A library of positional isomers of d-glucose ( O-1- O-6) as ligands and their 11 light-active ruthenium conjugates has been synthesized. A protecting group strategy without the necessity of using palladium on carbon for the modification for the 2- O and 4- O position allows for the incorporation of sulfur donor atoms as ligands for transition metal complexes.
A library of positional isomers of d-glucose ( n class="Chemical">O-1- O-6) as ligands and their 11 light-active ruthenium conjugates has been synthesized. A protecting group strategy without the necessity of using palladium on carbon for the modification for the 2- O and 4- O position allows for the incorporation of sulfurdonor atoms as ligands for transition metal complexes.
Carbohydrates are a class of biomolecules ubiquitously present
innature, comprising n class="Chemical">monosaccharides, oligosaccharides, and polysaccharides,
of which monosaccharides cannot be hydrolyzed further into smaller
units. These molecules are recognized as important building blocks
in the cell wall of bacteria,[1,2] in plants,[3] in the exoskeleton of insects,[4] in cell recognition processes,[5] and in the backbone of RNA and DNA[6] and
are associated with many different physiological and disease-related
processes.[7,8] Among them, d-glucose is the most
well-known monosaccharide as it serves as the primary source of chemical
energy in eukaryotic cells for the production of ATP.[9] Otto Warburg found that cancer cells have an increased
glycolysis rate for the production of ATP compared to normal cells.[10] As a consequence, glucose transporters (GLUTs)
1 and 3 are overexpressed in cancer cells.[11] In recent years, there has been a growing interest in using this
effect to selectively deliver molecules of interest to cancer cells.
In the field of diagnostic imaging, the well-known radiotracer 2-deoxy-2-[18F]fluoroglucose (2-FDG) selectively accumulates in cancer
cells since its metabolic breakdown is hampered by the replacement
of a hydroxyl group on the 2-position of d-glucose by fluoride.[12] This clinically approved agent allows PET imaging
of tumors anywhere in the whole body. In the field of medicinal chemistry,
glufosfamide has shown some success as a safer alternative for ifosfamide,
an alkylating agent used in cancer treatment. The therapeutic efficiency
of glufosfamide is thought to be higher due to its increased water
solubility and preferred uptake in malignant cells versus normal cells.[13] Recently, Palay et al. have demonstrated that
a series of glucose conjugates of platinum-based medicines are taken
up via GLUT1.[14,15] This result is in contrast to
the observation of Schubiger, who found that none of their radiodiagnostic
glycoconjugates based on 99mTc were taken up via glucose
transporters.[16]
For ruthenium(II) polypyridyl-based drugs, this effect has not
been thoroughly investigated. Our group has been involved in a research
program aimed at targeting n class="Chemical">ruthenium-based light-activated anticancer
prodrugs to GLUT transporters by glucose conjugation.[17,18] These photoactivated chemotherapeutic prodrugs are typically protected
from binding to biomolecules in the dark by thioether ligands, which
under visible light irradiation are photosubstituted by water, thereby
activating the prodrug.[19−21] En route to functionalizing such
complexes with glucose, it came out that all available synthetic routes
toward a series of positional isomers of glucose were incompatible
with the presence of thioether groups, which deactivate Pd/C catalysts
used to deprotect benzyl protecting groups. For that reason, we developed
and report here on a series of new synthetic routes toward all positional
isomers of glucose that are compatible with the presence of sulfur-based
ligands.[22] As traces of palladium also
often interfere with the biological activity of pharmaceuticals,[23] these new routes do not make use of palladium
catalysts. PEGylation of all positional isomers was also realized
to vary the spacer between the thioether ligands and the glucose moiety.
The coordination of the thioether–glucose ligands to known
photoactive ruthenium(II) polypyridyl precursors afford 11 ruthenium–glucose
conjugates (Figure ) as a demonstration that such molecules can be obtained on a synthetical
useful scale. Recent publications describe the more photophysical
and/or biological properties of these type of complexes.[17,18]
Figure 1
Overview of O-1 to O-6 positional d-glucose ruthenium(II) polypyridyl conjugates presented in
this study.
Overview of O-1 to O-6 positional d-glucoseruthenium(II) polypyridyl conjugates presented in
this study.
Results and Discussion
Five hydroxyl groups are available for modification in d-glucose, of which the 1-O position is modified
via chemical glycosylation.[24] Recently,
Patra et al. have demonstrated that the spacer length exerts influence
over the GLUT-mediated uptake of n class="Chemical">platinum complexes in cells;[14] however, there is currently no established understanding
of this effect in cationic ruthenium(II) polypyridyl compounds. Therefore,
oligoethylene glycol spacers [OCH2CH2] with varying lengths (n = 0–3)
were introduced in glycoconjugates [1](PF6)2–[5](PF6)2 (Figure ). The first
complex in this series ([1](PF6)2) was synthesized starting from precursor 12 (Scheme ).[25] This building block and NaSMe were used in a SN2 reaction, ensuring the installment of the thioether group, affording 13. This ligand was then reacted with [Ru(tpy)(bpy)Cl]Cl,
affording the orange (λmax = 450 nm) glycoconjugate
[1](PF6)2.
Scheme 1
Reaction conditions: (a) (i)
NaSMe in DMF, rt, 16 h, (ii) NaOMe in MeOH, 66% over two steps; (b)
[Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 16 h, 39%.
Reaction conditions: (a) (i)
NaSMe in DMF, rt, 16 h, (ii) NaOMe in MeOH, 66% over two steps; (b)
[Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 16 h, 39%.For complex [2](PF6)2, a three-step
one-pot synthesis starting from n class="Chemical">peracetylated glucose 14 (Scheme ) was adapted
from Valerio et al.,[26] which afforded the trans-glucopyranoside as the only diastereoisomer. Treatment
of this compound with sodium methoxide in methanol afforded fully
deprotected 15 in a 55% overall yield. Subsequent reaction
of this ligand with [Ru(tpy)(bpy)Cl]Cl then gave the orange complex
[2](PF6).
Scheme 2
Reaction conditions: (a) (i)
I2, Et3SiH in DCM, rt, 10 min, (ii) thiourea
in MeCN, 80 °C, 30 min, (iii) MeI, Et3N, rt, 10 min,
(iv) cat. NaOMe in MeOH, rt, overnight, 57% over four steps; (b) [Ru(tpy)(bpy)Cl]Cl
in H2O, 80 °C, 48 h, 28%.
Reaction conditions: (a) (i)
I2, Et3SiH in DCM, rt, 10 min, (ii) thiourea
in MeCN, 80 °C, 30 min, (iii) MeI, Et3N, rt, 10 min,
(iv) cat. NaOMe in MeOH, rt, overnight, 57% over four steps; (b) [Ru(tpy)(bpy)Cl]Cl
in H2O, 80 °C, 48 h, 28%.A different approach was employed for the installment of the ethylene
glycol-based linkers (n = 1–3) for complexes
[3](PF6)2–n class="Chemical">[5](PF6)2 and [11]Cl2 (Figure ). The disarmed
Schmidt donor 20 (Scheme ) was chosen due to its straightforward synthesis and
robustness. The benzoyl protecting group in this building block was
favored over the more common acetyl group, due to its lower reactivity.[27] Furthermore, this donor was chosen to reduce
the possible formation of orthoesters, a common side reaction when
using acetyl-bearing donors.[28] Commercially
available 2-(methylthio)ethanol was used as an acceptor and condensed
with donor 20 (Scheme ), affording 21, which after de-O-benzoylation acquired deprotected 24. Compounds 25, 26, and 28 were acquired in
a similar fashion using acceptors 18, 19, and 1,3-bis(methylthio)propan-2-ol, respectively. The synthesis
of the corresponding ruthenium complexes was found to be straightforward,
by reacting excess ligand with the ruthenium species [Ru(tpy)(bpy)Cl]Cl
or [Ru(bpy)2Cl2]. Their purification, however,
was found arduous due to the increased water solubility of these compounds.
Common workup methods were not applicable, and the lability of these
compounds on C-18 columns prevented reverse-phase chromatographic
purification. The most reproducible approach was by purification over
silica using a mixture of acetone, water, and aqueous KPF6, followed by Sephadex LH-20 size exclusion purification to remove
excess salt and minor impurities. This method afforded the orange
(λmax = 450 nm) ruthenium polypyridyl derivatives[3](PF6)2–[5](PF6)2 and [11]Cl2 in moderate to good yields (28–66%).
Scheme 3
Reaction conditions: (a) 2-(2-chloroethoxy)ethanol
or 2-[2-(2-chloroethoxy)ethoxy]ethanol, NaSMe in THF, reflux,
6 h, 89% for 18, 85% for 19; (b) 2-(methylthio)ethanol, 1,3-bis(methylthio)propanol, 18 or 19, cat. TMSOTf in DCM, 4 Å molecular
sieves, rt, 4 h, 81% for 21, 66% for 22,
85% for 23, 90% for 27; (c) NaOMe in MeOH,
rt, 88% for 24, 86% for 25, 91% for 26, 70% for 28; (d) [Ru(bpy)2Cl2] in H2O, 80 °C, 59% for [11]Cl2; (e) [Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 39%
for [3](PF6)2, 66% for [4](PF6)2, 65% for [5](PF6)2.
Reaction conditions: (a) 2-(2-chloroethoxy)ethanol
or 2-[2-(2-chloroethoxy)ethoxy]ethanol, NaSMe in THF, reflux,
6 h, 89% for 18, 85% for 19; (b) 2-(methylthio)ethanol, 1,3-bis(methylthio)propanol, 18 or 19, cat. TMSOTf in DCM, 4 Å molecular
sieves, rt, 4 h, 81% for 21, 66% for 22,
85% for 23, 90% for 27; (c) NaOMe in MeOH,
rt, 88% for 24, 86% for 25, 91% for 26, 70% for 28; (d) [Ru(bpy)2Cl2] in H2O, 80 °C, 59% for [11]Cl2; (e) [Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 39%
for [3](PF6)2, 66% for [4](PF6)2, 65% for [5](PF6)2.Park and co-workers have demonstrated that glucose bioprobes with
a formal charge of +1 are taken up preferentially over neutral and
negatively charged probes.[29] To allow future
study of the effect on the overall charge for n class="Chemical">ruthenium(II) polypyridyl
drugs on uptake and toxicity, a derivative of [Ru(tpy)(bpy)Cl]Cl bearing
a negative charge on the spectator terpyridine ligand was also synthesized.
Compound 31 (Scheme ) was prepared starting from thione 29,[30] which was oxidized using in situ generated
peracetic acid followed by hydrogenation using 10% palladium on carbon
to reverse partial overoxidation to its N-oxide,
affording ligand 30. A one-pot synthesis using (p-cymene)ruthenium(II) chloride dimer 30 and
bpy provided complex 31. Reaction of ligand 26 (Scheme ) with this
complex then gave the ruthenium complex [10](PF6)2.
Scheme 4
Reaction conditions: (a) (i)
H2O2 in AcOH, 70 °C, 6 h, (ii) H2, Pd/C, 40 °C, overnight, 24% over two steps; (b) bpy in MeOH,
60 °C, 72%; (c) 25, in H2O, 80 °C,
16 h, 38%.
Reaction conditions: (a) (i)
H2O2 in AcOH, 70 °C, 6 h, (ii) H2, Pd/C, 40 °C, overnight, 24% over two steps; (b) bpy in MeOH,
60 °C, 72%; (c) 25, in H2O, 80 °C,
16 h, 38%.Demonstrations of the covalent modification of the 2-O position of d-glucose with an alkyl-based linker have been
given by Dumas et al. and Patray and co-workers.[14,31] Both groups chose a similar approach starting from methyl 3,5,6-tri-O-benzyl-α/β-d-n class="Chemical">glucofuranoside followed by installment of the linker and subsequent
deprotection of the protection groups using dihydrogen and palladium
on carbon. Sulfur-based linkers, however, poisoned the palladium catalysts,
which made removal of the benzyl protecting groups impossible following
this approach.[22,32] Other methods to remove benzyl
groups, such as Birch reductions, have been reported to cleave thioethers.[33] Therefore, all described approaches for the
functionalization of the O-2 position in d-glucose with a metal-binding moiety, including the glucofuranoside
approach described by Schubiger or Lippard, or the approach via a
benzylorthoacetate intermediate described by Miao et al.[34] were found unsuitable for thioether-containing
compounds. We therefore devised a new protecting group strategy improving
the 10-step, 5% yield procedure published by Lippard et al.[14] and employing the α-oxirane method developed
by the group of Danishefsky[35,36] and attempted by Dumas
et al. (Scheme ).[31] Using this method, d-glucal was protected
using the p-methoxy benzyl (PMB) group, affording 34. Treatment of this compound with freshly prepared dimethyldioxirane
(DMDO) afforded its corresponding 1,2-anhydrosugar, which was then
condensed with p-methoxy benzyl alcohol (PMB–OH)
in the presence of anhydrous ZnCl2 in THF, affording β-substituted 35, while simultaneously liberating the 2-O position. This compound was then treated with tosylate 32 (Scheme ) for the
installment of the thioether moiety. This conversion proceeded smoothly,
which is in contrast to the observation of Schubiger et al., who had
to divert to the furanoside approach due to difficulties encountered
during the installment of their iminodiacetic acid-based spacer.[31] With compound 36 in hand, a recently
described method[37] using 37% hydrochloric
acid in hexafluoroisopropanol (HFIP) was used to remove all four PMB
groups simultaneously. After the reaction was quenched using Et3N ,an intermediate species was observed (m/z = 463.4 found, 463.2 calcd) corresponding to
the desired product H37 and a PMB group. This same intermediate
was also observed in the presence of a mild reducing agent such as
Et3SiH. However, when this intermediate was treated with
MeNH2 in MeOH,[38] the methyl
thioether could be liberated, acquiring hemiacetal H37 in five steps (18% overall yield). After reaction of this compound
with [Ru(tpy)(bpy)(H2O)](PF6)2 glycoconjugate
[Ru(tpy)(bpy)(37)]PF6, ([6]PF6)
was acquired instead of [Ru(tpy)(bpy)(H37)](PF6)2. This is most likely due to the relatively protic nature
of the anomeric proton, resulting in deprotonation during purification
on Sephadex and replacement of one of the PF6 counterions
by the “charged” deprotonated glucose species as interpreted
by elemental analysis. On mass, however, only the 2+ species is observed,
indicating that reprotonation occurs in solution. This behavior was
observed for all hemiacetal glucose derivatives.
Scheme 5
Reaction conditions: (a) 19, TsCl, Et3N in DCM, 0 °C to rt, 16 h, 92%;
(b) PMB–Cl, NaH in DMF, 0 °C to rt, 16 h, 84%; (c) (i)
DMDO (0.088 M in acetone) in DCM, 0 °C to rt, 3 h, (ii) PMB–OH,
ZnCl2 in THF, −78 °C to rt, 16 h, 39% over
two steps; (d) 32, NaH in DMF, 0 °C to rt, 6 h,
80%; (e) (i) cat. HCl in HFIP/DCM, 5 min, (ii) MeNH2 in
MeOH/H2O, 60 °C, 30 min, 67%; (f) [Ru(tpy)(bpy)(H2O)](PF6)2 in acetone/H2O,
80 °C, 24 h, 36%.
Reaction conditions: (a) 19, TsCl, Et3N in DCM, 0 °C to rt, 16 h, 92%;
(b) PMB–Cl, NaH in DMF, 0 °C to rt, 16 h, 84%; (c) (i)
DMDO (0.088 M in acetone) in DCM, 0 °C to rt, 3 h, (ii) PMB–OH,
ZnCl2 in THF, −78 °C to rt, 16 h, 39% over
two steps; (d) 32, NaH in DMF, 0 °C to rt, 6 h,
80%; (e) (i) cat. HCl in HFIP/DCM, 5 min, (ii) MeNH2 in
MeOH/H2O, 60 °C, 30 min, 67%; (f) [Ru(tpy)(bpy)(H2O)](PF6)2 in acetone/H2O,
80 °C, 24 h, 36%.The most straightforward thioether functionalization in these series
of ligands was the modification of the 3-O position
of n class="Chemical">d-glucose. Starting from diacetone glucose 38 (Scheme ),[39−41] the thioether moiety was installed using 32 (Scheme ), affording compound 39, which was subsequently hydrolyzed using Amberlite IR-120
H+, affording H40 in 42% overall yield. Glycoconjugation
of H40 with [Ru(tpy)(bpy)Cl]Cl gave the orange (λmax = 450 nm) complex [Ru(tpy)(bpy)(40)]PF6 ([7]PF6).
Scheme 6
Reaction conditions: (a) 32, NaH in DMF, 0 °C to rt, 16 h, 91%; (b) Amberlite
IR-120 H+ in H2O, 60 °C, 24 h, 46%; (c)
[Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 16 h, 37%.
Reaction conditions: (a) 32, NaH in DMF, 0 °C to rt, 16 h, 91%; (b) Amberlite
IR-120 H+ in H2O, 60 °C, 24 h, 46%; (c)
[Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 16 h, 37%.The 4-O position of d-glucose was modified
starting from acetobromo-α-n class="Chemical">d-glucose 40 (Scheme ). Using
a procedure first described by Kaji et al., this building block was
converted in situ to its anomeric iodide, followed by a Koenigs–Knorr-type
glycosylation with p-methoxy benzyl alcohol as an
acceptor and Ag2CO3 as a base.[42] De-O-acetylation furnished intermediate 41, followed by 4,6-O-benzylidenation and
installment of PMB groups, affording fully protected 43. With this building block in hand, a reductive opening using NaCNBH3 and TFA liberated the 4-O position, which
could then be alkylated via a Williamson etherification using 32 described in the previous sections, affording 45. Global deprotection was achieved by treatment with HFIP/HCl, which
gave thioether ligand H46 in an 11% overall yield. The
subsequent reaction of H46 with [Ru(tpy)(bpy)(H2O)](PF6)2 afforded glycoconjugate [Ru(tpy)(bpy)(46)]PF6 ([8]PF6). The synthesis of H46 was
also attempted via an alternative approach using α-methyl glucose
following a similar protecting group strategy. However, this proved
to be unsuccessful due to the inertness of the anomeric methyl acetal
toward acid.
Scheme 7
Reaction conditions: (a) (i)
PMB–OH, I2, Ag2CO3 in Et2O, rt, 24 h, (ii) NaOMe in MeOH, rt, 4 h, 72% over two steps;
(b) α,α,4-trimethoxytoluene, cat. p-TsOH·H2O in DMF, 60 °C, 16 h, 89%; (c) PMB–Cl, NaH in
DMF, 0 °C to rt, 78%; (d) NaCNBH3, TFA in DMF, 0 °C
to rt, 48 h, 95%; (e) 32, NaH in DMF, 0 °C to rt,
6 h, 78%; (f) cat. HCl in HFIP/DCM, 30 min, 29%; (g) [Ru(tpy)(bpy)Cl]Cl
in H2O, 80 °C, 64%.
Reaction conditions: (a) (i)
PMB–OH, I2, Ag2CO3 in Et2O, rt, 24 h, (ii) NaOMe in MeOH, rt, 4 h, 72% over two steps;
(b) α,α,4-trimethoxytoluene, cat. p-TsOH·H2O in DMF, 60 °C, 16 h, 89%; (c) PMB–Cl, NaH in
DMF, 0 °C to rt, 78%; (d) NaCNBH3, TFA in DMF, 0 °C
to rt, 48 h, 95%; (e) 32, NaH in DMF, 0 °C to rt,
6 h, 78%; (f) cat. HCl in HFIP/DCM, 30 min, 29%; (g) [Ru(tpy)(bpy)Cl]Cl
in H2O, 80 °C, 64%.Finally, the 6-O position of d-glucose
was easily modified starting from dimethyl glucose 48 (Scheme ),[43] which could be converted to 49 using
a Williamson etherification with tosylate 32, followed
by acid hydrolysis using dilute hydrochloric acid, affording methyl
thioether H50 in 55% over two steps. Glycoconjugation
with [Ru(tpy)(bpy)Cl]Cl afforded [Ru(tpy)(bpy)(50)]PF6 ([9]PF6).
Scheme 8
(a) 32, NaH in DMF,
0 °C to rt, 3 h, 78%; (b) 2 M HCl in H2O, 60 °C,
1 h, 70%; (c) [Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 16
h, 17%.
(a) 32, NaH in DMF,
0 °C to rt, 3 h, 78%; (b) 2 M HCl in H2O, 60 °C,
1 h, 70%; (c) [Ru(tpy)(bpy)Cl]Cl in H2O, 80 °C, 16
h, 17%.
Conclusion
In this work, we have presented efficient and robust routes to
all positional isomers of d-glucose bearing a n class="Chemical">thioether ligand
bound to a light-cleavable ruthenium(II) polypyridyl complex. The
general protecting–deprotecting group strategy presented in
this work is compatible with compounds bearing donor atoms such as
sulfur, without the need of palladium catalysts until final coordination
to the functional ruthenium compound. These routes might possibly
be extended to application with other functionalized ligands, such
as carboxylates, amines, or pyridines. The study of this library of
ruthenium(II) glycoconjugates might shed light on the influence of
the stereochemistry of glucose functionalization on GLUT-mediated
uptake and the metabolism of the ruthenium–glucose conjugates
by enzymes such as hexokinase II.
Experimental Section
General
Reagents were purchased from Sigma-Aldrich
and used without further purification. 2,2′:6′,2″-Terpyridine
(n class="Chemical">tpy) was ordered from ABCR GmbH & Co. Dry solvents were collected
from a Pure Solve MD5 solvent dispenser from Demaco. For all inorganic
reactions, solvents were deoxygenated by bubbling dinitrogen through
the solution for 30 min. All organic reactions were carried out under
a diniotrogen atmosphere at rt. Flash chromatography was performed
on silica gel (Screening devices B.V.) with a particle size of 40–64
μM and a pore size of 60 Å. TLC analysis was conducted
on TLC aluminum foils with a silica gel matrix (Supelco, silica gel
60, 56524) with detection by UV absorption (254 nm), by spraying with
10% H2SO4 in ethanol or with a solution of NH4Mo7O24·4H2O (25 g/L),
NH4CeSO4·H2O (10 g/L), 10% H2SO4 in H2O, followed by charring at
∼250 °C on a heating plate. Optical rotation measurements
were performed on a Propol automated polarimeter (sodium d line, λ = 589 nm) with a concentration of 10 mg/mL (c = 1) unless stated otherwise. Infrared spectra were recorded
on a PerkinElmer UATR (Single Reflection Diamond) Spectrum Two device
(4000–700 cm–1; resolution 4 cm–1). 1H NMR and 13C NMR were recorded in CD3OD and CDCl3 with a chemical shift (δ) relative
to the solvent peak on a Bruker AV 400 or AV 500 unit. High-resolution
mass spectra were recorded by direct injection (2 μL of 2 μM
solution in water/acetoneitrile; 50/50; v/v and 0.1% formic acid)
in a mass spectrometer (Thermo Finnigan LTQ Orbitrap) equipped with
an electrospray (250 °C) with a resolution (R) = 60 000
at m/z 400 (mass range m/z = 150–2000) and dioctylphtalate (m/z = 391.28428) as a lock mass. The high-resolution
mass spectrometer was calibrated prior to measurements with a calibration
mixture (Thermo Finnigan). Melting point ranges were determined on
a Stuart SMP30 unit. Elemental analysis for glycoconjugates [1](PF6)2–[5](PF6)2, [6]PF6–[10]PF6, and [11]Cl2 was
performed at Mikrolab Kolbe, Germany.
Synthesis
(2-Methylthio)ethyl-α-d-glucopyranoside (13)
2,3,4,6-Tetra-O-acetyl-(2-bromo)ethyl-α-d-glucopyranoside[25] (135 mg, 0.297
mmol) was dissolved in dry n class="Chemical">DMF (3 mL), and to this solution was added
fresh NaSMe (23 mg, 0.33 mmol). The reaction was stirred overnight,
after which it was diluted with EtOAc (25 mL), washed with water (2×)
and aq NaHCO3 (2×), and dried (Na2SO4). Concentration in vacuo was followed by purification of
the residue by silica column chromatography (10% MeOH in DCM), affording
the title compound (50.0 mg, 0.197 mmol, 66% over two steps) as a
colorless oil: R = 0.84
(20% MeOH in DCM); IR (neat) 3350, 2918, 1639, 1426, 1018; 1H NMR (400 MHz, CD3OD) δ 4.80 (d, J = 3.8 Hz, 1H, H-1), 3.91–3.75 (m, 2H, CHH H-6, CHH OCH2), 3.69–3.58 (m,
4H, H-4, H-5, CHH H-6, CHH OCH2), 3.37 (dd, J = 9.7, 3.8 Hz, 1H, H-2), 3.25
(d, J = 9.3 Hz, 1H, H-3), 2.73 (td, J = 6.9, 1.8 Hz, 2H, OCH2SMe), 2.12 (s,
3H, OCH2SMe); 13C NMR (101
MHz, CD3OD) δ 100.3 (C-1), 75.1 (C-4), 73.9 (C-5),
73.5 (C-2), 71.8 (C-3), 68.4 (OCH2), 62.7
(C-6), 34.3 (OCH2SMe), 15.8 (OCH2SMe); HRMS (ESI) m/z [M + Na]+ calcd for C9H18O6SNa 277.0716, found 277.0711.
Methylthio-β-d-glucopyranoside (15)
α/β-d-Glucosen class="Chemical">pentaacetate (4.99
g, 12.4 mmol) was dissolved in anhydrous DCM (20 mL), and to this
solution were added I2 (4.84 g, 19.0 mmol) and Et3SiH (2.90 mL, 18.2 mmol). This mixture was allowed to stir for 10
min, after which it was diluted with DCM (100 mL) and washed with
aqueous saturated Na2S2O3 (1×)
and Na2CO3 (1×). Layers were separated,
and the organic layer was dried (Na2SO4) and
concentrated in vacuo. The crude was coevaporated with toluene (3×)
and redissolved in dry MeCN (20 mL), followed by the addition of thiourea
(1.46 g, 19.2 mmol). The mixture was then heated for 30 min at 80
°C, after which it was allowed to cool down to rt, followed by
the addition of MeI (1.60 mL, 25.7 mmol) and Et3N (7.10
mL, 50.9 mmol). After an additional stirring for 10 min, the mixture
was concentrated in vacuo, followed by purification of the residue
over silica (0 to 50% Et2O in PE), yielding methyl 2,3,4,6-tetra-O-acetyl-1-thio-β-d-glucopyranoside as a
yellow foam (2.71 g, 7.24 mmol). This compound was then dissolved
in dry MeOH (70 mL) followed by the addition of a catalytic amount
of NaOMe, which after stirring overnight was quenched upon the addition
of Amberlite IR-120 H+. Filtration was followed by concentration
in vacuo, yielding the title compound as a colorless oil (1.48 g,
7.04 mmol, 57% over four steps): R = 0.63 (20% MeOH in DCM); IR (neat) 3336, 2923, 2881, 1425,
1017; 1H NMR (400 MHz, CD3OD) δ 4.35 (d, J = 9.6 Hz, 1H, H-1), 3.93 (d, J = 11.8
Hz, 1H, CHH H-6), 3.77–3.68 (m, 1H, CHH H-6), 3.48–3.35 (m, 3H, H-3, H-4, H-5), 3.31 (t, J = 9.1 Hz, 1H, H-2), 2.26 (s, 3H, SMe); 13C NMR (101 MHz, CD3OD) δ 87.1 (C-1), 81.8
(C-3), 79.3 (C-4), 73.5 (C-2), 71.3 (C-5), 62.7 (C-6), 12.0 (SMe); HRMS (ESI) m/z [M
+ Na]+ calcd for C7H14O5SNa 233.0454, found 233.0444.
2-(Methylthio)ethoxy)ethanol (18)
To a
flame-dried round-bottom flask was added freshly prepared NaSMe[44] (1.21 g, 15.5 mmol) under n class="Chemical">argon. Deoxygenated
THF (50 mL) was added, followed by the addition of 2-chloroethoxy)ethanol
(1.50 mL, 14.2 mmol). This solution was heated at 60 °C for 6
h, after which it was allowed to cool to room temperature. The mixture
was diluted with EtOAc (100 mL) and washed with aqueous NaHCO3 (2×) and water (1×). The layers were separated,
and the organic layer was dried (Na2SO4) and
concentrated in vacuo, affording a slightly yellowish oil (1.89 g,
13.9 mmol, 89%): IR (neat) 3480, 2907, 2866, 1611, 1512; 1H NMR (400 MHz, CDCl3) δ 3.68 (m, 2H, CH2), 3.62 (t, J = 6.7 Hz, 2H, CH2), 3.54
(d, J = 5.1 Hz, 2H, CH2), 2.94–2.81
(s, 1H, OH), 2.66 (t, J = 6.6 Hz, 2H, SCH2), 2.10 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 72.1 (CH2), 69.9 (CH2), 61.5 (CH2), 33.6 (SCH2), 15.8 (SCH3); HRMS (ESI) m/z [M + Na]+ calcd for C5H12O2SNa 159.0450, found 159.0457.
2-[2-(2-(Methylthio)ethoxy)ethoxy]ethanol (19)
The procedure was followed as described for 18 using
NaSMe[44] (4.23 g, 60.4 mmol) and 2-[2-(2-chloroethoxy)ethoxy]ethanol
(10.0 g, 59.3 mmol). 19 was afforded as a colorless oil
(9.25 g, 51.0 mmol, 85%): IR (neat) 3427, 2915, 2869, 1105, 1063; 1H NMR (400 MHz, CDCl3) δ 3.61–3.42
(m, 10H, 5 × CH2), 3.09 (s, 1H, OH), 2.60–2.50
(m, 2H, 1 × CH2), 2.03–1.94 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
72.4 (CH2), 70.2 (CH2), 70.1 (CH2), 70.0 (CH2), 61.3 (CH2) 33.13 (SCH2), 15.7 (SCH3);
HRMS (ESI) m/z [M + Na]+ calcd for C7H16O3SNa 203.0712,
found 203.0713.
[2,2′:6′,2″-Terpyridine]-4′(1′H)-thione[46] (534 mg, 2.01 mmol)
was suspended in acetic acid (6 mL). and to this mixture was added
30% H2O2 (1 mL). The resulting purple mixture
was heated at 70 °C for 12 h and concentrated in vacuo. The crude
was then redissolved in H2O, followed by the addition of
10% Pd/C (32 mg) and purged with H2 (5 min). After stirring
overnight at 40 °C under a H2 atmosphere, the reaction
was filtered over Celite, concentrated, and purified over silica (0
to 10% MeOH in DCM), affording the title compound as a bright yellow
powder (151 mg, 0.428 mmol, 24%): R = 0.37 (20% MeOH in DCM); IR (neat) 3391, 3064, 1622, 1398,
1189; 1H NMR (400 MHz, D2O) δ 8.09 (dd, J = 4.9, 1.9 Hz, 2H, T3, T3″),
7.84 (s, 2H, T3′, T5′), 7.61 (d, J = 7.4 Hz, 2H, T6, T6″), 7.54
(td, J = 7.7, 1.9 Hz, 2H, T4, T4″), 7.15 (ddd, J = 7.4, 5.0, 1.4 Hz, 2H,
T5, T5″); 13C NMR (101 MHz,
D2O) δ 154.9 (Cq arom), 152.7 (Cq arom), 152.7 (Cq arom), 148.1 (T3, T3″), 138.1 (T4, T4″), 124.9 (T5, T5″), 121.8 (T6, T6″), 116.5 (T3, T3″); HRMS (ESI) m/z [M +
H]+ calcd for C15H12N3O3S 314.0594, found 314.0600.
[Ru(S-tpy)(bpy)(Cl)] (31)
Compound 30 (134 mg, 0.428 mmol) was dissolved in MeOH (10 mL), and
to this solution was added 100 mg of washed Amberlite Na+. After the mixture stirred for 5 min at rt, the ion-exchange resin
was filtered off and the filtrate was concentrated in vacuo, affording
a pinkish solid. This compound was then together with n class="Chemical">dichloro(p-cymene)ruthenium(II) dimer (130 mg, 0.213 mmol) redissolved
in deoxygenated MeOH (5 mL) and heated to 60 °C. A solution of
bpy (69.0 mg, 0.440 mmol) in MeOH (2.3 mL) was then added dropwise
over 10 min from which the color of the solution changed from purple
to red. After stirring for 2 h under nitrogen, the solution was allowed
to cool to rt, after which Et2O (20 mL) was added. The
resulting precipitate was filtered and washed with Et2O
(3×), affording a brown powder (185 mg, 0.306 mmol, 72%): R = 0.29 (10% MeOH in DCM);
mp > 350 °C; HRMS (ESI) m/z [M + H]+ calcd for C25H19ClN5O3RuS 605.9935, found 605.9946.
Compound 19 (715 mg, 3.97
mmol) was dissolved in dry DCM (40 mL), and the mixture was cooled
to 0 °C. To this solution were added n class="Chemical">Et3N (850 ul,
6.09 mmol) and Ts-Cl (1.12 g, 5.87 mmol). The reaction was allowed
to stir overnight, after which it was diluted with DCM (100 mL) and
transferred to a separatory funnel. After washing with water (1×)
and brine (1×), the layers were separated, and the organic layer
was dried (Na2SO4) and concentrated in vacuo.
Purification of the residue by silica column chromatography (0 to
50% EtOAc in PE) afforded the title compound as a colorless oil (1.22
g, 3.64 mmol, 92%): R = 0.78 (50% EtOAc in PE); IR (neat) 2917, 2868, 1598, 1353, 1174; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H, Harom), 7.30 (d, J = 8.1 Hz, 2H, Harom), 4.18–4.02 (m, 2H, CH2), 3.65–3.61 (m, 2H, CH2), 3.57 (t, J = 6.8 Hz, 2H, CH2), 3.51 (m, 4H, 2 × CH2), 2.60 (t, J = 6.8 Hz, 2H, CH2), 2.39 (s, 3H, CH3 tosyl), 2.07 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 144.7 (Cq arom), 132.7 (Cq arom), 129.7 (CH arom), 127.7 (CH arom), 70.5 (CH2), 70.4 (CH2),
70.0 (CH2), 69.2 (CH2), 68.5 (CH2), 33.2 (SCH2), 21.5 (CH3 tosyl),
15.8 (SCH3); HRMS (ESI) m/z [M + Na]+ calcd for C14H22O5S2Na 357.0801, found 357.0800.
3,4,6-Tri-O-(4-methoxybenzyl)-d-glucal
(34)
To a cooled solution (0 °C) of d-glucal in dry DMF (230 mL) was slowly added n class="Chemical">NaH (60% dispersion
in mineral oil, 3.10 g, 77.5 mmol) followed by the addition of 4-methoxybenzyl
chloride (10.1 mL, 74.5 mmol). After the mixture stirred overnight
under a dinitrogen atmosphere, H2O (10 mL) was added and
the mixture was allowed to stir for another 10 min. The mixture was
further diluted with EtOAc (200 mL), transferred to a separatory funnel,
and washed with water (3×) and brine (3×). The organic layer
was dried over Na2SO4 and concentrated in vacuo.
Purification by silica column chromatography (0 to 15% EtOAc in PE)
afforded 34 (9.82 g, 19.4 mmol, 84%) as a clear oil that
solidified upon standing over a longer time: R = 0.66 (10% EtOAc in PE); IR (neat) 2999,
2863, 2907, 1647, 1512; 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.3 Hz, 4H, Harom), 7.04 (d, J = 8.5 Hz, 2H, Harom), 6.75
(dd, J = 11.9, 8.1 Hz, 6H, Harom), 6.31
(d, J = 6.2 Hz, 1H, H-1), 4.74 (dd, J = 6.2, 3.2 Hz, 1H, H-2), 4.64 (d, J = 10.9 Hz,
1H, CHH PMB), 4.52–4.35 (m, 5H, CHH PMB, 2 × CH2PMB), 4.07 (dd, J = 6.5, 2.2 Hz, 1H, H-3), 3.92 (dt, J = 8.6, 4.1
Hz, 1H, H-5), 3.70 (s, 3H, CH3 PMB), 3.69 (s, 4H, CH3 PMB, H-4), 3.69 (s, 3H, CH3 PMB), 3.66–3.58
(m, 2H, CH2 H-6); 13C NMR (101 MHz, CDCl3) δ 159.3 (CH arom), 159.3 (CH arom), 159.3 (CH arom), 144.7 (C-1), 130.6 (Cq arom), 130.4 (Cq arom), 130.1 (Cq arom), 129.7 (CH arom), 129.6 (CH arom), 129.5 (CH arom), 113.9 (CH arom), 113.9 (CH arom), 100.2 (C-2), 76.9 (C-5), 75.6
(C-2), 74.2 (C-4), 73.5 (CH2PMB), 73.2 (CH2PMB), 70.3 (CH2PMB), 68.3 (C-6), 55.4 (3 × CH3 PMB); HRMS (ESI) m/z [M
+ NH4]+ calcd for C30H38O7N 524.2643, found 524.2655.
To a solution of
protected glycoside 35 (821 mg, 1.62 mmol) inn class="Disease">dry DCM
(8 mL) under a dinitrogen atmosphere were added freshly activated
4 Å molecular sieves. After stirring for 15 min, the mixture
was allowed to cool to 0 °C and freshly prepared dimethyldioxirane
in acetone (20 mL, 88 mM) was slowly added. The mixture was stirred
for 3 h and allowed to reach rt, after which it was filtered over
Celite and concentrated in vacuo. The crude was then, together with
4-methoxyl benzyl alcohol (335 mg, 2.42 mmol), redissolved in dry
THF under a dinitrogen atmosphere, followed by the addition of freshly
activated 4 Å molecular sieves. After stirring for 15 min, the
mixture was cooled down to −78 °C and a cooled solution
(10 °C) of ZnCl2 in dry THF (2.43 mL, 1 M) was added
dropwise over 10 min. The mixture was allowed to stir overnight at
rt, after which it was filtered over Celite, concentrated in vacuo,
and purified by silica column chromatography (0 to 20% EtOAc in PE)
to afford 35 (413 mg, 0.625 mmol, 39% over two steps)
as a colorless oil: R = 0.48 (40% EtOAc in PE); IR (neat) 3480, 3000, 2907, 1611, 1511; 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 8.5, 4.8 Hz, 6H, Harom), 7.08 (d, J = 8.6 Hz, 2H, Harom), 6.98–6.77 (m,
8H, Harom), 4.87 (dd, J = 15.4, 11.2 Hz,
2H, CH2PMB), 4.76 (dd, J = 10.7, 6.4
Hz, 2H, CH2PMB), 4.63–4.42 (m, 4H, 2 × CH2PMB), 4.32 (d, J = 7.3 Hz, 1H, H-1), 3.80
(s, 6H, 2 × CH3 PMB), 3.79 (s, 3H, CH3 PMB),
3.79 (s, 3H, CH3 PMB), 3.70 (m, 2H, H-6), 3.62–3.50
(m, 3H, H-2, H-3, H-4), 3.45 (dd, J = 9.9, 4.1 Hz,
1H, H-5), 2.41 (s, 1H, OH); 13C NMR (101 MHz, CDCl3) δ 159.5 (Cq arom), 159.3 (Cq arom), 159.3 (Cq arom), 130.9 (Cq arom), 130.4 (Cq arom), 130.3 (Cq arom), 130.0 (CH arom), 129.7 (CH arom), 129.7 (CH arom), 129.6 (CH arom), 129.3 (Cq arom), 114.0 (CH arom), 113.9 (CH arom), 113.9 (CH arom), 101.5 (C-1), 84.3 (C-2), 77.4 (C-3), 75.3 (C-4), 74.9 (CH2PMB), 74.7 (C-5), 73.2 (CH2PMB), 70.8 (CH2PMB), 68.5 (C-6), 55.4 (4 × CH3 PMB); HRMS
(ESI) m/z [M + NH4]+ calcd for C38H48O10N 678.3273,
found 678.3302.
Compound 36 (241 mg, 0.293 mmol) was dissolved in a mixture of DCM/n class="Chemical">HFIP
(1:1, 3 mL), and to this solution were added 5 drops of 37% HCl in
H2O. The color immediately changed to dark red, and after
stirring for 5 min, the mixture was quenched upon the addition of
Et3N (500 μL, 3.59 mmol). The mixture was then concentrated
in vacuo and redissolved in H2O (5.8 mL), followed by the
addition of a solution of MeNH2 in MeOH (145 μL,
2M, 0.29 mmol). After the reaction mixture was heated for
30 min at 60 °C, the solvents were removed under reduced pressure
and the resulting residue was purified by silica column chromatography
(0 to 20% MeOH in DCM) to afford the fully deprotected hemiacetal H37 (67 mg, 0.196 mmol, 67%) as a clear oil: R = 0.54 (25% MeOH in DCM); IR (neat)
3411, 2917, 2865, 1115, 1042; 1H NMR (400 MHz, CD3OD) δ 5.29 (d, J = 3.5 Hz, 1H, H-1α),
4.53 (d, J = 7.8 Hz, 1H, H-1β), 4.04 (dt, J = 11.3, 4.4 Hz, 1H, CHH H-6), 3.89–3.70
(m, 8H), 3.70–3.59 (m, 19H), 3.42–3.32 (m, 1H, H-3β),
3.30–3.20 (m, 2H), 3.03–2.86 (m, 1H, H-2β), 2.68
(t, J = 6.8 Hz, 4H, 2 × CH2SMe), 2.13 (s, 6H, 2 × CH2SMe); 13C NMR (101 MHz, CD3OD) δ 98.1 (C-1β),
91.8 (C-1α), 85.1 (C-1β), 82.4, 77.9, 77.5, 73.9, 72.8,
72.6, 71.9, 71.9, 71.6, 71.6, 71.5, 71.5, 71.4, 71.2, 71.1, 71.0,
62.8 (C-6α), 62.7 (C-6β), 34.2 (2 × CH2SMe), 15.9 (2 × CH2SMe); HRMS (ESI) m/z [M + Na]+ calcd for C13H26O8SNa 365.1241,
found 365.1251.
To a suspension
of compound 38 inn class="Chemical">H2O was added Amberlite
IR-120 H+, and this mixture was stirred for 24 h at 60
°C, after which it was filtered and concentrated in vacuo. Purification
of the residue over silica (0 to 10% MeOH in DCM) afforded the title
compound H40 as a clear oil (α/β = 1:1, 81
mg, 0.24 mmol, 46%): R = 0.32 (10% MeOH in DCM); IR (neat) 3369, 2918, 2873, 1104, 1077; 1H NMR (400 MHz, CD3OD) δ 5.08 (d, J = 3.6 Hz, 1H, H-1α), 4.47 (d, J = 7.7 Hz, 1H, H-1β), 4.24–3.13 (m, 40H), 2.67 (t, J = 6.9 Hz, 4H, 2 × CH2SMe), 2.11 (s, 6H,
2 × CH2SMe); 13C NMR (101
MHz, CD3OD) δ 98.1 (C-1β), 94.0 (C-1α),
87.6, 84.5, 77.8, 76.1, 73.7, 73.1, 73.0, 72.2, 72.1, 71.6, 71.4,
71.4, 71.3, 71.1, 62.8 (C-6β), 62.6 (C-6α), 34.2 (2 ×
OCH2SMe), 15.9 (2 × OCH2SMe); HRMS (ESI) m/z [M + Na]+ calcd for C13H26O8SNa 365.1241, found 365.1243.
(4-Methoxybenzyl)-β-d-glucopyranoside (41)
To a solution of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (3.00 g, 7.30 mmol)
and n class="Chemical">4-methoxybenzyl alcohol (5.04 g, 36.5 mmol) in dry Et2O (75 mL) were added freshly activated 4 Å molecular sieves.
The resulting mixture was allowed to stir for 10 min, after which
Ag2CO3 (6.00 g, 21.8 mmol) and I2 (1.85 g, 7.30 mmol) were added. After the mixture stirred an additional
24 h under a dinitrogen atmosphere at rt in the dark, the reaction
mixture was filtered over Celite, diluted with EtOAc (200 mL), and
washed with 1 M Na2S2O3 (3×),
aq NaHCO3 (3×), and brine (3×). The organic layer
was dried (Na2SO4) and concentrated in vacuo.
Purification of the residue by silica column chromatography (20% EtOAc
in DCM) afforded (4-methoxybenzyl)-2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (2.39 g), which was then
redissolved in dry MeOH (70 mL) followed by the addition of a catalytic
amount of NaOMe. The resulting mixture was allowed to stir for 4 h,
after which Amberlite IR-120 H+ was added until a neutral
pH, filtered, and concentrated in vacuo, affording the title compound 41 as a clear oil (1.57 g, 5.23 mmol, 72% over two steps): R = 0.57 (20% MeOH in DCM);
IR (neat) 3335, 2924, 1612, 1027, 819; 1H NMR (400 MHz,
CD3OD) δ 7.32 (d, J = 8.6 Hz, 2H,
Harom), 6.95–6.71 (m, 2H, Harom), 4.85
(d, J = 18.0 Hz, 1H, CHH PMB), 4.58
(d, J = 11.3 Hz, 1H, CHH PMB), 4.31
(d, J = 7.8 Hz, 1H, H-1), 3.89 (dd, J = 12.0, 2.2 Hz, 1H, CHH H-6), 3.68 (dd, J = 12.0, 5.5 Hz, 1H, CHH H-6), 3.42–3.14
(m, 4H, H-2, H-3, H-4, H-5); 13C NMR (101 MHz, CD3OD) δ 160.8 (Cq arom), 130.9 (CH arom), 130.9 (Cq arom), 114.6 (CH arom), 102.9 (C-1), 78.0 (C-3), 78.0 (C-4), 75.1 (C-2), 71.7 (C-5), 71.4
(CH2PMB), 62.8 (C-6), 55.7 (CH3 PMB); HRMS
(ESI) m/z [M + Na]+ calcd
for C14H20O7Na 323.1107, found 323.1088.
Authors: Roosmarijn E Goldbach; Isabel Rodriguez-Garcia; Joop H van Lenthe; Maxime A Siegler; Sylvestre Bonnet Journal: Chemistry Date: 2011-07-27 Impact factor: 5.236
Authors: Johannes C Hermann; Yingsi Chen; Charles Wartchow; John Menke; Lin Gao; Shelley K Gleason; Nancy-Ellen Haynes; Nathan Scott; Ann Petersen; Stephen Gabriel; Binh Vu; Kelly M George; Arjun Narayanan; Shirley H Li; Hong Qian; Nanda Beatini; Linghao Niu; Qing-Fen Gan Journal: ACS Med Chem Lett Date: 2012-12-12 Impact factor: 4.345
Authors: David Sychantha; Dustin J Little; Robert N Chapman; Geert-Jan Boons; Howard Robinson; P Lynne Howell; Anthony J Clarke Journal: Nat Chem Biol Date: 2017-10-30 Impact factor: 15.040
Authors: Charles W Machan; Mario Adelhardt; Amy A Sarjeant; Charlotte L Stern; Jörg Sutter; Karsten Meyer; Chad A Mirkin Journal: J Am Chem Soc Date: 2012-10-05 Impact factor: 15.419
Authors: Marthe T C Walvoort; Chiara Testa; Raya Eilam; Rina Aharoni; Francesca Nuti; Giada Rossi; Feliciana Real-Fernandez; Roberta Lanzillo; Vincenzo Brescia Morra; Francesco Lolli; Paolo Rovero; Barbara Imperiali; Anna Maria Papini Journal: Sci Rep Date: 2016-12-23 Impact factor: 4.379
Figure 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8