H), 1.31 (d, J = 6.2 Hz,
12H). IR (neat, cm−1) 3020, 1605, and 1216. Anal. Calcd for C41H50N5O12P:
C, 58.92; H, 6.03; N, 8.38. Found: C, 58.89; H, 6.17; N. 8.23.

1582
M. Wu et al.
(
)-9-[1-[(di-tert -Butylcarbonyloxymethylphosphonomethoxy)meth-
yl][(3-monomethoxytrityloxy)butyl]-N6 -monomethoxytrityladenine (24f).
Compound 22 was converted to 23f by the same method used for 23a and
23f was converted to 24f by the method used for 24a. The product 24f was
1
obtained in 17% yield (two steps) as a colorless oil: H NMR (a mixture
of diastereomers, CDCl3): δ 8.00, 7.93, 7.62 (3s, 2H), 7.46–7.10 (m, 25H),
6.90–6.68 (m, 4H), 5.64–5.52 (m, 4H), 4.94–4.64 (m, 1H), 3.95–3.85, 3.79–
3.44, 3.35–3.25 (3m, 5H), 3.77 (m, 3H), 3.73 (s, 3H), 2.20–1.81, 1.76–1.56
(2m, 2H), 1.20, 1.19, 1.18 (3s, 18H), 0.92, 0.86 (2d, J = 6.2 Hz each, 3H).
HRMS Calcd for C63H70N5O11P (M+H)+ 1104.4887. Found: 1104.4882.
( )-9-[1-[(di-tert-Butylcarbonyloxymethylphosphonomethoxy)methyl]
[(3-hydroxy)propyl]adenine (25a). A solution of 24a (138 mg, 0.13 mmol)
in acetonitrile (28 mL) was treated with 0.2 M HCl (1.4 mL) and stirred for
14 h at room temperature. It was then carefully neutralized with 0.5 N NaOH
to pH 6.0 and was diluted with water (15 mL) and was concentrated to
remove acetonitrile. The residual material was again diluted with water (20
mL) and was extracted with chloroform:methanol (4:1, 2 ). The organic
layer was dried over MgSO4. After filtration, the filtrate was concentrated
and the residue was purified on a silica gel column using chloroform:
methanol (1:0 to 9:1) as eluent to give 42 mg (59%) of 25a as a colorless
oil.
Procedure for the fumarate salt of 25a: A solution of 25a (14.1 mg,
0.026 mmol) in 2-propanol (1.2 mL) was treated with a solution of fumaric
acid in propanol (20.3 mg/mL, 0.45 mL, 0.026 mmol) followed by slow
concentration under vacuum. The fumaric salt was obtained as a white solid:
1H NMR (DMSO-d6): δ 12.95 (bs, 2H), 7.89 (s, 1H), 7.87 (s, 1H), 6.97 (s,
2H), 6.40 (s, 2H), 5.31 (d, J = 3.4 Hz, 2H), 5.27 (d, J = 3.5 Hz, 2H), 4.64–
4.48 (bs, 1H), 4.44–4.24 (bs, 1H), 3.85 (t, J = 9.1 Hz, 1H), 3.73–3.60 (m,
3H), 3.16–2.91 (m, 2H), 1.97–1.84 (m, 1H), 1.84–1.68 (m, 1H), 0.90 (s,
18H). HRMS Calcd for C22H36N5O9P (M+H)+ 546.2329. Found: 546.2325.
( )-9-[1-[(di-tert-Butylcarbonyloxymethylphosphonomethoxy)methyl]
[(3-azido)propyl]adenine (25b). Compound 6 was converted to 23b in 44%
yield with the same method as used for 23a and 23b was converted to 24b in
64% yield by the method used for 24a. The resultant 24b was deprotected by
the same method used for 25a to give 25b. The compound 25b was obtained
1
in 82% yield as a colorless oil: H NMR (DMSO-d6): 8.16 (s, 1H), 8.10 (s,
1H), 7.22 (bs, 2H), 5.52 (dd, J = 12.6, 3.5 Hz, 4H), 4.77 (m, 1H), 4.03 (m,
1H), 3.92 (m, 3H), 3.29 (m, 1H), 3.16 (m, 1H), 2.27 (m, 1H), 2.09 (m, 1H),
1.13 (m, 18H). MS (ES+) 571.24 (M+H)+. Anal. Calcd for C22H35N8O8P:
C, 46.31; H, 6.18; N, 19.6. Found: C, 46.67; H, 6.22; N, 18.56. HPLC: tR =
23.42 min., 95.44%.

Synthesis of Possible Antiviral Agents
1583
( )-9-[1-[(di-Isopropyloxycarbonyloxymethylphosphonomethoxy)meth-
yl][(3-amino)propyl]adenine (25c). A solution of 24c (45 mg, 0.041 mmol)
in acetonitrile (6.6 mL) was treated with 0.2 M HCl (0.99 mL) and was
stirred for 16 h at room temperature. It was diluted with water (100 mL)
and was extracted with ethyl acetate (2 ) and chloroform (2 ). The aque-
ous layer was concentrated to dryness to give 25c as a gum. The product was
dissolved in 2.0 mL of water and its concentration was measured to be 11.9
mM (58%) by UV at 259 nm using adenosine monophosphate as standard.
1H NMR (D2O): δ 8.32 (s, 1H), 8.29 (s, 1H), 5.47–5.36 (m, 4H), 4.90–4.72
(m, 3H), 4.05–3.86 (m, 4H), 3.04–2.90 (m, 1H), 2.84–2.70 (m, 1H), 2.49–
2.35 (m, 1H), 2.35–2.20 (m, 1H), 1.17 (d, J = 6.5 Hz, 6H), 1.16 (d, J =
6.3 Hz, 6H). HRMS Calcd for C20H33N6O10P (M+H)+ 549.2074. Found:
549.2070. HPLC: tR = 15.11 min., 95.0%.
( )-9-[1-[(di-Isopropyloxycarbonyloxymethylphosphonomethoxy)meth-
yl][(3-methoxy)propyl]adenine (25d). This compound was prepared from
24d by the same procedure as given for 25a. The crude product was purified
on a silica gel column using chloroform:methanol (1:0 to 9:1) as eluent to
give 83% yield of product as a colorless oil: 1H NMR (CDCl3): δ 8.32 (s, 1H),
7.94 (s, 1H), 5.73 (s, 2H), 5.68–5.60 (m, 4H), 4.96–4.84 (m, 3H), 4.18 (dd,
J = 10.0, 6.6 Hz, 1H), 3.92 (dd, J = 9.9, 3.8 Hz, 1H), 3.86 (dd, J = 7.6, 1.1
Hz, 2H), 3.42–3.32 (m, 1H), 3.23 (s, 3H), 3.15–3.02 (m, 1H), 2.41–2.16 (m,
2H), 1.32 (d, J = 6.2 Hz, 6H), 1.31 (d, J = 6.3 Hz, 6H). IR (neat, cm−1
)
3328, 2928, 1761, 1646, 1598, and 1267. HRMS Calcd for C21H34N5O11P
(M+H)+ 564.2070. Found: 564.2071. HPLC: tR = 21.65 min., 95.0%.
( )-9-[1-[(di-tert-Butylcarbonyloxymethylphosphonomethoxy)methyl]
propyl]adenine (25e). Compound 23e was converted to 24e in 78% yield
with the method used for 24a and the resultant 24e was converted to 25e
by the same method as used for 25a. Compound 25e was obtained in 32%
yield as a colorless oil: 1H NMR (DMSO-d6): δ 8.4 (s, 1H), 8.35 (s, 1H), 7.45
(bs, 2H), 5.80 (m, 2H), 5.74 (m, 2H), 5.83 (m, 1H), 4.30 (m, 1H), 4.15 (m,
2H), 4.10 (m, 1H), 2.20 (m, 2H), 1.32 (s, 18H), 0.95 (t, J = 7.1 Hz, 3H). MS
(ES+) 552.29 (M+Na)+. Anal. Calcd for C22H36N5O8P: C, 49.90; H, 6.85; N,
13.22. Found: C, 49.97; H, 6.73; N, 13.21. HPLC: tR = 22.92 min., 98.26%.
( )-9-[1-[(di-tert-Butylcarbonyloxymethylphosphonomethoxy)methyl]
[(3-hydroxy)butyl]adenine (25f). This compound was prepared from 24f
by the same procedure as given for 25a. The crude product was purified on
a silica gel column using chloroform:methanol (1:0 to 9:1) as eluent to give
89% yield of product as a colorless oil: 1H NMR (a mixture of diastereomers,
CDCl3): δ 8.31, 8.12, 7.97 (3s, 2H), 6.11, 6.01 (2s, 2H), 5.74–5.58 (m, 4H),
5.04–4.91 (m, 1H), 4.25–3.78, 3.34–3.24 (2m, 4H), 3.92, 3.85 (2d, J =

1584
M. Wu et al.
7.2 Hz each, 2H), 2.28–2.01, 1.86–1.74 (2m, 2H), 1.24, 1.15 (2d, J = 6.2
Hz each, 3H), 1.21 (s, 18H). IR (neat, cm−1) 3020, 1754, 1632, 1216, and
764. HRMS Calcd for C23H38N5O9P (M+H)+ 560.2485. Found: 560.2469.
HPLC: tR = 22.01 min., 96.0%.
REFERENCES
1. (a) Schaeffer, H.J.; Beauchamp, L.; de Miranda, P.; Elion, G.B.; Bauer, D.J.; Collins, P. 9-(2-
Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature (London)
1978, 272(5654), 583–585; (b) Elion, G.B.; Furman, P.A.; Fyfe, J.A.; de Miranda, P.; Beauchamp, L.;
Schaeffer, H.J. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine.
Proc. Natl. Acad. Sci. U.S.A. 1977, 74(12), 5716–5720; (c) Collins, P.; Bauer, D.J. The activity in
vitro against herpes virus of 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine), a new antiviral
agent. J. Antimicrob. Chemother. 1979, 5(4), 431–436.
2. (a) Smith, K.O.; Galloway, K.S.; Kennell, W.L.; Ogilvie, K.K.; Radatus, B.K. A new nucleoside
analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine, highly active in vitro against
herpes simplex virus types 1 and 2. Antimicrob. Agents Chemother. 1982, 22(1), 55–61;
(b) Ashton, W.T.; Karkas, J.D.; Field, A.K.; Tolman, R.L. Activation by thymidine kinase and potent
antiherpetic activity of 2ꢀ-nor-2ꢀ-deoxyguanosine (2ꢀNDG). Biochem. Biophys. Res. Commun.
1982, 108(4), 1716–1721; (c) Martin, J.C.; Dvorak, C.A.; Smee, D.F.; Matthews, T.R.; Verheyden,
J.P.H. 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: A new potent and selective antiherpes agent.
J. Med. Chem. 1983, 26(5), 759–761; (d) Schaeffer, H.J. In Nucleosides, Nucleotides and their Biological
Applications; Rideout, J. L., Henry, D. W., Beacham, L. M., Eds.; Academic Press: New York, 1983;
1–17.
3. (a) Cheng, Y.-C.; Huang, E.-S.; Lin, J.-C.; Mar, E.-C.; Pagano, J.S.; Dutschman, G.E.; Grill, S.P.
Unique spectrum of activity of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine against herpesviruses
in vitro and its mode of action against herpes simplex virus type 1. Proc. Natl. Acad. Sci.
U.S.A. 1983, 80(9), 2767–2770; (b) Field, A.K.; Davies, M.E.; Dewitt, C.; Perry, H.C.; Liou, R.;
Germershausen, J.; Karkas, J.D.; Ashton, W.T.; Johnston, D.B.; Tolman, R.L. 9-([2-Hydroxy-1-
(hydroxymethyl)ethoxy]methyl)guanine: A selective inhibitor of herpes group virus replication.
Proc. Natl. Acad. Sci. U.S.A. 1983, 80(13), 4139–4143.
4. Smee, D.F.; Martin, J.C.; Verheyden, J.P.H.; Matthews, T.R. Anti-herpesvirus activity of the
acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Antimicrob. Agents Chemother.
1983, 23(5), 676–682.
5. Cundy, K.C. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and
adefovir. Clin. Pharmacokinet. 1999, 36, 127–143.
6. Holy, A.; Dvorakova, H.; Jindrich, J.; Masojidkova, M.; Budesinsky, M.; Balzarini, J.; Andrei, G.; De
Clercq, E. Acyclic nucleotide analogs derived from 8-azapurines: Synthesis and antiviral activity.
J. Med. Chem. 1996, 39, 4073–4088.
7. Balzarini, J.; Pannecouque, C.; De Clercq, E.; Aquaro, S.; Perno, C.-F.; Egberink, H.; Holy, A.
Antiretrovirus activity of a novel class of acyclic pyrimidine nucleoside phosphonates. Antimicrob.
Agents Chemother. 2002, 46, 2185–2193.
8. Balzarini, J.; Perno, C.F.; Schols, D.; De Clercq, E. Activity of acyclic nucleoside phosphonate
analogues against human immunodeficiency virus in monocyte/macrophages and peripheral
blood lymphocytes. Biochem. Biophys. Res. Commun. 1991, 178, 329–335.
9. De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P.C. A novel selective
broad-spectrum anti-DNA virus agent. Nature 1986, 323, 464–467.
10. Naesens, L.; De Clercq, E. Therapeutic potential of HPMPC (cidofovir), PMEA (adefovir) and
related acyclic nucleoside phosphonate analogues as broad-spectrum antiviral agents. Nucleosides
Nucleotides 1997, 16, 983–992.
11. Balzarini, J.; Holy, A.; Jindrich, J.; Naesens, L.; Snoeck, R.; Schols, D.; De Clercq, E. Differen-
tial antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleo-
side phosphonates: Potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-
phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob. Agents Chemother. 1993, 37, 332–338.

Synthesis of Possible Antiviral Agents
1585
12. Balzarini, J.; Aquaro, S.; Perno, C.-F.; Holy, A.; De Clercq, E. Activity of the (R)-enantiomers of 9-
(2-phosphonyl-methoxypropyl)adenine and 9-(2-phosphonyl-methoxypropyl)-2,6-diaminopurine
against human immunodeficiency virus in different human cell systems. Biochem. Biophys. Res.
Commun. 1996, 219, 337–341.
13. Perbost, M.; Lucas, M.; Chavis, C.; Imbach, J.-L. Synthesis of racemic carboacyclonucleosides
derived from butane-1,4-diol and hexane-1,6-diol. Nucleosides Nucleotides 1992, 11(8), 1489–
1505.
14. Perbost, M.; Lucas, M.; Chavis, C.; Imbach, J.-L. An expeditious synthesis of homochiral (R)
2-(9-purinyl)butane-1,4-diols from (S) butane-1,2,4-triol. Nucleosides Nucleotides 1992, 11(8),
1529–1537.
15. Jeffery, A.L.; Kim, J.-H.; Wiemer, D.F. Synthesis of acyclic nucleoside and nucleotide analogues
from amino acids: A convenient approach to a PMEA-PMPA hybrid. Tetrahedron 2000, 56, 5077–
5083.
16. Giller, S.A.; Getsova, I.N.; Goncharova, I.N.; Petrulyanis, L.N.; Mironova, L.I.; Nazarova, G.F.;
Bruk, E.I. Analogs of purine nucleosides and purine mono- and polynucleotides. II. Substituted
α-(9-purinyl)-γ-butyrolactones. Chem. Heterocycl. Compd. U.S.S.R. 1974, 10, 1477–1480.
17. Eisenberg, C.; Knochel, P. Catalytic asymmetric preparation of polyfunctional protected 1,2-diols
and epoxides. J. Org. Chem. 1994, 59, 3760–3761.
18. Caroll, S.S.; Tomassini, J.E.; Bosserman, M.; Getty, K.; Stahlhut, M.W.; Eldrup, A.B.; Bhat, B.;
Hall, D.; Simcoe, A.L.; LaFemina, R.; Rutkowski, C.A.; Wolanski, B.; Yang, Z.; Migliaccio, G.; De
Francesco, R.; Kuo, L.C.; MacCoss, M.; Olsen, D.B. Inhibition of hepatitis C virus RNA replication
by 2ꢀ-modified nucleoside analogs. J. Biol. Chem. 2003, 278, 11979–11984.