Palladium(II) Acetate Catalyzed Stereoselective C-Glycosidation of Peracetylated Glycals with Arylboronic Acids

Article abstract of DOI:10.1021/ol010070q

(matrix presented) Addition of a variety of arylboronic acids to peracetylated glycals takes place in the presence of a catalytic amount of Pd(OAc)₂. The reaction involves the syn addition of a σ-aryl-Pd complex to the glycal double bond followed by anti elimination of Pd(OAc)₂ to provide a carbon-Ferrier type product. This method provides a practical and convenient stereoselective synthesis of C-arylglycosides.

Full text of DOI:10.1021/ol010070q

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2013-2015
Palladium(II) Acetate Catalyzed
Stereoselective C-Glycosidation of
Peracetylated Glycals with Arylboronic
Acids
Jailall Ramnauth, Odile Poulin, Suman Rakhit, and Shawn P. Maddaford*
MCR Research Inc., York UniVersity, 4700 Keele Street,
Toronto, Ontario, Canada M3J 1P3
shawnm@mcr.chem.yorku.ca
Received April 16, 2001
ABSTRACT
Addition of a variety of arylboronic acids to peracetylated glycals takes place in the presence of a catalytic amount of Pd(OAc)2. The reaction
involves the syn addition of a σ-aryl-Pd complex to the glycal double bond followed by anti elimination of Pd(OAc)2 to provide a carbon-Ferrier
type product. This method provides a practical and convenient stereoselective synthesis of C-arylglycosides.
There is a great deal of interest in C-aryl glycosides due to
a number of factors that include their occurrence in natural
products with important pharmacological properties1 and their
potential use as inhibitors of carbohydrate-processing en-
zymes2. These compounds are also valuable as chiral building
blocks3. In particular, C-arylglycopyranosides with a double
bond in the 2,3-position are useful synthetic intermediates,
since this unsaturation can be further functionalized. A
number of synthetic methods are available for such unsatu-
rated compounds. Some of these include palladium(II)-
mediated arylation of glycals4, palladium- and nickel-
catalyzed addition of Grignard reagents to an unsaturated
glycopyranoside5, and palladium(0)-catalyzed addition of
arylzinc derivatives to hex-2-enopyranosides6. Although the
yields of these reactions are good, in most cases they involve
organometallic reagents that are air- and moisture-sensitive,
toxic, pyrophoric, and not easy to handle. Also, the aryl
groups are limited as a result of the incompatibility of
different functional groups with the reaction conditions. As
an alternative, we are interested in using arylboronic acids
as carbo- based nucleophiles for the construction of C-
arylglycosides. These reagents would be attractive because
of their air and moisture stability, availability, and low
toxicity.
The Lewis acid mediated carbon-Ferrier reaction of glycals
with carbon nucleophiles including mildly nucleophilic
organozinc reagents has been reported.7 However, our initial
attempts using a Lewis acid promoted carbon-Ferrier reaction
with phenylboronic acid and 3,4,6-tri-O-acetyl-D-glucal 1
were unsuccessful. Lewis acids that were tried included
BF3‚OEt2, SnCl4, and TMSOTf. We next focused our
attention to Czernecki’s work, which showed that σ-aryl-Pd
complexes undergo aryl palladation to glycal double bonds.4
While this work provides a route to C-aryl glycosides, it lacks
regioselectivity and generality in that it is limited by the
substituents on the aromatic ring. We thought that we could
generate a wide variety of σ-aryl-Pd complexes by a
transmetalation reaction of boronic acid derivatives with a
palladium(II) salt under very mild conditions. This method
for generating σ-aryl-Pd complexes would be very valuable
(1) Subadolnik, R. J. Nucleoside Antibiotics; Wiley-Interscience: New
York, 1970.
(2) Nicotra, F. Topics Curr. Chem. 1997, 187, 55.
(3) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976. (b) Paterson, L.; Kewon, L. E. Tetrahedron Lett. 1997, 38, 5727. (c)
Horika, K.; Sakkurai, Y.; Nagasawa, M.; Hachiya, S.; Yonemitsu, O. Synlett
1994, 43.
(4) (a) Kwok, D.-I.; Farr, R. N.; Daves, G. D., Jr. J. Org. Chem. 1991,
56, 3711. (b) Czernecki, S.; Dechavanne, V. Can. J. Chem. 1983, 61, 533.
(c) Daves, G. D., Jr. Acc. Chem. Res. 1990, 23, 201.
10.1021/ol010070q CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/26/2001

because of the regioselective control at the aromatic nucleus.
The efficiency of the transmetalation from boron to palladium
was previously demonstrated in the cross-coupling reaction
of organoboron compounds with organic electrophiles.8
When commercially available 3,4,6-tri-O-acetyl-D-glucal
1 was treated with 1 equiv of palladium(II) acetate and 2
equiv of phenylboronic acid in acetonitrile at room temper-
ature for 16 h, to our delight only product 2 was obtained in
an isolated yield of 82% (Scheme 1). The 1H and 13C NMR
material 1 after 3 days. It had been observed by others that
the organic groups on the boron atom readily displace AcO-
Pd(II)-X under neutral conditions, whereas the halogen-
metal complexes are quite inert to such transmetalation with
boronic acids.10 Also, the use of Pd(PPh3)4 as a catalyst did
not lead to any product.
The reaction is amenable to a variety of arylboronic acids;
both electron-withdrawing, electron-donating, and sterically
congested groups can be present on the phenyl ring (Scheme
2).11 Electron-withdrawing groups on the phenyl ring seem
Scheme 1. Palladium(II) Acetate Mediated C-Glycosidation of
Tri-O-acetyl-D-glucal 1
Scheme 2. Palladium(II) Acetate Catalyzed C-Glycosidation
of Tri-O-acetyl-D-glucal 1 with Arylboronic Acids
to lower the yields of the C-glycoside product. However,
the reaction does not seem to be affected by moderate steric
congestion on the phenyl group (example 4).
Similar results were obtained with the C-4 epimer of 1.
The galactal derivative 7 underwent addition with a variety
of arylboronic acids to furnish the carbon-Ferrier type
products (Scheme 3).
revealed the presence of a single anomer (2). Furthermore,
the spectral data of 2 is identical to that reported in the
literature,4b which had previously been assigned the R-con-
figuration at the anomeric center. The mechanism of the re-
action is believed to involve transmetalation of the phenyl-
boronic acid to Pd(II)(OAc)2 to give PhPdOAc,9 which then
undergoes syn addition to the R-face of the glycal double
bond followed by anti elimination of palladium(II) acetate
to give 2 (Scheme 1).4
Scheme 3. Palladium(II) Acetate Catalyzed C-Glycosidation
of Tri-O-acetyl-D-galactal 7 with Arylboronic Acids
Given the success of stoichiometric palladium in forming
2, we were obligated to examine the possibility of using
palladium(II) acetate in catalytic amounts. The yield of the
C-phenylglycoside was similar with as little as 10% catalyst.
Interestingly, in the reaction mixture we detected the presence
of a black precipitate, which indicated that Pd(0) had formed.
Upon examination of the nonpolar fraction we observed the
formation of biphenyl. It had been shown previously that
PhPdOAc can undergo a second transmetalation to give
PdPh2, which can undergo reductive elimination to give Pd(0)
and biphenyl.9 Although the formation of PdPh2 would lead
to the consumption of the catalyst, it could also add to the
glycal double bond and generate 2 and PhPdOAc after anti
elimination.
In all cases, only the R-anomer was obtained. This
assignment is based on the mechanism and was confirmed
by 13C NMR (see Supplementary Information). The chemical
shift of C-5 is diagnostic of the stereochemistry at the
anomeric position. Upfield chemical shifts with values of
It should be noted that the use of PdCl2 as catalyst lead to
2 in a poor yield of 8% with mostly unreacted starting
(10) (10) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S. J. Org. Chem.
1995, 60, 883.
(5) Moineau, C.; Bolitt, V.; Sinou, D. J. Org. Chem. 1998, 63, 582.
(6) (a) Dunkerton, L. V.; Serino, A. J. J. Org. Chem. 1982, 47, 2812.
(b) Dunkerton, L. V.; Euske, J. M.; Serino, A. J. Carbohydr. Res. 1987,
171, 89.
(7) Thorn, S. N.; Gallagher, T. Synlett 1996, 185.
(8) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 247.
(9) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61,
2346.
(11) General Procedure. To a mixture of the glycal (0.2 mmol) and
arylboronic acid (0.4 mmol) in 1 mL of acetonitrile was added Pd(OAc)2
(0.02 mmol). The resulting suspension was stirred at room temperature for
24 h. After this time, the mixture was diluted with 10 mL of CH2Cl2 and
filtered through a pad of silica gel. The filtrate was concentrated and
subjected to silica gel column chromatography using 80% hexanes/20%
ethyl acetate as eluant. The reaction with phenylboronic acid was scaled
up to a 5 g (1) scale with similar yield of the C-phenylglycoside product.
2014
Org. Lett., Vol. 3, No. 13, 2001

less than 75 ppm are characteristic of the trans relationship
between substituents at the C-1 and C-5 positions (R-anomer)
in unsaturated C-glycopyranosyl compounds.2
We also applied this methodology to a glycal derivative
with the opposite stereochemistry at the C-3 position
(Scheme 4). The reaction of phenylboronic acid with
basic conditions and higher temperature, the reductive
elimination to give biphenyl and Pd(0) predominated. We
also tried conditions reported by Uemura and Cho, who
showed that the Heck reaction of aliphatic alkenes with
boronic acid derivatives occurred in the presence of catalytic
Pd(OAc)2 and sodium acetate in acetic acid.13
Surprisingly, under these conditions with the galactal
derivative 7 only the product 8 was obtained in a yield of
15% along with recovered starting material. It seems that
under the mild transmetalation conditions employed, anti
elimination to give the C-Ferrier products is preferred over
the Heck-type â-hydride elimination. It may be that the
â-hydride elimination is reversible under these conditions.14
To conclude, we have disclosed preliminary results on a
simple and convenient method for the stereoselective prepa-
ration of C-arylglycosides using arylboronic acids and
Pd(OAc)2 as catalyst. With the wide variety of boronic acid
derivatives available and their stability toward moisture and
air, this method could have many useful applications.
Scheme 4. Palladium(II) Acetate Catalyzed C-Glycosidation
of Di-O-acetyl-L-rhamnal 13 with Phenylboronic Acids
L-rhamnal diacetate furnished a single product in 52% yield
whose spectral data is consistent with 14. We assigned the
product 14 as having a 1,5-trans stereochemistry on the basis
of the reaction mechanism and the 13C NMR data.
Acknowledgment. We wish to thank the Natural Sciences
and Engineering Research Council of Canada for providing
a fellowship to J.R.
Mechanistically, it is possible that the intermediates that
are generated under these reaction conditions could undergo
a Heck-type â-hydride elimination to give the corresponding
enol acetates. In fact, Czernecki and Daves, who used
different conditions to generate the σ-aryl-Pd complexes,
observed the Heck-type products.4 Czernecki’s method
involved high temperature, whereas Daves’ involved basic
conditions. When we raised the temperature of our reaction,
we did not observe any enol acetate, only unreacted starting
material and a low yield of the carbon-Ferrier type products.
Similar results were obtained under basic conditions using
aqueous KOH in the reaction mixture. In both cases, under
Supporting Information Available: Spectroscopic data
for compounds 2-6, 8-12, and 14. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL010070Q
(12) Brakta, M.; Farr, R. N.; Chaguir, B.; Massiot, G.; Lavaud, C.;
Anderson, W. R., Jr.; Sinou, D.; Daves, G. D., Jr. J. Org. Chem. 1993, 58,
2992.
(13) Cho, C. S.; Uemura, S. J. Organomet. Chem. 1994, 465, 85.
(14) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
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