Chemical synthesis of 1′-deoxy-1′-fluorosucrose

Article abstract of DOI:10.1021/ol401044h

The first chemical synthesis of 1′-deoxy-1′-fluorosucrose has been accomplished in eight steps from sucrose by an unlikely, but ultimately successful, S_N2 displacement reaction.

Full text of DOI:10.1021/ol401044h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Chemical Synthesis
of 10-Deoxy-10-fluorosucrose
Weijiang Ying, Vikram Gaddam, and Michael Harmata*
Department of Chemistry, University of Missouri;Columbia, Columbia,
Missouri 65211, United States
harmatam@missouri.edu
Received April 15, 2013
ABSTRACT
The first chemical synthesis of 10-deoxy-10-fluorosucrose has been accomplished in eight steps from sucrose by an unlikely, but ultimately
successful, SN2 displacement reaction.
As part of a program focusing on carbon partitioning in
higher plants,1 we have begun a study of the synthesis of
fluorosucroses. These syntheses are designed to be amen-
able to the incorporation of 18F so that the target com-
pounds can be used for the purpose of real-time PET
imaging of sucrose transport.
In order to provide a fluorosucrose for such studies that
would likely be more resistant to the action of invertase, we
decided to pursue a synthesis of 10-deoxy-10-fluorosucrose
(2). This compound has been prepared enzymatically via
coupling of 1-deoxy-1-fluorofructose and uridine dipho-
sphate glucose.3 However, the process required 24 h, too
long for application to the synthesis of hot material, with
18F having a half-life of only 110 min.4
The possibility of doing a direct nucleophilic substitu-
tion at the 10 position of sucrose was considered. This
position is hindered, flanked by two electron-withdrawing
oxygen atoms, and is formally neopentyl. These features
do not bode well for such a plan.5 Further, it had been
reported by Guthrie and co-workers that treatment of 3 or
4 with a variety of nucleophilic fluoride sources did not
result in the formation of 5 (Scheme 1).6 Nevertheless, we
felt that the progress that had been made since that report,
particularly with respect to cation-binding agents, and the
use of a triflate leaving group, might enable us to accom-
plish this difficult substitution reaction. This report details
our success in this effort.
Figure 1. 60-Deoxy-60-fluorosucrose (1) and 10-deoxy-10-fluoro-
sucrose (2).
For example, we recently reported the synthesis of
60-deoxy-60-fluorosucrose (1) in which the key fluorination
step was both simple and rapid (Figure 1).2 This metho-
dologyhas been successfully transferred tothe correspond-
ing hot synthesis, and imaging studies are currently in
progress.
(3) Card, P J.; Hitz, W. D. J. Am. Chem. Soc. 1984, 106, 5348–5350.
(4) Bejot, R.; Gouverneur, V. Mol. Med. Med. Chem. 2012, 335–382.
(5) Lowry, T. H.; Richardson, K. S.; Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987; pp 376ꢀ383.
(6) Guthrie, R. D.; Jenkins, I. D.; Watters, J. J. Aust. J. Chem. 1980,
33, 2487–2497.
(1) For recent reviews, see: (a) Ayre, B. G. Mol. Plant 2011, 4, 377–
394. (b) Geiger, D. Mol. Plant 2011, 4, 395–406. (c) Slewinski, T. L.;
Braun, D. M. Plant Sci. 2010, 178, 341–349. (d) Slewinski, T. L.; Meeley,
R.; Braun, D. M. J. Exp. Bot. 2009, 60, 881–892.
(7) Barros, M. T.; Maycock, C. D.; Thomassigny, C. Carbohydr. Res.
2000, 328, 419–423.
(2) Gaddam, V.; Harmata, M. Carbohydr. Res. 2013, 369, 38–41.
r
10.1021/ol401044h
XXXX American Chemical Society

Table 1. Optimization Studies for the Synthesis of 12
Scheme 1. Reported Attempted Synthesis of a
10-Deoxy-10-flourosucrose Derivative
time
yield
(%)
entry
reagent/equiv
CsF/1.0
(min)
We began our work with a selective desilylation7 at the
6- and 60- positions of the 6,10,60-tri-O-tert-butyldiphenyl-
silyl-2,3,4,30,40-penta-O-benzoylsucrose (7), which was
prepared from commercially available sucrose (6) in 70%
yield over two steps (Scheme 2). We found that selec-
tive desilylation could yield 10-O-tert-butyldiphenylsilyl-
2,3,4,30,40-penta-O-benzoylsucrose (8) in 60% yield in
acetonitrile. Other solvents such as ethyl acetate, dichloro-
methane, THF, and acetone required longer reaction
times and often suffered from low yields. After benzoylation
of 8 (99% yield), 10-O-tert-butyldiphenylsilyl-2,3,4,6,30,40,
60-hepta-O-benzoylsucrose (9) was desilylated with TBAF/
AcOH in refluxing THF to afford 2,3,4,6,30,40,60-hepta-O-
benzoylsucrose (10) in 98% yield. Triflation of 10 with triflic
anhydride and 2,6-lutidine gave 10-O-trifluoromethanesul-
fonyl-2,3,4,6,30,40,60-hepta-O-benzoylsucrose (11) in 95%
yield.
Due to the poor solubility of typical inorganic fluoride
sources such as KF and CsF and their low nucleophilicity,
fluorination of aliphatic halides or triflates by the fluoride
ion typically requires the use of crown ethers such as
18-crown-6 or cryptands such as Kryptofix 2228 to com-
plex the metal (e.g., Kþ) ions, increasing not only the
solubility of the salt but also the nucleophilicity of the
attendant anion.9
The optimization studiesofthe nucleophilic fluorination
of (11) are summarized in the Table 1. Our goal was not
only to demonstrate that we could synthesize the target but
also to develop a process that was simple and amenable to
application in the synthesis of a hot version of the target.
We knew at the outset that the reaction would be difficult,
but decided to investigate the possibility that rather mild
reaction conditions could effect it. In refluxing acetonitrile,
our solvent of choice for other fluorination reactions that
we have studied,2 none of the product 12 could be detected
(Table 1, entries 1, 3, and 5) regardless of the fluoride
source. Better results were obtained at higher temperatures
in a sealed tube. However, at these higher temperatures,
fluorides with metal counterions resulted in a side reaction
to form 2,3,4,6,10,30,40,60-octa-O-benzoylsucrose (13)
(Scheme 3) in approximately 5% yield (Table 1, entries 2,
4, 6, and 8).
1a
2b
3a
4b
5a
6b
7b
8b
9a
10b
20
20
20
20
20
20
20
20
10
10
0
CsF/1.0
0
AgF/1.0
trace
5
AgF/1.0
KF/1.0
0
KF/1.0
0
TBAF/1.2
50c
trace
49
60
KF/1.0 18-crown-6/1.0
KF/1.0 Kryptofix 222/1.0
KF/1.0 Kryptofix 222/1.0
a Compound 11 in refluxing acetonitrile at 0.05 M. b Compound 11 in
acetonitrile in a sealed tube at 135 °C. c Compound 13 formed in 29%
yield.
10-deoxy-10-fluoro-2,3,4,6,30,40,60-hepta-O-benzoylsucrose
(12) (Table 1, entry 7). In this case, the side product 13 was
isolated in29% yield. The complex of KF/18-crown-6gave
only a trace amount of 12 (entry 8), while the complex of
KF/Kryptofix 222 gave the best result, a 60% isolated
yield of 12 (entry 10).
The structure of the side product 13 was based on NMR
analysis and confirmed by the conversion of sucrose to 13
by exhaustive benzoylation (Scheme 3). How this side
product arises is not clear, but it is quite conceivable that
adventitious water is converted to hydroxide via reaction
with fluoride10 and results in some hydrolysis of the
starting material. The resulting benzoate could displace
the triflate in 11 to readily form 13. This is consistent with
the formation of 13 with TBAF, since it likely contains
hydroxide ions.
The 13C NMR spectrum (125 MHz, CDCl3) of product
12 displayed a peak centered at 103.6 ppm (d, J = 21.4 Hz,
C-20), due to the coupling of C-20 with the fluorine atom at
C-10, as well as another peak centered at 82.5 ppm (d, J =
179.8 Hz, C-10), due to the coupling of C-10 with the
fluorine atom at C-10. The 19F NMR spectrum (235
MHz, CDCl3) showed a triplet centered at ꢀ228.3 ppm
(J = 46.5 Hz), arising from the coupling of the fluorine
atom on C-10 with the two hydrogen atoms on the same
carbon. The 1H NMR spectrum of 12 was not exception-
ally revealing as the protons attached to C10 were obscured
by other signals.
To prepare the target compound 2, compound 12 was
hydrolyzed with potassium carbonate in refluxing metha-
nol for 5 min. This afforded 10-deoxy-10-fluorosucrose in
Interestingly, tetrabutylammonium fluoride (TBAF)
provided a 50% isolated yield of desired product
(8) Marcus, Y. Rev. Anal. Chem. 2004, 23, 269–302.
(9) Curci, R.; Di, F. F. Int. J. Chem. Kinet. 1975, 7, 341–349.
(10) Clark, J. H. Chem. Rev. 1980, 80, 429–452.
Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 2. Preparation of Key Triflate 11 from Sucrose
SpinWorks spectrum simulation software and obtained
excellent agreement with the experimental results. The 13C
NMR sprectrum (125 MHz, D2O) of 2 displayed a peak
centered at101.7 (d, J = 20.1Hz, C-20), duetothe coupling
of C-20 with the fluorine atom on C-10, as well as another
peak centered on 80.6 (d, J = 173.5 Hz, C-10), due to the
coupling of C-10 with the fluorine atom on C-10. The 19F
NMR spectrum (235 MHz, D2O) of 2 displayed a triplet
centered at ꢀ229.1 (J = 46.5 Hz), arising from the
coupling of the fluorine atom on C-10 with the two hydro-
gen atoms on the same carbon.
Scheme 3. Preparation of 2,3,4,6,10,30,40,60-Octa-O-
benzoylsucrose 13
In conclusion, we have developed the first purely che-
mical synthesis of 10-deoxy-10-fluorosucrose, with the ad-
vantages of good yieldsand short reaction times for the last
two steps, which open the door for application of 18F
labeling for PET studies. This radioactive labeling and
related plant studies are under investigation. Results will
be reported in due course.
Scheme 4. Synthesis of 10-Deoxy-10-fluorosucrose 2
Acknowledgment. This work was generously supported
by a grant from the U.S. Department of Energy (DE-
SC0002040). We thank Dr. Wei Wycoff (Missouri-
Columbia) for assistance with spectral simulation.
91% yield. To affirm that no change in the molecular
skeleton occurred, the product was benzoylated and the
precursor 12 was obtained in 86% yield (Scheme 4).
Supporting Information Available. Experimental pro-
cedures and characterization data (1H, 13C, and 19F
NMR). This material is available free of charge via the
Internet at http://pubs.acs.org.
1
The H NMR spectrum (500 MHz, D2O) of 2 showed
two second-order doublet of doublets at 4.40 ppm (J =
10.5, 46.5 Hz) and 4.33 ppm, due to the coupling between
two hydrogen atoms at C-10 and the coupling of them with
the fluorine atom. We modeled the spin system using
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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