Nitrone cycloadditions to isolevoglucosenone: Ready access to a new class of directly linked (1→3)-imino-C-disaccharides

Article abstract of DOI:10.1021/ol0342507

(Matrix presented) Straightforward access to a new class of D-gulo- and D-allo-derived directly linked (1→3)-imino-C-disaccharides by means of cycloaddition reactions of enantiopure polyhydroxylated pyrroline N-oxides with isolevoglucosenone is reported. The cycloaddition reactions display a high level of double asymmetric induction, which allows a partial kinetic resolution of a racemic nitrone.

Full text of DOI:10.1021/ol0342507

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1475-1478
Nitrone Cycloadditions to
Isolevoglucosenone: Ready Access to a
New Class of Directly Linked
(1f3)-Imino-C-disaccharides
Francesca Cardona,* Andrea Goti, and Alberto Brandi
Dipartimento di Chimica Organica “Ugo Schiff”, Polo Scientifico,
UniVersita` di Firenze, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Firenze, Italy
francesca.cardona@unifi.it
Received February 12, 2003
ABSTRACT
Straightforward access to a new class of D-gulo- and D-allo-derived directly linked (1f3)-imino-C-disaccharides by means of cycloaddition
reactions of enantiopure polyhydroxylated pyrroline N-oxides with isolevoglucosenone is reported. The cycloaddition reactions display a high
level of double asymmetric induction, which allows a partial kinetic resolution of a racemic nitrone.
Iminosugars have recently attracted a great deal of interest
due to their ability to inhibit glycosidases1 and hence their
enormous potential in application in the treatment of numer-
ous pathologies such as diabetes,2 viral infections,3 and
cancer.4
Glycosidases display aglycon specificity in that they
recognize oligosaccharides having subtle differences in the
aglycon portion and glycosidic linkage. In this respect, it
has been postulated5 that glycosidase inhibitors able to
interact with the aglycon binding site may show increased
potency and selectivity.
Compounds bearing an additional C-substituent (particu-
larly a sugar) at the pseudoanomeric center linked through
a nonhydrolyzable bond (such as imino-C-disaccharides) can
mimic the aglycon part of an oligosaccharide. For this reason,
several syntheses of imino-C-disaccharides have been
reported,6-8 and some of these compounds have shown
significant biological activities.6c,d,7d
Structural diversity is of extreme importance in order to
get information about structure-activity relationship. Thus,
synthetic efforts have regarded the preparation of compounds
(5) (a) Legler, G. In Carbohydrate Mimics; Chapleur, Y., Ed; Wiley-
VCH: Weinheim, Germany, 1998; pp 461-490. (b) Martin, O. R. In
Carbohydrate Mimics. Concepts and Methods; Chapleur, Y., Ed; Wiley-
VCH: Weinheim, Germany, 1998; p 259.
(6) (a) Johnson, C. R.; Miller, M. W.; Golebiowski, A.; Sundram, H.;
Ksebati, M. B. Tetrahedron Lett. 1994, 35, 8991-8994. (b) Martin, O. R.;
Liu, L.; Yang, F. Tetrahedron Lett. 1996, 37, 1991-1994. (c) Johns, B.
A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R. J. Am. Chem. Soc. 1997, 119,
4856-4865. (d) Leeuwenburgh, M. A.; Picasso, S.; Overkleeft, H. S.; van
der Marel, G. A.; Vogel, P.; van Boom, J. H. Eur. J. Org. Chem. 1999,
1185, 5-1189. (e) Duff, F. J.; Vivien, V.; Wightman, R. H. Chem. Commun.
2000, 2127-2128. (f) Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org.
Chem. 2002, 67, 7203-7214.
(1) Iminosugars as Glycosidase Inhibitors. Nojirimycin and Beyond;
Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, Germany, 1999.
(2) See, e.g.: (a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano,
N.; Matsui, K. J. Med. Chem. 1986, 29, 1038-1046. (b) Elbein, A. D.
Annu. ReV. Biochem. 1987, 56, 497-594.
(3) See, e.g.: (a) Karlsson, G. B.; Butters, T. D.; Dwek, R. A.; Platt, F.
M. J. Biol. Chem. 1993, 268, 570-576. (b) Fenouillet, E.; Papandreou,
M.-J.; Jones, I. M. Virology 1997, 231, 89-95.
(4) See, e.g.: (a) Humphries, M. J.; Matsumoto, K.; White, S. L.; Olden,
K. Cancer Res. 1986, 46, 5215-5222. (b) Goss, P. E.; Baptiste, J.;
Fernandes, B.; Baker, M.; Dennis, J. W. Cancer Res. 1994, 54, 1450-
1457.
10.1021/ol0342507 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/09/2003

of different structures such as “linear” (1f6)- and (1f5)-
C-linked iminodisaccharides6 (e.g., 16a), “branched” (1f1)-,
(1f2)-, (1f3)-, and (1f4)-C-linked iminodisaccharides7,6c
(e.g., 27g), and homo-C-linked iminodisaccharides8 (e.g., 38b),
in which the imino sugar is linked to the monosaccharide
by a two carbon linker.
We envisaged that isolevoglucosenone (7) could be an
excellent dipolarophile in 1,3-dipolar cycloadditions to
nitrones. Indeed, the presence of the activated double bond
should ensure high reactivity and regioselectivity.
In this field, we have recently synthesized (1f2)-linked
pseudo imino-C-disaccharides 6, where the iminosugar is
directly linked at C-2 of monosaccharides.9,10 The synthetic
approach was based on highly selective 1,3-dipolar cycload-
ditions of enantiopure polyhydroxylated pyrroline N-oxides
4 with 1,2-glycals 5, followed by simple elaborations of the
adducts.9,10 The major limitation of the process was the low
reactivity of nitrones toward glycals in the crucial cyclod-
dition step, which forced us to use a 3 equiv excess of glycal,
high temperatures, and long reaction times. The problem was
partially resolved by performing the cycloaddition reactions
at high pressure.11
To our knowledge, the use of 7 in cycloaddition reactions
has no precedent in the literature. In contrast, cycloaddition
reactions of isomeric levoglucosenone (8)13 to nitrones and
nitrile oxides have been reported by Paton and co-workers.14
Both 7 and 8 are C6 chiral building blocks that are
extremely attractive from a synthetic point of view, since
they contain the information of a saccharide unit blocked in
the 1,6-anhydro bridge, which avoids the use of protecting
groups at C-1 and C-6 OH. Furthermore, the bridge sterically
hinders the â-face of both molecules, forcing the reactions
to occur on the R-face (the exo face), usually with a high
degree of stereoselectivity. Their use in the syntheses of
imino-C-disaccharides has been exploited by Vogel and co-
workers.7e,g,i,8
Isolevoglucosenone (7), readily derived from D-glucose
in four synthetic steps,15,16 was reacted with 1 equiv of
(8) (a) Cardona, F.; Robina, I.; Vogel, P. J. Carbohydr. Chem. 2000,
19, 555-571. (b) Marquis, C.; Cardona, F.; Robina, I.; Wurth, G.; Vogel,
P. Heterocycles 2002, 56, 181-208.
(9) Cardona, F.; Valenza, S.; Goti, A.; Brandi, A. Tetrahedron Lett.
1997, 38, 8097-8100.
(10) Cardona, F.; Valenza, S.; Picasso, S.; Goti, A.; Brandi, A. J. Org.
Chem. 1998, 63, 7311-7318.
In this Letter, we report a straightforward access to a new
class of directly linked (1f3)-imino-C-disaccharides belong-
ing to D-allo and D-gulo series (9 and 10, respectively) by
means of cycloaddition reactions between enantiopure poly-
hydroxylated pyrroline N-oxides 4 and isolevoglucosenone
(7).12
(11) Cardona, F.; Salanski, P.; Chmielewski, M.; Valenza, S.; Goti, A.;
Brandi, A. Synlett 1998, 1444-1446.
(12) For recently reported cycloadditions of nitrones 4 to sugar-derived
R, â-unsaturated lactones, see: (a) Jurczak, M.; Rabiczko, J.; Socha, D.;
Chmielewski, M.; Cardona, F.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry
2000, 11, 2015-2022. (b) Socha, D.; Jurczak, M.; Frelek, J.; Klimek, A.;
Rabiczko, J.; Urban´czyk-Lipkowska, Z.; Suwin´ska, K.; Chmielewski, M.;
Cardona, F.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry 2001, 12, 3163-
3172.
(13) LeVoglucosenone and LeVoglucosans, Chemistry and Applications;
Witczak, Z. J., Ed.; ALT Press, Inc., Science Publishers: Mount Prospect,
IL, 1994.
(14) (a) Blake, A. J.; Forsyth, A. C.; Paton, R. M. J. Chem. Soc., Chem.
Commun. 1988, 440-442. (b) Blake, A. J.; Cook, T. A.; Forsyth, A. C.;
Gould, R. O.; Paton, R. M. Tetrahedron 1992, 48, 8053-8064.
(15) Horton, D.; Norris, P.; Roski, J. J. Org. Chem. 1996, 61, 3783-
3793.
(7) (a) Fre´rot, E.; Marquis, C. Vogel, P. Tetrahedron Lett. 1996, 37,
2023-2026. (b) Baudat, A.; Vogel, P. Tetrahedron Lett. 1996, 37, 483-
484. (c) Baudat, A.; Vogel, P. J. Org. Chem. 1997, 62, 6252-6260. (d)
Kraehenbuehl, K.; Picasso, S.; Vogel, P. HelV. Chim. Acta 1998, 81, 1439-
1479. (e) Zhu, Y.-H.; Vogel, P. Chem. Commun. 1999, 1873-1874. (f)
Marquis, C.; Picasso, S.; Vogel, P. Synthesis 1999, 1441-1452. (g) Zhu,
Y.-H.; Vogel, P. J. Org. Chem. 1999, 64, 666-669. (h) Cheng, X.; Kumaran,
G.; Mootoo, D. R. Chem. Commun. 2001, 811-812. (i) Navarro, I.; Vogel.
P. HelV. Chim. Acta 2002, 85, 152-160.
1476
Org. Lett., Vol. 5, No. 9, 2003

D-tartaric acid-derived nitrone 1117 in toluene at room
temperature, affording after 1.5 h a single adduct 13 in 89%
yield. Analogously, L-malic acid-derived nitrone 1218 af-
forded the sole adduct 14 (Scheme 1). Hence, the cycload-
Scheme 2a
Scheme 1a
a Reaction conditions: (a) 2 equiv of (rac)-15, toluene, rt, 2.5
h.
The high facial preference shown allowed partial kinetic
resolution19 of the cis-disubstituted racemic nitrone 15.20
Reaction of isolevoglucosenone (7) with 2 equiv of
racemic nitrone 15 gave a major exo-anti adduct 16, whose
structure has been determined by X-ray analysis, in 32%
yield, and 50% of enantioenriched (3S,4R)-nitrone 15 was
recovered (54% ee).21,22 The presence of a minor adduct,
which has not been fully characterized yet, was visible in
a Reaction conditions: (a) toluene, rt, 1.5-2.5 h; 89% for 13,
89% for 14.
dition reactions were completely regio- and stereoselective,
1
as confirmed by H NMR analysis of the crude reaction
mixtures.
1
The unambiguous structure determination relies on spectral
data, including two-dimensional COSY and NOESY NMR
spectra. For instance, adduct 13 displayed cross-peaks
between signal pairs at δ 4.36 (H-2) and 2.67 ppm (H-4′), δ
4.02 (H-2′) and 3.41 ppm (H-3), and δ 3.90 (Hendo-6) and
the H NMR spectrum of the crude reaction mixture.
Cycloadducts 13, 14, and 16 can be readily converted into
imino-C-disaccharides. For example, stereoselective reduc-
tion of the carbonyl moiety at C-4 of 14 using either
DIBAL-H at low temperature or NaBH4 at room-temperature
opens the way to D-gulo and D-allo imino-C-disaccharides,
respectively (Scheme 3). When adduct 14 was reacted with
1
3.41 ppm (H-3) in the two-dimensional NOESY H NMR
spectrum. The single cycloaddition product isolated in both
cases is the result of the preferred approach of the nitrones,
in an exo fashion, to the lower face of isolevoglucosenone 7
(the R-face). By this approach (Figure 1), repulsive van der
Scheme 3a
a Reaction conditions: (a) DIBAL-H (1.5 equiv), CH2Cl2, -78
°C, 4 h, 74%. (b) NaBH4 (3.5 equiv), EtOH, rt, 2.5 h, 90%. (c)
Ac2O, py, rt, 5.5 h and 75% yield for 18, 16 h and 90% yield for
20.
Figure 1. Preferred exo approach of nitrones 11 and 12 to the
R-face of isolevoglucosenone (7), anti to the 1,6-anhydro bridge
and the vicinal t-butoxy.
Waals interactions with the vicinal OR group of the nitrone
and the 1,6-anhydro bridge of 7 are avoided.
Reactions of nitrones 11 and 12 with 7 occur with double
asymmetric induction through “matched” interactions.
1.5 equiv of DIBAL-H at -78 °C, the sole endo alcohol 17
was formed. Reaction of 14 with an excess of NaBH4 at
(19) For an account on kinetic resolutions by means of cycloaddition
reactions, see: Cardona, F.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 2001,
2999-3011.
(16) For more recent syntheses of 7, see: (a) Witczak, Z. J.; Chen, H.;
Kaplon, P. Tetrahedron: Asymmetry 2000, 11, 519-532. (b) Kadota, K.;
ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Synthesis 2000, 1372-1374.
(c) Witczak, Z. J.; Kaplon, P.; Kolodziej, M. J. Carbohydr. Chem. 2002,
21, 143-148.
(17) Cicchi, S.; Ho¨ld, I.; Brandi, A. J. Org. Chem. 1993, 58, 5274-
5275.
(18) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743-
4748.
(20) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi,
A. Eur. J. Org. Chem. 2000, 3633-3645.
(21) By means of cycloadditions to triacetyl-D-glucal, (3S,4R)-nitrone
15 could be recovered with 37% ee: Cardona, F.; Valenza, S.; Goti, A.;
Brandi, A. Eur. J. Org. Chem. 1999, 1319-1323.
(22) Ee of the recovered nitrone was determined by 1H NMR experiment
with Yb(hfc)3 as a chiral shift reagent: Cicchi, S.; Corsi, M.; Brandi, A.;
Goti, A. J. Org. Chem. 2002, 67, 1678-1681.
Org. Lett., Vol. 5, No. 9, 2003
1477

room temperature, on the contrary, afforded a 4:1 mixture
of 19 and 17 (with LiAlH4 at -78 °C, a 1:1 mixture of the
two alcohols was formed). The relative configurations of 17
Scheme 5a
1
and 19 were determined by analysis of H NMR and two-
dimensional COSY spectra of their acetates 18 and 20 and
by X-ray analysis of 20, which also confirms the stereo-
chemistry assigned to adduct 14 (Scheme 3).
The dioxolane ring opening of the anhydropyranose moiety
was troublesome. No bridge opening occurred upon treatment
of 17 with anhydrous methanol saturated with HCl (65 °C,
15 h) or with a 2-fold excess of pTsOH in MeOH at reflux
temperature for 3.5 h. The methodology proposed by Witczak
and co-workers23 for the hydrolysis of anhydropyranoses,
already used by Vogel et al.,8b was successfully applied.
After deprotection of the tBu group of 17 with pTsOH,
N-O bond cleavage was readily achieved by hydrogenation
of crude diol 21 over Pd(OH)2/C (Scheme 4). Protection of
a Reaction conditions: (a) TFA, Ac2O, 24 h, 93%.
mixture of the â- and R-isomers, which could be partially
separated by flash column chromatography (Scheme 5). It
should be noted that acetolysis on 17 or on the diacetate of
21 did not succeed, showing that assistance of the acetoxy
group at C-2 is needed.
Compound 25 is an immediate precursor of a new directly
linked (1f3)-imino-C-disaccharide in the D-gulo series.
In conclusion, we have presented the potential of the
present approach for the synthesis of a broad new class of
directly linked (1f3)-imino-C-disaccharides, by means of
cycloadditions of polyhydroxylated cyclic nitrones to isolevo-
glucosenone. Work is underway in our laboratories to widen
the scope of this approach for a general synthesis of imino-
C-disaccharides and to evaluate their efficiency as glycosi-
dase inhibitors.
Scheme 4a
a Reaction conditions: (a) pTsOH, reflux, 3.5 h. (b) Pd(OH)2/
C, H2, MeOH, overnight. (c) TFFA, TFA, overnight, then MeOH,
aqueous NH3, 10 min. (d) Ac2O, py, overnight, 29% yield from
17.
Acknowledgment. We thank Dr. Cristina Faggi for her
determinant contribution on X-ray crystal structure deter-
mination. This work was supported by a research grant from
the University of Florence, Italy (Progetto Giovani Ricer-
catori 2002) and by the Ministry of Instruction, University
and Research (MIUR, Cofin 2002), Italy.
the amine moiety of crude 22 as a trifluoroacetamide was
carried out by treatment with (CF3CO)2O and trifluoroacetic
acid, followed by methanolysis in the presence of catalytic
ammonia,24 which led to 23. Peracetylation of crude 23 under
standard conditions (Ac2O, pyridine) gave triacetate 24,
obtained after FCC in 29% yield over four steps starting from
17 (Scheme 4).
Supporting Information Available: Experimental pro-
cedures for all new compounds. Full characterization for
compounds 13, 14, 16, 18, 20, and 25; 1H NMR, 13C NMR,
MS, and IR spectra for compounds 17 and 19; 1H NMR and
13C NMR spectra for compound 24; X-ray data for com-
Finally, acetolysis of 24 with acetic anhydride and
trifluoroacetic acid afforded 25 in 93% yield as a 1.4:1
pounds 16 and 20 in CIF format; and Copies of 1H and 13
C
NMR spectra of compounds 13, 14, 16-20, 24, 25R, and
25â. This material is available free of charge via the Internet
at http://pubs.acs.org.
(23) Witczak, Z. J.; Chhabra, R.; Chen, H.; Xie, X.-Q. Carbohydr. Res.
1997, 301, 167-175.
(24) Chen, X.-Y.; Link, T. M.; Schramm, V. L. J. Am. Chem. Soc. 1996,
118, 3067-3068.
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