Solid-supported reagents composed of a copolymer possessing 2-O-sulfonyl mannosides and phase-transfer catalysts for the synthesis of 2-fluoroglucose

Article abstract of DOI:10.1016/j.bmcl.2015.10.068

We described the synthesis of a solid-supported co-polymer possessing mannosides and phase-transfer catalysts and synthesis of 2-fluoroglucoside from it. We first prepared a soluble copolymer from two allene monomers possessing a precursor for the synthesis of 2-fluoroglycose and a crown ether. The copolymerization of the monomers via the π-ally nickel-catalyst smoothly proceeded at room temperature to provide a desired copolymer without decomposition of the sulfonate esters. The copolymer exhibited high reactivity towards fluorination in comparison with a conventional precursor. We next synthesized the solid-supported copolymer by using the solid-supported initiator attached with TentaGel resins. TentaGel enabled polymerization under stirring with stirring bar without decomposition. The solid-supported copolymer exhibited comparable reactivity towards fluorination in comparison with the soluble copolymer. In addition, it can be easily separated from the reaction vessel by filtration.

Full text of DOI:10.1016/j.bmcl.2015.10.068

Bioorganic & Medicinal Chemistry Letters 25 (2015) 5500–5503
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Solid-supported reagents composed of a copolymer possessing 2-O-
sulfonyl mannosides and phase-transfer catalysts for the synthesis of
2-fluoroglucose
b,
Ryota Takeuchi a, Yuki Sakai b, Hiroshi Tanaka a, , Takashi Takahashi
⇑
⇑
a Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1-H-101 Ookayama, Meguro, Tokyo 152-8552, Japan
b Yokohama University of Pharmacy, 601, Matana-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We described the synthesis of a solid-supported co-polymer possessing mannosides and phase-transfer
catalysts and synthesis of 2-fluoroglucoside from it. We first prepared a soluble copolymer from two
allene monomers possessing a precursor for the synthesis of 2-fluoroglycose and a crown ether. The
Received 20 August 2015
Revised 19 October 2015
Accepted 22 October 2015
Available online 23 October 2015
copolymerization of the monomers via the p-ally nickel-catalyst smoothly proceeded at room tempera-
ture to provide a desired copolymer without decomposition of the sulfonate esters. The copolymer
exhibited high reactivity towards fluorination in comparison with a conventional precursor. We next syn-
thesized the solid-supported copolymer by using the solid-supported initiator attached with TentaGelÒ
resins. TentaGelÒ enabled polymerization under stirring with stirring bar without decomposition. The
solid-supported copolymer exhibited comparable reactivity towards fluorination in comparison with
the soluble copolymer. In addition, it can be easily separated from the reaction vessel by filtration.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Positron emission tomography
Sulfonate linker
Solid-supported reagents
Glucose
Fluorination
Positron emission tomography (PET) is used to visualize the tar-
get cells and organs via radioactive tracers that possess a suitable
radionucleotide. The process is used in the clinics and in small ani-
mal researches to noninvasively study the molecular basis of dis-
ease and to guide the development of novel molecular-based
purification protocol (Scheme 1).5,6 With this process, the precur-
sors are linked to a phase tag through a sulfonate ester7,8 and are
release the fluorinated product by nucleophilic attack with the
activated [18F]potassium fluoride via a phase transfer catalyst.
The remaining tagged precursors were easily separated from the
fluorinated products based on the guidance of the tag. Omitting
the HPLC purification process simplifies the manipulation for the
purification and shortens the time required for purification to
improve the yield of the [18F]PET tracers.3 Use of a polymer-sup-
port as a phase-tag enabled purification of the [18F]PET tracers by
filtration.9,10 Brown and co-workers reported on the synthesis of
treatments.1–3 18F]Fluoride is a useful radionucleotide for PET
[
imaging due to a relatively long half-life time (105 min).4 Nucle-
ophilic substitution with [18F]fluoride ion is an effective to synthe-
size [18F]fluorides for use as PET probes with high specific activity
because carrier-free [18F]fluorides are adaptable. The yield of the
radioactive tracers largely depends not only on the efficiency of
the labeling reaction with [18F]fluoride, but also on total manipula-
tion time due to the half-life time of [18F]fluoride. However, the
nucleophilicity of the fluoride ion is very low. In addition, purifica-
tion of the [18F]tracer involves the separation of picomolar to
nanomolar amounts of a radioisotope-labeled tracer from the large
excess of non-radioactive precursors. The containing precursors
should act as competitors against the tracers. To overcome the
problems, the phase tag-assisted synthesis of [18F]fluoride-labeled
tracers has emerged as an effective method for simplification of the
[
18F]2-deoxy-2-fluoroglucose (2-FDG) from the solid-supported
precursor. However, immobilization of the reagents on a solid-sup-
port frequently reduces the reactivity against the soluble reagents
due to an enhanced steric hindrance and their reduced mobility.
Application of fluorous-tag technology11 to the synthesis of the
[
18F]PET tracers allowed removal of the precursor attached to a flu-
orous tag by solid-phase extraction with fluorous column chro-
matography with a minimum unfavourable effect of the tag.12,13
In these methodology, activation of the fluoride ion was achieved
by addition of crown ethers such as Kriptfix[2.2.2]. The crown
ethers should be carefully removed for the process of [18F] PET
probes due to their toxicity.
⇑
Corresponding authors. Tel.: +81 3 5734 2471 (H.T.); tel.: +81 45 859 1381; fax:
+81 45 859 1382 (T.T.).
In this Letter, we planed to prepare the solid-supported copoly-
mer 1 possessing 2-O-sulfonyl mannosides and phase-transfer
E-mail addresses: thiroshi@apc.titech.ac.jp (H. Tanaka), ttak@ym.hamayaku.ac.jp
(T. Takahashi).
http://dx.doi.org/10.1016/j.bmcl.2015.10.068
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

R. Takeuchi et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5500–5503
5501
H
N
6
)
(
O
H
N
O
x
( )
1) Fluorination
HO
HO
HO
O
F
2
4
F
(
)
4
F
F
y
4
2) Deprotection
(
)
OH
F
O
O
NH
F
O
Z
F
F
F
S
O
O
O
O
O
O
O
O
O
OSE
EOMO
O
H
N
6
)
(
O
1
Ni(0)
O
3
•
H
N
(
)
4
O
O
•
(
)
O
NH
4
F
(
)
4
F
F
F
O
F
O
F
O
F
O
O
O
S
O
F
O
O
EOMO
O
O
OSE
O
4
5
Scheme 1. Synthesis of the 2-fluoroglucose 2 from the solid-supported copolymer 1.
catalysts as a solid-supported reagent for the synthesis of 2-FDG
(Scheme 1). The cyclic protection minimizes b-elimination
of the sulfonate ester during fluorination.7a The 18-crown-6 was
selected as a phase-transfer catalyst. Treatment of the copolymer
1 with potassium fluoride results in activation of fluoride ion
with the crown ether. Subsequent fluorination with the activated
fluoride releases the fluorinated product. The copolymer 1 can be
separated from the products by filtration. The copolymerization
Scheme 2. Synthesis of the allene monomer 4 and copolymer 16.
Table 1
of the precursor
enhance the reactivity of the precursor towards fluorination.14
The solid-supported copolymer 1 was prepared by -allyl nickel-
catalyzed coordinating copolymerization of the allene monomers
4 and 5 with the solid-supported -allyl nickel-catalyst 3. The
4 and the phase-transfer catalyst 5 could
Radical coupling of 8
Entry
Reagents
Product
Yield (%)
p
1
2
3
4-Pentynoic acid
4-Pentenoic acid
Ethylvinyl ether
9
10
86
58
59
p
11 and 12
polymerization was compatible with various polar functional
groups involved in biologically active compounds and proceeded
under ambient temperature without decomposition of the sul-
fonate linker.15
We first prepared the soluble copolymer 16 possessing manno-
sides and crown ethers by using initiator 15 (Scheme 2). Treatment
of mannoside 6 possessing a free hydroxy group at the C2 position
with the sulfonyl fluoride 7 in the presence of sodium hexamethyl-
disilazide (NaHMDS) provided the sulfonyl ester 8 in 90% yield. We
next examined the incorporation of a carboxylic acid to 8 via the
radical coupling reaction of the terminal iodide (Table 1). Accord-
ing to the reported method7a, the treatment of iodide 8 and
catalyst 15 for 12 h at room temperature to provide copolymer
16 in 92%. 1H NMR analysis of 16 revealed that the ratio of the
incorporated monomers 4 and 5 in the copolymer 16 was 1.0:1.0
(4:5). The molecular weight and poly disparity index of the
polymer 16 was estimated by a size-exclusive chromatography to
be 2.2 Â 104 (Mw/Mn = 1.1).
Fluorination of the polymer-supported precursor 16 was exam-
ined (Scheme 3 and Table 2). A mixture of potassium fluoride and
two equivalents of the polymer-supported precursor 16 in CH3CN
was heated at 95 °C for 15 min to provide the fluorinated product
17 in 74% yield along with glycal 18 in 22% yield. On the other
hand, reaction of 1:1 mixture of the monomers 4 and 5 under
the same reaction conditions provided the fluorinated product 17
in a dramatically reduced yield (14%). The precursor 19 connected
with a phase-transfer catalyst provided the fluorinated product 17
in a moderate yield (38%). These results clearly indicate that the
copolymerization of the precursor 4 and the phase-transfer cata-
lyst 5 improved the reactivity of the precursor towards fluorina-
tion. The reaction mixture using the copolymer 16 could involve
higher local concentration area than 19. Fluorination of the poly-
mer-supported precursor 16 at 95 °C for 5 min resulted in the
reduced yield (36%) of the fluorinated product 17. However, fluori-
nation of 16 at 50 °C provided the fluorinated compound 17 in a
comparable yield (67%). We further examined the effect of the
counter cation of fluoride ion on fluorination. Sodium fluoride
did not provide the fluorinated compound 17. Cesium fluoride
ethylvinyl ether with Na2S2O3 provided
a mixture of the
aldehyde 11 and the enal 12 in 59% yield. The reaction of 8 with
4-pentenoic acid under the same conditions provided the alkyl
iodide 10 in 58% yield. Although the reaction clearly proceeded,
the starting material did not disappeared. On the other hand, use
of 4-pentynoic acid as a radical acceptor resulted in a 86% yield
of the vinyl iodide
9
as
a
stereomixture. Subsequent
hydrogenolysis of the vinyl iodide 9 provided the carboxylic
acid 14 in 90% yield. Amidation of the carboxylic acid 14
with 5-amino-1,2-heptadiene (13) in the presence of 1-[Bis
(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU), diisopropylethylamine
(DIEA) and dimethylaminopyridine (DMAP) yielded the allene
monomer 4 in 86% yield. Next, copolymerization of the allene
monomers 4 and 5 was examined. The 1.0:1.0 mixture of the
allene monomers 4 and 5 was reacted by 5 mol %
p-ally nickel

5502
R. Takeuchi et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5500–5503
Scheme 4. Synthesis of the solid-supported polymer 25.
Table 3
Polymerization of the allene monroe 24 by the initiators 3a and 3b
Scheme 3. Flurorination of the copolymer 16.
Entry
Initiator
Solvent
Yield (%)
1
2
3
4
3a
3a
3b
3b
CH3OH
CH2Cl2
CH3OH
CH2Cl2
95
55
0
Table 2
Fluorination of the copolymer 16
43
Entry
M
Time (min)
Temp (°C)
Yield of 17 (%)
Yield of 18 (%)
1
2
3
4
5
K
K
K
Na
Cs
15
5
15
15
15
95
95
50
95
95
74
36
67
0
22
Trace
20
0
12
44
resulted in the reduced yield of 17 (44%). Forming a 1:2 complex of
cesium ion and the 18-crown ether might promote fluorination.16
Next the synthesis of the solid-supported copolymer 1 by using
the solid-supported p-ally nickel initiator 3 was achieved. We first
tested polymerization of polymer-supported initiators 3a and 3b
attached at two different resins (TentaGelÒ and ArgoPoreÒ)
(Scheme 4 and Table 3). TentaGelÒ resins are a poly(styrene-oxy-
ethylene) graft copolymers and are swelling with polar solvents.
ArgoPoreÒ are macroporous polystyrene resins. Treatment of the
amino-functional resins 20a and 20b with the carboxylic acid 21
and PyBrop in the presence of DIEA at room temperature till the
amino groups were disappeared based on Kaizer Test. Subsequent
acylation of the alcohol with TFAA provided the solid-supported
allyl trifluoroacetate 22a and 22b. Polymerization of allenes 24
by the solid-supported initiator 3a and 3b was examined. The
solid-supported TFA ester 22a and 22b was treated with Ni
(COD)2 in toluene at room temperature under nitrogen atmosphere
for 20 min. After the resin was washed with toluene by three times,
a solution of allene 24 were added at room temperature. The
TentaGelÒ-bound initiator 3a with monomer 24 were stirring for
18 h at room temperature. On the other hand, ArgoPoreÒ-bound
resins 3b was shaking with monomer 24 under the same reaction
conditions because ArgoPoreÒ is mechanically destroyed by stir-
ring with a stirring bar. The yield of the resin-supported polymer
25a and 25b was estimated based on the increasing weight of
the resin. Use of TentaGelÒ-bound initiator 3a in MeOH provided
the resin-supported polymer 25a in the best yield (95%). On the
other hand, the ArgoPoreÒ-bound initiator 3b did not worked in
MeOH Stirring should be important for polymerization from the
solid-supported initiator 3a.
Scheme 5. Synthesis of the solid-supported copolymer 1.
Synthesis of the solid-supported copolymer 1 from the allenes 4
and 5 by the solid-supported initiator 3a was examined (Scheme 5).
The solid-supported TFA ester 22a was treated with Ni(COD)2 in

R. Takeuchi et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5500–5503
5503
toluene at room temperature under nitrogen atmosphere for
20 min to provided the solid-supported -ally nickel initiator 3.
Acknowledgments
p
After the resin was washed with toluene by three times, a MeOH
solution of the allenes 4 and 5 were added at room temperature.
After being stirring for 5 days at room temperature, the solid-
supported copolymer 1 was obtained in 64% yield. The yield of
the solid-supported copolymer 1 was estimated based on the
increasing weight of the resin. The loading amount of the
mannoside was calculated based on a weight of the released
2-iodoglucoside 26 by treatment with a large excess amount of
tetrabutylammonium iodide (TBAI) to be 0.491 mmol/g.
We thank Dr. Ikuyoshi Tomita, professor in Department of
Electric Chemistry, Tokyo Institute of Technology for his support
to a polymerization technology transfer.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.10.
068.
Preparation of 2-fluoroglucoside 17 from the solid-supported
copolymer 1 was examined. Two equivalents of copolymer 1 was
treated with an equivalent of KF in CH3CN for 15 min. HPLC analy-
sis of the reaction solvents based on a evaporative light scattering
detector indicated that fluoride 17 were generated with 81% purity.
Separation of the resin through a filter paper, followed by purifica-
tion of the filtrate provided the fluoride 17 in 70% isolated yield.
These results indicated that reactivity of selectivity of the solid-
supported copolymer 1 toward fluorination would be comparable
with those of the soluble copolymer 16. Finally, removal of the
protecting groups of 17 under acidic conditions provided
2-fluoro-glucose 2 in 80% yield.
References and notes
1. Corbetta, M.; Miezin, F. M.; Dobmeyer, S.; Shulman, G. L.; Petersen, S. E. J.
Neurosci. 1991, 11, 2380.
2. Massoud, T. F.; Gambhir, S. S. Genes Dev. 2003, 17, 545.
3. Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem., Int. Ed. 2007, 47,
8998.
4. Cai, L.; Lu, S.; Pike, V. W. Eur. J. Org. Chem. 2008, 2853.
5. (a) Maclean, D.; Zhu, J.; Chen, M.; Hale, R.; Sathymurthy, N.; Barrio, J. R. J. Am.
Chem. Soc. 2003, 125, 10168; (b) Spivey, A. C.; Martin, L. J.; Noban, C.; Jones, T.
C.; Ellames, G. J.; Kohler, A. D. J. Label. Compd. Radiopharm. 2007, 50, 281; (c)
Ohta, H.; Channig, M. A.; Kubodera, A.; Eckelman, W. C. Nucl. Med. Biol. 1995,
22, 37; (d) Donvan, A.; Forbes, J.; Droff, P.; Schaffer, P.; Babich, J.; Valliant, J. F. J.
Am. Chem. Soc. 2006, 128, 3536.
In conclusion, we described the synthesis of a solid-supported
co-polymer 1 possessing both mannosides and phase-transfer cat-
alysts as a solid-supported reagent for the synthesis of 2-fluorogly-
cose. We first prepared a soluble copolymer 16 from the allene
6. Boldon, S.; Stenhagen, I. S. R.; Moore, J. E.; Luthra, S. K.; Gouverneur, V. Synthesis
2011, 24, 3929.
7. (a) Brown, L. J.; Bouvet, D. R.; Champion, S.; Gibson, A. M.; Yulai, Y.; Jackson, A.;
Khan, I.; Ma, N.; Millot, N.; Nicholas, W.; Wadsworth, H.; Brown, R. C. D. Angew.
Chem., Int. Ed. 2007, 46, 941; (b) Brown, L. J.; Ma, N.; Bouvet, D. R.; Champion, S.;
Gibson, A. M.; Hu, Y.; Jackson, A.; Khan, I.; Millot, N.; Topley, A. C.; Wadsworth,
H.; Wynnb, D.; Brown, R. C. D. Org. Biomol. Chem. 2009, 7, 564; (c) Topley, A. C.;
Isoni, V.; Logothetis, T. A.; Wynn, D.; Wadsworth, H.; Gibson, A. M.; Khan, I.;
Wells, N. J.; Perrio, C.; Brown, R. C. D. Chem. Eur. J. 2013, 5, 1720.
8. Demizu, Y.; Sano, K.; Terayama, N.; Hakamata, W.; Sato, Y.; Inoue, H.; Okuda,
H.; Kurihara, M. Synth. Commun. 2012, 42, 1724.
9. (a) Pan, Y.; Ruhland, B.; Holmes, C. P. Angew. Chem., Int. Ed. 2001, 40, 4488; (b)
Pan, Y.; Holmes, C. P. Org. Lett. 2001, 3, 2769.
10. Zhang, C.-P.; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C. Tetrahedron 2013, 69, 10955.
11. Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.; Jeger, P.; Wipf, P.; Curran, D. P.
Science 1997, 275, 823.
monomers 4 and 5. The copolymerization of 4 and 5 via the p-ally
nickel-catalyst smoothly proceeded to provide copolymer without
decomposition of sulfonate esters. The copolymer exhibited high
reactivity towards fluorination in comparison with a mixture of
the two monomers 4 and 5 and the heterodimer 19 of the precur-
sor and the phase-transfer catalyst. We next synthesized the solid-
supported copolymer 1 by using the solid-supported initiators 3a
attached with TentaGelÒ resins. TentaGel was suitable for immobi-
lization of the initiator because they are swelling under polar sol-
vents and can be stirred with a stirring bar without decomposition.
The solid-supported copolymer 1 exhibited comparable reactivity
towards fluorination in comparison with the soluble copolymer
16. In addition, it can be easily separated from the reaction vessel
by filtration. The property of the solid-supported copolymer 1
would be suitable for application to radioisotope labeling experi-
ments. Now we plan to apply the solid-supported reagent 1 to
the synthesis of [18F]2-deoxy-2-fluoroglucose.
12. Bejot, R.; Fowler, T.; Carroll, L.; Boldon, S.; Moore, J. E.; Declerck, J.; Gouverneur,
V. Angew. Chem. 2009, 121, 594.
13. Blom, E.; Karimi, F.; Långström, B. J. Label. Compd. Radiopharm. 2010, 53, 24.
14. Al-huniti, M. H.; Lu, S.; Pike, V. W.; Lepore, S. D. J. Fluorine Chem. 2014, 158, 48.
15. (a) Takagi, K.; Tomita, T.; Endo, T. Macromolecules 1997, 30, 7386; (b) Takagi, K.;
Tomita, T.; Nakamura, Y.; Endo, T. Macromolecules 1998, 31, 2779; (c) Taguchi,
M.; Tomita, T.; Endo, T. Angew. Chem. 2000, 112, 3813.
16. Kim, J.; Shamsipur, M.; Huang, S. Z.; Huang, R. H.; Dye, J. L. J. Phys. Chem. A 1999,
103, 5615.