Synthesis of analogues of naturally occurring 3-O-(β-d-glucopyranosyl)-fagomine

Article abstract of DOI:10.1016/j.tetlet.2006.11.116

Stereoselective synthesis of 3-α-C-glucosides of d- and l-fagomine from the corresponding C-disaccharides is reported. The ethyl glycoside of perbenzylated C-disaccharide 8 was converted via the corresponding thioglycoside 10 and reducing C-disaccharide 1

Full text of DOI:10.1016/j.tetlet.2006.11.116

Tetrahedron Letters 48 (2007) 609–612
Synthesis of analogues of naturally occurring
3-O-(b-D-glucopyranosyl)-fagomine
a
a,
b
*
´
´
´
Lukasˇ Werner, Ladislav Kniezˇo and Hana Dvorˇakova
aDepartment of Chemistry of Natural Compounds, Institute of Chemical Technology, Technicka´ 5, 166 28 Prague 6, Czech Republic
bNMR Laboratory, Institute of Chemical Technology, Technicka´ 5, 166 28 Prague 6, Czech Republic
Received 24 October 2006; revised 6 November 2006; accepted 17 November 2006
Available online 12 December 2006
Abstract—Stereoselective synthesis of 3-a-C-glucosides of D- and L-fagomine from the corresponding C-disaccharides is reported.
The ethyl glycoside of perbenzylated C-disaccharide 8 was converted via the corresponding thioglycoside 10 and reducing C-disac-
charide 11, into substituted alditol 12 which, upon oxidation and double reductive amination stereoselectively afforded pure
perbenzylated D-fagomine C-glucoside 14. In the same manner, the ethyl glycoside of perbenzylated C-disaccharide 9 was
stereoselectively converted into perbenzylated L-fagomine C-glucoside 15.
Ó 2006 Elsevier Ltd. All rights reserved.
Many polyhydroxylated piperidines mimic the structure
and spatial arrangement of pyranoses very well, differing
only in the presence of a nitrogen atom instead of the
ring oxygen atom. Therefore these compounds,
together with other hydroxylated nitrogen heterocycles,
are part of a greater family of compounds denoted as
iminosugars. Some iminosugars occur naturally and
have significant biological effects.1 Replacement of the
pyranose oxygen by nitrogen means that iminosugars
are capable of strong interactions with the active site
of glycosidases, acting as their inhibitors. Glycosidases
participate in many biologically important processes
such as intestinal digestion, post-translational process-
ing of glycoproteins or lysosomal catabolism of glyco-
conjugates. As compounds influencing these processes
by direct or indirect inhibition of glycosidases, imino-
sugars represent considerable therapeutic potential: they
may exhibit antiviral, cancerostatic or antidiabetic
effects. Methods of preparation of iminosugars, their
natural occurrence and possibilities for therapeutic
utilization are the subject of a recent special issue of
Current Topics in Medicinal Chemistry.2 Iminosugars
have been comprehensively reviewed several times
and pertinent data on hydroxylated piperidines can
be found in the recent review and references cited
therein.3
OH
H
OH
OH
H
H
N
N
HO
N
HO
HO
HO
HO
HO
OH
OH
OH
1
2
3
OH
H
OH
OH
N
OH
HO
O
H
N
O
O
O
HO
HO
HO
HO
HO
HO
HO
4
5
Keywords: Iminosugars; C-Glycosides; Stereoselective synthesis; Reductive amination.
*
Corresponding author. Tel.: +420 220 444 265; fax: +420 220 444 422; e-mail: Ladislav.Kniezo@vscht.cz
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.116

610
L. Werner et al. / Tetrahedron Letters 48 (2007) 609–612
Fagomine 1, which can be regarded as either a deoxy
derivative of 1-deoxynojirimycin 2 or a dideoxy deriva-
tive of nojirimycin 3, was isolated from the seeds of
the Japanese buckwheat Fagopyrum esculentum
Moench4 and also from the seeds of Castanospermum
australe (Leguminosae).5 Together with 6-deoxyfago-
mine and the group of tropane alkaloids, it was derived
from the Chinese crude drug ‘Ti-koppi’, the root of
Lycium chinenese (Solanaceae).6 It has been found7
that the leaves and roots of the legume Xanthocersis
zambesiaca contain not only fagomine 1 and its stereo-
isomers 3-epi-fagomine and 3,4-di-epi-fagomine but also
glucosides of fagomine, that is, 3-O-(b-D-glucopyranos-
yl)-fagomine 4, together with a small amount of 4-O-(b-
D-glucopyranosyl)-fagomine 5.
undergo enzymatic hydrolysis and thus cannot liberate
the iminosugar under in vivo conditions.
In the present letter we describe our approach to the
synthesis of 3-deoxy-3-(a-D-glucopyranosylmethyl)-D-
fagomine 6 and its stereoisomer 3-deoxy-3-(a-D-gluco-
pyranosylmethyl)-L-fagomine 7. Our interest in L-imino-
saccharides has been aroused by recent publications
drawing attention to the fact that both D-enantiomers
and L-enantiomers of iminosaccharides show inhibitory
activity toward glycosidases; D-iminosaccharides are
competitive inhibitors whereas their L-enantiomers are
noncompetitive ones.15
In our previous papers,16 we described a simple and
expedient stereoselective synthesis of a-C-(1 ! 3)-linked
disaccharides in which D-glucose is linked by a methyl-
ene bridge with 2,3-dideoxy-arabino-hexopyranose of
the D- or L-configuration. Compounds 8 and 9, easily
accessible by this synthesis16 (Scheme 1), may serve as
starting material for the synthesis of other compounds;
among other things, their dideoxy-arabino-hexopyranose
ring can be easily transformed into a piperidine for
formation of D- and L-fagomine 3-a-C-glucosides 6
and 7. We decided to perform such a transformation
using a method based on double reductive amination
of the corresponding dicarbonyl sugar intermediate.
This reaction has been reported to give very good results
in the preparation of all-equatorial substituted piperi-
dines and it was used in the highly stereoselective
preparation of 1-deoxynojirimycin17 and b-homonojiri-
mycin18 from D-glucose derivatives. Although this
method had not previously been employed for the
synthesis of fagomine, we supposed that derivatives of
2-deoxyhexopyranose might afford stereoselectively
fagomine derivatives in an analogues fashion.
Several syntheses of D-fagomine have been described.
The first time, it was prepared starting from D-glucose8
and later from D-glucal.9 Another synthesis made use
of enzymatically catalyzed aldolization,10 and recently,
a synthesis of all the four possible D-fagomine stereo-
isomers (fagomine, 3-epi-fagomine, 4-epi-fagomine, and
3,4-di-epi-fagomine), starting from the Garner aldehyde
and using ring-closing metathesis,11 has been described.
The biological activity of fagomine 1 is not as broad as
that of deoxynojirimycin 2 and nojirimycin 3, however,
it has been proven that fagomine 1 and 3-epi-fagomine
show inhibitory activity against mammalian gut a-glu-
cosidase and b-galactosidase.7 Furthermore, fagomine
exhibits a potent antihyperglycemic effect in strepto-
zocin-induced diabetic mice and potentiates glucose-
induced insulin secretion.12 Also, inhibition of lyso-
somal a-galactosidase A activity in Fabry lymphoblasts
by 4-epi-fagomine has been reported.13
So far, the role of the glycosides of iminosaccharides in
Nature is not quite clear. Thus, for example, it has been
found7 that the inhibitory activity of fagomine against
glycosidases is lost in the case of 3-O-(b-D-glucopyranos-
yl)-fagomine 4 and 4-O-(b-D-glucopyranosyl)-fagomine
5. On the other hand, inhibition studies on various gluco-
sylated1-deoxynojirimycinshaveshownthat, forexample,
the inhibitory activity of 3-O-(a-D-glucopyranosyl)-
1-deoxynojirimycin toward rat intestinal sucrase is the
same as the activity of 1-deoxynojirimycin, whereas its
inhibitory activity toward rice a-glucosidase is even
slightly higher than the activity of 1-deoxynojirimycin
itself.14 In order to gain more information on the role of
glycosylated iminosaccharides in these processes, we set
out to synthesize some of their C-glycosides. In these
compounds the glycosidic bond is replaced by the C–C
bond which mimics the glycosidic bond well but cannot
Since classical hydrolysis of the starting ethyl glycoside 8
to C-disaccharide 11 gave unsatisfactory results, this
conversion was performed in two steps. Ethyl glycoside
8 on reaction with thiophenol afforded an anomeric mix-
ture of thioglycosides 10 in 80% yield. By treating the
thioglycosides 10 with N-bromosuccinimide in aqueous
acetone, the thiophenyl group was replaced by a free
OH group, thus affording an anomeric mixture of
benzylated C-disaccharides 11. This mixture was reduced
in situ with NaBH4 to give the corresponding alditol 12,
with the overall yield from 10 to 12 being 95%. Swern
oxidation of 12 smoothly afforded keto aldehyde 13
which, without isolation, was subjected to reductive
amination, resulting in a 65% yield (after two steps) of
pure protected D-fagomine C-glucopyranoside 14 as a
crystalline substance, mp 125–127 °C. Another stereo-
isomer was not detected in the crude reaction mixture.
Application of the same procedure to ethyl glycoside 9
afforded pure protected L-fagomine C-glucopyranoside
15 in the same overall yield. In addition to NOE experi-
ments, the structure of the fagomine moiety (all-equato-
rial substitution) in compounds 14 and 15 was
unequivocally confirmed by the values of coupling
OH
OH
O
HO
HO
HO
O
OH
HO
HO
H
HO
HO
N
HO
HO
1
N
H
constants in H NMR spectra19 (for 14: J H-3/H-4 =
J H-4/H-5 = 9.7 Hz, and for 15: J H-3/H-4 = J H-4/
H-5 = 9.8 Hz).
6
7

L. Werner et al. / Tetrahedron Letters 48 (2007) 609–612
611
OBn
OBn
OBn
O
OBn
O
BnO
BnO
OBn
ii
O
i
BnO
BnO
OBn
BnO
BnO
BnO
BnO
O
BnO
BnO
O
BnO
BnO
O
OEt
SPh
OH
8
10 (80%)
11
OBn
O
OBn
OBn
6´
3´
4´
O
5´
OBn
OBn
OH
iii
O
BnO
BnO
BnO
BnO
OBn
BnO
6
1´
BnO
H
BnO
BnO
4
O
BnO
BnO
5
BnO
BnO
N
O
OH
1
2
1´´
3
12 (95%)
13
14 (65%)
OBn
OBn
O
O
i -iii
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
N
OEt
BnO
BnO
O
H
9
15 (50%)
Scheme 1. Reagents and conditions: (i) PhSH, BF3ÆEt2O, CH2Cl2, 3 h, ꢀ78 °C, then ! rt; (ii) (a) NBS, moist acetone (1% H2O), ꢀ15 °C, 1 h,
exclusion of light; (b) NaBH4, MeOH; (iii) (a) DMSO, COCl2, Et3N, CH2Cl2, ꢀ78 °C; (b) NH4þHCOOꢀ, NaBH3CN, MeOH.
7. Kato, A.; Asano, N.; Kizu, H.; Matsui, K.; Watson, A. A.;
Nash, R. J. J. Nat. Prod. 1997, 60, 312–314.
8. (a) Fleet, G. W. J.; Smith, P. W. Tetrahedron Lett. 1985,
26, 1469–1472; (b) Fleet, G. W. J.; Fellows, L. E.; Smith,
P. W. Tetrahedron 1987, 43, 979–990; (c) Fleet, G. W. J.;
Witty, D. R. Tetrahedron: Asymmetry 1990, 1, 119–
136.
In conclusion, we have shown that the 2-deoxyhexo-
pyranose moiety in the easily accessible perbenzylated
a-C-(1 ! 3)-linked disaccharides 8 and 9 can be conver-
ted in high yields to the corresponding dicarbonyl inter-
mediates, which undergo stereoselective double
reductive amination to the perbenzylated C-glucosides
of D-fagomine and L-fagomine (14 and 15, respectively).
´
´
9. Desire, J.; Dransfield, P. J.; Gore, P. M.; Shipman, M.
Synlett 2001, 1329–1331.
10. (a) Pederson, R. L.; Wong, C.-H. Heterocycles 1989, 28,
477; (b) von der Osten, C. H.; Sinskey, A. J.; Barbas, C.
F.; Pederson, R. J.; Wang, Y.-F.; Wong, C.-H. J. Am.
Chem. Soc. 1989, 111, 3924–3927; (c) Effenberger, F.;
Null, V. Liebigs Ann. Chem. 1992, 1211–1212.
11. (a) Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.;
Takahata, H. Tetrahedron: Asymmetry 2001, 12, 817–819;
(b) Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi,
I. J. Org. Chem. 2003, 68, 3603–3607.
Acknowledgments
This study was supported by the Ministry of Education,
Youth and Sport of the Czech Republic (Grant No. VZ
6046137305) and by the Grant Agency of the Czech
Republic (Grant No. 203/03/0497).
12. (a) Nojima, H.; Kimura, I.; Chen, F.-J.; Sugiura, Y.;
Haruno, M.; Kato, A.; Asano, N. J. Nat. Prod. 1998, 61,
397–400; (b) Taniguchi, S.; Asano, N.; Tomino, F.; Miwa,
I. Horm. Metab. Res. 1998, 30, 679–683.
References and notes
1. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680.
2. Iminosugars: Recent Insights into their Bioactivity and
Potential as Therapeutic Agents; Martin, O. R., Compain,
P., Eds.; Curr. Top. Med. Chem. 2003, 3, No 5.
3. Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005,
16, 1239–1287.
13. Fan, J.-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nature Med.
1999, 5, 112–115.
14. (a) Asano, N.; Oseki, K.; Kaneko, E.; Matsui, K.
Carbohydr. Res. 1994, 258, 255–266; (b) Asano, N.; Oseki,
K.; Tomioka, E.; Kizu, H.; Matsui, K. Carbohydr. Res.
1994, 259, 243–255.
15. (a) Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.;
Yu, L.; Okamoto, T.; Banba, Y.; Ouchi, H.; Takahata, H.;
Asano, N. J. Med. Chem. 2005, 48, 2036–2044; (b) Asano,
N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi,
I.; Kato, I.; Ouchi, H.; Takahata, H.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2005, 16, 223–229.
4. Koyama, M.; Sakamura, S. Agric. Biol. Chem. 1974, 38,
1111.
5. Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. H.;
Elbein, A. D. J. Nat. Prod. 1988, 51, 1198–1206.
6. Asano, N.; Kato, A.; Miyauchi, M.; Kizu, H.; Tomimori,
T.; Matsui, K.; Nash, R. J.; Molyneux, R. J. Eur. J.
Biochem. 1997, 248, 296–303.
ˇ
´
´
´ˇ
16. (a) Steˇpanek, P.; Kniezˇo, L.; Dvorakova, H.; Vojtısek, P.
ˇ´
ˇ
´
´
Synlett 2003, 963–966; (b) Steˇpanek, P.; Vıch, O.; Kniezˇo,

612
L. Werner et al. / Tetrahedron Letters 48 (2007) 609–612
´
´
´ˇ
´
L.; Dvorˇakova, H.; Vojtısek, P. Tetrahedron: Asymmetry
73.43, 72.80, 71.35, 69.11 (CH2), 82.19, 80.02, 78.17, 71.35
(CH-20, CH-30, CH-40, CH-50), 81.55 (CH-4), 75.38 (CH-
10), 61.39 (CH-5), 45.54 (CH2-1), 42.55 (CH-3), 32.68
(CH2-2), 26.54 (CH2-100). ES MS: 848.3 (M+1).
ˇ´
´
2004, 15, 1033–1041; (c) Vıch, O.; Kniezˇo, L.; Dvorakova,
H.; Raich, I.; Valenta, S. Collect. Czech. Chem. Commun.
2005, 70, 2086–2100.
ˇ
17. (a) Reitz, A. B.; Baxter, E. W. Tetrahedron Lett. 1990, 31,
6777–6780; (b) Matos, C. R. R.; Lopes, R. S. C.; Lopes, C.
C. Synthesis 1999, 571–573.
18. Saavedra, O. M.; Martin, O. R. J. Org. Chem. 1996, 61,
6987–6993.
Selected data of compound 15: 1H NMR (500.13 MHz,
CDCl3) d 7.12–7.44 (m, 30H, H arom.), 4.32–4.99 (m,
12H, CH2Ph), 4.10 (ddd, 1H, H-10, J(10,20) =
J(10,100A) = 2.6 Hz, J(10,100B) = 12.4 Hz), 3.53–3.86 (m,
8H, H20, H30, H40, H50, CH2-60, CH2-6), 3.04–3.16
(m,2H, overlap H-1, H-4), 2.74 (m, 1H, H-5), 2.60
(ddd, 1H, H-1ax, J(1ax,1eq) = J(1ax,2ax) = 12.3 Hz,
19. Selected data of compound 14: 1H NMR (500.13 MHz,
CDCl3) d 7.11–7.42 (m, 30H, H arom.), 4.42–4.99 (m,
12H, CH2Ph), 4.22 (ddd, 1H, H-10, J(10,100A) = 12.7 Hz,
J(10,20) = 5.8 Hz, J(10,100B) = 2.6 Hz), 3.56–3.80 (m, 8H,
H20, H30, H40, H50, CH2-60, CH2-6), 3.03 (dd, 1H, H-4,
J(4,3) = J(4,5) = 9.7 Hz), 2.95 (ddd, 1H, H-1eq,
J(1eq,1ax) = 12.2 Hz, J(1eq,2ax) = 4.0 Hz, J(1eq,2eq) ꢁ
1 Hz), 2.78 (m, 1H, H-5), 2.57 (ddd, 1H, H-1ax,
J(1ax,1eq) = 12.2 Hz, J(1ax,2ax) = 10.3 Hz, J(1ax,2eq) =
2.1 Hz), 2.33 (ddd, 1H, H-100B, J(100B,100A) = 14.6 Hz,
J(100B,10) = 2.6 Hz, J(100B,3) = 3.4 Hz), 2.14 (dddd,
1H, H-2eq, J(2eq,2ax) = 10.8 Hz, J(2eq,1ax) = 2.1,
J(2eq,3) = J(2eq,1eq) ꢁ 1 Hz), 1.74 (m, 1H, H-3), 1.48
(ddd, 1H, H-100A, J(100A,100B) = 14.6 Hz, J(100A,10) =
12.7 Hz, J(100A,3) = 8.3 Hz), 1.24 (dddd, 1H, H-2ax,
J(1ax,2eq) = 1.8 Hz),
2.31
(ddd,
1H,
H-100B,
J(100B,100A) = 13.5 Hz, J(100B,10) = 12.4 Hz, J(100B,3) ꢁ
0 Hz), 1.90 (dddd, 1H, H-2eq, J(2eq,2ax) = 12.2 Hz,
J(2eq,1ax) = 1.8 Hz, J(2eq,3) = J(2eq,1eq) ꢁ 1 Hz), 1.69
(m, 1H, H-3), 1.30 (ddd, 1H, H-100A, J(100A,100B) =
13.5 Hz, J(100A,3) = 12.0 Hz, J(100A,10) = 2.6 Hz), 1.20
(dddd, 1H, H-2ax, J(2ax,2eq) = 12.2 Hz, J(2ax,1ax) =
1
J(2ax,3) = 12.5 Hz, J(2ax,1eq) = 3.2 Hz). H NMR of H-
4 and H-1eq (500.13 MHz, CD2Cl2) d 3.13 (dd, 1H, H-4,
J(4,3) = J(4,5) = 9.8 Hz), 3.09 (m, 1H, H-1eq). 13C NMR
(125.77 MHz, CDCl3) d 138.80, 138.68, 138.29, 138.28,
138.01, 137.91, 137.88 (C arom.), 128.57, 128.44, 128.34,
128.22, 128.17, 128.07, 127.99, 127.95, 127.89, 127.80,
127.78, 127.58, 127.55, 127.40 (CH arom.), 75.44, 74.97,
74.63, 73.51, 73.23, 73.18, 68.90 (CH2), 82.54, 80.14, 78.13,
70.50 (CH-20, CH-30, CH-40, CH-50), 80.14 (CH-4), 70.13
(CH-10), 61.60 (CH-5), 45.23 (CH2-1), 37.78 (CH-3), 30.34
(CH2-2), 26.46 (CH2-100). ES MS: 848.3 (M+1).
J(2ax,2eq) = 10.8 Hz,
J(2ax,1ax) = J(2ax,3) = 12.5 Hz,
J(2ax,1eq) = 4.0 Hz). 13C NMR (125.77 MHz, CDCl3) d
138.71, 138.19, 138.11, 138.01 (C arom.), 128.42, 128.36,
128.29, 127.91, 127.85, 127.79, 127.73, 127.69, 127.62,
127.60, 127.54 (CH arom.), 75.31, 75.01, 73.86, 73.47,