Synthesis of dicobalt hexacarbonyl 5-p-tolylethynyl-2′-deoxyuridine

Article abstract of DOI:10.1039/b109501c

Reactions of 5-p-tolylethynyl-2′-deoxyuridine and 3′,5′-diO-acetyl-5-p-tolylethynyl-2′-deoxyuridine with Co₂(CO)₈ in THF gave 5-p-tolC₂[Co₂(CO)₆]-2′-deoxyuridine and 3′,5′-diO-acetyl-5-p-tolC₂[Co₂(CO) ₆]-2′-deoxyuridine (92 and 66%).

Full text of DOI:10.1039/b109501c

Synthesis of dicobalt hexacarbonyl 5-p-tolylethynyl-2A-deoxyuridine†
Noor Esho, Brian Davies, Janet Lee and Roman Dembinski*
Department of Chemistry and Center for Biomedical Research, Oakland University, 2200 N. Squirrel Road,
Rochester, MI 48309-4477, USA. E-mail: dembinsk@oakland.edu
Received (in Purdue, IN, USA) 17th October 2001, Accepted 18th December 2001
First published as an Advance Article on the web 30th January 2002
Reactions of 5-p-tolylethynyl-2A-deoxyuridine and 3A,5A-di-
O-acetyl-5-p-tolylethynyl-2A-deoxyuridine with Co2(CO)8 in
THF gave 5-p-tolC2[Co2(CO)6]-2A-deoxyuridine and 3A,5A-di-
O-acetyl-5-p-tolC2[Co2(CO)6]-2A-deoxyuridine (92 and
66%).
equiv.), gave after 2.5 h and workup 2a as a white powder in
84% yield (Scheme 1). 5-Arylalkynyl uridines with unprotected
hydroxyl groups are reportedly difficult to purify,14 and the
observed yields are moderate.15 Separation from ammonium
salts is usually accomplished by protection/chromatography/
deprotection,14 quenching with ion-exchange resin,15,16 or
multiple column chromatography. Since relevant 5-alkynyl
uridines are precursors for potent anti-VZV agents,4c,15 we have
optimized an isolation of 2a. Two subsequent precipitations
(MeOH and CHCl3) provided material without any detectable
trialkylammonium, Pd(PPh3)4, or Ph3P impurities (by NMR).
Silica gel short column chromatography (CHCl3–CH3OH)
allowed the removal of traces of unreacted 1a,‡ and afforded
spectroscopically pure 2a. The 5-p-tolylethynyl substituted 2A-
deoxyuridine 2a was characterized by NMR, IR, and UV–vis
Inert, stable molecules containing redox-active centers are
valuable as probes of biological systems. In particular, transi-
tion metal complexes attached to a nucleoside, nucleotide, or
oligonucleotide at site-specific locations are of interest for
analytical applications (DNA/RNA sequencing, hybridization
assays), therapeutic uses (anticancer, antiviral pharmaceuti-
cals), and structural and mechanistic studies (DNA-mediated
electron and energy transfer).1,2
Acetylenes and their higher homologues (polyynes) have
been found to promote strong electronic communication
between terminal subunits and to favor rigid, rod-like structures,
which have found an application in molecular wires design.3
Interest in the utilization of the ethynyl (acetylenic) fragment
for modification of nucleoside bases has resulted in a great
number of contributions in recent years.4 The linear, sp carbon
chain facilitates exact positioning of the metal containing
moiety for oligonucteotide arrays, and provides an opportunity
for metal–nucleobase communication.
We are interested in synthetic exploration and utilization of
the metal complexes covalently attached to nucleobases at non-
hydrogen bonding sites. Targeted metallo-nucleosides serve as
models and, after determining their basic properties, as
precursors for the corresponding metal-derivatized oligonucleo-
tides.5 Nucleosides with a linked metal complex can subse-
quently be converted into phosphoramidites (building blocks
for solid-phase synthesis) to access metallo-oligonucleotides.6,7
Alternatively, modification during automated solid-phase syn-
thesis,8 or postmodifications of available oligonucleotides can
be used to incorporate the relatively sensitive transition metal
functionality.9
spectroscopy.
A
combination of NMR techniques (1H,
13C{1H}, 13C, and COSY) allowed assignment of signals based
upon the coupling constants pattern. When 3A,5A-di-O-acetyl-
5-iodo-2A-deoxyuridine 1b was treated in a classical manner (50
°C) with HC·CC6H4CH3, Pd(PPh3)4, Et3N, and CuI, the 3A,5A-
di-O-acetyl-5-p-tolylethynyl-2A-deoxyuridine (2b) was readily
isolated by single silica gel column chromatography (hexane–
ethyl acetate) in 77% yield.
As shown in Scheme 1, the acetylated 5-p-tolylethynyl-2A-
deoxyuridine 2b and Co2(CO)8 were combined in THF (1+2
mol ratio). The latter compound is known to form relatively
stable dicobalt hexacarbonyl complexes, which participate in
the Pauson–Khand reaction.11 After 1.5 h, column chromatog-
raphy gave a brown–red relatively air-stable powder, which
showed properties consistent with the dicobalt hexacarbonyl
complex of 3A,5A-di-O-acetyl-5-p-tolylethynyl-2A-deoxyuridine
(3b), in 66% unoptimized yield. The unprotected nucleoside 2a,
which contains potentially reactive hydroxyl groups was
similarly reacted. Workup gave 5-p-tolC2[Co2(CO)6]-2A-deoxy-
uridine (3a) in 92% yield. The protected cobalt complex was
pursued also in order to produce material suitable for X-ray
We have extended metal–alkynyl–nucleoside chemistry to
the (m-acetylene)dicobalt hexacarbonyl complexes because: (i)
the alkyne C–C–C angles in this type of cluster are reduced to
ca. 140°, placing the aryl (p-tolyl) sensor in a new rigid position
relative to the base, (ii) the electrochemistry of relevant
complexes containing the (m-acetylene)dicobalt carbonyl unit
–C2[Co2(CO)6]– is well documented, and provides evidence
that coordination of the redox-active Co2 cluster does not
quench communication along an alkyne unit,10 (iii) the dicobalt
hexacarbonyl complex is a key intermediate for further
synthetic transformations.11
We have prepared the 5-p-tolylethynyl-2A-deoxyuridine (2a)
at room temperature by Sonogashira coupling,12 as we also
observed that elevated temperature leads to cyclization prod-
uct.13 A DMF solution of unprotected iodouridine 1a (1.0
equiv.) and Et3N (2.0 equiv.), when treated with excess
HC·CC6H4CH3 (1.2 equiv.) in the presence of Pd(PPh3)4 (0.11
equiv.), n-Bu4NI (1.0 equiv.), Ph3P (1.0 equiv.), and CuI (0.1
† Electronic supplementary information (ESI) available: experimental
section, NMR and mass spectra and cyclic voltammograms. See http://
www.rsc.org/suppdata/cc/b1/b109501c/
Scheme 1
332
CHEM. COMMUN., 2002, 332–333
This journal is © The Royal Society of Chemistry 2002

¶ Anal. Calc. for C28H22Co2N2O13: C, 47.21; H, 3.11. Found: C, 46.81; H,
3.43%.
structural analysis. However, crystallization efforts for both 3a
and 3b were not successful.
The 1H and 13C NMR spectra supported the structural
assignments of 3a and 3b.§ First, the CoCO signals appeared at
200.5 and 199.2 for 3a and 3b. Second, the C·C 13C signals
showed chemical shifts (96.7, 86.4 and 93.6, 81.1 ppm, DMSO-
d6 and CDCl3) characteristic for phenylalkynyl–cobalt li-
gands.17 Distinctive changes occurred as referred to free
alkynes 2a and 2b (91.8, 82.1 and 94.0, 79.7 ppm, acetone-d6
and CDCl3). Third, the –C6H4– 13C signals exhibited a reversed
order of chemical shifts for the m/o carbons, as established by a
gated decoupling experiment for 3b. We were unable to resolve
the i/p carbon multiplicity due to the low intensity of the signals.
The IR nCoCO values were essentially identical to those reported
for other, chiral alkynyl–cobalt complexes (2094–2023 vs.
2096–2020 cm21).18 MS spectra exhibited strong parent ions
and adequate fragmentation for 3a and 3b. The latter complex
also gave correct elemental analysis.¶ Thermal stability of the
unprotected cobalt nucleoside was determined by DSC: 3a
endothermically decomposed at 125 °C (Te) without melting.19
Although alkynyl precursor 2a exhibited fluorescence (lem/lex
= 401/311 nm, MeOH), we were not able to observe well
pronounced emission signals for 3a.
1 (a) Probing of Nucleic Acids by Metal Ion Complexes of Small
Molecules, ed. A. Sigel and H. Sigel, Metal Ions in Biological Systems,
Marcel Dekker, New York, 1996, vol. 33, pp. 1–678; (b) Interactions of
Metal Ions with Nucleotides, Nucleic Acids, and their Constituents, ed.
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2 See for example: (a) P. K. Bhattacharya and J. K. Barton, J. Am. Chem.
Soc., 2001, 123, 8649–8661; (b) F. D. Lewis, S. A. Helvoigt and R. L.
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4 For recent examples of alkynyl non-metal modifications of uridines see:
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2587–2591; (b) K. Matsuura, M. Hibino, Y. Yamada and K. Kobayashi,
J. Am. Chem. Soc., 2001, 123, 357–358; (c) A. Brancale, C. McGuigan,
G. Andrei, R. Snoeck, E. De Clerq and J. Balzarini, Bioorg. Med. Chem.
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The cobalt complexes exhibit one, irreversible oxidation
potential at room temperature (Ep,a/V = 0.99, 3a; 1.06 3b,
CH2Cl2), as established by cyclic voltammetry. Both are stable
in chlorinated (CHCl3, 1,2-dichloroethane), polar (acetone,
DMSO), or protic (MeOH) solvents, and also towards silica gel.
The study towards synthetic utilization of cobalt nucleosides is
in progress.
In conclusion, we have synthesized modified nucleoside
bearing electrochemical ‘reporter’ groups.
We thank Oakland University, Research Excellence Fund
program in biotechnology for support of this research, Pro-
fessors J. A. Gladysz and C. S. Chow for helpful discussions,
Mr C. Sergeant for technical assistance, Professor C. A. Fierke
and Ms N. Westerberg for fluorescence, and Mr R. Misener for
DSC measurements.
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Notes and references
‡ This step may be omitted on the route to 3a.
§ NMR data: 3a (acetone-d6): 1H 10.32 (s, 1H, N3), 8.43 (s, 1H, H6), 7.53
(AB, J 8.0 Hz, 2H, m-C6H4CH3), 7.19 (AB, J 8.0 Hz, 2H, o-C6H4CH3), 6.43
(t, J 6.9 Hz, 1H, H1A), 4.52 (br, 1H, OH5A), 4.43 (d, J 2.7 Hz, 1H, OH3A), 4.24
(t, J 4.5 Hz, 1H, H3A), 4.06–4.02 (m, 1H, H4A), 3.83–3.68 (m, 2H, H5A), 2.32
(s, 3H, CH3), 2.08–2.02 (m, 2H, H2A); 13C{1H} 200.5 (CoCO), 160.8 (C4),
150.8 (C2), 139.8 (C6), 138.8 (i-C6H4CH3), 136.3 (p-C6H4CH3), 130.6 and
130.2 (m,o-C6H4CH3), 113.6 (C5), 89.2 (C4A), 86.4 (C1A), 96.7 and 86.2
(C·CC6H4), 73.1 (C3A), 63.3 (C5A), 41.9 (C2A), 21.4 (CH3). 3b (CDCl3): 1H
9.73 (s, 1H, N3), 7.91 (s, 1H, H6), 7.43 (AB, J 7.8 Hz, 2H, m-C6H4CH3),
7.16 (AB, J 7.8 Hz, 2H, o-C6H4CH3), 6.32 (dd, J 8.6, 5.1 Hz, 1H, H1A), 5.14
(d, J 5.7, 1H, H3A), 4.38–4.22 (m, 2H, H5A), 4.17–4.02 (m, 1H, H4A), 2.56
(dd, J 14.0, 4.9 Hz, 2H, H2A), 2.35 (s, 3H, CH3), 2.12 and 1.81 (2s, 2 3 3H,
2 COCH3); 13C 199.2 (s, CoCO), 170.5, 170.3 (m, 2 COCH3), 160.8 (d, J
9.5 Hz, C4), 150.0 (d, J 8.7 Hz, C2), 138.5 (m, i-C6H4CH3), 135.4 (dd, J
180.4, 2.7 Hz, C6), 135.2 (t, J 8.1 Hz, p-C6H4CH3), 129.8 (dqnt, J 159.2, 5.7
Hz, o-C6H4CH3), 129.3 (dd, J 159.4, 6.2 Hz, m-C6H4CH3), 113.8 (d, J 3.9
Hz, C5), 93.6 (td, J 7.7, 2.8 Hz, C·CC6H4), 85.5 (dm, J 170.8 Hz, C1A), 82.5
(dm, J 149.6 Hz, C4A), 81.1 (s, C·CC6H4), 74.4 (dm, J 162.0 Hz, C3A), 63.9
(td, J 148.5, 1.7 Hz, C5A), 38.1 (dd, J 139.4, 131.3 Hz, C2A), 21.5 (qt, J 126.4,
4.2 Hz, CH3), 21.1 (q, J 130.0 Hz, COCH3), 20.4 (q, J 129.8 Hz,
COCH3).
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