Synthesis of N6-substituted 9-[3-(phosphonomethoxy)propyl] adenine derivatives as possible antiviral agents

Article abstract of DOI:10.1080/15257770500265760

□ A number of N⁶-substituted 9-[3-(phosphonomethoxy)propyl] adenine derivatives having hydroxymethyl at C-1′-position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds

Full text of DOI:10.1080/15257770500265760

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Synthesis of N6-Substituted 9-[3-
(Phosphonomethoxy)Propyl]Adenine Derivatives As
Possible Antiviral Agents
Yahya El-Kattan a , Tsu-Hsing Lin a , Minwan Wu a , V. Satish Kumar a , Pravin L. Kotian a , Ajit
Ghosh 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: Yahya El-Kattan , Tsu-Hsing Lin , Minwan Wu , V. Satish Kumar , Pravin L. Kotian , Ajit Ghosh ,
Xiaogang Cheng , Shanta Bantia , Yarlagadda S. Babu & Pooran Chand (2005) Synthesis of N6-Substituted 9-[3-
(Phosphonomethoxy)Propyl]Adenine Derivatives As Possible Antiviral Agents, Nucleosides, Nucleotides and Nucleic Acids,
24:10-12, 1597-1611, DOI: 10.1080/15257770500265760
To link to this article: http://dx.doi.org/10.1080/15257770500265760
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Nucleosides, Nucleotides, and Nucleic Acids, 24:1597–1611, 2005
c
Copyright ꢀ Taylor & Francis Group, LLC
ISSN: 1525-7770 print/1532-2335 online
DOI: 10.1080/15257770500265760
SYNTHESIS OF N6-SUBSTITUTED
9-[3-(PHOSPHONOMETHOXY)PROPYL]ADENINE DERIVATIVES AS
POSSIBLE ANTIVIRAL AGENTS
Yahya El-Kattan, Tsu-Hsing Lin, Minwan Wu, V. Satish Kumar, Pravin L.
Kotian, Ajit Ghosh, Xiaogang Cheng, Shanta Bantia, Yarlagadda S. Babu,
ᮀ
and Pooran Chand
BioCryst Pharmaceuticals, Inc., Birmingham, Alabama, USA
A number of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having
hydroxymethyl at C-1ꢀ-position were prepared from the appropriate 6-chloroadenine derivative. The
syntheses of the corresponding prodrugs of these compounds are also reported. These compounds
showed poor activity against HCV in replicon assay.
ᮀ
Keywords Acyclic nucleosides; Prodrugs; Antiviral
INTRODUCTION
Extensive studies have been done on 9-[2-(phosphonomethoxy)ethyl]
adenine and guanine derivatives.[1–7] A number of lead compounds (Chart
1), such as PMEA (1a), PMEDAP (1g), and PMEG (2a) evolved from those
studies and adefovir dipivoxil (1b), the prodrug of PMEA, was approved by
FDA for HBV infections. All these compounds are unsubstituted acyclic nu-
cleoside derivatives. Substituting the C-2ꢁ-position by methyl, hydroxymethyl,
fluoromethyl resulted in some more lead compounds (Chart 1), such as
PMPA (1c), HPMPA (1e), FPMPA (1f), HPMPDAP (1h), PMPG (2b), and
HPMPG (2c). These studies resulted in a FDA-approved compound, teno-
fovir disoproxil (1b), the prodrug of PMPA for HIV infections.
Various N6-substituted adenosine derivatives as agonists and partial ago-
nists of adenosine receptors have been reported.[8–10] Recently, a number of
Dedicated to the memory of John A. Montgomery.
Received 2 February 2005; accepted 5 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
1597

1598
Y. El-Kattan et al.
CHART 1
adenosine analogs, where ribose has been replaced by 2ꢁ-methylribose have
been reported as potent hepatitis C viral (HCV) polymerase inhibitors. Fur-
ther replacement of 6-amino of adenosine by thiophene; 6-thiomethyl; hy-
drazine derivatives, such as methylhydrazino, acetylhydrazino, hydroxyethyl-
hydrazino, methylsulphonylhydrazino; amine derivatives, such as hydroxyl-
amino, methoxylamino, aminoethylamino; and hydroxy derivatives, such as
tert-butyloxycarbonylaminohydroxyl, and benzyloxycarbonylaminohydroxyl
have been studied for HCV inhibitory activity and found to have HCV repli-
cation EC50 values less than 10 M.[11–16]
In one of the preceding papers, we have described the synthesis of 9-[3-
(phosphonomethoxy)propyl]adenine derivatives substituted at C-1ꢁ-position
with hydroxymethyl, fluoromethyl, aminomethyl, azidomethyl, etc., as pos-
sible antiviral agents. We now wish to report the synthesis of N6-substituted
9-[3-(phosphonomethoxy)propyl]adenine derivatives, having the hydroxy-
methyl group at the C-1ꢁ-position.
RESULTS AND DISCUSSION
The synthesis of all the compounds reported here started from racemic
1-tert-butyldimethylsilyl-4-pivaloylbutan-1,2,4-triol (3) reported in the pre-
ceding papers. Compound 3 under Mitsunobu reaction conditions with 6-
chloropurine, triphenylphosphine (TPP) and diisopropylazodicarboxylate
(DIAD) in dioxane gave desired nucleoside 4 (Scheme 1). The displace-
ment of the chloro group in 4 by substituted amino at the 6-position was
achieved by heating the mixture of 4 with corresponding amine in ethanol
at 60◦C. Since the TBDMS group was not found compatible for the phos-
phonomethylation reaction, it became necessary to replace TBDMS with

Synthesis of Possible Antiviral Agents
1599
SCHEME 1 Reagents: i) 6-chloropurine, Ph3P, DIAD; ii) amine, EtOH, Et3N; iii) Bu4NF, THF; iv) TrCl,
pyridine; v) NaOMe; vi) NaH, TsO-CH2-P(O)(O-iPr)2; vii) TMSI, Et3N; viii) ClCH2OC(O)C(CH3)3 or
ClCH2OC(O)OCH(CH3)2, Et3N; ix) HCl, CH3CN.

1600
Y. El-Kattan et al.
trityl, which was achieved by deprotection of TBDMS, with tetrabutylammo-
nium fluoride (TBAF) and treating the resultant free hydroxyl with trityl-
chloride. Further basic hydrolysis of the pivaloyl group resulted in the de-
sired nucleosides, 5a-m. The phosphonomethylation of 5a-m was obtained
by reacting with p-toluenesulfonyloxymethylphosphonate using sodium hy-
dride as base to give the phosphonomethoxy derivatives, which upon hy-
drolysis of ester with TMS-iodide in the presence of triethylamine gave the
desired phosphonic acid derivatives 6a-m. The use of triethylamine was es-
sential to keep the trityl protecting group intact. The reaction of phospho-
nic acids 6a-m with an appropriate chloromethyl pivalate or chloromethyl-
2-propylcarbonate in the presence of triethylamine gave diprotected pro-
drugs, which upon deprotection of trityl under mild acidic conditions with
HCl in acetonitrile yielded the targets 7a-m. In the case of the secondary
amine, the yield of the formation of the prodrugs was low due to the for-
mation of a side product corresponding to a coupling of the amine with
chloromethyl pivalate.
BIOLOGICAL ACTIVITY
These compounds showed poor activity against HCV in replicon assay.[17]
EXPERIMENTAL
All reagents and solvents were purchased from Aldrich and used as
1
received. H NMR, 13C NMR, and 31P NMR were recorded on a Bruker
300 MHz instrument. Chemical shifts ( ) are reported in parts per million
(ppm) referenced to TMS at 0.00 or respective deuterated solvent peak.
31P NMR chemical shifts are reported with respect to D3PO4 in D2O as
the external standard. 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. 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. 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.

Synthesis of Possible Antiviral Agents
1601
( )-9-[(1-tert-Butyldimethylsilyloxymethyl)(3-pivaloyloxy)propyl]-6-
chloropurine (4). To a mixture of 3 (92 g, 0.302 mol), triphenylphosphine
(158 g, 0.60 mol) and 6-chloropurine (95 g, 0.60 mol) in anhydrous dioxane
(1.5 L) was added a solution of DIAD (0.6 mol) in dioxane (60 mL) over
a period of 3.5 h at room temperature and the mixture stirred further for
16 h. The reaction mixture was filtered through a short pad of Celite to
remove insoluble materials and the residue purified on a column of silica
gel eluting with CHCl3:MeOH (100:0 to 95:5) to provide 95 g (72%) of 3 as a
gum. 1H NMR (CDCl3): 8.87 (s, 1H), 8.27 (s, 1H), 4.85 (m, 1H), 4.18–4.02
(m, 2H), 3.95–3.82 (m, 2H), 2.42–2.28 (m, 2H), 1.15 (s, 9H), 0.82 (s, 9H),
0.0 (m, 6H). IR (KBr, cm−1) 3019, 2400, 1724, 1592, 1215, 765. MS (ES+)
463.38 (M+Na)+. Anal. Calcd for C20H33ClN4O3Si: C, 55.04; H, 7.66; N,
12.46. Found: C, 54.72; H, 7.53; N, 12.19.
GeneralProcedure for the Conversion of 4 to 5a-m
To a solution of 4 in EtOH (15 mL/mmol) was added 10 eq. of Et3N
and 6 eq. of the corresponding amine. The resulting solution was stirred at
60◦C for 16 h, evaporated to dryness and partitioned between chloroform
and water. The organic layer was collected, washed 3 times with water, dried
over MgSO4 and evaporated to dryness to give an oil. The resulting oil
was dissolved in THF (10 mL/mmol) and a solution of 1 M TBAF in THF
added (1.1 eq.). The reaction was stirred at room temperature for 30 min,
evaporated to dryness, then adsorbed on silica gel and chromatographed
using chloroform:methanol as eluent to give the desilylated derivative.
To the latter were added pyridine (10 mL/mmol) and trityl chloride
(2 eq.) and the reaction mixture stirred at 70◦C for 16 h. The reaction
mixture was then evaporated to dryness, the residue was dissolved in ethyl
acetate and washed with water 3 times. The organic layer on concentration
and purification on a silica gel column using hexanes:ethyl acetate (100:0 to
90:10) as eluent gave tritylated product, which was dissolved in MeOH (10
mL/mmol) and treated with 5.4 N NaOMe in MeOH (2 eq.). The reaction
mixture was stirred at room temperature for 16 h and neutralized with acetic
acid. The resulting mixture was then evaporated to dryness, the residue
was dissolved in CHCl3 and washed with water. The organic layer was dried
over MgSO4, filtered, and the filtrate was concentrated and the residue was
purified on a silica gel column eluting with CHCl3:MeOH (100:0 to 95:5)
to provide the desired compounds 5a-m.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-diethylaminopurine
(5a). Using the general procedure, 4 gave 5a (80%). 1H NMR (DMSO-d6):
8.30 (s, 1H), 8.12 (s, 1H), 7.30–7.00 (m, 15H), 4.85 (m, 1H), 4.56 (t, 1H,

1602
Y. El-Kattan et al.
J = 4.9 Hz), 3.99 (m, 4H), 3.39 (m, 1H), 3.30 (m, 1H partially masked by
water peak in DMSO-d6), 3.19 (m, 2H), 2.33 (m, 1H), 2.02 (m, 1H), 1.22
(t, 6H, J = 6.7 Hz). IR (KBr, cm−1) 2927, 1583, 1442, 1282, 1031. HRMS
Calcd for C32H35N5O2 (M+H)+ 522.2868. Found 522.2854.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-(N-methyl-N-ethyl)
aminopurine (5b). Using the general procedure, 4 gave 5b (73%). 1H NMR
(DMSO-d6): 8.30 (s, 1H), 8.13 (s, 1H), 7.30–7.00 (m, 15H), 4.87 (m, 1H),
4.56 (t, 1H, J = 4.9 Hz), 4.10 (m, 2H), 3.49–3.25 (m, 5H), 3.20 (m, 2H),
2.32 (m, 1H), 2.01 (m, 1H), 1.19 (t, 3H, J = 6.9 Hz). IR (KBr, cm−1) 2870,
1586, 1284, 1025, 898. HRMS Calcd for C31H33N5O2 (M+H)+ 508.2712.
Found 508.2689.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-ethylaminopurine (5c).
Using the general procedure, 4 gave 5c (90%). 1H NMR (DMSO-d6): 8.88
(br s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.30–7.00 (m, 15H), 4.84 (m, 1H),
4.55 (t, 1H, J = 5.0 Hz), 3.53 (m, 2H), 3.40 (m, 1H), 3.29 (m, 1H, partially
masked by water peak in DMSO-d6), 3.19 (m, 2H), 2.32 (m, 1H), 1.99 (m,
1H), 1.22 (m, 3H). IR (KBr, cm−1) 2978, 2878, 1710, 1615, 1446, 1221, 1105,
1043. HRMS Calcd for C30H31N5O2 (M+H)+ 494.2555. Found 494.2552.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-allylaminopurine (5d).
1
Using the general procedure, 4 gave 5d (90%). H NMR (DMSO-d6):
8.88 (br s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.30–7.00 (m, 15H), 5.99 (m,
1H), 5.18 (dd, 1H, J = 1.6 and 15.4 Hz), 5.05 (dd, 1H, J = 1.6 and 11.8
Hz), 4.85 (m, 1H), 4.56 (t, 1H, J = 5.0 Hz), 4.13 (m, 2H), 3.40 (m, 1H),
3.29 (m, 1H, partially masked by water peak in DMSO-d6), 3.19 (m, 2H),
2.32 (m, 1H), 2.00 (m, 1H). IR (KBr, cm−1) 3284, 2980, 1710, 1615, 1448,
1221, 1105, 1041. HRMS Calcd for C31H31N5O2 (M+H)+ 506.2555. Found
506.2547.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-N-thiazolidinopurine
1
(5e). Using the general procedure, 4 gave 5e (40%). H NMR (DMSO-
d6): 8.39 (s, 1H), 8.22 (s, 1H), 7.30–7.00 (m, 15H), 5.12 (m, 1H), 4.91
(m, 1H), 4.31 (m, 2H), 3.50–3.10 (m, 8H), 2.34 (m, 1H), 2.02 (m, 1H).
IR (KBr, cm−1) 2931, 2877, 1691, 1582, 1456, 1218, 1032. HRMS Calcd for
C31H31N5O2S (M+H)+ 538.2276. Found 538.2262.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-N-azetidinopurine (5f).
Using the general procedure, 4 gave 5f (88%). 1H NMR (DMSO-d6): 8.26
(s, 1H), 8.12 (s, 1H), 7.30–7.00 (m, 15H), 4.85 (m, 1H), 4.54 (t, 1H, J =
4.9 Hz), 4.36 (m, 4H), 3.41 (m, 1H), 3.28 (m, 1H), 3.19 (m, 2H), 2.44 (m,
2H, partially masked by DMSO), 2.30 (m, 1H), 2.00 (m, 1H). IR (KBr, cm−1
)

Synthesis of Possible Antiviral Agents
1603
2934, 1589, 1465, 1296, 1221, 1072, 1049, 896. HRMS Calcd for C31H31N5O2
(M+H)+ 506.2555. Found 506.2531.
(
)-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-N-piperidinopurine
(5g). Using the general procedure, 4 gave 5g (22%). 1H NMR (DMSO-d6):
8.32 (s, 1H), 8.13 (s, 1H), 7.30–7.00 (m, 15H), 4.87 (m, 1H), 4.55 (t, 1H,
J = 5.0 Hz), 4.22 (m, 4H), 3.39 (m, 1H), 3.29 (m, 1H), 3.20 (m, 2H), 2.32
(m, 1H), 2.01 (m, 1H), 1.63 (m, 6H). IR (KBr, cm−1) 2849, 1584, 1444,
1338, 1248, 1048, 982. HRMS Calcd for C33H35N5O2 (M+H)+ 534.2868.
Found 534.2842.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-N-morpholinopurine
(5h). Using the general procedure, 4 gave 5h (22%). 1H NMR (DMSO-d6):
8.34 (s, 1H), 8.19 (s, 1H), 7.30–7.00 (m, 15H), 4.90 (m, 1H), 4.55 (t, 1H,
J = 4.9 Hz), 4.23 (m, 4H), 3.73 (m, 4H), 3.41 (m, 1H), 3.30 (m, 1H), 3.20
(m, 2H), 2.31 (m, 1H), 2.00 (m, 1H). IR (KBr, cm−1) 2853, 1580, 1444,
1251, 1111, 1066, 995. HRMS Calcd for C32H33N5O3 (M+H)+ 536.2661.
Found 536.2639.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-N-pyrrolidinopurine
(5i). Using the general procedure, 4 gave 5i (20%). 1H NMR (DMSO-d6):
8.32 (s, 1H), 8.14 (s, 1H), 7.30–7.00 (m, 15H), 4.86 (m, 1H), 4.55 (t, 1H,
J = 5.0 Hz), 4.09 (m, 2H), 3.66 (m, 2H), 3.43 (m, 1H), 3.28 (m, 1H), 3.18
(m, 2H), 2.30 (m, 1H), 1.95 (m, 5H). IR (KBr, cm−1) 2925, 1588, 1467,
1323, 1220, 972. HRMS Calcd for C32H33N5O2 (M+H)+ 520.2712. Found
520.2689.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-N-phenylaminopurine
(5j). Using the general procedure, 4 gave 5j (22%). 1H NMR (DMSO-d6):
9.90 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.40–7.00 (m, 20H), 4.90 (m, 1H),
4.60 (t, 1H, J = 4.8 Hz), 3.46 (m, 1H), 3.36 (m, 1H), 3.25 (m, 2H), 2.37
(m, 1H), 2.02 (m, 1H). IR (KBr, cm−1) 2926, 1615, 1576, 1468, 1437, 1364,
1218, 1050, 898. HRMS Calcd for C34H31N5O2 (M+H)+ 542.2555. Found
542.2543.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-cyclopentylaminopu-
rine (5k). Using the general procedure, 4 gave 5k (80%). 1H NMR (DMSO-
d6): 8.27 (s, 1H), 8.10 (s, 1H), 7.30–7.00 (m, 15H), 4.83 (m, 1H), 4.55 (t,
1H, J = 4.9 Hz), 3.40 (m, 1H), 3.29 (m, 1H, partially masked by D2O), 3.19
(m, 2H), 3.00 (m, 1H), 2.43 (m, 1H partially masked by DMSO), 2.32 (m,
1H), 2.00-41.97 (m, 2H), 1.63 (m, 6H). IR (KBr, cm−1) 2938, 1710, 1614,
1476, 1222, 1105, 1039. HRMS Calcd for C33H35N5O2 (M+H)+ 534.2868.
Found 534.2851.

1604
Y. El-Kattan et al.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-cyclopropylaminopu-
rine (5l). Using the general procedure, 4 gave 5l (88%). 1H NMR (DMSO-
d6): 8.28 (s, 1H), 8.16 (s, 1H), 7.88 (br s, 1H), 7.30–7.00 (m, 15H), 4.86 (m,
1H), 4.56 (t, 1H, J = 4.9 Hz), 3.41 (m, 1H), 3.30 (m, 1H, partially masked
water peak in DMSO-d6), 3.17 (m, 3H), 2.32 (m, 1H), 2.00 (m, 1H), 0.95
(m, 2H), 0.80 (m, 2H). IR (KBr, cm−1) 1615, 1575, 1473, 1353, 1214, 1050.
HRMS Calcd for C31H31N5O2 (M+H)+ 506.2555. Found 506.2539.
( )-9-[(1-Trityloxymethyl)(3-hydroxy)propyl]-6-cyclobutylaminopurine
1
(5m). Using the general procedure, 4 gave 5m (78%). H NMR (DMSO-
d6): 8.27 (s, 1H), 8.10 (s, 1H), 7.94 (m, 1H), 7.30–7.00 (m, 15H), 4.80 (m,
2H), 4.54 (t, 1H, J = 5.0 Hz), 3.40 (m, 1H), 3.30 (m, 1H, partially masked
by water peak in DMSO-d6), 3.20 (m, 2H), 2.16 (m, 6H), 1.66 (m, 2H).
IR (KBr, cm−1) 2929, 1612, 1575, 1471, 1219, 1048, 896. HRMS Calcd for
C32H33N5O2 (M+H)+ 520.2712. Found 520.2690.
GeneralProcedure for the Conversion of 5a-m to 6a-m
A solution of 5a-m in DMF (7.5 mL/mmol) was treated with sodium
hydride (4 eq.) at room temperature and the mixture stirred for 1 h. To
this solution was then added a solution of p-toluenesulfonyloxymethylphos-
phonate (1.2 eq.) in DMF (5 mL) and the mixture stirred at room temper-
ature for 24 h. The reaction mixture was diluted with ethyl acetate, neu-
tralized with acetic acid and washed with water 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 1:1:0.05) as an eluent to give the desired phos-
phonomethoxy derivatives.
The phosphonomethoxy derivative was taken in DMF (10 mL/mmol)
and treated with triethylamine (1 mL/mmol) followed by trimethylsilyl-
iodide (1.5 mL/mmol) and the reaction mixture flask covered with alu-
minum foil to protect from light and stirred for 14 h at room tempera-
ture. It was then diluted with 1 N tetraethylammonium bicarbonate buffer
(10 mL/mmol), water (30 mL/mmol) and chloroform (40 mL/mmol) and
was stirred for 1 h. The organic phase was collected and the aqueous phase
was re-extracted with chloroform and the combined organic phases 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 (1:0 to 0:1), as eluent to give the free phos-
phonates 6a-m.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-diethyl-
aminopurine (6a). Using the general procedure, 5a gave 6a (6%). 1H NMR

Synthesis of Possible Antiviral Agents
1605
(DMSO-d6): 8.29 (s, 1H), 8.08 (s, 1H), 7.30–7.00 (m, 15H), 4.80 (m, 1H),
3.95 (m, 4H), 3.50–3.10 (m, 6H), 2.33 (m, 1H), 2.04 (m, 1H), 1.22 (t, 6H,
J = 6.7 Hz). 31P NMR: 13.20. HRMS Calcd for C33H38N5O5P (M+H)+
616.2688. Found 616.2690.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-N-methyl-N-
ethylaminopurine (6b). Using the general procedure, 5b gave 6b (6.5%).
1H NMR (DMSO-d6): 8.30 (s, 1H), 8.11 (s, 1H), 7.30–7.00 (m, 15H), 6.10
(br s, 2H), 4.82 (m, 1H), 4.07 (m, 2H), 3.50–3.10 (m, 9H), 2.35 (m, 1H,
partially masked by DMSO-d6), 2.07 (m, 1H), 1.19 (t, 3H, J = 6.8 Hz).
31P NMR: 13.20. HRMS Calcd for C32H36N5O5P (M+H)+ 602.2532. Found
602.2518.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-ethylamino-
1
purine (6c). Using the general procedure, 5c gave 6c (11%). H NMR
(DMSO-d6): 8.29 (s, 1H), 8.08 (s, 1H), 7.87 (br s, 1H), 7.3–7.0 (m, 15H),
5.99 (m, 1H), 5.16 (dd, 1H, J = 1.7 and 17.1 Hz), 5.07 (dd, 1H, J = 1.7
and 17.0 Hz), 4.80 (m, 1H), 4.17 (m, 2H), 3.77 (m, 2H), 3.50–3.00 (m, 6H),
2.35 (m, 1H), 2.04 (m, 1H). 31P NMR: 13.19. HRMS Calcd for C32H34N5O5P
(M+H)+ 600.2375. Found 600.2370.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-allylamino-
1
purine (6d). Using the general procedure, 5d gave 6d (5.5%). H NMR
(DMSO-d6): 8.26 (s, 1H), 8.10 (s, 1H), 7.30–7.00 (m, 15H), 4.83 (m,
1H), 4.60 (br s, 2H), 4.08 (m, 2H), 3.65 (m, 2H), 3.48 (m, 1H), 3.30–3.00
(m, 5H), 2.30 (m, 1H), 1.93 (m, 5H). 31P NMR: 13.38. HRMS Calcd for
C33H36N5O5P (M+H)+ 614.2532. Found 614.2551.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-N-thiazoli-
dinopurine (6e). Using the general procedure, 5e gave 6e (6%). 1H NMR
(DMSO-d6): 8.39 (s, 1H), 8.18 (s, 1H), 7.30–7.00 (m, 15H), 5.12 (m, 2H),
4.88 (m, 1H),4.60 (br s, 2H), 4.30 (m, 2H), 3.50 (m, 1H), 3.18 (m, 7H),
2.35 (m, 1H, partially masked by DMSO-d6), 2.07 (m, 1H). 31P NMR: 13.03.
HRMS Calcd for C32H34N5O5SP (M+H)+ 632.2096. Found 632.2094.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-N-azetidi-
1
nopurine (6f). Using the general procedure, 5f gave 6f (6.5%). H NMR
(DMSO-d6): 8.35 (s, 1H), 8.15 (s, 1H), 7.30–7.00 (m, 15H), 5.30 (br s,
2H), 4.86 (m, 1H), 4.23 (m, 4H), 3.72 (m, 4H), 3.48 (m, 1H), 3.40–3.10
(m, 5H), 2.35 (m, 1H), 2.05 (m, 1H). 31P NMR: 13.19. HRMS Calcd for
C33H36N5O6P (M+H)+ 630.2481. Found 630.2507.

1606
Y. El-Kattan et al.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-N-piperidi-
1
nopurine (6g). Using the general procedure, 5g gave 6g (9%). H NMR
(DMSO-d6): 8.30 (s, 1H), 8.10 (s, 1H), 7.30–7.00 (m, 15H), 4.83 (m,
1H), 4.60 (br s, 2H), 4.21 (m, 4H), 3.46 (m, 1H), 3.40–3.00 (m, 5H), 2.35
(m, 1H), 2.06 (m, 1H), 1.64 (m, 6H). 31P NMR: 13.15. HRMS Calcd for
C34H38N5O5P (M+H)+ 628.2688. Found 628.2685.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-N-morpho-
linopurine (6h). Using the general procedure, 5h gave 6h (6%). 1H NMR
(DMSO-d6): 8.28 (s, 1H), 8.09 (s, 1H), 7.30–7.00 (m, 15H), 4.82 (m, 1H),
4.60 (br s, 2H), 4.37 (m, 2H), 3.48 (m, 1H), 3.28 (m, 1H), 3.14 (m, 4H),
2.46 (m, 2H, partially masked by DMSO-d6), 2.30 (m, 1H), 2.04 (m, 1H).
31P NMR: 13.05. HRMS Calcd for C32H34N5O5P (M+H)+ 600.2375. Found
600.2369.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-N-pyrrolidi-
1
nopurine (6i). Using the general procedure, 5i gave 6i (10%). H NMR
(DMSO-d6): 8.27 (s, 1H), 8.15 (s, 1H), 7.3–7.0 (m, 15H), 4.83 (m, 1H),
4.51 (br s, 2H), 4.10 (m, 2H), 3.65 (m, 2H), 3.52 (m, 1H), 3.3–3.0 (m, 5H),
2.38 (m, 1H), 2.0 (m, 5H). 31P NMR: 13.64. HRMS Calcd for C33H36N5O5P
(M+H)+ 614.2532. Found 614.2551.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-N-phenyl-
aminopurine (6j). Using the general procedure, 5j gave 6j (5.5%). 1H NMR
(DMSO-d6): 9.86 (br s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 7.40–7.00 (m, 20H),
5.20 (br s, 2H), 4.91 (m, 1H), 3.51 (m, 1H), 3.21 (m, 5H), 2.36 (m, 1H),
2.08 (m, 1H). 31P NMR: 13.27. HRMS Calcd for C35H34N5O5P (M+H)+
636.2375. Found 636.2364.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-cyclopentyl-
aminopurine (6k). Using the general procedure, 5k gave 6k (10%) in
ppm (DMSO-d6): 8.26 (s, 1H), 8.05 (s, 1H), 7.58 (br s, 1H), 7.30–7.00 (m,
15H), 4.81 (m, 1H), 4.53 (m, 2H), 3.50–3.00 (m, 6H), 2.35 (m, 2H), 1.95
(m, 2H), 1.63 (m, 6H). 31P NMR: 13.91.
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-cyclopro-
1
pylaminopurine (6l). Using the general procedure, 5l gave 6l (6.5%). H
NMR (DMSO-d6): 8.29 (s, 1H), 8.13 (1H), 7.80 (br s, 1H), 7.30–7.00 (m,
15H), 4.82 (m, 1H), 4.50 (br s, 2H), 3.46 (m, 3H), 3.30–3.10 (m, 4H),
2.35 (m, 1H, partially masked by DMSO-d6), 2.05 (m, 1H), 0.70 (m, 4H).
31P NMR: 12.75. HRMS Calcd for C32H34N5O5P (M+H)+ 600.2373. Found
600.2378.

Synthesis of Possible Antiviral Agents
1607
( )-9-[(1-Trityloxymethyl)(3-phosphonomethoxy)propyl]-6-cyclobutyl-
aminopurine (6m). Using the general procedure, 5m gave 6m (6.5%). 1H
NMR (DMSO-d6): 8.29 (s, 1H), 8.07 (s, 1H), 7.96 (br s, 1H), 7.30–7.00
(m, 15H), 5.00 (br s, 2H), 4.79 (m, 2H), 3.45 (m, 1H), 3.30 (m, 1H), 3.15
(m, 4H), 2.36–2.00 (m, 6H), 1.66 (m, 2H). 31P NMR: 12.94. HRMS Calcd
for C33H36N5O5P (M+H)+ 614.2532. Found 614.2538.
GeneralProcedure for the Conversion of 6a-m to 7a-m
A solution of 6a-m in DMF (10 mL/mmol) was treated with triethyl-
amine (12 mL/mmol) followed by chloromethyl pivalate or chloromethyl-
2-propylcarbonate (25 eq.) and stirred for 2 days at room temperature. The
mixture was then diluted with ethyl acetate and washed with water and the
organic layer was dried over MgSO4. After filtration, the filtrate was con-
centrated and the residue purified on a silica gel column using chloroform:
methanol (100:0 to 95:5) as eluent to give diprotected prodrugs of phospho-
nic acids. The resultant prodrugs were taken in acetonitrile:0.2 M HCl (1:1,
10 mL/mmol) and stirred for 14 h at room temperature. The solution was
then very carefully neutralized with Et3N to pH 6.0, diluted with water, and
concentrated to remove most of the organic solvent. The residual material
was again diluted with water and extracted with chloroform and the organic
layer was dried over MgSO4. After filtration, the filtrate was concentrated
and the residue purified on a silica gel column using chloroform:methanol
(1:0 to 9:1) as eluent to give the desired targets 7a-m as colorless oil.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-diethylaminopurine (7a). Using the general pro-
cedure, 6a gave 7a (46%). 1H NMR (DMSO-d6): 8.16 (s, 1H), 8.10 (s, 1H),
5.56 (m, 4H), 5.04 (t, 1H, J = 5.3 Hz), 4.80 (m, 2H), 4.58 (m, 1H), 4.10 (m,
4H), 3.83 (m, 3H), 3.66 (m, 1H), 3.45 (m, 1H), 3.30 (m, 1H partially masked
by water in DMSO-d6), 2.17 (m, 2H), 1.21 (m, 18H). 31P NMR: 22.83. MS
(ES+) 606.66 (M+H)+. Anal. Calcd for C24H40N5O11P 0.25 H2O: C, 47.25;
H, 6.69; N, 11.47. Found: C, 47.10; H, 6.85; N, 11.28.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-N-methyl-N-ethylaminopurine (7b). Using the
general procedure, 6b gave 7b (20%). 1H NMR (DMSO-d6): 8.17 (s, 1H),
8.11 (s, 1H), 5.59 (m, 4H), 5.05 (t, 1H, J = 5.4 Hz), 4.80 (m, 2H), 4.59
(m, 1H), 4.05 (m, 2H), 3.82 (m, 3H), 3.66 (m, 1H), 3.40 (m, 2H), 2.49 (s,
3H, partially masked by DMSO-d6), 2.17 (m, 2H), 1.24 (m, 15H). 31P NMR:
22.80. MS (ES+) 592.08 (M+H)+. Anal. Calcd for C23H38N5O11P 0.5 H2O:
C, 45.99; H, 6.54; N, 11.66. Found: C, 46.22; H, 6.57; N, 11.36.

1608
Y. El-Kattan et al.
( )-9-[(1-Hydroxymethyl)(3-(di-tert-butylcarbonyloxymethylphosphono)
methoxy)propyl]-6-ethylaminopurine (7c). Using the general procedure,
6c gave 7c (31%).1H NMR (DMSO-d6): 8.14 (s, 1H), 8.08 (s, 1H), 7.71 (br
s, 1H), 5.60 (m, 4H), 5.04 (t, 1H, J = 5.4 Hz), 4.55 (m, 1H), 3.82 (m, 3H),
3.70 (m, 1H), 3.48 (m, 3H), 3.29 (m, 1H partially masked by water peak in
DMSO-d6), 2.18 (m, 2H), 1.13 (m, 21H). 31P NMR: 22.87. MS (ES+) 596.31
(M + Na)+.
( )-9-[(1-Hydroxymethyl)(3-(di-tert-butylcarbonyloxymethylphosphono)
methoxy)propyl]-6-allylaminopurine (7d). Using the general procedure,
1
6d gave 7d (32%). H NMR (DMSO-d6): 8.15 (s, 1H), 8.10 (s, 1H), 7.89
(br s, 1H), 5.93 (m, 1H), 5.59 (m, 4H), 5.14 (m, 1H), 5.05 (m, 2H), 4.56
(m, 1H), 4.10 (m, 2H), 3.82 (m, 3H), 3.69 (m, 1H), 3.45 (m, 1H), 3.29
(m, 1H partially masked by water peak in DMSO-d6), 2.19 (m, 2H), 1.17
(m, 18H). 31P NMR: 22.87. MS (ES+) 608.33 (M + Na)+. Anal. Calcd for
C25H40N5O9P: C, 50.45; H, 6.76; N, 11.72. Found: C, 50.45; H, 7.14; N, 11.03.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-N-thiazolidinopurine (7e). Using the general
1
procedure, 6e gave 7e (27%). H NMR (DMSO-d6): 8.26 (s, 1H), 8.21
(s, 1H), 5.57 (m, 4H), 5.05 (m, 2H), 4.81 (m, 2H), 4.61 (m, 1H), 4.28
(m, 2H), 3.83 (m, 3H), 3.70 (m, 1H), 3.45 (m, 1H), 3.29 (m, 2H partially
masked by water peak in DMSO-d6), 3.12 (m, 2H), 2.20 (m, 2H), 1.22
(m, 12H). 31P NMR: 22.80. MS (ES+) 622.08 (M+H)+. Anal. Calcd for
C23H36N5O11PS 0.5 H2O: C, 43.80; H, 5.91; N, 11.10. Found: C, 44.58; H,
6.10; N, 10.67.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-N-azetidinopurine (7f). Using the general pro-
cedure, 6f gave 7f (24%). 1H NMR (DMSO-d6): 8.15 (s, 1H), 8.09 (s, 1H),
5.58 (m, 4H), 5.04 (t, 1H, J = 5.4 Hz), 4.81 (m, 2H), 4.56 (m, 1H), 4.33 (m,
4H), 3.83 (m, 3H), 3.70 (m, 1H), 3.43 (m, 1H), 3.27 (m, 1H partially masked
by water in DMSO-d6), 2.42 (m, 2H), 2.16 (m, 2H), 1.23 (m, 12H). 31P NMR:
22.79. MS (ES+) 590.04 (M+H)+. Anal. Calcd for C23H36N5O11P 0.75 H2O:
C, 45.80; H, 6.26; N, 11.61. Found: C, 45.96; H, 6.44; N, 11.25.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-N-piperidinopurine (7g). Using the general pro-
1
cedure, 6g gave 7g (43%). H NMR (DMSO-d6): 8.16 (s, 1H), 8.11 (s,
1H), 5.57 (m, 4H), 5.04 (t, 1H, J = 5.4 Hz), 4.81 (m, 2H), 4.59 (m, 1H),
4.19 (m, 4H), 3.83 (m, 3H), 3.68 (m, 1H), 3.43 (m, 1H), 3.29 (m, 1H par-
tially masked by water in DMSO-d6), 2.19 (m, 2H), 1.70–1.30 (m, 6H), 1.23
(m, 12H). 31P NMR: 22.81. MS (ES+) 618.34 (M+H)+. Anal. Calcd for

Synthesis of Possible Antiviral Agents
1609
C25H40N5O11P 0.75 H2O: C, 47.57; H, 6.62; N, 11.09. Found: C, 47.86; H,
6.56; N, 10.62.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-N-morpholinopurine (7h). Using the general
1
procedure, 6h gave 7h (18%). H NMR (DMSO-d6): 8.22 (s, 1H), 8.17
(s, 1H), 5.57 (m, 4H), 5.04 (t, 1H, J = 5.3 Hz), 4.81 (m, 2H), 4.60 (m,
1H), 4.19 (m, 4H), 3.83 (m, 3H), 3.71 (m, 5H), 3.43 (m, 1H), 3.29 (m, 1H
partially masked by water in DMSO-d6), 2.18 (m, 2H), 1.23 (m, 12H). 31P
NMR: 22.79. MS (ES+) 620.29 (M+H)+. Anal. Calcd for C24H38N5O12P 0.5
H2O: C, 45.85; H, 6.25; N, 11.14. Found: C, 46.05; H, 6.21; N, 10.42.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-N-pyrrolidinopurine (7i). Using the general
1
procedure, 6i gave 7i (28%). H NMR (DMSO-d6): 8.16 (s, 1H), 8.08
(s, 1H), 5.58 (m, 4H), 5.05 (t, 1H, J = 5.4 Hz), 4.81 (m, 2H), 4.58 (m,
1H), 4.05 (m, 2H), 3.83 (m, 3H), 3.67 (m, 3H), 3.43 (1H), 3.28 (m, 1H
partially masked by water peak in DMSO-d6), 2.19 (m, 2H), 1.94 (m, 4H),
1.22 (m, 12H). 31P NMR: 22.78. MS (ES+) 604.29 (M+H)+. Anal. Calcd for
C24H38N5O11P 0.5 CHCl3: C, 44.99; H, 5.94; N, 10.75. Found: C, 45.09; H,
6.03; N, 10.16.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-N-phenylaminopurine (7j). Using the general
1
procedure, 6j gave 7j (31%). H NMR (DMSO-d6): 9.84 (br s, 1H), 8.32
(s, 1H), 8.30 (s, 1H), 7.94 (m, 2H), 7.31 (m, 2H), 7.02 (m, 1H), 5.58 (m,
4H), 5.07 (t, 1H, J = 5.3 Hz), 4.80 (m, 2H), 4.63 (m, 1H), 3.84 (m, 3H),
3.73 (m, 1H), 3.46 (m, 1H), 3.29 (m, 1H partially masked by water peak in
DMSO-d6), 2.21 (m, 2H), 1.21 (m, 12H). 31P NMR: 22.81. MS (ES+) 626.23
(M+H)+. Anal. Calcd for C26H36N5O11P H2O: C, 48.52; H, 5.95; N, 10.88.
Found: C, 48.66; H, 5.89; N, 10.39.
( )-9-[(1-Hydroxymethyl)(3-(di-tert-butylcarbonyloxymethylphosphono)
methoxy)propyl]-6-cyclopentylaminopurine (7k). Using the general proce-
1
dure, 6k gave 7k (45%). H NMR (DMSO-d6): 8.14 (s, 1H), 8.08 (s, 1H),
7.60 (br s, 1H), 5.58 (m, 4H), 5.04 (t, 1H, J = 5.4 Hz), 4.54 (m, 2H), 3.78 (m,
3H), 3.68 (m, 1H), 3.42 (m, 1H), 3.29 (m, 1H partially masked by water in
DMSO-d6), 2.17 (m, 2H), 1.90 (m, 2H), 1.80–1.50 (m, 6H), 1.12 (m, 18H).
31P NMR: 22.88. MS (ES+) 614.44 (M+H)+. Anal. Calcd for C27H44N5O9P:
C, 50.53; H, 7.04; N, 10.83. Found: C, 50.64; H, 7.12; N, 10.44.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-cyclopropylaminopurine (7l). Using the general

1610
Y. El-Kattan et al.
procedure, 6l gave 7l (7%). 1H NMR (CDCl3): 8.38 (s, 1H), 7.89 (s, 1H),
6.20 (br s, 1H), 5.71 (m, 5H), 4.92 (m, 2H), 4.71 (m, 1H), 4.08 (m, 2H),
3.84 (m, 2H), 3.65 (m, 1H), 3.23 (m, 1H), 3.02 (br s, 1H), 2.27 (m, 2H), 1.29
(m, 12H), 0.94 (m, 2H), 0.66 (m, 2H). 31P NMR: 22.69. MS (ES+) 590.19
(M+H)+.
( )-9-[(1-Hydroxymethyl)(3-(di-isopropyloxycarbonyloxymethylphos-
phono)methoxy)propyl]-6-cyclobutylaminopurine (7m). Using the general
1
procedure, 6m gave 7m (29%). H NMR (DMSO-d6): 8.14 (s, 1H), 8.10
(s, 1H), 7.95 (br s, 1H), 5.58 (m, 4H), 5.04 (t, 1H, J = 5.3 Hz), 4.80 (m,
2H), 4.60 (m, 2H), 3.84 (m, 3H), 3.68 (m, 1H), 3.44 (m, 1H), 3.27 (m, 1H
partially masked by water peak in DMSO-d6), 2.15 (m, 6H), 1.64 (m, 2H),
1.24 (m, 12H). 31P NMR: 22.81. MS (ES+) 604.13 (M+H)+. Anal. Calcd for
C24H38N5O11P 0.75 H2O: C, 46.71; H, 6.45; N, 11.34. Found: C, 47.14; H,
6.65; N, 11.04.
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