Synthesis and biological evaluation of novel tert-azido or ten-amino substituted penciclovir analogs

Article abstract of DOI:10.1039/b401100g

tert-Azido or amino substituted penciclovir analogs, 1-3 were synthesized for the purpose of improving the efficacy and bioavailability of penciclovir and searching for novel antiviral agents. Among several methods attempted to insert an azido group into

Full text of DOI:10.1039/b401100g

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Synthesis and biological evaluation of novel tert-azido or
tert-amino substituted penciclovir analogs
Hea Ok Kim,a Hye Won Baek,a Hyung Ryong Moon,b Dae-Kee Kim,a Moon Woo Chunc and
Lak Shin Jeong*a
a Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea. E-mail: lakjeong@ewha.ac.kr; Fax: 822 3277 2851; Tel: 822 3277 3466
b College of Pharmacy, Pusan National University, Pusan 609-735, Korea
c College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Received 23rd January 2004, Accepted 23rd February 2004
First published as an Advance Article on the web 16th March 2004
tert-Azido or amino substituted penciclovir analogs, 1–3 were synthesized for the purpose of improving the efficacy
and bioavailability of penciclovir and searching for novel antiviral agents. Among several methods attempted to
insert an azido group into the α,β-unsaturated ester 6, only Brønsted acid-catalysed 1,4-conjugate addition
conditions (NaN3, 75% acetic acid, 80 ЊC) gave the desired tert-azido product 7. The synthesized final penciclovir
analogs 1–3 were evaluated in vitro against several viruses such as HIV-1, HSV-1 and 2, poliovirus, VZV,
and VSV. Compound 2 only showed weak antiviral activity against HSV-1 without cytotoxicity. Although the
synthesized compounds did not exhibit an excellent antiviral activity, the successful method used in introducing
the tert-azido group is expected to be generally utilized for the synthesis of nucleoside analogs with a tert-azido
substituent.
replaced by their oral prodrugs, valaciclovir,5 valganciclovir6
Introduction
and famciclovir,7 respectively. Improvement of oral bio-
availability of their prodrugs results from an increase of their
lipophilicity by protection of their hydroxyl groups and/or
removal of the 6-oxo group of guanine base. The diacetyl-6-
deoxy derivative of penciclovir, famciclovir can be quickly
absorbed due to its increased lipophilicity and sequentially
deacetylated in the intestine wall and liver to afford 6-deoxy-
penciclovir, which, in turn, can be oxidized by xanthine oxidase
in the liver to give rise to the parent drug, penciclovir.8 It is of
interest to note that all of acyclovir, ganciclovir and penciclovir
retain the guanine base and have been found to selectively
inhibit the replication of HSV-1 and 2, VZV and other herpes
viruses (HCMV and Epstein–Barr virus) and to have a poor
bioavailability.
Acyclonucleosides1 such as acyclovir,2 ganciclovir3 and penci-
clovir4 exhibit several potent antiviral activities (Fig. 1).
A number of azido- and fluoro-substituted nucleoside deriv-
atives have been reported to have potent antiviral activities:
-FIAC9 [1-(2-deoxy-2-fluoro-β--arabinofuranosyl)-5-iodo-
cytosine] and -FMAU9 [1-(2-deoxy-2-fluoro-β--arabino-
furanosyl)thymine] (anti-HSV activity), -FIAU9 (anti-HSV
activity and anti-HBV activity), -FLT10 (-2Ј,3Ј-dideoxy-3Ј-
fluorothymidine) (anti-HIV-1 activity), -FMAU11 (anti-HBV
activity, undergoing clinical trials), and AZT12 (3-azido-2Ј,3Ј-
dideoxythymidine) (anti-HIV-1 activity). In particular,
ADRT13 in which an azido functional group is introduced at
the 4Ј-position (tert-position) showed a significant anti-HIV
activity (Fig. 1). Also among tert-fluoro substituted nucleoside
analogs, nucleocidin14 showed antibacterial activity and tert-
fluoro substituted penciclovir15 has been reported to exhibit
potent anti-herpes viruses and anti-HIV activities. Thus, sub-
stitution at the 4Ј-position in nucleosides is also important for
the exhibition of potent biological activities.
As a part of our efforts to search for novel antiviral agents
with good bioavailability as well as potent antiviral activity,
it was interesting to synthesize tert-azido or tert-amino
substituted penciclovir analogs 1–3. Herein, we wish to report
the synthesis of novel tert-azido and tert-amino substituted
acyclic nucleoside analogs, using Brønsted acid-catalysed 1,4-
conjugate addition for the introduction of an azido group
to the α,β-unsaturated ester as a key step and their antiviral
activities.
Fig. 1 The rationale for the design of the target nucleosides.
Acyclovir has become the drug of choice for the treatment
of HSV-1 and 2 (herpes simplex virus type 1 and 2) and VZV
(varicella–zoster virus) infections as a potent and selective
inhibitor and ganciclovir, a homolog of acyclovir, has become
the drug of choice for the treatment of HCMV (human cyto-
megalovirus) infections, particularly HCMV retinitis which
causes blindness in AIDS patients.
Penciclovir in which the ethereal oxygen of ganciclovir is
replaced by a carbon atom showed anti-HBV (hepatitis B virus)
activity as well as a similar activity spectrum to acyclovir i.e.,
anti-HSV-1 and 2 and anti-VZV activities and was currently
approved for the treatment of VZV infection by the FDA (Food
and Drug Administration). However, because of their poor oral
bioavailability, acyclovir, ganciclovir and penciclovir have been
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 6 4 – 1 1 6 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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of NaN3 under Brønsted acid-catalysed 1,4-conjugate addition
Results and discussion
conditions (75% aqueous acetic acid, 80 ЊC)19 gave β-tert-azido
product 7 in excellent yield. Reduction of the azido compound
7 with Dibal-H at Ϫ78 ЊC followed by reduction of the resulting
aldehyde with NaBH4 gave the desired tert-azido alcohol 9
(66%) and the allylic alcohol 8 (3%), resulting from the elimin-
ation of tert-azido group. Treatment of 9 with mesyl chloride
and pyridine afforded the corresponding mesylate 10 in
quantitative yield, which was ready for the condensation with
nucleobase.
Chemistry
A strategy for the synthesis of tert-azido and tert-amino sub-
stituted acyclic nucleoside analogs 1–3 is outlined in Scheme 1.
Condensation of mesylate 10 with 2-amino-6-chloropurine
in the presence of NaH in DMF at 50 ЊC gave many spots on
TLC. However, coupling of mesylate 10 with 2-amino-6-chloro-
purine in the presence of potassium carbonate in DMF at
60 ЊC produced the N-9 isomer 11 as a major product (79%)
along with N-7 isomer 12 (9%) as seen in Scheme 3. The regio-
isomers were easily assigned based on the comparison with UV
literature data20. Deprotection of the benzyl group with excess
BBr3 (10 equiv) finally produced the desired tert-azido sub-
stituted 2-amino-6-chloropurine derivative 1 in 83% yield,
while treatment with BCl3 (10 equiv) gave a mixture of the
desired product 1 and partially debenzylated product. Azido
substituted 2-amino-6-chloropurine derivative 1 was converted
to its guanosine analog 2 by hydrolysis with 0.5 M NaOH and
tertiary amino substituted 2-aminopurine nucleoside analog 3
using catalytic hydrogenation.
Scheme 1 Retrosynthetic analysis of the target nucleosides with tert-
azido or tert-amino substituent.
It was envisioned that α,β-unsaturated ester 6 derived from
2-methylene-propane-1,3-diol could be an appropriate inter-
mediate to introduce an azido functionality at the β position.
The resultant tert-azido compound could be reduced and
condensed with a nucleobase to afford the target nucleoside
analogs 1–3.
Biological evaluation
Antiviral assays21 against HIV-1, HSV-1 and 2, poliovirus,
HCMV, VZV, and VSV were performed on the final nucleoside
analogs 1–3. Compound 1 showed toxicity-induced anti-HIV-1
activity (EC50 = 81.32 µg cmϪ3) and exhibited neither anti-
viral activity nor cytotoxicity in other viruses. Compound 2
Synthesis of the protected tert-azido substituted acyclic
glycosyl donor 10 is shown in Scheme 2.
Benzyl ether derivative 416 was derived from a commercially
available 2-methylene-propane-1,3-diol in quantitative yield.
Oxidative cleavage of compound 4 employing OsO4 and NaIO4
in acetone and H2O (4 : 1) gave 517 in moderate yield (51%),
while ozonolysis afforded the same ketone 5 in higher yield
(82%). Horner–Emmons olefination of 5 using triethyl phos-
phonoacetate and NaH gave α,β-unsaturated ester 617, which
would be an appropriate intermediate to insert an azido group
into the β-position. As seen in Scheme 2, several methods to
introduce an azido group18 were attempted. Base-catalysed
1,4-conjugate addition (TMSN3/Et3N in benzene) or Lewis
acid-catalysed 1,4-conjugate addition (TMSN3/Et2AlCl in THF
and TMSN3/BF3ؒOEt2 in THF) at various temperatures and
reaction times failed to give the desired product, while reaction
of α,β-unsaturated ethyl ester 6 with large excess amounts
exhibited a weak anti-HSV-1 activity (EC50 = 68.30 µg cmϪ3
)
without cytotoxicity up to 100 µg cmϪ3 and showed neither
antiviral activity nor cytotoxicity in other viruses. It is
speculated that lack of antiviral activity may be attributed to
their poor affinity to viral or cellular nucleoside and/or
nucleotide kinases.
Conclusion
We synthesized penciclovir analogs 1–3 with a tert-azido or tert-
amino substituent, starting from 2-methylene-propane-1,3-diol.
Introduction of the tert-azido substituent was successfully
achieved employing Brønsted acid-catalysed 1,4-conjugate add-
Scheme 2 Reagents and conditions: (a) BnBr, n-Bu4NI, NaH, DMF, 40 ЊC, overnight; (b) O3, MeOH, Ϫ78 ЊC, 2 h; (c) (EtO)2POCH2CO2Et, NaH,
THF, rt, 1 h; (d) i) Dibal-H, CH2Cl2, Ϫ78 ЊC, 2 h; ii) NaBH4, EtOH, Ϫ20 ЊC, 15 min; (e) MeSO2Cl, pyridine, 0 ЊC, 15 min.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 6 4 – 1 1 6 8
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Scheme 3 Reagents and conditions: (a) 2-amino-6-chloropurine, K2CO3, DMF, 60 ЊC, overnight; (b) BBr3 (10 equiv), CH2Cl2, Ϫ78 ЊC, 1 h; (c) 0.5 M
NaOH, 80 ЊC, overnight; (d) H2, Pd/C, MeOH, rt, 3 h.
ition conditions. Although the synthesized nucleoside analogs
did not exhibit good antiviral activity, the insertion method for
introducing a tert-azido group will be of great help in synthesiz-
ing many nucleoside analogs with tert-azido substituents.
to give ketone 5 (4.328 g, 82%) as a colorless syrup along with
recovered starting material (880 mg, 17%). Rf = 0.29 (hexane/
ethyl acetate = 5 : 1); (Found: C, 75.9; H, 6.9. Calc. for
C17H18O3: C, 75.5; H, 6.7%); δH (400 MHz; CDCl3) 4.24 (4 H,
s, 2 × BnOCH2), 4.57 (4 H, s, 2 × PhCH2), 7.31–7.36 (10 H, m,
2 × Ph).
Experimental
Materials and methods
4-Benzyloxy-3-benzyloxymethyl-but-2-enoic acid ethyl ester
(6).17 Compound 5 (1.016 g, 3.76 mmol) was converted to com-
pound 6 (1.105 g, 86%) according to the reported procedure.17
Ultraviolet (UV) spectra were recorded on a Beckman DU-68
1
spectrophotometer. H and 13C NMR spectra were recorded
on a Varian-400 spectrometer, using CDCl3, DMSO-d6 or
CD3OD and chemical shifts are reported in parts per million
(ppm) downfield from tetramethylsilane as internal standard.
Elemental analyses were performed by the general instrument
laboratory of Ewha Womans University, Korea. IR spectra
were recorded on a Bio-RAD FTS-135-IR spectrophotometer.
TLC was performed on Merck precoated 60F254 plates. Column
chromatography was performed using silica gel 60 (230–400
mesh, Merck). All the anhydrous solvents were distilled over
CaH2 or P2O5 or Na/benzophenone prior to use.
3-Azido-4-benzyloxy-3-benzyloxymethyl-butyric acid ethyl
ester (7). To a stirred solution of ethyl ester 6 (1.105 g, 3.25
mmol) in glacial acetic acid (22.5 cm3) and distilled water
(7.5 cm3) was added NaN3 (8.44 g, 129.84 mmol) and the reac-
tion mixture was heated at 80 ЊC for 7 d. After removal of a
large part of the solvent under reduced pressure, the residue
was partitioned between CH2Cl2 and H2O. The organic layer
was successively washed with saturated aqueous NaHCO3
solution and brine, dried over anhydrous MgSO4, filtered and
evaporated. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 10 : 1) to give azido
ester 7 (1.102 g, 89%) as a colorless syrup. Rf = 0.5 (hexane/ethyl
acetate = 5 : 1); (Found: C, 65.9; H, 6.9; N, 11.2. Calc. for
C21H25N3O4: C, 65.8; H, 6.6; N, 11.0%); νmax(film)/cmϪ1 2116
(N3); δH (400 MHz; CDCl3) 1.23 (3 H, t, J 7.2, CH3), 2.70 (2 H,
s, CH2CO2Et), 3.66 (2 H, d, J 9.2, 2 × BnOCHH), 3.72 (2 H, d,
J 9.2, BnOCHH ), 4.10 (2 H, q, J 7.2, OCH2CH3), 4.55 (4 H, s,
2 × PhCH2), 7.28–7.34 (10 H, m, 2 × Ph).
1,3-Bis-benzyloxy-2-methylene-propane (4).16 To a stirred
solution of NaH (2.9 g, 70.40 mmol, 60% in mineral oil) in
DMF (10 cm3) were added a solution of 2-methylene-propane-
1,3-diol (2.215 g, 25.14 mmol) in DMF (5 cm3), benzyl bromide
(8.4 cm3, 70.40 mmol) and n-tetrabutylammonium iodide
(2.8 g, 7.54 mmol) and the reaction mixture was stirred at 40 ЊC
overnight. The reaction mixture was partitioned between ether
and brine and the organic layer was washed with brine, dried
over anhydrous MgSO4, filtered and evaporated. The resulting
residue was purified by flash column chromatography (hexane/
ethyl acetate = 4 : 1) to give benzyl ether 4 (7.64 g, 100%) as a
colorless syrup. Rf = 0.8 (hexane/ethyl acetate = 2 : 1); δH (400
MHz; CDCl3) 4.06 (4 H, t, J 1.2, 2 × BnOCH2), 4.51 (4 H, s, 2 ×
PhCH2), 5.26 (2 H, t, J 1.2, vinylic CH2), 7.32 (10 H, m, 2 × Ph).
4-Benzyloxy-3-benzyloxymethyl-but-2-en-1-ol (8) and 3-
azido-4-benzyloxy-3-benzyloxymethyl-butan-1-ol (9). To
a
stirred solution of azido ester 7 (460 mg, 1.2 mmol) in
anhydrous CH2Cl2 (10 cm3) at Ϫ78 ЊC was added Dibal-H
(2.5 cm3, 2.5 mmol, 1.0 M solution in toluene) and the reaction
mixture was stirred at Ϫ78 ЊC for 2 h. After the mixture was
quenched with methanol (2.5 cm3) and stirred for 10 min at
Ϫ78 ЊC, saturated aqueous Na, K-tartrate solution and CH2Cl2
were added. The organic layer was washed with brine, dried
over MgSO4, filtered and evaporated. The crude aldehyde,
without further purification, was reduced by treatment with
NaBH4 (78.0 mg, 2.0 mmol) in ethanol (20 cm3) at Ϫ20 ЊC for
15 min. After neutralization with acetic acid followed by con-
centration of the solvent under reduced pressure, the residue
was dissolved in CH2Cl2, washed with brine, dried over MgSO4,
filtered and evaporated. The resulting residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate =
4 : 1) to give azido alcohol 9 (270 mg, 66%) as a colorless syrup
and elimination product 8 (12 mg, 3%) as a syrup.
1,3-Bis-benzyloxy-propan-2-one (5).17 To a stirred solution of
olefin 4 (6.12 g, 22.81 mmol) in anhydrous MeOH (175 cm3)
was added O3 gas at Ϫ78 ЊC, and the reaction mixture was
stirred at the same temperature for 2 h. When the blue color of
the reaction mixture had disappeared, O3 gas supply was ceased
and O2 gas was bubbled into the mixture. The mixture was
warmed to room temperature and dimethyl sulfide (16.7 cm3,
228.1 mmol) was added to remove excess ozone. The solvent
was removed under reduced pressure to give the residue, which
was partitioned between EtOAc and brine. The organic layer
was washed with brine, dried over anhydrous MgSO4, filtered,
and evaporated. The resulting residue was purified by flash
silica gel column chromatography (hexane/ethyl acetate = 25 : 1)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 6 4 – 1 1 6 8
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Compound 8: Rf = 0.18 (hexane/ethyl acetate = 2 : 1); δH (400
MHz; CDCl3) 1.89 (1 H, t, J 5.6, OH), 4.05 (2 H, s, BnOCH2),
4.11 (2 H, s, BnOCH2), 4.22 (2 H, t, J 5.6, CH2OH), 4.51 (2 H, s,
PhCH2), 4.51 (2 H, s, PhCH2), 5.96 (1 H, t, J 6.4, vinylic H),
7.28–7.36 (10 H, m, 2 × Ph).
Compound 9: (Found: C, 66.9; H, 6.6; N, 12.2. Calc. for
C19H23N3O3: C, 66.8; H, 6.8; N, 12.3%); νmax(film)/cmϪ1 2109
(N3); δH (400 MHz, CDCl3) 1.85 (2 H, t, J 6.0, CH2CH2OH),
2.52 (1 H, t, J 6.0, OH), 3.62 (4 H, s, 2 × BnOCH2), 3.72 (2 H, q,
J 6.0, CH2OH), 4.56 (4 H, s, 2 × PhCH2), 7.30–7.35 (10 H, m,
2 × Ph).
solid. Rf = 0.8 (methylene chloride/methanol = 2 : 1); mp 186–
187 ЊC; (Found: C, 38.2; H, 4.3; N, 35.55. Calc. for C10H13-
ClN8O2: C, 38.4; H, 4.2; N, 35.8%); λmax(MeOH)/nm 310;
νmax(film)/cmϪ1 2110 (N3); δH (400 MHz; DMSO-d6) 1.95 (2 H,
t, J 8.0, CH2CH2N), 3.52 (2 H, d, J 11.2, 2 × HOCHH), 3.56
(2 H, d, J 7.6, 2 × HOCHH ), 4.14 (2 H, t, J 7.6, CH2N), 6.88
(2 H, s, NH2), 8.14 (1 H, s, H-8); δC (100 MHz; DMSO-d6) 32.0,
39.2, 63.4, 67.0, 124.0, 143.9, 149.9, 154.7, 160.3.
2-Amino-9-(3-azido-4-hydroxy-3-hydroxymethyl-butyl)-1,9-
dihydro-purin-6-one (2). Compound 1 (25 mg, 0.08 mmol) in
aqueous 0.5 M NaOH solution (4 cm3, 2.0 mmol) was heated to
80 ЊC overnight. The reaction mixture was cooled to room
temperature and neutralized with AcOH. The volatiles were
evaporated and the resulting residue was purified by reversed
phase ODS column chromatography (water/methanol = 10 : 1)
to give compound 2 (20 mg, 88%) as a white solid. Rf = 0.34
(water/methanol = 4 : 1); mp 239 ЊC (dec.); (Found: C, 40.9; H,
4.7; N, 38.25. Calc. for C10H14N8O3: C, 40.8; H, 4.8; N, 38.1%);
λmax(MeOH)/nm 254; νmax(film)/cmϪ1 2109 (N3); δH (400 MHz;
DMSO-d6) 1.90 (2 H, t, J 8.0, CH2CH2N), 3.51 (2 H, d, J 11.6,
2 × HOCHH), 3.54 (2 H, d, J 11.6, 2 × HOCHH ), 4.02 (2 H,
t, J 8.0, CH2N), 6.45 (2 H, s, NH2), 7.68 (1 H, s, H-8), 10.53
(1 H, s, amide-H); δH (400 MHz; MeOH-d4) 2.06 (2 H, m,
CH2CH2N), 3.69 (4 H, s, 2 × HOCH2), 4.02 (2 H, m, CH2N),
7.74 (1 H, s, H-8); δC (100 MHz; DMSO-d6) 32.6, 38.8, 63.4,
67.0, 117.2, 137.9, 151.7, 154.0, 157.4.
Methanesulfonic
acid
3-azido-4-benzyloxy-3-benzyloxy-
methyl-butyl ester (10). To a stirred solution of azido alcohol 9
(616 mg, 1.80 mmol) in pyridine (10 cm3) under nitrogen was
added methanesulfonyl chloride (0.22 cm3 2.70 mmol) and the
reaction mixture was stirred at 0 ЊC for 15 min. After the
reaction mixture was partitioned between methylene chloride
and H2O, the organic layer was washed with brine, dried over
anhydrous MgSO4, filtered and evaporated. The resulting oily
residue was purified by flash silica gel column chromatography
(hexane/ethyl acetate = 4 : 1) to give the mesylate 10 (756 mg,
100%) as a colorless syrup. Rf = 0.375 (hexane/ethyl acetate =
2 : 1); νmax(film)/cmϪ1 2105 (N3); δH (400 MHz; CDCl3) 2.07
(2 H, t, J 6.8, CH2CH2OMs), 2.92 (3 H, s, CH3), 3.57 (2 H, d,
J 9.6, 2 × BnOCHH), 3.60 (2 H, d, J 9.6, 2 × BnOCHH ), 4.32
(2 H, t, J 6.8, CH2OMs), 4.54 (4 H, s, 2 × PhCH2), 7.30–7.37
(10 H, m, 2 × Ph).
2-Amino-2-[2-(2-amino-purin-9-yl)-ethyl]-propane-1,3-diol
(3). To a stirred solution of compound 1 (12.0 mg, 0.04 mmol)
in MeOH (4 cm3) was added 10% Pd/C (6 mg) and the reaction
mixture was stirred at room temperature for 3 h under H2. The
reaction mixture was filtered through a pad of Celite, washed
with MeOH and evaporated. The resulting residue was crystal-
lized from MeOH and ethyl ether to give compound 3 (8.0 mg,
77%) as a white solid. Rf = 0.3 (water/methanol = 4 : 1); mp
236 ЊC (dec.) (from MeOH); (Found: C, 47.7; H, 6.7; N, 33.5.
Calc. for C10H16N6O2: C, 47.6; H, 6.4; N, 33.3%); λmax(MeOH)/
nm 306; δH (400 MHz; MeOH-d4) 2.24 (2 H, m, CH2CH2N),
3.68 (4 H, s, 2 × HOCH2), 4.30 (2 H, m, CH2N), 8.06 (1 H, s,
H-8), 8.56 (1 H, s, H-6).
9-(3-Azido-4-benzyloxy-3-benzyloxymethyl-butyl)-6-chloro-
9H-purin-2-ylamine (11) and 7-(3-azido-4-benzyloxy-3-benzyl-
oxymethyl-butyl)-6-chloro-7H-purin-2-ylamine (12). A suspen-
sion of 2-amino-6-chloropurine (164 mg, 0.97 mmol) and
K2CO3 (268 mg, 1.93 mmol) in DMF (3 cm3) was stirred at
60 ЊC for 2 h. To this mixture was added a solution of mesylate
10 (271 mg, 0.64 mmol) in DMF (3 cm3) at room temperature
and the mixture was stirred at 60 ЊC overnight and poured into
methylene chloride and water. The organic layer was dried
over anhydrous MgSO4, filtered and evaporated. The resulting
residue was purified by flash silica gel column chromatography
(hexane/ethyl acetate = 2 : 1) to give N-9 isomer 11 (250 mg,
79%) as a colorless sticky syrup and N-7 isomer 12 (30 mg, 9%)
as a colorless syrup.
Acknowledgements
Compound 11: Rf = 0.32 (hexane/ethyl acetate = 1 : 1);
(Found: C, 58.7; H, 4.95; N, 22.9. Calc. for C24H25ClN8O2: C,
58.5; H, 5.1; N, 22.7%); λmax(MeOH)/nm 309; νmax(film)/cmϪ1
2113 (N3); δH (400 MHz; CDCl3) 2.13 (2 H, m, CH2CH2N), 3.57
(2 H, d, J 10.0, 2 × BnOCHH), 3.61 (2 H, d, J 10.0, 2 × Bn-
OCHH ), 4.16 (2 H, m, CH2N), 4.52 (2 H, d, J 12.0, PhCH2),
4.56 (2 H, d, J 12.0, PhCH2), 5.02 (2 H, s, NH2), 7.31–7.37
(10 H, m, 2 × PH), 7.67 (1 H, s, H-8).
Compound 12: Rf = 0.10 (hexane/ethyl acetate = 1 : 1);
λmax(MeOH)/nm 321; νmax(film)/cmϪ1 2116 (N3); δH (400 MHz;
CDCl3) 2.12 (2 H, m, CH2CH2N), 3.58 (2 H, d, J 9.6, 2 ×
BnOCHH), 3.61 (2 H, d, J 10.0, 2 × BnOCHH ), 4.09 (2 H, m,
CH2N), 4.52 (2 H, d, J 12.0, PhCH2), 4.53 (2 H, s, NH2), 4.55
(2 H, d, J 12.0, PhCH2), 7.29–7.36 (10 H, m, 2 × Ph), 7.41 (1 H,
s, H-8).
This study was supported by a grant of the Korea Health 21
R&D Project, Ministry of Health & Welfare, Republic of
Korea (01-PJ2-PG6-01NA01-0002).
References
1 In Acyclic, Carbocyclic and L-Nucleosides, eds. L. A. Agrofoglio and
S. R. Challand, Kluwer Academic Publishers, Dordrecht, 1998;
p. 18–173.
2 (a) G. B. Elion, P. A. Furman, J. A. Fyfe, P. de Miranda,
L. Beauchamp and H. J. Schaeffer, Proc. Natl. Acad. Sci. USA, 1977,
74, 5716–5720; (b) H. J. Schaeffer, L. Beauchamp, P. de Miranda,
G. B. Elion, D. J. Bauer and P. Collins, Nature, 1978, 272, 583–585.
3 S. A. Spector, G. F. McKinley, J. P. Lalezari, T. Samo, R. Andruczk,
S. Follansbee, P. D. Sparti, D. V. Havlir, G. Simpson, W. Buhles,
R. Wong and M. Stempien, N. Engl. J. Med., 1996, 334, 1491–1497.
4 R. A. Vere Hodge and Y. C. Cheng, Antiviral Chem. Chemother.,
1993, 4, 13–24.
2-[2-(2-Amino-6-chloro-purin-9-yl)-ethyl]-2-azido-propane-
1,3-diol (1). To a stirred solution of compound 11 (94 mg,
0.19 mmol) in anhydrous methylene chloride (8 cm3) was added
tribromoboron (1.9 cm3, 1.9 mmol, 1.0 M solution in methylene
chloride) at Ϫ78 ЊC and the reaction mixture was stirred at the
same temperature for 1 h. To this mixture was added MeOH
(20 cm3) and the reaction mixture was neutralized with silver
carbonate and filtered through a pad of Celite. The filtrate
was evaporated and the residue was purified by flash silica gel
column chromatography (methylene chloride/methanol = 20 : 1
to 10 : 1) to give azido compound 1 (49 mg, 83%) as a white
5 R. J. Crooks and A. Murray, Antiviral Chem. Chemother., 1994, 5,
31–37.
6 D. Jung and A. Dorr, J. Clin. Pharmacol., 1999, 39, 800–804.
7 (a) H. J. Field, Expert Opin. Invest. Drugs, 1996, 5, 925–938;
(b) R. A. Vere Hodge, Antiviral Chem. Chemother., 1993, 4, 67–84.
8 C. M. Perry and A. J. Wagstaff, Drugs, 1995, 50, 396–415.
9 (a) K. A. Watanabe, U. Reichman, K. Hirota, C. Lopez and J. J. Fox,
J. Med. Chem., 1979, 22, 21–24; (b) K. A. Watanabe, T.-L. Su,
R. S. Klein, C. K. Chu, A. Matsuda, M. W. Chun, C. Lopez and
J. J. Fox, J. Med. Chem., 1983, 26, 152–156; (c) C. H. Tann,
P. R. Brodfuehrer, S. P. Brundidge, C. Sapino and H. G. Howell,
J. Org. Chem., 1985, 50, 3644–3647.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 6 4 – 1 1 6 8
1167

View Article Online
10 E. Matthes, C. Lehmann, D. Scholz, H. A. Rosenthal and P. Langen,
Biochem. Biophys. Res. Commun., 1988, 153, 825–831.
11 C. K. Chu, T. Ma, K. Shanmuganathan, C. Wang, Y. Xiang,
S. B. Pai, G.-Q. Yao, J.-P. Sommadossi and Y.-C. Cheng, Antimicrob.
Agents Chemother., 1995, 39, 979–981.
12 (a) P. A. Furman, J. A. Fyfe, M. H. St. Clair, K. Weinhold,
J. L. Rideout, G. A. Freeman, S. N. Lehrman, D. P. Bolognesi,
S. Broder, H. Mitsuya and D. W. Barry, Proc. Natl. Acad. Sci. USA,
1986, 83, 8333–8337; (b) H. Mitsuya, K. J. Weinhold, P. A. Furman,
M. H. St. Clair, S. N. Lehrman, R. C. Gallo, D. Bolognesi,
D. W. Barry and S. Broder, Proc. Natl. Acad. Sci. USA, 1985, 82,
7096–7100.
L. M. Pruess, J. N. Porter, J. H. Mowat and N. Bohonos, Antibiot.
Ann., 1957, 716–721.
15 J. HannahR. L. Tolman, Eur. Patent EP 381531, 1990; (Chem.
Abstr., 1990, 114, 102701).
16 T. Izawa, S. Nishiyama, S. Yamamura, K. Kato and T. Takita,
J. Chem. Soc., Perkin Trans. 1, 1992, 2519–2525.
17 R. Csuk and G. Thiede, Tetrahedron, 1999, 55, 739–750.
18 E. F. V. Scriven and K. Turnbull, Chem. Rev., 1988, 88, 297–368.
19 L. S. Jeong, J. W. Beach and C. K. Chu, J. Heterocycl. Chem., 1993,
30, 1445–1452.
20 T. Naka, N. Minakawa, H. Abe, D. Kaga and A. Matsuda, J. Am.
Chem. Soc., 2000, 122, 7233–7243.
13 H. Maag, R. M. Rydzewski, M. J. McRoberts, D. Crawford-Ruth,
J. P. Verheyden and E. J. Prisbe, J. Med. Chem., 1992, 35, 1440–1451.
14 S. O. Thomas, V. L. Singleton, J. A. Lowery, R. W. Sharpe,
21 L. S. Jeong, S. J. Yoo, K. M. Lee, M. J. Koo, W. J. Choi, H. O. Kim,
H. R. Moon, M. Y. Lee, J. G. Park, S. K. Lee and M. W. Chun,
J. Med. Chem., 2003, 46, 201–203.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 6 4 – 1 1 6 8
1168