Radical-based alkylation of guanine derivatives in aqueous medium

Article abstract of DOI:10.1039/c0ob01264e

The radical-based alkylation of 8-bromoguanosine (1a) and 8-bromo-2′-deoxyguanosine (1b) at the C8 position has been investigated in aqueous solutions. Alkyl radicals were generated by scavenging of the primary species of γ-radiolysis by the alcohol substrate. These reactions result in the efficient formation of intermolecular C-C bonds in aqueous media, by using the reactivity of α-hydroxyalkyl radicals derived from alcohols with 1a and 1b. A mechanism for the formation of C8 guanine alkylated adducts has been proposed, based on the quantification of radiation chemical yields for the disappearance of starting material and the formation of all products. Two α-hydroxyalkyl radicals are needed to form an alkylated guanine, the first one adding to C8 followed by ejection of Br^- with formation of guanyl adduct and the second one acting as reducing agent of the guanyl adduct.

Full text of DOI:10.1039/c0ob01264e

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Organic &
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PAPER
Radical-based alkylation of guanine derivatives in aqueous medium†
Chryssostomos Chatgilialoglu,* Clara Caminal‡ and Quinto G. Mulazzani§
Received 28th December 2010, Accepted 22nd February 2011
DOI: 10.1039/c0ob01264e
The radical-based alkylation of 8-bromoguanosine (1a) and 8-bromo-2¢-deoxyguanosine (1b) at the C8
position has been investigated in aqueous solutions. Alkyl radicals were generated by scavenging of the
primary species of g-radiolysis by the alcohol substrate. These reactions result in the efficient formation
of intermolecular C–C bonds in aqueous media, by using the reactivity of a-hydroxyalkyl radicals
derived from alcohols with 1a and 1b. A mechanism for the formation of C8 guanine alkylated adducts
has been proposed, based on the quantification of radiation chemical yields for the disappearance of
starting material and the formation of all products. Two a-hydroxyalkyl radicals are needed to form an
alkylated guanine, the first one adding to C8 followed by ejection of Br- with formation of guanyl
adduct and the second one acting as reducing agent of the guanyl adduct.
reactions of 2¢-deoxyguanosine with 2-propanol afforded the C8
Introduction
a-hydroxylalkyl derivative in 25% and 41% yield, respectively.12
Photochemical (acetone sensitized) reaction of guanosine with 8-
bromoguanosine affords the C8–C8 coupling.13
Radical adducts of guanine derivatives at the C8 position are
of great importance in DNA damage. The best example is the
hydroxyl radical adduct being the precursor of 8-oxoG and
FapyG, the most well known lesion of DNA damage caused by
oxidative stress.1–3 Another example is the covalent attachment
of the phenoxyl radical to a guanine moiety, which can occur
either through oxygen (O-bonded adducts) or carbon (C-bonded
adducts), due to the delocalization of the unpaired electron in
phenoxyl radicals.4–6 These adducts are biomarkers for phenol
exposure and related to phenol-mediated carcinogenesis. Early
work was reported on the C8 a-hydroxyalkylation of adenine and
guanine moieties in DNA and the reaction responsible for these
substitution products was suggested to be the addition of the a-
hydroxyalkyl radicals to the C8 position of the purine ring.7 It
was also found that the primary species formed after g-irradiation
in water are trapped by isopropanol to form secondary radicals
capable of deactivating DNA.8
Water is still rarely used as a solvent for radical reactions in
organic synthesis,14–16 mostly due to the lack of solubility for
the majority of organic compounds in this medium. In the last
decade, we developed several radical reactions in water owing to
their relevance for biomimetic chemistry,17,18 but also to provide an
easy access to modified biomolecules. For example, the aqueous
procedure is advantageous in the synthesis of modified nucleosides,
due to the elimination of protection–deprotection steps owing
to the selectivity of the radical approach when compared to
the “traditional” methods. Examples of radical reductions,19
radical oxidation20 and radical cyclizations21,22 can be found in the
literature. Herein, we report the success of an intermolecular C–C
bond formation in water by using the reaction of a-hydroxylalkyl
radicals derived from alcohols with 8-bromoguanine derivatives.
From a synthetic point of view, generally there are two routes to
substituted guanosines at the C8 position. One is by Pd-catalyzed
coupling of protected 8-bromoguanosine,9 as is exemplified by
the reaction with terminal alkynes (C–C bond formation)10 or
aromatic amines (C–N bond formation).11 Alternatively, radical-
based approaches have seldom been used, with specific sub-
stituents and generally poor yields. Thus, light- and g-ray-induced
Results and discussion
Radiolytic production of transients
Radiolysis of neutral water leads to the reactive species eaq-, HO∑
and H∑ together with H+ and H2O2 as shown in eqn (1). The values
in parentheses represent the radiation chemical yields (G) in units
of mmol J-1.23,24 In a N2O-saturated solution (~0.02 M of N2O), eaq
-
are transformed into HO∑ radical with a rate constant k2 = 9.1 ¥
109 M-1 s-1 (eqn (2)), affording a G(HO∑) = 0.55 mmol J-1, i.e., HO∑
radicals and H∑ atoms account for 90% and 10%, respectively, of
the reactive species.
ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, I-40129
Bologna, Italy. E-mail: chrys@isof.cnr.it; Fax: +39 051 639 8349; Tel: +39
051 639 8309
† Dedicated to the memory of Athel Beckwith, a pioneer in radical
chemistry.
‡ Present Address: Institute for Research in Biomedicine (IRB Barcelona),
Parc Cient´ıfic de Barcelona, c/Baldiri Reixac 10-12, 08028 Barcelona,
Spain.
H2O ⎯g⎯→e−aq (0.27), HO⋅(0.28),H⋅(0.06),H+ (0.27), H2O2(0.07)
§ Deceased January 2010.
(1)
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Table 1 Collected rate constants for the reactions of HO∑ radicals and
H∑ atoms with alcohols and reduction potential of the corresponding a-
hydroxylalkyl radicals
was taken up in water and purified on reverse-phase silica gel. The
main products with methanol, ethanol and isopropanol were the
C8-alkylated guanine derivative and in particular a-hydroxylalkyl
adducts 3, 4 and 5, respectively (Scheme 1), with good to excellent
yields (Table 2). In all cases, the replacement of Br with H was
also observed as a minor product. The debromination in low
conversion was the only reaction observed when tert-butanol is
used as the alcohol. Table 2 shows that the C8-alkylation products
increased in both ribo and deoxyribo series in the order methanol,
ethanol, isopropanol. When the alcohol used as a scavenger for
hydroxyl radicals is ethanol, the alkylated products 4a and 4b were
formed in two different diastereoisomeric forms and in a 1/1 ratio.
Alcohol
k(HO∑)a/M-1 s-1
k(H∑)a/M-1 s-1
E◦b,c/V
CH3OH
2.6 ¥ 106
1.7 ¥ 107
7.4 ¥ 107
1.7 ¥ 105
9.7 ¥ 108
1.9 ¥ 109
1.9 ¥ 109
6.0 ¥ 108
-1.18
-1.25
-1.39
MeCH2OH
Me2CHOH
Me3COH
a Ref. 23 and 24. b E◦[R1R2C(O), H+/R1R2C∑OH]. c Ref. 25.
∑
eaq + N2O + H2O → HO + N2 + HO-
-
(2)
When an alcohol is added to the solution, this acts as a scavenger
of HO∑ radicals and H-atoms, to generate a-hydroxyalkyl radicals
in an equivalent amount:
Reaction mechanism
The changes in the concentration of the starting material and
products were determined in the initial stages of the reactions (up
to 2 kGy) by HPLC using authentic samples as references. From
the concentration values, the radiation chemical yields (G) can be
calculated by dividing the disappearance of the starting material
or the formation of the products (mol kg-1) by the absorbed dose
(1 Gy = 1 J kg-1). Analysis of the data in terms of radiation
chemical yield (G) can give important information of the reaction
mechanism. As an example, Fig. 1 shows the plot of G for the
disappearance of 8-bromoguanosine (1a) and the formation of
products 5a and 6a versus dose in the experiment with isopropanol.
The extrapolation to zero dose gives G(-1a) = 0.34, G(5a) = 0.24,
and G(6a) = 0.06 mmol J-1.
In Table 3, the radiation chemical yields (G), extrapolated to
zero dose, are given for all the experiments done for both the ribo
and deoxyribo series. The estimated percentage error for these
values is about 10%. On the basis of the known rate constants for
the reactions of eaq-, HO∑ and H∑ reported above, the following
observations are underlined: firstly, in all cases the value of G(-1)
is similar to the sum of G values of the two products within
experimental error, e.g., G(-1b) = 0.35 vs. G(4b) + G(6b) = 0.34 for
ethanol; secondly, the G(-1) is approximately half of the calculated
G for the a-hydroxylalkyl radicals (eqn (1)–(3)), which suggests
that two a-hydroxylalkyl radicals are needed for each molecule of
starting material to be alkylated; thirdly, we noted that the G values
of a-hydroxylalkyl adducts are ca. 0.25, whereas the G(6) values are
close to 0.07 mmol J-1. In Scheme 2 the proposed mechanism that
is in agreement with the above mentioned observations is depicted
and can be explained as follows: the addition of an a-hydroxyalkyl
(3)
In Table 1, the rate constants for the reactions of various
alcohols used in this work with hydroxyl radical and hydrogen
atom are shown.23,24 Together with the rate constants, the reduction
potentials for the a-hydroxyalkyl radicals of the corresponding
alcohols are also reported.25 It is worth mentioning that hy-
droxyl radicals and hydrogen atoms are effectively scavenged by
isopropanol and the resulting a-hydroxyalkyl radical is a good
reducing radical. t-Butanol reacts quite well with hydroxyl radicals
but only poorly with hydrogen atoms (Table 1). On the other
hand, the rate constants of eaq and H∑ with 8-bromoguanosine
-
are 1.1 ¥ 1010 and 4.5 ¥ 108 M-1 s-1, respectively.26 In order to study
the reaction of a-hydroxyalkyl radicals with 8-bromoguanosine
(1a) and 8-bromo-2¢-deoxyguanosine(1b), N2O-saturated buffered
solutions (pH 7) of substrate (1.5 mM) in the presence of 0.25 M
alcohol were irradiated.
Product studies
Sample solutions (1.5 mM) of 1a and 1b in phosphate buffer
(the buffer avoids the acidity in the solutions that could lead to
hydrolysis of the nucleosides) and in the presence of 0.25 M alcohol
were saturated by N2O prior to irradiation. Irradiation doses were
in the 5–7 kGy range and in some cases pushed up to 15 kGy in
order to achieve the complete conversion of starting material (cf .
Table 2). The crude reaction mixture was lyophilised, the residue
Table 2 Product studies for the reaction of alcohols with 8-bromoguanosine (1a) and 8-bromo-2¢-deoxyguanosine (1b) under g-irradiation in N2O-
saturated aqueous solutions
Substratea
Alcohol (2)a
Doseb/kGy
Conv.c (%)
3d (%)
4d,e (%)
5d (%)
95
6d (%)
1a
CH3OH
15
10
7
5
5
5
6
5
100
100
100
9
75
95
75
25
10
5
100
35
15
10
100
MeCH2OH
Me2CHOH
Me3COH
CH3OH
MeCH2OH
Me2CHOH
Me3COH
90
1b
65
85
100
10
90
a Conditions: 1.5 mM substrate, 0.25 M alcohol, N2O-saturated buffered aqueous solution (pH 7). b Dose rate: 16 Gy min-1. c Conversion of starting
material. d Yield based on consumed starting material and HPLC analysis using authentic samples as reference for calibration curves. e Formation of two
diastereoisomers in a 1/1 ratio.
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Scheme 1 The reaction of 8-bromoguanine derivatives 1a and 1b with alcohols 2 under g-irradiation in N2O-saturated aqueous solutions at pH 7.
Fig. 1 Radiation chemical yields (G) of 8-bromoguanosine 1a (ꢀ),
C8-adduct 5a ( ), and guanosine 6a ( ) vs. dose; G(-1) = 0.34, G(5a) =
0.24, and G(6a) = 0.06 mmol J-1 are obtained when the lines are extrapolated
to zero dose.
Table 3 Radiation chemical yield (G, mmol J-1) for the reaction of alkyl
radicals with 8-bromoguanosine (1a) and 8-bromo-2¢-deoxyguanosine
(1b)a
Substrate
Alcohol (2)
G(-1)
G(3)
G(4)
G(5)
0.25
0.28
G(6)
1a
CH3OH
0.32
0.33
0.34
0.09
0.30
0.35
0.34
0.06
0.24
0.11
0.09
0.07
0.06
0.08
0.07
0.07
0.06
Scheme 2 Reaction mechanism for the a-hydroxylalkyl C8-adduct for-
mation of guanine derivatives.
MeCH2OH
Me2CHOH
Me3COH
CH3OH
MeCH2OH
Me2CHOH
Me3COH
0.26
guanine derivatives 6.28,29 Also H-atoms are expected to follow
two distinct reactions pathways. In the presence of tert-butanol
it is expected that the majority of H-atoms will afford the
adduct 10 followed by Br- ejection,30 whereas in the presence of
methanol H-atoms will be equally partitioned between hydrogen
abstraction from the alcohol and addition to C8 position of 1.
In ethanol or isopropanol, H-atoms are mainly scavenged by
hydrogen abstraction. Therefore, the products 6 arise from all
possible reduction processes, as reported in Scheme 3.
1b
0.22
0.27
a Estimated errors about 10%.
radical to the C8 position leads to radical 7 which, after loss of
bromide ion, leads to the radical cation of the alkylguanosine 8,
that is in equilibrium with its deprotonated form, 9 (a pKa ~ 4
is expected27). This neutral radical can be reduced by a second
a-hydroxyalkyl radical, to give the product substituted at the 8
position (3, 4 or 5).28
Conclusions
In the N2O-saturated aqueous solution and in the presence
of 1.5 mM 1a or 1b, solvated electrons are transformed in HO∑
radicals (90–92%) and 8–10% of them react with 1a or 1b. It is
well known that the reaction of 1 with eaq- produces debrominated
The radical-based alkylation of 8-bromoguanosine (1a) and
8-bromo-2¢-deoxyguanosine (1b) at the C8 position has been
disclosed. These reactions resulted in the efficient formation
of an intermolecular C–C bond in aqueous media, through
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5.81 (d, 1H, J = 6 Hz, H1¢); 5.5 (br s, 1H, disappeared on D2O
shake, OH); 5.28 (br s, 2H, disappeared on D2O shake, 2OH); 5.07
(br s, 1H, disappeared on D2O shake, OH); 4.74 (t, 1H, J = 6 Hz
collapsing to d J = 6 Hz upon irradiation at d 5.81, H2¢); 4.53 (1H,
A part of an AB system, JAB = 13 Hz); 4.46 (1H, B part of an AB
system, JAB = 13 Hz); 4.1 (1H, dd, J1 = 6 Hz, J2 = 3.5 Hz collapsing
to d J = 3.5 Hz upon irradiation at d 4.74, H3¢); 3.84 (q, 1H, J =
3.5 Hz, collapsing to t J = 3.5 Hz upon irradiation at d 4.1, H4¢);
3.65 (dd, 1H, J1 = 12 Hz, J2 = 3.5 Hz, collapsing to d J = 12 Hz
upon irradiation at d 3.84, H5¢); 3.50 (br s, 1H, collapsing to br
d J = 12 Hz upon irradiation at d 3.8 and to dd J1 = 12 Hz, J2 =
3.5 Hz on D2O shake, H5¢); 13C-NMR (100.6 MHz, DMSO-d6)
d 57.2 (CH2); 62.6 (CH2); 71.1 (CH); 72.4 (CH); 86.2 (CH);88.8
(CH); 116.2 (q); 148.1 (q); 152.5 (q); 154.3 (q); 158.0 (q); MS (ES-)
m/z 313 (M-1)-, MS(ES+) m/z 336 (M + Na)+
8-(1-Hydroxyethyl)guanosine (4a). Epimer A: 1H-NMR
(400 MHz, DMSO-d6) d 6.43 (br s, 2H, disappeared on D2O shake,
NH2); 5.92 (d, 1H, J = 6 Hz, H1¢); 5.8–5.0 (br s, 3H, disappeared
on D2O shake, 3 OH); 4.82 (q, 1H, J = 6 Hz collapsing to s upon
irradiation at d 1.45); 4.73 (t, 1H, J1 = 6 Hz; collapsing to d J = 6 Hz
upon irradiation at d 5.92, H2¢); 4.09 (dd, 1H, J1 = 6 Hz J2 = 2.5 Hz
collapsing to d J = 2.5 Hz upon irradiation at d 4.73, H3¢); 3.85 (m,
Scheme 3 Possible reductive paths of 8-bromoguanine derivatives (1).
the intermolecular addition of a-hydroxyalkyl radicals, derived
from alcohols, with 1a or 1b. Water was confirmed to be a
solvent with obvious advantages and provided a convenient media
for synthetically useful free radical reactions of biomolecules.
Furthermore, a mechanism for the formation of the C8 guanine
alkylated adducts has been proposed (Scheme 2), showing that
two molecules of a-hydroxyalkyl radicals are needed to form
the alkylated guanine, which is in good agreement with the
experimental evidence.
1H, H4¢); 3.65 (1H, A part of an ABX system JAB = 12 Hz, JAX
=
3.5 Hz, H5¢); 3.51 (1H, B part of an ABX system, JAB = 12 Hz,
JBX = 3 Hz, H5¢); 1.45 (d, 3H, J = 6 Hz); 13C-NMR (100.6 MHz,
DMSO-d6) d 26.9 (CH3); 66.8 (CH); 67.6 (CH2); 76.1 (CH); 77.2
(CH); 91.1 (CH); 93.7 (CH); 120.8 (q); 155.4 (q); 157.1 (q); 159.1
(q); 163.1 (q); MS (ES-) m/z 326 (M-1)-, MS(ES+) m/z 350 (M +
1
Na)+. Epimer B: H-NMR (400 MHz, DMSO-d6) d 10.90 (br s,
Experimental
1H, disappeared on D2O shake, NH); 6.37 (br s, 2H, disappeared
on D2O shake, NH2); 6.0 (d, 1H, J = 5.5 Hz, H1¢); 5.5 (br s, 1H,
disappeared on D2O shake, OH); 5.3 (br s, 1H, disappeared on
D2O shake, OH); 5.2 (br s, 1H, disappeared on D2O shake, OH);
5.0 (br s, 1H, disappeared on D2O shake, OH); 4.89 (t, 1H, J =
5.5 Hz, H2¢); 4.82 (q, 1H, J1 = 6.5 Hz); 4.20 (dd, 1H, J1 = 5.5 Hz,
J2 = 4 Hz,H3¢); 3.84 (q, 1H, J = 4 Hz H4¢); 3.64 (1H, A part of
an ABX system JAB = 11.5 Hz, JAX = 4 Hz, H5¢); 3.49 (br d, 1H,
collapsing to B part of an ABX system, JAB = 11.5 Hz, JBX = 4 Hz,
H5¢); 1.46 (d, 3H, J = 6.5 Hz); 13C-NMR (100.6 MHz, DMSO-d6)
d 22.8 (CH3); 62.9 (CH2); 63.3 (CH); 71.4 (CH); 71.9 (CH); 86.1
(CH); 89.0 (CH); 116.3 (q); 151.0 (q); 152.5 (q); 153.9 (q); 157.8
(q); MS (ES-) m/z 326 (M-1)-, MS(ES+) m/z 350 (M + Na)+.
8-Bromoguanosine 1a (Aldrich) and 8-bromo-2¢-deoxyguanosine
1b (Berry & Associates) were used as received. Solutions were
freshly prepared by using water purified with a Millipore (Milli-Q)
system. The pH was buffered with phosphates (pH 7). Continuous
radiolysis was performed at room temperature (22
2
◦C) on
250 mL samples using a 60Co-Gammacell, with dose rates between
20 and 22 Gy min-1. The absorbed radiation dose was determined
with the Fricke chemical dosimeter, by taking G(Fe3+) = 1.56 mmol
J-1.31 The reactions of 1a and 1b with a-hydroxyalkyl radicals were
studied using 1.5 mM buffered solutions (pH 7) of nucleoside and
using N2O-saturated solutions in the presence of 0.25 M alcohol,
irradiated with appropriate doses. The crude reaction mixture was
lyophilised and the residue was taken up in water and purified
on reverse-phase silica gel, eluting with 0 and 3% acetonitrile-
containing water. The UV-positive fractions were collected and
lyophilised to obtain the desired products as pure materials that
were spectroscopically characterised. 1H NMR and 13C NMR
spectra were obtained on a Varian Mercury 400 MHz. Qualitative
and quantitative HPLC studies were performed on a Waters
Associates Unit equipped with a model 600 multisolvent delivery
system and controller, a Waters 996 Photodiode Array Detector
and a Millenium 21 data workstation. The aqueous solutions of the
samples were loaded after dilution onto a reverse-phase analytical
column (Waters XTerra MS C18 5 mm 4.6 ¥ 150 mm), eluted in
50 mM ammonium with 0–20% acetonitrile gradient over 25 min
at a flow rate of 1 mL min-1, and detected at 254 nm.
8-(1-Hydroxy-1-methylethyl)guanosine
(5a). 1H-NMR
(400 MHz, DMSO-d6) d 10.8 (br s, 1H, disappeared on D2O
shake, NH); 6.5 (d, 1H, J = 6 Hz, H1¢); 6.27 (br s, 2H, disappeared
on D2O shake, NH2); 5.5 (br s, 1H, disappeared on D2O shake,
OH); 5.18 (br s, 1H, disappeared on D2O shake, OH); 5.12 (br
s, 1H, disappeared on D2O shake, OH); 4.89 (t, 1H, J = 6 Hz
collapsing to d J = 6 Hz upon irradiation at d 4.18, H2¢); 4.18 (dd,
1H, J1 = 6 Hz, J2 = 4 Hz; collapsing to d J = 6 Hz upon irradiation
at d 3.81, H3¢); 3.80 (q, 1H, J = 4 Hz collapsing to t J = 4 Hz
upon irradiation at d 4.18, H4¢); 3.66 (dd, 1H, J1 = 12 Hz, J2 =
4 Hz, collapsing to d J = 12 Hz upon irradiation at d 3.8, H5¢);
3.50 (dd, 1H, J1 = 12 Hz, J2 = 4 Hz, collapsing to d J = 12 Hz
upon irradiation at d 3.8, H5¢); 3.4 (br s, 1H, disappeared on
D2O shake, OH); 1.54 (s, 3H); 13C-NMR (100.6 MHz, DMSO-d6)
d 35.6 (CH3); 35.9 (CH3); 67.9 (CH2); 75.0 (q); 76.2 (CH); 76.6
(CH); 90.7 (CH); 94.6 (CH); 120.5 (q); 157.5 (q); 158.0 (q); 158.1
8-(Hydroxymethyl)guanosine (3a). 1H-NMR (400 MHz,
DMSO-d6) d 11.0 (br s, 1H, disappeared on D2O shake, NH);
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(q); 162.0 (q); MS (ES-) m/z 340 (M-1)-, MS(ES+) m/z 364 (M +
(q); 77.1 (CH); 90.7 (CH); 93.4 (CH); 120.8 (q); 157.2 (q); 157.4
(q); 158.6 (q); 162.9 (q); MS (ES-) m/z 324 (M-1)-, MS(ES+) m/z
348 (M + Na)+
Na)+
8-(Hydroxymethyl)-2¢-deoxyguanosine
(3b). 1H-NMR
(400 MHz, DMSO-d6) d 11.0 (br s, 1H, disappeared on
D2O shake, NH); 6.26 (dd, 1H, J1 = 8 Hz, J2 = 6 Hz, H1¢);
5.52 (br s, 1H, disappeared on D2O shake, OH); 5.24 (br s, 2H,
Acknowledgements
The support and sponsorship of COST Action CM0603 on
“Free Radicals in Chemical Biology (CHEMBIORADICAL)” are
gratefully acknowledged.
disappeared on D2O shake, OH); 4.51 (2H, AB system JAB
=
13 Hz; inner line separation 8 Hz); 4.36 (br s, 1H, H3¢); 3.82 (m,
1H, H4¢); 3.63 (A part of an ABX system, 1H, JAB = 12 Hz, JAX
5 Hz, H5¢); 3.53 (B part of an ABX system, 1H, JAB = 12 Hz, JBX
=
=
References
5 Hz, H5¢); 2.92 (ddd, 1H, J1 = 14 Hz, J2 = 8 Hz, J3 = 6 Hz, H2¢);
2.04 (ddd, 1H, J1 = 14 Hz, J2 = 6 Hz, J3 = 2 Hz, H2¢); 13C-NMR
(100.6 MHz, DMSO-d6) d 41.6 (CH2); 60.2 (CH2); 65.5 (CH2);
74.6 (CH); 87.5 (CH); 91.1 (CH); 119.0 (q); 150.5 (q); 155.2 (q);
157.1 (q); 160.8 (q); MS (ES-) m/z 296 (M-1)-, MS(ES+) m/z 320
(M + Na)+
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8-(1-Hydroxyethyl)-2¢-deoxyguanosine (4b). Epimer A: 1H-
NMR (400 MHz, DMSO-d6) d 6.48 (br s, 2H, disappeared on
D2O shake, NH2);6.43 (dd, 1H, J1 = 7 Hz, J2 = 6 Hz, H1¢); 5.5(br
s, 1H, disappeared on D2O shake, OH); 5.4 (br s, 1H, disappeared
on D2O shake, OH); 5.20 (br s, 1H, disappeared on D2O shake,
OH); 4.86 (br q, 1H, collapsing to q J = 6.5 Hz on D2O shake);
4.35 (m, 1H, H3¢); 3.80 (m, 1H, H4¢); 3.65 (A part of an ABX
system, 1H, JAB = 12 Hz, JAX = 4 Hz, H5¢); 3.53 (B part of an
ABX system, 1H, JAB = 12 Hz, JBX = 3.5 Hz, H5¢); 2.91 (ddd, 1H,
J1 = 13 Hz, J2 = J3 = 6.5 Hz, H2¢); 2.00 (dd, 1H, J1 = 13 Hz,
J2 = 7 Hz, H2¢); 1.45 (d, 3H, J = 6.0 Hz); 13C-NMR (100.6 MHz,
DMSO-d6) d 22.5 (CH3); 38.8 (CH2); 62.8 (CH2); 63 (CH); 71.9
(CH); 84.7 (CH); 88.4 (CH); 116.0 (q); 150.1 (q); 152.4 (q); 154.6
(q); 158.7 (q); MS (ES-) m/z 310 (M-1)-, MS(ES+) m/z 334 (M +
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1
Na)+. Epimer B: H-NMR (400 MHz, DMSO-d6) d 10.80 (br s,
1H, disappeared on D2O shake, NH); 6.36 (t, 1H, J1 = 7 Hz,
H1¢); 6.29 (br s, 2H, disappeared on D2O shake, NH2); 5.51 (br
d, 1H, J = 6 Hz disappeared on D2O shake, OH); 5.25 (br s, 1H,
disappeared on D2O shake, OH); 5.21 (br s, 1H, disappeared on
D2O shake, OH); 4.81 (m, 1H, collapsing to d J = 6 Hz on D2O
shake); 4.38 (br s,1H, H3¢); 3.81 (br s, 1H, H4¢); 3.63 (A part of an
ABX system, 1H, JAB = 12 Hz, JAX = 4 Hz, H5¢); 3.48 (br d, B part
of an ABX system, 1H, JAB = 12 Hz, JBX = 3.5 Hz, H5¢); 3.00 (ddd,
1H, J1 = 13 Hz, J2 = J3 = 7 Hz, H2¢); 2.02 (dd, 1H, J1 = 13 Hz,
J2 = 7 Hz, H2¢); 1.46 (d, 3H, J = 7.0 Hz); 13C-NMR (100.6 MHz,
DMSO-d6) d 21.9 (CH3); 38.2 (CH2); 62.3 (CH); 63.0 (CH2); 72.1
(CH); 85.0 (CH); 88.6 (CH); 116.4 (q); 150.4 (q); 152.3 (q); 153.7
(q); 157.6 (q); MS (ES-) m/z 310 (M-1)-, MS(ES+) m/z 334 (M +
Na)+
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8-(1-Hydroxy-1-methylethyl)-2¢-deoxyguanosine
(5b). 1H-
NMR (400 MHz, DMSO-d6) d 11.0 (br s, 1H, disappeared on
D2O shake; NH); 6.94 (dd, 1H, J1 = 7 Hz, J2 = 6 Hz, H1¢);
6.28 (br s, 2H, disappeared on D2O shake, NH2); 5.61 (br s, 1H,
disappeared on D2O shake, OH); 5.44 (br s, 1H, disappeared on
D2O shake, OH); 5.16 (br s, 1H, disappeared on D2O shake, OH);
4.40 (m, 1H, H3¢); 3.83 (m, 1H, H4¢); 3.68 (A part of an ABX
system, 1H, JAB = 12 Hz, JAX = 4 Hz, H5¢); 3.54 (B part of an
ABX system, 1H, JAB = 12 Hz, JBX = 3 Hz, H5¢); 2.99 (ddd, 1H,
J1 = 12 Hz, J2 = 8.5 Hz, J3 = 7 Hz, H2¢); 1.99 (dd, 1H, J1 = 12 Hz,
J2 = 6 Hz, H2¢); 1.53 (s, 3H); 1.51 (s, 3H); 13C-NMR (100.6 MHz,
DMSO-d6) d 35.2 (CH3); 35.6 (CH3); 42.9 (CH2); 68.0 (CH2); 74.9
3498 | Org. Biomol. Chem., 2011, 9, 3494–3498
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