IPy2BF4-mediated glycosylation and glycosyl fluoride formation

Article abstract of DOI:10.1002/ejoc.200700038

A facile method to convert thioglycosides to glycosyl fluorides with Ipy₂BF₄ (py = pyridine) is presented. Alternatively, activation of thioglycosides with Ipy₂BF₄ in the presence of acids and glycosyl acceptors

Full text of DOI:10.1002/ejoc.200700038

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700038
IPy2BF4-Mediated Glycosylation and Glycosyl Fluoride Formation
Kuo-Ting Huang[a] and Nicolas Winssinger*[a]
Keywords: Carbohydrates / Glycosylation / Thioglycosides / Iodine
A facile method to convert thioglycosides to glycosyl fluo-
rides with Ipy2BF4 (py = pyridine) is presented. Alternatively,
activation of thioglycosides with Ipy2BF4 in the presence of
acids and glycosyl acceptors led to glycosylation reactions.
nantly the β-anomeric product. This methodology is compati-
ble with one-pot sequential glycosylation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Perbenzylated (armed) glycosyl donors yielded predomi- Germany, 2007)
The success of glycoside bond-forming reactions in the
An important asset of thioglycosides is the ability to con-
context of complex carbohydrate synthesis remains fickly. vert them into glycosyl fluorides for reiterative glycosyla-
Though a number of powerful glycosylation technologies tion between glycosyl fluoride donor and thioglycoside ac-
have already been developed, the success of complex syn- ceptor. The procedure most often employed involves the use
thesis often hinges on the different scope of these various of NBS in the presence of DAST.[18] Alternative methods
[19]
methods and there clearly remains a need for new reagents involving 4-MePhIF2
and Selectfluor {1-chloromethyl-
to promote glycosylation.[1–3] In fact, few complex carbo- 4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
hydrates have been assembled by a single glycosylation borate)}[20] have also been reported. We found that in the
method. Thioglycosides are attractive glycosyl donors as absence of acid, Ipy2BF4 smoothly converted armed thio-
the anomeric thioether is stable to most protecting group glycosides into glycosyl fluorides. As shown in Table 1, per-
manipulation and they are compatible with a number of benzylated thioglucose, galactose, mannose, as well as 4,6-
other glycosylation methods. Not surprisingly, a series of benzyledenegalactose afforded the glycosyl fluoride as the
thiophilic reagents have been described to promote glycosy- α-anomer in moderate-to-good yield (50–86%).
lation including N-bromosuccinamide (NBS),[4] dimethyl-
(thiomethyl)sulfonium trifluoromethane sulfonate promote glycosylation. It is known that a protic acid or
We then turned our attention to the use of Ipy2BF4 to
(DMTST),[5] MeSOTf (Tf = trifluorosulfonate),[6] iodonium Lewis acid is necessary to coordinate to pyridine to reveal
dicollidine perchlorate (IDCP),[7] and NIS/TfOH (NIS = N- the iodonium species. In fact, this can be monitored visually
iodosuccinamide).[8,9] More recently, benzynesulfinyl piperi- with the appearance of a deep red color upon addition of
dine/Tf2O[10] and N-(phenylthio)-ε-caprolactam/Tf2O[11] TfOH, HBF4, TMSOTf, or BF3–Et2O. Glycosylation was
were shown to be potent activators. Interestingly, although found to be effective with all these acids but further optimi-
the iodonium activation of thioglycosides is well known and zation of glycosylations were carried out strictly with
typically carried out with NIS/TfOH, the efficiency of Ip- TfOH. With the use of isopropyl alcohol as a model glyco-
[12]
y2BF4
has never been evaluated in glycosylation reac- syl acceptor, glycosylation was not effective from –100 °C
tions. Ipy2BF4 has proven to be an extremely powerful to –60 °C (Table 2, Entries 1–3) but proceeded smoothly at
source of iodonium, as exemplified by the diversity of –35 °C in the presence of at least 1 equiv. of acid; the reac-
chemistry that it can engender,[13–17] and it has become tion remained buffered, however, by pyridine (Table 2, En-
commercially available in large quantities. Herein we report tries 8 and 9). A catalytic amount of acid afforded mixtures
the use of Ipy2BF4 to convert thioglycosides to glycosyl of glycosyl fluoride and glycosylation product (Table 2, En-
fluorides and its application as a promoter of glycosylation tries 4–7). It is interesting to note the predominance of the
by using thioglycosides.
β-anomer in these reactions as glycosylation of perbenzyl-
ated (armed) donors is known to proceed through either an
SN2 mechanism or through the oxocarbenium intermediate;
both reaction pathways lead to the product corresponding
to the α-anomer. The high ratio of the observed β-anomer
in these reactions may be attributed to the participation of
pyridine, which results in a double inversion. This type of
double inversion is well-documented for acetonitrile and a
pyridinium glycoside intermediate has recently been charac-
terized by using 2-chloropyridine.[21]
[a] Organic and Bioorganic Chemistry Laboratory, Institut de
Science et Ingénierie Supramoléculaires, Université Louis
Pasteur – CNRS,
8 allée Gaspard Monge 67000 Strasbourg, France
Fax: +33-3-90-24-51-12
E-mail: winssinger@isis.u-strasbg.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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K.-T. Huang, N. Winssinger
SHORT COMMUNICATION
Table 1. Ipy2BF4 mediated conversion of thioglycosides into glyco- ford the product in good-to-excellent yield for both armed
syl fluorides.
and disarmed donors. For perbenzylated thioglucose (En-
tries 1 and 2), the reaction afforded 80% of the β-anomer
for a 1Ǟ6 glycosylation and 64% for a 1Ǟ4 glycosylation.
The greater steric demand of a C-4 hydroxyl favors the α-
anomeric product. The perbenzoylated thioglucose afforded
exclusively the expected β-anomer in both cases (Entries 3
and 4) by virtue of neighboring group participation. The
“armed” perbenzylated galactose afforded 85% of the β-
anomer for a 1Ǟ6 glycosylation (Entry 5); however, the
selectivity was rather poor for a 1Ǟ4 glycosylation (En-
try 6). In the case of mannose, the 1Ǟ6 glycosylation reac-
tion afforded strictly the β-anomer albeit in moderate yield
(Entry 7) whereas the sterically more demanding 1Ǟ4 gly-
cosylation afforded the α-anomer in good yield (Entry 8).
Table 3. Ipy2BF4 mediated disaccharide formation.
Table 2. Optimization of Ipy2BF4 mediated glycosylation.
A significant advance in the field of carbohydrate synthe-
With these results in hand, we then investigated the util- sis is the development of one-pot sequential glycosylation
ity of Ipy2BF4 for the preparation of disaccharides. As methods that rely predominantly on the tuning of the donor
shown in Table 3, the reaction proceeds smoothly with a reactivity. The spectrum of reactivity, from “armed” to
variety of donors (glucose, galactose, and mannose) to af- “disarmed” glycosyl donors, can be tuned by choosing the
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Eur. J. Org. Chem. 2007, 1887–1890

IPy2BF4-Mediated Glycosylation and Glycosyl Fluoride Formation
SHORT COMMUNICATION
Scheme 1. One-pot glycosylation reaction.
appropriate protecting groups.[22–24] In this context, the
ability to form a β-glycosidic bond with a fully armed gly-
cosyl donor is valuable. This is exemplified by the one-pot
synthesis of trisaccharide 22 from monomeric units 1, 21,
and 11 respectively (Scheme 1). Trisaccharide[25] 22 was ob-
tained in 42% yield as a 6:4 mixture in favor of the β-ano-
mer.
ceptor 21 was added at –35 °C. After completion of the first glyco-
sylation reaction (1 h, monitored by TLC), glycosyl acceptor 11
(0.11 mmol, 1.1 equiv.) was added followed by a second batch of
TfOH (0.11 mmol, 1.1 equiv.) and Ipy2BF4 (0.11 mmol, 1.1 equiv.).
The reaction was stirred for an additional 60 min at –35 °C before
the addition of excess diisopropylethylamine (82.6 µL, 0.5 mmol,
5 equiv.). The reaction was diluted with ethyl acetate (20 mL) and
washed sequentially with NaHCO3 (satd.) (2ϫ15 mL) and brine
(15 mL). The organic layer was dried with Na2SO4, concentrated
in vacuo, and purified by silica gel flash column chromatography
In conclusion, the activation of thioglycosides with
Ipy2BF4 was demonstrated either to yield glycosyl fluorides
or to promote glycosylation, depending on the reactions to obtain trisaccharide 22 in 42% yield.
conditions. Glycosylation of perbenzylated “armed” glyco-
sides affords predominantly β-anomeric products with un-
hindered acceptors, which provides unique reactivity. This
can be exploited in one-pot glycosylation reactions as was
exemplified with the formation of a trisaccharide contain-
ing β-linkages prepared from an “armed” and a “disarmed”
donor.
Supporting information (see footnote on the first page of this arti-
cle): Characterization data for compounds 2, 4, 6, 8, 9, 13–20, 22.
Acknowledgments
A fellowship from the French Ministry of Science (K.-T. H.) is
gratefully acknowledged.
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Experimental Section
General Procedure for the Conversion of Thioglycoside to Glycosyl
Fluoride: Ipy2BF4 (55.8 mg, 0.15 mmol, 1.5 equiv.) was added to a
solution of thioglycoside (0.10 mmol, 1.0 equiv.) in CH2Cl2 (5 mL)
at 23 °C, and the mixture was stirred for 3 h. The reaction mixture
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General Procedure for Ipy2Bf4-Mediated Glycosylation: A solution
of thioglycoside (0.15 mmol, 1.5 equiv.) and acceptor (0.1 mmol,
1.0 equiv.) in CH2Cl2 (5 mL) were stirred in the presence of 3 Å
molecular sieves for 20 min at 23 °C room temperature and then
cooled to –35 °C prior to the addition of TfOH (13.3 µL,
0.15 mmol, 1.5 equiv.). The reaction mixture was stirred at this
temperature for 10 min and Ipy2BF4 (55.8 mg, 0.15 mmol,
1.5 equiv.) was added. The solution was stirred at –35 °C for 1 h
then quenched with an excess diisopropylethylamine (82.6 µL,
0.5 mmol, 5 equiv.). The reaction was diluted with ethyl acetate
(20 mL) and was washed sequentially with NaHCO3sat.
(2ϫ15 mL) and brine (15 mL). The organic layer was dried with
Na2SO4, concentrated in vacuo and purified by silica gel flash col-
umn chromatography.
One-Pot Sequential Glycosylation: A solution of thioglycoside 1
(0.11 mmol, 1.1 equiv.) in CH2Cl2 (5 mL) of was stirred for 20 min
at room temperature in the presence of 3 Å molecular sieves and
then cooled to –35 °C followed by the addition of TfOH
(0.11 mmol, 1.1 equiv.). The solution was stirred at this tempera-
ture for 10 min, and Ipy2BF4 (0.11 mmol, 1.1 equiv.) was added.
The solution was stirred at –35 °C for 20 min, and glycosyl ac-
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Eur. J. Org. Chem. 2007, 1887–1890
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K.-T. Huang, N. Winssinger
SHORT COMMUNICATION
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Published Online: March 9, 2007
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Eur. J. Org. Chem. 2007, 1887–1890