Ring-opening reactions of iminosugar-derived aziridines: Application to the general synthesis of α-1-C-substituted derivatives of fagomine

Article abstract of DOI:10.1016/S0957-4166(03)00364-1

A general approach to α-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-α-C-glycosides) by ring-opening reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate, is reported.

Full text of DOI:10.1016/S0957-4166(03)00364-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1969–1972
Ring-opening reactions of iminosugar-derived aziridines:
application to the general synthesis of a-1-C-substituted
derivatives of fagomine
Jean-Yves Goujon,a David Gueyrard,a Philippe Compain,a,* Olivier R. Martina,* and Naoki Asanob
aInstitut de Chimie Organique et Analytique, CNRS-Universite´ d’Orle´ans, rue de Chartres, BP 6759, 45067 Orle´ans, France
bFaculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan
Received 14 April 2003; accepted 29 April 2003
Abstract—A general approach to a-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-a-C-glycosides) by ring-opening
reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate, is
reported. The nine-step reaction sequence proceeded in an overall yield of 14–28% from tri-O-benzyl-D-glucal. In the course of
this study, the synthesis of a-1-C-ethyl-fagomine as well as of 1,N-anhydro derivatives of fagomine has been achieved for the first
time. © 2003 Elsevier Ltd. All rights reserved.
our knowledge, only one example of a natural fagomine
C-glycoside (compound 3)5 and four examples of imi-
nosugar-derived aziridines having the 1-azabicyclo-
[4.1.0]heptane skeleton have been reported to date: one
independently by Ganem,6a compound 4, and its enan-
tiomer by Paulsen,6b one by Vasella,7 compound 5, and
two by our group, compounds 6a8a and 6b8b (Scheme
2).
Several classes of aziridine-containing natural products
exhibit useful biological activity against a wide range of
cancers or as antibiotic agents.1 These properties are
intimately associated with the chemical reactivity of the
aziridine ring. Baeyer strain combined with the elec-
tronegativity of the nitrogen atom explain the ability of
the three-membered saturated heterocycle to undergo
ring-opening reactions under relatively mild condi-
tions.1 As a result, aziridines have a great value in
organic synthesis as chemical intermediates. In order to
take advantage of both the biological and synthetic
properties of aziridines, we have designed a strategy for
the preparation of iminosugar-derived aziridines 1 as
potential irreversible inhibitors of glycosidases (P=H)
and as advanced intermediates for the general synthesis
of a-1-C-substituted derivatives of fagomine 2 of bio-
logical significance (P=protecting group) (Scheme 1).
Scheme 1.
Owing to their properties as inhibitors of carbohydrate-
processing enzymes,2 iminosugars promise a new gener-
ation of carbohydrate-based therapeutics for the
control of various diseases3 including cancer, viral
infection and lysosomal storage disorders. In addition,
fagomine was found recently to have potent antihyper-
glycemic effect in streptozotocin-induced diabetic mice
and to enhance glucose-induced insulin secretion.4 To
* Corresponding authors. Fax: +33 (0) 2 38 41 72 81; e-mail:
philippe.compain@univ-orleans.fr; olivier.martin@univ-orleans.fr
Scheme 2.
0957-4166/03/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00364-1

1970
J.-Y. Goujon et al. / Tetrahedron: Asymmetry 14 (2003) 1969–1972
chemical outcome of the cyclization of the latter hep-
tenitol. To avoid degradation, the mixture of the two
stereoisomers 12 was directly engaged, without purifica-
tion, in the subsequent cyclization promoted by DBU.
The aziridine 13 was obtained in 74% yield from 11
after purification by flash chromatography. Having the
key bicyclic iminosugar 13 in hand, we first investigated
ring-opening reactions of the aziridine with various
heteroatomic nucleophiles including thiol, amine, alco-
hol, carboxylate and phosphate (Table 1 and Scheme
4).
Herein, we report the first synthesis of a 1,N-anhydro
derivative of fagomine 1, its deprotection and its uti-
lization as an advanced intermediate for the synthesis
of a-1-C-substituted derivatives of fagomine 2 by way
of regioselective opening reaction of the aziridine ring.
The synthesis of the key intermediate 13 was performed
in eight steps and 34% overall yield from tri-O-benzyl-
D
-glucal 7 (Scheme 3). Alkene 99 was obtained in two
steps by the conversion of 7 into the corresponding
2-deoxysugar 8 by a mild one-pot procedure,10 followed
by Wittig reaction. We then examined the introduction
of the amino group at C6 of the -xylo heptenitol 9 by
D
way of a double Mitsunobu reaction. The configuration
at C6 of 9 was inverted efficiently in 79% yield by
reaction with p-nitrobenzoic acid in the presence of
Ph3P and DIAD,8a followed by debenzoylation under
basic conditions to give the
second Mitsunobu reaction using phthalimide as nitro-
gen nucleophile afforded the expected -xylo amino
L
-arabino heptenitol 10. A
D
Scheme 4. Ring-opening reactions of aziridine 13.
sugar 11 in 72% yield after removal of the phthalimido
group. The amino-heptenitol 11 was then cyclized using
NIS as the source of electrophile to produce the rela-
tively unstable 1-C-iodomethyl derivatives of fagomine
12 with a good diastereoselectivity in favor of the
a-diastereoisomer (70% de). The two epimers could be
separated by flash chromatography, even though partial
decomposition occurred.
Table 1.
Scheme 3. Reagents and conditions: (a) (i) NIS (1.1 equiv.),
CH3CN/H2O (95/5), 0°C, 15 mn; (ii) Na2S2O4 (4 equiv.),
NaHCO3 (10 equiv.), DMF/H2O (1/1), 5 h; (b) Ph3P+CH3Br−
(3.5 equiv.), nBuLi (3.3 equiv.), THF, 0°C to rt, 16 h, 81%
(three steps); (c) PPh3 (3 equiv.), p-nitrobenzoic acid (3
equiv.), DIAD (3 equiv.), toluene, 0°C to rt, 16 h; (d) Na (0.2
equiv.), MeOH, 1 h, 79% (two steps); (e) Phthalimide (3
equiv.), PPh3 (3 equiv.), DIAD (3 equiv.), toluene, 0°C to rt,
16 h; (f) ethylenediamine (10 equiv.), EtOH, 80°C, 5 h, 72%
(two steps); (g) NIS (1.2 equiv.), CH2Cl2, 1 h; (h) DBU (10
equiv.), THF, D, 6 h, 74% (two steps).
a
Yields determined after purification by flash chromatography.
Not optimised.
b
By contrast, the NIS-promoted cyclization of the N-
benzyl-tetra-O-benzyl
D
-gluco analogue of 1111 is com-
It is noteworthy that there has been few investigations
on the ring-opening reactions of N-alkylated aziridines
in comparison with aziridines N-activated by sub-
pletely diastereoselective: this comparison confirms the
important role of the 3-O-benzyl group in the stereo-

J.-Y. Goujon et al. / Tetrahedron: Asymmetry 14 (2003) 1969–1972
1971
stituents such as sulfonyl, phosphoryl or carbonyl
groups.1 We were pleased to find that the correspond-
ing ring-opening products 14 could be obtained in good
yields and with a high degree of regioselectivity.12
Bicyclic iminosugar 13 was readily opened with thio-
phenol in the presence of triethylamine at room temper-
ature. In the presence of a catalytic amount of lithium
perchlorate, aziridine 13 underwent cleavage by pri-
mary or secondary amines under the mild conditions
recently developed by Yadav et al. for N-tosyl aziridine
(Table 1, entries 2–4).13 Aziridine 13 was opened by
MeOH in the presence of camphorsulfonic acid (0.1
equiv.) to give 14e in 40% yield (not optimized).
Regioselective ring opening also occurred with various
carboxylic acids in dichloromethane to provide the
corresponding 2-deoxy-a-homonojirimycin derivatives
14f-h in 74 to 82% yield (Table 1, entries 6–8).7,14 The
same experimental conditions using dibenzyl phosphate
afforded protected iminosugar phosphate 14i which was
debenzylated with 10% Pd/C in MeOH/HCl 4N (20/1)
to furnish the corresponding significant glycosyl phos-
phate mimetic 14j in 85% yield (Scheme 5). To our
knowledge, this is the first example of a ring-opening
reaction of an N-alkylated aziridine by a phosphate.15
Compound 14j is a potential inhibitor of enzymes pro-
cessing Glc-1-P and could be the precursor of novel
UDP-Glc analogs as glycosyltransferase inhibitors.2c,d
reaction led to an untractable mixture of products
(using Na/NH3) or to the cleavage of the aziridine ring
to give the a-1-C-methyl analogue of 15 in quantitative
yield (using H2, Pd/C). To overcome this difficulty, we
first cleaved the benzyl groups at the stage of the
a-1-C-iodomethyl derivative 12a to generate 16. The
expected bicyclic iminosugar 17 was then obtained by
intramolecular nucleophilic substitution promoted by
K2CO3 in water (Scheme 7).18
Scheme 7. Reagents and conditions: (a) TMSI (8.5 equiv.),
CH2Cl2, 0°C to rt, 16 h, 84%; (b) K2CO3 (1.8 equiv.), H2O, 4
h, 90%.
In conclusion, ring-opening reactions of aziridine 13
with various heteroatomic nucleophiles provided a gen-
eral approach to fagomine a-C-glycosides and related
compounds. The nine-step reaction sequence proceeded
in an overall yield of 14–28% from tri-O-benzyl-D-glu-
cal 7. In the course of this study, the first synthesis of
a-1-C-ethyl-fagomine 16 has been achieved as well as
that of 1,N-anhydro derivatives of fagomine. Investiga-
tions on the activity of the synthesized fagomine C-gly-
cosides, especially as glycosidase and glycogen
phosphorylase inhibitors, are in progress and will be
reported in due course.
Scheme 5. Reagents and conditions: (a) (BnO)2P(O)OH (1.3
equiv.), CH2Cl2, 16 h, 78%; (b) H2, Pd/C, MeOH/HCl 4N
cat., 24 h, 85%.
Acknowledgements
We then turned our attention to organometallic nucleo-
philes in order to synthesize inter alia a-1-C-ethyl-
fagomine 3, the only example of a fagomine C-gly-
coside recently isolated from Adenophora triphylla var.
japonica.5 The reaction of aziridine 13 with various
organometallic reagents (MeLi, Me2CuLi, MeCeCl2)
failed to give the desired product 15 under various
experimental conditions. However, 15 could be
obtained in 65% yield after purification by flash chro-
matography by the reaction of Me2CuLi with the mix-
ture of the two stereoisomers 12 (Scheme 6).16
The authors express their gratitude to Yann Bilbille for
assistance with synthetic work and to Kyoko Ikeda for
optical activity and spectral data measurements. Finan-
cial support of this study by grants from CNRS and the
association ‘Vaincre les Maladies Lysosomales’ is also
gratefully acknowledged.
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Scheme 6. Reagents and conditions: (a) Me2CuLi (1.1 equiv.),
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fagomine 17. Under usual debenzylation conditions, the

1972
J.-Y. Goujon et al. / Tetrahedron: Asymmetry 14 (2003) 1969–1972
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1
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6.0, 9.6 Hz), 3.34 (dd, 1H, J=8.7, 9.6 Hz), 3.76 (dd, 1H,
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