Synthesis of 5-(pyridinyl and pyridiniumyl)-2'-deoxyuridine nucleosides: reversible electron traps for DNA.

Article abstract of DOI:10.1081/NCN-120015725

The desire to produce reversible electron traps for direct, room temperature studies of excess electron transport in DNA duplexes and hairpins motivated our efforts first to link pyridines to 2'-deoxyuridine (pyridinyl-dU) and then to convert these new co

Full text of DOI:10.1081/NCN-120015725

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SYNTHESIS OF 5-(PYRIDINYL AND PYRIDINIUMYL)-2′-
DEOXYURIDINE NUCLEOSIDES: REVERSIBLE ELECTRON
TRAPS FOR DNA
Samir T. Gaballah a & Thomas L. Netzel a
a Department of Chemistry , Georgia State University , Atlanta, GA, 30303, U.S.A.
Published online: 17 Aug 2006.
To cite this article: Samir T. Gaballah & Thomas L. Netzel (2002) SYNTHESIS OF 5-(PYRIDINYL AND PYRIDINIUMYL)-2′-
DEOXYURIDINE NUCLEOSIDES: REVERSIBLE ELECTRON TRAPS FOR DNA, Nucleosides, Nucleotides and Nucleic Acids, 21:10,
681-694, DOI: 10.1081/NCN-120015725
To link to this article: http://dx.doi.org/10.1081/NCN-120015725
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 21, No. 10, pp. 681–694, 2002
SYNTHESIS OF 5-(PYRIDINYL
AND PYRIDINIUMYL)-20-DEOXYURIDINE
NUCLEOSIDES: REVERSIBLE ELECTRON
TRAPS FOR DNA
Samir T. Gaballah and Thomas L. Netzel*
Department of Chemistry, Georgia State University,
Atlanta, GA 30303
ABSTRACT
The desire to produce reversible electron traps for direct, room tem-
perature studies of excess electron transport in DNA duplexes and
hairpins motivated our efforts first to link pyridines to 20-deoxyuridine
(pyridinyl-dU) and then to convert these new conjugates into pyr-
idiniumyl-dU nucleosides. Base sensitivity studies presented here rule out
general use of bipyridinediiumyl compounds, but show that pyridiniumyl
compounds are suitable for use under the strand cleavage and base
deprotection procedures required for automated solid-phase oligonu-
cleotide synthesis. This paper presents the synthesis of four 50-O-DMT-
protected 5-(N-methylpyridiniumyl)-dU conjugates using either ethynyl
or ethylenyl linkers to join the pyridiniumyl and dU subunits.
*Corresponding author. Fax: (404) 651-3129; E-mail: tnetzel@gsu.edu
681
DOI: 10.1081=NCN-120015725
Copyright # 2002 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

682
GABALLAH AND NETZEL
INTRODUCTION
Interest in the mechanisms and possible lessening of radiation damage
to deoxyribonucleic acid (DNA) in biological systems has prompted a
number of studies of charge transport in model DNA systems.[1] The vast
majority of these studies focused on the mechanisms of hole transport.[2–35] A
few recent ones using naturally occurring DNA with added intercalating
electron acceptors have studied excess electron transport at low tempera-
tures.[36–38] Importantly a recent study of photoinduced excess electron
transfer in DNA at room temperature implies that excess electrons can hop
over distances as large as 24 A to reductively repair thymine dimers.[39] The
timescale for this biologically desirable electron transport is, however,
unknown as the dynamics of this process have not yet been directly observed.
Even for the case of hole transport in DNA duplexes at room temperature
there are only a small number of direct observations of elementary electron
transfer reactions and no direct observations of the dynamics of hole
transport.[7,8,10,11,29–31,40,41]
We desired to advance real-time studies of excess electron transport in
DNA by creating additional electron trapping nucleosides that can be
incorporated into DNA duplexes and that offer a range of trap depths (ease
of reduction). To this end we sought to link pyridines to 20-deoxyuridine
(pyridinyl-dU) and then to convert these new conjugates into pyridiniumyl-
dU nucleosides. By analogy to 4,40-bipyridinediium (methyl viologen),[42,43]
we reasoned that pyridiniumyl-dU nucleoside conjugates could function as
reversible electron acceptors when incorporated into DNA duplexes.
Importantly, pyridinyl radicals are known to have intense absorbances in
the near-UV and moderately strong absorbances in the visible spectral
regions.[44,45] Thus pyridiniumyl-dU nucleosides should serve as good indi-
cators of excess electron trapping in kinetics studies of electron transport in
DNA. Our prior work on the synthesis 5-(2,20-bipyridinediiumyl)-dU con-
jugates alerted us to the necessity of testing the stability of quaternized
aromatic heterocycles toward bases commonly used in the base deprotection
and strand cleavage reactions that follow automated DNA synthesis.[46] As
will be discussed below, bipyridinediiumyl-dU nucleosides are base sensitive,
but pyridiniumyl-dU nucleosides are not.
To date our work in the area of nucleoside conjugate chemistry has
produced a number of pyrenyl-dU (Py-dU) conjugates that are capable of
photoinjecting an excess electron into a DNA p-stack.[47–51] In these con-
jugates the lowest electronic, excited singlet-state of pyrene reduces the
attached uracil in less than 30 ps, and in methanol the resulting primary
electron transfer (ET) product, Pyꢀþ=dUꢀ ꢁ , lives from 6 ps to 2.1 ns
depending upon the type of linker that joins the pyrenyl and uracil subunits.
To further increase the lifetime of a photogenerated uracil anion in a DNA
duplex, we have also synthesized several dimethylanilino-dU conjugates

REVERSIBLE ELECTRON TRAPS FOR DNA
683
(DMA-dU) to serve as secondary electron donors.[52] In duplexes labeled
with both Py-dU and DMA-dU, secondary ET from DMA to Pyꢀþ=dUꢀ ꢁ
should produce the DMAꢀþ=Py=dUꢀ ꢁ ET product that is expected to live
significantly longer than Pyꢀþ=dUꢀ ꢁ . Thus the time is right to develop
electron-trapping nucleoside conjugates. In addition to the syntheses of four
pyridinyl-dU nucleosides, this paper also reports the synthesis of four pyr-
idiniumyl-dU nucleoside traps.
Our approach to constructing electron-trapping nucleoside conjugates
focused initially on nitrogen-containing aromatic heterocycles as a class of
compounds in which imine nitrogen atoms could be quaternized to give p-
electron-deficient heterocycles. N,N0-Dimethyl-4,40-bipyridinediium (MV2þ),
N,N0-polymethylene-2,20-bipyridinediium (2,20-BpyEt2þ and 2,20-BpyPr2þ),
and N-methylpyridinium (MPþ) salts were thus candidates for attachment to
dU (see Fig. 1 for structures).The base sensitivity studies presented below
ruled out general use of bipyridinediiumyl compounds, but showed that
pyridiniumyl compounds were not base sensitive. Importantly MPþ showed
remarkable stability towards a variety of basic conditions used during
phosphoramidite creation and strand cleavage following automated oligo-
nucleotide synthesis. Additionally, MPþ could be attached to dU at a
number of pyridinyl positions, and could also be substituted prior to
attachment to vary its reduction potential.[44,53–55]
A straightforward way of positioning an electron trap in the DNA
major groove is to attach covalently an easily reducible subunit to the 5-
position of uridine. Based on reduction potential considerations alone, either
uridine or cytidine could be used as the reducible nucleoside in an electron
trapping conjugate: these two nucleosides are the easiest of naturally
occurring nucleosides to reduce, and they have the same reduction poten-
tial.[56–58] However, uridine is simpler to modify, and the anion radical of
uridine is not protonated in DNA while that of cytidine is.[59–64] Thus other
factors remaining the same, excess electron hopping from a reduced uridine
should proceed more rapidly than from a reduced cytidine. In addition to
locating the electron trap in the major groove, it is also important to provide
strong electronic coupling between the trapping subunit and the initially
reduced uracil base in the nucleoside conjugate. Thus both ethynyl and
ethylenyl linkers are of interest in this context. This paper reports the
Figure 1. Structural drawings of four electron-trap candidates.

684
GABALLAH AND NETZEL
synthesis of four pyridiniumyl-dU nucleoside conjugates: 2- and 3-pyri-
diniumyl subunits attached with both ethynyl and ethylenyl linkers to
C5-uracil (see Sch. 1). The ethylenyl linked pyridiniumyl-dU conjugates are
formed via selective hydrogenation of the corresponding ethynyl-linked
conjugates. To our knowledge no pyridiniumyl-dU conjugates have been
made previously and among the precursor pyridinyl-dU conjugates only
30,50-O-di-trimethylsilyl-5-(2-ethynylpyridinyl)-20-deoxyuridine has been syn-
thesized previously.[65] Also in that prior work, the starting 2-ethynylpyridine
was first lithiated and then transformed into 2-ethynylpyridylzinc before
PdL2 (or nickel) catalyzed coupling to 30,50-O-di-trimethylsilyl-dU. This work
presents a shorter synthetic route with a higher yield to either protected or
unprotected 5-(2- and 3-ethynylpyridinyl)-dU compounds. A related pyr-
idiniumyl-dG covalent adduct has been reported in work on an a,o-diether
linked di(1-methyl-2-pyridiniumaldehyde) bifunctional compound that inhi-
bits growth of cultured tumor cells.[66] At room temperature the di(pyidi-
niumaldehyde) reagent associates with the outside of a self-complementary
Scheme 1. (a) PdL4, CuI, Et3N, THF; (b) H2 (50 psi), Pd/C, MeOH; (c) MeI, MeCN, 50ꢂC.

REVERSIBLE ELECTRON TRAPS FOR DNA
685
DNA decamer mainly at the central 50-CpG-30 site. At 38ꢂC the exocylic
amino group of this central dG forms a covalent bond with one of the
di(pyridiniumaldehyde)0s carbonyl groups. The resulting reversible, covalent
adduct has not been isolated.
In this paper, we present the synthesis of four 50-O-DMT-protected 5-
(N-methylpyridinium)-dU conjugates as precursors to phosphoramidites that
can be incorporated into DNA strands via automated synthesis. To create
these conjugates, we connected 2- and 3-ethynylpyridines to the 5-position of
50-O-DMT-dU using Pd(0) cross-coupling chemistry.[67] This was followed
when desired by heterogeneous catalytic reduction of the alkyne linkers.[68]
Lastly, we selectively quaternized the pyridinyl nitrogen atoms of both the
ethynyl- and the ethylenyl-linked, DMT-protected dU conjugates.
RESULTS AND DISCUSSION
To produce nucleoside conjugates that can function as traps for excess
electrons in DNA duplexes, we decided to join electron deficient moieties to
dU as discussed above. After this was accomplished, the DMT-protected
nucleoside traps would be ready to be phosphorylated and incorporated into
DNA strands. During the course of DNA strand synthesis, bases would be
used in capping, deprotection, and strand cleavage reactions.[69,70] Since the
electron-deficient centers in the nucleoside traps could possibly be attacked
by nucleophiles during these reactions, we tested the chemical stability of
several potential electron trapping moieties against bases used in DNA
synthesis. Based on the base-stability results presented below, we selected the
trapping moieties to be used as labels in nucleoside conjugate traps.
Model Salt Stability in 0.05 M K2CO3=Methanol (MeOH). Solutions
of MV2, 2,20-BpyEt2þ, and 2,20-BpyPr2þ in 0.05 M K2CO3=MeOH71 (by
vol.) turned bright yellow immediately after addition of the test salt and
progressively darkened until they became light red after two h of stirring at
room temperature. (Solutions of these compounds in MeOH, however,
remained pale yellow.) After this time TLC showed a mobile organic spot (Rf
about 0.65) in 2% MeOH (by vol.) in dichloromethane. After continued
stirring overnight, the solution became dark red and no organic spot was seen
on the TLC plate. In contrast for MPþunder the same conditions, color,
1
TLC, and H NMR showed no changes compared to solution of the salt in
MeOH.
Model Salt Stability in 10% Diethyl Amine=MeOH. Solutions of the
salts of MV2, 2,20-BpyEt2þ, and 2,20-BpyPr2þ in 10% diethyl amine in
MeOH (by vol.) showed a rapid color change from yellow to red over a 1 m
time period. After 2 h TLC showed a mobile organic spot (Rf about 0.5) in

686
GABALLAH AND NETZEL
2% MeOH (by vol.) in dichloromethane. The same results were observed for
solutions of the salts in 60% diethyl amine in MeOH except that the organic
spots in TLC were smaller. As above MPþunder the same conditions showed
1
no changes in color, TLC behavior, or H NMR signal compared to a
solution of the salt in MeOH.
Model Salt Stability in 10% 2,6-Lutidine=Dimethylsulfoxide (DMSO).
Solutions of the salts of MV2þ, 2,20-BpyEt2þ, and 2,20-BpyPr2þ in 10% 2,6-
Lutidine (by vol.) in DMSO showed an immediate change in color from
yellow to yellowish-green and turned dark green after 2 h. TLC analysis in
water and MeOH (1:1 by vol.) showed that ca. half of the initial amount of
BpyPr2þ was still present after stirring for 2 h along with two mobile organic
spots. For solutions of MV2þ and 2,20-BpyET2þ, however, TLC analysis
showed complete loss of the initial material after stirring for 2 h. After
continuous stirring overnight, all three solutions became dark red, and TLC
analysis showed complete loss of the initial dications. However, as in the
previous tests, MPþ under the same conditions showed no change in color,
1
TLC behavior, or H NMR signal compared to a solution of the salt in
MeOH.
Clearly the three bipyridinediiumyl compounds MV2þ, 2,20-BpyEt2þ
,
and 2,20-BpyPr2þ are not stable in the presence of the above bases, and thus
will not survive DNA base deprotection and strand cleavage reactions. In
contrast the MPþ cation survived the above tests of base stability and thus,
with respect to basic reagents, is compatible with automated solid-phase
oligonucleotide synthesis. Based on these results, we decided invest our time
to synthesize four N-methylpyridiniumyl-dU conjugates.
Syntheses of N-Methylpyridiniumyl-dU Conjugates. Syntheses of N-
methylpyridiniumyl-dU conjugates were achieved as described in Sch. 1.
Initially (not shown) 50-O-(4,40-dimethoxytrityl)-5-iodo-20-deoxyuridine was
synthesized according to a published procedure,[72] then it was cross-coupled
to 2-ethynyl pyridine using Sonogashira67 PdL4 catalytic chemistry to afford
1a in 70% yield.[73–75] The same Pd(0) cross-coupling approach, produced 1b
in low yield (<28%). Because an active Pd-catalyst can be generated in situ
from PdL2Cl2 and CuI and this procedure may facilitate alkynylation of
a palladium(II) intermediate,[76] we ran the reaction to produce 1b with
PdL2Cl2 and CuI instead of PdL4 and thereby increased its yield to 69%.
Heterogeneous catalytic hydrogenation[68] of 1a and 1b in dry MeOH using
H2 (50 psi) over 10% Pd=C was performed by stirring at room temperature in
a sealed glass vessel. The glass vessel was sealed with either stainless steel or
brass fittings and topped with a pressure gauge. Before adding the reactants
(1a and 1b), the Pd=C-catalyst in MeOH was activated by pressurizing
the hydrogenation vessel with hydrogen (50 psi) and stirring the slurry for

REVERSIBLE ELECTRON TRAPS FOR DNA
687
15–20 m. After complete consumption of the reactants, the hydrogenation
reaction afforded 2a and 2b in yields, respectively, of 71 and 93%.
Compounds 1 and 2 quaternized readily in dry acetonitrile containing
freshly distilled iodomethane to give, respectively, compounds 3 and 4 in
yields of ranging from 54 to 72%.
EXPERIMENTAL
General Procedures
5-Iodo-20-deoxyuridine (IdU), 2- and 3-ethynylpyridines, iodomethane,
and 4,40-dimethoxytrityl chloride (DMTCl) were obtained from Aldrich
Chemicals and were used after drying. Dichlorodi(triphenylphosphine)
palladium(II) (PdL2Cl2) and copper(I) iodide (CuI) were obtained from
Strem Chemicals and used without further purification. Tetrakis-
(triphenylphosphine)palladium(0) (PdL4) was prepared according to the
literature and stored in a glove-box freezer (ꢁ33ꢂC).[77] The following solvents
were dried and redistilled in continuous circulation distillation apparati:
tetrahydrofuran (THF, dried with benzophenone=Na0), triethylamine (Et3N,
dried with CaH2), N,N-dimethylformamide (DMF, dried with CaH2), and
MeOH (dried with Mg turnings). PdL4 and DMTCl were handled in a
Vacuum AtmospheresTM M040-2 glove box that was pressurized with dry
nitrogen gas. All other reactions were carried out on the benchtop under a
dry nitrogen atmosphere. Chromatography was carried out on a Biotage
Flash-40TM system using either prepackaged KP-SilTM cartridges, or Flash-
40TM cartridge housings repacked with WhatmanTM flash silica (80 A pore,
230–400 mesh). WhatmanTM flash silica was also used for pad filtrations and
dry powder sample loading for silica gel chromatography. Mass spectrometry
1
was performed at the Georgia Institute of Technology. H and 13C NMR
spectra were recorded at GSU on a Varian Unityþ300 spectrometer oper-
ating, respectively, at 300- and 75-MHz frequencies.
Stability Studies of Model Electron Traps in Basic Solutions. To 10 mg
each of MV2þ, 2,20-BpyEt2þ, 2,20-BpyPr2þ, and MPþ (dried over a vacuum
manifold), 10 mL of 0.05 M K2CO3=MeOH (or 10% diethyl amine=MeOH
or 10% 2,6-lutidine=DMSO, v=v) was added under a nitrogen atmosphere,
and the solutions were allowed to stir overnight. Reaction progress was
monitored with NaBr-treated TLC plates[78] every 30 m for 3 h and after
overnight stirring.
50-O-(4,40-Dimethoxytrityl)-5-(pyridin-2-yl-ethynyl)-20-deoxyuridine, 1a.
To a solution of 50-O-(4,40-dimethoxytrityl)-5-iodo-20-deoxyuridine (650 mg,
1.00 mmol), PdL4 (57 mg, 0.05 mmol), CuI (19 mg, 0.10 mmol), and Et3N

688
GABALLAH AND NETZEL
(275 mL, 2.00 mmol) in DMF (5 mL) was added 2-ethynylpyridine (352 mL,
3.00 mmol) in a glove box. The reaction mixture was stirred at 50–60ꢂC for
30–50 min. After drying in vacuo, the solid was applied to a column packed
with silica gel or purified by flash chromatography. In both cases the
adsorbent was pretreated with 1% pyridine or Et3N (by vol.) in dichlor-
omethane. Purification using flash chromatography on silica gel with the
following elutions, 50% hexane (by vol.) in dichloromethane, dichlor-
omethane, and 1% MeOH (by vol.) in dichloromethane, gave 445 mg (70%
1
0
0
yield) of 1a. H NMR (CDCl3, 300 MHz) d: 2.41–2.62 (2 H, m, H2 a=H2 b),
0
0
3.31–3.46 (2 H, m, H5 a=H5 b), 3.67 (6 H, s, DMT-(OCH3)2), 4.10 (1 H, m,
0
0
0
0
H4 ), 4.16 (1H, br, OH3 ), 4.58 (1 H, m, H3 ), 6.33 (1 H, t, J ¼ 6.3 Hz, H1 ),
6.76 (4 H, d, J ¼ 7.7 Hz, Ar), 7.04–7.33 (9 H, m, Ar), 7.38–7.43 (3 H, m,
pyridine), 8.23 (1 H, s, H6), 8.47 (1 H, d, J ¼ 4.0 Hz, pyridine), 9.80 (1 H, br,
HN3). 13C NMR (CDCl3, 75 MHz) d: 41.25, 55.13, 63.57, 71.10, 81.29, 85.88,
86.10, 86.67, 92.10, 99.03, 113.20, 122.76, 126.81, 127.53, 127.88, 129.92,
130.00, 135.57, 135.67, 136.09, 142.44, 144.04, 144.64, 149.27, 149.31, 158.45,
161.18. HRMS (FAB) m=z for C37H34N3O7 (M þ H)þ: calc’d. 632.2396,
found 632.2407.
2-[50-O-(4,40-dimethoxytrityl)-20-deoxyuridine-5-yl-ethynyl]-N-methyl-
pyridiniumyl Iodide, 3c. In a Schlenk-like flask, 1a (100 mg, 0.16 mmol) was
co-evaporated 3 times with dry THF at 5610ꢁ4 torr. The Schlenk-like flask
was then brought inside a glove box, charged with 6 mL of dry acetonitrile
and 300 mL of freshly distilled iodomethane. The solution was degassed 3
times at 5610ꢁ4 torr. The solution was stirred overnight at 50ꢂC in vacuo.
The acetonitrile solution was removed in vacuo, and the greenish-yellow solid
was washed several times with hexane, dichloromethane, and acetone and
purified by repeated precipitations with hexane to afford 65 mg of 3c (56%
1
0
0
yield). H NMR (DMSO-d6, 300 MHz) d: 2.23–2.42 (2 H, m, H2 a=H2 ,b),
0
3.14–3.26 (3 H, m, H5 a=H5 b=H4 ), 3.63 (3 H, s, DMT-OCH3), 3.64 (3 H, s,
0
0
0
DMT-OCH3), 3.97 (3 H, s, CH3), 4.33 (1 H, m, H3 ), 5.38 (1 H, d, J ¼ 4.8 Hz,
0
0
OH3 ), 6.10 (1 H, t, J ¼ 6.0 Hz, H1 ), 6.86–6.82 (4 H, m, Ar), 7.44–7.10 (10 H,
m, Ar), 7.98 (1 H, t, J ¼ 6.3 Hz, pyridinium), 8.39 (1 H, t, J ¼ 8.4 Hz, pyr-
idinium), 8.48 (1 H, s, H6), 8.95 (1 H, d, J ¼ 6.3 Hz, pyridinium), 12.05 (1 H,
br, HN3). 13C NMR (DMSO-d6, 75 MHz) d: 46.55, 55.05, 55.07, 69.51, 79.20,
83.73, 85.87, 86.05, 95.15, 100.38, 113.32, 126.20, 127.61, 128.00, 129.64,
129.72, 130.18, 135.44, 135.51, 136.73, 144.43, 144.76, 146.94, 147.09, 149.11,
þ
158.07, 158.11, 161.01. HRMS (FAB) m=z for C38H36N3O7 (Mþ): calc’d.
646.2553, found 646.2527.
50-O-(4,40-Dimethoxytrityl)-5-(pyridin-2-yl-ethylenyl)-20-deoxyuridine, 2a.
Dry 1a (280 mg, 0.44 mmol) was dissolved in 60 mL of dry MeOH and added to
30 mL MeOH solution containing 150 mg of 10% Pd=C previously activated by
stirring under H2 (50 psi) for 20 m at room temperature. The reaction mixture

REVERSIBLE ELECTRON TRAPS FOR DNA
689
was further stirred under H2 (50 psi) at room temperature until complete
consumption of the starting materials (18 h). The solution was then filtered,
reduced in volume to 0.5 mL, and purified on a silica gel column or by flash
chromatography. In both cases the adsorbent was pretreated with 1% pyridine
or Et3N (by vol.) in dichloromethane. Eluting with hexane, 50% hexane (by
vol.) in dichloromethane, and 1.5%–3.5% MeOH (by vol.) in dichloromethane
afforded a yellow foam of 2a (198 mg, 71% yield). 1H NMR (CDCl3, 300MHz)
0
0
d: 2.13 (1 H, m, H2 b), 2.23–2.34 (2 H, m, CH2), 2.42 (1 H, m, H2 a), 2.67–2.82 (2
0
H, m, CH2), 3.20–3.36 (2 H, m, H5 a=H5 b) 3.60 (6 H, s, DMT-(OCH3)2), 3.96 (1
0
0
0
0
H, m, H4 ), 4.16 (1 H, br, OH3 ), 4.45 (1 H, m, H3 ), 6.30 (1 H, t, J ¼ 6.5 Hz,
0
H1 ), 6.66–6.71 (5 H, m, Ar), 6.91–7.38 (12 H, m, Ar), 8.34 (1 H, d, J ¼ 4.2 Hz,
pyridine), 10.12 (1 H, s, HN3). 13C NMR (CDCl3, 75 MHz) d: 27.02, 36.51,
40.25, 55.17, 63.70, 72.01, 84.33, 85.43, 86.64, 113.19, 114.35, 121.17, 123.08,
126.99, 127.91, 128.10, 130.03, 135.51, 136.23, 136.41, 144.43, 148.82, 150.35,
158.57, 160.59, 163.20. HRMS (FAB) m=z for C37H38N3O7 (M þ H)þ: calc’d.
636.2709, found 636.2824.
2-[50-O-(4,40-Dimethoxytrityl)-20-deoxyuridine-5-yl-ethylenyl]-N-methyl-
pyridiniumyl Iodide, 4c. In a Schlenk-like flask, 2a (191 mg, 0.30 mmol) was
co-evaporated 3 times with dry THF at 5610ꢁ4 torr. The Schlenk-like flask
was then brought inside a glove box, charged with 6 mL of dry acetonitrile
containing 280 mL of freshly distilled iodomethane. The solution was free-
ze=pump (5610ꢁ4 torr)=thaw degassed 3 times and stirred overnight at 50ꢂC
in vacuo. The acetonitrile solution was removed in vacuo, and the greenish-
yellow solid was washed several times with hexane, dichloromethane, and
acetone. Finally the solid was purified by repeated precipitations with hexane
1
to afford 125 mg (54% yield). H NMR (DMSO-d6, 300 MHz) d: 2.15–2.42
0
(4 H, m, H2 a=H2 b=CH2), 2.82–3.04 (2 H, m, CH2), 3.12 (1 H, m, H5 b), 3.25
0
0
0
(1 H, m, H5 a), 3.67 (6 H, s, DMT-(OCH3)2), 3.86 (1 H, m, H4 ), 4.05 (3 H,
0
0
0
s, CH3), 4.32 (1 H, m, H3 ), 5.34 (1 H, d, J ¼ 4.8 Hz, OH3 ), 6.20 (1H, t,
0
J ¼ 6.6 Hz, H1 ), 6.85 (4 H, dd, J ¼ 2.7, 9.1 Hz, Ar), 7.13–7.38 (9 H, m, Ar),
7.56 (1 H, d, J ¼ 7.5 Hz, pyridinium), 7.67 (1 H, s, H6), 7.91 (1 H, t,J ¼ 6.4 Hz,
pyridinium), 8.39 (1 H, t, J ¼ 7.5 Hz, pyridinium), 8.89 (1 H, d, J ¼ 7.2 Hz,
pyridinium), 11.50 (1 H, s, HN ). 13C NMR (DMSO-d6, 75 MHz) d: 24.07,
30
31.57, 44.91, 55.06, 63.51, 70.21, 83.97, 85.42, 85.67, 111.14, 113.22, 125.41,
126.81, 127.58, 127.74, 127.90, 129.74, 135.35, 137.66, 144.60, 145.01,þ146.56,
150.19, 156.88, 158.09, 163.31. HRMS (FAB) m=z for C38H40N3O7 (Mþ):
calc’d. 650.2866, found 650.2920.
50-O-(4,40-Dimethoxytrityl)-5-(pyridin-3-yl-ethynyl)-20-deoxyuridine, 1b.
To a solution of 5-O-(4,40-dimethoxytrityl)-5-iodo-20-deoxyuridine (650 mg,
1.00 mmol), PdL2Cl2 (35 mg, 0.05 mmol), CuI (19 mg, 0.10 mmol), and Et3N
(300 mL, 2.00 mmol) in DMF (6 mL) was added 3-ethynylpyridine (356 mL,
3.00 mmol) in a glove box. The reaction mixture was stirred at 50–60ꢂC for

690
GABALLAH AND NETZEL
30–50 m. After drying in vacuo, the solid was applied to a column packed
with silica gel or purified by flash chromatography. In both cases the
adsorbent was pretreated with 1% pyridine or Et3N (by vol.) in dichloro-
methane. Purification by flash chromatography on silica gel using the
following elutions, 50% (by vol.) hexane in dichloromethane, dichlor-
omethane, and 1% MeOH (by vol.) in dichloromethane, gave 1b (437 mg,
69% yield). 1H NMR (CDCl3, 300 MHz) d: 2.34 (1 H, m, H2 b), 2.58 (1 H, m,
0
0
H2 a), 3.28 (1 H, m, H5 b), 3.46 (1 H, m, H5 a), 3.65 (3 H, s, DMT-OCH3), 3.66
0
0
0
(3 H, s, DMT-OCH3), 4.15 (1 H, m, H4 ), 4.58 (1 H, m, H3 ), 5.40 (1 H, d,
0
0
0
J ¼ 4.0 Hz, OH3 ), 6.39 (1 H, t, J ¼ 6.0 Hz, H1 ), 6.76 (4 H, dd, J ¼ 2.2, 9.0 Hz,
Ar), 7.00–7.44 (11 H, m, Ar), 8.20, (1 H, s, H6), 8.34 (1 H, s, pyridine), 8.39
(1 H, d, J ¼ 3.6 Hz, pyridine), 10.07 (1 H br, HN3). 13C NMR (CDCl3,
75 MHz) d: 41.81, 55.16, 63.38, 72.26, 83.17, 85.84, 86.75, 87.14, 90.27, 99.92,
113.32, 119.61, 122.58, 127.06, 127.84, 128.05, 129.87, 135.38, 135.47, 138.56,
142.88, 144.36, 148.38, 148.98, 151.95, 158.61, 160.98. HRMS (FAB) m=z for
C37H34N3O7 (M þ H)þ: calc’d. 632.2396, found 632.2425.
3-[50-O-(4,40-Dimethoxytrityl)-20-deoxyuridine-5-yl-ethynyl]-N-methyl-
pyridiniumyl Iodide, 3d. In a Schlenk-like flask, 1b (75 mg, 0.11 mmol) was
co-evaporated 3 times with dry THF at 5610ꢁ4 torr. The Schlenk-like flask
was then brought inside a glove box, charged with 4 mL of dry acetonitrile
containing 110 mL of freshly distilled methyl iodide. The solution was free-
ze=pump (2610ꢁ4 torr)=thaw degassed 3 times. The solution was stirred for
20 h at 60ꢂC in vacuo. The acetonitrile solution was removed in vacuo, and
the greenish-yellow oily material was washed several times with hexane,
dichloromethane, and acetone. Finally the solid was purified by repeated
1
precipitations with hexane to afford 60 mg of 3d (69% yield). H NMR
0
0
(DMSO-d6, 300 MHz) d: 2.28–2.36 (2 H, m, H2 a=H2 b), 3.28–3.13 (2 H, m,
0 0
5 a=H5 b), 3.66 (3 H, s, DMT-OCH3), 3.67 (3 H, s, DMT-OCH3), 3.95 (1 H,
H
0
0
0
m, H4 ), 4.24 (3 H, s, CH3), 4.32 (1 H, m, H3 ), 5.35 (1 H, d, J ¼ 4.6 Hz, OH3 ),
0
6.12 (1 H, t, J ¼ 6.3 Hz, H1 ), 6.83 (4 H, d, J ¼ 8.7 Hz, Ar), 7.11–7.42 (9 H, m,
Ar), 7.71 (1 H, d, J ¼ 8.8 Hz, pyridinium), 7.95 (1 H, t, J ¼ 7.0 Hz, pyr-
idinium), 8.36 (1 H, s, H6), 8.73 (1 H, s, pyridinium), 8.87 (1 H, d, J ¼ 6.1 Hz,
pyridinium), 11.89 (1 H, s, HN3). 13C NMR (DMSO-d6, 75 MHz) d: 48.11,
55.02, 69.84, 78.51, 78.95, 79.40, 84.94, 85.91, 86.01, 89.88, 96.44, 113.25,
122.56, 126.76, 127.29, 127.50, 127.94, 129.58, 129.64, 135.45, 135.51, 144.85,
þ
145.34, 146.69, 149.16, 158.06, 161.01. HRMS (FAB) m=z for C38H36N3O7
(Mþ): calc’d. 646.2553, found 646.2556.
50-O-(4,40-Dimethoxytrityl)-5-(pyridin-3-yl-ethylenyl)-20-deoxyuridine, 2b.
Dry 1b (320 mg, 0.50mmol) was dissolved in 220 mL of dry MeOH and added
to 30mL MeOH solution containing 200 mg of 10% Pd=C previously acti-
vated by stirring under H2 (50 psi) for 20 m at room temperature. The reaction
mixture was then stirred under H2 (50 psi) at room temperature until the

REVERSIBLE ELECTRON TRAPS FOR DNA
691
starting materials were completely consumed (18 h). The solution was filtered
and solvent was removed in vacuo to afford a yellow foam of 2b (300mg, 93%
1
0
yield). H NMR (CDCl3, 300 MHz) d: 1.84 (1 H, m, H2 b), 2.00–2.32 (2 H, m,
0
0
CH2), 2.36–2.46 (2 H, m, CH2), 2.63 (1 H, m, H2 a), 2.95 (1 H, br, OH3 ), 3.33
0
0
(1 H, dd, J ¼ 2.0, 10.4 Hz, H5 b), 3.53 (1 H, dd, J ¼ 2.8, 10.5 Hz, H5 a), 3.71 (6
0
H, s, DMT-(OCH3)2), 4.06 (1 H, m, H4 ), 4.53 (1 H, m, H3 ), 6.43 (1 H, t,
0
0
J ¼ 6.4 Hz, H1 ), 6.76–6.80 (4 H, m, Ar), 7.04–7.40 (11 H, m, Ar), 7.53 (1 H, s,
H6), 8.02 (1 H, s, pyridine), 8.34 (1 H, d, J ¼ 4.8 Hz, pyridine), 9.03 (1 H, br,
HN3). 13C NMR (CDCl3, 75MHz) d: 28.59, 31.81, 41.02, 55.20, 63.46, 72.30,
84.66, 86.15, 86.81, 99.93, 113.25, 114.09, 123.15, 127.24, 128.00, 128.23,
130.03, 130.13, 135.20, 135.36, 135.96, 136.33, 144.08, 147.13, 149.60, 150.23,
158.69, 158.72, 163.13. HRMS (FAB) m=z for C37H38N3O7 (M þ H)þ: calc’d.
636.2709, found 636.2670.
3-[50-O-(4,40-Dimethoxytrityl)-20-deoxyuridine-5-yl-ethylenyl]-N-methyl-
pyridiniumyl Iodide, 4d. In a Schlenk-like flask, 2b (74 mg, 0.11 mmol) was
co-evaporated 3 times with dry THF at 5610ꢁ4 torr. The flask was then
brought inside a glove box and charged with 5 mL of dry acetonitrile con-
taining 110 mL of freshly distilled iodomethane. The solution was free-
ze=pump (2610ꢁ4 torr)=thaw degassed 3 times and stirred for 10 h at 70ꢂC in
vacuo. The acetonitrile solvent was removed in vacuo, and the greenish-
yellow solid was washed several times with hexane, dichloromethane, and
acetone. Finally the solid was purified by repeated precipitations with hexane
1
to afford 65 mg of 4d (72% yield). H NMR (DMSO-d6, 300 MHz) d: 2.10–
0
2.37 (4 H, m, H2 a=H2 b=CH2), 2.57–2.81 (2 H, m, CH2), 3.12–3.27 (2 H, m,
0
0 0 0
5 a=H5 b), 3.68 (6 H, s, DMT-(OCH3)2), 3.87 (1 H, m, H4 ), 4.26 (3 H, s,
H
0
0
CH3), 4.30 (1 H, m, H3 ), 5.31, (1 H, d, J ¼ 3.9, OH3 ), 6.18 (1 H, t, J ¼ 6.5 Hz,
0
H1 ), 6.86, (4 H, d, J ¼ 8.1 Hz, Ar), 7.38–7.18 (9 H, s, Ar), 7.55 (1 H, s, H6),
7.93–7.99 (2 H, m, pyridinium), 8.68 (1 H, s, pyridinium), 8.80 (1 H, d,
J ¼ 4.2 Hz, pyridinium), 11.43 (1 H, s, HN3). 13C NMR (DMSO-d6, 75 MHz)
d: 26.78, 31.00, 47.75, 55.07, 63.64, 70.33, 83.98, 85.42, 85.68, 111.99, 113.22,
126.83, 127.05, 127.71, 127.90, 129.68, 129.73, 135.37, 137.06, 141.21, 143.17,
144.24, 144.52, 144.62, 150.18, 158.08, 158.10, 163.20. HRMS (FAB) m=z for
þ
C38H40N3O7 (Mþ): calc’d. 650.2866, found 650.2871.
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Received March 12, 2002
Accepted July 12, 2002