Stereoselective synthesis of α-C-glucosamines via anomeric organosamarium reagents

Article abstract of DOI:10.1055/s-1998-1944

The direct coupling of the pyridyl sulfone of N-acetylglucosamine with aldehydes or ketones is promoted by samarium diiodide affording the corresponding α-C-glycosides preferentially. A C-disaccharide has been synthesized using this approach.

Full text of DOI:10.1055/s-1998-1944

December 1998
SYNLETT
1393
Stereoselective Synthesis of α-C-Glucosamines via Anomeric Organosamarium Reagents
a
a
b
a
Lise Andersen , Lise Munch Mikkelsen , Jean-Marie Beau , and Troels Skrydstrup*
a
b
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark Laboratoire de Synthèse de Biomolécules associé au
CNRS, Institut de Chimie Moléculaire d'Orsay, Université de Paris-Sud, F-91405 Orsay, France
Fax 45 86 19 61 99; Bitnet ts@kemi.aau.dk
Received 24 August 1998
Abstract: The direct coupling of the pyridyl sulfone of N-
acetylglucosamine with aldehydes or ketones is promoted by samarium
diiodide affording the corresponding α-C-glycosides preferentially. A
C-disaccharide has been synthesized using this approach.
1 (entries 2-5). In the case of aldehydes (entries 3-5), a stereoselectivity
of 4.3-10:1 was observed at the newly created exocyclic stereocenter of
8
4c-e implying that the anomeric samarium species is more selective
9
than that noted for the corresponding C1-lithium reagent. We
tentatively assign the major isomers of entries 3-5 to possess the (S)-
configuration at the exocyclic stereocenter based on earlier results both
In the past few years C-disaccharides and C-trisaccharides have become
2c-f
in SmI -induced α-C-glycosylations
under reductive lithiation conditions. In all these cases the same
as well as those performed
2
important biological tools for the study of carbohydrate-protein
10
1
interactions in lectins and glycosidases. Despite the tremendous work
stereoisomer was obtained as the major product. The C-glycosides 4a-e
carried out in the development of synthetic techniques to obtain C-
disaccharides and higher C-oligomers, none have been applied to 2-
acetamido-2-deoxy sugars at the nonreducing position. In this paper, we
present an extremely mild approach for the synthesis of α-C-glycoside
analogues of N-acetylglucosamine by a simple titration of a THF
solution of 2-acetamido-2-deoxyglucosyl 2-pyridyl sulfone and a
carbonyl compound with samarium diiodide. These results contribute to
our overall study on anomeric organosamarium reagents for the
also possess abnormal ring conformations as seen from the small
8
coupling constants J
, J
and J
of less than 2 Hz. The
H2,H3 H3,H4
H4,H5
4
expected
C conformation with trans-diaxial orientations of the H2,
1
H3, H4 and H5 protons would require coupling constants of approx. 9
Hz. This deviation has been observed before with other α-C-glycosides
1,3
2f,11
and is probably due to some A strain.
2,3
stereoselective synthesis of C-glycosides. We show that this approach
may be applicable for the synthesis of a C-disaccharide containing N-
acetylglucosamine in the non-reducing end which is the first of its kind.
The synthesis of the 2-pyridyl sulfone of N-acetylglucosamine 1, as
illustrated in Scheme 1, began with the hemiacetal 2 easily prepared
4
from the azidonitration of 3,4,6-tri-O-benzylglucal.
Hence
transformation of 2 to the α-oriented 2-pyridyl sulfide 3 was made
possible via a two-step procedure involving formation of the β-
trichloroimidate followed by its treatment with 2-mercaptopyridine and
BF ·Et O. Subsequent reduction of the azide using the Bartra
3
2
5
procedure and acetylation, and then oxidation of the sulfide with
MCPBA led to the glycosyl 2-pyridyl sulfone 1.
Scheme 1
Subjecting a THF solution of the pyridyl sulfone 1 and cyclohexanone
to SmI led to an instantaneous consumption of the one-electron
2
reducing agent with the production of a C-glycoside mixture in 77%
yield after chromatography (Table 1, entry 1). As was observed earlier
2c,f,g
with N-acetylgalactosamine,
the use of 1 led to the predominant
7
formation of the α-C-glycoside 4a with an α:β ratio of 3.6:1. We note
again the efficiency of this coupling reaction considering the availability
of a potentially acidic proton of the acetamide group. The coupling of 1
with other carbonyl compounds was also α-selective as shown in Table
The α-selectivity observed is explained by the strong complexation
between the N-acetamide group and the metal ion in the initially formed
α-organosamarium 5. A conformational change to an inverted chair or
skew boat conformation could then occur placing the C1-Sm bond in an

1394
LETTERS
SYNLETT
12
energetically more favorable equatorial position (see Figure 1).
A
configurational change may competitively occur to give the β-
organosamarium species. However, this anomerization process is
sufficiently retarded because of the strong complexation between the
metal ion and the acetamide group, such that coupling of the carbonyl
compound with the α-anomer is favored. It is interesting to note that
pyridyl sulfone 1 affords reduced α:β-selectivities compared with the N-
acetylgalactosamine case (approx. 3.5:1 compared to 4-20:1 for the
latter). It is expected that the conformational change should be more
advantageous for 6 than for 5 as the placement of an axially oriented
C4-OBn group in a pseudo-equatorial position would lead to a greater
stability of this conformer and hence higher α-selectivity for 6.
Scheme 3
change in the nitrogen substituent to a non-coordinating group could
lead to the formation of the corresponding β-C-glycosides.
Aknowledgements
Financial support from the Danish National Science Foundation is
greatfully acknowledged.
References and Notes
(1) a) Espinosa, J.-F.; Cañada, F.J.; Asensio, J.L.; Dietrich, H.;
Martin-Lomas, M.; Schmidt, R.R.; Jiménez-Barbero, J. Angew.
Chem., Int. Ed. Engl. 1996, 35, 303; b) Espinosa, J.-F.; Cañada,
F.J.; Asensio, J.L.; Martin-Pastor, M.; Dietrich, H.; Martin-Lomas,
M.; Schmidt, R.R.; Jiménez-Barbero, J. J. Am. Chem. Soc. 1996,
118, 10862; c) Espinosa, J.-F.; Montero, E.; Vian, A.; Garcia, J.L.;
Dietrich, H.; Schmidt, R.R.; Martin-Lomas, M.; Imberty, A.;
Cañada, F.J.; Jiménez-Barbero, J. J. Am. Chem. Soc. 1998, 120,
1309; d) Wei, A.; Boy, K.M.; Kishi, Y. J. Am. Chem. Soc. 1995,
117, 9432.
Figure 1
Other N-protecting groups such as the phthalimide in 7, and the
sulfonamides in 8 and 9 (Scheme 2) were also tested in order to examine
their influence on the stereoselectivity of the coupling at the anomeric
center. Surprisingly, in all cases these proved to be unrewarding in that
considerable degradation was observed with no sign of any coupling
(2) Mazéas, D.; Skrydstrup, T.; Beau, J.-M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 909; b) Jarreton, O.; Skrydstrup, T.; Beau, J.-M. J.
Chem. Soc., Chem. Commun. 1996, 1661; c) Urban, D.;
Skrydstrup, T.; Riche, C.; Chiaroni, A.; Beau, J.-M. J. Chem. Soc.,
Chem. Commun. 1996, 1883; d) Jarreton, O.; Skrydstrup, T.;
Beau, J.-M. Tetrahedron Lett. 1997, 36, 1767; e) Skrydstrup, T.;
Jarreton, O.; Mazéas, D.; Urban, D.; Beau, J.-M. Chem. Eur. J.,
1998, 4, 655; f) Urban, D.; Skrydstrup, T.; Beau, J.-M. J. Org.
Chem. 1998, 63, 2507; g) Urban, D.; Skrydstrup, T.; Beau, J.-M.
Chem. Commun. 1998, 955.
products. Competitive reduction of these protecting groups by SmI
may take place.
2
(3) For a recent use of glycosyl pyridyl sulfones and phenylsulfones
for the preparation of C-glycosides of N-acetylneuraminic acid
and KDN, see: Vlahov, I.R.; Vlahova, P.I., Linhardt, R.J. J. Am.
Chem. Soc. 1997, 119, 1480; Du, Y. T.; Linhardt, R.J. Carbohydr.
Res. 1998, 308, 161; Du, Y; Polat, T.; Linhardt, R.J. Tetrahedron
Lett. 1998, 39, 5007.
Scheme 2
(4) Lemieux, R.U.; Ratcliffe, R.M. Can. J. Chem. 1979, 57, 1244;
Gauffeny, F.; Marra, A.; Shun, L.K.S.; Sinaÿ, P.; Tabeur, C.
Carbohydr. Res., 1991, 219, 237; Briner, K.; Vasella, A. Helv.
Chim. Acta, 1987, 70, 1341.
Finally, we show that the pyridyl sulfone 1 can be used for the facile
synthesis of a C-disaccharide. Treatment of a THF solution of 1 and
13
14
10 with SmI afforded the C-disaccharide 11 in a 60% yield with an
2
α:β-selectivity of 4:1 (Scheme 3). This represents the first C-
disaccharide containing an N-acetylglucosamine unit at the nonreducing
position.
(5) Bartra, M.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1987, 47, 5941;
Bartra, M.; Romea, P.; Urpf, F.; Vilarrasa, J. Tetrahedron, 1990,
46, 587.
In conclusion, the anionic approach to the synthesis of C-glycosides
including a C-disaccharide employing samarium diiodide has now been
expanded to the N-acetylglucosamine case which displays a preference
for the α-anomer. Further work is in progress to investigate whether a
(6) Typical procedure: A 0.1 M THF solution of SmI (2.2 equiv.)
2
was added quickly to a well degassed solution of pyridyl sulfone 1
(1 equiv.) and the carbonyl substrate (2.0 equiv.) in THF (5 ml /

December 1998
SYNLETT
1395
mmol of 1). The reaction mixture was treated with saturated
NH Cl, extracted twice with CH Cl , and the organic phase was
610.3 (M + Na), 588.3 (M + 1), 570.3 (M – H O); HRMS m/e
2
calcd for C
H NNaO (M +Na) 410.3145, found 410.3133.
36 45 6
4
2
2
dried and evaporated to dryness. The crude product was purified
by flash chromatography.
(9) Hoffmann, M.; Kessler, H. Tetrahedron Lett. 1994, 35, 6067.
(10) Lesimple, P.; Beau, J.-M. Bioorg. Med. Chem. 1994, 2, 1319.
(7) In an earlier paper (ref. 2f) we reported that coupling of 1 with
cyclohexanone led only to the product of desulfonylation. As the
pyridyl sulfone 1 in this case was prepared from 2 via the
(11) Skrydstrup, T.; Mazéas, D.; Elmouchir, M; Doisneau, G.; Riche,
C.; Chiaroni, A.; Beau, J.-M. Chem. Eur. J. 1997, 8, 1342.
(12) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152;
Rychnovsky, S.D.; Mickus, D.E.; Tetrahedron Lett. 1989, 30,
3011.
reduction of the azide group with Ph P and subsequent hydrolysis
3
and acetylation, it is possible that 1 was contaminated with
Ph PO. We have previously observed that contamination of the
3
(13) Dong, W.; Jespersen, T.M.; Bols, M.; Skrydstrup, T.; Sierks, M.R.
corresponding pyridyl sulfone of N-acetylgalactosamine with
Biochemistry 1996, 35, 2788.
Ph PO does not lead to the formation of C-glycosides, but rather
3
1
(14) Selected H NMR (200 MHz, CDCl ) data for the major isomer of
3
the 1-deoxy derivative (ref. 2f).
11: δ 6.31 (1H, d, J = 9.4 Hz, NH), 4.31 (1H, d, J = 3.6 Hz, H1),
4.30 (1H, bd, J = 9.4 Hz, H2’), 4.33 (1H, bdd, J = 7.8, 6.2 Hz,
H5’), 3.86 (1H, dd, J = 10.0, 8.0 Hz, H6a’), 3.83-3.58 (5H, m,
H1’, H3, H3’, H5, H6a’, H6b’), 3.50 (1H, bs, H4’), 3.39 (1H, dd, J
1
(8) Selected H NMR (200 MHz, CDCl ) data for the major isomer of
3
4d: δ 6.58 (1H, d, J = 9.2 Hz, NH), 4.33 (1H, bdd, J = 7.8, 6.2 Hz,
H5), 4.24 (1H, bd, J = 9.2 Hz, H2), 3.93 (1H, bd, J = 7.1 Hz, H1),
3.90 (1H, dd, J = 10.1, 7.8 Hz, H6a), 3.74 (1H, bs, H3), 3.60 (1H,
dd, J = 10.1, 6.2 Hz, H6b), 3.44 (1H, bs, H4), 3.39 (1H, dd, J =
= 9.5, 3.6 Hz, H2), 3.21 (1H, m, H7), 3.18 (3H, s, OCH ), 3.16
3
(1H, dd, J = 9.5, 9.5 Hz, H4), 2.01 (1H, m, H6a), 1.78 (1H, m,
7.1, 2.2 Hz, H7), 1.84 (3H, s, COCH ). MS (electrospray) m/z
H6b), 1.68 (3H, s, COCH ).
3
3