Synthesis and biological evaluation of the first example of an eight-membered iminoalditol

Article abstract of DOI:10.1016/j.tetlet.2003.10.195

The synthesis of the first examples of eight-membered iminoalditols has been achieved from 2,3,4,6-tetra-O-benzyl-D-glucopyranose by way of a ring-closing metathesis. The (2R,3R,4R,5S)-2-hydroxymethyl-azocane-3,4,5-triol (3a), which has the D-gluco config

Full text of DOI:10.1016/j.tetlet.2003.10.195

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 579–581
Synthesis and biological evaluation of the first example of an
eight-membered iminoalditol
Guillaume Godin,a Elodie Garnier,a Philippe Compain,a,* Olivier R. Martin,a,*
Kyoko Ikedab and Naoki Asanob
aInstitut de Chimie Organique et Analytique, UMR CNRS 6005, Universiteꢀ d’Orleꢀans, BP 6759, 45067 Orleꢀans Cedex 2, France
bFaculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan
Received 19 September 2003; revised 21 October 2003; accepted 30 October 2003
Abstract—The synthesis of the first examples of eight-membered iminoalditols has been achieved from 2,3,4,6-tetra-O-benzyl-
D
-glucopyranose by way of a ring-closing metathesis. The (2R,3R,4R,5S)-2-hydroxymethyl-azocane-3,4,5-triol (3a), which has the
-gluco configuration for C-2–C-5 and appears to exist predominantly in a boat–chair conformation, is a weak inhibitor of glyco-
sidases.
D
Ó 2003 Elsevier Ltd. All rights reserved.
It may seem paradoxical that such diverse, ubiquitous,
and important biomolecules as carbohydrates are used
by Nature almost exclusively in the furanose or pyra-
nose form. This structural feature is shared by imi-
nosugars, one of the most fascinating classes of
glycomimetics reported so far. Despite the spectacular
development of these modified sugars in which the ring
oxygen is replaced by nitrogen, few examples of syn-
thetic seven-membered azacyclitols have been reported.1
To our knowledge, no eight-membered iminoalditol
has been isolated or synthesized to date. Owing to their
properties as carbohydrate-processing enzyme inhibi-
tors,2 iminosugars have recently entered the clinical field
for assessment of their therapeutic potential in a wide
range of diseases including tumor metastasis, viral
infection, and lysosomal storage disorders.3 Two imi-
nosugars have been approved as drugs: N-hydroxyethyl-
1-deoxynojirimycin (GlysetTM) 14 to treat complications
associated with type II diabetes since 1996 and N-butyl-
1-deoxynojirimycin 25 (ZavescaTM) for the treatment of
GaucherÕs disease since 2003. Considering the high
potential of iminosugars for drug discovery,3;6 it seemed
important to explore original structural frameworks,
such as medium-sized rings, in order to access new
spatial distribution of the hydroxyl groups and to in-
crease conformational flexibility. The main objectives
are thus to find more potent/selective inhibitors and to
provide new insights into the mechanism of carbohy-
drate-processing enzymes by probing further their
binding specificity.7
OH
OH
OH
Me
N
N
HO
HO
HO
HO
OH
OH
1
2
OH
OH
H
N
H
N
HO
HO
HO
HO
OH
OH
4
3a
In this context, our current work on iminosugars and
olefin metathesis reactions8 led us to design a concise
synthesis of the eight-membered iminoalditol 3a, a
higher homolog of 1-deoxynojirimycin 4. The key step
of our synthetic strategy is the ring-closing metathesis
(RCM) reaction of the 1,8-diene B obtained in four steps
from 2,3,4,6-tetra-O-benzyl-D-glucopyranose (5) by way
of a reductive amination (Scheme 1). Although RCM
reactions have been widely used to form five-, six-, and
seven-membered heterocycles, the synthesis of eight-
membered rings still remains challenging due to entropic
Keywords: Iminoalditols; Azocanes; Glycosidase inhibitors.
* Corresponding authors. Tel.: +33-2-38-49-45-81; fax: +33-2-38-41-
72-81; e-mail addresses: philippe.compain@univ-orleans.fr; olivier.
martin@univ-orleans.fr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.195

580
G. Godin et al. / Tetrahedron Letters 45 (2004) 579–581
P
N
reaction of 6 with allylamine and acetic acid in the
presence of NaBH3CN afforded an inseparable mixture
of -gluco and -ido aminoheptenitols 7a and 7b in
P
N
BnO
BnO
BnO
BnO
BnO
D
L
3
7
excellent yield (ratio 2.3:1). As a prelude to the RCM
reaction, the secondary amines 7 were derivatized as
carbamates in order to avoid detrimental chelation of
the metal center of the ruthenium–carbene catalyst.8;14
The epimeric mixture of 7a and 7b was reacted with
benzyl chloroformate in the presence of K2CO3 to pro-
duce the protected dienes 8a,b in good yield. Although
no conformational constraints were effective in our
system, the RCM reaction using catalyst 10 proceeded
smoothly to give the epimeric mixture of azocanes 9a,b
in 73% yield. Finally, the one-step removal of protecting
groups and reduction of the endocyclic double bond was
conducted using hydrogen over palladium on carbon to
complete the synthesis of the eight-membered imino-
sugars 3a,b. After various attempts, careful purification
of the mixture of epimers 3a,b by ion-exchange chro-
matography15 allowed the isolation of a pure sample of
(2R,3R,4R,5S)-2-hydroxymethyl-azocane-3,4,5-triol 3a
according to 1H NMR spectra (de > 98%).16 The 1H and
13C NMR signals of 3a were assigned by 2D experiments
(COSY and HMQC) (for selected data see Table 1). The
definite NOE interaction between H-4 and H-2 indicated
that these two protons were on the same side of the ring
6
BnO
OBn
OBn
A
B
OBn
OBn
O
O
BnO
BnO
BnO
BnO
OH
OBn
OBn
6
5
Scheme 1.
(probability of terminal olefins meeting) and enthalpic
influences (transition-state strains).9 Nevertheless, a few
recently published examples have demonstrated that it is
possible to synthesize efficiently substituted azocanes
by way of RCM using conformational constraints or
a stereoelectronic effect.10 It is noteworthy that the
unsaturated iminosugar A with a double bond tactically
positioned at C(6)–C(7) is potentially an advanced
intermediate in the preparation of various glycomi-
metics.
and thus that 3a had a pseudo
D-gluco configuration.
Commercially available 2,3,4,6-tetra-O-benzyl-D-gluco-
pyranose (5) was converted to the heptenulose 6 by
Wittig methylenation11 followed by oxidation of the
resulting secondary alcohol with PCC12 (Scheme 2). The
convergent introduction of the allylamino group at C-6
was performed by way of a reductive amination.13 The
3
Interestingly, the JH;H-coupling constants observed for
3a appear to indicate that this compound exists pre-
dominantly in a boat–chair conformation with most
substituents adopting a pseudo equatorial position. This
result is in agreement with the NMR conformational
study of Anet et al.17 on azocane, the simplest example
of an azacyclooctane.
OBn
OBn
a, b
O
Eight-membered alditol 3a was assayed toward a panel
of nine glycosidases (Table 2). Despite its pseudo
D-gluco configuration, 3a was found to be a very weak
inhibitor of glucosidases and to display better inhibition
O
BnO
BnO
BnO
BnO
OH
OBn
OBn
6
5
Cbz
N
R
N
BnO
BnO
BnO
BnO
c, d
e
BnO
Table 1. Selected 13C and 1H NMR data for compound 3a in D2O16
BnO
H3
OH
OBn
OBn
H
N
9
7a,b R = H
8a,b R = Cbz
9a,b
HO
HO
H5
de 40%
H2
H4
H
N
OH
3a
HO
HO
Mes
N
N Mes
f
Position
13Ca
J (Hz)b
Cl
Ru
2
3
4
5
6
7
8
9
61.4
73.7
81.6
72.9
29.0
26.9
42.5
62.9
J2;3 ¼ 10:5
J3;4 ¼ 9:2
J4;5 ¼ 3:7
J5;6a ¼ 1:0
J5;6b ¼ 8:7
J2;9a ¼ 9:2
J2;9b ¼ 3:7
Cl
Ph
PCy3
HO
OH
3a,b
10
Scheme 2. Reagents and conditions: (a) Ph3PþCH3Brꢀ (3 equiv),
n-BuLi (6 equiv), THF, 24 h; 90%; (b) PCC (1.8 equiv), molecular
ꢁ
sieves 3 A, CH2Cl2, 1 h; 89%; (c) allylamine (10 equiv), AcOH
ꢁ
(5.2 equiv), NaBH3CN (5 equiv), molecular sieves 3 A, MeOH, 0–
40 °C, 5 days; 98%; (d) CBzCl (3.7 equiv), K2CO3 (3 equiv), THF, 16 h;
78%; (e) 10 (6 mol %), CH2Cl2, 40 °C, 30 h; 73%; (f) H2, Pd/C, MeOH/
HCl 1 N, 24 h; 82%.
a Recorded at 125 MHz in D2O (ppm from TSPc).
b Recorded at 500 MHz in D2O (ppm from TSPc).
c TSP ¼ sodium 3-(trimethylsilyl)propionate.

G. Godin et al. / Tetrahedron Letters 45 (2004) 579–581
Table 2. Inhibition values of 3a toward selected glycosidases
581
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D. D. Tetrahedron 2003, 59, 1873.
Enzyme
Inhibition rate at 1 mM
a-Glucosidase
Rice
Yeast
33%
22.1%
28.8%
33.9%
NIa
€
2. (a) Stutz, A. E. Iminosugars as Glycosidase Inhibitors:
Rat intestinal maltase
Rat intestinal isomaltase
Rat intestinal sucrase
Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999; (b)
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b-Glucosidase
Sweet almond
37%
a-Fucosidase
Bovine epididymis
Human placenta
NIa
28.3%
a-L-Rhamnosidase
Penicillium decumbens
(110)b
a NI: no inhibition at ½Iꢁ ¼ 1mM.
b IC50 (lM).
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110 lM. No significant inhibition of a-fucosidases was
observed.
In conclusion, we have achieved a rapid synthesis of
the first examples of eight-membered iminoalditols 3 by
way of RCM. Preliminary biological evaluation of
(2R,3R,4R,5S)-2-hydroxymethyl-azocane-3,4,5-triol (3a)
indicates that this compound is a weak inhibitor of
glycosidases. This result may be explained in part by the
absence of hydroxyl groups at C-6 and C-7 (corre-
sponding to OH-3 and OH-2 in the parent glucosides).
Future work will focus on the improvement and the
extension of our synthetic strategy to other eight-
membered alditols functionalized at C-6 and C-7.
€
11. (a) Pougny, J. R.; Nassr, M. A.; Sinay, P. J. J. Chem. Soc.,
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Acknowledgements
Financial support of this study by grants from CNRS
and the association ÔVaincre les Maladies LysosomalesÕ
is gratefully acknowledged. G.G. thanks the council of
Rꢀegion Centre and the CNRS for a fellowship.
12. Lubineau, A.; Billault, I. J. Org. Chem. 1998, 63, 5668.
13. Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett. 1996,
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15. The mixture of epimers 3 was chromatographed over a
Dowex 1-X2 (OHꢀ form) with H2O as the eluant. A
further chromatography on Amberlite CG-50 column
(NHþ4 form) (H2O then 0.5 M NH4OH elution) gave a
sample of pure 3a.
References and Notes
1. For selected references see: (a) Paulsen, H.; Todt, K.
Chem. Ber. 1967, 100, 512; (b) Farr, R. A.; Holland, A. K.;
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F.; Mignani, S. Tetrahedron Lett. 1999, 40, 6005; (f)
Fuentes, J.; Olano, D.; Pradera, M. A. Tetrahedron Lett.
1999, 40, 4063; (g) Andersen, S. M.; Ekhart, C.; Lundt, I.;
16. Selected data for iminoalditol 3a: 1H NMR (500 MHz,
D2O–TSP): d 1.58 (m, 1H, H-7a), 1.72–1.81 (m, 2H, H-7b,
H-6a), 1.92 (m, 1H, H-6b), 2.69 (m, 1H, H-8a), 2.81 (m,
1H, H-8b), 2.84 (ddd, 1H, J ¼ 3:7, 9.2, 10.5 Hz, H-2), 3.60
(dd, 1H, J ¼ 3:7, 9.2 Hz, H-4), 3.67 (dd, 1H, J ¼ 9:2,
10.5 Hz, H-3), 3.69 (dd, 1H, J ¼ 9:2, 11.5 Hz, H-9a), 3.88
(dd, 1H, J ¼ 3:7, 11.5 Hz, H-9b), 3.98 (ddd, 1H, J ¼ 1:0,
20
3.7, 8.7 Hz, H-5); ½aꢁ +10.5 (c 0.2, H2O); HRMS (CI) m=z
D
192.1235 [M+H]þ (C8H18NO4 requires 191.1236).
17. Anet, F. A. L.; Degen, P. J.; Yavari, I. J. Org. Chem. 1978,
43, 3021.
€
Stutz, A. E. Carbohydr. Res. 2000, 326, 22; (h) Painter, G.
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