2-Nitro thioglycoside donors: Versatile precursors of β-D-glycosides of aminosugars

Article abstract of DOI:10.1021/ol049729t

2-Nitro thioglycosides can be prepared by the Michael addition of thiophenol to 2-nitroglycal derivatives. NIS/TMSOTf activation of these 2-nitro thioglycosides, in the presence of alcohols, rapidly and cleanly led to the desired glycosides in good yield

Full text of DOI:10.1021/ol049729t

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1551-1554
2-Nitro Thioglycoside Donors: Versatile
Precursors of â-D-Glycosides of
Aminosugars
Nadine Barroca and Richard R. Schmidt*
Department of Chemistry, UniVersity of Konstanz, Fach M 725,
78457 Konstanz, Germany
richard.schmidt@uni-konstanz.de
Received February 16, 2004
ABSTRACT
2-Nitro thioglycosides can be prepared by the Michael addition of thiophenol to 2-nitroglycal derivatives. NIS/TMSOTf activation of these
2-nitro thioglycosides, in the presence of alcohols, rapidly and cleanly led to the desired glycosides in good yield and â-selectivity. Reduction
of the nitro group allowed generation of the corresponding 2-acetamido glycosides.
The application of 2-nitroglycals to the synthesis of mucin-
type glycopeptides has recently attracted our attention1
because of the fundamental role the latter play in biological
processes such as cell-cell adhesion, cell growth, fertiliza-
tion, parasitic infection, and inflammation.2a,c We previously
demonstrated that 2-nitrogalactal concatenation is a useful
tool for forming R-glycosidic bonds to L-serine or L-
threonine. Via this methodology we synthesized all the
members of the mucin family,1,3 as well as many O-, S-, P-,
and C-glycosides4 and nucleosides.5
the behavior of these compounds as glycosyl donors was
never investigated. The synthesis of 2-nitro glycoside donors
through Michael-type addition reactions and their use in
glycosylation reactions is now reported here.
The 2-nitroglycals 1, 2,3a, 3,6 and 47 (Table 1), obtained
by standard nitration conditions (addition of acetyl nitrate
and elimination of acetic acid),3a-c were converted to the
2-nitro thioglycoside by base-catalyzed glycosylation with
thiophenol and 0.1 equiv of potassium tert-butoxide. The
2-nitro thioglycosides (5-8) were obtained in excellent yield
Although the synthesis of 2-nitro thioglycosides from
2-nitroglycals has already been reported by Holzapfel et al.,6
(4) (a) Pachamuthu, K.; Gupta, A.; Das, J.; Schmidt, R. R.; Vankar, Y.
D. Eur. J. Org. Chem. 2002, 1479-1483. (b) Pachamuthu, K.; Schmidt, R.
R. Synlett 2003, 1355-1357. (c) Khodair, A. I.; Winterfeld, G. A.; Schmidt,
R. R. Eur. J. Org. Chem. 2003, 1847-1852. (d) Khodair, A. I.; Pachamuthu,
K.; Schmidt, R. R. Synthesis 2004, 53-58. (e) Geiger, J.; Barroca, N.;
Schmidt, R. R. Synlett 2004, accepted for publication.
(1) Winterfeld, G. A.; Schmidt, R. R. Angew. Chem. 2001, 113, 2718-
2721; Angew. Chem., Int. Ed. 2001, 40, 2654-2657.
(2) (a) Varki, A. Glycobiology 1993, 3, 97-130. (b) Brockhausen, I.
Biochim. Biophys. Acta 1999, 1473, 67-95. (c) Brocke, C.; Kunz, H. Bioorg.
Med. Chem. 2002, 10, 3085-3112.
(3) (a) Das, J.; Schmidt, R. R. Eur. J. Org. Chem. 1998, 1609-1613.
(b) Winterfeld, G. A.; Ito, Y.; Ogawa, T.; Schmidt, R. R. Eur. J. Org. Chem.
1999, 1167-1171. (c) Winterfeld, G. A.; Khodair, A. I.; Schmidt, R. R.
Eur. J. Org. Chem. 2003, 1009-1021.
(5) Winterfeld, G. A.; Das, J.; Schmidt, R. R. Eur. J. Org. Chem. 2000,
3047-3050.
(6) Holzapfel, C. W.; Marais, C. F.; van Dyk, M. S. Synth. Commun.
1988, 18, 97-114.
(7) Pedretti, V.; Veyrie`res, A.; Sinay¨, P. Tetrahedron 1990, 46, 77-88.
10.1021/ol049729t CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/14/2004

Table 1. Base-Catalyzed Addition of Thiophenol to Glycals 1-4a
a Reactions were conducted at room temperature in toluene in the presence of 0.1 equiv of potassium tert-butoxide. b TDS ) thexyldimethylsilyl.
Table 2. Coupling Reactions of 2-Nitrothioglycosides
1552
Org. Lett., Vol. 6, No. 10, 2004

Table 2 (Continued)
a Reactions, unless stated otherwise, were conducted in CH2Cl2. Anomeric ratios were determined by isolated products. b Reactions were conducted in
propionitrile at -15 °C. c SE ) trimethylsilylethyl. d TBDMS ) tert-butyldimethylsilyl.
(70-88%). As previously reported,8 concatenation with soft
nucleophiles such as thiophenol yields mainly the â-anomer
in a time-dependent manner. The â-linkage was confirmed
by 1H NMR studies, which showed a coupling constant J1,2
) 6 Hz, which contrasted with a J1,2 of 4 Hz for the
R-anomer.
With the requisite thiophenylglycosides in hand, a series
of coupling reactions with different acceptors 9, 10,9 11, 12,
13,10 14,11 15,10 16, and 1712 (Table 2) were carried out.
Activation simply involved cooling a 1:1.2:1.5 mixture of
the thioglycoside, the acceptor, and NIS in CH2Cl2 at 0 °C
and then adding 0.15 equiv of TMSOTf (Method A).
Alternatively, the same protocol could be carried out at -15
°C in propionitrile (Method B). Workup thereafter afforded
the desired glycosides.
A series of compounds, selected to illustrate the wide range
of possible coupling types, was prepared. The results are
presented in Table 2. In the case of highly reactive acceptor
alcohols (entries 1, 3, 10, and 16) only the â anomers were
detected. For less reactive primary and secondary hydroxy
acceptors, â-selectivity was conserved but was not exclusive.
To improve selectivity, propionitrile was used as solvent,
and with the help of the nitrile effect,13 the â-selectivity was
further increased (entries 5, 7, and 12). The presence of a
nitro group at position 2 seemed to allow anchimeric
assistance and consequently orientated the glycosylations in
the direction of the â-anomer as the major product.
To investigate the influence of a 4,6-O-benzylidene acetal
protecting group on the outcome of the glycosidation,14a-d
nitro thioglucoside donor 8a, b was tested under the same
reaction conditions. Unfortunately, in this case, activation
(8) Winterfeld, G. A., Dissertation, University of Konstanz, 2000.
(9) Liu, H. W.; Nakanishi K. J. Am. Chem. Soc. 1982, 104, 1178-1185.
(10) Bore´n, H. B.; Garegg, P. J.; Kenne, L.; Pilotti, A.; Svensson, S.;
Swahn, C. G. Acta Chem. Scand. 1973, 27, 2740-2748.
(11) See Experimental Section.
(12) Klaffke, W.; Warren, C. D.; Jeanloz, R. W. Carbohydr. Res. 1993,
244, 171-179.
(13) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694-697.
(14) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506-4507. (b) Crich,
D.; Cai, W. J. Org. Chem. 1999, 64, 4926-4930. (c) Crich, D.; Smith, M.
Org Lett. 2000, 2, 4067-4069. (d) Crich, D.; Smith, M. J. Am. Chem. Soc.
2001, 123, 9015-9020.
Org. Lett., Vol. 6, No. 10, 2004
1553

of the thiophenyl group by NIS was found to be difficult,
the R/â-ratios and the yields often being poor. The rigidity
induced by the 4,6-O-benzylidene ring could explain this
result.
Table 4. Reduction of the 2-Nitro Group
Also the use of 1-benzenesulfinyl piperidine (BSP)/
trifluoromethanesulfonic anhydride in the presence of 2,4,6-
tri-tert-butylpyrimidine (TTBP) was investigated for thiogly-
coside activation.14a-d Unfortunately, however, the 2-nitrothio-
phenyl donors were not activated under these conditions.
Only low yields of the desired compounds were usually
obtained; side products from elimination of the intermediate
triflate14a-d typically predominated (Figure 1).
aqueous 1 N HCl in aqueous AcOH was employed and then
followed by acetylation. This method gave access to the
desired acetamido derivatives 41-44.4c,11 A one-pot reaction,
using acetic anhydride instead of acetic acid, was also
explored. Unfortunately, although reduction of the nitro
group occurred without hitch, the one-pot acetylation was
never observed and only the free amine could ever be isolated
at the end of reaction. An additional step of acetylation was
necessary.
Figure 1. Activation with BSP, Tf2O, and TTBP.
Overall, our studies have demonstrated that glycosidations
with 2-nitro thiophenylglycosides generate â-anomers with
high yield and selectivity. These results, along with Michael-
type additions of alcohols to 2-nitrogalactals,3a-d thus allow
access to both types of glycoside, as described in Table 3.
In summary, 2-nitro thioglycoside donors can be success-
fully activated in the presence of NIS/TMSOTf to allow the
preparation of â-glycosides in good yield and selectivity. The
nitro group could then be reduced to afford the corresponding
acetamido glycosides. Starting from 2-nitroglycals, both R
or â selectivity can now be attained using Michael-type
addition or thioglycoside coupling, respectively. This dem-
onstrates the versatility of 2-nitro sugars as glycosyl donors
in glycoside synthesis. Applications of these donors are
currently underway in the synthesis of core 3 and 6 mucin
types; the results of these studies will be reported in due
course.
Table 3. Comparison between Glycosidation and Michael
Addition
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft, the European Community
(Grant HPRN-CT-2000-00001/GLYCOTRAIN), and the
Fonds der Chemischen Industrie. N.B. is grateful for an E.U.
Network Fellowship.
Supporting Information Available: Experimental pro-
cedures and spectral/analytical data for key intermediates and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Because in nature most amino sugars are mainly N-
acetamido glycosides, some of our nitroglycoside compounds
were submitted to reduction of the nitro group, as depicted
in Table 4. A method using an excess of zinc dust15 and
OL049729T
(15) Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31, 991.
1554
Org. Lett., Vol. 6, No. 10, 2004