Nucleophilic addition of potassium alkynyltrifluoroborates to D-glucal mediated by BF3·OEt2: Highly stereoselective synthesis of α-C-glycosides

Article abstract of DOI:10.1021/ol8022177

(Chemical Equation Presented) A convenient, mild and highly stereoselective method for C-glycosidation (alkynylation) of D-glucal with various potassium alkynyltrifluoroborates, mediated by BF₃·OEt₂ and involving oxonium intermediates, preferentially provides the α-acetylene glycoside products with good yields.

Full text of DOI:10.1021/ol8022177

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5215-5218
Nucleophilic Addition of Potassium
Alkynyltrifluoroborates to D-Glucal
Mediated by BF3·OEt2: Highly
Stereoselective Synthesis of
r-C-glycosides
Adriano S. Vieira,† Pedro F. Fiorante,† Thomas L. S. Hough,† Fernando
P. Ferreira,‡ Diogo S. Lu¨dtke,*,† and He´lio A. Stefani*,†,‡
Faculdade de Cieˆncias Farmaceˆuticas, UniVersidade de Sa˜o Paulo, AV. Prof. Lineu
Prestes, 580 Sa˜o Paulo, Brazil, and Departamento de Biof´ısica, UniVersidade Federal
de Sa˜o Paulo, SP, Brazil
hstefani@usp.br
Received September 22, 2008
ABSTRACT
A convenient, mild and highly stereoselective method for C-glycosidation (alkynylation) of D-glucal with various potassium alkynyltrifluoroborates,
mediated by BF3·OEt2 and involving oxonium intermediates, preferentially provides the r-acetylene glycoside products with good yields.
The study of glycosides has become very significant in the
fields of carbohydrate and biological chemistry.1 Glycosides
containing a C-glycosidic bond exist in some subunits of
biologically active natural products,2 are potential inhibitors
of carbohydrate processing enzymes, and are stable analogs
of glycans involved in important intra- and intercellular
processes.3 These compounds are also potentially useful as
chiral building blocks in organic chemistry4 and the develop-
ment of methods leading to the efficient and stereoselective
syntheses of C-glycosides has attracted considerable attention
in the recent years. C-glycosidation is very important in the
synthesis of optically active compounds, since it allows for
the introduction of carbon chains into sugar chirons and the
use of sugar nuclei as chiral pools as well as carbon sources.5
In particular, sugar acetylenes are attractive due to the
presence of a triple bond that can be easily transformed into
† Universidade de Sa˜o Paulo.
‡ Universidade Federal de Sa˜o Paulo.
(1) (a) Subadolnik, R. J. Nucleoside Antibiotics; Wiley-Interscience: New
York, 1970. (b) Marquez, V. E.; Lim, M. I. Med. Res. ReV. 1986, 6, 1. (c)
Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon: Oxford,
1995. (d) Ritchie, G. E.; Moffatt, B. E.; Sim, R. B.; Morgan, B. P.; Dwek,
R. A.; Rudd, P. M. Chem. ReV. 2002, 102, 305. (e) Hanessian, S.; Lou, B.
Chem. ReV. 2000, 100, 4495.
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104, 4976. (b) Paterson, L.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727.
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Synlett 1994, 43. (d) Jiang, Y.-M.; Ichikawa, Y.; Isobe, M. Synlett 1995,
285. (e) Tsuboi, K.; Ichikawa, Y.; Jiang, Y.; Naganawa, A.; Isobe, M.
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Press: Oxford, 1984.
10.1021/ol8022177 CCC: $40.75
Published on Web 10/23/2008
2008 American Chemical Society

other chiral molecules and carbohydrate analogues.6 Among
the methods of C-glycosidation, the alkynylation reaction
of sugar derivative oxocarbeniums generated from glucals
such as 1 with silylacetylenes was reported by Isobe’s group
in 1984.7 This reaction has been developed as an important
method to prepare sugar acetylenes.8 C-Glycosidation with
silylacetylene compounds has been reported to proceed under
various conditions and with various Lewis acids9 such as
SnCl4, (CH3)3SiOTf, BF3·OEt2, TiCl4, InBr3,10 and ZrCl4.11
Iodine is also an efficient catalyst for this reaction.12
In recent years, organoboron compounds have become
some of the most popular organometallic reagents for
forming carbon-carbon bonds.13 The organoboron com-
pounds used most, boronic acids and boronate esters, have
some drawbacks, including low stability, very high price,
and high sensitivity to air and moisture. To solve these
problems, organoborons have been replaced by potassium
organotrifluoroborate salts,14 which are crystalline solids,
very stable in air and moisture, easily prepared from
inexpensive materials, and more nucleophilic.
examples of glucals undergoing classical Ferrier-type alky-
nylation, to our best knowledge this is the first example of
a Ferrier-type rearrangement mediated by BF3·OEt2 using
potassium alkynyltrifluoroborates as nucleophilic partners
(Scheme 1).
Scheme 1. Alkynylation Reaction of 3,4,6-tri-O-Acetyl-D-glucal
1 with Potassium Phenylethynyltrifluoroborate
Our initial studies were focused on the development of
an optimum set of reaction conditions. For initial screening
experiments, 3,4,6-tri-O-acetyl-D-glucal 1 and potassium
phenylethynyltrifluoroborate 2a were selected as starting
materials and dichloromethane was selected as the solvent.
The reaction of D-glucal 1 with potassium phenylethynyl-
trifluoroborate 2a in the absence of a Lewis acid at 0 °C did
not lead to the desired product, and the starting material was
recovered unchanged (Table 1, entry 1).
In connection with our research interest in the preparation
and reactivity of potassium organotrifluoroborates and their
potential use as intermediates in organic synthesis,15 we
report here an easy and highly diastereoselective method to
synthesize C-glycosidate glucal 1 with potassium alkynyl-
trifluoroborates 2 with good yields. Although there are
The requirement for Lewis acidic activation strongly
implies the intermediacy of oxonium ions in this kind of
reaction. In view of this result, we initially chose BF3·OEt2
as the Lewis acid because we believe that it is best for
reactions involving potassium organotrifluoroborates.14,15b
For this purpose, the commercially available 3,4,6-tri-O-
acetyl-D-glucal 1 was treated with potassium phenylethy-
nyltrifluoroborate 2a in the presence of BF3·OEt2 (2.0 equiv)
in CH2Cl2 at -23 °C to ensure in situ formation of the
corresponding oxonium ion, which was formed in 15 min
as evidenced by the consumption of 1 by TLC analysis. The
reaction was allowed to warm to room temperature and
stirred for 1 h. The corresponding alkynyl C-glycoside 3a
was obtained with an isolated yield of only 45% as a 90:10
mixture of the R and ꢀ anomers (Table 1, entry 2). The
diastereomeric ratio was determined by GC analysis of the
crude mixture. The effect of the solvent in this reaction on
the yield and diastereoselectivity was noteworthy. When the
reaction was performed in acetonitrile or toluene, appreciable
improvements in the yield and diastereoselectivity were
observed and the C-glycoside was obtained at 84 and 78%
yield, respectively, with 95:05 R/ꢀ selectivity (Table 1,
entries 3 and 4). By using N,N-dimethylformamide as
the solvent, no product could be obtained, and 1,2-dichlo-
roethane produced results similar those obtained with CH2Cl2
(Table 1, entries 5 and 6). This alkynylation reaction takes
place efficiently with acetonitrile as the solvent, unlike the
commonly used BF3·OEt2-mediated processes, which employ
chlorinated solvents.
(6) Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishizawa, T. Chem.
Commun. 1998, 2665.
(7) (a) Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Tetrahedron Lett.
1984, 25, 5049. (b) Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T.
Carbohydr. Res. 1987, 171, 193.
(8) Tsukiyama, S.; Isobe, M. Tetrahedron Lett. 1992, 33, 7911.
(9) (a) Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Carbohydr. Res.
1987, 171, 193. (b) Tsukiyama, T.; Peters, S. C.; Isobe, M. Synlett 1993,
413. (c) Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa, T. Chem.
Commun. 1998, n/a, 2665. (d) Hosokawa, S.; Kirschbaum, B.; Isobe, M.
Tetrahedron Lett. 1998, 39, 1917. (e) Huang, G.; Isobe, M. Tetrahedron
2001, 57, 10241. (f) Isobe, M.; Phoosaha, W.; Saeeng, R.; Kira, K.; Yenjai,
C. Org. Lett. 2003, 5, 4883. (g) Procopio, A.; Dalpozzo, R.; De Nino, A.;
Nardi, M.; Russo, B.; Tagarelli, A. Synthesis 2006, 332. (h) Yadav, J. S.;
Raju, A. K.; Sunitha, V. Tetrahedron Lett. 2006, 47, 5269.
(10) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Rao, C. V. Tetrahedron
Lett. 2002, 43, 5437.
(11) Smitha, G.; Reddy, S. C. Synthesis 2004, 834.
(12) Yadav, J. S.; Reddy, B. V.; Rao, C. V.; Reddy, M. S. Synthesis
2003, 247. (b) Saeeng, R.; Sirion, U.; Sahakipitchan, P.; Isobe, M.
Tetrahedron Lett. 2003, 44, 6211.
(13) (a) Matteson, D. S. Stereodirected Synthesis With Organoboranes;
Springer: Berlin, 1995. (b) Pelter, A.; Smith, K.; Brown, H. C. Borane
Reagents; Academic: London, 1988.
(14) For reviews of organotrifluoroborate salts, see: (a) Darses, S.; Geneˆt,
J.-P. Eur. J. Org. Chem. 2003, 4313. (b) Molander, G. A.; Figueroa, R.
Aldrichim. Acta 2005, 38, 49. (c) Molander, G. A.; Ellis, N. Acc. Chem.
Res. 2007, 40, 275. (d) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron
2007, 63, 3623. (e) Darses, S.; Geneˆt, J.-P. Chem. ReV. 2008, 108, 288.
(15) (a) Guadagnin, R. C.; Suganuma, C. A.; Singh, F. V.; Vieira, A. S.;
Cella, R.; Stefani, H. A. Tetrahedron Lett. 2008, 49, 4713. (b) Vieira, A. S.;
Ferreira, F. P.; Fiorante, P. F.; Guadagnin, R. C.; Stefani, H. A. Tetrahedron
2008, 64, 3306. (c) Paixa˜o, M. W.; Weber, M.; Braga, A. L.; de Azeredo,
J. B.; Deobald, A. M.; Stefani, H. A. Tetrahedron Lett. 2008, 49, 2366. (d)
Cella, R.; Cunha, R. L. O. R.; Reis, A. E. S.; Pimenta, D. C.; Klitzke,
C. F.; Stefani, H. A. J. Org. Chem. 2006, 71, 224. (e) Cella, R.; Stefani,
H. A. Tetrahedron 2006, 62, 5656. (f) Stefani, H. A.; Cella, R.; Do¨rr, F. A.;
Pereira, C. M. P.; Zeni, G.; Gomes, M., Jr. Tetrahedron Lett. 2005, 46,
563. (g) Stefani, H. A.; Cella, R.; Do¨rr, F. A.; Pereira, C. M. P.; Zeni, G.;
Gomes, M., Jr. Tetrahedron Lett. 2005, 46, 563. (h) Cella, R.; Orfa˜o,
A. T. G.; Stefani, H. A. Tetrahedron Lett. 2006, 47, 5075. (I) Cella, R.;
Venturoso, R. C.; Stefani, H. A. Tetrahedron Lett. 2008, 49, 16. (j) Stefani,
H. A.; Cella, R.; Zukerman-Schpector, J.; Caracelli, I. Z. Kristallogr. NCS
2006, 221, 167. (k) Caracelli, I.; Stefani, H. A.; Vieira, A. S.; Machado,
M. M. P.; Zukerman-Schpector, J. Z. Kristallogr. NCS 2007, 222, 345.
We were interested in testing other Lewis acids in this
Ferrier-type alkynylation. To our surprise, potassium phe-
nylethynyltrifluoroborate 2a did not react when MgBr2 and
InCl3 were used as Lewis acids (Table 1, entries 7 and 8),
5216
Org. Lett., Vol. 10, No. 22, 2008

Table 1. Alkynylation Reaction of 3,4,6-tri-O-Acetyl-D-glucal 1
with Potassium Phenylethynyltrifluoroborate 2a
Table 2. BF3·OEt2-Mediated Alkynylation Reaction of
3,4,6-tri-O-Acetyl-D-glucal with Potassium
Alkynyltrifluoroborates 2a-hc
Lewis acid
entry (2 equiv)
yield
solvent
Ch2Cl2
conditions
1 h 0 °C
1 h r.t.
1 h r.t.
1 h r.t.
1 h r.t.
(%)a R/ꢀ ratiob
1
2
3
4
-
-
45
84
78
-
-
90:10
94:06
94:06
-
BF3·OEt2 Ch2Cl2
BF3·OEt2 CH3CN
BF3·OEt2 PhCH3
BF3·OEt2 DMF
5
6
7
8
9
10
11d
12
13c
14e
BF3·OEt2 (CH2)2Cl2 1 h r.t.
43
-
-
62
70
81
89
90:10
-
MgBr2
InCl3
SnCl4
TiCl4
CH3CN
CH3CN
CH3CN
CH3CN
1 h r.t.
1 h r.t.
1 h r.t.
1 h r.t.
-
85:15
80:20
95:05
94:06
96:04
90:10
BF3·OEt2 CH3CN
BF3·OEt2 CH3CN
BF3·OEt2 CH3CN
BF3·OEt2 CH3CN
6 h r.t.
10 min 0 °C
20 min -45 °C 85
1 h r.t. 27
a Isolated yield. b Ratio of R and ꢀ anomers was determined by GC
analysis. c Reaction with 4.0 equiv of BF3·OEt2. d Reaction with 5.0 equiv
of BF3·OEt2. e Reaction with 1.0 equiv of BF3·OEt2.
and the use of SnCl4 and TiCl4 led to lower yields (Table 1,
entries 9 and 10). The addition of BF3·OEt2 made this
reaction very efficient, and when the reaction was performed
with 4.0 equiv of Lewis acid in acetonitrile, it proceeded to
completion in 20 min at -45 °C (condition a), affording the
product 3a with a very good yield and a high R/ꢀ diaster-
eomeric ratio (Table 1, entry 13). However, a higher
temperature (0 °C) dramatically reduced the reaction time
to 10 min (condition b) and the required Lewis acid amount
(2.0 equiv), affording the desired glycoside with an isolated
yield of 89% (Table 1, entry 12). At a higher stoichiometry
of the Lewis acid (5.0 equiv), no improvements in the yield
or selectivity were observed, even when the reaction was
performed at room temperature for 6 h (Table 1, entry 11).
The use of smaller amounts of BF3·OEt2 resulted in lower
yields (Table 1, entry 14).
Among the several reaction conditions tested, one in
particular is notable: the use of 2.0 equiv of BF3·OEt2 as a
Lewis acid and 1.2 equiv of the potassium organotrifluo-
roborate 2a in CH3CN at 0 °C for 10 min, under an
anhydrous and inert atmosphere (condition b), afforded the
alkynyl glycoside 3a with an isolated yield of 89%, in a 94:
06 diastereomeric ratio in favor of the R-anomer (determined
by GC and 1H NMR analysis). Furthermore, the spectral data
of 3a are identical to those reported in the literature,10 which
had previously been assigned the R-configuration at the
anomeric center. These best-achieving mild conditions were
applied to the reactions of 3,4,6-tri-O-acetyl-D-glucal 1 with
various potassium alkynyltrifluoroborate salts 2b-h to afford
the acetylene glycoside products 3b-h. All reactions were
monitored by TLC until consumption of D-glucal was
complete. The results are summarized in Table 2.
a Isolated yield of the pure products. b The ratio of R and ꢀ anomers
was determined by GC analysis of the crude mixture. c Condition a: 4.0
equiv BF3·OEt2, 20 min, -45 °C. Condition b: 2.0 equiv BF3·OEt2, 10
min, 0 °C.
All reactions showed good yields and high diastereose-
lectivity and the R-anomer was obtained as the predominant
product in each reaction. The stereochemistries of the
products 3a-h were determined by 1H and 13C NMR
observations of H-5 and C-5 and the correlation of the
chemical shifts and coupling constants with those of similar
compounds already described in the literature.12b In fact,
Isobe9f,16 established an empirical rule to deal with the
chemical shift of H-5: the value falls between 4.07 and 4.09
ppm for the R-anomer due to the anisotropic effect of the
R-acetylene at C-1, and between 3.74 and 3.77 ppm for the
ꢀ-anomer. Moreover, the R-anomer exhibits a chemical
shift17 of C-5 lower than 75 ppm.
(16) (a) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993,
34, 5757. (b) Tanaka, S.; Isobe, M. Tetrahedron 1994, 50, 5633.
(17) Price, S.; Edwards, S.; Wu, T.; Minehan, T. Tetrahedron Lett. 2004,
45, 5197.
Org. Lett., Vol. 10, No. 22, 2008
5217

In the case of alkynylation with trimethylsilylacetylene,
Isobe explained the R-selectivity by electronic effects on the
oxocarbenium intermediates involved in the transformation.
In terms of reaction mechanism, this process could involve
the generation of the oxonium cation species 1a from the
Ferrier rearrangement of the Lewis acid-catalyzed C-gly-
cosidation of glucal as depicted in Scheme 2.
oxonium and nucleophilic species. Thus, the active nucleo-
phile in this kind of reaction may be the [R-B(OAc)F2]-
Scheme 3. BF3·OEt2-Mediated Generation of RBF2 Species
species, which attacks the oxonium cation at C-1 from the
R-side, affording the respective R-anomer of the alkynyl
C-glycoside.
Scheme 2. Ferrier Rearangement Mechanism
In summary, we have developed a new and very mild
method for stereoselective introduction of an alkynyl group
to D-glucal, demonstrating that potassium alkynyltrifluo-
roborate-mediated alkynalation represents a convenient method
for the production of R-C-glycosides with good yields and
high diastereoselectivties.
Acknowledgment. We acknowledge Conselho Nacional
de Desenvolvimento Cient´ıfico e Tecnolo´gico (CNPq) and
Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo
(FAPESP 06/50190-7 and 07/59404-2) for financial support.
We believe the C-glycosidation reaction was initiated by
the reaction of BF3 with the alkynyltrifluoroborate, to
generate, as described by Kaufmann at al.,18 organoboron
difluoride, which was detected by 11B NMR18,19 (Scheme
3). The organoboron difluoride is also a Lewis acid, which
is able to activate 3,4,6-tri-O-acetyl-D-glucal and generate
Supporting Information Available: General experimental
procedures for reactions, NMR (1H and 13C) characterization
data for new compounds. This material is available free of
chage via Internet at http://pubs.acs.org.
(18) Bir, G.; Schacht, W.; Kaufmann, D. J. Organomet. Chem. 1988,
340, 267.
(19) Billard, T.; Langois, B. R. J. Org. Chem. 2002, 67, 997
.
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