Reaction of 1,2-orthoesters with HF-pyridine: A method for the preparation of partly unprotected glycosyl fluorides and their use in saccharide synthesis

Article abstract of DOI:10.1021/ol901630d

Glycosyl fluorides can be prepared In an efficient manner by treatment of pyranose- or furanose-derlved 1,2-orthoesters, with hydrogen fluoride pyridine (HF-py). The method Is compatible with the presence of a variety of protecting groups, including fert-

Full text of DOI:10.1021/ol901630d

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4128-4131
Reaction of 1,2-Orthoesters with
HF-Pyridine: A Method for the
Preparation of Partly Unprotected
Glycosyl Fluorides and Their Use in
Saccharide Synthesis
J. Cristo´bal Lo´pez,*,† Juan Ventura,† Clara Uriel,† Ana M. Go´mez,† and
Bert Fraser-Reid*,‡
Instituto de Qu´ımica Orga´nica General (CSIC), Juan de la CierVa 3, 28006 Madrid,
Spain, and Natural Products and Glycotechnology Research Institute Inc. (NPG), 595F
Weathersfield Road, Pittsboro, North Carolina 27312
clopez@iqog.csic.es; dglucose@aol.com
Received July 17, 2009
ABSTRACT
Glycosyl fluorides can be prepared in an efficient manner by treatment of pyranose- or furanose-derived 1,2-orthoesters, with hydrogen fluoride
pyridine (HF-py). The method is compatible with the presence of a variety of protecting groups, including tert-butyldiphenyl silyl ethers, and
can be applied to sugar derivatives with free hydroxyl groups, thus avoiding the need for the protection-deprotection steps.
Oligosaccharides have been recognized as fundamental
compounds in many biological recognition processes.1
Consequently, glycosylation, the key event in their prepara-
tion, receives continuous attention.2,3 Efficiency in this
process often relies on the choice of the glycosyl donor4 and
the minimization of protecting group manipulations,5 this
being, for example, by strategic placement of rationally
designed protecting groups6 or by regioselective coupling
of polyol glycosyl acceptors.7 In this regard, the regioselec-
tive glycosylation of polyol acceptors with partially unpro-
tected glycosyl donors appears as an attractive alternative.8
The latter strategy can be useful in orthogonal9 (or semior-
thogonal)10 glycosylation strategies and has been incorpo-
rated in a two-directional approach for the convergent
(6) 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.
(7) Fraser-Reid, B.; Lo´pez, J. C.; Go´mez, A. M.; Uriel, C. Eur. J. Org.
Chem. 2004, 1387–1395.
† Instituto de Qu´ımica Orga´nica General (CSIC).
‡ Natural Products and Glycotechnology Research Institute Inc. (NPG).
(1) (a) Varki, A. Glycobiology 1993, 3, 97–130. (b) Reuter, G.; Gabius,
H. J. Cell. Mol. Life Sci. 1999, 55, 368–422. Burton, D. R.; Dwek, R. A.
Science 2006, 313, 627–628. (c) McReynolds, K. D.; Gervay-Hague, J.
Chem. ReV. 2007, 107, 1533–1552.
(8) (a) Boons, G.-J.; Zhu, T. Synlett 1997, 809–811. (b) Matsuo, I.;
Isomura, M.; Miyazaki, T.; Sakakibara, T.; Ajisaka, K. Carbohydr. Res.
1998, 305, 401–413. (c) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.;
Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545–9554. (d) Lo´pez, J. C.;
Agocs, A.; Uriel, C.; Go´mez, A. M.; Fraser-Reid, B. Chem. Commun. 2005,
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(2) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503–1531
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A. V. Lett. Org. Chem. 2005, 2, 580–589. (c) Zhu, X.; Schmidt, R. R.
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10.1021/ol901630d CCC: $40.75
Published on Web 08/21/2009
 2009 American Chemical Society

synthesis of oligosaccharides.11 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.12
Glycosyl 1,2-orthoesters, first introduced in glycosylation
studies by Kochetkov and co-workers,13-15 have been
revitalized by the advent of n-pentenyl orthoesters
(NPOEs).16,17 Other research groups have also illustrated the
value of 1,2-orthoesters in oligosaccharide synthesis.18,19
could not be applied to partially unprotected NPOE substrates
because addition of IF across the double bond was the
preferred reaction. In this manuscript, we disclose that
furanose- and pyranose-derived 1,2-O-alkyl orthoesters, 1,
can be efficiently transformed into glycosyl fluorides, 2, upon
treatment with the HF-pyridine complex26,27 (Scheme 1),
and that this transformation can be applied to partly
unprotected substrates. In this reaction, HF-pyridine plays
a dual role as the acid, necessary to promote unravelling of
the 1,2-orthoester,28 and as the source of the nucleophilic
fluoride ion.
Scheme 1
.
Transformation of 1,2-Orthoesters into Glycosyl
Fluorides
Table 1. HF-Pyridine Mediated Transformation of
1,2-Orthoesters into Furanosyl Fluorides in CH2Cl2 at -40 °C
We have recently described the transformation of partially
unprotected n-pentenyl glycosides (NPGs),20 and thiogly-
cosides,21 into glycosyl fluorides22 mediated by bis(pyridi-
ne)iodonium tetrafluoroborate23/HF-pyridine24 or N-io-
dosuccinimide/HF-pyridine.25 These methods, however,
a Addition of 3 to a precooled solution of HF-py in CH2Cl2. b Addition
of the HF-py complex to a solution of 3 in CH2Cl2.
(10) (a) Demchenko, A. V.; De Meo, C. Tetrahedron Lett. 2002, 43,
8819–8822. (b) Lo´pez, J. C.; Uriel, C.; Guillamo´n-Martin, A.; Valverde,
S.; Go´mez, A. M. Org. Lett. 2007, 9, 2759–2762.
(11) (a) Zhu, T.; Boons, G. J. Tetrahedron Lett. 1998, 39, 2187–2190.
(b) Zhu, T.; Boons, G. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 1898–
2000.
We first studied the HF-pyridine mediated transformation
of ribose 1,2-orthoesters 3 (Table 1). The reactions, which
took place smoothly at -40 °C in CH2Cl2,29 were usually
completed within 5-10 min. In some instances, the yield of
glycosyl fluoride could be improved by increasing the amount
of HF-pyridine (Table 1, entry i vs ii). n-Pentenyl orthoe-
sters (NPOEs), e.g., 3b, could also be used in the preparation
of glycosyl fluorides (Table 1, entry iii). Finally, from an
experimental standpoint, it is crucial that the orthoester be
added to the solution of HF-pyridine in CH2Cl2, to avoid
acid-catalyzed rearrangement to glycosides (Table 1, entry
iV).
(12) Hanessian, S.; Lu, P. P.; Ishida, H. J. Am. Chem. Soc. 1998, 120,
13296–13330.
(13) (a) Kochetkov, N. K.; Khorlin, A. J.; Bochkov, A. F. Tetrahedron
Lett. 1964, 5, 289–293. (b) Kochetkov, N. K. Tetrahedron 1987, 43, 2389–
2436
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(14) Fraser-Reid, B.; Lo´pez, J. C. Orthoesters and Related Derivatives.
In Handbook of Chemical Glycosylation: AdVances in StereoselectiVity and
Therapeutic ReleVance; Demchenko, A. V., Ed.; Wiley-VCH: New York,
2008; Chapter 5.1
(15) Kong, F. Carbohydr. Res. 2007, 342, 345–373
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(16) (a) Allen, J. G.; Fraser-Reid, B. J. Am. Chem. Soc. 1999, 121, 468–
469. (b) Mach, M.; Schlueter, U.; Mathew, F.; Fraser-Reid, B.; Hazen, K. C.
Tetrahedron 2002, 58, 7345–7354. (c) Lu, J.; Jayaprakash, K. N.; Schlueter,
U.; Fraser-Reid, B. J. Am. Chem. Soc. 2004, 126, 7450–7457. (d) Lu, J.;
Fraser-Reid, B. Chem. Commun. 2005, 862–864. (e) Jayaprakash, K. N.;
The procedure was next applied to ribo- and arabino-
orthoesters, 6-11 (Table 2). As previously observed, methyl
or NPOEs could be used without appreciable changes in
Lu, J.; Fraser-Reid, B. Angew. Chem., Int. Ed. 2005, 44, 5894–5898
(17) Fraser-Reid, B.; Lu, J.; Jayaprakash, K. N.; Lo´pez, J. C. Tetrahe-
dron: Asymmetry 2006, 17, 2449–2463
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659–660. (b) Sanchez, S.; Bamhaoud, T.; Prandi, J. Tetrahedron Lett. 2000,
41, 7447–7452. (c) Marotte, K.; Sanchez, S.; Bamhaoud, T.; Prandi, J. Eur.
(25) Lo´pez, J. C.; Bernal-Albert, P.; Uriel, C.; Go´mez, A. M. Eur. J.
Org. Chem. 2008, 5037–5041.
J. Org. Chem. 2003, 3587–3598
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(19) (a) Liu, X.; Wada, R.; Boonyarattanakalin, S.; Castagner, B.;
Seeberger, P. H. Chem. Commun. 2008, 3510–3512. (b) Boonyarattanakalin,
S.; Liu, X.; Michieletti, M.; Lepenies, B.; Seeberger, P. H. J. Am. Chem.
Soc. 2008, 130, 16791–16799. (c) Ravida`, A.; Liu, X.; Kovacs, L.;
(26) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.;
Olah, J. A. J. Org. Chem. 1979, 44, 3872–3881
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(27) The 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,
Seeberger, P. H. Org. Lett. 2006, 8, 1815–1818
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J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927–942.
(21) Oscarson, S. Carbohydrates in Chemistry and Biology; Ernst, B.,
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H. B.; Kim, K. S. Org. Lett. 2006, 8, 3971–3974
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(28) In this context, treatment of orthoester 3a, with Et3N·HF, less acidic
than HF-pyridine but yet a good source of fluoride ion ( McClinton, M. A.
Aldrichim. Acta 1995, 28, 31-35), left compound 3a unchanged.
(29) Reaction at -378 °C (HF-py, 20 equiv) was sluggish, leaving
considerable amounts of unreacted 1,2-orthoester among other compounds,
in a complex reaction mixture.
(22) Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590–5614.
(23) Barluenga, J.; Gonza´lez, J. M.; Campos, P. J.; Asensio, G. Angew.
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Org. Lett., Vol. 11, No. 18, 2009
4129

reaction yields (Table 2, entries: i vs ii; iii vs iV; and V vs
Vii). The use of benzyl or benzoyl substituents at O-3 and
O-5 does not seem to affect the yield of glycosyl fluorides.
Glycosyl fluorides 15 and 16 (Table 2, entries Vii and Viii,
respectively), with secondary OH groups, were obtained
uneventfully. However, orthoester 11 with a primary 5-OH
group furnished 1,5-anhydro derivative 17, upon treatment
with HF-pyridine (Table 2, entry ix).
Table 3. Reaction of Pyranose 1,2-Orthoesters, 18-24, with
HF-Pyridine (20 equiv) in CH2Cl2 at -40 °C, Leading to
Pyranosyl Fluorides, 25-31
Table 2. Reaction of Ribo- And Arabino-1,2-orthoesters, 6-11,
with HF-Pyridine in CH2Cl2 at -40 °C
sters, glucose- or galactose-derived 1,2-orthoesters could also
be successfully transformed into pyranosyl fluorides (Table
3, entries Vi and Vii, respectively).
Similarly, pyranosyl 1,2-orthoesters 18-24 afforded pyra-
nosyl fluorides 25-31, under the same reaction conditions
(Table 3). Notably, similar yields were obtained from either
n-pentenyl, methyl, or allyl 1,2-orthoesters (Table 3, entries:
iii, iV, V). Diol 23 was readily prepared by silylation of triol
24, the latter having been uneventfully obtained by de-O-
benzoylation (NaOMe/MeOH) of 19a.
The reaction is compatible with the presence of secondary
hydroxyl groups in the 1,2-orthoester (Table 3, entries Viii,
ix). In addition, the excellent yield of 30 shows that
fluoridation is so rapid that it can even compete with
HF-pyridine mediated de-O-silylation (Table 3, entry ix).
Equally remarkable is that triol 24 could be successfully
transformed into glycosyl fluoride 31, in 83% yield30 (Table
3, entry x). Finally, although most of the transformations
depicted in Table 3 were performed with mannose orthoe-
A single glycosyl fluoride was obtained in each case, to
which we have assigned an anti-1,2-orientation based on
comparison with literature data, mechanistic grounds, and
31
1
on the observed H NMR couplings.
To illustrate the usefulness of this transformation when
used in combination with selective activation strategies, we
have carried out the synthesis of trisaccharide 34 (Scheme
2). Thus, fluoride 15 (Table 2, entry Vii) was glycosylated
with NPOE 6a [NIS, Yb(OTf)3]32 to give disaccharide 32,
which was now used as a donor in the glycosylation of NPG
33, to yield linear trisaccharide 34.
Finally, we have performed the synthesis of tetrasaccharide
39 by using fluoride triol 31, as the key intermediate (Scheme
3). Thus, NPOE 19a was used to regioselectively33 glyco-
(31) (a) Hall, L. D.; Steiner, P. R.; Pedersen, C. Can. J. Chem. 1970,
48, 1155–1165. (b) Hall, L. D.; Manville, J. F.; Bhacca, N. S. Can. J. Chem.
1969, 47, 1–17.
(30) Neither 1,6-anhydro derivative formation or 1,2,6 internal orthoester
formation were observed:Hiranuma, S.; Kanie, O.; Wong, C.-H. Tetrahedron
Lett. 1999, 40, 6423–6426.
(32) (a) Jayaprakash, K. N.; Radhakrishnan, K. V.; Fraser-Reid, B.
Tetrahedron Lett. 2002, 43, 6953–6955. (b) Jayaprakash, K. N.; Fraser-
Reid, B. Synlett 2004, 301–305.
4130
Org. Lett., Vol. 11, No. 18, 2009

Scheme 2
.
Synthesis of Triarabino Derivative 34 via Key
Intermediate 15
Scheme 3
.
Triol 31 as the Key Intermediate in the Synthesis of
Branched Tetrasaccharide 39
sylate triol 31 to give glycosyl fluoride 35 (58% yield) as
the only detected disaccharide. The latter was then used to
glycosylate NPG 36, upon selective activation with
Yb(OTf)3, leading to trisaccharide 37, in 60% yield, no other
trisaccharide being observed. Finally, treatment of diol 37
with pyranosyl fluoride donor 38, under the agency of
BF3·Et2O, yielded tetrasaccharide 39 in 58% yield.34 This
strategy serves to illustrate the usefulness of triol 31, able
to function as an acceptor, a donor, and an acceptor,
respectively. The last steps in the synthetic sequence (i.e.,
35 + 36 and then 37 + 38) can be regarded as a
two-directional strategy,11 wherein compound 35 was first
used as a donor to give trisaccharide 37, that later functioned
as an acceptor to generate tetrasaccharide 39.
lead to alternative reaction pathways.37,38 The usefulness of
this strategy was illustrated with the preparation of triol
glycosyl fluoride 31 (which maintains a participating 2-OBz
group), in just two steps from NPOE 19a.39 In our opinion,
this reaction might prove to be useful in block, orthogonal,
or two-directional strategies for oligosaccharide synthesis.3
In summary, we have shown that the HF-pyridine
complex can be used to successfully convert furanosyl and
pyranosyl 1,2-orthoesters to glycosyl fluorides. This trans-
formation is presumed to take place by acid -induced
unraveling of the 1,2-orthoester moiety leading to an
oxocarbenium (dioxolenium or trioxolenium)35 ion that
subsequently reacts with the fluoride ion. The reaction takes
place rapidly, is refractory to free -OH groups in the
substrate-donor, and permits the use of tert-butyl diphenyl-
silyl protecting groups. When compared with diethylamino-
sulfur trifluoride36 (DAST)-mediated anomeric fluorinations
on fully protected compounds, the use of HF-pyridine does
not require an additional step for the liberation of the
anomeric OH functionality. On the other hand, (DAST)-
mediated anomeric fluorinations are not compatible with the
presence of free OH groups in the molecule since they might
Acknowledgment. This research was supported with funds
from the Direccio´n General de Ensen˜anza Superior (Grant:
CTQ2006-15279-C03-02). BFR (NPG Research Institute)
thanks the National Science Foundation (Grant: CHE 0717702)
for financial support. We thank Ms. Marina Rodriguez
(IQOG, CSIC) for skillful technical support.
Supporting Information Available: Experimental pro-
cedures and characterization data and copies of 1H, 13C, and
two-dimension NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL901630D
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