IPy2BF4/HF-pyridine: A new combination of reagents for the transformation of partially unprotected thioglycosides and n-pentenyl glycosides to glycosyl fluorides

Article abstract of DOI:10.1021/jo7018653

(Chemical Equation Presented) The combination of bis(pyridinium)iodonium (I) tetrafluoroborate (IPy₂BF₄), and hydrogen fluoride pyridine (HF-py) forms an iodine monofluoride (IF) synthetic equivalent that can be used in the preparati

Full text of DOI:10.1021/jo7018653

deprotection steps in a glycosylation strategy has been
accomplished by the use, among others, of rationally designed
protecting groups13 or by regioselective coupling of polyol
glycosyl acceptors.14 In this context, we believe that the design
of methods that allow the direct exchange of anomeric leaving
groups between partially unprotected sugar building blocks
(glycosyl donors or acceptors) would be useful.15
We have been interested in the study of regioselective
glycosylation strategies16 of partially unprotected glycosyl
donors with diol acceptors.17,18 More recently we have described
the use of bis(pyridinium)iodonium (I) tetrafluoroborate (IPy2-
BF4)19 for the transformation of NPGs into glycosyl fluorides
(e.g., 1a f 2, Scheme 1).20 A recent report by Huang and
Winssinger21 on the use of IPy2BF4 for the transformation 1b
f 2 and for promoting glycosylation of thioglycosides has
prompted us to disclose our own results in this area.
IPy2BF4/HF-Pyridine: A New Combination of
Reagents for the Transformation of Partially
Unprotected Thioglycosides and n-Pentenyl
Glycosides to Glycosyl Fluorides
J. Cristo´bal Lo´pez,* Paloma Bernal-Albert, Clara Uriel,
Seraf´ın Valverde, and Ana M. Go´mez*
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la
CierVa 3, Madrid 28006, Spain
clopez@iqog.csic.es; anago@iqog.csic.es
ReceiVed August 31, 2007
On the basis of the similar reactivity displayed by NPGs and
thioglycosyl donors toward iodonium-based promoters,22 and
our own experience with these donors,23 we decided to
investigate: (i) the use of IPy2BF4 as a promoter for glycosy-
lation of NPGs, (ii) the use of IPy2BF4 for the transformation
of thioglycosides into glycosyl fluorides (e.g., 1b f 2, Scheme
1), and (iii) the transformation of partially unprotected NPGs
and thioglycosides to glycosyl fluorides. To the best of our
knowledge, no direct method for the transformation of partially
The combination of bis(pyridinium)iodonium (I) tetrafluo-
roborate (IPy2BF4), and hydrogen fluoride pyridine (HF-py)
forms an iodine monofluoride (IF) synthetic equivalent that
can be used in the preparation of partially unprotected
glycosyl fluorides from partially unprotected n-pentenyl
glycosides and thioglycosides, thus avoiding the need for
the protection/deprotection steps normally required in that
transformation.
(10) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B.
J. Am. Chem. Soc. 1988, 110, 5583-5584. (b) Fraser-Reid, B.; Wu, Z.;
Udodong, U. E.; Ottosson, H. J. Org. Chem. 1990, 55, 6068-6070.
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26, 4551.4554. (c) Kanie, O. In Carbohydrates in Chemistry and Biology;
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1, Chapter 16.
(12) Demchenko, A. V.; De Meo, C. Tetrahedron Lett. 2002, 43, 8819-
Oligosaccharides are pivotal compounds in many biological
recognition processes.1,2 Consequently considerable research has
been directed toward the development of strategies for glyco-
sylation.3,4 The efficiency of these strategies often relies on the
choice of the glycosyl donor5 and the minimization of protect-
ing-group manipulations.6 Thioglycosides,7 n-pentenyl glyco-
sides (NPGs),8 and glycosyl fluorides9 are reliable glycosyl
donors, which can also function as glycosyl acceptors in armed/
disarmed,10 and orthogonal11 (or semi-orthogonal)12 glycosy-
lation strategies. Minimization in the number of protection/
8822.
(13) Litjens, R. E. J. N.; van den Bos, L. J.; Code´e, J. D. C.; Overkleeft,
H. S. van der Marel, G. A. Carbohydr. Res. 2007, 342, 419-429.
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Chem. 2004, 1387-1395.
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Org. Lett. 2005, 7, 4899-4902.
(17) Lo´pez, J. C.; Agocs, A.; Uriel, C.; Go´mez, A. M.; Fraser-Reid, B.
Chem. Commun. 2005, 5088-5090.
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S.; Kahne, D. E. J. Am. Chem. Soc. 2007, 129, 3080-3081. (b) Gu, G.;
Du, Y.; Linhardt, R. J. J. Org. Chem. 2004, 69, 5497-5500. (c) Plante, O.
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2001, 123, 9545-9554. (d) Green, L.; Hinzen, B.; Ince, S. J.; Langer, P.;
Ley, S. V.; Warriner, S. L. Synlett 1998, 440-442. (e) Boons, G. J.; Zhu,
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(21) Huang, K-T.; Winssinger, N. Eur. J. Org. Chem. 2007, 1887-1890.
(22) (a) Konradsson, P; Mootoo, D. R.; McDevitt, R. E.; Fraser-Reid,
B. J. Chem. Soc., Chem. Commun. 1990, 270-272. (b) Veenenman, G.
H.; van Boom, J. H. Tetrahedron Lett. 1990, 31, 275-278. (c) Konradsson,
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Org. Chem. 1995, 60, 3859-3870. (b) Lo´pez, J. C.; Go´mez, A. M.;
Valverde, S.; Fraser-Reid, B. Tetrahedron Lett. 2003, 44, 1417-1420. (c)
Uriel, C.; Go´mez, A. M.; Lo´pez, J. C.; Fraser-Reid, B. Synlett 2003, 2203-
2207.
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10.1021/jo7018653 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/29/2007
10268
J. Org. Chem. 2007, 72, 10268-10271

TABLE 1. IPy2BF4-Mediated Transformation of Thioglycosides to
Glycosyl Fluorides in the Presence of an Acid in CH2Cl2 at -40 °C
SCHEME 1. Transformation of n-Pentenyl Glycosides and
Thioglycosides into Glycosyl Fluorides
SCHEME 2. Attempted Glycosylation of 8 with NPG 7
Mediated by IPy2BF4
unprotected thioglycosides, or NPGs, into partially unprotected
glycosyl fluorides (e.g., 3 f 4) has been reported. In fact, the
standard procedure for such transformation (e.g., 3a,b f 4,
Scheme 1) would require two additional protection-deprotection
steps (e.g., 3 f 1 and 2 f 4, Scheme 1) since the intermediate
oxocarbenium ion (5) could also experience self-condensation
to yield saccharide(s) 6.
glycosylation process (e.g., 3 f 6). The first step was to confirm
that thioglycosides could be transformed into glycosyl fluorides
under the agency of IPy2BF4.21
Phenyl 1-thioglycosides 11-16 were transformed to glycosyl
fluorides by the action of IPy2BF4 (see Table 1). HBF4, BF3‚
Et2O, and Yb(OTf)3 were evaluated as pyridine scavengers, and
better yields of glycosyl fluorides were obtained with the system
IPy2BF4/HBF4 (Table 1, compare entries i-iii). These fluorinat-
ing conditions were then used with substrates 12-16 and proved
to be compatible with the presence of benzyl, benzoyl, tert-
butyldiphenylsilyl, and benzylidene protecting groups (Table
1, entries i-viii).
We next turned our attention to the transformation of partially
unprotected NPGs, 23, 24, and thioglycosides, 25, 26, to
glycosyl fluorides (Table 2). When NPGs containing a secondary
free OH group were treated with IPy2BF4 in the presence of
HBF4 in CH2Cl2 at -40 °C, the major reaction products obtained
were the expected glycosyl fluorides, although a respectable
amount of fluoride disaccharides was also obtained (Table 2,
entries i,ii). Phenyl 1-thioglycoside 25, containing a primary
6-OH free, furnished upon treatment with IPy2BF4/HBF4
fluoride 31 in only 23% yield, the major product of the reaction
being anhydro-derivative 32 (Table 2, entry iii). The use of
conformationally restricted thioglycoside 26 prevented the
formation of the anhydro derivative; however, the sought-for
fluoride 33 was still obtained as the minor reaction product (33%
We first studied the reaction of primary acceptor 8 with NPG
7 in the presence of IPy2BF4 and HBF4, in CH2Cl2 (Scheme 2).
The reaction furnished disaccharide 9 in 35% yield. However,
the major reaction product was glycosyl fluoride 10 (60% yield).
IPy2BF4 is a stable reagent that acts as a mild source of iodonium
ions. In the presence of an acid that neutralizes the supply of
pyridine molecules24 IPy2BF4 can be contemplated as a synthetic
equivalent of iodine monofluoride,25 and thus, the formation of
compound 10 can be explained by the presence of nucleophilic
fluoride that competes with the glycosyl acceptor 8 for the
oxocarbenium ion.26
The formation of compound 10 in Scheme 2, suggested that
an exchange of anomeric leaving groups could be performed
without tampering with the free OH groups in unprotected
NPGs. We then decided to search for reaction conditions that
could induce such transformations on NPGs and thioglycosides
(e.g., 3a,b f 4, Scheme 1) without the competing self-
(24) Barluenga, J. Pure Appl. Chem. 1999, 71, 431-436.
(25) Barluenga, J.; Campos, P. J.; Gonza´lez, J. M.; Sua´rez, J. L. J. Org.
Chem. 1991, 56, 2234-2237.
(26) A related IBr-mediated bromination of thioglycosides has been
reported: Kartha, K. P. R.; Field, R. A. Tetrahedron Lett. 1997, 38, 8233-
8236.
J. Org. Chem, Vol. 72, No. 26, 2007 10269

TABLE 2. IPy2BF4/HBF4-Mediated Transformation of Partially
Unprotected NPGs and Phenylthioglycosides to Glycosyl Fluorides
in CH2Cl2
TABLE 3. IPy2BF4/HF-Pyridine-Mediated Transformation of
Partially Unprotected NPGs and Phenylthioglycosides to Glycosyl
Fluorides, in CH2Cl2
a BF3.Et2O was used instead of HBF4
yield) (Table 2, entry iv), and the major observed compound
was now disaccharide 34 (51% yield) resulting from self-
glycosylation of either 26 or 33 (vide infra).
From the results outlined in Table 2, several conclusions were
drawn: (a) the concentration of nucleophilic fluoride in the
reaction media is not sufficient to ensure the sole formation of
glycosyl fluorides, a tendency even more pronounced when
primary OHs were present in the molecule (Table 2, compare
entries i, ii with entries iii, iv), (b) HBF4, that has been reported
as a useful promoter for glycosylation of glycosyl fluorides,27
might not be fully compatible with the final glycosyl fluorides,
and thus, the formation of disaccharides could arise either from
direct glycosyl coupling of the starting thioglycosides or by acid-
catalyzed activation of initially formed glycosyl fluorides.
Along these lines we selected Olah’s HF-pyridine com-
plex28,29 as partner to Barluenga’s IPy2BF4 in order to ac-
complish the sought-for transformation. HF-Pyridine complex
could play a dual role as the source of additional nucleophilic
fluoride and as the acid to neutralize the supply of nucleophilic
pyridine. On the other hand, HF-pyridine complex would be
harmless to glycosyl fluorides under our reaction conditions.
Accordingly, we submitted NPGs 23, 24, and thioglycosides
25, 26, 36-40 to the action of IPy2BF4 (2 equiv)/HF-pyridine30
(5-20 equiv) in CH2Cl2 at low temperature (-40 to -55 °C).
Our results, outlined in Table 3, showed that partially unpro-
tected NPGs and thioglycosides can be successfully transformed
(27) HBF4, BF3‚Et2O, and Yb(OTf)3 have been reported as useful
promoters for glycosylation of glycosyl fluorides. See ref 9c.
(28) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.;
Olah, J. A. J. Org. Chem. 1979, 44, 3872-3881.
(29) HF-pyridine complex has been used as a source of fluoride in the
preparation of glycosyl fluorides: (a) Hayashi, M.; Hashimoto, S.; Noyori,
R. Chem. Lett. 1984, 1747-1750. (b) Szarek, W. A.; Grynkiewicz, G.;
Doboszewski, B.; Hay, G. W. Chem. Lett. 1984, 1751-1754. (c) Bro¨der,
W.; Kunz, H. Carbohydr. Res. 1993, 249, 221-241. (d) Palme, M.; Vasella,
A. HelV. Chim. Acta 1995, 78, 959-969. (e) Lee, Y. J.; Lee, B. Y.; Jeon,
H. B.; Kim. K. S. Org. Lett. 2006, 8, 3971-3974.
(30) The reaction of compounds 27-32 with the system IPy2BF4/HBF4
normally yielded a mixture of compounds.
10270 J. Org. Chem., Vol. 72, No. 26, 2007

0.12 mmol) in dry CH2Cl2 (1 mL) under argon and cooled at -40
°C was treated with tetrafluoroboric acid (13 µL, 0.12 mmol). After
5 min, a solution of the thioglycoside (0.10 mmol) dissolved in
dry CH2Cl2 (2 mL) was added. When all the starting material
disappeared, the reaction mixture was diluted with dichloromethane
(30 mL) and washed with 10% aqueous sodium thiosulphate
containing sodium bicarbonate and water. The organic layer was
dried and concentrated, and the residue was purified by flash
chromatography using hexane-ethyl acetate mixtures.
General Procedure for the IPy2BF4/HF.Py-Mediated Trans-
formation of Partially Protected NPGs and Phenyl 1-Thiogly-
cosides to Glycosyl Fluorides. A solution of bis(pyridine)iodonium-
(I) tetrafluoroborate (IPy2BF4) (0.2 mmol) in dry CH2Cl2 (3 mL)
was cooled to the appropriate temperature (See Table 3). HF-
pyridine complex (5, 10, or 20 equiv) was then added, and the
resulting solution was stirred for 5 min. A solution of NPG or
phenylthioglycoside (0.1 mmol) in dry CH2Cl2 (2 mL) was then
added dropwise. The resulting solution was then stirred at low
temperature (as indicated in Table 3). The reaction was then diluted
with methylene chloride (20 mL), and the resulting solution was
carefully added to an aqueous solution containing NaHCO3 and
Na2S2O3. The resulting layers were separated, and the aqueous layer
was extracted with methylene chloride. The combined organic layers
were washed with saturated aqueous NaCl. The resultant organic
phase was dried over Na2SO4, filtered, and concentrated. Purifica-
tion by flash chromatography (hexane-ethyl acetate) afforded the
corresponding glycosyl fluorides.
to glycosyl fluorides. The reaction of NPGs 23 and 24 furnished
glycosyl fluorides 27 and 29, respectively (Table 3, entries i-iii).
The formation of glycosyl fluoride 27, however, was ac-
companied by some iodofluorination on the n-pentenyl chain
to give 35 (Table 3, entry i). Compound 35 was undoubtedly
formed by bimolecular fluorination of the cyclopropyliodonium
ion intermediate in the cationic cascade arising from NPGs,8b
(Table 3, entry i). The amount of 35 formed could be reduced
by lowering the amount of HF-pyridine employed (Table 3,
compare entries i and ii). Reaction of thioglycoside 25 with
IPy2BF4 (2 equiv)/HF-pyridine (20 equiv), -45 °C, yielded
glycosyl fluoride 31 as the major product in 71% yield; however,
a minor amount of anhydro sugar derivative 32 (18%), was still
present (Table 3, entry iv). The formation of anhydro sugar
derivatives could be avoided with the incorporation of Ley’s
diacetal protecting groups31,32 (Table 3, entries v-vii). This
reaction could be applied to diols (Table 3, entries v-vii, ix,x),
and an acid-sensitive trityl protecting group was shown to
survive the reaction conditions (Table 3, entry viii).
In summary, we have shown that IPy2BF4 can be used in
combination with HF-pyridine to successfully convert partially
unprotected NPGs and thioglycosides to glycosyl fluorides. This
transformation can be useful in block or orthogonal strategies
for oligosaccharide synthesis since it reduces the number of
protection/deprotection steps in the interconversion of glycosyl
acceptors.
Acknowledgment. This research was supported with funds
from the Direccio´n General de Ensen˜anza Superior (Grants:
PPQ2003-00396, CTQ2006-15279-C03-02). P.B-A. thanks the
CSIC for financial support. We thank Prof. J. Barluenga
(University of Oviedo, Spain) for a generous gift of IPy2BF4.
Experimental Section
General Procedure for the IPy2BF4/HBF4-Mediated Trans-
formation of Thioglycosides to Glycosyl Fluorides. A solution
of bis(pyridine)iodonium(I) tetrafluoroborate (IPy2BF4) (44.6 mg,
Supporting Information Available: Preparation and physical
data for compounds 17-22, 27-34, and 41-45. This material is
available free of charge via the Internet at http://pubs.acs.org.
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