Stereodirected synthesis of aryl α-C-glycosides from 2-O-arylsilyl-glucopyranosides

Article abstract of DOI:10.1021/ol035529q

(Matrix presented) An efficient procedure for the stereoselective synthesis of aryl α-C-glycosides is presented. The key step of the method is the intramolecular delivery of the aryl group from a 2-O-aryldialkylsilyl substituent to the anomeric carbon by

Full text of DOI:10.1021/ol035529q

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3763-3766
Stereodirected Synthesis of Aryl
-C-Glycosides from
2-O-Arylsilyl-glucopyranosides
r
Cyril Rousseau and Olivier R. Martin*
Institut de Chimie Organique et Analytique (ICOA), Faculte´ des Sciences et CNRS,
BP 6759, 45067 Orle´ans Cedex 2, France
oliVier.martin@uniV-orleans.fr
Received August 13, 2003
ABSTRACT
An efficient procedure for the stereoselective synthesis of aryl
r-C-glycosides is presented. The key step of the method is the intramolecular
delivery of the aryl group from a 2-O-aryldialkylsilyl substituent to the anomeric carbon by an electrophilic ipso-desilylation; this process
leads exclusively to the product having the 1,2-cis configuration.
The C-aryl glycosidic linkage is found in a variety of natural
products, many of which exhibit useful biological activities
(e.g., C-glycosyl flavonoids, antibiotics of the gilvocarcin
family, the pluramycins, etc).1-3 In most of these structures,
in particular those carrying a common hexopyranoid unit,
the pseudoglycosidic linkage is in the thermodynamically
more favorable â-configuration: for example, with two
exceptions,4,5 all of the numerous C-glycosyl flavonoids that
have been isolated have a â-C-glycosidic linkage.5 Also, the
synthetic procedures developed for the C-arylation of
activated hexopyranose derivatives,6-8 by Friedel-Crafts-
type processes or by reactions with arylmetals, have generally
led predominantly or exclusively to â-C-glycosylated aro-
matic compounds. In fact, procedures yielding only the
R-epimers are very rare:9 in these methods, the stereoselec-
tivity depends strongly on the nature of the aglycone and on
the conditions of the reaction, and the selectivity is not easily
rationalized, which makes them unpredictable. One notable
exception is the intramolecular 1,2-cis-C-glycosylation of
2-O-benzylated glycosides, a method originally developed
in our laboratory in the furanose series10 and extended to a
glucopyranose derivative.11
To generalize the intramolecular C-arylation procedure and
make it a reliable synthesis of R-C-aryl glucopyranosides,
we have investigated a wide variety of tethers between O-2
and an aromatic group in order to achieve an intramolecular
delivery of the aromatic aglycone (“IAD”-type process)12
(1) Suzuki, K.; Matsumoto, T. In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products; Lukacs, G., Ed.;
Springer-Verlag, Berlin, 1993; Vol. 2, pp 352-403.
(2) Franz, G.; Gru¨n, M. Planta Med. 1983, 47, 131-140.
(3) Hacksell, U.; Davies, G. D., Jr. Prog. Med. Chem. 1985, 22, 1-65.
(4) Epiorientin: Bhatia, V. K.; Seshadri, T. R. Phytochemistry 1967, 6,
1033-1034. Parkinsonin B: Bhatia, V. K.; Gupta, S. R.; Seshadri, T. R.
Tetrahedon 1966, 22, 1147-1152. However, the structure of these
compounds appears to be erroneous; see: Besson, E.; Chopin, J.; Gunase-
garan, R.; Nair, A. G. R. Phytochemistry 1980, 19, 2787-2788. See also:
Kumazawa, T.; Kimura, T.; Matsuba, S.; Sato, S.; Onodera, J. Carbohydr.
Res. 2001, 334, 183-193.
(5) Wagner, H. Fortschr. Chem. Organ. Naturst. 1974, 31, 153-216.
(6) Jaramillo, C.; Knapp S. Synthesis 1993, 1-20.
(7) Du, Y.; Linhardt, R. J. Tetrahedron 1998, 54, 9913-9959.
(8) (a) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca
Raton, 1995. (b) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Pergamon: Oxford, 1995.
(9) See the following for selected examples. Pyridyl thioglycosides with
dimethoxybenzene: Stewart, A. O.; Williams, R. M. J. Am. Chem. Soc.
1985, 107, 4289-4296. Trichloroacetimidates with furans: Schmidt, R.
R.; Effenberger, G. Liebigs Ann. Chem. 1987, 825-831. Trifluoroacetates
with bis(TMS)resorcinol: Cai, M. S.; Qiu, D.-X. Carbohydr. Res. 1989,
191, 125-129. See ref 6 for the R/â ratio in several C-arylation processes.
(10) Martin, O. R.; Hendricks, C. A. V.; Deshpande, P. P.; Cutler, A.
B.; Kane, S. A.; Rao, S. P. Carbohydr. Res. 1990, 196, 41-58.
(11) Verlhac, P.; Leteux, C.; Toupet, L.; Verrie`res, A. Carbohydr. Res.
1996, 291, 11-20.
10.1021/ol035529q CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/06/2003

(Figure 1). We wish to report here the most significant results
of this investigation.
aromatic aglycone by way of an ipso electrophilic substitution
process. We have already reported a series of C-glycosyla-
tions in the furanose series that are believed to occur by way
of this process,15 and an example of phenyl group migration
from silicon to carbon by this type of reaction has recently
been described.16 This method is expected to provide
stereocontrol of the aglycone transfer since the intramolecular
substitution must occur by way of a five-membered cyclic
intermediate (Figure 2) and should thus lead to a 1,2-cis-C-
aryl glycoside (an R-C-glycoside in the gluco series).
Figure 1. Intramolecular aromatic aglycone delivery.
Prompted by successful internal reactions of 4-pentenyl
â-glucopyranosides carrying various benzyl groups at O-2,13
we have performed our investigations using a 4-pentenyl
group as a convenient latent activator of the anomeric
position.14
In our first plan, we envisaged the utilization of a silaketal
linker between the glycoside O-2 position and a phenolic
function of the aromatic aglycone. The aryloxysilyl group
might in fact react either by transferring the O-aryl group to
C-1 (intramolecular O-glycoside formation12) or by undergo-
ing the alkylation of the electron-rich aglycone. Remarkably,
the silaketal 1 led, upon reaction with iodonium dicollidine
perchlorate (IDCP) followed by complete desilyation of the
resulting products, to C-aryl glycosides only. These products
were, however, obtained as a mixture of R- and â-epimers
and of regioisomers, with predominance of the â-anomers
(Scheme 1).
Figure 2. σ-Complex of the ipso substitution.
Preliminary studies with the 2-O-(p-tolyldimethylsilyl)
derivative of 3, prepared by silylation of 3 with commercial
pTolSiMe2Cl, were unsuccessful. As silylating reagents
carrying an activated aromatic group were not commercially
available, we elected to create the aryldialkylsilyl substituent
directly onto the glucopyranoside scaffold.
For this purpose, the required precursor, namely, the
partially protected 4-pentenyl â-D-glucopyranoside 3, was
prepared in three steps and in an overall yield of 59% from
tetra-O-acetyl-R-D-glucopyranosyl bromide as described
previously.13 Compound 3 was treated with butyllithium at
-78 °C and then with an excess of the corresponding
dichlorodialkylsilane (alkyl ) methyl or ethyl) in THF
(Scheme 2); the product thus formed was freed from excess
Scheme 1a
Scheme 2a
a Conditions: (a) IDCP (2 equiv), CH2Cl2; (b) Bu4NF, THF; (c)
Ac2O, pyridine. Yield ) 39% (three steps). Ratio of 2a:2b:2c )
2:2:1.
In view of these results, we sought to shorten the tether
and decided to use an arylsilyl group as the source of the
(12) O-Glycoside formation by IAD: Jung, K.-H.; Mu¨ller, M.; Schmidt,
R. R. Chem. ReV. 2000, 100, 4423-4442. C-Glycoside formation by IAD
via silicon tether: Bols, M.; Skrydstrup, T. Chem. ReV. 1995, 95, 1253-
1277.
a Conditions: (a) (i) BuLi (1.1 equiv), THF, -78 °C; (ii) R2SiCl2
(b) ArLi, THF, -78 f 0 °C.
(13) Rousseau, C.; Martin, O. R. Tetrahedron: Asymmetry 2000, 11,
409-412.
(14) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottoson, H.; Merritt, J.
R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927-942.
silylating agent and solvent by evaporation in vacuo. The
resulting crude 2-O-chlorodialkylsilyl derivatives 4 were then
3764
Org. Lett., Vol. 5, No. 20, 2003

reacted with the aryllithium derived from ortho- or para-
bromoanisole. The 2-O-arylsilyl derivatives of 3, compounds
5 (ortho series) and 6 (para series) were sufficiently stable
to be purified by flash chromatography on silica gel and
could be isolated in yields ranging from 50 to 65%.
Treatment of compounds 5 and 6 with IDCP in dichlo-
romethane followed by complete desilylation17 using TBAF
in THF gave the internal C-arylation products 7 and 8 in
good to excellent yields18 (Scheme 3). As shown by NMR
The complete 1,2-cis stereoselectivity of the reaction and
its complete regioselectivity with respect to the aglycone
substitution is strong evidence that the reaction occurs by
way of an internal substitution of the Ar-Si bond by the
electrophilic anomeric carbon generated upon activation of
the pentenyl group with IDCP (intermediate shown in Figure
2). Alternate mechanisms involving preliminary cleavage of
the aromatic group or arylsilyl group and intermolecular
arylation are highly unlikely.
To facilitate the structural analysis of the final products,
compounds 7 and 8 were acetylated to afford 9 and 10,
respectively; 7 and 8 were also debenzylated by hydro-
genolysis (H2/Pd) and acetylated to give 11 and 12 (Figure
3).
Scheme 3a
Figure 3. Acetylated derivatives.
a Conditions. (a) (i) IDCP (2 equiv), CH2Cl2; (ii) Bu4NF, THF.
According to 1H NMR data,19 it is evident that the
pyranose ring in the ortho-disubstituted C-aryl glycoside
derivatives 9 and 11 adopts a conformation remote from the
4C1 conformation characteristic of the â-anomer. The mag-
data (see below), the products are obtained exclusively as
the R-anomer. Overall, the yields of the reactions were higher
and the operations somewhat more convenient using the
diethylsilyl linker compared to the dimethylsilyl linker.
3
nitude of the JH,H coupling constants indicates that these
compounds exist in a flexible conformation or as an
equilibrium between the 1C4 and 4C1 chair forms. In the para-
disubstituted derivatives, the ring adopts a conformation
closer to the 4C1 conformation with a nearly axial aryl group,
in particular in the peracetate 12. Studies concerning the
conformation of R-C-aryl glycosides have been very lim-
(15) Martin, O. R.; Rao, S. P.; Kurz., K. G.; El-Shenawy, H. A. J. Am.
Chem. Soc. 1988, 110, 8698-8700.
(16) Tomooka, K.; Nakazaki, A.; Nakai, T. J. Am. Chem. Soc. 2000,
122, 408-409.
(17) The nature of the silylated species formed in the reaction and isolated
before treatment with TBAF could not be identified.
(18) Typical Experimental Procedure: Formation of the Arylsilyl
Group. Compound 3 (220 mg, 0.38 mmol) was stirred in dry THF (3 mL)
at -78 °C under argon. Butyllithium (312 µL, 1.36 M in hexane, 0.42 mmol)
was added, and the mixture was stirred for 30 min at -78 °C before the
addition of freshly distilled dichlorodiethylsilane (288 µL, 1.93 mmol).
Stirring was continued at room temperature over a period of 2 h. The solvent
and excess silane were then evaporated in vacuo. Butyllithium (709 µL,
1.36 M in hexane, 0.96 mmol) was added to a solution of para-bromoanisole
(216 mg, 3 equiv) in dry THF (3 mL) at -78 °C under argon, and the
mixture was stirred for 45 min at -78 °C. The crude chlorosilylated sugar
derivative was dissolved in dry THF (1 mL), and this solution was added
to the solution of aryllithium. The mixture was stirred for 10 min at -78
°C and then warmed to room temperature. When the reaction was complete
(TLC), the solvent was evaporated; ethyl acetate (20 mL) was added, and
the organic phase was washed with saturated aqueous NaHCO3. The organic
phase was dried over MgSO4, and the solvent was removed in vacuo. Flash
chromatography (silica gel, eluent petroleum ether/AcOEt 9:1) provided
the desired product 6b (175 mg, 64%). C-Arylation. A solution of 2-O-
arylsilyl sugar derivative 6b (118 mg, 0.17 mmol) in dry CH2Cl2 (15 mL)
was stirred in the presence of 4 Å molecular sieves. After 1 h, IDCP
(iodonium dicollidine perchlorate) (154 mg, 2 equiv) was added and the
mixture was stirred in the dark at room temperature for 4 h. The solids
were removed by filtration, and the organic phase was successively washed
with 10% aqueous Na2S2O4, 1 N HCl, and saturated aqueous NaHCO3.
The organic layer was dried over MgSO4 and the solvent removed in vacuo.
Bu4NF (90 mg, 2 equiv) was added to a solution of the residue in THF (15
mL) at 0 °C. After 2 h, the solvent was removed in vacuo. Flash
chromatography (silica gel, eluent petroleum ether/AcOEt 7:1) provided
the desired product 8 (69 mg, 74%).
(19) Compound 9: selected 1H NMR data (250 MHz, CDCl3) δ 3.76-
3.88 (m, 6H, H-4,6a,6b, OCH3), 3.92 (d, 1H, J ) 3.1, 4.7 Hz, H-3), 4.20
(m, 1H, J ) 4.7, 4.7, 6.6 Hz, H-5), 5.42 (t, 1H, J ) 2.8 Hz, H-2), 5.52 (d,
1H, J1,2 ) 2.0 Hz, H-1). Compound 10: selected 1H NMR data (250 MHz,
CDCl3) δ 3.65-3.85 (m, 7H, H-4,5,6a,6b, OCH3), 4.05 (t, 1H, J ) 6.7 Hz,
H-3), 5.20 (d, 1H, J1,2 ) 4.7 Hz, H-1), 5.26 (dd, 1H, J ) 4.7, 6.9 Hz, H-2).
Compound 11: syrup; [R]D23+24.7 (c ) 1.0, CHCl3); 1H NMR (250 MHz,
C6D6; ref δ ) 7.16) δ 1.44, 1.62, 1.63, 1.68 (4s, 4 × 3H, 4 COCH3), 3.30
(s, 3H, OCH3), 4.34 (dd, 1H, J5,6a ) 4.0, J6a,6b ) 11.6 Hz, H-6a), 4.47 (q,
1H, J ≈ 4 Hz, H-5), 4.61 (dd, 1H, J5,6b ) 6.1 Hz, H-6b), 5.47 (t, 1H, J ≈
5.6 Hz, H-4), 5.76 (t, 1H, J ≈ 4.7 Hz, H-3), 5.89 (t, 1H, J ≈ 3.5 Hz, H-2),
5.94 (d, 1H, J1 2 ) 2.9 Hz, H-1), 6.56 (d, 1H, J ) 8.3 Hz, H-3′), 7.0 and
7.17 (2t, 2H, J ) 7-8 Hz, H-4′,5′), 7.95 (d, 1H, J ) 7.6 Hz, H-6′); 13C
NMR (62.9 MHz, C6D6) δ 20.04, 20.24, 20.30 (COCH3), 55.1 (OCH3),
62.06 (C-6), 67.78, 67.95, 69.66, 71.10, 73.10 (C-1-5), 110.48, 120.36,
125.7, 129.10 (CHAr), ∼128 (CAr), 156.62 (CAr-OMe), 168.8-170 (Cd
23
1
O). Compound 12: mp 104-105 °C; [R]D +86.5 (c ) 1.1, CHCl3); H
NMR (250 MHz, C6D6; ref δ ) 7.16) δ 1.53, 1.63, 1.69 and 1.74 (4s, 4 ×
3H, 4 COCH3), 3.27 (s, 3H, OCH3), 3.85 (ddd, 1H, J4,5 ) 8.6, J5,6a ) 2.9,
J5,6b ) 5.1 Hz, H-5), 4.08 (dd, 1H, J6a,6b ) 12.2 Hz, H-6a), 4.31 (dd, 1H,
H-6b), 5.37 (d, 1H, J1,2 ) 6 Hz, H-1), 5.39 (t, 1H, J ) 8.8 Hz, H-4), 5.55
(dd, 1H, J1,2 ) 5.3, J2,3 ) 8.4 Hz, H-2), 5.97 (t, 1H, J ) 8.2 Hz, H-3), 6.71
(d, 2H, J ) 8.8 Hz, H-2′,6′), 7.51 (d, 2H, H-3′,5′); 13C NMR (62.9 MHz,
C6D6) δ 20.14, 20.23, 20.29, 20.36 (4 × COCH3), 54.79 (OCH3), 62.09
(C-6), 69.22 (C-4), 70.68 (C-5), 71.17 (C-3), 71.57 (C-2), 73.29 (C-1),
114.27 (CHAr), 128.19 (CqAr), 129.93 (CHAr), 159.95 (CAr-OMe), 169.09,
169.29, 169.82, 170.03 (CdO).
Org. Lett., Vol. 5, No. 20, 2003
3765

ited: simple R-C-glucopyranosyl benzene derivatives were
also the first example of a “traceless” intramolecular delivery
of an aromatic aglycone to form a C-aryl glycoside. The
application of this methodology to more complex aromatic
aglycones and its extension to mannopyranoside substrates,
with the goal of achieving exclusive â-selectivity, are under
investigation in our laboratory and will be reported in due
course.
shown to be characterized by a solvent-dependent confor-
4
mational equilibrium in which the C1 form was predomi-
nant.20
In conclusion, the intramolecular reactions of 4-pentenyl
2-O-arylsilyl glucopyranosides promoted by a mild Lewis
acid provided a convenient and completely stereoselective
approach to R-C-aryl glucosides. This process provides the
first reliable and generalizable method of synthesis of the
challenging R-epimers of the C-aryl glycoside family. It is
Supporting Information Available: Spectral data for
compounds 2c, 5b, 6b, and 9-12. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) Bellosta, V.; Chassagnard, C.; Czernecki, S. Carbohydr. Res. 1991,
219, 1-7.
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