A highly selective route to beta-C-glycosides via nonselective samarium iodide induced coupling reactions.

Article abstract of DOI:10.1039/b301805a

Stereoselective preparation of beta-C-glycosides has been developed from acetylated glycopyranosyl 2-pyridyl sulfones, involving a samarium-Barbier coupling procedureoxidation-isomerization sequence.

Full text of DOI:10.1039/b301805a

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A highly selective route to ꢀ-C-glycosides via nonselective
samarium iodide induced coupling reactions
Sara Palmier, Boris Vauzeilles and Jean-Marie Beau*
Université Paris-Sud, Laboratoire de Synthèse de Biomolécules associé au CNRS,
Institut de Chimie Moléculaire et des Matériaux, F-91405 Orsay Cedex, France.
E-mail: jmbeau@icmo.u-psud.fr; Fax: (ϩ33) 1 69 85 37 15
Received 14th February 2003, Accepted 18th February 2003
First published as an Advance Article on the web 28th February 2003
Stereoselective preparation of ꢀ-C-glycosides has been
developed from acetylated glycopyranosyl 2-pyridyl sul-
fones, involving a samarium-Barbier coupling procedure–
oxidation–isomerization sequence.
A wide range of methodologies has been developed over the
last two decades for the synthesis of C-glycosyl compounds,
carbohydrate analogs in which a carbon atom replaces the
anomeric oxygen or nitrogen atoms of natural glycosides.1,2 In
this area, our group has focused on the “umpolung” of the
anomeric center with results showing that the reductive samari-
ation of anomeric 2-pyridyl sulfones in the presence of carb-
onyl compounds (samarium-Barbier procedure) provides a
versatile approach to C-glycosyl compounds. 1,2-cis C-Glyco-
sides (α-Glc, β-Man, ؒ ؒ ؒ ) are only obtained through a
samarium() iodide induced intramolecular 5-exo radical
cyclization on a temporarily tethered “aglycon”,3 whereas 1,2-
trans C-glycosides (β-Glc, β-Gal, β-Fuc, α-Man, ؒ ؒ ؒ ) are the
Scheme 1 Reagents and conditions: i, AcCl, 25 ЊC, 16 h, 76%; ii, 2-
exclusive products, readily available via intermolecular addition
of a glycosyl-samarium species onto a ketone or an aldehyde.4
This highly stereoselective step can be followed by a Barton–
McCombie type deoxygenation of the resulting alcohols if a
methylene linked C-glycoside is targeted.
PySH, K2CO3, toluene–acetone, 50 ЊC, 3 h, 71%; iii, MCPBA,
NaHCO3, CH2Cl2, 25 ЊC, 2.5 h, 79%.
Interestingly, intermolecular coupling reactions performed
with glycopyranosides bearing an acetamido group at C-2
(GlcNAc and GalNAc derivatives) provided a major exception
to these observations, since the α-linked C-glycosides are
obtained as major products with moderate to good selectivities,
results rationalized as a chelation-controlled C-glycosylation.5
This procedure thus left unsolved the important access to
C-glycosides mimicking the biologically ubiquitous β-GlcNAc
motif. Another more expectable exception appeared in the
2-deoxy series, where the lack of a directing group at the
2-position led to a complete loss of selectivity in the coupling
step.4 We now report a solution from simple precursors which
relies on the above intermolecular samarium-Barbier reaction
followed by an oxidation–isomerization sequence. The pro-
cedure also capitalizes on the observation made earlier that
these anionic conditions remarkably tolerate the presence of
standard O-acetyl protecting groups4 as well as acidic protons
in the acetamido groups.5
Scheme 2 Reagents and conditions: i, 2-PySH, PTSA, CH2Cl2, reflux,
30 min (54%); ii, MCPBA, NaHCO3, CH2Cl2, 25 ЊC, 2.5 h, 89%
(α–β 4 : 1).
The starting sulfones 4, 5 and 7 were easily prepared in the
following way. Sulfone 4 was obtained in 79% yield via MCPBA
oxidation of 2Ј-pyridylthioglycoside 36 (Scheme 1). Sulfone 5
was prepared similarly† starting from the octaacetyl chito-
biose.7 We also prepared sulfones 7 from tri-O-acetylglucal 6
by a 2-mercaptopyridine addition in the presence of p-toluene-
sulfonic acid (54%),8 followed by oxidation (89%, Scheme 2).
In an initial experiment, treatment of sulfone 4 with samar-
ium diiodide (2.3 equiv.) in the presence of excess cyclo-
hexanecarboxaldehyde at room temperature provided alcohols
8 and 9 which were subjected to PCC oxidation in the presence
of 4 Å molecular sieves (Scheme 3). The two anomeric ketones
Scheme 3 Reagents and conditions i, Cyclohexanecarboxaldehyde,
SmI2, THF, 25 ЊC; ii, PCC, 4 Å MS, CH2Cl2, 25 ЊC, 26% (8), 26% (9);
iii, K2CO3, MeOH, 25 ЊC; iv, Ac2O, Py, 25 ЊC, 70% (α–β < 1 : 20).
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 9 7 – 1 0 9 8
1097

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chloride were then added, and the reaction mixture was diluted with
dichloromethane. The organic layer was washed with water, and the
resulting aqueous phase was extracted again twice with CH2Cl2. The
combined organic layers were dried over sodium sulfate and concen-
trated. The residue was dissolved in CH2Cl2 (3.0 mL) and treated with
PCC (260 mg, 1.2 mmol) in the presence of 4 Å mol sieves (400 mg).
After 3 h of reaction, Et2O was added, and the reaction mixture was
filtered through a silica pad. After concentration, the residue was dis-
solved in MeOH (3.0 mL) and treated with K2CO3 (14 mg, 100 µmol)
overnight. The solvent was then evaporated, pyridine (5.0 ml) and Ac2O
(2.5 ml) were added, and the mixture was stirred for another hour.
Concentration and silica gel chromatography (cyclohexane–EtOAc,
1 : 1), afforded the β ketone 11 (44 mg, 100 µmol): mp 163 ЊC
(dichloromethane–methanol). [α]2D0 ϩ3.5 (c 0.23, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ 5.67 (d, 1H, J = 9.3 Hz, NH), 5.22 (dd, 1H,
J2,3 = 10.0 Hz, J3,4 = 9.4 Hz, H-3), 5.15 (dd, 1H, J4,5 = 9.8 Hz, H-4), 4.26–
4.20 (m, 2H, H-6a, 6b), 4,20 (ddd, 1H, J1,2 = 10.5 Hz, H-2), 3.88 (d, 1H,
H-1), 3.72 (ddd, 1H, J5,6a = 3.3 Hz, J5,6b = 5.6 Hz, H-5), 2.81 (m, 1H,
C–H cyclohexyl), 2.09, 2.04, 2.03 and 1.90 (4s, 12H, 4 COCH3), 1.91–
10 and 11 were easily separated by silica gel chromatography
and obtained in equimolar amounts (26% of 10 and 26% of
11 from 4). At this point we noted that the samarium-induced
C-glycosylation on the acetylated electron acceptor 4 was not
stereoselective, in contrast with the corresponding benzylated
sulfone which selectively provided the α-C-glycosides. Treat-
ment of ketone 10 with catalytic amounts of potassium
carbonate in methanol afforded, following acetylation, the iso-
meric β-ketone 11 (70% yield) with high stereoselectivity (11–10
1
ratio >20 : 1), as evaluated by H-NMR spectroscopy on the
crude mixture.9
This encouraged us to pursue this process without chromato-
graphy of the intermediates using a samarium-Barbier coup-
ling–oxidation–isomerization sequence. Pure ketone 11‡ was
thus furnished from sulfone 4 in a 42% overall yield. Treatment
of disaccharidic sulfone 5 under similar conditions led to a 30%
yield of pure β-C-glycoside 12§ (Fig. 1), whereas an overall yield
of 53% of β-C-glycoside 13§ was obtained starting from 7.
1.07 (m, 10H, 5 CH2). 13C NMR (62.5 MHz, CDCl3): δ 208.8 (C᎐O),
᎐
171.1, 170.6, 170.2, and 169.3 (4 COCH3), 82.2 (C-1), 75.7, 73.5, and
68.3 (C-3, 4, 5), 62.1 (C-6), 51.4 (C-2), 46.5 (C–H cyclohexyl), 29.7,
28.6, 27.9, 25.7, and 25.4 (5 CH2), 23.1, 20.7, 20.7, and 20.6 (COCH3).
ESI-MS: m/z = 464 [M ϩ Na]; HR-MS (ESI) for C21H31NNaO9
[M ϩ Na]: calcd: 464.1897; found: 464.1903.
§ Selected 1H NMR data for 12: (400 MHz, CDCl3–CD3OD 10 : 1):
δ 5.16 (dd, 1H, J2Ј,3Ј = 10.4 Hz, J3Ј,4Ј = 9.4 Hz, H-3Ј), 5.02 (dd, 1H,
J2,3 = 10.2 Hz, J3,4 = 8.9 Hz, H-3), 4.58 (d, 1H, J1Ј,2Ј = 8.4 Hz, H-1Ј),
4.14 (dd, 1H, J1,2 = 10.5 Hz, H-2), 3.82 (dd, 1H, H-2Ј), 3,72 (dd, 1H,
J4,5 = 9.5 Hz, H-4), 3.72 (d, 1H, J1,2 = 10.5 Hz, H-1). Selected 1H
NMR data for 13: (250 MHz, CDCl3): δ 5.04 (ddd, 1H, J2eq,3 = 5.1 Hz,
J2ax,3 = 9.4 Hz, J3,4 = 9.4 Hz, H-3), 4.96 (dd, J4,5 = 9.4 Hz, H-4), 4.01 (dd,
J1,2eq = 2.2 Hz, J1,2ax = 12.0 Hz, H-1), 2.44 (ddd, 1H, J2eq,2ax = 12.9 Hz, H-
2eq), 2.08, 2.04 and 2.02 (3s, 9H, 3 COCH3), 1.60 (ddd, 1H, H-2ax).
Selected 1H NMR data for 15 (atom numbering of a tridecopyrano-
side): (250 MHz, CDCl3): 5.50 (d, 1H, J = 9.0 Hz, NH), 5.17 (dd, 1H,
J9,10 ∼J10,11 = 9.3 Hz, H-10), 5.09 (dd, 1H, J11,12 = 9.3 Hz, H-11), 4.58 (d,
1H, J1,2 = 2.0 Hz, H-1), 4.06 (ddd, 1H, J8,9 = 10.7 Hz, H-9), 3.90 (dd, 1H,
J2,3 = 3.0 Hz, J3,4 = 9.3 Hz, H-3), 3.78 (dd, 1H, H-2), 3.74 (d, 1H, H-8),
3.68 (dd, 1H, J4,5 = 9.6 Hz, H-4).
Fig. 1
To illustrate the utility of this procedure we also performed
the synthesis of a C-disaccharide by coupling sulfone 4 with
aldehyde 144c (1.5 equiv.). After oxidation, epimerization and
reacetylation, the β-linked C-disaccharide 15§, a protected
analog of the GlcNAc-β-(1 6)-Man motif of tri- and tetra-
antennary complex-type N-glycans, was obtained in a 40%
overall yield based on the starting sulfone (Fig. 2).
1 Recent reviews: J.-M. Beau and T. Gallagher, Topics Curr. Chem.,
1997, 187, 1; Y. Du, R. J. Linhardt and I. R. Vlahov, Tetrahedron,
1998, 54, 9913; A. Dondoni and A. Marra, Chem. Rev., 2000, 100,
4395; L. Somsák, Chem. Rev., 2001, 101, 81; L. Liu, M. McKee and
M. H. D. Postema, Curr. Org. Chem., 2001, 5, 1133.
2 Reviews with emphasis on C-oligomers: T. Skrydstrup, B. Vauzeilles
and J.-M. Beau, in Oligosaccharides in Chemistry and Biology –
A Comprehensive Handbook, Vol. 1, eds. B. Ernst, P. Sinaÿ and
G. Hart, Wiley-VCH, Weinheim, 2000, pp. 495–530; J.-M. Beau,
B. Vauzeilles and T. Skrydstrup, in Glycoscience: Chemistry and
Chemical Biology, Vol. 3, eds. B. Fraser-Reid, K. Tatsuta and
J. Thiem, Springer Verlag, Heidelberg, 2001; see also A. Dondoni,
A. Marra, M. Mizuno and P. P. Giovannini, J. Org. Chem., 2002, 67,
4186 and references cited.
Fig. 2
3 D. Mazéas, T. Skrydstrup, O. Doumeix and J.-M. Beau,
Angew. Chem., Int. Ed. Engl., 1994, 33, 1383; T. Skrydstrup,
D. Mazéas, M. Elmouchir, G. Doisneau, C. Riche, A. Chiaroni and
J.-M. Beau, Chem. Eur. J., 1997, 3, 134.
In summary we have disclosed a method for the selective
synthesis of 1Ј-carbonylalkyl β-C-glycosides10 from simple
derivatives of 2-deoxy or 2-acetamido-2-deoxy glycopyrano-
sides that complement previous stereochemical results in this
area. The carbonyl group may obviously be further exploited
for derivatization and we believe that this procedure could be
extended to other biologically relevant carbohydrates.
We are grateful to Patricia Bertho for technical assist-
ance. This work was supported by a grant from the European
Communities (Training and Mobility of Researchers Program,
contract no. ERBFMRX-CT98-0243).
4 (a) D. Mazéas, T. Skrydstrup and J.-M. Beau, Angew. Chem., Int. Ed.
Engl., 1995, 34, 909; (b) T. Skrydstrup, O. Jarreton, D. Mazéas,
D. Urban and J.-M. Beau, Chem. Eur. J., 1998, 4, 655; (c) N. Miquel,
G. Doisneau and J.-M. Beau, Angew. Chem., Int. Ed., 2000, 39, 4111.
5 D. Urban, T. Skrydstrup, C. Riche, A. Chiaroni and J.-M. Beau,
Chem. Commun., 1996, 1883; D. Urban, T. Skrydstrup and
J.-M. Beau, J. Org. Chem., 1998, 63, 2507; D. Urban, T. Skrydstrup
and J.-M. Beau, Chem. Commun., 1998, 955; L. Andersen, L. M.
Mikkelsen, J.-M. Beau and T. Skrydstrup, Synlett, 1998, 1393.
6 H. B. Mereyala and G. V. Reddy, Carbohydr. Res., 1993, 242, 277.
7 S.-I. Nishimura, H. Kuzuhara, Y. Takiguchi and K. Shimahara,
Carbohydr. Res., 1989, 194, 223; E. W. Thomas, Carbohydr. Res.,
1973, 26, 225.
Notes and references
† Octaacetyl chitobiose, obtained by controled degradation of chitin,7
was subjected to the following transformations: i. HCl, AcCl; (55%)
ii. 2-PySH, K2CO3, toluene–acetone (76%); iii. MCPBA, NaHCO3,
CH2Cl2 (84%).
‡ In a typical experiment, a solution of SmI2 in THF (0.1 M) was added
under Ar in a flask containing sulfone 4 (106 mg, 240 µmol) and cyclo-
hexanecarboxaldehyde (125 µL, 1.0 mmol) until a persistent blue color-
ation was observed (5.3 mL). A few drops of aqueous ammonium
8 H. B. Mereyala, Carbohydr. Res., 1987, 168, 136.
9 For acid or base-catalyzed isomerization of C-formyl glycosides see:
W. R. Kobertz, C. R. Bertozzi and M. D. Bednarski, Tetrahedron
Lett., 1992, 33, 737; E. Fernandez-Megia, N. Gourlaouen, S. V. Ley
and G. J. Rowlands, Synlett, 1998, 991.
10 For a recent synthesis of 2Ј-carbonylalkyl β-C-glycopyranosides by
epimerization see H. Shao, Z. Wang, E. Lacroix, S.-H. Wu,
H. J. Jennings and W. Zou, J. Am. Chem. Soc., 2002, 124, 2130.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 9 7 – 1 0 9 8
1098