1-Fluoropyridinium triflates: Versatile reagents for transformation of thioglycoside into O-glycoside, glycosyl azide and sulfoxide

Article abstract of DOI:10.1016/S0040-4039(03)01206-1

1-Fluoropyridinium triflates are versatile reagents to transform thioglycoside into O-glycoside, glycosyl azide and sulfoxide. The electronic nature of the substituents on the pyridine ring can control their ability to activate thioglycosides.

Full text of DOI:10.1016/S0040-4039(03)01206-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5247–5249
1-Fluoropyridinium triflates: versatile reagents for transformation
of thioglycoside into O-glycoside, glycosyl azide and sulfoxide
Hirokazu Tsukamoto* and Yoshinori Kondo
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
Received 7 April 2003; revised 14 May 2003; accepted 15 May 2003
Abstract—1-Fluoropyridinium triflates are versatile reagents to transform thioglycoside into O-glycoside, glycosyl azide and
sulfoxide. The electronic nature of the substituents on the pyridine ring can control their ability to activate thioglycosides. © 2003
Elsevier Science Ltd. All rights reserved.
Biological activities of complex glycoconjugates drive
chemist to develop efficient methods for the assembly of
oligosaccharides as drug candidates or chemical
probes.1 For chemical synthesis of oligosaccharides,
thioglycosides are the most versatile glycosyl donors in
terms of stability towards chemical manipulations and
high reactivity to the glycosylation. In order to trans-
form thioglycosides into O-glycosides, a lot of thio-
philic electrophiles have been developed, i.e. methyl
triflate (MeOTf),2 iodonium di-sym-collidine perchlo-
rate (IDCP),3 dimethyl(methylthio)sulfonium triflate
(DMTST),4 methyl- or phenylsulfenyl triflate
(MeSOTf5a or PhSOTf5b), N-iodosuccinimide-triflic
Figure 1.
aromatics, alkenes,10 sulfides11 and hydrolysis of
dithioacetals.12 Their thiophilic property encouraged us
to employ them as a promoter for transformation of
thioglycosides into O-glycosides.7 Their fluorinating
ability increases as the electron density of the positive
nitrogen sites decreases10 and should be in proportion
to ability to activate thioglycosides. We chose electron-
acid (NIS-TfOH),6 Selectfluor™-BF3·OEt2 and some
7
others.8 However, most of them require either their
preparation beforehand, or mixing more than two
reagents to prepare active species in situ. For simple
operation, there is still a need to search an alternative
promoter to be able to activate thioglycosides without
any additive including Lewis or Bro¨nsted acid. We
report here new efficient method for the transformation
of thioglycoside into O-glycoside, glycosyl azide and
sulfoxide using commercially available 1-fluoropyri-
dinium triflates 1 and 2 (Fig. 1).
rich
1-fluoro-2,4,6-trimethylpyridinium
triflate
(FTMPT; 1) as a less reactive promoter and electron-
poor 1-fluoro-2,6-dichloropyridinium triflate (FDCPT;
2) as a more reactive one (Fig. 1). They would generate
2,6-disubstituted pyridine during the glycosylation and
their sterically hindered nitrogen atom would not
attack
thioglycoside.
on
oxocarbenium
ion
derived
from
The results of glycosylation of glycosyl acceptors 6–12
with glycosyl donors 4 and 5 using 1-fluoropyridinium
triflates 1 and 2 are summarized in Table 1.13 Electron-
rich FTMPT 1 could activate reactive O-benzylated
(armed) thioglycoside 4 by itself to give disaccharides
13–16 and 18 in good yields (entries 1–5). This method
was compatible with acid-labile p-methoxybenzyl
group, tert-butyldimethylsilyl group and allyl group
having an olefin (entries 3–5). As expected from struc-
tural similarity to IDCP,3 1 turned out to be a less
reactive promoter, which required room temperatures,
1-Fluoropyridinium triflates were synthesized by
Umemoto et al.9 and some of them are commercially
available. They are composed of an electrophilic
fluorine atom attached to a pyridine ring and a triflate
counteranion, which are utilized for fluorination of
Keywords: 1-fluoropyridinium triflate; thioglycoside; O-glycoside; gly-
cosyl azide; glycosyl sulfoxide.
* Corresponding author. Tel./fax: +81-22-217-6849; e-mail:
hirokazu@mail.pharm.tohoku.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01206-1

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H. Tsukamoto, Y. Kondo / Tetrahedron Letters 44 (2003) 5247–5249
Table 1.
12 h of reaction time and could not activate a less
reactive O-benzoylated (disarmed) thioglycoside
Finally, some other nucleophiles were examined for the
transformation of 5 (Scheme 1). When trimethylsilyl-
azide was utilized as nucleophile, 2 could transform 5
into glycosyl azide 22b along with a minor a-product
22a,16 which can be useful for the synthesis of N-linked
glycopeptide. The use of NIS-TfOH instead of 2 gave
not 22 but succinimide derivative 23.17
5
(entry 6). Based on the difference of reactivity of thio-
glycosides, 1 could promote chemoselective glycosyla-
tion of disarmed thioglycoside acceptors 11 and 12
having a free hydroxyl at C-6 or C-4 with the armed
thioglycoside donor 4 to give disaccharides 20 and 21 in
70 and 92% yield, respectively (entries 7 and 8).
When water was utilized as co-solvent, 2 oxidized 5 to
give glycosyl sulfoxide 25 in excellent yield as well as
Selectfluor.18 This result means attack of an excess of
water on the fluorosulfonium cation intermediate 24
would be faster than the formation of oxocarbenium
ion 26. In the glycosylation of alcohol, 1-hydroxy
derivative 27 was obtained as a minor by-product due
to slower attack of the least amount of water on 24
than the formation of 26. Furthermore, it is noteworthy
that this method was not accompanied by overoxida-
tion to the corresponding sulfone observed in the oxi-
dation using m-chloroperoxybenzoic acid even when an
excess of 2 was used.
Instead of 1, electron-poor FDCPT 2 was used for the
glycosylation of 6 and 7 (entries 9–12). FDCPT 2 with
higher fluorinating ability could activate not only the
armed thioglycoside 4, but also the disarmed 5 to give
disaccharides 13, 17, 18 and 19 in good yields with
predominant b-selectivity (entries 9–12). The higher
b-selectivity for 4 without neighboring-group participa-
tion would result from lower reaction temperature
required for 2 in acetonitrile14 as co-solvent (entries 1
and 2 versus 9 and 10).15
In order to examine the effect of counteranion of
1-fluoropyridinium salts, tetrafluoroborate derivative
3 was used for the glycosylation of 7 with 5 to give 19
as efficiently as triflate derivative 2 (entry 13). It is
noteworthy that Selectfluor™, a fluorinating reagent
having the same tetrafluoroborate anion gave no
glycosylated product without BF3·OEt2 (entry 14).7 In
the latter case, nucleophilic tertiary amine generated
from Selectfluor™ may disturb the glycosylation
process.
Thus, we have succeeded in transformation of thiogly-
cosides into O-glycosides, glycosyl azide and sulfoxide
using 1-fluoropyridinium triflates 1 and 2. These pro-
moters are commercially available and work well with-
out any additive. Further studies on solid-phase
synthesis of oligosaccharides using combination of thio-
glycosides and 1-fluoropyridinium triflates are under-
way in our laboratory.

H. Tsukamoto, Y. Kondo / Tetrahedron Letters 44 (2003) 5247–5249
5249
Scheme 1. Reagents and conditions: (a) 2 (1.5 equiv.), TMSN3 (6 equiv.), CH2Cl2–CH3CN (4:1), 0°C, 1 h, 22, 77% (a:b=10:90);
(b) 2 (2.0 equiv.), CH3CN–H2O (9:1), 0°C, 1 h, 25, 91% (2:1 mixture).
11. Umemoto, T.; Tomizawa, G. Bull. Chem. Soc. Jpn. 1986,
59, 3625–3629.
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