Synthesis and characterization of monodeoxynucleotide tethered platinum-(II) and -(IV) complexes

Article abstract of DOI:10.1039/a808705i

Improved syntheses of platinum-(II) and -(IV) complexes with pendant hydroxy groups have been elaborated. When the hydroxy groups of the platinum(II) complexes were subjected to phosphoramidite coupling agents to synthesize the corresponding phosphoramidites, intramolecular displacement of the chloride on the platinum by the incoming phosphoramidite group occurred. This generated chloro{N-2-[(2-cyanoethyl)(diisopropylamino)phosphinoxy]-ethylenediamine} platinum(II) chloride, which was characterized by a number of physical techniques including X-ray diffraction study. It crystallized from methanol-diethyl ether as white block crystals. Single crystal X-ray analysis revealed that the platinum adopts a four-co-ordinate square planar configuration, provided by the two amine nitrogens, one phosphorus, and one chloride ion. The co-ordination of the phosphoramidite group prevents further manipulation of this group to connect with other hydroxy groups. Intramolecular electron transfer reaction occurred when the platinum(IV) complexes were used in the same reaction. A new strategy has been developed to couple monodeoxynucleotides with the hydroxy groups of the tethered platinum-(II) and -(IV) complexes through the use of monodeoxynucleotide phosphoramidite agents. Every peak in the ¹H, ¹³C-{¹H} and ¹⁹⁵Pt NMR spectra for all the compounds reported has been assigned through the combination of 1-D ¹H, ¹³C-{¹H}, 2-D COSY, XHCORR (heteronuclear chemical shift correlation), HMQC (heteronuclear multiple quantum correlation), and the comparison of chemical shifts among analogs.

Full text of DOI:10.1039/a808705i

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Synthesis and characterization of monodeoxynucleotide tethered
platinum-(II) and -(IV) complexes†
Sumei Ren, Lisheng Cai* and Brent M. Segal
Department of Chemistry, The University of Illinois at Chicago, Chicago, Illinois 60607, USA
Received 6th November 1998, Accepted 25th February 1999
Improved syntheses of platinum-() and -() complexes with pendant hydroxy groups have been elaborated. When
the hydroxy groups of the platinum() complexes were subjected to phosphoramidite coupling agents to synthesize
the corresponding phosphoramidites, intramolecular displacement of the chloride on the platinum by the incoming
phosphoramidite group occurred. This generated chloro{N-2-[(2-cyanoethyl)(diisopropylamino)phosphinoxy]-
ethylenediamine}platinum() chloride, which was characterized by a number of physical techniques including
X-ray diffraction study. It crystallized from methanol–diethyl ether as white block crystals. Single crystal X-ray
analysis revealed that the platinum adopts a four-co-ordinate square planar configuration, provided by the two
amine nitrogens, one phosphorus, and one chloride ion. The co-ordination of the phosphoramidite group prevents
further manipulation of this group to connect with other hydroxy groups. Intramolecular electron transfer reaction
occurred when the platinum() complexes were used in the same reaction. A new strategy has been developed to
couple monodeoxynucleotides with the hydroxy groups of the tethered platinum-() and -() complexes through
the use of monodeoxynucleotide phosphoramidite agents. Every peak in the 1H, 13C-{1H} and 195Pt NMR spectra
for all the compounds reported has been assigned through the combination of 1-D 1H, 13C-{1H}, 2-D COSY,
XHCORR (heteronuclear chemical shift correlation), HMQC (heteronuclear multiple quantum correlation), and
the comparison of chemical shifts among analogs.
for sequence specific binding through mRNA and DNA
Introduction
duplex/triplex formation.7 Three stages of this study are
reported here: first, the improved synthesis and detailed charac-
terization of the platinum-() and -() complexes with tethered
hydroxy group(s) (Scheme 1); second, coupling of the above
cis-Diamminedichloroplatinum() (cis-DDP; cis-platin) is an
effective anticancer drug routinely prescribed for testicular,
ovarian, bladder, lung and other carcinomas.1 The mechanism
of its cytotoxicity toward cancer cells has been extensively
studied, and its preferences in binding, i.e. to the amine func-
tionality of adjacent purine sites in double stranded (ds) DNA,
have been noted.2 In vitro, approximately 65% of drug–DNA
adducts formed occur at d(GpG) sites, and 25% at d(ApG)
sites, minor products at d(GpNpG) or interstrand sites.3 The
product of the association at d(GpG) sites is also a square
planar platinum() complex, where the original chloride lig-
ands have been displaced by the N-7 amino groups of adjacent
guanine bases, and where the ammonia ligands serve as hydro-
gen bond donors to the oxygen atoms of the intervening phos-
phodiester linkage and other hydrogen bond acceptor sites.4
Despite the availability of molecular details relevant to the
cis-DDP binding and function, many questions of importance
to its clinical utility and effectiveness remain: cis-DDP use is
hindered by intrinsic and induced resistance, and mitigated
by the general cytotoxicity of the drug. Recent investigations on
cis-platin analogs focus on platinum complexes with carrier
molecules as ligands5 and complexes containing more than one
platinum atom.6
X
O
H2N
Cl
NH
Cl
Pt
X
Scheme 1 Generic form of the compounds in this study.
platinum complexes with phosphoramidite agents; third, the
synthesis of the tethered platinum complexes with monodeoxy-
nucleotide(s).
Metal-containing oligonucleotides have been designed and
synthesized for a variety of reasons including: (1) incorporation
of photo- and redox-active transition metal ions to study the
energy and electron-transfer processes through DNA;8 (2)
development of DNA hybridization probes and sensors;9 (3)
search for new modes of covalent attachment of metal com-
plexes to DNA;10 (4) mimic of endogenous nuclease activity
that effects selective RNA hydrolysis;11 (5) incorporation of
platinum center in specific site of DNA or RNA for the mech-
anistic study of cis-DDP anticancer activity.12 They are con-
structed via three major pathways: (a) the synthesis of a
chelator-containing oligonucleotide followed by metal com-
plexation;7b,13 (b) the synthesis of an end-functionalized oligo-
nucleotide to which a metal complex can be conjugated;11b,14 and
(c) the incorporation of metal-containing phosphoramidites or
H-phosphonates.11a,12,15 The first method depends on the selec-
tivity between the chelator and the oligonucleotide backbone,
the second on the specificity of the conjugation method and its
We are interested in the use of the platinum center as a
molecular fragment or moiety to recognize GG base pairs when
connecting to an oligodeoxynucleotide (ODN). This new agent
may recognize a specific sequence or gene with unprecedented
affinity and efficiency, providing a mechanism for targeting
platinum drugs to specific sites in the genome. For our initial
studies, the ODN was chosen on the basis of its characteristics
† Supplementary data available: COSY and XHCORR spectra of
complex 1, diagrams of possible stereoisomers. Available from BLDSC
(No. SUP 57515, 5 pp.). See Instructions for Authors, 1999, Issue 1
(http://www.rsc.org/dalton).
J. Chem. Soc., Dalton Trans., 1999, 1413–1422
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1
Table 1 The H NMR chemical shifts of various compounds containing the dichloro[N-(2-hydroxyethyl)ethylenediamine]platinum fragment in
DMSO-d6 unless indicated otherwise
Compound
a
b
c
d
f
h
N–H or O–H
Ia
I
1
2.62, m, 2 H
2.50, m, 2 H
2.28, m, 2 H
2.62, m, 2 H
2.50, m, 2 H
2.70, m, 1 H;
2.43, m, 1 H
2.78, m, 2 H
2.53, m, 2 H
3.25, m, 1 H;
3.00, m, 1 H
3.61, t, 2 H
3.42, t, 2 H
3.58, m, 1 H;
3.53, m, 1 H
2.50–2.90, br s
2.40–2.60, br s
6.05, br s, 1 H;
5.26, br s, 1 H;
5.02, br s, 1 H;
4.66, s, 1 H
2
2.81, m, 2 H
2.81, m, 2 H
2.84, m, 2 H
2.52, m, 2 H
2.62, m, 1 H;
2.05, m, 1 H
3.78, m, 1 H;
2.90, m, 1 H
3.65, m, 2 H
3.70, m, 2 H
3.76, t, 2 H
1.96, s, 3 H
1.96, s, 3 H
1.96, s, 3 H
1.96, s, 3 H
10.48, br s, 1 H;
9.62, br s, 1 H;
8.05, br s, 1 H;
5.10, br s, 1 H
10.19, br s, 1 H;
10.05, br s, 1 H;
9.28, br s, 1 H;
6.37, br s, 1 H
7.61, br s, 1 H;
7.48, br s, 1 H;
7.19, br s, 1 H;
5.72, s, 1 H
2b
3
2.74, m, 1 H;
2.13, m, 1 H
3.78, m, 1 H;
3.15, m, 1 H
2.79, m, 1 H;
2.47, m, 1 H
3.57, m, 1 H;
3.10, m, 1 H
4
3.03, m, 1 H;
2.91, m, 1 H
2.52, m, 1 H;
3.03, m, 1 H
3.87, m, 1 H;
4.27, m, 1 H
7.84, br s, 1 H;
5.64, br s, 1 H;
5.52, br s, 1 H
7
2.89, m, 1 H;
2.68, m, 1 H
3.21, m, 1 H;
2.97, m, 1 H
2.89, m, 1 H;
2.68, m, 1 H
2.43, m, 2 H
3.79, m, 2 H
4.16, m, 2 H
3.97, m, 2 H
4.21, m, 2 H
2.09, s, 3 H
1.95, s, 3 H
8c
a In chloroform. b In CD3CN. c In D2O.
compatibility with the metal complex and the third on the
inertness of the metal complex toward the reaction conditions
of the oxidation and deprotection during the oligonucleotide
synthesis or the nature of the metal complex is not critical.
All the three methods are not directly suitable for the con-
struction of the generic compound outlined in Scheme 1.
Platinum sources such as K2PtCl4 should react with both the
nucleic bases and a chelator such as ethylenediamine, making
method (a) impractical. Platinum() complexes such as 1 in
Scheme 2 are subject to ligand substitution reactions in concen-
and does not interfere with the platinum complex, requiring
development of new strategies for method (b). Here we report
our effort to develop synthetic strategies along the general
method (c).
Results and discussion
The first step in our program is the synthesis of a platinum
complex with a pendant OH group to serve as an ODN tether-
ing site. This assumes that the reactivity of the OH group is not
dramatically changed by the metal fragment.
Cl
Cl
Cl
Cl
K2
Pt
Dichloro[N-(2-hydroxyethyl)ethylenediamine]platinum(II) 1
The synthesis of this compound was reported as early as 1974.16
It shows significant anticancer activity against Sarcoma-180
ascites tumour cells in mouse or cancer cell line L1210 and little
toxicity to the host, not more effective than cis-DDP.17 How-
ever, no spectroscopic characterization of this compound has
been reported. After co-ordination to the platinum center, the
central nitrogen of the ligand becomes a chiral center, and only
one set of 13C-{1H} NMR signals is observed. The assignment
of the peaks comes from the combination of 1-D 1H, 13C-{1H},
and 2-D COSY, and XHCORR (heteronuclear chemical shift
correlation) experiments (Tables 1 and 2 and Scheme 2). The 1H
2-D COSY and 13C-{1H}–1H XHCORR spectra are given in
SUP 57515. The assignment began with the methylene bound
to the hydroxy group, which gave the most downfield 13C-{1H}
peak and non-exchangeable 1H peaks. Two different sets of
1H peaks were observed for this CH2 group, suggesting that
the rotation around the C–C single bond is somewhat restricted.
This is consistent with the co-ordination of the hydroxyl group
with the platinum center. Scalar coupling between methyl-
ene group c and d, or between a and b, was clearly observed in
a
b
c
d
N
H
H2N
OH
I
O
e
f
H2
N
O
Pt
O
H2
N
a
Cl
a
Cl
Cl
Pt
b
(1) H2O2
NH
b
NH
Cl
O
h
c
c
(2) Ac2O
g
d
d
HO
1
2
HO
HCl, 20%
H2
Cl
Cl
Pt
Cl
Cl
Cl
a
N
Cl
Cl
Cl
I
K2
Pt
Cl
b
NH
Cl
c
d
3
HO
Scheme 2 Synthetic scheme for hydroxy group tethered platinum
1
the H 2-D COSY spectrum. The distinction between a and b
complexes.
was based on the scalar coupling of b with the proton on the
trated ammonia solution with prolonged heating, which is
required for the deprotection of nucleotides, if the platinum
fragment is attached before deprotection. Otherwise a specific
connection method to join 1 with oligonucleotides needs to
differentiate between the hydroxy group and amino group,
central NH group, which couples with c. The two different sets
of H NMR peaks for each of groups a, b, and c apparently
come from the central chiral amine center. The clearly
prolonged relaxation time for the hydroxy proton allows the
identification of its peak from those of the NH groups, whose
1
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J. Chem. Soc., Dalton Trans., 1999, 1413–1422

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Table 2 The 13C-{1H} NMR chemical shifts of various compounds containing the dichloro[N-(2-hydroxyethyl)ethylenediamine]platinum fragment
in DMSO-d6 unless indicated otherwise
Compound
a
b
c
d
e
f
g
h
Ia
I
41.4
42.3
47.4
48.7
48.8
48.1
42.4
47.3
49.3,
48.3,
47.2,
46.0,
45.7
51.6
52.5
56.9
56.8
56.9
57.2
52.9
57.0
52.0
53.2
55.3
53.8
54.0
55.8
60.4
56.3
60.3
61.1
59.2
58.0
58.1
57.8
64.9
59.4
63.6,
63.0,
61.8,
61.4,
61.1
1
2
181.9
182.9
23.7
24.2
181.4
182.5
21.2
24.1
2b
3
4
7
172.9
23.0
172.9
22.6
8
57.2, 56.4, 55.3,
54.7, 53.5, 52.0,
51.4
a In chloroform. b In CD3CN.
relaxation time is shortened by the quadrupole moment of the
abundant 14N nucleus.18
The OH group is apparently weakly co-ordinated. The chem-
ical shift of the CH2O group is within the range for primary
alcohols, not for ester groups. Reaction of complex 1 with
acetic anhydride gives the corresponding acetate ester cleanly.
All this information converges on the conclusion that there is an
interaction between the hydroxy group and platinum() center
but it may be quite weak. This suggests that reactions at the OH
group should occur without much interference from Pt. How-
ever, under basic conditions, intramolecular displacement of
the chloride by the alkoxide group has been reported.19
Diacetatodichloro[N-(2-hydroxyethyl)ethylenediamine]-
platinum(IV) 2
Multiple attempts to oxidize platinum-() to -() complexes
by hydrogen peroxide in different solvents failed to generate
the
dichlorodihydroxy[N-(2-hydroxyethyl)ethylenediamine]-
platinum() complex as predicted by the synthesis of
analogous compounds.17b,20 Oxidation has only been realized
through the combination of a controlled amount of hydrogen
peroxide and acetic anhydride in acetic acid. For 2 there is no
possibility for co-ordination of the hydroxy group with the
platinum center. The difference of the 1H and 13C NMR
spectra for the CH2OH group of 1 and 2 confirms the conclu-
sion drawn above that an interaction exists between the hydroxy
group and platinum in compound 1. A total of 6 isomers,
including two diastereomers and two pairs of enantiomers (see
SUP 57515), are possible from the platinum center for this
compound. Combined with the central chiral amine center,
a total of 12 isomers is possible. A single peak for each carbon
in the 13C-{1H} NMR spectrum and a single set of peaks for
Fig. 1 The COSY NMR spectrum of compound 4; im = impurity.
Chloro{N-2-[(2-cyanoethyl)(diisopropylamino)phosphinoxy]-
ethylenediamine}platinum(II) chloride 4
The structure of complex 4 is shown on Scheme 3, and the
H2
N
H2
N
Cl
a
b
Cl
Cl
6"'
a
b
c
1
Pt
(1) Tetrazole–DMF
O
each proton in the H NMR spectrum (Tables 1 and 2) may
imply that only one enantiomer pair exists in solution, as
shown in Scheme 2.
Pt
NH
CN
7"'
P
NH
d
5"'
Cl
(2) (i-Pr2N)2POCH2CH2CN
c
O
N
II
3"'
HO
d
4"'
1"'
1
2"'
Tetrachloro[N-(2-hydroxyethyl)ethylenediamine]platinum(IV) 3
4
This compound was first mentioned in 1983 in the screening of
platinum compounds as anticancer agents,17b however no report
about its synthesis or characterization has appeared. In this
study it was synthesized through the substitution of the acetato
group in 2 by chloride in 20% hydrochloric acid (Scheme 2 and
Tables 1 and 2); also through the direct reaction of potassium
hexachloroplatinate() with 2-(2-aminoethylamino)ethanol in
low yield upon prolonged refluxing in an aqueous solution.
Most of the side product is a yellowish insoluble material.
When we tried an initial coupling reaction we were surprised
to find displacement of a chloride accompanying linkage of
the phosphoramidite with the tethering OH group. Detailed
description of the reaction follows.
Scheme 3 Synthetic scheme for compound 4.
interaction between the Pt and phosphite center is established
through the observation of scalar coupling in both 195Pt and
31P NMR spectra, and later on confirmed by X-ray diffrac-
tion studies. A doublet in the 195Pt NMR gives a coupling
constant of 4911 Hz for JPt–P. In the 31P NMR spectrum a
1
central singlet at δ 81.1 with 2/3 of the intensity symmetric-
ally flanked by a doublet, each peak of which has 1/6 of the
total intensity, with a coupling constant of 4911 Hz. The
COSY and XHCORR spectra are shown in Figs. 1 and 2.
Labelling and assignments for this compound are summarized
J. Chem. Soc., Dalton Trans., 1999, 1413–1422
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Table 3 The 1H NMR chemical shifts of various compounds containing the phosphoramidite fragment
Compound
1ٞ,3ٞ
2ٞ
4ٞ
5ٞ
6ٞ
4a
4.27, m, 4 H
3.48, m, 2 H
1.23, s, 6 H
1.13, s, 3 H;
1.11, s, 3 H
1.23, s, 6 H
1.06, s, 3 H;
1.00, s, 3 H
4.27, m, 2 H
3.62, m, 2 H
2.91, m, 2 H
2.58, m, 1 H;
2.49, m, 1 H
3.00, m, 1 H;
2.76, m, 1 H
2.97, m, 2 H
IIIb
7a
8a
3.74, m, 1 H;
3.54, m, 1 H
3.21, m, 2 H
a In DMSO-d6. b In CD3CN. c In D2O.
Table 4 The 13C-{1H} NMR chemical shifts of various compounds
containing the phosphoramidite fragment
Table 5 Bond lengths (Å) and angles (Њ) for compound 4
Pt(1)–N(2)
Pt(1)–P(1)
N(1)–C(1)
C(2)–N(2)
C(3)–C(4)
O(1)–P(1)
P(1)–N(3)
C(5)–C(6)
C(7)–N(4)
N(3)–C(8)
C(8)–C(10)
C(11)–C(12)
2.047(10)
2.211(3)
1.480(14)
1.486(13)
1.51(2)
1.597(9)
1.624(11)
1.50(2)
1.12(2)
1.48(2)
1.55(2)
1.60(2)
Pt(1)–N(1)
Pt(1)–Cl(1)
C(1)–C(2)
N(2)–C(3)
C(4)–O(1)
P(1)–O(2)
O(2)–C(5)
C(6)–C(7)
N(3)–C(11)
C(8)–C(9)
C(11)–C(13)
2.113(9)
2.300(4)
1.470(13)
1.495(13)
1.43(2)
1.613(9)
1.408(14)
1.43(2)
Compound
1ٞ,3ٞ
2ٞ
4ٞ
5ٞ
6ٞ
7ٞ
4a
49.2,
49.1
43.9
24.1,
23.9
25.0
24.1,
23.9
25.0
62.5
19.9,
19.8
21.0
19.0
23.3,
22.9
119.4
IIIb
7a
59.6
64.7
65.8
119.4
118.1
120.0
8c
1.45(2)
1.54(2)
1.42(2)
a In DMSO-d6. b In CD3CN. c In D2O.
N(2)–Pt(1)–N(1)
N(1)–Pt(1)–P(1)
N(1)–Pt(1)–Cl(1)
C(1)–N(1)–Pt(1)
C(1)–C(2)–N(2)
C(2)–N(2)–Pt(1)
N(2)–C(3)–C(4)
C(4)–O(1)–P(1)
O(1)–P(1)–N(3)
O(1)–P(1)–Pt(1)
N(3)–P(1)–Pt(1)
O(2)–C(5)–C(6)
N(4)–C(7)–C(6)
C(11)–N(3)–P(1)
N(3)–C(8)–C(9)
C(9)–C(8)–C(10)
81.8(4)
173.7(3)
91.0(3)
N(2)–Pt(1)–P(1)
N(2)–Pt(1)–Cl(1)
P(1)–Pt(1)–Cl(1)
C(2)–C(1)–N(1)
C(2)–N(2)–C(3)
C(3)–N(2)–Pt(1)
O(1)–C(4)–C(3)
O(1)–P(1)–O(2)
O(2)–P(1)–N(3)
O(2)–P(1)–Pt(1)
C(5)–O(2)–P(1)
C(7)–C(6)–C(5)
C(11)–N(3)–C(8)
C(8)–N(3)–P(1)
N(3)–C(8)–C(10)
94.4(3)
171.9(3)
93.03(14)
106.8(9)
110.6(9)
118.2(7)
113.1(11)
98.7(5)
104.6(6)
113.8(3)
121.2(9)
113.0(12)
117.6(11)
118.6(9)
109.3(12)
107.2(6)
108.8(9)
109.4(7)
112.3(10)
118.2(7)
107.1(5)
111.0(4)
119.4(4)
111.1(13)
178(2)
123.2(10)
110.9(12)
113.0(13)
C(13)–C(11)–N(3) 119.9(13)
N(3)–C(11)–C(12) 109(2)
C(13)–C(11)–C(12) 106(2)
Structure of the platinum complex 4
Complex 4 crystallizes from methanol–diethyl ether as white
rectangular blocks. Owing to the poor quality of the crystals
only a limited amount of diffraction data was collected (up to
45Њ). Therefore, relatively large errors are anticipated. Signifi-
cant bond distances and angles in the co-ordination sphere are
presented in Table 5 and the ORTEP22 diagram of the structure
is shown in Fig. 3.
Fig. 2 The XHCORR NMR spectrum of compound 4.
in Tables 1–4. Clear identification of the isopropyl groups was
possible in the 13C-{1H} spectrum based on their distinctive
intensities. Since the nitrogen center is adjacent to a chiral
phosphorus center the two isopropyl groups have different
chemical shifts in the 13C-{1H} spectrum, although identical
peaks were observed in the 1H NMR spectrum. Methylene
group 6ٞ has also two distinctive 13C-{1H} chemical shifts at
δ 19.8 and 19.9, as determined by comparing with those of
analogous compounds.21 Scalar coupling in 1H 2-D COSY
allows the identification of 5ٞ to be either δ 62.5 or 64.9. One of
those two peaks would belong to methylene group d, which is
also bound to an alkoxide group. Since d is within a six mem-
bered ring, the axial and equatorial hydrogens have quite dif-
ferent environments, requiring larger chemical shift separation
of the two protons on this carbon in the 1H NMR spectrum. So,
5ٞ was assigned to be at δ 62.5 and d at δ 64.9. The assignment
of b and c was based on analogous arguments. Somehow, the
chemical shift of the methylene group a in the 13C-{1H} NMR is
distinct from the other groups, and was assigned by comparing
with those of analogous compounds such as 1.
The platinum atom adopts a four-co-ordinate square
planar geometry, provided by the two amino nitrogens, one
phosphorus, and one chloride ion. The five membered ring
formed by the ethylenediamine fragment and platinum adopts
a half envelope conformation with carbon C(1) at the apex
position. The six membered ring formed by the central nitro-
gen and phosphorus atom adopts a chair-like conformation.
Both the phosphorus and central nitrogen atoms are asym-
metric centers. In the unit cell two molecules exist as (NS,
PR), the other two as (NR, PS). No molecules with the com-
bination of (NR, PR) and (NS, PS) are observed. Atom N(3)
adopts a trigonal planar configuration, being sp2 hybridized.
Probably the lone pair of electrons on this nitrogen interacts
with the empty d orbital of the phosphorus. The interaction
may also be strengthened by the co-ordination of the phos-
phorus with the platinum. The other chlorine atom (Cl2) free
from the co-ordination sphere of Pt lies just above the central
nitrogen atom N(2) with an internuclear distance of 3.1 Å,
and with a bonding angle around the hydrogen atom on N(2)
of 176Њ, consistent with hydrogen-bonding formation. Other
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Table 6 The 195Pt NMR chemical shifts for compounds in DMSO-d6
Compound
PtII
PtII–P
PtIV
1
2
3
4
Ϫ2355
1015.2
Ϫ286.5
Ϫ3936.2
(1JPt–P = 4911 Hz)
Ϫ3661.3, Ϫ3676.5
(1JPt–P = 5479 Hz)
5
6
7
Ϫ2350
1034, 795, 760,
755, 580, 331 or
1008, 829, 741,
726, 520, 298a
448.0a
8
a In water–CH3OH.
Fig. 3 Molecular structure of compound 4 with atomic numbering
(ORTEP, 50% probability ellipsoids, hydrogen atoms omitted for
clarity).
δ Ϫ3660 and Ϫ2350 respectively in the 195Pt NMR spectrum.
Since the chemical shift of the 195Pt NMR signal is sensitive to
the immediate co-ordination environment of the central plat-
inum atom, comparison of the chemical shifts with those of the
established compounds in Table 6 and discussion about “195Pt
NMR studies of the platinum complexes” below allow the
assignment of the structures of 5 and 6 as shown in Scheme 4.
Integration of the 195Pt NMR signals allows the estimation of
the relative proportion of 5 and 6 to be 35:65. Two isomers are
observed for 5 with the relative ratio of about 2:1. The relative
composition of 5 and 6 remains constant during the reaction
time of 2–3 h. However, the number of NMR peaks in each
region increases with time after this period, but the overall
shape of the peaks remains.
Both complexes 5 and 6 are not very stable, changing to
complicated mixtures if left in solution overnight or if exposed
to air, probably because of the sensitivity of the phosphite
group toward hydrolysis and oxidation.23 They were not iso-
lated. Instead, direct oxidation by H2O2 with acetic anhydride in
acetic acid was performed to generate 7. The upfield 31P-{1H}
chemical shift of 7 confirms the oxidation state of the phos-
phorus to be ϩ5. The presence of platinum() is indicated by
the observation of 195Pt signals around δ 300 to 1000 and by the
absence of oxidation waves in cyclic voltammetry. A total of 4
isomers is expected based on the 2 stereochemical centers gen-
erated during the reaction. However 6 peaks are observed on a
RP18 column in HPLC analysis, and 195Pt NMR peaks from
δ 330 to 1030. This means that more than one geometrical or
stereochemical isomer was generated at the platinum center. A
total of 6 isomers, including two diasteromers and two pairs of
enantiomers, is possible from the platinum center (see SUP
57515). When this is combined with the two newly generated
chiral centers, a total of 24 isomers is possible for 7. No attempt
was made to separate them and to identify their individual
peaks.
portions of the molecule have normal structures for the same
type of compounds.
The synthetic scheme for compound 4 is shown in Scheme 3.
The reagent 2-cyanoethyltetraisopropylphosphorodiamidite
gives the cleanest reaction in the presence of tetrazole, which
functions as the catalyst for this coupling reaction and other
analogous reactions. Two other common coupling agents used
in DNA synthesis, tris(1,1,1,3,3,3-hexafluoropropyl) phosphite
and 2-cyanoethyl diisopropylphosphoramidochloridite, give
only mixtures or no reactions at all. Our initial design is to use
the phosphoramidite group as a bridge to connect with mono-
or oligo-deoxynucleotides. Co-ordination of the phosphorus in
4 dramatically changes the chemical properties of the phos-
phoramidite group. In this case no reaction with other alcohols
is observed under a variety of conditions with tetrazole or
5-methylsulfanyltetrazole as the catalyst. Oxidation of 4 by
H2O2, H2O2–AcOH, or H2O2–Ac2O–AcOH gives a mixture
as revealed by the appearance of multiplets in the 31P NMR
spectra.
Mechanistic implication
The formation of compound 4 in less than one hour has impli-
cations for factors that affect the rate of ligand substitution of
platinum() complexes. Since no reaction is observed without
tetrazole, substitution of the chloride by the phosphoramidite
group is unlikely to be the first step in the overall transform-
ation. The most reasonable assumption for the mechanism is
that the hydroxy group is connected with the coupling agent
first, and then intramolecular substitution of the chloride by
the tethered phosphoramidite group occurs. In that sense, the
half life of the intramolecular substitution should be less than
0.5 h, which is much shorter than that of the solvolysis of 1 in
DMSO. This was measured to be about 3.5 h by 195Pt NMR at
room temperature.
It is apparent that the different isomers show identical NMR
signals for those groups beyond the phosphate from the plat-
inum center and for the two acetate groups on the platinum,
since only one set of peaks was observed and assigned (Tables
1–4 and 7–10). However, multiple peaks belonging to each of
the four methylene groups from a to d were observed, due to
different isomers existing in solution.
Complexes 5–7
The structures and labelling of the complexes are shown in
Scheme 4. The reaction of compound III with complex 1 and
tetrazole as the catalyst generates 5 and 6 as revealed by a com-
bination of NMR studies. The 31P-{1H} NMR spectrum of 5
shows one doublet of multiplets with a coupling constant of
5197 Hz, while that of 6 shows a set of two peaks around δ 140
and 139. The chemical shift of the latter resembles those of
free phosphite ligands. Since no reaction is observed without
tetrazole, direct co-ordination without a covalent tether is
unlikely. The coexistence of 5 and 6 is also deduced from the
simultaneous observation of two sets of peaks located around
Complex 8
Multiple attempts have been tried to remove the protection
group DMT from the 3Ј position. Typical conditions for remov-
ing such a group failed in this case. Hydrolysis in the presence
of 15% hydrochloric acid solution resulted in a deep red solu-
tion with minimum deprotection. Complete deprotection by
the acid solution was observed when the reaction mixture
was repeatedly extracted with CH2Cl2 to remove DMT–X
J. Chem. Soc., Dalton Trans., 1999, 1413–1422
1417

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Table 7 The 1H NMR chemical shifts of various compounds containing the thymine nucleoside fragment in DMSO-d6 unless indicated otherwise
Compound
1Ј
2Ј
3Ј
4Ј
5Ј
5
6
7
N–H or O–H
9.10, br s
IIIa
6.22, m, 1 H
1.63, m, 2 H
4.62, d, 1 H
or
4.27, s, 1 H
or
3.66, m, 2 H
7.23, s, 1 H
1.78, s, 3 H
4.57, d, 1 H
4.36, m, 1 H
or
4.31, m, 1 H
4.62, m, 1 H
3.99, s, 1 H
4.05, m, 1 H
or
3.91, m, 1 H
3.97, m, 1 H
7b
8c
6.24, m, 1 H
6.36, m, 1 H
1.92, m, 1 H;
1.82, m, 1 H
4.24, m, 2 H
4.59, m, 2 H
7.34, s, 1 H
7.74, s, 1 H
1.76, s, 3 H;
1.74, s, 3 H
8.37, br s
2.13, m, 2 H
8.48, s;
7.97, s;
7.78, s
a In CD3CN. b In DMSO-d6. c In D2O.
O
O
N
4"'
3
HN
4
7
3"'
N
HN
H2
5
6
NH
H2N
O
2"'
2
N
NH
d
Cl
Cl
1
N
a
O
Tetrazole–
DMF
O
O
Pt
O
+
P
Pt+
P
b
c
O
5'
4'
1"'
O
Cl-
O
1'
2'
Cl
O
5"'
HO
1
3'
6"'
NC
7"'
III
5
ODMT
ODMT
CN
6" 7"
5"
10"
9"
DMT
OMe
8"
MeO
C
O
HN
2"
3"
1"
4"
NH
Cl
O
H2N
O
O
N
Pt
P
O
Cl
O
6
ODMT
CN
H2O2 in Ac2O–AcOH
O
N
O
N
HN
HN
O
e
OH
f
O
O
O
O
O
O
O
O
O
NH
Cl
H2N
Cl
P
P
O
NH
Cl
H2N
O
Pt
Pt
O
O
HCl 15%–
CH2Cl2
Cl
O
g
h
OH
8
NC
NC
7
OH
ODMT
O
Scheme 4 Synthetic scheme for monodeoxynucleotide tethered platinum complexes.
compounds (X = Cl or OH). To our surprise, the acetate groups
on the platinum are also hydrolyzed, supporting the conclusion
that the chemical properties of the Pt–OH group resemble
those of alcohols.20
alcohol under a variety of conditions including different deriv-
atives of tetrazole as the catalyst, making this reaction not
useful in the construction of our complexes. However, such co-
ordinative ability is much smaller for the phosphite group than
that for phosphoramidite, making 5 and 6 exist in equilibrium.
Oxidation of the phosphite shifts the equilibrium to generate a
single product 7. Analogous oxidation of 4 on prolonged heat-
ing resulted in a mixture of products instead. Attempted phos-
phitylation of 3 under the same conditions as for 1 resulted in a
mixture in a variety of conditions; presumably electron transfer
reactions occurred among the reactants. Extension of this strat-
egy to other conjugates between platinum and oligonucleotides
is anticipated.
The same number of isomers was anticipated for both com-
1
plexes 7 and 8 (see SUP 57515). Their H NMR spectra were
quite similar for the corresponding sites (Tables 1–4, and 7 and
8). However, the 13C-{1H} signals for 8 are quite different from
those of 7. The multiple peaks belonging to each methylene
group from a to d were spread out and severely overlapped,
and each site from most of the sugar and heterobase portion
also showed multiple peaks due to different isomers in solution.
However, only one peak was observed on 195Pt and 31P-{1H}
NMR for 8.
Electrochemical studies of the platinum complexes
Reflection of our strategy
All the oxidation and reduction reactions of the platinum-() or
-() complexes are irreversible. The values listed in Table 11
correspond to those of the maxima or minima of oxidation and
reduction waves in cyclic voltammograms. Complex 1 shows
only one oxidation wave at 1.1 V; no reduction wave is observed
within the range 0 to Ϫ1.7 V. It looks like only the platinum
center is available for oxidation. Complexes 2 and 3 only show
Among the three general strategies to synthesize metal-
containing oligonucleotides, we selected to develop method (c)
to construct our platinum-based complexes. Phosphitylation
of 1 generated 4 as described above. The intramolecular co-
ordination of the phosphoramidite group dramatically reduces
its activity to such an extent that no reaction is observed for any
1418
J. Chem. Soc., Dalton Trans., 1999, 1413–1422

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Table 8 The 13C-{1H} NMR chemical shifts of various compounds containing the thymine nucleoside fragment in DMSO-d6 unless indicated
otherwise
Compound
1Ј
2Ј
3Ј
4Ј
5Ј
2
4
5
6
7
IIIa
7b
88.3
86.8
86.3
40.1
38.1
39.2, 39.1,
39.0, 38.7
75.9
74.5
71.7, 71.5,
71.3, 71.2
85.7
83.5
85.6, 85.4
64.7
62.6
64.6
164.7
163.5
167.1
151.5
150.5
152.3
111.3
110.0
112.3, 112.2
136.5
135.7
138.2, 137.9,
137.8
12.8
12.0
12.4,
12.3
8c
a In CD3CN. b In DMSO-d6. c In D2O.
Table 9 The 1H NMR chemical shifts of various compounds contain-
ing the DMT fragment in CDCl3 unless indicated otherwise
Table 11 Redox waves for the compounds from cyclic voltammograms
measured in CH3CN with 0.1 M tetrabutylammonium hexafluoro-
phosphate as electrolyte
Compound
Compound
PtII
P
PtIV
Peak
IIIa
7b
1
2
3
4
Ox: 1.08
2Љ
3Љ
4Љ
6Љ
7.45, m, 2 H
7.32, m, 2 H
7.32, m, 1 H
7.32, d, 4 H
6.87, d, 4 H
3.75, s, 3 H
7.42, m, 2 H
7.35, m, 2 H
7.29, m, 1 H
7.29, d, 4 H
6.92, d, 4 H
3.74, s, 3 H
Re: Ϫ1.00
Re: Ϫ0.55
Re: Ϫ1.14
Re–Ox: Ϫ0.58
Re: Ϫ0.77, Ϫ1.46
Re–Ox: Ϫ1.03, Ϫ0.61
Ox: 1.34
7Љ
7
10Љ
II
III
Ox: 1.10
Ox: 1.20
a In CD3CN. b In DMSO-d6.
Ox = Oxidation, Re = reduction, Re–Ox = reoxidation after initial
reduction.
Table 10 The 13C-{1H} NMR chemical shifts of various compounds
containing the DMT fragment in CDCl3 unless indicated otherwise
Compound
195Pt NMR studies of the platinum complexes
Peak
IIIa
7b
The 195Pt NMR signal(s) help to establish the co-ordination
environment, oxidation state of platinum, the interaction of
platinum with phosphorus, and the stereoisomerism in some
cases. The chemical shifts of cis- and trans-{Pt(NH3)2}2ϩ mono-
functional adducts [PtIIN3Cl] of nucleobases are from δ Ϫ2030
to Ϫ2360, bifunctional adducts [PtIIN4] from δ Ϫ2430 to
Ϫ2870,25,26 PtIIN2SCl from δ Ϫ3120 to Ϫ3190,27 PtIIN2Cl2
from δ Ϫ2200 to Ϫ2300,28 PtIIN2O2 from δ Ϫ1620 to Ϫ1980,28,29
PtIIN3O2 from δ Ϫ2310 to Ϫ2350,30 PtIVN3O2Cl from δ ϩ360
to ϩ370,30 PtIVN2O2Cl2 from δ ϩ600 to ϩ1120,28 and PtIV-
N2Cl4 from δ Ϫ80 to Ϫ250.28 The 195Pt NMR signals for the
compounds of this study are summarized in Table 6. All the
PtIIN2Cl2 centers give 195Pt NMR chemical shifts around δ
Ϫ2350, the PtIVN2O2Cl2 from δ ϩ300 to ϩ1050, and the one
with PtIVN2Cl4 gives δ Ϫ287. The platinum complexes with a
platinum–phosphoramidite bond PtIIN2PCl give 195Pt NMR
chemical shifts from δ Ϫ3650 to Ϫ3950, the highest upfield
chemical shift among the platinum() complexes reported.
Except for compound 4, no platinum complex having the co-
ordination sphere PtIIN2PCl has been reported where crystal
structure and 31P and 195Pt NMR studies have been conducted
at the same time to allow the comparison and correlation
intended here. However, evaluation of platinum() phosphor-
amidite or phosphite complexes reported, where such studies
have been conducted, reveals two features which are useful for
structural deduction from NMR studies. They are the one-
bond scalar coupling constant JPt–P and the chemical shifts
of co-ordinated phosphorus() and PtII. A qualitative trend of
1Љ
2Љ
3Љ
4Љ
5Љ
6Љ
7Љ
8Љ
9Љ
10Љ
146.6
129.1
129.1
128.1
137.3
131.3
114.4
160.0
86.4
145.0
128.0
127.8
127.0
135.7
129.9
113.4
158.3
83.8
56.0
55.1
a In CD3CN. b In DMSO-d6.
reduction waves at Ϫ1.0 and Ϫ0.55 V; no oxidation wave is
observed within the range 0–1.6 V, consistent with the reduc-
tion of PtIV to either PtIII or PtII. Complex 4 shows both an
oxidation wave at 1.34 and reduction waves at Ϫ0.58 and Ϫ1.14
V, respectively. This is consistent with the structure of the
compound having a Pt–P bond. The phosphoramidite group
as a ligand is known to stabilize low oxidation states of plat-
inum. Most probably, the two reduction waves observed corre-
spond to the couples Pt2ϩ–Ptϩ and Ptϩ–Pt0. The intrinsic
instability of the Ptϩ makes the processes irreversible. The
coupling agent 2-cyanoethyltetraisopropylphosphorodiamid-
ite itself only gives an oxidation wave at 1.10 V, while the
corresponding phosphate, which was obtained by oxidation
of the coupling agent in CH2Cl2 with H2O2, does not show
any redox activity within the range Ϫ1.7 to 1.6 V. Two reduc-
tion waves (Ϫ0.77 and Ϫ1.46 V) and their corresponding two
re-oxidation waves (Ϫ1.03 and Ϫ0.61 V) have been observed
for 7. The corresponding phosphate without platinum, which
was obtained by the oxidation of III in CH2Cl2 with H2O2,
does not show any redox activity within the range of Ϫ1.7 to
1.6 V. The redox waves for 7 have been assigned to the
couples Pt4ϩ–Pt3ϩ and Pt3ϩ–Pt2ϩ. The reduction potentials for
the platinum() complexes are within the range of Ϫ0.5 to
Ϫ1.5 V, while the oxidation potentials for the platinum()
complexes are within the range 1.0–1.4 V. These results show
that the reduction of platinum() complexes is feasible under
physiological conditions.24
1
the average Pt–P bond distance vs. JPt–P in platinum() phos-
phoramidite or phosphite complexes has been established: Pt–P
2.26–2.34 Å vs. 1JPt–P 3000–4300 Hz; Pt–P 2.15–2.22 Å vs. 1JPt–P
1
5500–6300 Hz.31 The parameters for 4, Pt–P 2.21 Å vs. JPt–P
4911 Hz, fall nicely within the range. The chemical shifts of co-
ordinated phosphoramidite or phosphite are shifted upfield as
compared with that of free phosphoramidite or phosphite, with
individual values depending on the substituents. Values ranging
from δ 77 to 126 have been reported for co-ordinated phosphor-
amidite,31e–f and δ 50 to 130 for co-ordinated phosphite.31b,c,h–j,32
This is in contrast with the chemical shifts of free phosphor-
amidite, δ 140–160, and of phosphite, δ 115–150.31h,i,33 Platinum
J. Chem. Soc., Dalton Trans., 1999, 1413–1422
1419

View Article Online
complexes with the co-ordination sphere PtIIP2Cl2 give 195Pt
NMR chemical shifts from δ Ϫ4300 to Ϫ4400,32c and PtIIP2I2,
of δ Ϫ3500.31f From the limited amount of 195Pt NMR chemical
shifts, it seems that phosphorus-based ligands shift the chem-
ical shift upfield, consistent with the observation for 4. The
31P-{1H} and 195Pt chemical shifts and coupling constants for 5
and 6 fall nicely within the above ranges.
obtained on a Varian 300 spectrometer, and the chemical shifts
referenced to cis-DDP in DMSO-d6 at δ Ϫ2124, which was cali-
brated by using K2PtCl4 in water (δ Ϫ1623 relative to Na2PtCl6)
as an external standard. Typical parameters were: frequency
64.224–64.414 MHz (varied according to the windows used for
different compounds), spectral width 100 000 Hz, acquisition
time 6 ms, relaxation delay 0 s, pulse width 14 µs, temperature
23 ЊC, decoupler off, line broadening 150 Hz, and FT size
1
1024. The 2-D H COSY experiments were performed on a
Conclusion
Bruker AC 400 spectrometer. Typical parameters were: data size
1024 × 256, dummy scan 2, magnitude processing, relaxation
delay 1 s, evolution time 3 µs, 90Њ pulse width 6.5 µs, scan
number 16. Typical parameters for 2-D XHCORR experiments
were: data size 2048 × 256, dummy scan 2, magnitude process-
ing, relaxation delay 0 s, evolution time 3 µs, mixing time 3.3 ms,
increment dwelling time of 1H, scan number 128. Typical
parameters for 2-D HMQC experiments were: 2048 × 512,
dummy scan 4, phase sensitive processing, relaxation delay 1.5
s, evolution time 6 µs, mixing time 3 ms, increment dewelling
time of 1H, scan number 32.
We have improved the synthetic procedures for the synthesis of
some hydroxy group tethered platinum-() and -() complexes.
Phosphoramidite coupling agents were shown to react with the
tethered hydroxy groups of the platinum complexes. However,
intramolecular displacement of the chloride by the incoming
phosphoramidite group prevents further manipulation of the
latter to connect with other hydroxy group(s) such as those
of oligodeoxynucleotides to synthesize ODN-tethered platinum
complexes. A new strategy has been developed to couple mono-
deoxynucleotides with the hydroxy group(s) of the tethered
platinum() complexes through the use of the monodeoxy-
1
nucleotide phosphoramidite agents. Every peak in the H and
Electrochemical measurements
13C-{1H} NMR spectra of all the compounds reported in this
Electrochemical measurements were performed using an
EG&G Model 283 potentiostat under a dinitrogen atmosphere.
For cyclic voltammetry experiments, a solution for each com-
pound at 1–10 mM containing 0.1 M Bu4NPF6 supporting
electrolyte and a platinum micro disc working electrode were
used. Potentials were determined vs. an AgCl–NaCl reference
electrode. The stability of the reference electrode was checked
1
study has been assigned through the combination of 1-D H,
13C-{1H}, 2-D COSY, XHCORR, HMQC (heteronuclear mul-
tiple quantum correlation), and the comparison of chemical
shifts among analogs. Extension of the strategy to other oligo-
deoxynucleotides and evaluation of the anticancer activities
of these compounds are in progress.
Ϫ
by performing the same experiment with added FeCp2ϩPF6
(EЊ1/2 = 0.454 V).
Experimental
Materials, methods, and instrumentation
Preparations
Potassium tetrachloroplatinate (K2PtCl4) and potassium
hexachloroplatinate (K2PtCl6) were purchased from Sausville
Chemical Company (Garfield, NJ), 2-cyanoethyl tetra-
isopropylphosphoramidite, tris(1,1,1,3,3,3-hexafluoropropyl)
phosphite, 2-cyanoethyl diisopropylphosphoramidochloridite,
tetrazole, 5-methylthiotetrazole, 2-(2-aminoethylamino)eth-
Dichloro[N-(2-hydroxyethyl)ethylenediamine]platinum(II) 1.16
Potassium tetrachloroplatinate (200 mg, 0.482 mmol) was
placed in a 20 mL vial. Dilute hydrochloric acid solution (4.0
mL, concentrated HCl solution:deionized water = 3:100) was
added to form a pink solution. 2-(2-Aminoethylamino)ethanol
from a graduated cylinder was added drop by drop with a
pipette until the pH reached 8.0, as monitored by pH paper.
The amount added was calculated; 70% more by volume was
then added. The solution was stirred for 30 min. During this
time the color changed from pink to pale yellow, and a lot of
yellow precipitate appeared. The solution was allowed to stand
for about 30 min until it became almost colorless. The solid was
filtered through a fine-filter paper, washed by 3 × 1 mL cold
water and 3 × 1 mL ether, then dried to give 152 mg of complex
1. Yield 85%. Electrospray MS: m/z 413, [M ϩ CH3CN]ϩ, 10;
376, [M ϩ CH3CN Ϫ Cl]ϩ, 3; and 335, [M Ϫ Cl]ϩ, 10%
(Found: C, 12.83; H, 3.25; Cl, 19.21; N, 7.60; Pt, 52.57. Calc.
for C4H12Cl2N2OPt: C, 12.98; H, 3.27; Cl, 19.16; N, 7.57; Pt,
52.70%).
Ϫ
anol, FeCp2ϩPF6Ϫ, and Bu4NϩPF6 from Aldrich (Milwaukee,
WI), H3PO4 (85%), hydrogen peroxide, acetic acid, dimethyl
sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile
and methylene chloride, from Fisher Scientific (Pittsburgh, PA),
acetic anhydride from Mallinckrodt Chemical (Paris, KY),
hydrochloric acid from EM Science (Gibbstown, NJ), com-
pound III from Glen Research (Sterling, VA) and deuteriated
dimethyl sulfoxide, water, methanol and dimethylformamide
from Cambridge Isotope Company (Cambridge, MA). All
chemicals were used as received unless otherwise stated.
Air-sensitive materials were handled either in a Vacuum
Atmospheres glove-box or by using standard Schlenk tech-
niques under dinitrogen. Solvents used in the glove-box were
purified by standard methods. Elemental analyses were per-
formed by Galbraith Laboratories, Inc. (Knoxville, TN, USA),
Midwest Microlab (Indianapolis, IN, USA), and H. Kolbe
Mikroanalytisches Laboratorium (Mülheim, Germany).
Diacetatodichloro[N-(2-hydroxyethyl)ethylenediamine]plat-
inum(IV) 2. Complex 1 (100 mg, 0.270 mmol) was suspended
in 1.5 mL acetic acid. A total of 9.3 equivalents of acetic
anhydride was added in one portion (2.56W, where W is the
weight of 1). The mixture was then stirred for one minute, 1.5
equivalents of H2O2 solution (30%, 0.445W) were added in one
portion and the solution was stirred for one more hour or until
it became almost clear. Methanol (1 mL) was added to quench
the reaction, and the mixture was filtered. The solvent was
removed, and the solid was washed with diethyl ether to get the
product 2 as a yellow powder (95 mg, 80%). Electrospray MS:
m/z 429, [M Ϫ OAc]ϩ; 411, (M Ϫ OAc Ϫ H2O]ϩ; 392, [M Ϫ
OAc Ϫ Cl]ϩ; 385, [M Ϫ OAc Ϫ CH2CH2OH]ϩ; 369, [M Ϫ
2OAc]ϩ; and 333, [M Ϫ 2OAc Ϫ HClϩ]. FAB MS: m/z 487, Mϩ;
453 [M Ϫ Cl]ϩ; 427, [M Ϫ OAc]ϩ; 393, [M Ϫ OAc Ϫ Cl]ϩ; 333,
[M Ϫ 2OAc Ϫ HCl]ϩ; 309, 275, 195, Ptϩ (Found: C, 19.61; H,
NMR measurements
All platinum() complexes undergo solvolysis at various
speeds in DMSO solutions. Minimum time exposure is required
when conducting NMR studies in this solvent. Owing to solu-
bility limitations of some platinum() complexes, use of this
1
solvent sometimes is unavoidable. The 1-D H and 13C-{1H}
NMR spectra were obtained on either a Bruker AC 200 or 400
spectrometer, and the chemical shifts referenced to the residual
solvent peaks. Standard parameters were used. The 1-D 31P-
{1H} NMR spectra were obtained on a Varian 300 spec-
trometer, and the chemical shifts referenced to external 85%
phosphoric acid in water. The 1-D 195Pt NMR spectra were also
1420
J. Chem. Soc., Dalton Trans., 1999, 1413–1422

View Article Online
Table 12 Crystal data and structure refinement for compound 4
3.79; Cl, 14.50; N, 5.69; Pt, 39.78. Calc. for C8H18Cl2N2O5Pt: C,
19.68; H, 3.72; Cl, 14.52; N, 5.74; Pt, 39.95%).
Empirical formula
C13H27Cl2N4O2PPt
M
568.35
White
Monoclinic
P21/c
16.7474(4)
14.1010(3)
8.7566(3)
95.747(2)
2057.52(10)
4
1.835
7.169
1104
8522
2680 [R(int) = 0.1129]
0.0469, 0.0678
0.0991, 0.0843
0.985
2666/84/208
0.816 and Ϫ0.951
Tetrachloro[N-(2-hydroxyethyl)ethylenediamine]platinum(IV)
3. Complex 2 (165 mg, 0.445 mmol) was suspended in 20% HCl
aqueous solution and stirred at room temperature for 8 h.
After the insoluble material was filtered off, the solvent was
removed and the resulting solid washed by diethyl ether to
afford the product 3 (80 mg, 41%). Electrospray MS: m/z 411,
[M Ϫ CH2OH]ϩ; 369, [M Ϫ 2Cl]ϩ; and 333, [M Ϫ 3Cl]ϩ (Found:
C, 11.13; H, 2.78; Cl, 31.98; N, 6.50; Pt, 44.55. Calc. for C4H12-
Cl4N2OPt: C, 10.89; H, 2.74; Cl, 32.14; N, 6.35; Pt, 44.22%).
Alternatively K2PtCl6 (20 mg, 0.0411 mmol) was suspended
in 2 mL of water. The solution was heated at 70 ЊC until the
compound was completely dissolved. 2-(2-Aminoethylamino)-
ethanol (4.7 mg, 0.0452 mmol) was added in one portion. The
mixture was heated at 70 ЊC overnight. After removal of the
solvent, the solid was washed with diethyl ether, and extracted
with CH3OH. The product formed upon removal of CH3OH
was characterized by NMR study in DMSO-d6.
Crystal habit
Crystal system
Space group
a/Å
b/Å
c/Å
β/Њ
V/Å3
Z
Dc/Mg mϪ3
µ/mmϪ1
F(000)
Total reflections
Independent reflections
Final R1, wR2 [I > 2σ(I)]
(all data)
Goodness of fit on F 2
Data/restraints/parameters
Maximum and minimum difference
peaks/e ÅϪ3
Chloro{N-2-[(2-cyanoethyl)(diisopropylamino)phosphinoxy]-
ethylenediamine}platinum(II) chloride 4. Complex 1 (100 mg,
0.270 mmol) was dissolved in 2 mL of DMF. 2-Cyano-
ethyltetraisopropylphosphoramidite (86.5 µl, 0.270 mmol) and
5-methylsulfanyltetrazole (28.2 mg, 0.243 mmol) were added
sequentially in one portion. The reaction mixture was stirred at
room temperature (RT) for 1.0 h. The solvent was removed
under vacuum, and the solid washed with diethyl ether to afford
a yellow powder. The solid was then extracted with 100 mL
CH3CN to get rid of a white solid. Removal of the solvent
generated an oily solid, which was washed with diethyl ether to
give a very light yellow powder 4 (110 mg, 71%). 31P-{1H}
OH]ϩ; 453, [OCH2CH2NHCH2CH2NH2Pt(OAc)2Cl]ϩ; and 413,
[OCH2CH2NHCH2CH2NH2Pt(OOC)Cl2]ϩ (Found: C, 44.29;
H, 4.87; Cl, 5.11; N, 7.31. Calc. for C42H53Cl2N5O14PPt: C,
43.90; H, 4.66; Cl, 6.17; N, 6.10%).
Complex 8. Complex 7 (40 mg, 0.0348 mmol) was dissolved
in 2 mL 15% HCl in water solution, CH2Cl2 (3 mL) was added
and the mixture stirred for 15 min. The CH2Cl2 was removed
and fresh added. The process was repeated two more times until
no DMT–OH spot was observable on TLC. The aqueous solu-
tion was separated, neutralized to pH 7 and then filtered. Upon
removal of the solvent to about 2 mL some white precipitate
appeared and was discarded. After all solvent was removed a
pale yellow solid resulted, which was extracted with DMF to
get rid of a residual amount of NaCl. Removal of DMF
afforded the product 8 (18 mg, 61%). 31P-{1H} NMR in water–
CH3OH (1:1), δ 0.918. Electrospray MS: m/z 761, [M ϩ H]ϩ;
735, [M ϩ H Ϫ CH3CN]ϩ; 719, [M Ϫ CH2CN]ϩ (Found: C,
26.61; H, 3.99; Cl, 9.60; N, 10.27. Calc. for C17H30Cl2N5O10PPt:
C, 26.81; H, 3.97; Cl, 9.60; N, 9.19%).
2
NMR in DMSO-d6: δ 81.1 (s), 81.1 (d, JPt–P = 4911 Hz). Elec-
trospray MS: m/z 614, [M ϩ CH3CN]ϩ; 535, [M Ϫ Cl]ϩ; 498,
[M Ϫ 2Cl]ϩ; 435, [M Ϫ Cl Ϫ NiPr2]ϩ, theoretical for C7H15-
ClN3O2PPt (Found: C, 26.10; H, 5.13; Cl, 11.64; N, 11.64; Pt,
32.46. Calc. for C13H27Cl2N4O2PPt: C, 27.38; H, 5.12; Cl, 12.43;
N, 9.82; Pt, 34.20%).
Complexes 5 and 6. Complex 1 (25 mg, 0.0676 mmol) was
dissolved in 1.0 mL DMF. Compound III (50 mg, 0.0671
mmol) and 5-methylsulfanyl tetrazole (6.3 mg, 0.0541 mmol)
were added sequentially in one portion. The reaction was
stirred at RT for 2–3 h, or until just completed as checked by
31P-{1H} NMR. A small amount of insoluble material was
removed by filtration, the solvent was removed under vacuum,
and the resulting solid washed with diethyl ether to get a yellow
solid 5 and 6 (55 mg, 74%). 31P-{1H} NMR in DMF: δ 73.5 (s),
73.2 (s), 72.8 (s), 72.5 (s), 72.6 (dm, 2JPt–P = 5197 Hz) for 5, and
139 (s), 140 (s) for 6.
Collection and reduction of X-ray data for complex 4
The crystal of complex 4 was transferred to a Siemens SMART/
CCD three circle (χ fixed at 54.65Њ) diffractometer equipped
with a cold stream of N2 gas and a graphite-monochromated
Mo-Kα radiation source (λ 0.71073 Å). Data collection was
performed at Ϫ60 ЊC. A total of 1104 frames of two-
dimensional diffraction images were collected, each of which
was measured for 10 s. Crystallographic data are summarized in
Table 12.
Complex 7. Complex 1 (30 mg, 0.0811 mmol) was dissolved
in 1.0 mL DMF. Compound III (60 mg, 0.0806 mmol) and
5-methylsulfanyl tetrazole (8.4 mg, 0.0716 mmol) were added
sequentially in one portion. The reaction was stirred at RT for
2–3 h, or until just completed as checked by 31P-{1H} NMR.
Acetic acid (0.550 g, 9.17 mmol), acetic anhydride (0.130 g, 1.27
mmol), and 30% H2O2 (30 mg, 0.203 mmol) were added sequen-
tially in one portion. The mixture was stirred for 15–30 min
until the reaction was complete as checked by 31P-{1H} NMR.
The DMF solution was poured into a large quantity of diethyl
ether, and an oily solid precipitated. When the diethyl ether
solution was almost clear it was decanted. The oily solid was
dried under vacuum, and the solid was washed with diethyl
ether to afford the product 7 (50 mg, 54% based on III). 31P-
{1H} NMR in DMSO-d6: δ 0.599 (s). Electrospray MS: m/z
1074, [M Ϫ Ph]ϩ; 976, [M Ϫ Ph Ϫ OAc Ϫ Cl]ϩ; 871, [M Ϫ
Ph Ϫ OAc Ϫ Cl Ϫ C6H4OCH3]ϩ; 806, [M Ϫ DMT Ϫ Cl Ϫ
CH3CO ϩ CH3CN]ϩ; 527, [3Ј-DMT Ϫ deoxythymidine Ϫ
The raw data frames were processed to produce conventional
intensity data by the program SAINT.34 An initial background
was determined from the first 12Њ of data. Integration was per-
formed with constant spot sizes of 1.75Њ in the detector plane
and 0.9Њ in ω. Absorption corrections were performed using the
program SADABS.35 The intensity data were also corrected for
Lorentz-polarization effects.
Solution and refinement. The structure was solved by direct
methods and standard Fourier-difference techniques. Four
independent platinum molecules were found in the asymmetric
unit cell. All final refinements were completed using SHELXL
93.35 Refinement was carried out on F2 for all reflections except
for those with either very negative F or reflections flagged for
potential systematic errors, normally for reflections besides
strong ones.
CCDC reference number 186/1377.
J. Chem. Soc., Dalton Trans., 1999, 1413–1422
1421

View Article Online
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Acknowledgements
Support from Department of Chemistry, The University of
Illinois at Chicago is gratefully acknowledged.
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Paper 8/08705I
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J. Chem. Soc., Dalton Trans., 1999, 1413–1422