Stereoselective C-glycoside formation by a rhodium(I)-catalyzed 1,4-addition of arylboronic acids to acetylated enones derived from glycals

Article abstract of DOI:10.1021/ol016245d

(Equation presented) A new method for the formation of C-glycosides has been developed employing a cationic rhodium(l)-catalyzed 1,4-addition of arylboronic acids to enones derived from glycals. The reaction is stereoselective for the α-anomer and is highly dependent on the nature of the rhodium catalyst.

Full text of DOI:10.1021/ol016245d

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2571-2573
Stereoselective C-Glycoside Formation
by a Rhodium(I)-Catalyzed 1,4-Addition
of Arylboronic Acids to Acetylated
Enones Derived from Glycals
Jailall Ramnauth, Odile Poulin, Svetoslav S. Bratovanov, Suman Rakhit, and
Shawn P. Maddaford*
MCR Research Inc., 4700 Keele St., Chemistry and Computer Sciences Bldg.,
York UniVersity, Toronto, Ontario, Canada M3J 1P3
shawnm@mcr.chem.yorku.ca
Received June 7, 2001
ABSTRACT
A new method for the formation of C-glycosides has been developed employing a cationic rhodium(I)-catalyzed 1,4-addition of arylboronic
acids to enones derived from glycals. The reaction is stereoselective for the r-anomer and is highly dependent on the nature of the rhodium
catalyst.
C-Glycosides and C-nucleosides are interesting carbohydrate
congeners of O-glycosides and N-nucleosides that are
resistant to enzymatic cleavage.1 Several C-nucleosides and
C-glycosides possess potent antibacterial, antiviral, and
antitumor activity.2 For example, several halogenated benz-
imidazole C-nucleosides are known to be active against
human cytomegalovirus.3
While the importance of C-glycosides is evident from their
range of biological activities, methods for their preparation
are quite limited. Typically they have been synthesized by
the addition of an appropriate organometallic reagent to a
carbohydrate lactone to form a hemiketal that could be
subsequently reduced to the cyclic ether.4 Alternatively they
have been made by the addition of organometallics such as
Grignards, stannanes, and organomecurials to 1-halo sugars,
alkyl and acylsilanes to glucals, or 1,2-anhydro-sugars and
electron-rich aromatics to glycosyl donors.4 Cross-coupling
reactions of a suitable 1-vinylstannane or boronic acid have
also been reported.4 An interesting example of a palladium-
catalyzed C-glycosidation of tert-butylphenyl-R-O-∆2-gly-
copyranoside with various arylmagnesium bromides has been
reported by Sinou and co-workers.5 An approach that we
were particularly interested in investigating involved the
palladium(II)-mediated arylation of acetylated enones derived
from glycals.6 This reaction proceeded by the addition of
the σ-arylpalladium complex to the enone double bond but
was limited to simple phenyl substitution. We therefore
sought a more general methodology allowing for the addition
of various substituted aryl groups. To this end, we felt that
the rhodium(I)-catalyzed addition of arylboronic acids to
acyclic and cyclic enones reported by Miyaura7 would
provide a suitable means for introducing a C1-aryl group
into the pyranose ring.
(1) (a) Jarmillo, C.; Knapp, S. Synthesis 1994, 1. (b) Postema, M. H. D.
Tetrahedron 1992, 48, 8545.
(5) Moineau, C.; Bolitt, V.; Sinou, D. J. Chem. Soc., Chem. Commun.
1995, 1103.
(6) Benhaddou, R.; Czernecki, S.; Ville, G. J. Org. Chem. 1992, 57,
4612.
(7) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998,
120, 5579. (c) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem.
2000, 65, 5951.
(2) Hacksell, C. V.; Daves, G. D., Jr. J. Med. Chem. 1985, 22, 1.
(3) (a) Townsend, L. B.; Devivar, R. V.; Turk, S. R.; Nassiri, M. R.;
Drach, J. C. J. Med. Chem. 1995, 38, 4098. (b) Gudmunsson, K. S.; Drach,
J. C.; Townsend. L. B. J. Org. Chem. 1997, 62, 3453.
(4) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913
and references therein.
10.1021/ol016245d CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/07/2001

The enone 1 was synthesized by direct oxidation of tri-
O-acetyl-D-glucal with [hydroxy(tosyloxy)-iodo]benzene.8
Using the conditions reported by Miyaura, we attempted a
rhodium-catalyzed 1,4-addition of phenylboronic acid. Un-
fortunately, reaction of 1 with Rh(acac)(C2H4)2 in the
presence of phosphine ligands such as R- and S-BINAP,
dppf, and others did not lead to 1,4-addition products. A
series of other rhodium(I) catalysts were tried, including Rh-
(PPh3)3Cl, Rh(bicyclo[2.2.1]heptadiene-dppb BF4, and Rh2-
Cl2(bicyclo[2.2.1]heptadiene)2, but were unsuccessful. Also,
conventional Lewis acid catalysts such as BF3OEt2, SnCl4,
and TMSOTf failed to give any 1,4-addition product.
However, this problem could be overcome by the use of the
cationic rhodium complex Rh(cod)2BF4. To our delight, when
enone 1 was heated with phenylboronic acid in the presence
of Rh(cod)2 BF4 in dioxane/water at 100 °C, a 76% yield of
the 1,4-addition product 2 was obtained (Scheme 1).
Table 1. Rhodium(I)-Catalyzed 1,4-Addition of Boronic Acid
Derivatives to Enone 1
Scheme 1. Rhodium(I)-Catalyzed 1,4-Addition of
Phenylboronic Acid to Enone 1
1
The H and 13C NMR revealed the presence of a single
anomer that was assigned the R-configuration at the anomeric
a Isolated yields after chromatography.
1
center. This assignment was based on the H NMR data of
2 that was reported in the literature.6 It was shown that 2
4
similar arguments for the phenyl derivative 2, the configu-
ration at the anomeric center in each case is R.
adopts a C1(D) conformation bearing two bulky groups in
equatorial positions and the phenyl group in an axial position
at the anomeric center. On the basis of this conformation,
the coupling constant for the anomeric proton (5.52 ppm) is
small (J1,2′ ) 5.2 Hz) as the result of an axial-equatorial
coupling, consistent with an axial aryl group. In addition,
the 13C NMR revealed an upfield shift of the C-5 carbon
(<75 ppm) that is indicative of a 1,5-trans relationship of
substituents.9 The lack of epimerization at C-4 and the axial-
axial relationship of H4 and H5 in compound 2 was
confirmed by the doublet at 5.28 ppm with a large coupling
constant (J4,5 ) 10.1 Hz).
The 1,4-addition reaction could be applied to other enones
that are derived from glycals. The acetylated enones 7 and
8 were synthesized by the oxidation of 2,4,6-tri-O-acetyl-
D-galactal and 3,6-di-O-acetyl-4-deoxy-D-glucal,11 respec-
tively, with [hydroxy(tosyloxy)-iodo]benzene. Addition of
phenylboronic acid using the general procedure gave the 1,4-
addition products 9 and 10 in yields of 70% and 75%,
respectively (Scheme 2).
A variety of boronic acid derivatives can be used, including
electron-donating, vinyl, electron-withdrawing, and sterically
conjested groups, with isolated yields ranging from modest
to good (Table 1).10
In all cases, the 1H and 13C NMR indicated that only one
anomer is present (see Supporting Information). Based on
Scheme 2. Rhodium(I)-Catalyzed 1,4-Addition of
Phenylboronic Acid to Enones 7 and 8
(8) Kirschning, A.; Drager, G.; Harders, J. Synlett 1993, 289.
(9) 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.
(10) General Procedure. A mixture of the enone (0.2 mmol), boronic
acid (0.4 mmol), Rh(I)(cod)2BF4 (0.01 mmol), 0.05 mL of H2O, and 1.0
mL of dioxane was heated at reflux for 4 h. After this time, the reaction
mixture was diluted with ethyl acetate (10 mL) and filterd through a pad
of silica gel. The filtrate was concentrated and subjected to silica gel flash
column chromatography using 80% hexanes/20% ethyl actetate as eluant.
In both cases, the 1H and 13C NMR indicated that a single
anomer is present. The stereochemistry of 9 was assigned
(11) Greico, P. A.; Speake, J. D. Tetrahedron Lett. 1998, 39, 1275.
Org. Lett., Vol. 3, No. 16, 2001
2572

the R configuration at the anomeric center on the basis of
the 1H NMR data reported in the literature.6 It was reported
1
that 9 adopts a C4(D) conformation, in which one bulky
group out of the three is in the axial position. This results in
a J1,2′ larger than that of the corresponding glucal derivative
2 suggesting an axial position for H1. The 13C NMR spectra
for compounds 9 and 10 indicated an upfield shift of the
C-5 carbon (<75 ppm) that is indicative of a 1,5-trans
1
relationship of substituents. Also, the H NMR data for 10
is consistent with the R-anomer since the J1,2′ value is similar
to that of 2. If it were the â-anomer, the substituents would
be in equatorial positions, placing the anomeric proton in
an axial position and thus resulting in a larger coupling
constant for J1,2′. It is interesting that the reaction is
stereoselective for the R-anomer. This had been observed
for the addition of organopalladium reagents to carbohydrate
enones.6
Similar to the catalytic cycle proposed by Miyaura, the
mechanism for the rhodium(I)-catalyzed 1,4-addition of
arylboronic acid derivatives to the carbohydrate enones is
shown in Figure 1.7 Initial transmetalation of the aryl group
from boron to rhodium occurs, which is probably facilitated
by fluoride anion.12 The organometallic species then adds
stereoselectively to the R-face of the enone double bond with
subsequent hydrolysis of the Rh-O bond. Under anhydrous
conditions, a low yield (<5%) of the 1,4-addition product 2
was obtained, suggesting a need for H2O. Presumably, water
serves to protonate the Rh-O bond. It is noteworthy that
the use of rhodium(I)(cod)2OTf as a catalyst did not give
any product. However, when a catalytic amount of KOH is
added to the reaction mixture (1:1 catalyst/KOH), the reaction
is complete after 15 min of heating at 100 °C. The role of
hydroxide could be to facilitate the transmetalation,13 or it
could react with the rhodium triflate precatalyst to give
HORh(cod)2 or a combination of both. Fu¨rstner and Krause
observed a similar effect of the base on the rhodium-
catalyzed addition of arylboronic acids to aldehydes.14 Using
our new system, the molar ratio of the catalyst can be reduced
to 1% with a similar yield of the 1,4-addition product 2.
Unlike the 1,4-addition to cyclic and acyclic enones, the
present reaction is inhibited by the addition of phosphine
ligands. It seems that the pyranose oxygen may reduce the
Figure 1. Proposed catalytic cycle.
reactivity of the double bond and the addition of phosphine
ligands might reduce the cationic nature of the rhodium
catalyst. Oi has reported a similar inhibition with the addition
of phosphine ligand for the cationic rhodium-catalyzed
addition of trimethylstannane to benzaldehydes.15
In summary, we have reported the first rhodium-catalyzed
1,4-addition reaction for the stereoselective synthesis of
C-glycosides. With the availability of a number of boronic
acid derivatives, this method could have many useful
applications.
Acknowledgment. We wish to thank the Natural Sciences
and Engineering Research Council of Canada for providing
a fellowship to J.R.
Supporting Information Available: Spectroscopic data
for compounds 2-6, 9, and 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL016245D
(12) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095.
(13) Suzuki, A. Acc. Chem. Res. 1982, 15, 178.
(14) Fu¨rstner, A.; Krause, H. AdV. Synth. Catal. 2001, 4, 343.
(15) Oi, S.; Moro, M.; Inoue, Y. J. Chem. Soc., Chem. Commun. 1997,
1621.
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