Synthesis of 8-phenoxy-2′-deoxyguanosine nucleoside analogues

Article abstract of DOI:10.1002/ejoc.201100013

Nucleobase adducts, which form in vivo by nucleophilic attack of nucleobases on electrophilic chemical species, can impact on the conformation and biological influences of the adducted nucleoside. Contemporary studies aim to address the occurrence and relevance of 8-phenoxypurine adducts. However, preparative techniques for synthesizing these nucleosides have not previously been described. Reported herein is a relatively facile synthesis of 8-dG phenol adducts using a wide variety of electron-donating, electron-withdrawing, and sterically demanding phenols. 8-Phenoxy-2′-deoxyguanosines have been synthesized by nucleophilic substitution withvarious electron-donating, electron-withdrawing, and sterically bulky phenols.

Full text of DOI:10.1002/ejoc.201100013

FULL PAPER
DOI: 10.1002/ejoc.201100013
Synthesis of 8-Phenoxy-2Ј-deoxyguanosine Nucleoside Analogues
Heidi A. Dahlmann[a] and Shana J. Sturla*[a]
Keywords: DNA / Nucleosides / Nucleophilic substitution / DNA damage
Nucleobase adducts, which form in vivo by nucleophilic at-
tack of nucleobases on electrophilic chemical species, can
impact on the conformation and biological influences of the
adducted nucleoside. Contemporary studies aim to address
the occurrence and relevance of 8-phenoxypurine adducts.
However, preparative techniques for synthesizing these nu-
cleosides have not previously been described. Reported
herein is a relatively facile synthesis of 8-dG phenol adducts
using a wide variety of electron-donating, electron-with-
drawing, and sterically demanding phenols.
been chemically prepared either by biomimetic direct ad-
duction of N-acetoxyamines[9] to DNA under neutral con-
ditions or by Pd-catalyzed cross-coupling between aryl-
amines and protected 8-bromopurines.[10] The latter method
has become common for preparing 8-(arylamino)purine nu-
cleosides for insertion into oligonucleotides, which are fur-
ther used to study the chemical and biological impacts of
specific arylamine lesions (particularly those linked to carci-
nogenesis) on DNA structure and replication.[10c–10e,11]
Contemporary studies aim to address the occurrence and
relevance of analogous 8-phenoxypurines, such as those de-
rived from Ochratoxin A (OTA), a food-borne mycotoxin
derived from Aspergillus, and pentachlorophenol (PCP), a
common environmental contaminant.[12] In the case of
OTA, adducts have been shown to form in vitro, but the
role of the adducts on cancer etiology, and whether the ad-
ducts exist in vivo, is debated.[12a,13] For PCP, DNA adducts
have been identified in vivo, but their overall biological im-
pact is unknown.[12b] An explicit limitation for the further
study of these adducts is that synthetic methods for prepar-
ing 8-phenoxypurine adducts are considerably less devel-
oped than for preparing their N-linked 8-(arylamino)purine
counterparts, although 8-alkoxy- and 8-(thiophenoxy)pu-
rines have been prepared by the nucleophilic substitution of
8-bromopurines.[14] A previously reported investigation of
the formation of 8-phenoxypurine adducts involved the per-
oxidase activation of chlorophenols to form phenoxyl radi-
cals that react at the 8-position of dG, the most easily oxid-
ized nucleoside.[12b,15] A major drawback of extending this
approach to preparative reactions is that many phenols are
not suitable substrates for the enzymatic reaction, over-oxi-
dation of phenols leads to the generation of diverse side-
products, and the method produces adducts on a very small
scale. Thus, reported herein is a relatively facile method for
synthesizing 8-phenoxy-dG nucleoside analogues with a
variety of electron-donating, electron-withdrawing, and ste-
rically demanding phenols. Such adducts are expected to
Introduction
Nucleosides and nucleotides containing altered nucleo-
bases have been used as therapeutics,[1] as probes for de-
tecting DNA damage,[2] in monitoring charge transfer in
DNA,[3] signaling hybridization,[4] or sensing pH,[5] and as
templates for mutagenesis research.[6] Studies with the latter
have revealed that nucleobase adducts, which form in vivo
by the nucleophilic attack of nucleobases on electrophilic
species, can exert a profound impact on the conformation
and biochemical processing of the adducted nucleoside. If
an adduct persists and escapes DNA repair processes, the
resulting mutations to cell-cycle regulatory genes may cause
uncontrolled cell division leading to cancer. Structural de-
termination studies and bioassays, which make it possible
to elucidate the molecular mechanisms underlying the
chemical and biological influences of specific lesions, are
enabled by an ability to synthesize nucleoside adducts.
Modifications at the 8-position of purines disrupt the
natural anti conformation depending on whether they are
located in a nucleoside, nucleotide, or oligonucleotide.[7]
Furthermore, the distortion to DNA may alter its replica-
tion properties. As an illustration, polymerase-mediated
DNA synthesis with chemically modified templates revealed
that the arylamine adduct 8-AF-dG, which equilibrates be-
tween syn and anti conformations, and 8-AAF-dG, which
is in essence locked into the syn conformation by an acetyl
group that hinders rotation of the nucleobase around the
glycosidic bond, possess strikingly different mutational
spectra.[8] These and other 8-(arylamino)purine adducts,
such as those formed in vivo following the consumption of
cooked meats and exposure to environmental toxins, have
[a] ETH Zürich, Institute of Food, Nutrition and Health,
Schmelzbergstrasse 9, 8006 Zürich, Switzerland
Fax: +41-44-6321123
E-mail: shana.sturla@agrl.ethz.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100013.
Eur. J. Org. Chem. 2011, 2987–2992
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2987

H. A. Dahlmann, S. J. Sturla
FULL PAPER
be useful as probes to gain a greater understanding of the Table 1. Influence of conditions on the conversion of 1 to 2a.
structural and toxicological impacts of DNA major-groove-
binding events.
Results and Discussion
The overall synthetic strategy for constructing 8-phen-
oxy-dG adducts 3a–g involved the addition of substituted
phenols to protected 8-Br-dG 1 (prepared according to pre-
viously described procedures[10b,16]) to form deoxyguanos-
Entry Solvent Pd(OAc)2 Ligand Temp. Atm.[a] 1/2a[b]
ine adducts 2a–h, followed by purification and deprotection
[%]
[%]
[°C]
(Scheme 1). A variety of conditions were tested for both
Pd-catalyzed and simple base-promoted reactions of phenol
with precursor 1 (Table 1). At 110 °C in toluene, Pd cataly-
sis in the presence of ligand A promoted the reactions
(Table 1, entry 2), whereas at 80 °C in DME no appreciable
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
DME
DME
DME
DME
0
6
6
8
8
0
0
3
3
3
0
0
0
A (5)
B (5)
A (11)
A (11)
0
110
110
110
110
110
85
85
85
85
air
air
air
air
N2
air
N2
air
N2
N2
N2
air
53:47
26:74
45:55
45:55
53:47
67:33
56:44
63:37
59:41
0:100
0:100
0:100
1
catalysis was observed, as monitored by H NMR (Table 1,
0
entries 6–9). However, at 135 °C in xylenes, both Pd-cata-
lyzed and Pd-free reactions proceeded to completion after
only 6 h (Table 1, entries 10–12). The Pd-free reaction sim-
plifies the reaction set-up and obviates the need for an ex-
pensive catalyst.
A (6)
A (6)
A (6)
0
9
10
11
12
xylenes
xylenes
xylenes
135
135
135
0
[a] Atmosphere under which the reactions were conducted. [b] Per-
cent ratio of starting material 1 to target compound 2a as deter-
1
mined by H NMR analysis of the crude reaction mixtures.
Table 2. Synthesis of protected adducts 2a–h.
Product
Substrate
Yield [%][a]
Scheme 1. Synthesis of the 8-phenoxy-dGs prepared in this study.
2a
2b
2c
2d
2e
2f
phenol
77
84
80
80
82
85
64
85
2-methylphenol
4-methylphenol
4-methoxyphenol
4-chlorophenol
2,4,6-trichlorophenol
2,3,4,5,6-pentachlorophenol
4-bromophenol
To test the scope of this reaction with respect to the
chemical properties of the phenol, the base-mediated substi-
tution reaction was performed in xylenes under nitrogen
and adducts 2a–h were obtained in yields of 64–85%
(Table 2). The phenol substrates studied ranged from highly
electron-withdrawing pentachlorophenol (PCP) to modestly
electron-donating 4-methylphenol, with substituents at the
2g
2h
[a] Isolated yield of analytically pure material.
ortho positions (2b,f,g) well tolerated. The reaction effi- and to a lesser extent reversed-phase HPLC; significant hy-
ciency appears to have no dependence on the acid dissoci- drolysis of the nucleosides occurred during initial attempts
ation constants of the phenol substrates (pKa values were at normal-phase chromatography. We found that minor
between approximately 5 and 10). Aniline was also tested amounts of triethylamine in the eluent could prevent hy-
as a substrate, but no adduct formation was observed; this drolysis but could also introduce further impurities in some
emphasizes the importance of previously described Pd-cata- cases. Therefore, the compounds were purified by tritura-
1
lyzed cross-coupling methods for arylamine adduct forma- tion in acetone to provide analytically pure (Ͼ95% by H
tion.[10]
NMR) material in isolated yields of 27–64% after both de-
Free nucleosides were obtained by TBAF-mediated desi- protection steps (Table 3). The low yields in part reflect the
lylation of the 3Ј- and 5Ј-hydroxys followed by catalytic hy- solubility of the nucleosides in the small volumes of acetone
drogenation to remove the O6-benzyl protecting group. Ad- used during purification (the more soluble chlorinated ad-
ducts 3a–g were sensitive to normal phase chromatography ducts were obtained in lower yields) as well as common
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Eur. J. Org. Chem. 2011, 2987–2992

Phenoxy-deoxyguanosine Nucleoside Analogues
purification challenges in obtaining extremely pure nucleo-
sides. However, the yields of material obtained with 90–
95% purity, which would not be suitable for biological
study but which would be synthetically useful, were 90%
after both deprotection steps for both the phenol (3a) and
4-chlorophenol adducts (3e). Debenzylation of the halogen-
substituted phenols was nontrivial; dehalogenated products
were observed in the NMR and mass spectra of the crude
reaction mixtures following catalytic hydrogenation of tri-
chlorophenol and 4-bromophenoxy compounds 2f and 2h.
To avoid this drawback, substitution reactions were at-
tempted with 3Ј,5Ј-bis(tert-butyldimethylsilyl)-substituted
8-Br-dG under the same conditions used for the fully pro-
tected starting material 1. Although partial conversion to
the desired product was observed in the NMR and mass
Conclusions
We have reported herein a simple synthesis of 8-phenoxy-
dG nucleosides that is complementary to known methods
for preparing 8-alkoxy- and 8-(thiophenoxy)purine nucleo-
sides. In contrast to techniques used to prepare 8-(aryl-
amino)purine adducts, the method presented herein does
not require the use of Pd catalysis. The substitution reac-
tions are efficient and free of side-products, with overall
yields after deprotection influenced by the rigor of the puri-
fication procedure. This work extends the scope of nucleo-
philic substitutions to produce 8-phenoxy-dG nucleosides.
Experimental Section
spectra, the complex reaction mixtures were difficult to pu- General: Chemicals were purchased from Sigma–Aldrich (Milwau-
kee, WI) or TCI (Tokyo, Japan) and used without further purifica-
tion. Xylenes were dried with POCl3 and vacuum distilled prior to
use. Dry toluene for substitution reactions was obtained from an
M-Braun solvent purification system in which the solvent is passed
through a column of activated alumina before being dispensed un-
rify and the strategy was no longer pursued. No product
formation was detected in analogous base-mediated reac-
tions performed with unprotected 8-Br-dG in H2O, DMSO,
or DMF.
1
der nitrogen. H NMR spectra were acquired at 500 or 400 MHz,
Table 3. Deprotection of adducts 2a–h.
and 13C NMR at 125 or 100 MHz, with a 500 MHz Varian or
400 MHz Bruker NMR spectrometer. Chemical shifts are reported
relative to the non-deuteriated solvent signals (CHCl3 was set to
7.26 and 77.23 ppm, and MeOD to 3.31 and 49.15 ppm for 1H and
13C NMR spectra, respectively). Flash chromatography (silica gel,
60 Å, 200–400 mesh) was used for product purification. Normal-
phase thin-layer chromatography (plates obtained from Silicycle,
QB, Canada) was used to monitor the reactions and the spots were
visualized under UV light (254 nm). High-resolution ESI-MS was
performed with a Bruker BioTOF II or Thermo Scientific Exactive
mass spectrometer. Infrared spectra were acquired with an FT-IR
instrument from thin-film samples prepared on NaCl plates and
are reported in cm–1. Reported yields represent an average of two
to three trials.
Product
Substrate
Yield [%][a]
44 (90)[b]
3a
3b
3c
3d
3e
3f
phenol
2-methylphenol
4-methylphenol
4-methoxyphenol
4-chlorophenol
2,4,6-trichlorophenol
2,3,4,5,6-pentachlorophenol
4-bromophenol
64
54
61
24 (90)[c]
29
6-O-Benzyl-8-bromo-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-2Ј-deoxy-
guanosine (1): Guanosine 1 was prepared according to a published
procedure.[10b]
3g
27
0[d]
[a] Isolated yields of analytically pure material following desi-
lylation and debenzylation, unless otherwise indicated. [b] Isolated
yield of 95% pure material. [c] Isolated yield of 90% pure material.
[d] Product decomposed during debenzylation.
General Procedure for the Synthesis of 6-O-Benzyl-3Ј,5Ј-O-bis(tert-
butyldimethylsilyl)-8-phenoxy-2Ј-deoxyguanosines 2a–h: In a nitro-
gen-filled glove box, K3PO4 (2 equiv.), phenol (4 equiv.), and
xylenes (0.25 m) were added to a vial containing 6-O-benzyl-8-
bromo-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-2Ј-deoxyguanosine (ca.
0.2 mmol). The vial was sealed with a Teflon®-lined cap, removed
Based on our observations of product decomposition
during chromatography, we conclude that adducts 3a–g are from the glove box, and submerged in an oil bath at 130 °C. Alter-
natively, reactions were prepared in air or nitrogen-flushed vials
and sealed with Teflon®-lined caps. After 12 h, the reaction vial
was allowed to cool to room temperature and then diluted in ethyl
acetate (1–2 mL). The resulting solution was loaded onto a Biotage
Isolute PE-AX acid-scavenging column (500 mg, 3 mL capacity,
pre-equilibrated with ethyl acetate) and eluted with ethyl acetate to
remove excess phenol. The solution was then concentrated by ro-
tary evaporation and purified by silica gel chromatography (3–30%
gradient of ethyl acetate in hexanes). Yields are reported for mate-
acid-labile. The depurination of deoxyguanosines bearing
bulky or electronegative adducts at the 8-position is well
known and is proposed to lead to abasic site formation in
DNA.[17] Recent studies by Wetmore and Manderville and
co-workers suggest that under physiological conditions,
homolytic cleavage during adduct formation rather than hy-
drolysis following adduct formation may be responsible for
the depurination, particularly for purines substituted with
small aryl adducts.[18] However, the C8–O linkage for ad-
1
rial of 95% or greater purity as judged by H NMR analysis and
ducts 3a–g differs significantly from the C8–aryl linkage of represent an average of two to three experiments.
the adducts studied by Wetmore and Manderville, which
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-phenoxy-2Ј-deoxy-
guanosine (2a): Yield 77%. TLC: 0.44 (15% ethyl acetate in hex-
may render their lability relevant under physiological condi-
tions. Incorporation of adducts 3 into oligonucleotides will
enable the testing of this hypothesis in further studies.
anes). IR: ν = 35125 (w), 3348 (w), 2954 (m), 3215 (w), 2955 (m),
˜
2930 (m), 2892 (m), 2857 (m), 1621 (s), 1601 (s), 1588 (s), 1554 (m),
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2989

H. A. Dahlmann, S. J. Sturla
1471 (s), 1417 (m), 1353 (m), 1253 (m), 1228 (m), 1206 (m), 1075 Bn-H2), 4.68 (m, 1 H, 3Ј-H), 4.65 (s, 2 H, NH2), 3.93 (ddd, JH,H
FULL PAPER
=
(m), 1030 (m), 836 (s), 777 (m) cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.35 (m, 9 H, Ar-H), 7.21 [app. dt, JH,H = 1.0, 7.5 Hz, 1 H,
Ar-H], 6.41 (app. t, JH,H = 7.0 Hz, 1 H, 1Ј-H), 5.50 (d, JH,H = 3 Hz,
2 H, Bn-H2), 4.69 (m, 3 H, 3Ј-H, NH2), 3.93 (ddd, JH,H = 3.0, 5.0,
3.0, 5.0, 7.5 Hz, 1 H, 4Ј-H), 3.80 (s, 3 H, OMe), 3.77 (m, 1 H, 5Ј-
H), 3.68 (dd, JH,H = 5.0, 10.5 Hz, 1 H, 5Ј-H), 3.30 (ddd, JH,H
=
6.0, 8.0, 12.5 Hz, 1 H, 2Ј-H), 2.18 (ddd, JH,H = 4.0, 7.0, 12.5 Hz, 1
H, 2Ј-H), 0.93 (s, 9 H, SiCMe3), 0.84 (s, 9 H, SiCMe3), 0.12 (s, 6
7.0 Hz, 1 H, 4Ј-H), 3.77 (dd, JH,H = 7.0, 11.0 Hz, 1 H, 5Ј-H), 3.67 H, SiMe2), 0.004 (s, 3 H, SiMe), –0.019 (s, 3 H, SiMe) ppm. 13C
(dd, JH,H = 5.0, 11.0 Hz, 1 H, 5Ј-H), 3.30 (ddd, JH,H = 6.0, 7.5, NMR (125 MHz, CDCl3): δ = 159.3, 157.9, 157.2, 153.8, 153.1,
13.0 Hz, 2Ј-H), 2.19 (ddd, JH,H = 3.5, 7.0, 13.0 Hz, 1 H, 2Ј-H), 0.92 147.0, 137.0, 128.6, 128.4, 128.0, 121.4, 114.9, 111.1, 87.5, 82.8,
(s, 9 H, SiCMe3), 0.84 (s, 9 H, SiCMe3), 0.12 (s, 6 H, SiMe2), –0.01
(s, 3 H, SiMe), –0.03 (s, 3 H, SiMe) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.5, 158.0, 153.70, 153.66, 152.4, 137.0, 129.9, 128.6,
128.5, 128.1, 125.6, 120.2, 111.1, 87.6, 82.9, 73.0, 68.0, 63.4, 36.9,
26.11, 26.05, 18.6, 18.3, –4.41, –4.45, –5.16, –5.21 ppm. HRMS:
calcd. for [MH]+ 678.3501; found 678.3628.
73.0, 67.9, 63.4, 55.9, 36.8, 26.1, 18.6, 18.3, –4.43, –4.48, –5.17,
–5.23 ppm. HRMS: calcd. for [MH]+ 708.3607; found 708.3454.
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-(4-chlorophen-
oxy)-2Ј-deoxyguanosine (2e): Yield 82 %. TLC: 0.50 (15 % ethyl
acetate in hexanes). IR: ν = 3508 (w), 3356 (w), 3219 (w), 2956 (m),
˜
2930 (m), 2884 (m), 2858 (m), 1622 (s), 1603 (s), 1589 (s), 1553 (s),
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-(2-methylphen- 1495 (s), 1487 (s), 1471 (s), 1417 (m), 1353 (m), 1312 (w), 1253 (m),
oxy)-2Ј-deoxyguanosine (2b): Yield 84 %. TLC: 0.44 (15 % ethyl
1229 (m), 1090 (m), 1030 (w), 1014 (w), 958 (w), 836 (s), 778 (m),
1
acetate in hexanes). IR: ν = 3494 (w), 3340 (w), 2954 (m), 2929
697 (w) cm–1. H NMR (400 MHz, CDCl3): δ = 7.73 (m, 2 H, Ar-
˜
(m), 2857 (m), 1652 (w), 1634 (m), 1622 (vs), 1598 (vs), 1577 (m), H), 7.31 (m, 7 H, Ar-H), 6.37 (app. t, JH,H = 7.0 Hz, 1 H, 1Ј-H),
1471 (s), 1417 (m), 1352 (m), 1252 (m), 1225 (m), 1128 (w), 1109 5.50 (d, JH,H = 3.0 Hz, 2 H, Bn-H2), 4.69 (m, 3 H, 3Ј-H, NH2),
(m), 1077 (m), 1031 (w), 956 (w), 834 (s), 776 (m), 747 (w), 694 3.92 (ddd, JH,H = 3.0, 5.0, 7.0 Hz, 1 H, 4Ј-H), 3.76 (dd, JH,H = 7.0,
1
(w), 663 (w) cm–1. H NMR (500 MHz, CDCl3): δ = 7.41 (app. d, 11.0 Hz, 1 H, 5Ј-H), 3.65 (dd, JH,H = 5.0, 11.0 Hz, 1 H, 5Ј-H), 3.31
JH,H = 7.0 Hz, 2 H, Ar-H), 7.25 (m, 6 H, Ar-H), 7.12 (app. dt, JH,H
(ddd, JH,H = 6.0, 7.1, 13.2 Hz, 1 H, 2Ј-H), 2.18 (ddd, JH,H = 3.6,
= 1.5, 7.5, 7.5 Hz, 1 H, Ar-H), 6.43 (app. t, JH,H = 7.0 Hz, 1 H, 1Ј- 6.8, 13.2 Hz, 1 H, 2Ј-H), 0.93 (s, 9 H, SiCMe3), 0.84 (s, 9 H,
H), 5.48 (d, JH,H = 2.5 Hz, 2 H, Bn-H2), 4.68 (m, 3 H, 3Ј-H, NH2),
3.94 (ddd, JH,H = 3.0, 5.0, 7.5 Hz, 1 H, 4Ј-H), 3.75 (dd, JH,H = 7.5,
SiCMe3), 0.12 (s, 6 H, SiMe2), 0.01 (s, 3 H, SiMe), –0.02 (s, 3 H,
SiMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.6, 158.1, 153.6,
11.0 Hz, 1 H, 5Ј-H), 3.67 (dd, JH,H = 5.0, 11.0 Hz, 1 H, 5Ј-H), 3.33 152.11, 152.08, 136.9, 130.9, 129.9, 128.57, 128.52, 128.1, 121.7,
(ddd, JH,H = 5.5, 7.0, 13.0 Hz, 1 H, 2Ј-H), 2.25 (s, 3 H, Ar-Me),
2.19 (ddd, JH,H = 3.0, 7.0, 13.0 Hz, 1 H, 2Ј-H), 0.93 (s, 9 H,
SiCMe3), 0.83 (s, 9 H, SiCMe3), 0.12 (s, 6 H, SiMe2), –0.01 (s, 3
H, SiMe), –0.03 (s, 3 H, SiMe) ppm. 13C NMR (125 MHz, CDCl3):
δ = 159.3, 157.9, 153.8, 152.6, 151.9, 137.0, 131.7, 129.7, 128.6,
128.5, 128.0, 127.4, 125.9, 120.9, 111.2, 87.6, 82.9, 73.0, 67.9, 63.4,
36.8, 26.0, 26.0, 18.6, 18.3, 16.5, –4.45, –4.46, –5.21, –5.29 ppm.
HRMS: calcd. for [MH]+ 692.3658; found 692.3785.
111.1, 87.6, 82.9, 72.9, 68.0, 63.3, 36.9, 26.1, 18.6, 18.3, –4.39,
–4.44, –5.15, –5.21 ppm. HRMS: calcd. for [MH]+ 712.3112; found
712.3089.
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-(2,4,6-trichloro-
phenoxy)-2Ј-deoxyguanosine (2f): Yield 85%. TLC: 0.53 (15% ethyl
acetate in hexanes). IR: ν = 3512 (w), 3341 (w), 2954 (m), 2930
˜
(m), 2886 (m), 2857 (m), 1652 (w), 1622 (s), 1599 (s), 1471 (s), 1413
(m), 1351 (m), 1312 (w), 1253 (m), 1228 (m), 1077 (m), 1031 (m),
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-(4-methylphen- 954 (w), 836 (s), 777 (m), 732 (w), 695 (w), 668 (w) cm–1. 1H NMR
oxy)-2Ј-deoxyguanosine (2c): Yield 80 %. TLC: 0.48 (15 % ethyl
acetate in hexanes). IR: ν = 3504 (w), 3368 (w), 3207 (w), 2955 (m),
(CDCl3, 400 MHz): δ = 7.41 (m, 4 H, Ar-H), 7.30 (m, 3 H, Ar-H),
6.46 (app. t, JH,H = 7.0 Hz, 1 H, 1Ј-H), 5.50 (s, 2 H, Bn-H2), 4.69
˜
2930 (m), 2857 (m), 1622 (s), 1595 (s), 1577 (m), 1507 (m), 1472 (m, 3 H, 3Ј-H, NH2), 3.98 (ddd, JH,H = 3.0, 5.5, 7.0 Hz, 1 H, 4Ј-
(s), 1418 (m), 1351 (m), 1312 (w), 1253 (m), 1228 (m), 1205 (m), H), 3.77 (dd, JH,H = 7.0, 10.5 Hz, 1 H, 5Ј-H), 3.74 (dd, JH,H = 5.5,
1079 (m), 1031 (m), 953 (w), 836 (s), 778 (m), 732 (w), 696 (w), 668 10.5 Hz, 1 H, 5Ј-H), 3.29 (ddd, JH,H = 6.0, 7.5, 13.0 Hz, 1 H, 2Ј-
1
(w) cm–1. H NMR (400 MHz, CDCl3): δ = 7.43 (m, 2 H, Ar-H), H), 2.22 (ddd, JH,H = 3.5, 6.5, 13.0 Hz, 1 H, 2Ј-H), 0.93 (s, 9 H,
7.30 (m, 3 H, Ar-H), 7.18 (m, 4 H, Ar-H), 6.40 (app. t, JH,H
7.0 Hz, 1 H, 1Ј-H), 5.50 (d, J = 3.0 Hz, 2 H, Bn-H2), 4.68 (m, 3 H,
=
SiCMe3), 0.84 (s, 9 H, SiCMe3), 0.134 (s, 3 H, SiMe), 0.132 (s, 3
H, SiMe), 0.01 (s, 3 H, SiMe), –0.01 (s, 3 H, SiMe) ppm. 13C NMR
3Ј-H, NH2), 3.93 (m, 1 H, 4Ј-H), 3.77 (dd, JH,H = 7.0, 11.0 Hz, 1 (100 MHz, CDCl3): δ = 159.5, 158.1, 154.0, 150.6, 144.6, 137.0,
H, 5Ј-H), 3.67 (dd, JH,H = 5.0, 11.0 Hz, 1 H, 5Ј-H), 3.30 (ddd, JH,H
= 6.0, 7.0, 13.0 Hz, 2Ј-H), 2.34 (s, 3 H, Ar-Me), 2.19 (ddd, JH,H
132.4, 129.9, 129.3, 128.51, 128.48, 128.0, 110.9, 87.8, 83.1, 73.1,
68.0, 63.6, 37.0, 26.10, 26.08, 21.0, 18.6, 18.3, –4.42, –4.44, –5.15,
–5.25 ppm. HRMS: calcd. for [MH]+ 782.2308; found 782.2437.
=
3.5, 7.0, 13.0 Hz, 1 H, 2Ј-H), 0.93 (s, 9 H, SiCMe3), 0.85 (s, 9 H,
SiCMe3), 0.13 (s, 6 H, SiMe2), 0.01 (s, 3 H, SiMe), –0.01 (s, 3 H,
SiMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.4, 158.0, 153.7,
152.8, 151.4, 137.0, 135.2, 130.3, 128.6, 128.5, 128.0, 120.0, 111.2,
87.6, 82.9, 73.0, 68.0, 63.5, 36.9, 26.1, 21.0, 18.6, 18.3, –4.43, –4.47,
–5.17, –5.23 ppm. HRMS: calcd. for [MNa]+ 714.3477; found
714.3422.
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-(2,3,4,5,6-penta-
chlorophenoxy)-2Ј-deoxyguanosine (2g): Yield 64 %. TLC: 0.57
(15% ethyl acetate in hexanes). IR: ν = 3519 (w), 3360 (w), 2956
˜
(m), 2930 (m), 2888 (w), 2857 (m), 1622 (s), 1597 (vs), 154 (w),
1466 (s), 1415 (m), 1386 (s), 1363 (s), 1311 (w), 1258 (m), 1229 (m),
1107 (m), 1075 (m), 1029 (m), 953 (w), 836 (s), 774 (m), 717 (m),
1
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-(4-methoxyphen-
oxy)-2Ј-deoxyguanosine (2d): Yield 80 %. TLC: 0.34 (15 % ethyl
663 (w) cm–1. H NMR (400 MHz, CDCl3): δ = 7.41 (m, 2 H, Ar-
H), 7.30 (m, 3 H, Ar-H), 6.44 (app. t, JH,H = 7.0 Hz, 1 H, 1Ј-H),
5.49 (d, J = 3.0 Hz, 2 H, Bn-H2), 4.71 (m, 3 H, 3Ј-H, NH2), 3.96
(ddd, JH,H = 3.0, 5.0, 7.0 Hz, 1 H, 4Ј-H), 3.77 (dd, JH,H = 7.0,
11.0 Hz, 1 H, 5Ј-H), 3.73 (dd, JH,H = 5.0, 11.0 Hz, 1 H, 5Ј-H), 3.31
(ddd, JH,H = 6.0, 7.0, 13.0 Hz, 1 H, 2Ј-H), 2.23 (ddd, JH,H = 3.5,
7.0, 13.0 Hz, 1 H, 2Ј-H), 0.93 (s, 9 H, SiCMe3), 0.83 (s, 9 H,
acetate in hexanes). IR: ν = 3504 (w), 3376 (w), 2955 (m), 2930
˜
(m), 2893 (w), 2837 (m), 1622 (s), 1595 (s), 1557 (m), 1505 (w),
1471 (s), 1418 (m), 1351 (m), 1310 (w), 1250 (w), 1228 (w), 1203
(w), 1077 (w), 1032 (w), 953 (w), 836 (s), 778 (m), 731 (w), 696 (w),
1
668 (w) cm–1. H NMR (500 MHz, CDCl3): δ = 7.42 (m, 2 H, Ar-
H), 7.27 (m, 5 H, Ar-H), 6.89 (app. d, JH,H = 9.0 Hz, 2 H, Ar-H), SiCMe3), 0.141 (s, 3 H, SiMe), 0.137 (s, 3 H, SiMe), 0.02 (s, 3 H,
6.40 (app. t, JH,H = 7.0 Hz, 1 H, 1Ј-H), 5.49 (d, J = 3.0 Hz, 2 H,
SiMe), –0.01 (s, 3 H, SiMe) ppm. 13C NMR (125 MHz, CDCl3): δ
2990
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2987–2992

Phenoxy-deoxyguanosine Nucleoside Analogues
1
= 159.5, 158.2, 153.9, 150.1, 145.5, 136.9, 132.6, 132.1, 128.52,
128.50, 128.12, 128.10, 110.9, 87.7, 83.1, 72.7, 68.0, 63.4, 37.0, 26.1,
(w), 758 (w) cm–1. H NMR (500 MHz, MeOD): δ = 7.28 (d, JH,H
= 7.6 Hz, 1 H, Ar-H), 7.20 (m, 3 H, Ar-H), 6.42 (dd, JH,H = 6.5,
18.6, 18.3, –4.41, –4.44, –5.15, –5.25 ppm. HRMS: calcd. for 8.0 Hz, 1 H, 1Ј-H), 4.56 (m, 1 H, 3Ј-H), 4.01 (m, 1 H, 4Ј-H), 3.81
[MH]+ 850. 1529; found 850.1501.
(dd, JH,H = 4.0, 12.0 Hz, 1 H, 5Ј-H), 3.71 (dd, JH,H = 4.5, 12.0 Hz,
1 H, 5Ј-H), 3.10 (ddd, JH,H = 6.0, 8.0, 13.5 Hz, 1 H, 2Ј-H), 2.34
(ddd, JH,H = 3.0, 6.5, 13.5 Hz, 1 H, 2Ј-H), 2.25 (s, 3 H, Ar-
Me) ppm. 13C NMR (100 MHz, MeOD): δ = 158.7, 154.8, 153.4,
152.0, 151.8, 132.7, 131.0, 128.5, 127.3, 121.9, 113.0, 89.5, 85.0,
73.4, 64.2, 39.2, 16.4 ppm. HRMS: calcd. for [MNa]+ 396.1278;
found 396.1283.
6-O-Benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-8-(4-bromophen-
oxy)-2Ј-deoxyguanosine (2h): Yield 85%. TLC: 0.50 (15% ethyl
acetate in hexanes). IR: ν = 3515 (w), 3365 (w), 3207 (w), 2955 (m),
˜
2930 (m), 2889 (w), 2857 (m), 1622 (s), 1599 (s), 1417 (m), 1351
(m), 1252 (m), 1228 (m), 1111 (m), 1069 (m), 1030 (m), 1011 (m),
953 (w), 836 (s), 778 (m), 692 (w), 667 (w) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.49 (m, 2 H, Ar-H), 7.44 (m, 2 H, Ar-H),
8-(4-Methylphenoxy)-2Ј-deoxyguanosine (3c): Yield 54%. TLC: 0.21
7.31 (m, 3 H, Ar-H), 7.23 (m, 2 H, Ar-H), 6.37 (app. t, JH,H
=
(10% methanol in dichloromethane). IR: ν = 3167 (s), 2935 (m),
˜
7.0 Hz, 1 H, 1Ј-H), 5.51 (d, J = 3.0 Hz, 2 H, Bn-H2), 4.70 (m, 3 H,
3Ј-H, NH2), 3.92 (m, 1 H, 4Ј-H), 3.77 (dd, JH,H = 7.0, 11.0 Hz, 1
H, 5Ј-H), 3.66 (dd, JH,H = 5.0, 11.0 Hz, 1 H, 5Ј-H), 3.31 (ddd, JH,H
= 6.0, 7.5, 13.0 Hz, 1 H, 2Ј-H), 2.19 (ddd, JH,H = 3.5, 7.0, 13.0 Hz,
1 H, 2Ј-H), 0.93 (s, 9 H, SiCMe3), 0.84 (s, 9 H, SiCMe3), 0.13 (s, 6
H, SiMe2), 0.01 (s, 3 H, SiMe), –0.01 (s, 3 H, SiMe) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.6, 158.1, 153.6, 152.6, 152.0, 136.9,
132.9, 128.52, 128.50, 128.1, 122.1, 118.5, 111.1, 87.6, 82.9, 72.9,
68.0, 63.3, 36.9, 26.12, 26.07, 18.6, 18.3, –4.40, –4.44, –5.15,
–5.21 ppm. HRMS: calcd. for [MH]+ 758.2592; found 758.2610.
1680 (s), 1559 (s), 1499 (m), 1410 (m), 1368 (w), 1342 (w), 1278
1
(w), 1203 (w), 1102 (w), 979 (w), 818 (w), 776 (w) cm–1. H NMR
(400 MHz, MeOD): δ = 7.18 (m, 4 H, Ar-H), 6.37 (dd, JH,H = 3.9,
7.7 Hz, 1 H, 1Ј-H), 4.56 (m, 1 H, 3Ј-H), 3.99 (m, 1 H, 4Ј-H), 3.80
(dd, JH,H = 3.9, 12.0 Hz, 1 H, 5Ј-H), 3.70 (dd, JH,H = 4.5, 12.0 Hz,
1 H, 5Ј-H), 3.05 (ddd, JH,H = 6.2, 8.0, 13.5 Hz, 1 H, 2Ј-H), 2.34 (s,
3 H, Ar-Me), 2.26 (ddd, 3JH,H = 2.8, 6.6, 13.5 Hz, 1 H, 2Ј-H) ppm.
13C NMR (100 MHz, MeOD): δ = 158.9, 154.9, 153.3, 151.9, 151.7,
136.6, 131.4, 120.6, 113.1, 89.5, 85.0, 73.4, 64.2, 39.2, 21.0 ppm.
HRMS: calcd. for [MNa]+ 396.1278; found 396.1275.
General Procedure for the Synthesis of 8-Phenoxy-2Ј-deoxyguanos-
ines 3a–g: A solution of 0.5 m TBAF in THF (3 equiv.) was added
to a vial containing 6-O-benzyl-3Ј,5Ј-O-bis(tert-butyldimethylsilyl)-
8-phenoxy-2Ј-deoxyguanosine (2; ca. 0.15 mmol). The vial was
capped and allowed to stand at room temperature. After monitor-
ing the consumption of the starting material by thin-layer
chromatography (reaction complete in about 30 min), the mixture
was concentrated by rotary evaporation and purified by silica gel
chromatography (0–10% gradient of methanol in dichloromethane)
to yield a yellow oil that was analyzed by NMR and mass spec-
trometry and used in a debenzylation reaction without further
characterization. The oil, 10% Pd/C (15% by weight), and anhy-
drous methanol (reaction concentration = 0.05 m) were combined
in a 25 mL flask fitted with a three-way adapter. The flask was
sequentially evacuated and then purged with hydrogen (from at-
tached balloon) three times, then left open to the hydrogen balloon.
When the starting material could no longer be observed by TLC
(10% methanol in dichloromethane), the reaction mixture was fil-
tered through a plug of Celite rinsed through with 1:1 MeOH/
EtOAc and then concentrated by rotary evaporation. The solid
product was purified by sequential trituration with 0.1–0.5 mL por-
tions of acetone.
8-(4-Methoxyphenoxy)-2Ј-deoxyguanosine (3d): Yield 61%. TLC:
0.20 (10% methanol in dichloromethane). IR: ν = 3126 (s), 1667
˜
(s), 1552 (s), 1500 (s), 1410 (m), 1361 (m), 1350 (m), 1248 (w), 1200
(w), 1099 (w), 1050 (w), 825 (w), 776 (w) cm–1. 1H NMR
(400 MHz, MeOD): δ = 7.23 (d, JH,H = 9.0 Hz, 2 H, Ar-H), 6.95
(d, JH,H = 9.0 Hz, 2 H, Ar-H), 6.38 (app. t, JH,H = 7.3 Hz, 1 H, 1Ј-
H), 4.56 (m, 1 H, 3Ј-H), 4.00 (m, 1 H, 4Ј-H), 3.81 (dd, JH,H = 4.0,
12.0 Hz, 1 H, 5Ј-H), 3.80 (s, 3 H, OMe), 3.71 (dd, JH,H = 4.5,
12.0 Hz, 1 H, 5Ј-H), 3.07 (ddd, JH,H = 6.5, 8.0, 13.8 Hz, 1 H, 2Ј-
H), 2.27 (ddd, JH,H = 2.8, 6.5, 13.4 Hz, 1 H, 2Ј-H) ppm. 13C NMR
(100 MHz, MeOD): δ = 158.9, 158.7, 154.8, 152.4, 151.8, 148.7,
122.2, 115.9, 113.0, 89.4, 84.9, 73.4, 64.2, 56.3, 39.2 ppm. HRMS:
calcd. for [MNa]+ 412.1228; found 412.1226.
8-(4-Chlorophenoxy)-2Ј-deoxyguanosine (3e): Yield 24% (analytical
purity), 90% (90% purity). TLC: 0.13 (10% methanol in dichloro-
methane). IR: ν = 3297 (m), 2927 (m), 1683 (s), 1642 (m), 1594
˜
(m), 1559 (s), 1485 (m), 1414 (w), 1373 (w), 1212 (m), 1088 (m),
1056 (w), 1013 (w), 970 (w), 822 (w), 776 (w) cm–1. 1H NMR
(400 MHz, MeOD): δ = 7.42 (d, JH,H = 9.0 Hz, 2 H, Ar-H), 7.35
(d, JH,H = 9.0 Hz, 2 H, Ar-H), 6.45 (app. t, JH,H = 7.3 Hz, 1 H, 1Ј-
H), 4.55 (m, 1 H, 3Ј-H), 3.98 (m, 1 H, 4Ј-H), 3.80 (dd, JH,H = 3.9,
12.0 Hz, 1 H, 5Ј-H), 3.69 (dd, JH,H = 4.5, 12.0 Hz, 1 H, 5Ј-H), 3.07
(ddd, JH,H = 6.4, 8.0, 13.4 Hz, 1 H, 2Ј-H), 2.26 (ddd, JH,H = 2.9,
6.6, 13.4 Hz, 1 H, 2Ј-H) ppm. 13C NMR (100 MHz, MeOD): δ =
158.9, 155.1, 154.0, 151.8, 151.3, 131.9, 131.0, 122.6, 113.1, 89.4,
85.0, 73.3, 64.1, 39.2 ppm. HRMS: calcd. for [MNa]+ 416.0738;
found 416.0731.
8-Phenoxy-2Ј-deoxyguanosine (3a): Yield 44% (analytical purity),
90% (95% purity). TLC: 0.21 (10% methanol in dichloromethane).
IR: ν = 3312 (w), 3132 (w), 2945 (w), 1682 (s), 1597 (m), 1557 (s),
˜
1487 (m), 1417 (m), 1372 (m), 1346 (w), 1278 (w), 1203 (m), 1098
(m), 1053 (m), 967 (w), 776 (w) cm–1. 1H NMR (400 MHz, MeOD):
δ = 7.43 (dd, JH,H = 7.5, 8.5 Hz, 2 H, Ar-H), 7.31 (app. d, JH,H
=
8.0 Hz, 2 H, Ar-H), 7.26 (app. t, JH,H = 7.5 Hz, 1 H, Ar-H), 6.37
(dd, JH,H = 6.8, 7.7 Hz, 1 H, 1Ј-H), 4.56 (m, 1 H, 3Ј-H), 3.99 (m,
1 H, 4Ј-H), 3.80 (dd, JH,H = 4.0, 12.0 Hz, 1 H, 5Ј-H), 3.71 (dd,
JH,H = 4.5, 12.0 Hz, 1 H, 5Ј-H), 3.07 (ddd, JH,H = 6.2, 7.9, 13.7 Hz,
1 H, 2Ј-H), 2.27 (ddd, JH,H = 2.7, 6.6, 13.4 Hz, 1 H, 2Ј-H) ppm.
13C NMR (100 MHz, MeOD): δ = 158.8, 155.5, 154.9, 151.7, 151.6,
131.0, 126.7, 120.8, 113.1, 89.4, 85.0, 73.4, 64.2, 39.2 ppm. HRMS:
calcd. for [MNa]+ 382.1122; found 382.1134.
8-(2,4,6-Trichlorophenoxy)-2Ј-deoxyguanosine (3f): Yield 29%.
TLC: 0.26 (10% methanol in dichloromethane). IR: ν = 3351 (s),
˜
2933 (m), 1686 (s), 1587 (s), 1561 (s), 1443 (m), 1416 (m), 1340 (w),
1241 (w), 1101 (w), 1051 (w), 968 (w), 819 (w), 774 (w) cm–1. 1H
NMR (400 MHz, MeOD): δ = 7.63 (s, 2 H, Ar-H), 6.45 (app. t,
JH,H = 7.2 Hz, 1 H, 1Ј-H), 4.56 (m, 1 H, 3Ј-H), 4.03 (m, 1 H, 4Ј-
H), 3.82 (dd, JH,H = 4.0, 12.0 Hz, 1 H, 5Ј-H), 3.76 (dd, JH,H = 4.5,
12.0 Hz, 1 H, 5Ј-H), 3.09 (ddd, JH,H = 6.2, 8.0, 13.6 Hz, 1 H, 2Ј-
8-(2-Methylphenoxy)-2Ј-deoxyguanosine (3b): Yield 64%. TLC: H), 2.33 (ddd, JH,H = 2.8, 6.4, 13.6 Hz, 1 H, 2Ј-H) ppm. 13C NMR
0.20 (10% methanol in dichloromethane). IR: ν = 2940 (w), 1672 (125 MHz, MeOD): δ = 158.8, 155.1, 152.1, 150.1, 145.9, 134.0,
(s), 1654 (s), 1588 (m), 1558 (s), 1419 (m), 1367 (m), 1345 (m), 1280 131.1, 130.5, 112.9, 89.6, 85.1, 73.4, 64.3, 39.4 ppm. HRMS: calcd.
(w), 1225 (m), 1176 (m), 1105 (m), 1053 (w), 991 (w), 972 (w), 774
for [MNa]+ 483.9958; found 483.9950.
˜
Eur. J. Org. Chem. 2011, 2987–2992
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2991

H. A. Dahlmann, S. J. Sturla
FULL PAPER
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8-(2,3,4,5,6-Pentachlorophenoxy)-2Ј-deoxyguanosine (3g): Yield
27%. TLC: 0.30 (10% methanol in dichloromethane). IR: ν = 3327
˜
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(m), 2922 (m), 1680 (s), 1631 (m), 1586 (m), 1563 (m), 1420 (w),
1381 (m), 1098 (m), 775 (w), 713 (m) cm–1. 1H NMR (400 MHz,
MeOD): δ = 6.45 (dd, JH,H = 6.9, 7.6 Hz, 1 H, 1Ј-H), 4.56 (m, 1
H, 3Ј-H), 4.03 (m, 1 H, 4Ј-H), 3.82 (dd, JH,H = 4.2, 12.0 Hz, 1 H,
5Ј-H), 3.76 (dd, JH,H = 4.8, 12.0 Hz, 1 H, 5Ј-H), 3.11 (ddd, JH,H
=
6.2, 7.8, 13.5 Hz, 1 H, 2Ј-H), 2.34 (ddd, JH,H = 2.9, 6.6, 13.5 Hz, 1
H, 2Ј-H) ppm. 13C NMR (100 MHz, MeOD): δ = 155.2, 152.2,
149.7, 147.1, 133.6, 133.1, 129.4, 112.8, 89.6, 85.1, 73.3, 64.2,
39.3 ppm. HRMS: calcd. for [MNa]+ 551.9149; found 551.9153.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of compounds 2a–h and 3a–g.
Acknowledgments
The authors thank John W. Giraldes, Rahul R. Lad, and Thu N. T.
Nygen for carrying out preliminary studies. Funding from the U.S.
National Institutes of Health, National Cancer Institute (CA-
108604), the Engebretson Foundation, and the European Research
Council (260341) is acknowledged.
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Received: January 6, 2011
Published Online: April 21, 2011
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