Stereoselective synthesis of azasugar thioglycosides

Article abstract of DOI:10.1016/S0040-4039(03)01685-X

Bicyclic (2-oxapyrrolizidines) and monocyclic (piperidine) azasugar ethyl thioglycosides, a new type of azasugar derivative, are stereoselectively prepared from suitable glycosylenamines, through anhydroazasugar derivatives.

Full text of DOI:10.1016/S0040-4039(03)01685-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6605–6608
Stereoselective synthesis of azasugar thioglycosides
M. Angeles Pradera, Francisco J. Sayago, Jos e´ M. Illangua, Consolaci o´ n Gasch and Jos e´ Fuentes*
Departamento de Qu ´ı mica Org a´ nica, Facultad de Qu ´ı mica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 16 May 2002; revised 3 July 2003; accepted 4 July 2003
Abstract—Bicyclic (2-oxapyrrolizidines) and monocyclic (piperidine) azasugar ethyl thioglycosides, a new type of azasugar
derivative, are stereoselectively prepared from suitable glycosylenamines, through anhydroazasugar derivatives.
©
2003 Elsevier Ltd. All rights reserved.
The thioglycosides, a type of glycoside in which the
anomeric oxygen atom has been substituted by a sul-
phur atom, are interesting compounds as the stability
of the thioglycosidic linkage in enzymatic processes
involving the corresponding O-glycosides has been
1
reported, and consequently, they are inhibitors of gly-
2
cosidases. The thioglycosides have also been used as
chiral inductors in enzymatic syntheses. At the same
3
1
5
Reaction of b- -glucopyranosylenamine 2 with p-
D
time, the azasugars (iminocyclitols), and among them
polyhydroxylated-pyrrolizidines, belong to an impor-
tant class of alkaloids having glycosidase- and glycosyl-
methoxybenzaldehyde dimethyl acetal quantitatively
gave the corresponding 4,6-O-p-methoxybenzylidene
derivative, which was 2,3-di-O-benzoylated with ben-
zoyl chloride/pyridine and reduced with sodium
cyanoborohydride to have the partially O-protected
glucosylenamine 20. Successive treatments of 20 with
mesyl chloride and sodium methoxide/DMF afforded
the anhydroazasugar 4 in high yield. The 2,3-di-O-
4
transferase-inhibitory properties. They are useful, not
only as biological tools for studying the biofunctions of
5
oligosaccharides, but also as potential drugs to treat a
6–10
variety of carbohydrate-mediated diseases.
Over the past decade, much interest has arisen in the
preparation of iminocyclitols, in many cases, the con-
trol of the stereochemistry being an important prob-
18
mesyl derivatives 5 and 6 were prepared from the
D
-gluco (2) and
D
-xylo (3) pyranosylenamines,
respectively.
1
1
lem.
The data on 2-thioalcoxy derivatives of
iminocyclitols (1), that is azasugar thioglycosides, are
Reaction of 4–6 with ethanethiol in dichloromethane in
the presence of PTSA and at rt for 5 min produced the
ethyl thioglycosides of azasugars 7–9, respectively, in
virtually quantitative yield. Scheme 2 shows the mecha-
nism of formation of 7–9 taking 7 as example. O-Proto-
nation of 4 with PTSA produced 21, increasing the
electrophilicity of the anomeric carbon. The attack of
ethanethiol on 21 produces the ethylthiopyrrolidine 22,
which by internal cycloaddition of the OH on the
carbonꢀcarbon 1 double bond gave the 2-oxa-
very scarce, and limited to thioanalogues of the bicyclic
12–14
alkaloids australine and castanospermine
the sulphur atom in the ring.
having
In this communication, we report on the stereoselective
preparation of bicyclic (7–9, 14–16, 7a) and monocyclic
(
19) azasugar ethyl thioglycosides, which can also be
considered thioalkoxy alkaloid derivatives (Scheme 1).
The starting materials are glycosylenamines with
D
-
1
5
15
gluco (2),
D
-xylo (3),
L
-rhamno (10), and
D-ribo
9
1
6
pyrrolizidine 7. Compound 7 (98% yield) is formed
(
17), configurations. The key intermediates are the
as a pair of 5R and 5S diasteroisomers in a 1:4 ratio.
NOE experiments performed on 7 (Fig. 1) confirmed
the configuration of C-5 and C-3. The cycloaddition
reaction was completely stereoselective (only the
product with 3R configuration was formed) and the
attack of the EtSH was 80% stereoselective.
anhydroazasugars 4–6, 11–13, and 18, which were pre-
pared through conventional strategies using appropri-
17
ate O-protecting groups.
*
Corresponding author. Tel.: +34-954557150; fax: +34-954624960;
e-mail: jfuentes@us.es
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01685-X

6
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M. A. Pradera et al. / Tetrahedron Letters 44 (2003) 6605–6608
Scheme 1. Reagents and conditions: (i) several steps depending on the protecting groups (see text); (ii) EtSH, CH Cl (DMF for
2
2
19), PTSA, rt, 5 min (60 min for 19); (iii) NaOMe/MeOH.
Scheme 2. Formation of 7.
O-Debenzoylation of 7 with NaOMe quantitatively
yielded the dihydroxythioethoxy-2-oxapyrrolizidine
2
0
7a.
The
from
L
L
-talo-anhydroazasugars 11–13 were prepared
15
-rhamnopyranosylenamine (10). The 2,3 selec-
tive O-acetalation with p-methoxybenzaldehyde
dimethyl acetal, followed by O-mesylation (“23) and
reaction with sodium methoxide, gave 11. Compound
1
3 was obtained from 23 by removing the p-methoxy-
benzylidene group followed by O-benzoylation. A two-
Figure 1. NOE experiments on 7.

M. A. Pradera et al. / Tetrahedron Letters 44 (2003) 6605–6608
6607
step transacetalation of 23 and reaction with sodium
methoxide afforded the isopropylidene derivative 12.
Modern Methods in Carbohydrate Synthesis; Khan, S. H.;
O’Neil, R. A., Eds.; Harwood Academic: Amsterdam,
1996; pp. 316–351.
When compounds 11–13 were treated with ethanethiol,
in a similar way to that commented above for 4–6, the
thioglycosides 14–16 were isolated. In the case of 11,
the ethanethiol remove the benzylidene group and the
fully unprotected oxapyrrolizidine 14 was obtained. For
2. See as examples: (a) Pocsi, I.; Kiss, L.; Zsoldos-M a´ dy, V.;
Pinter, I. Biochem. Biophys. Acta 1990, 1039, 119–122; (b)
Iori, P.; Rollin, P.; Thiem, J.; Palmieri, S. FEBS Lett.
1996, 385, 87–90; (c) Kuhn, C. S.; Lehmann, J.; Steck, J.
Tetrahedron 1990, 46, 3129–3134; Kuhn, C. S.; Lehmann,
J.; Sandhoff, K. Bioconjugate Chem. 1992, 3, 230–233; (d)
Fitz, W.; Rosenthal, P.; Wong, C. H. Bioorg. Med. Chem.
Lett. 1996, 4, 1349–1353; (e) Witczak, Z. J.; Boryczewski,
D. Bioorg. Med. Chem. Lett. 1998, 8, 3265–3268.
1
4–16 only the 3R stereoisomer was formed and the
stereocontrol on the configuration of C-5 was lower
than for 7. In the case of 15 the isopropylidene group
remained after the reaction with EtSH. For 14 and 16
the yields were 60 and 98%, whereas for 15 was only
3
. Defaye, J.; Gelas, J. Studies in Natural Products Chem-
istry, Vol. 8; Attaur-Rahman, Ed.; Elservier Science Pub-
lisher: Amsterdam, 1991.
5
0%, which suggest that the vicinal O-protection (iso-
propylidene ring) hinders the cyclisation. The stereo-
chemistry of 14 was confirmed by NOE experiments.
4
. For a review, see: (a) Lillelund, V. H.; Jensen, H. H.;
Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515–553; (b)
Heigtman, T. D.; Vasella, A. Angew. Chem., Int. Ed.
1999, 38, 750–770; (c) St u¨ tz, A. E. Iminosugars as Gly-
cosidases Inhibitors Nojirimycin and Beyond, Wiley-VCH:
Weinheim, 1999.
5
. (a) Dwek, R. A. Chem. Rev. 1996, 96, 683–720; (b)
Albein, A. D. Ann. Rev. Biochem. 1987, 56, 497–534.
. Hughs, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 35–162.
. (a) Papandreou, G.; Tong, M. K.; Ganem, B. J. Am.
Chem. Soc. 1993, 115, 11682–11690; (b) Cipolla, L.; Lay,
L.; Nicotra, F.; Pangrazio, C.; Panza, L. Tetrahedron
6
7
1
6
Compound 18 was prepared from 17 by successive
treatments with mesyl chloride and sodium methoxide.
Reaction of 18 with ethanethiol and PTSA in DMF
1
995, 51, 4679–4690; (c) Wischnat, R.; Mart ´ı n, R.;
Takayama, S.; Wong, C.-H. Bioorg. Med. Chem. Lett.
998, 8, 3353–3358.
21
yielded (90%) the azasugar thioglycoside 19, which
was characterized in a similar way to 7–9, 14–16, and
1
8
. See as example: Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.;
Suhara, Y. J. Am. Chem. Soc. 1998, 120, 3007–3018.
. Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2,
7a. The attack of EtSH was 100% stereoselective.
9
In conclusion, we have developed a method to prepare
bicyclic and monocyclic azasugar ethyl thioglycosides
from anhydroazasugars, which are easily obtained from
glycosylenamines. The thioethoxy group is introduced
through a highly stereoselective substitution. In the case
of bicyclic compounds, 2-oxapyrrolizidines, the forma-
tion of the oxazolic ring is 100% stereoselective. The
scope and limitations of the method are currently under
study in our laboratory.
1
99–215.
1
0. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1645–1680; (b)
Deshpande, P. P.; Danishefsky, S. J. Nature 1997, 387,
164.
11. For five-membered iminocyclitols see as examples: (a)
Kiess, F. M.; Poggendorf, P.; Picasso, S.; J a¨ ger, V. Chem.
Commun. 1998, 119–120; (b) Blanco, M. J.; Sardina, F. J.
J. Org. Chem. 1998, 63, 3411–3416; (c) Hummer, W.;
Dubois, E.; Gracza, T.; J a¨ ger, V. Synthesis 1997, 634–
642; (d) Fuentes, J.; Olano, D.; Pradera, M. A. Tetra-
Acknowledgements
hedron: Asymmetry 1997, 8, 3443–3456. For
six-membered iminocyclitols see as examples: (a) Banba,
Y.; Abe, C. H.; Nemoto, H.; Kato, A.; Adachi, I.;
Takahata, H. Tetrahedron: Asymmetry 2001, 12, 817–819;
(b) Joseph, C. C.; Regelin, H.; Zwanenburg, B.; Chitten-
den, G. J. F. Carbohydr. Res. 2002, 337, 1083–1087; (c)
Budzinska, A.; Sas, W. Tetrahedron Lett. 2001, 42, 105–
107.
We thank the Direcci o´ n General de Ense n˜ anza Supe-
rior e Investigaci o´ n Cient ´ı fica of Spain and the Junta de
Andalucia for financial support (grant numbers
BQU2001-3740 and FQM-134), and the Ministerio de
Educaci o´ n Cultura y Deporte, and the Fundaci o´ n
C a´ mara of the University of Seville, for the award of
fellowships to F.J.S. and J.M.I., respectively. This work
is part of the European Programme COST D13, action
number D13/0001/98.
12. Berges, D. A.; Fan, J.; Devinck, S.; Liu, N.; Dalley, N.
K. Tetrahedron 1999, 55, 6759–6770.
13. Marek, D.; Wadouachi, A.; Uzau, R.; Beaupere, D.;
Nowogrocki, G.; Laplace, G. Tetrahedron Lett. 1996, 37,
49–52.
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S. J. Org. Chem. 1992, 57, 5661–5666.
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in Glycobiology; Driguez, H.; Thiem, J., Eds.; Top. Curr.
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A.; Scheiddegger, V. An. Real Soc. Espa n˜ . Fis. Quim.
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6. Fuentes, J.; Mostowicz, D.; Ortiz, C.; Pradera,
M. A.; Robina, I. Carbohydr. Res. 1994, 257, 305–
16.
7. Pradera, M. A.; Olano, D.; Fuentes, J. Tetrahedron Lett.
995, 36, 8653–8656.
20. Selected spectroscopic data for (1S,3S,5S,6R,7S,7aS) 3-
diethoxycarbonylmethyl-5-ethylthio-1-p-methoxybenzyl-
1
3
oxymethyl-2-oxapyrrolizidine (7a). H NMR (500 MHz,
1
MeOD) l 5.41 (d, 1H, J3,CH=8.5, H-3), 4.35 (m, 1H,
H-1), 4.20–4.15 (m, 3H, H-5, 6, 7), 4.10 (m, 1H, H-7a),
3.73 [d, 1H, CH(CO Et) ], 2.65–2.55 (m, 2H, SCH CH ).
1
1
1
8. For the preparation of compound 6 see reference 11d.
9. Selected spectroscopic data for (1S,3S,5S,6R,7S,7aS) 6,7-
2
2
2
3
HRCIMS m/z obsd. 514.2112 calcd for C H NO S
24
36
9
dibenzoyloxy-3-diethoxycarbonylmethyl-5-ethylthio-1-p-
514.2111.
1
methoxybenzyloxymethyl-2-oxapyrrolizidine
(7).
H
21. Selected spectroscopic data for (2S,3R,4R,5R) 1-
NMR (500 MHz, CDCl ) l 5.82 (dd, 1H, J5,6=6.3,
J6,7=3.7, H-6), 5.61 (d, 1H, J3,CH=8.8, H-3), 5.34 (dd,
diethoxycarbonylvinyl-2-ethylthio-5-hydroxy-3,4-O-iso-
3
1
propylidenepiperidine (19). H NMR (500 MHz, CDCl
)
3
1
1
H, J7,7a=1.8, H-7), 4.35 (d, 1H, J5,6=6.3, H-5), 4.33 (m,
H, H-1), 3.80 (dd, 1H, J1,7a=8.0, J7,7a=1.8, H-7a), 3.78
l 7.45 (s, 1H, HCꢁ), 4.63 (d, 1H, J2,3=3.0, H-2), 4.61 (m,
1H, H-5), 4.51 (dd, 1H, J3,4=7.7, H-3), 4.40 [dd, 1H,
[
2
d, 1H, CH(CO Et) ], 3.77–3.70 (m, 2H, H COMBn),
J
4,5=1.7, H-4), 3.50 (dd, 1H, J5,6a=6.2, J6a,6b=11.9,
2
2
2
3
2
.72, 2.66 (each dq, each 1H, JH,H=11.5, JH,H=7.5,
H-6a), 3.07 (dd, 1H, J5,6b=11.0, H-6b), 2.63, 2.61(each
13
2
3
13
SCH CH ). C NMR (125.7 MHz, CDCl ) l 95.2 (C-3),
8
6
dq, each 1H,
NMR (125.7 MHz, CDCl
76.2 (C-4), 72.9 (C-3), 68.9 (C-2), 63.4 (C-5), 46.3 (C-6),
J
H,H=13.0,
J
H,H=7.5, SCH
2
CH ).
3
C
2
3
3
0.8 (C-1), 80.4 (C-6), 79.0 (C-7), 72.1 (C-5), 69.6 (C-7a),
3
) l 150.0 (HCꢁ), 96.2 (ꢁC),
9.0 (H COMBn), 58.5 [CH(CO Et) ], 22.3 (SCH CH ).
2
2
2
2
3
HRCIMS m/z obsd. 722.2608 calcd for C H NO S
25.7 (SCH
2
CH ). HREIMS m/z obsd. 403.1666 calcd for
3
38
44
11
7
22.2635.
C
18
H
29NO S 403.1665.
7