Synthesis and hydrolysis studies of novel glyco-functionalized platinum complexes

Article abstract of DOI:10.1016/j.carres.2011.08.024

Cisplatin and some of its derivatives are among the most active cytostatics for cancer treatment. Unfortunately, application of platinum complexes always indicates side effects, and frequently primary or developed resistance of tumour cells appear. Theref

Full text of DOI:10.1016/j.carres.2011.08.024

Carbohydrate Research 348 (2012) 14–26
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis and hydrolysis studies of novel glyco-functionalized
platinum complexes
⇑
Janina Möker, Joachim Thiem
Department of Chemistry, Faculty of Science, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 April 2011
Received in revised form 8 August 2011
Accepted 24 August 2011
Available online 7 September 2011
Cisplatin and some of its derivatives are among the most active cytostatics for cancer treatment. Unfor-
tunately, application of platinum complexes always indicates side effects, and frequently primary or
developed resistance of tumour cells appear. Therefore, development of novel analogues especially with
natural ligands is expedited. Glyco-functionalized ligands were obtained via ether synthesis with
x-halo
ethers, Finkelstein reaction, with further treatment with malonate and final deprotection followed by
preparation of the disodium salts. Subsequent complexation led to novel platinum derivatives, the stabil-
ities of which in aqueous solution media were studied.
Keywords:
Antitumour agents
Platinum complexes
Sugar ethers
Ó 2011 Elsevier Ltd. All rights reserved.
Sugar-functionalized complexes
1. Introduction
as ammine ligands for platinum. These complexes all showed high-
er IC50 values compared to cisplatin and carboplatin in preliminary
The biological activity of platinum complexes was found by
chance in 1965 by B. Rosenberg.1 Nowadays cisplatin (diammine
dichloro platinum(II), 1) and some of its derivatives are used for
treatment of a large variety of cancers such as testicular, vesicle,
cervix and head–neck-tumours as well as oesophagus and small-
cell lung carcinoma.2 Due to side effects such as renal, neural,
nephro- and ototoxicity3 which always accompany the application
of cisplatin (1), approaches to develop new active derivatives rep-
resent contemporary research. Change of chloro ligands which are
substituted in cells to give the active compounds induces altered
stabilities of the complexes. Different stabilities in turn lead to
other side effects4 shown for example by carboplatin (2), in which
the chloro ligands are substituted by a 2,2-cyclobutane dicarboxy-
lato group5 or nedaplatin (4), which shows less nephro- and neuro-
toxicity compared to cisplatin.6 Derivatization of the ammine
ligands like those shown in oxaliplatin (3) leads to a different
structure of Pt–DNA-adducts which are responsible for the cyto-
toxic activity.7 Change of the structure of Pt–DNA-adducts induces
altered and enhanced activity, and thus treatment of cisplatin
resistant tumours can be accomplished (Fig. 1).8
biological tests.10 1,2- or 1,3-Diaminopropanol glycosidically
linked to saccharides was also used for complexation to platinum
to give five- or six-membered rings by Mikata et al., and their activ-
ity was shown to be comparable to cisplatin against two different
cell lines.11 A glucuronic acid containing platinum complexes was
developed by Tromp et al. to function as a prodrug releasing the ac-
tive compound via enzymatic cleavage of the glycolytic bond with
b-glucuronidase.12
2. Results and discussion
In order to reach lower toxicity combined with enhanced up-
take carbohydrates were connected to platinum using an arbi-
trarily chosen hydrophobic spacer and malonic acid as chelating
moiety in this approach.
2.1. Synthesis of monosaccharide platinum complexes
Following the facile approach via Williamson’s ether synthesis
(GP 1),13 Finkelstein reaction (GP 2)14 and reaction with di-tert-bu-
tyl malonate (GP 3)15 previously shown to be advantageous for
synthesis of gluco- and galacto-derivatives and to achieve glyco-
functionalized platinum complexes,16 a series of other saccharides
were prepared as precursors for novel complexes. Therefore, selec-
tively protected alkylidene (isopropylidene or Ley’s group)
Due to the side effects and the primary or developed resistance
of some tumours a number of novel platinum compounds were
introduced over the last decades. Some of these approaches also
incorporate natural ligands, for example, carbohydrates.9 For
example, 2,3-diaminosugars were used by Berger et al. to serve
protected D-fructose, D-arabinose, D-ribose and D-mannose deriva-
tives were chosen. Williamson’s ether synthesis employing 50%
aqueous sodium hydroxide and 1-bromo-4-chlorobutane could
⇑
Corresponding author. Tel.: +49 40 428384241; fax: +49 40 42838 4325.
E-mail address: thiem@chemie.uni-hamburg.de (J. Thiem).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.08.024

J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
15
O
H2
O
O
Pt
O
N
O
O
H3N
O
O
H3N
H3N
H3N
H3N
Cl
Cl
Pt
Pt
Pt
N
H3N
O
H2
O
O
1
2
4
3
Figure 1. Platinum complexes for cancer treatment.
be achieved in yields from 37% to 87% depending on the used pro-
tected saccharide. For Finkelstein reaction yields between 53% and
98% were obtained, and after reaction with di-tert-butyl malonate/
potassium tert-butoxide as base the products could be isolated in
yields between 23% and 95% (Scheme 1, Table 1).
plexation of disodium salt 76 with platinum was achieved in 47%
yield to give methyllactoside platinum complex 77 (Scheme 4).
2.4. Synthesis of 2,6- and 4,6-substituted glucopyranoside bis
platinum complexes
Simultaneous deprotection of all blocking groups in compounds
obtained by GP 3 was performed using trifluoroacetic acid in
dichloromethane to give the disodium salts of the unprotected sac-
charides following treatment with 1 M sodium hydroxide solution
(GP 4) in yields between 19% and 94%. The novel glyco-functional-
ized ligands were readily complexed to platinum. Starting with cis-
platin and substitution of the chloro ligands with aqua ligands by
using silver nitrate gave the reagent which was used for transfer
into the glyco-functionalized compounds (GP 5)15 in yields be-
tween 28% and 80% (Scheme 2, Table 2). Complexation could be
verified via 1H NMR spectroscopy apparent by a downfield shift
of the spacer protons. Especially the CH2-groups at the 4th position
of the spacer (CH2-40) are shifted downfield from about 1.8 ppm in
the free ligands to 2.5 ppm in the complexes.
Attaching two platinum-binding malonato groups to one sac-
charide via a butyl spacer could be achieved facilely employing
two different gluco-derivatives protected with Ley’s group.
Therefore, methyl
a-D-glucopyranoside (78) was converted into a
mixture of 3,4- (79) and 2,3-protected derivatives (80)18 (99%
yield). Following the synthesis of 6-O-silyl ethers19, isomeres 81
and 82 were easily separated by column chromatography (84%
yield). Cleavage of 6-O-silyl ether gave the two protected gluco-
derivatives (yields: 98% for 79 and 87% for 80) which were reacted
with 1-bromo-4-chlorobutane following GP 1, however, reducing
the amount of sodium hydroxide solution. Additional to dialkylat-
ed products 83 (43% yield) and 85 (48% yield) a mixture of mono-
alkylated products 35 and 84 (28% yield using 3.3 equiv sodium
hydroxide) as well as 41 and 86 (50% yield) were obtained. Using
4.8 equiv sodium hydroxide for ether synthesis with 83 only 6-
OH unprotected derivative 35 (47% yield) was obtained as side
product. A small amount of 41 (37%) could be separated by column
chromatography. The mixture of 35 and 84 as well as the mixture
of 41 and 86 was reacted with TBDPSCl to give 32 (67%) and 38
(41%), which also were converted to platinum-complexing ligands
like those shown in Table 1.
2.2. Preparation of a di-O-methyl glucofuranose platinum
complex
Due to the results of first biological tests for 4516 which showed
nearly the same activity for this novel complex compared to carbo-
platin more hydrophobic glyco-functionalized platinum complexes
were synthesized. To obtain this partial methylated complex which
perhaps can cross the cell membrane more facilely 3-(40-chlorobu-
tyl)-diacetone glucose (5) was selectively deprotected with 0.4%
sulfuric acid (yield 70%)17 and the free 5,6-positions methylated
in 31% yield. Following the general procedures 2–5 the more
hydrophobic glucose platinum complex 71 was synthesized in
yields between 37% (complexation) and 68% (Finkelstein reaction)
(Scheme 3).
Finkelstein reaction on both side chains with yields of 77% (to
give 87) and 94% (to give 88) followed by reaction with di-tert-bu-
tyl malonate in yields of 24% (to give 89) and 60% (to give 90) were
performed. After deprotection of the sugar moiety, cleavage of di-
tert-butyl ester gave tetra sodium salts 91 and 92, respectively, and
complexation to platinum could be achieved to give bis-platinum
complexes 93 (yield 54%) and 94 (yield 70%) (Scheme 5).
2.3. Synthesis of lactoside platinum complex
2.5. Hydrolysis studies
In addition to the synthesis for monosaccharide platinum com-
All presently applied platinum complexes in medicine represent
prodrugs which are activated in cells by substitution of the non-
amino ligands. Therefore, it was of interest to study the stability
of the novel complexes. Previously, for the substitution of 2,2-
cyclobutane dicarboxylato group in carboplatin (0.02 M) a rate
constant was determined to be kobs = 1.2 ꢀ 10ꢁ6 sꢁ1 in a chloride
(0.14 M) and hydrogen phosphate (0.1 M) solution by 1H NMR
analysis. The concentration of carboplatin (2) at equilibrium was
measured to be 12 mM (64.1% did not react).20
plexes a lactoside ligand 76 was obtained. Starting with methyl
2,3,6-tri-O-benzyl-4-O-(20,30,60-tri-O-benzyl)-b-
D-galctopyrano-
syl)-b-
D-glucopyranoside (72) Williamson’s ether synthesis with 1-
bromo-4-chlorobutane leads to compound 73 in 25% yield.
Following Finkelstein reaction (80%) the transformation with di-
tert-butyl malonate gave 74 in 45% yield. Removal of the benzyl
groups by hydrogenolysis (palladium on charcoal) followed by
acidic cleavage of tert-butyl esters was obtained in 93% yield. Com-
O
OH
O
O
O
GP 1
GP 2
GP 3
R
R
Cl
R
I
R
OtBu
OtBu
O
Scheme 1. Construction of monosaccharide-tethered malonates. Reagents and conditions: GP 1: 50% NaOH-solution, 1-bromo-4-chlorobutane, DMSO; GP 2: NaI, acetone; GP
3: di-tert-butyl malonate, KOtBu, THF.

16
J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
Table 1
Construction of monosaccharide-tethered malonates
R
Reaction GP 1
No. (yield)
Reaction GP 2
No. (yield)
Reaction GP 3
No. (yield)
O
O
O
5 (87%16
)
)
6 (83%16
)
)
7 (67%16
)
O
O
O
O
O
8 (64%16
9 (85%16
10 (71%16
)
O
O
O
O
O
11 (59%)
12 (84%)
13 (60%)
O
O
O
OMe
OMe
14 (37%)
17 (43%)
15 (98%)
18 (84%)
16 (83%)
19 (95%)
O
O
O
O
O
OMe
O
20 (59%)
21 (74%)
22 (50%)
O
O
O
OMe
23 (66%)
26 (48%)
24 (90%)
27 (88%)
25 (55%)
28 (29%)
O
O
OTrt
OMe
O
O
O
OMe
OMe
OMe
OMe
O
O
29 (50%)
30 (99%)
31 (34%)
34 (23%)
O
OMe
R = TBDPS
R = H
32 (67%)a
35 (47%)b
33 (74%)
36 (91%)
OR
37 (80%/80%c)
OMe
O
O
O
OMe
OMe
OR
OMe
R = TBDPS
R = H
38 (41%)a
41 (37%)b
39 (53%)
42 (78%)
40 (26%)
43 (66%/74%c)
O
O
O
OMe
OMe
Reagents and conditions: GP 1: 50% NaOH-solution, 1-bromo-4-chlorobutane, DMSO; GP 2: NaI, acetone; GP 3: di-tert-butyl malonate, KOtBu, THF.
a
Obtained by silylation with TBDPSCl of mixtures of 34 and 84 as well as 40 and 86.
Obtained as side product by synthesis of 83 and 85 following GP 1.
Obtained by cleavage of the TBDPS-groups from 34 and 40.
b
c

J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
17
H3N
H3N Pt
O
tBuO
tBuO
O
NaO
NaO
O
O
O
O
O
O
O
GP 4
GP 5
O
O
O
OPG
O
O
Scheme 2. Formation of monosaccharide-functionalized platinum complexes. Reagents and conditions: GP 4: CH2Cl2/TFA 3:1; GP 5: cisplatin, AgNO3, H2O.
Table 2
Formation of monosaccharide-functionalized platinum complexes
Protected sugar derivative
Reaction GP 4
No. (yield)
Reaction GP 5
No. (yield)
Platinum complex
OtBu
OtBu
HO
O
O
O
O
O
HO
O
O
O
O
HO OH
O
44 (66%16
)
45 (60%16
)
H3N Pt
O
NH3
O
O
O
OtBu
NH3
O
O
O
Pt NH3
O
OtBu
O
O
HO
HO
O
O
O
46 (58%16
)
47 (70%16
)
O
O
O
HO OH
O
O
OH
OH
O
O
O
O
O
O
O
O
OH
48 (67%)
49 (77%)
OH
O
OtBu
Pt NH3
O
O
O
O
NH3
O
OtBu
tBuO
tBuO
O
H3N
H3N
O
O
O
Pt
O
O
O
O
O
OMe
50 (54%)
51 (55%)
OMe
OH
O
O
OH
O
O
O
HO
O
OMe
OMe
O
O
OH
O
52 (63%)
53 (61%)
O
O
O
O
O
H3N Pt
tBuO
O
tBuO
NH3
O
O
O
O
O
O
tBuO
tBuO
O
OH OH
OMe
OH
O
O
H3N Pt
54 (19%)
55 (28%)
O
NH3
O
O
OtBu
NH3
OMe
O
O
O
O
O
OMe
O
Pt
O
NH3
OtBu
O
O
56 (80%)
57 (28%)
O
OH
O
O
HO
(continued on next page)

18
J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
Table 2 (continued)
Protected sugar derivative
Reaction GP 4
No. (yield)
Reaction GP 5
No. (yield)
Platinum complex
OtBu
OtBu
NH3
O
O
O
O
Pt
NH3
OTrt
OH
O
O
OMe
O
O
58 (54%)
59 (62%)
HO
O
O
O
HO
O
OMe
OMe
O
OMe
OMe
O
OMe
OH
OMe
O
O
O
O
O
HO
60 (44%)
61 (42%)
O
O
O
Pt
tBuO
tBuO
OMe
H3N
H3N
O
O
OR
OH
OMe
O
O
HO
HO
O
O
O
OMe
O
O
OMe
OMe
62 (94%)
63 (59%)
R = TBDPS
R = H
O
O
O
O
H3N Pt
tBuO
O
NH3
tBuO
tBuO
tBuO
O
H3N
OR
OMe
O
O
OH
Pt
O
H3N
O
O
O
O
O
64 (83%)
65 (80%)
O
HO
O
O
OH
OMe
OMe
OMe
Reagents and conditions: GP 4: CH2Cl2/TFA 3:1; GP 5: cisplatin, AgNO3, H2O.
As a follow-up to this study, the stabilities of some of the novel
glyco-functionalized complexes were examined by 1H NMR
spectroscopy. Selection for comparison to 2 was based on consid-
erations for structural diversity as well as access to the required
amount of material available. Thus, 3-substuituted glucopyranose
derivative 45, 6-substituted galacto isomer 47, 5-substituted
ribofuranose 55, and 2-substituted mannopyranoside 59 were pre-
liminary measured. Studies of glucofuranose, the lactose and the
bis-glucopyranose complexes 71, 77, 93, and 94 will be done in
due course.
A favourable and facile analysis could be based on the large
downfield shift of the protons of butyl spacer’s CH2 groups when
the ligand is complexed to platinum. As depicted in Figure 2, espe-
cially the CH2-40 protons were shifted widely from 1.8 ppm with
free ligand to 2.5 ppm in the complex (Scheme 6, Fig. 2). The de-
crease of the signal at 2.5 ppm is proportional to the decrease of
the concentration of complex in solution (phosphate buffered solu-
tion, pH 7.08 in D2O). For examinations the different complexes (2,
45, 47, 55 and 59) were first dissolved in D2O and lyophilized, and
then a 9 mmol/L of complex in buffered solution (D2O) was pre-
pared. NMR-spectra were taken after several days over a period
of about one month.
and with assumption of a pseudo-first order reaction with a steady
state at equilibrium the constant kobs for different complexes was
determined (Table 3).
As shown in Table 3 all determined rate constants of the substi-
tution of the glyco-functionalized ligands are in the same range
and comparable to kobs for carboplatin measured by Frey et al.20
Only kobs for 55 showed that the ribofuranose ligand was substi-
tuted more slowly. Comparing the concentration of complex at
equilibrium determined in this study with the concentration deter-
mined by Frey et al. shows that less complex is left using a 9 M
solution instead of a 20 M solution of complex.
2.6. Conclusion
In this work carbohydrates were chosen as natural ligands for
complexation with platinum. Following a facile route thirteen no-
vel complexes could be generated. The method chosen consists of
four steps:
1. Selective protection of the different carbohydrates,
2. Williamson’s ether synthesis, Finkelstein reaction and sub-
stitution with malonate to connect carbohydrates with an
ideal bidentate-chelating moiety,
3. Deprotection of carbohydrates and
4. Complexation of different ligands to platinum.
For analysis the decrease of the signal at 2.5 ppm was converted
into concentration of the complex at the time the NMR spectra
were taken. These values were plotted against the time (Fig. 3),

J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
19
HO
HO
MeO
MeO
O
O
Cl
Cl
Cl
O
O
O
O
O
O
a
b
O
O
O
O
O
O
5
67
66
O
OtBu
OtBu
MeO
MeO
MeO
MeO
I
O
O
O
O
GP 2
GP 3
O
O
O
O
O
69
68
NH3
O
O
O
O
ONa
ONa
Pt
MeO
MeO
MeO
MeO
NH3
O
GP 4
O
O
GP 5
O
O
OH
OH
O
OH
OH
70
71
Scheme 3. Synthesis of dimethoxy glucofuranose platinum complex. Reagents and conditions: (a) 0.4% H2SO4, MeOH/H2O 1:1; (b) MeI, 50% NaOH-solution, DMSO; GP 2: NaI,
acetone; GP 3: di-tert-butyl malonate, KOtBu, THF; GP 4: CH2Cl2:TFA 3:1; GP 5: cisplatin, AgNO3, H2O.
OBn
OBn
OBn
O
OBn
O
O
O
GP 1
BnO
BnO
O
O
BnO
OMe
BnO
OMe
OBn
OBn
OH
O
OBn
OBn
GP 2
R
72
73
R = Cl
74 R = I
OH
OBn
OH
O
OBn
O
O
O
GP 3
a
HO
BnO
O
O
HO
O
BnO
OMe
OMe
O
O
OH
OBn
O
OH
OBn
76
tBuO
tBuO
75
NaO
NaO
O
O
O
OH
OH
O
HO
O
HO
GP 5
OMe
O
O
O
OH
O
OH
77
H3N
Pt
H3N
O
Scheme 4. Formation of lactoside platinum complex. Reagents and conditions: GP 1: 50% NaOH-solution, 1-bromo-4-chlorobutane, DMSO; GP 2: NaI, acetone; GP 3: di-tert-
butyl malonate, KOtBu, THF; (a) H2, C–Pd; GP 5: cisplatin, AgNO3, H2O.
All syntheses could be achieved in moderate to very good yields.
The stability of selected glyco-funtionalized platinum com-
plexes (45, 47, 55 and 59) was measured in a PBS-buffer system.
Employing NMR-spectroscopy the downfield shifts of the signals
of the spacer protons were used to determine the decrease of the
concentration of the glyco-functionalized complexes. It could be
shown, that the gluco-ligand 45 was substituted the fastest with
a rate constant of kobs = 1.91 ꢀ 10ꢁ6 1/s.
0
Further, biological tests employing different tumour cell lines
such as small-cell lung carcinoma (H526) and fibroblast of lung

20
J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
OH
OH
OH
OMe
OMe
O
O
O
O
HO
a
O
HO
HO
O
O
+
OH
OH
OMe
OMe
OMe
OMe
78
80
79
OMe
b
OR1
OR1
OMe
OMe
O
O
O
HO
O
O
O
+
OH
OMe
OMe
OMe
OMe
82 R1 = TBDPS
80 R1 = H
81 R1 = TBDPS
79 R1 = H
c
c
GP 1
GP 1
OR3
OR2
O
OMe
OMe
O
R2O
O
O
O
OR3
O
OMe
OMe
OMe
OMe
GP 2
85 R2 = (CH2)4Cl, R3 = (CH2)4Cl
41 R2 = (CH2)4Cl, R3 = H
86 R2 = H, R3 = (CH2)4Cl
GP 2
83 R2 = (CH2)4Cl, R3 = (CH2)4Cl
35 R2 = H, R3 = (CH2)4Cl
84 R2 = (CH2)4Cl, R3 = H
88 R2 = (CH2)4I, R3 = (CH2)4I
87 R2 = (CH2)4I, R3 = (CH2)4I
O
OtBu
OtBu
GP 3
GP 3
O
OtBu
OtBu
tBuO
tBuO
O
O
O
OMe
O
O
OMe
O
O
O
O
O
O
O
O
OMe
O
OMe
OMe
OMe
90
GP 4
O
ONa
ONa
O
tBuO
O
NaO
NaO
O
O
tBuO
89
O
O
OH
O
HO
GP 4
O
O
ONa
ONa
OMe
92
GP 5
O
NH3
O
O
O
O
NH3
Pt
O
Pt
O
O
O
NH3
HO
HO
NH3
NH3
O
O
O
H3N
O
O
Pt
O
OMe
O
GP 5
O
O
O
O
91
HO
94
HO
HO
O
OH
OMe
O
O
OMe
NaO
O
NaO
O
O
O
H3N Pt
O
NH3
93
Scheme 5. Construction of disubstituted glucopyranoside platinum complexes. Reagents and conditions: (a) butandione, CSA, trimethyl orthoformate, MeOH; (b) TBDPSCl,
imidazole, THF; (c) TBAF, THF; GP 1: 50% NaOH-solution, 1-bromo-4-chlorobutane, DMSO; GP 2: NaI, acetone; GP 3: di-tert-butyl malonate, KOtBu, THF; GP 4: CH2Cl2/TFA 3:1;
GP 5: cisplatin, AgNO3, H2O.

J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
21
Figure 2. NMR survey of hydrolysis.
Glc
Glc
O
O
O
O
O
O
O
H3N
H3N
Nu
Nu
O
O
H3N
H3N
+ 2 Nu
Pt
Pt
CH2
H-4'
CH2
H-4'
O
Scheme 6. Hydrolysis of saccharide-tethered platinum complexes.
Table 3
Hydrolysis constants of saccharide-tethered platinum complexes
Complex
kobs (1/s)
cequilibrium (%)
Carboplatin (2)
Glc3Pt 45
Gal6Pt 47
1.41 ꢀ 10ꢁ6
1.91 ꢀ 10ꢁ6
1.46 ꢀ 10ꢁ6
5.30 ꢀ 10ꢁ7
1.40 ꢀ 10ꢁ6
50
35
30
22
22
Rib5Pt 55
Man2Pt 59a
a
Data not shown in Figure 3; only one series of measurements.
(MRC-5) to obtain the IC50 values of the novel glycol-platinum
complexes in comparison to carboplatin (2) are under way and will
be reported elsewhere.
3. Experimental
3.1. General methods
Commercially available starting materials were used without
further purification. Solvents were dried according to standard
methods. TLC was performed on precoated aluminium plates (Silica
Gel 60 F254, Merck 5554), and charring was with 10% H2SO4 in eth-
anol for visualization. For column chromatography Silica Gel 60,
Figure 3. Plots for hydrolysis of saccharide-tethered platinum complexes.

22
J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
230–400 mesh, 40–63
l
m (Merck) was used. 1H NMR and 13C NMR
3.3.1. 3-O-(40-Chlorobutyl)-1,2:4,5-di-O-isopropylidene-
a-D-
spectra were recorded on Bruker AMX-400 (400 MHz for 1H,
100.6 MHz for 13C) and on Bruker DRX-500 (500 MHz for 1H,
125.8 MHz for 13C) at 300 K. Chemical shifts were calibrated to sol-
vent residual peaks.21 The signals were assigned by H,H-COSY,
HSQC and HMBC experiments. Optical rotations were measured
using a Krüss Optronic P8000 (589 nm) at 20 °C. MALDI-TOF-MS
was performed on a Bruker Biflex III with dihydroxybenzoic acid
as matrix in positive reflector mode. HRFAB-MS was performed
on a VG 70S mass spectrometer in positive ion mode with a xenon
FAB-gun and m-nitrobenzyl alcohol as matrix at 5000 resolution.
fructopyranose (11)
3.3.2. 3-O-(40-Iodobutyl)-1,2:4,5-di-O-isopropylidene-
a-D-
fructopyranose (12)
3.3.3. 3-O-(50,50-Di-tert-butoxycarbonylpentyl)-1,2:4,5-di-O-
isopropylidene-a-D-fructopyranose (13)
3.3.4. Methyl 4-O-(40-chlorobutyl)-2,3-O-isopropylidene-b-
D
-
-
ribopyranoside (14)
3.3.5. Methyl
ribopyranoside (15)
3.3.6. Methyl 4-O-(50,50-di-tert-butoxycarbonylpentyl)-2,3-O-
4-O-(40-iodobutyl)-2,3-O-isopropylidene-b-
D
isopropylidene-b-D-ribopyranoside (16)
3.2. General procedures
3.3.7. Methyl 2-O-(40-chlorobutyl)-3,4-O-isopropylidene-b-
D-
ribopyranoside (17)
3.2.1. GP 1
3.3.8. Methyl 2-O-(50,50-di-tert-butoxycarbonylpentyl)-3,4-O-
The selectively protected saccharide (1 equiv) was dissolved in
DMSO and for each hydroxyl group 1.3 equiv 50% sodium hydrox-
ide solution and 1.5 equiv 1-bromo-4-chlorobutane were added.
The mixture was stirred at room temperature for 20 h. Distilled
water was added, and the solution was extracted three times with
diethyl ether. The combined organic fractions were washed with
saturated sodium chloride solution and dried with Na2SO4. The sol-
vent was removed under reduced pressure and the residue was
purified by column chromatography to give the product.
isopropylidene-b-
3.3.8.1. Methyl
2-O-(40-iodobutyl)-3,4-O-isopropylidene-b-
ribopyranoside (18)
3.3.8.2. Methyl 2-O-(50,50-di-tert-butoxycarbonylpentyl)-3,4-O-
D-ribopyranoside (19)
D-
isopropylidene-b-D-ribopyranoside (19)
3.3.9.
Methyl 5-O-(40-chlorobutyl)-2,3-O-isopropylidene-b-
D-
ribofuranoside (20)
3.3.10. Methyl-5-O-(40-iodobutyl)-2,3-O-isopropylidene-b-
D-
ribofuranoside (21)
3.3.11. Methyl 5-O-(50,50-di-tert-butoxycarbonylpentyl)-2,3-O-
3.2.2. GP 2
isopropylidene-b-D-ribofuranoside (22)
3.3.12. Methyl 2-O-(40-chlorobutyl)-3,4-O-isopropylidene-b-
D
-
-
Sodium iodide (1 equiv) was added to a solution of compound
received from GP 1 (1 equiv) in acetone. The mixture was heated
under reflux for 24 h. Filtration, evaporation of the solvent and col-
umn chromatography gave the product.
arabinopyranoside (23)
3.3.13. Methyl
arabinopyranoside (24)
3.3.14. Methyl 2-O-(50,50-di-tert-butoxycarbonylpentyl)-3,4-O-
isopropylidene-b- -arabinopyranoside (25)
2-O-(40-iodobutyl)-3,4-O-isopropylidene-b-
D
3.2.3. GP 3
D
3.3.15. (20S,30S)-Methyl 2-O-(400-chlorobutyl)-3,4-O-(20,30-dim-
Potassium tert-butoxide (1 equiv) was added under nitrogen to
a solution of di-tert-butyl malonate (1.3 equiv) in anhydrous tetra-
hydrofuran. After consumption of potassium tert-butoxide at re-
flux, compound received from GP 2 was added (1 equiv) and the
mixture was heated under reflux for 20–30 h. Tetrahydrofuran
was removed under reduced pressure, and dichloromethane was
added. The mixture was washed twice with 5% acetic acid, once
with water and dried with Na2SO4. The solvent was removed under
reduced pressure, and the residue was purified with column
chromatography to give the product.
ethoxybutane-20,30-diyle)-6-O-trityl-
a-D-mannopyran-
oside (26)
3.3.16. (20S,30S)-Methyl-2-O-(400-iodobutyl)-3,4-O-(20,30-dim-
ethoxybutane-20,30-diyle)-6-O-trityl-
a-D-mannopyran-
oside (27)
3.3.17. (20S,30S)-Methyl-2-O-(500,500-di-tert-butoxycarbonylpen-
tyl)-3,4-O-(20,30-dimthox-ybutane-20,30-diyle)-6-O-tri-
tyl-
3.3.18. (20S,30S)-Methyl-4-O-(400-chlorobutyl)-2,3-O-(20,30-dim-
ethoxybutane-20,30-diyle)-b-
-arabinopyranoside (29)
3.3.19. (20S,30S)-Methyl-4-O-(400-iodobutyl)-2,3-O-(20,30-dim-
ethoxybutane-20,30-diyle)-b-
-arabinopyranoside (30)
a-D-mannopyranoside (28)
D
3.2.4. GP 4
Compound received from GP 3 was solubilised in dichlorometh-
ane and trifluoroacetic acid (ratio 3:1), and the mixture was stirred
at room temperature for several hours. The solvent was removed
under reduced pressure, and water was added. The mixture was
extracted twice with diethyl ether and neutralized with 1 M
sodium hydroxide solution. The product was purified on Biogel P2.
D
3.3.20. Methyl-4-O-(500,500-di-tert-butoxycarbonylpentyl)-2,3-
O-(20,30-dimethoxybutane-20,30-diyle)-b-
D-arabinopyr-
anoside (31)
3.3.21. (20S,30S)-Methyl-6-O-tert-butyldiphenylsilyl-2-O-(400-
chlorobutyl)-3,4-O-(20,30-dimethoxybutane-20,30-diyl)-
a
-
D
-glucopyranoside (32)
3.3.22. (20S,30S)-Methyl-6-O-tert-butyldiphenylsilyl-2-O-(400-
iodobutyl)-3,4-O-(20,30-dimethoxybutane-20,30-diyl)-
3.2.5. GP 5
Cisplatin (1 equiv) and silver nitrate (2 equiv) were dissolved in
bidistilled water and stirred at room temperature overnight. After
filtration of the precipitated silver chloride, compound received
from GP 4 (0.5 equiv) was added, and the mixture was stirred at
room temperature for several hours. The water was removed under
reduced pressure, and the product was purified on Biogel P2.
a-
D
-glucopyranoside (33)
3.3.23. (20S,30S)-Methyl-6-O-tert-butyldiphenylsilyl-2-O-(500,500-
di-tert-butoxycarbonyl-pentyl)-3,4-O-(20,30-dim-
ethoxybutane-20,30-diyle)-
a-D
-glucopyranoside (34)
3.3.24. (20S,30S)-Methyl-2-O-(400-iodobutyl)-3,4-O-(20,30-dim-
ethoxybutane-20,30-diyle)-
-glucopyranoside (36)
a-D
3.3.25. (20S,30S)-Methyl-2-O-(500,500-di-tert-butoxycarbonylpen-
3.3. Syntheses
tyl)-3,4-O-(20,30-dimethoxybutane-20,30-diyle)-
a-D-
All novel prepared compounds are listed here with their ra-
tional names. If only the name is given the corresponding detailed
experimental and analytical description with all physical and spec-
troscopic data are found in the Supplementary data.
glucopyranoside (37)
3.3.26. (20R,30R)-Methyl-6-O-tert-butyldiphenylsilyl-4-O-(400-
chlorobutyl)-2,3-O-(20,30-dimethoxybutane-20,30-diyl)-
a-D-glucopyranoside (38)

J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
23
3.3.27. (20R,30R)-Methyl-6-O-tert-butyldiphenylsilyl-4-O-(400-
iodobutyl)-2,3-O-(20,30-dimethoxybutane-20,30-diyl)-
-glucopyranoside (39)
3.3.28. (20R,30R)-Methyl-6-O-tert-butyldiphenylsilyl-4-O-
(500,500-di-tert-butoxycarbonyl-pentyl)-2,3-O-(20,30-dim-
ethoxybutane-20,30-diyle)-
-glucopyranoside (40)
3.3.29. (20S,30S)-Methyl-2-O-(400-iodobutyl)-3,4-O-(20,30-dim-
ethoxybutane-20,30-diyle)-
-glucopyranoside (42)
3.3.38.
Using GP 5 compound 54 (100 mg, 273
with cisplatin (174 mg, 569 mol) and silver nitrate (206 mg,
1.14 mmol) in water (7 mL) to give 55; (42.7 mg, 28%); 1H NMR
(D2O, 400 MHz): d 5.29 (d, 1H, J1,2 3.9 Hz, H-1 ), 4.13 (ddd, 1H,
J3,4 8.0 Hz, J4,5a 3.0 Hz, J4,5b 5.1 Hz, H-4 ), 4.05–3.96 (m, 2H, H-2
H-3 ), 3.63 (dd, 1H, J4,5a 3.0 Hz, J5a,5b 11.3 Hz, H-5 a), 3.60–3.50
(m, 4H, H-5
b, CH2-10, CCH-50), 2.50–2.44 (m, 2H, CH2-40), 1.67–
1.58 (m, 2H, CH2-20), 1.44–1.35 (m, 2H, CH2-30); 1H NMR (D2O,
a
/b-
D
-Ribofuranose platinum complex (55)
a-
lmol) was reacted
D
l
a
a
-
D
a
a,
a
a
a-
D
a
3.3.30. (20R,30R)-Methyl-4-O-(500,500-di-tert-butoxycarbonyl-
3
3
pentyl)-2,3-O-(20,30-dimethox-ybutane-20,30-diyle)-
a-D
-
400 MHz): d 5.16 (d, 1H, J1,2 1.7 Hz, H-1b), 4.10 (dd, 1H, J1,2
3
glucopyranoside (43)
1.7 Hz, J2,3 4.7 Hz, H-2b), 3.98 (ddd, 1H, J3,4 6.8 Hz, J4,5a 3.0, J4,5b
3.3.31. 3-O-(50,50-Disodium carboxypentyl)-
D
-fructose (48)
3.7 Hz, H-4b) 3.91 (dd, 1H, J2,3 4.7 Hz, J3,4 6.8 Hz, H-3b), 3.68 (dd,
1H, J4,5a 3.0 Hz, J5a,5b 11.3 Hz, H-5ba), 3.58–3.48 (m, 4H, H-5bb,
CH2-10, CCH-50), 2.50–2.44 (m, 2H, CH2-40), 1.67–1.58 (m, 2H,
CH2-20), 1.44–1.35 (m, 2H, CH2-30); 13C NMR (D2O, 100.6 MHz): d
3.3.32.
Using GP 5 compound 48 (100 mg, 262
cisplatin (175 mg, 583 mmol) and silver nitrate (175 mg,
1.03 mmol) in water (6 mL) to give 49; (110 mg, 77%); 1H NMR
D-Fructose platinum complex (49)
lmol) was reacted with
162.3 (2 ꢀ C@O), 96.2 (C-1
a
), 81.5 (C-4
a), 71.2 (C-5a), 70.8 (C-
l
2a
), 70.7 (C-3
a
), 70.0 (C-10), 65.8 (C-50), 30.6 (C-40), 28.1 (C-20),
23.5 (C-30); 13C NMR (D2O, 100.6 MHz): d 164.1 (2 ꢀ C@O), 101.1
(C-1b), 80.7 (C-4b), 75.0 (C-2b), 71.7 (C-5b), 71.1 (C-10), 70.7 (C-
3b), 65.8 (C-50), 30.6 (C-40), 28.1 (C-20), 23.5 (C-30). MALDI-TOF:
m/z 535.9 [M+H]+, 558.9 [M+Na]+.
(D2O, 400 MHz): d 3.04 (t, 1H, J4 ,5 7.4 Hz, CCH-50), 1.74–1.64 (m,
2H, CH2-40), 1.61–1.47 (m, 2H, CH2-20), 1.33–1.19 (m, 2H, CH2-30);
13C NMR (D2O, 100.6 MHz): d 29.6 (C-20), 28.8 (C-40), 24.1 (C-30);
both pyranose forms and both furanose forms could be observed
in the NMR thus assignment of signals was not possible and except
for significant groups of the spacer HR-ESI-MS: m/z [M+Na]+ found
588.1130, calcd 588.1133.
0
0
3.3.39. Methyl 2-O-(50,50-disodium carboxypentyl)-b-
D-arabi-
nopyranoside (56)
3.3.33. Methyl-4-O-(50, 50-disodium carboxypentyl)-b-
D
-ribo-
3.3.40. Methyl b-
Following GP 5 compound 56 (100 mg, 50
with cisplatin (35 mg, 0.10 mmol) and silver nitrate (35 mg,
D
-arabinopyranoside platinum complex I (57)
pyranoside (50)
lmol) was reacted
20
0.20 mmol) in water (2.4 mL) to give 57; (7.5 mg, 28%), ½ ꢂ
a
546
3.3.34. Methyl-b-
Following GP 5 compound 50 (50.0 mg, 136
with cisplatin (91.5 mg, 304 mol) and silver nitrate (102 mg,
602
D
-ribopyranoside platinum complex I (51)
ꢁ35.6 (c 0.1, H2O); 1H NMR (D2O, 400 MHz): d 4.99 (d, 1H, J1,2
3.6 Hz, H-1), 3.96 (ddd, 1H, J3,4 2.5 Hz, J4,5a 3.4 Hz, J4,5b 6.3 Hz, H-
4), 3.86–3.78 (m, 2H, H-3, H-5a), 3.71–3.49 (m, 5H, H-2, H-5b,
CH2-10, CH-50), 3.37 (s, 3H, OMe), 2.57–2.41 (m, 2H, CH2-40), 1.71–
1.62 (m, 2H, CH2-20), 1.49–1.40 (m, 2H, CH2-30); 13C NMR (D2O,
100.6 MHz): d 97.6 (C-1), 76.4 (C-2), 70.6 (C-10), 68.8 (C-4), 68.0
(C-3), 65.5 (C-5), 57.8 (C-50), 55.1 (OMe), 30.7 (C-40), 28.7 (C-20),
23.7 (C-30); the carbonyl-C was not detected. MALDI-TOF: m/z
550.1 [M+H]+.
lmol) was reacted
l
20
l
mol) in water (12 mL) to give 51; (41.3 mg, 55%); ½ ꢂ
a
546
ꢁ67.3 (c 0.2, H2O); 1H NMR (D2O, 400 MHz): d 4.67 (d, 1H, J1,2
5.4 Hz, H-1), 4.18 (dd, 1H, J2,3 3.5 Hz, J3,4 1.9 Hz, H-3), 3.85 (dd,
1H, J4,5a 3.8 Hz, J5a,5b 11.7 Hz, H-5a), 3.80 (dd, 1H, J4,5b 6.9 Hz,
J5a,5b 11.7 Hz, H-5b), 3.75–3.59 (m, 4H, H-4, CH2-10, CCH-50), 3.56
(dd, 1H, J1,2 5.4 Hz, J2,3 3.5 Hz, H-2), 3.49 (s, 3H, OMe), 2.58–2.41
(m, 2H, CH2-40), 1.76–1.66 (m, 2H, CH2-20), 1.54–1.45 (m, 2H,
CH2-30); 13C NMR (D2O, 100.6 MHz): d 167.2 (2 ꢀ C@O), 101.5 (C-
1), 75.2 (C-4), 70.2 (C-2) 69.2 (C-10), 66.7 (C-3), 65.3 (C-50), 60.5
(C-5), 56.3 (OMe), 30.6 (C-20), 28.4 (C-40), 23.5 (C-30). MALDI-TOF-
MS: m/z = 550.1 [M+H]+.
3.3.41. Methyl 2-O-(50, 50-disodium carboxypentyl)-
a-D-man-
nopyranoside (58)
3.3.42. Methyl a-D-mannopyranoside platinum complex (59)
3.3.35. Methyl-2-O-(50, 50-disodium carboxypentyl)-b-
D
-ribo-
Compound 58 (40 mg, 0.10 mmol) was reacted with cisplatin
pyranoside (52)
(70 mg, 0.20 mmol) and silver nitrate (70 mg, 0.40 mmol) in water
20
(5 mL) following GP 5 to give 59; (36 mg, 62%); ½
a
ꢂ
+35.3 (c 0.2,
546
H2O); 1H NMR (D2O, 400 MHz): d 4.79 (d, 1H, J1,2 1.0 Hz, H-1), 3.90
(dd, 1H, J5,6a 1.6 Hz, J6a,6b 12.8 Hz, H-6a), 3.80 (dd, 1H, J2,3 3.5 Hz,
J3,4 9.1 Hz, H-3), 3.76 (dd, 1H, J5,6b 5.8 Hz, J6a,6b 12.8 Hz, H-6b),
3.73–3.67 (m, 3H, H-2, CH2-10), 3.66–3.57 (m, 3H, H-4, H-5, CH-50),
3.42 (s, 3H, OMe), 2.59–2.48 (m, 2H, CH2-40), 1.78–1.66 (m, 2H,
CH2-20), 1.53–1.43 (m, 2H, CH2-30); 13C NMR (D2O, 100.6 MHz): d
98.4 (C-1), 78.1 (C-2), 72.6 (C-5), 71.5 (C-10), 70.4 (C-3), 67.0 (C-4),
60.8 (C-6), 57.9 (C-50), 54.7 (OCH3), 30.4 (C-40), 28.6 (C-20), 23.5 (C-
30). Carbonyl-C was not detected. MALDI-TOF: m/z 580.4 [M+H]+.
3.3.36. Methyl-b-
Compound 52 (18 mg, 50
(35 mg, 0.10 mmol) and silver nitrate (35 mg, 0.20 mmol) in
D
-ribopyranoside platinum complex II (53)
l
mol) was reacted with cisplatin
20
water (2.4 mL) following GP 5 to give 53; (17 mg, 61%); ½ ꢂ
a
546
ꢁ43.2 (c 0.1, H2O); 1H NMR (D2O, 400 MHz): d 4.68 (d, 1H, J1,2
5.9 Hz, H-1), 4.16 (dd, 1H, J2,3 3.2 Hz, J3,4 3.3 Hz, H-3), 3.89–3.83
(m, 2H, H-4, H-5a), 3.80–3.69 (m, 3H, CH2-10, H-5b), 3.75–3.59
(m, 2H, H-2, CCH-50), 3.55 (s, 3H, OMe), 2.59–2.45 (m, 2H, CH2-
40), 1.79–1.68 (m, 2H, CH2-20), 1.55–1.45 (m, 2H, CH2-30); 13C
NMR (D2O, 100.6 MHz): d 169.2 (2 ꢀ C@O), 100.5 (C-1), 76.2 (C-
2), 69.1 (C-10), 68.3 (C-4), 66.6 (C-3), 64.3 (C-50), 60.2 (C-5), 56.3
(OMe), 30.6 (C-20), 28.7 (C-40), 23.6 (C-30). MALDI-TOF: m/z
550.4 [M+H]+.
3.3.43. Methyl 4-O-(50, 50-disodium carboxypentyl)-b-
D-arabi-
nopyranoside (60)
3.3.44. Methyl b-
D
-arabinopyranoside platinum complex II (61)
mol) was reacted with cis-
Using GP 5 compound 60 (19 mg, 50
l
3.3.37. 5-O-(50, 50-Disodium carboxylpentyl)-
a/b-
D
-ribofura-
platin (35 mg, 0.10 mmol) and silver nitrate (35 mg, 0.20 mmol) in
20
nose (54)
water (2.4 mL) to give 61; (11 mg, 42%); ½
aꢂ
ꢁ89.2 (c 0.1, H2O); 1H
546

24
J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
NMR (D2O, 400 MHz): d 4.80 (d, 1H, J1,2 3.4 Hz, H-1), 3.87–3.79 (m,
3H, H-2, H-5a/b), 3.37–3.66 (m, 3H, CH2-10a, H-3, H-4), 3.62–3.56
(m, 2H, CH2-10b, CH-50), 3.38 (s, 3H, OMe), 2.56–2.47 (m, 2H, CH2-
40), 1.75–1.65 (m, 2H, CH2-20), 1.52–1.42 (m, 2H, CH2-30); 13C NMR
(D2O, 100.6 MHz): d 200.1 (2 ꢀ C@O), 99.8 (C-1), 77.1 (C-3), 70.1
(C-10), 68.8, 68.6 (C-2, C-4), 59.6 (C-5), 57.9 (C-50), 55.3 (OMe),
30.7 (C-40), 28.5 (C-20), 23.6 (C-30). MALDI-TOF: m/z 550.2 [M+H]+.
4H, CH2-20a/b), 1.46–1.35 (m, 4H, CH2-30a/b); 13C NMR (D2O,
100.6 MHz): d 172.7 (4 ꢀ C@O), 102.5 (C-1b), 96.9 (C-1 ), 83.5 (C-
), 82.4 (C-2b), 78.5 (C-4b), 77.4 (C-3 ), 77.3 (C-5 ), 77.2 (C-5b),
), 70.5 (C-10a/b), 70.1 (C-6b),
/b), 30.9 (C-40a/b), 28.5 (C-
a
4
a
a
a
76.1 (C-3b), 73.3 (C-2a), 70.4 (C-6a
57.7 (CH-50a/b), 57.4, 57,2 (4 ꢀ OMe
a
2
0a/b), 26.1 (C-30a/b). MALDI-TOF: m/z 383.1 [M+H]+.
3.3.55. Methyl 2,3,6-tri-O-benzyl-4-O-(20,30,60-tri-O-benzyl-40-
3.3.45. Methyl 2-O-(50, 50-disodium carboxypentyl)-
a-
D-gluco-
O-(400-chlorobutyl)-b-
D-galactopyranosyl)-b-D-glucopy-
pyranoside (62)
ranoside (73)
3.3.56. Methyl 2,3,6-tri-O-benzyl-4-O-(20,30,60-tri-O-benzyl-40-
O-(400-iodobutyl)-b-
D-galactopyranosyl)-b-D-glucopy-
3.3.46. Methyl
a
-
D
-glucopyranoside platinum complex I (63)
ranoside (74)
Compound 62 (20 mg, 50
(35 mg, 0.10 mmol) and silver nitrate (35 mg, 0.20 mmol) in water
(2.4 mL) to give 63 following GP 5. ½
lmol) was reacted with cisplatin
3.3.57. Methyl-2,3,6-tri-O-benzyl-4-O-(20,30,60-tri-O-benzyl-40-
O-(500,500-di-tert-butoxy-carbonylpentyl)-b-
pyranosyl)-b- -glucopyranoside (75)
3.3.58. Methyl 3-O-(40-O-(500,500-disodium carboxypentyl)-b-
galactopyranosyl)-b- -glucopyranoside (76)
D-galacto-
20
546
aꢂ
ꢁ12.2 (c 0.1, H2O); 1H NMR
D
(D2O, 400 MHz): d; 4.96 (d, 1H, J1,2 3.6 Hz, H-1), 3.82 (dd, 1H, J5,6a
2.2 Hz, J6a,6b 12.3 Hz, H-6a), 3.71 (dd, 1H, J5,6b 5.5 Hz, J6a,6b
12.3 Hz, H-6b), 3.70–3.59 (m, 5H, H-3, H-5, CH2-10a/b, CH-50),
3.42–3.35 (m, 4H, H-4, OMe), 3.30 (dd, 1H, J1,2 3.6 Hz, J2,3 9.8 Hz,
H-2), 2.58–2.50 (m, 2H, CH2-40), 1.75–1.65 (m, 2H, CH2-20), 1.52–
1.42 (m, 2H, CH2-30); 13C NMR (D2O, 100.6 MHz): d 194.0 (2 ꢀ C@O),
97.8 (C-1), 79.8 (C-2), 73.4 (C-3), 71.9 (C-5), 72.4 (C-10), 69.4 (C-4),
60.8 (C-6), 59.2 (C-50), 55.0 (OMe), 30.9 (C-40), 29.7 (C-20), 26.0 (C-
30). MALDI-TOF: m/z 579.9 [M+H]+, 602.5 [M+Na]+.
D-
D
3.3.59. Methyl b-
Following GP 5 compound 76 (28 mg, 50
with cisplatin (35 mg, 0.10 mmol) and silver nitrate (35 mg,
D
-lactoside platinum complex (77)
l
mol) was reacted
20
546
0.20 mmol) in water (2.4 mL) to give 77; (17 mg, 70%); ½ ꢂ
a
ꢁ10.0 (c 0.4, H2O); 1H NMR (H2O, 400 MHz): d 4.32 (d, 1H, J1,2
7.6 Hz, H-1), 4.16 (d, 1H, J1 ,2 7.8 Hz, H-10), 3.92–3.85 (m, 2H, H-
0
0
3.3.47. Methyl 4-O-(50, 50-disodium carboxypentyl)-
a-D-gluco-
60a, CH2-100a), 3.81 (dd, 1H, J5 ,6 b 2.3 Hz, J6 a,6 b 12.1 Hz, H-60b),
3.78–3.62 (m, 3H, H-4, H-6a, CH2-100b), 3.65 (dd, 1H, J5,6b 4.6 Hz,
J6a,6b 11.5 Hz, H-6b), 3.55–3. 52 (m, 2H, H-40, H-5), 3.50 (dd, 1H,
J1,2 7.6 Hz, J2,3 9.7 Hz, H-2), 3.49–3.46 (m, 4H, H-30, OMe), 3.44–
0
0
0
0
pyranoside (64)
3.34 (m, 3H, H-3, H-50, CH-500), 3.18 (dd, 1H, J1 ,2 7.8 Hz, J2 ,3
0
0
0
0
3.3.48. Methyl
a-
D-glucopyranoside platinum complex II (65)
Compound 64 (20 mg, 50
l
mol) was reacted with cisplatin
8.2 Hz, H-20), 2.52–2.45 (m, 2H, CH2-400), 1.83–1.74 (m, 2H, CH2-
200), 1.46–1.40 (m, 2H, CH2-300); 13C NMR (H2O, 100.6 MHz): d
180.3 (2 ꢀ C@O), 104.3 (C-10), 105.2 (C-1), 80.7 (C-40), 77.1 (C-5),
76.5 (C-50), 76.5 (C-30), 74.9 (C-3), 74.8 (C-20), 72.6 (C-2), 70.4 (C-
4), 64.2 (C-100), 62.5 (C-6), 61.9 (C-60), 56.4 (OMe), 54.1 (C-500),
30.8 (C-400), 29.3 (C-200), 25.3 (C-300).
(35 mg, 0.10 mmol) and silver nitrate (35 mg, 0.20 mmol) in water
(2.4 mL) to give 65 following GP 5. ½a 20
ꢂ
546 +83.2 (c 1.2, H2O); 1H NMR
(D2O, 400 MHz): d 4.87 (d, 1H, J1,2 3.7 Hz, H-1), 3.94–3.83 (m, 2H,
H-6a, CH2-10a), 3.85–3.75 (m, 2H, H-6b, H-3), 3.73–3.63 (m, 3H,
H-5, CH2-10b, CH-50), 3.63 (dd, 1H, J1,2 3.7 Hz, J2,3 9.4 Hz, H-2),
3.50 (s, 3H, OMe), 3.34 (dd, 1H, J3,4 9.3 Hz, J4,5 9.3 Hz, H-4), 2.50–
2.43 (m, 2H, CH2-40), 1.76–1.65 (m, 2H, CH2-20), 1.54–1.44 (m,
2H, CH2-30); 13C NMR (D2O, 100.6 MHz): d 199.2 (2 ꢀ C@O), 99.8
(C-1), 77.6 (C-4), 73.4 (C-3), 73.9 (C-10), 71.9 (C-2), 71.4 (C-5),
60.6 (C-6), 58.2 (C-50), 54.9 (OMe), 30.9 (C-40), 29.8 (C-20), 25.7
(C-30); MALDI-TOF: m/z 580.3 [M+H]+.
3.3.60. (20S,30S)-Methyl 3,4-O-(20,30-dimethoxybutane-20,30-
diyle)-a-D-glucopyranoside (79)
Compound 8119 (3.61 g, 6.60 mmol) was reacted with 1 M tetra-
butyl ammonium fluoride solution in anhydrous THF (13 mL) at
room temperature for 20 h. The solvent was removed to give 79 after
column chromatography (CH2Cl2/MeOH 9:1); (1.99 g, 98%); mp
20
3.3.49. 3-O-(40-Chlorobutyl)-1,2-O-isopropylidene-b-
D
-gluco-
157.0 °C; ½
aꢂ
+258.5° (c 1.2, CHCl3); 1H NMR (CDCl3, 400 MHz): d
546
furanose (66)
4.80 (d, 1H, J1,2 3.8 Hz, H-1), 3.93 (dd, 1H, J2,3 10.2 Hz, J3,4 9.2 Hz,
H-3), 3.82 (dd, 1H, J5,6a 8.9 Hz, J6a,6b 13.2 Hz, H-6a), 3.79–3.64 (m,
4H, H-2, H-4, H-5, H-6b), 3.43 (s, 3H, OMe at C-1), 3.31, 3.26
(2 ꢀ s, 2 ꢀ 3H, 2 ꢀ OMe), 1.34, 1.30 (2 ꢀ s, 2 ꢀ 3H, 2 ꢀ CH3); 13C
NMR (CDCl3, 100.6 MHz): d 100.3, 99.9 (2 ꢀ C(OMe)CH3), 99.6 (C-
1), 70.2 (C-3), 70.0, 69.7 (C-2, C-4), 66.0 (C-5), 61.3 (C-6), 55.3
(OMe at C-1), 48.0, 47.9 (2 ꢀ OMe), 17.7, 17.6 (2 ꢀ CH3). ESI-
HRMS(+): m/z found 331.1365, calcd [M+Na]+ 331.1363.
3.3.50. 3-O-(40-Chlorobutyl)-1,2-O-isopropylidene-5, 6-di-O-
methyl-b-
3.3.51. 3-O-(40-Iodobutyl)-1,2-O-isopropylidene-5,6-di-O-
methyl-b- -glucofuranose (68)
3.3.52. 3-O-(50,50-Di-tert-butoxycarbonylpentyl)-1,2-O-isopro-
pylidene-5,6-di-O-methyl-b- -glucofuranose (69)
3.3.53. 5,6-Di-O-methyl-4-O-(50,50-disodium carboxypentyl)-
b- -glucopyranose (70)
D-glucofuranose (67)
D
D
a
/
D
3.3.61. (20R,30R)-Methyl 2,3-O-(20, 30-dimethoxybutane-20,30-
diyle)-a-D-glucopyranoside (80)
3.3.54. 5,6-Di-O-methyl-a/b-D-glucofuranose platinum complex
(71)
Using GP 5 compound 70 (37 mg, 0.10 mmol) was reacted with
cisplatin (70 mg, 0.20 mmol) and silver nitrate (70 mg, 0.40 mmol)
in water (4.8 mL) to give 71; (22 mg, 37
400 MHz): d 5.50 (d, 1H, J1 4.1 Hz, H-1
3.3.62. (20S,30S)-Methyl 6-O-tert-butyldiphenylsilyl-3,4-O-(20,30-
dimethoxybutane-20,30-diyle)-
-glucopyranoside (81) and
(20R,30R)-Methyl 6-O-tert-butyldiphenylsilyl-2,3-O-(20,30-
a-D
l
mol); 1H NMR (D2O,
a
), 5.36 (s, 1H, H-1b),
dimethoxybutane-20,30-diyle)-
a-D-glucopyranoside (82)
a,2a
4.24–4.20 (m, 1H, H-2
3.70 (m, 5H, H-4
, H-4b, H-5 , H-6
4 ꢀ 3H, 2 ꢀ OMe
a
/b), 3.92–3.81 (m, 2H, H-3b, H-6ba), 3.82–
A mixture of compounds 79 and 8022 (6.867 g, 22.28 mmol) was
reacted with imidazole (2.725 g; 40.02 mmol) and tert-butyldiphe-
nyl chlorosilane (5.6 mL, 22 mmol) at room temperature for 48 h.
After filtration and evaporation of the solvent, 81 and 82 were ob-
a
, H-5b, H-6bb, CH2-10a/ba), 3.68–3.50 (m, 9H, H-
3a
a
a
a/b, CH2-10a/bb, CH-50a/b), 3.46, 3.40 (2 ꢀ s,
a
/b), 2.49–2.41 (m, 2H, CH2-40a/b), 1.77–1.70 (m,

J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
25
tained after column chromatography (petroleum ether/ethyl ace-
tate 2:1); (81: 4.334 g, 37%); (82: 5.532, 47%); 81: mp 63.7 °C;
following GP 2 after column chromatography (petroleum ether/
20
ethyl acetate 9:1); (469 mg, 77%); ½
aꢂ
+124° (c 1.0, CHCl3); 1H
546
20
546
½
aꢂ
+140 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.72–7.70
NMR (CDCl3, 400 MHz): d 4.81 (d, 1H, J1,2 3.5 Hz, H-1), 4.06 (dd,
1H, J2,3 10.1 Hz, J3,4 9.8 Hz, H-3), 3.82 (dd, 1H, J5,6a 8.9 Hz, J6a,6b
13.2 Hz, H-6a), 3.72–3.43 (m, 12H, H-2, H-4, H-5, H-6b, 2 ꢀ CH2-
100, 2 ꢀ CH2-400), 3.30 (s, 3H, OMe at C-1), 3.29, 3.25 (2 ꢀ s,
2 ꢀ 3H, 2 ꢀ OMe), 1.96–1.80 (m, 4H, 2 ꢀ CH2-300), 1.76–1.65 (m,
4H, 2 ꢀ CH2-200), 1.31, 1.29 (2 ꢀ s, 2 ꢀ 3H, 2 ꢀ CH3); 13C NMR
(CDCl3, 100.6 MHz): d 99.6, 99.5 (2 ꢀ C(OMe)CH3), 98.5 (C-1),
77.3 (C-2), 70.9, 70.8 (2 ꢀ C-100), 69.5 (C-4), 68.7 (C-6), 68.6 (C-3),
66.2 (C-5), 55.0 (OMe at C-1), 48.0, 47.9 (2 ꢀ OMe), 29.5, 29.4
(2 ꢀ C-300), 27.2, 27.1 (2 ꢀ C-200), 17.8, 17.7 (2 ꢀ CH3), 6.7 (2 ꢀ C-
400). MALDI-TOF: m/z 695.1 [M+Na]+, 711.2 [M+Na]+.
(m, 4H, o-Ph), 7.43–7.34 (m, 6H, p,m-Ph), 4.80 (d, 1H, J1,2 4.0 Hz,
H-1), 3.93 (dd, 1H, J2,3 10.2 Hz, J3,4 9.2 Hz; H-3), 3.92–3.86 (m,
2H, H-6a/b), 3.80–3.68 (m, 3H, H-2, H-4, H-5), 3.40 (s, 3H, OMe
at C-1), 3.31, 3.19 (2 ꢀ s, 2 ꢀ 3H, 2 ꢀ OMe), 1.34, 1.28 (2 ꢀ s,
2 ꢀ 3H, 2 ꢀ CH3), 1.04 (s, 9H, Bu); 13C NMR (CDCl3, 100.6 MHz):
t
d 135.9, 135.6 (4 ꢀ o-Ph), 133.0 (2 ꢀ q. Ph), 129.8, 127.7 (6 ꢀ p,m-
Ph), 99.9, 99.5 (2 ꢀ C(OMe)CH3), 97.9 (C-1), 71.3 (C-2), 70.0 (C-4),
69.3 (C-3), 68.2 (C-5), 64.7 (C-6), 54.9 (OMe at C-1), 48.0, 47.8
(2 ꢀ OMe), 26.8 (C(CH3)3), 19.2 (C(CH3)3), 17.8, 17.7 (2 ꢀ CH3).
MALDI-TOF: m/z 568.1 [M+Na]+, 584.0 [M+K]+. Compound 82:
20
546
mp 65.0 °C;
½a
ꢂ
ꢁ41.6 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz): d 7.72–7.68 (m, 4H, o-Ph), 7.45–7.37 (m, 6H, p,m-Ph),
4.72 (d, 1H, J1,2 3.6 Hz, H-1), 4.05 (dd, 1H, J2,3 10.2 Hz, J3,4 9.3 Hz,
H-3), 3.91–3.85 (m, 2H, H-6a/b), 3.79 (dd, 1H, J3,4 9.3 Hz, J4,5
3.3.66. (20R,30R)-Methyl
4,6-di-O-(400-iodobutyl)-2,3-O-(20,30-
-glucopyranoside (88)
3
dimethoxybutane-20,30-diyle)-
a-D
3
1.8 Hz, H-4), 3.75–3.68 (m, 2H, H-2, H-5), 3.38 (s, 3H, OMe at C-
1), 3.31, 3.27 (2 ꢀ s, 2 ꢀ 3H, 2 ꢀ OMe), 1.36, 1.33 (2 ꢀ s, 2 ꢀ 3H,
3.3.67. (20S,30S)-Methyl 2,6-di-O-(500,500di-tert-
t
2 ꢀ CH3), 1.06 (s, 9H, Bu); 13C NMR (CDCl3, 100.6 MHz): d 135.6
butoxycarbonylpentyl)-3, 4-O-(20,30-dimethoxybutane-20,30-
(4 ꢀ o-Ph), 133.0 (2 ꢀ q-Ph), 129.8, 127.7 (6 ꢀ p,m-Ph), 99.9, 99.5
(2 ꢀ C(OCH3)CH3), 97.9 (C-1), 71.3 (C-2), 70.0 (C-4), 69.3 (C-3),
68.2 (C-5), 64.7 (C-6), 54.9 (OMe at C-1), 48.0, 47.8 (2 ꢀ OMe),
26.8 (C(CH3)3), 19.2 (C(CH3)3), 17.8, 17.7 (2 ꢀ CH3); MALDI-TOF:
m/z 568.1 [M+Na]+, 584.1 [M+K]+.
diyle)-
Following GP 3 compound 87 (871 mg, 1.39 mmol) was reacted
with solution of di-tert-butyl malonate (730 L, 700 mg,
a-D-glucopyranoside (89)
a
l
3.25 mmol) and potassium tert-butoxide (292 mg, 2.60 mmol) in
THF (25 mL) to give 89 as syrup after purification (petroleum
20
546
ether/ethyl acetate 9:1); (703 mg, 60%); ½
aꢂ
+95.8 (c 0.9, CHCl3);
3.3.63. (20S,30S)-Methyl 2,6-di-O-(400-chlorobutyl)-3,4-O-(20,30-
1H NMR (CDCl3, 400 MHz): d 4.72 (d, 1H, J1,2 3.4 Hz, H-1), 4.06 (dd,
1H, J2,3 10.8 Hz, J3,4 9.6 Hz, H-3), 3.89 (m, 1H, H -100a), 3.73 (dd, 1H,
J1,2 3.4 Hz, J2,3 10.8 Hz, H-2), 3.65–3.57 (m, 3H, H-5, H-6a/b), 3.57–
3.39 (m, 4H, H -100b/c/d, H-4), 3.38 (s, 3H, OMe at C-1), 3.29 3.24
(2 ꢀ s, 2 ꢀ 3H, 2 ꢀ OMe), 3.14–3.06 (m, 2H, 2 ꢀ CH-500), 1.85–1.77
(m, 4H, 2 ꢀ CH2-400), 1.66–1.52 (m, 4H, 2 ꢀ CH2-200), 1.45, 1.44
dimethoxybutane-20,30-diyle)-
a
-
D
-glucopyranoside (83)
Following GP 1 compound 79 (1.440 g, 4.669 mmol) was re-
acted with 50% sodium hydroxide solution (410 L; 15.5 mmol)
l
and 1-bromo-4-chlorobutane (1.6 mL; 14 mmol) in DMSO
(12 mL) to give 83 after purification (petroleum ether/ethyl acetate
t
2:1); (987 mg, 43%). Additionally 35 and 84 were obtained
(2 ꢀ s, 2 ꢀ 18H, 4 ꢀ Bu), 141–1.34 (m, 4H, 2 ꢀ CH2-300), 1.33, 1.29
20
546
(518 mg, 28%); 79: ½
aꢂ
+156 (c 1.0, CHCl3); 1H NMR (CDCl3,
(2 ꢀ s, 2 ꢀ 3H, 2 ꢀ CH3); 13C NMR (CDCl3, 100.6 MHz): d 168.9
(4 ꢀ C@O), 99.2 (2 ꢀ C(OMe)CH3), 97.8 (C-1), 75.1 (C-4), 72.4 (C-
100a/b), 71.4 (C-100c/d), 70.7 (C-5), 70.3 (C-3), 69.3 (C-6), 68.3 (C-2),
54.9 (OMe an C-1), 53.9, 53.8 (2 ꢀ C-500), 47.9, 47.7 (2 ꢀ OMe), 30.1,
400 MHz): d = 4.81 (d, 1H, J1,2 3.8 Hz, H-1), 4.06 (dd, 1H, J2,3
10.2 Hz, J3,4 9.2 Hz, H-3), 3.82 (dd, 1H, J5,6a 2.9 Hz, J6a,6b 13.2 Hz,
H-6a), 3.72–3.44 (m, 12H, H-2, H-4, H-5, H-6b, 2 ꢀ CH2-100,
2 ꢀ CH2-400), 3.39 (s, 3H, OMe at C-1), 3.29, 3.26 (2 ꢀ s, 2 ꢀ 3H,
2 ꢀ OMe), 1.90–1.81 (m, 4H, 2 ꢀ CH2-300), 1.76–1.70 (m, 4H,
2 ꢀ CH2-200), 1.31, 1.30 (2 ꢀ s, 2 ꢀ 3H, 2 ꢀ CH3); 13C NMR (CDCl3,
100.6 MHz): d 99.6, 99.5 (2 ꢀ C(OMe)CH3), 98.6 (C-1), 77.4 (C-2),
70.9, 70.8 (2 ꢀ C-100), 69.5 (C-4), 68.8 (C-6), 68.7 (C-3), 66.3 (C-5),
55.0 (OMe at C-1), 48.0, 47.9 (2 ꢀ OMe), 44.9, 44.8 (2 ꢀ C-400),
29.5, 29.4 (2 ꢀ C-300), 27.2, 27.1 (2 ꢀ C-200), 17.8, 17.7 (2 ꢀ CH3).
t
29.4 (2 ꢀ C-200), 28.5, 28.4 (2 ꢀ C-400), 27.9 (4 ꢀ Bu), 24.0, 23.9
(2 ꢀ C-300), 17.9, 17.7 (2 ꢀ CH3). MALDI-TOF: m/z 871.5 [M+Na]+.
3.3.68. (20R,30R) Methyl 4, 6-di-O-(500,500di-tert-butoxycarbonyl-
pentyl)-2, 3-O-(20,30-dimethoxybutane-20,30-diyle)-
a-D-
glucopyranoside (90)
MALDI-TOF: m/z 511.2 [M+Na]+, 527.2 [M+K]+. Compound 35:
20
546
mp 106.3 °C,
½a
ꢂ
+197 (c 1.0, CHCl3); 1H NMR (CDCl3,
3.3.69. Methyl 2,6-di-O-(50,50-disodium carboxypentyl)-
a-D-
glucopyranoside (91)
400 MHz): d 4.79 (d, 1H, J1,2 3.5 Hz, H-1), 4.08 (dd, 1H, J2,3 9.8 Hz,
3J3,4 9.8 Hz, H-3), 3.82 (dd, 1H, J5,6a 2.9 Hz, J6a,6b 11.7 Hz, H-6a),
Following GP 4 compound 89 (594 mg, 670 lmol) was reacted
3.79–3.66 (m, 5H, H-4, H-5, H-6b, CH2-100a/b), 3.58 (t, 2H, J3 ,4
with trifluoroacetic acid (4 mL) in CH2Cl2 (12 mL) to give 91 as solid;
00 00
6.7 Hz, CH2-400), 3.44 (dd, 1H, J1,2 3.5 Hz, J2,3 9.8 Hz, H-2), 3.40
(s, 3H, OMe at C-1), 3.29, 3.27 (2 ꢀ s, 2 ꢀ 3H, 2 ꢀ OMe), 1.93–
1.83 (m, 2H, CH2-300), 1.78–1.68 (m, 2H, CH2-200), 1.31, 1.30 (2 ꢀ s,
2 ꢀ 3H, 2 ꢀ CH3); 13C NMR (CDCl3, 100.6 MHz): d 99.6, 99.5
(2 ꢀ C(OMe)CH3), 98.6 (C-1), 77.5 (C-2), 71.0 (C-100), 69.3 (C-5),
69.1 (C-3), 66.5 (C-4), 61.3 (C-6), 55.1 (OMe at C-1), 48.0, 47.9
(2 ꢀ OMe), 44.8 (C-400), 29.4 (C-300), 27.2 (2 ꢀ C-200), 17.8, 17.6
(2 ꢀ CH3). MALDI-TOF: m/z 421.1 [M+Na]+, 437.1 [M+K]+.
(341 mg, 85%); mp 217.1 °C; ½a 20
ꢂ
546 +21.7 (c 0.1, H2O); 1H NMR (D2O,
400 MHz): d 4.88 (d, 1H, J1,2 3.6 Hz, H-1), 3.68–3.59 (m, 4H, H-6a/b,
CH2-10a/b), 3.57–3.48 (m, 4H, H-3, H-5, CH2-10c/d), 3.36–3.30 (m,
4H, H-4, OMe), 3.29 (dd, 1H, J1,2 3.6 Hz, J2,3 9.4 Hz, H-2), 3.10 (t, 2H,
3
3
J4 ,5 7.7 Hz, CH-50), 1.74–1.66 (m, 4H, CH2-40), 1.60–1.53 (m, 4H,
CH2-20), 1.34–1.24 (m, 4H, CH2-30); 13C NMR (D2O, 100.6 MHz): d
180.3 (4 ꢀ C@O), 97.1 (C-1), 78.1 (C-2), 73.1 (C-10c/d), 72.5 (C-3),
71.6 (C-10a/b), 70.3 (C-4), 69.5 (C-5), 68.4 (C-6), 58.6 (2 ꢀ C-50),
55.3 (OMe), 30.3, 30.1 (C-40), 29.4, 28.7 (C-20), 24.3 (2 ꢀ C-30).
0
0
3.3.64. (20R,30R)-Methyl 4, 6-di-O-(400-chlorobutyl)-2, 3-O-(20,30-
dimethoxybutane-20,30-diyle)-
a-
D-glucopyranoside (85)
3.3.70. Methyl 4, 6-di-O-(50,50-disodium carboxypentyl)-
a-D-
glucopyranoside (92)
3.3.65. (20S,30S)-Methyl-2,6-di-O-(400-iodobutyl)-3,4-O-(20,30-
dimethoxybutane-20,30-diyle)-
Compound 83 (473 mg, 966
dide (290 mg, 1.93 mmol) in acetone (10 mL) to give 87 as syrup
a
l
-
D
-glucopyranoside (87)
3.3.71. Methyl
Using GP 5 compound 91 (21 mg, 35
cisplatin (35 mg, 0.10 mmol) and silver nitrate (35 mg, 0.20 mmol)
a
-
D
-glucopyranoside bisplatinum complex I (93)
mol) was reacted with sodium io-
lmol) was reacted with

26
J. Möker, J. Thiem / Carbohydrate Research 348 (2012) 14–26
3. Cooley, M. E.; Davis, L.; Abraham, J. Cancer Nurs. 1994, 17, 283–293.
4. Ranford, J. D.; Sadler, P. J.; Balmanno, K.; Newell, R. Magn. Reson. Chem. 1991, 29,
125–129.
5. Kwon, Y.-E.; Whang, K.-J.; Park, Y.-J.; Kim, K. H. Bioorg. Med. Chem. 2003, 11,
1669–1676.
6. Alberto, M. E.; Lucas, M. F.; Pavelka, M.; Russo, N. J. Phys. Chem. 2009, 113,
14473–14479.
7. Connors, T. A.; Jones, M.; Ross, W. C. J.; Braddock, P. D.; Khokhar, A. R.; Tobe, M.
L. Chem. Biol. Interact. 1972, 5, 415–424.
8. Rixe, O.; Ortuzar, W.; Alvarez, M.; Parker, R.; Reed, E.; Paull, K.; Fojo, T. Biochem.
Pharmacol. 1996, 52, 1855–1865.
9. Hartinger, C. G.; Nazarov, A. A.; Ashraf, S. M.; Dyson, P. J.; Keppler, B. K. Curr.
Med. Chem. 2008, 15, 2574–2591.
10. Berger, I.; Nazarov, A. A.; Hartinger, C. G.; Groessl, M.; Valiahdi, S.-M.; Jakupec,
M. A.; Keppler, B. K. ChemMedChem 2007, 2, 505–514.
11. (a) Mikata, Y.; Shinohara, Y.; Yoneda, K.; Nakamura, Y.; Esaki, K.; Tanahashi, M.;
Brudziñska, I.; Yokoyama, M.; Mogami, K.; Tanase, T.; Kitayama, T.; Takashiba,
K.; Nabeshima, K.; Takagi, R.; Takatani, M.; Okamoto, T.; Kinoshita, I.; Doe, M.;
Hamazawa, A.; Morita, M.; Nishida, F.; Sakakibara, T.; Orvig, C.; Yano, S. J. Org.
Chem. 2001, 66, 3783–3789; (b) Mikata, Y.; Shinohara, Y.; Yoneda, K.;
Nakamura, Y.; Brudziñska, I.; Tanase, T.; Kitayama, T.; Takagi, R.; Okamoto,
T.; Kinoshita, I.; Doe, M.; Orvig, C.; Yano, S. Bioorg. Med. Chem. Lett. 2001, 11,
3045–3047.
12. Tromp, R. A.; van Boom, S. S. G. E.; Timmers, C. M.; van Zutphen, S.; van der
Marel, G. A.; Overkleeft, H. S.; van Boom, J. H.; Reedijk, J. Bioorg. Med. Chem. Lett.
2004, 14, 4273–4276.
13. Wang, H.; Sun, L.; Galzebnik, S.; Zhao, K. Tetrahedron Lett. 1995, 36,
2953–2956.
14. Finkelstein, H. Ber. Dtsch. Chem. Ges. 1910, 43, 1528–1532.
15. Aronov, O.; Horowitz, A. T.; Gabizon, A.; Gibson, D. Bioconjugate Chem. 2003, 14,
563–574.
16. Möker, J.; Thiem, J. Eur. J. Org. Chem. 2009, 4842–4847.
17. Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318–325.
18. Nepogodiev, S. A.; Dedola, S.; Marmuse, L.; De Oliveira, M. T.; Field, R. A.
Carbohydr. Res. 2007, 529–540.
in water (2.4 mL) to give 93 as solid; (18.3 mg, 54%); mp 177.2 °C;
20
½
a
ꢂ
+17.2 (c 0.1, H2O); 1H NMR (D2O, 400 MHz): d 4.81 (d, 1H, J1,2
546
3.7 Hz, H-1), 3.78–3.56 (m, 8H, H-3, H-5, H-6a/b, CH2-10a/b,
2 ꢀ CH-50), 3.58–3.47 (m, 3H, H-2, CH2-10c/d), 3.45 (s, 3H, OMe),
3.28 (dd, 1H, J3,4 9.4 Hz, J4,5 9.6 Hz, H-4), 2.53–2.42 (m, 4H,
2 ꢀ CH2-40), 1.75–1.64 (m, 2H, 2 ꢀ CH2-20), 1.56–1.44 (m, 2H,
2 ꢀ CH2-30), 13C NMR (D2O, 100.6 MHz): d 199.8 (4 ꢀ C@O), 100.0
(C-1), 78.0 (C-4), 74.1 (C-10c/d), 72.6 (C-3), 72.7 (C-10a/b), 71.9
(C-2), 69.7 (C-5), 69.3 (C-6), 58.9 (2 ꢀ C-50), 55.1 (OMe), 30.6,
30.5 (2 ꢀ C-40), 29.5, 28.8 (2 ꢀ C-20), 24.7 (2 ꢀ C-30).
3.3.72. Methyl
a-
D-glucopyranoside bisplatinum complex II (94)
Using GP 5 compound 92 (15 mg, 25
lmol) was reacted with
cisplatin (35 mg, 0.10 mmol) and silver nitrate (35 mg, 0.20 mmol)
in water (2.4 mL) to give 93 as solid; (17 mg, 70%); mp 175.6 °C;
20
546
½
aꢂ
+64.9 (c 0.1, H2O); 1H NMR (D2O, 400 MHz): d 4.98 (d, 1H,
J1,2 3.6 Hz, H-1), 3.72–3.58 (m, 6H, H-6a/b, CH2-10a/b, 2 ꢀ CH-50),
3.62–3.51 (m, 4H, H-3, H-5, CH2-10c/d), 3.39–3.32 (m, 4H, H-4,
OMe), 3.39 (dd, 1H, J1,2 3.6 Hz, J2,3 9.5 Hz, H-2), 2.53–2.42 (m, 4H,
2 ꢀ CH2-40), 1.75–1.64 (m, 4H, 2 ꢀ CH2-20), 1.56–1.44 (m, 4H,
2 ꢀ CH2-30); 13C NMR (D2O, 100.6 MHz): d 200.3 (4 ꢀ C@O), 99.1
(C-1), 78.8 (C-2), 73.4 (C-10c/d), 72.7 (C-3), 71.9 (C-10a/b), 70.8
(C-4), 69.6 (C-5), 68.4 (C-6), 59.6 (2 ꢀ C-50), 55.0 (OMe), 30.5,
30.2 (2 ꢀ C-40), 29.5, 28.7 (2 ꢀ C-20), 24.7 (2 ꢀ C-30) ppm.
Supplementary data
19. (a) Grice, P.; Ley, S. V.; Pietruszka, J.; Priepke, H. W. M.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1 1997, 351–363; (b) Hanessian, S.; Lavallee, P. Can. J. Chem.
1975, 53, 2975–2977.
20. Frey, U.; Ranford, J. D.; Sadler, P. J. Inorg. Chem. 1993, 32, 1333–
1340.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.08.024.
References
21. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512–7515.
1. van Camp, L.; Krigas, T.; Rosenberg, B. Nature 1965, 205, 698–699.
2. Prestayko, A. W.; D’Aoust, J. C.; Issell, B. F.; Crooke, S. T. Cancer Treat. Rev. 1979,
6, 17–39.
22. Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, D. R.; Poisson, R. F.; Warriner, S. L.;
Wesson, K. E. J. Chem. Soc., Perkin Trans. 1 1997, 2023–2031.