Synthesis and x-ray structure of (2r, 3r, 4r, 5r)-3,4,5-tris-benzyloxy-2- benzyloxymethyl-piperidin-1-ol, the n-hydroxy-analogue of 2,3,4,6-tetra-o- benzyl-1-deoxymannojirimycin

Article abstract of DOI:10.1007/s10870-008-9506-8

The title compound 8 was obtained for the first time by hydride-mediated reduction of the d-fructose-derived nitrone 9. The N-hydroxy piperidine 8 is a precursor of the N-hydroxy analogue of DMJ, a potent inhibitor of α-mannosidases. It was isolated as co

Full text of DOI:10.1007/s10870-008-9506-8

J Chem Crystallogr (2009) 39:494–499
DOI 10.1007/s10870-008-9506-8
ORIGINAL PAPER
Synthesis and X-ray Structure of (2R, 3R, 4R, 5R)-3,4,5-Tris-
Benzyloxy-2-Benzyloxymethyl-Piperidin-1-ol, the N-Hydroxy-
Analogue of 2,3,4,6-Tetra-O-Benzyl-1-Deoxymannojirimycin
Emilie Racine Æ Christian Philouze Æ
Sandrine Py
Received: 7 October 2008 / Accepted: 13 November 2008 / Published online: 11 December 2008
Ó Springer Science+Business Media, LLC 2008
Abstract The title compound 8 was obtained for the first
time by hydride-mediated reduction of the D-fructose-
derived nitrone 9. The N-hydroxy piperidine 8 is a precursor
of the N-hydroxy analogue of DMJ, a potent inhibitor of a-
mannosidases. It was isolated as colorless crystals (triclinic,
P1 space group) exhibiting the following cell parameters:
[5], tumor metastasis [6], and lysosomal storage disorders
[7, 8]. They are generally admitted to inhibit glycoprocessing
enzymes by mimicking an oxonium intermediate of the
catalytic process, thus being considered as transition state
analogues [9].
The first iminosugar to be reported was nojirimycin (1),
a natural product isolated from Streptomyces roseochrom-
ogenes [10] that demonstrated to be a powerful inhibitor of
b-D-glucosidases (Fig. 1) [11]. However its short lifetime
in vivo has limited its usefulness and soon, more stable
analogues lacking the hemiaminal functionality such as
1-deoxynojirimycin [12] (DNJ, 2) have been developed.
Intense research in this area culminated in the approval of
ZavescaÒ (N-butyl deoxynojirimycin or miglustat, 3) for
the treatment of type-1 Gaucher’s disease and of GlysetÒ
(N-hydroxyethyl deoxynojirimycin or miglitol, 4) for the
treatment of type-2 diabetes mellitus, both currently used
as oral drugs [1–3]. Based on the hypothesis that DNJ
mimics the oxonium of gluco- configuration and inhibits
preferentially glucosidases, 1-deoxymannojirimycin (DMJ,
5) was next considered as a mannosidase inhibitor [13–15],
1-deoxygalactonojirimycin (DGJ, 6) as a galactosidase
inhibitor [16, 17], etc. (Fig. 1).
˚
˚
˚
a = 9.947(2) A; b = 12.155(2) A; c = 13.864(5) A; a =
100.98(3)°; b = 97.94(2)°; c = 109.50(1)°. The X-ray
analysis of a monocrystal of 8 allowed confirmation of its
relative configurations and showed the anti orientation of its
N-hydroxy group. This structural feature should be useful for
considering the interaction of N-hydroxy iminosugars with
the recognition site of carbohydrate processing enzymes.
Keywords Iminosugars ꢀ N-Hydroxypiperidines ꢀ
Deoxymannojirimycin ꢀ Glycosidase inhibitors ꢀ
Crystal structure ꢀ Binding properties
Introduction
Iminosugars, also named iminocyclitols, are polyhydroxy-
lated heterocycles containing a basic endocyclic nitrogen
atom. They are one of the most important class of glycosi-
dase inhibitors [1, 2] and, more generally, of glycoprocessing
enzyme modulators [3]. Since these enzymes are involved in
a number of important biological processes, iminosugars
have tremendous potential as therapeutic agents against a
wide range of diseases such as diabetes [4], viral infections
However, establishing structure–activity relationship in
the class of iminosugars was quickly found to not be that
trivial. Crystallographic studies, combined with theoretical
calculations are often needed to rationalize the inhibitory
activity of iminosugars towards specific enzymes. As the
available crystallographic data relating to carbohydrate-
processing enzymes and their respective active sites have
been recently increasing, rational inhibitor design studies
can now be undertaken. For representative studies using
crystallographic data of enzyme–inhibitor complexes to
define and quantify the interaction of inhibitors with their
active site, see [18–20]. For examples of computational
E. Racine ꢀ C. Philouze ꢀ S. Py (&)
´
Departement de Chimie Moleculaire (SERCO) UMR-5250,
ICMG FR-2607, CNRS, Universite Joseph Fourier, BP 53,
´
´
38041 Grenoble Cedex 09, France
e-mail: Sandrine.Py@ujf-grenoble.fr
123

J Chem Crystallogr (2009) 39:494–499
495
Fig. 1 Piperidine iminosugars
R
N
H
N
H
N
H
N
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
2, R = -H: DNJ
OH
OH
OH
OH
OH
OH
OH
1: Nojirimycin
5: DMJ
6: DGJ
3, R = -(CH2)3CH3: Miglustat
4, R = -(CH2)2OH: Miglitol
OH
studies by molecular dynamics of complexes of imino-
sugars with the active site of glycoprocessing enzymes
using X-ray crystallographic data see [21–24]. For such
studies, crystallographic data on iminosugar-type ligands/
inhibitors are of major importance to define their favoured
conformations, bond angles and coordinates of specific
substituents. In this paper, we report the synthesis and
crystallographical data of a novel N-hydroxypiperidine 8 of
manno- configuration, which would be useful for a better
understanding of the positioning of DMJ derivatives in the
active site of mannosidases (Fig. 2).
OH
N
NH
2
H
H
Me
N
CO H
2
O
OTBS
HO
OH
O
OH
11
10: SB-219383
Fig. 3 Known N-hydroxypiperidines
OH
7
O
The important biological activities of iminosugars have
motivated great interest among synthetic chemists. How-
ever, while synthetic and biological studies on piperidines
have been extensively investigated [25–27] only very few
reports describe the synthesis and the properties of their N-
hydroxy analogues. To the best of our knowledge, the only
example of bioactive N-hydroxypiperidine reported in the
literature is SB-219383 (10) a natural product extracted
from Micromonospora sp. that has been developped by
GlaxoSmithKline as a potent and selective inhibitor of
bacterial tyrosyl tRNA synthetase (Fig. 3) [28–30]. In
N
L-Selectride (2 equiv), THF
N
OBn
OBn
OBn
2
−80 °C to −10 °C, 9.5 h
5
OBn
BnO
BnO
86 %
OBn
OBn
8
9
Scheme 1
confirmation of the configuration at the newly created C-2
stereogenic center, but also the spatial orientation of the N–
OH bond.
¨
terms of crystallographic studies, the group of Jager has
published the X-ray structure of N-hydroxy piperidine 11
obtained by sodium borohydride reduction of a (E,Z)
mixture of 2-O-tert-butyldimethylsilyl-3,4-O-isopropyli-
dene-L-arabino-5-hexenose oxime, followed by a Cope-
House cyclization [31].
Experimental
To a solution of nitrone 9 (50 mg, 0.09 mmol) in distilled
THF (1 mL), L-selectride (1 M solution in THF,
0.186 mL, 0.18 mmol, 2 equiv) was added at -80 °C. The
reaction mixture was stirred at -80 °C during 2.5 h, then
at -10 °C during 7 h. Aqueous saturated solution of
NH4Cl (0.5 mL) was added. The aqueous layer was
extracted three times with Et2O. The organic phase was
stirred with an aqueous saturated solution of KHF2 (2 mL)
during 1 h. The aqueous layer was extracted three times
In the course of an ongoing program [32–35] based on
the use of carbohydrate-derived nitrones [36] as synthetic
intermediates for the preparation of novel iminosugars,
nitrone 9 was stereoselectively reduced to the N-hydroxy-
piperidine 8 using L-selectride as a hydride source
(Scheme 1) [37]. Crystallization of 8 in a pentane/diethyl
ether mixture afforded white crystals that turned out suit-
able for single crystal X-ray analysis, allowing not only the
Fig. 2 Synthesis of DMJ and
N-OH-DMJ from nitrone 9
R
OH
N
OH
N
Chemo- and
stereoselective
reduction
O
N
Benzyl group
deprotection
N
HO
HO
BnO
BnO
OBn
OBn
OBn
OBn
OH
OBn
BnO
BnO
OH
OBn
OBn
OBn
5: R=H: DMJ
7: R=OH: N-OH-DMJ
8
9
123

496
J Chem Crystallogr (2009) 39:494–499
with Et2O. The organic phase was washed with brine,
dried, filtered and concentrated. Purification of the residue
by chromatography on silica gel (pentane/AcOEt: 3:1, 1:1,
0:1) afforded pure, colorless crystals of N-hydroxypiperi-
dine 8 (43 mg, 86%).
Table 1 Crystal data and structure refinement
Compound 8
(2R, 3R, 4R, 5R)-3,4,5-tris-
benzyloxy-2-benzyloxymethyl-
piperidin-1-ol
CCDC deposit no.
Color/shape
683365
Colorless/prism
(2R, 3R, 4R, 5R)-3,4,5-Tris-Benzyloxy-2-
Benzyloxymethyl-Piperidin-1-ol
Chemical formula
Formula weight
Temperature, K
Crystal system
Space group
C34H37NO5
539.67
293
20
Colorless crystals, mp 78–80 °C; ½aꢁD ¼ þ1:9 (c 1.00;
Triclinic
P1
CHCl3); IR (neat) m (cm-1) 3,393 (m), 3,026 (m), 2,857
(m), 1,494 (m), 1,449 (s), 1,351 (m), 1,095 (s); H NMR
1
˚
a = 9.947(2) A
Unit-cell dimensions
(24 reflections)
(400 MHz, CD3OD) d ppm 2.43 (br d, 1 H, J = 9.4 Hz,
˚
b = 12.155(2) A
7
5CH), 2.50 (d, 1 H, J = 11.9 Hz, CH2), 3.52 (dd, 1 H,
˚
c = 13.864(5) A
3
J = 3.3, 9.6 Hz, CH), 3.59 (dd, 1 H, J = 3.4, 12.0 Hz,
a = 100.98(3)°
b = 97.94(2)°
c = 109.50(1)°
1514.0(8)
2
6
7CH2), 3.79 (dd, 1 H, J = 2.6, 10.2 Hz, CH2), 3.89–3.98
2
6
4
(m, 2 H, CH and CH2), 4.11 (t, 1 H, J = 9.6 Hz, CH),
4.44 (d, 1 H, J = 11.8 Hz, OCH2Ph), 4.49–4.68 (m, 5 H,
OCH2Ph), 4.74 (d, 1 H, J = 12.1 Hz, OCH2Ph), 4.84 (d, 1
3
Unit-cell volume [A ]
˚
Z
H, J = 10.6 Hz, OCH2Ph), 7.16–7.30 (m, 20 H, CHar); 13
C
Density (calculated) (g/cm3)
Absorption coefficient (mm-1
Diffractometer/scan
1.184
NMR (75 MHz, CD3OD) d ppm 59.5 (7CH2), 67.3 (6CH2),
)
0.632
5
72.4, 72.5, 72.8 and 72.9 (2CH, CH and 2 9 OCH2Ph),
Bruker–Enraf-Nonius CAD4/
omega
74.5 (OCH2Ph), 76.2 (OCH2Ph), 76.3 (4CH), 84.3 (3CH),
128.5–129.2 (CHar), 139.8, 139.9, 140.1 (Cqar); MS (ESI?)
m/z 540 (M ? H?); Anal. Calcd for C34H37NO5: C, 75.68;
H, 6.92; N, 2.60; Found: C, 75.90; H, 7.03; N, 2.68.
A prismatic crystal, 0.25 9 0.12 9 0.08 mm3 of size,
was mounted on a glass fibre using epoxy resin (araldite).
The crystal was then centered on a Bruker-AXS-Enraf-
Nonius CAD-4 automated 4-circle diffractometer, working
at room temperature and at the monochromated (graphite)
h range for data collection (°)
Reflections measured
3.33–74.90
6,505
Independent/observed
reflections
6,237 (Rint = 0.013)/4,620
[I [ 2r(I)]
4,620/0/722
Data/restraints/parameters
Goodness of fit on F
1.945
Final R indices [I [ 2r(I)]
R indices (all data)
R1 = 0.0541, wR2 = 0.0735
R1 = 0.0643, wR2 = 0.0765
˚
CuKa radiation k = 1.54178 A. Data reduction, cell
determination and refinement were performed using the
CAD-4 software [38]. The cell parameters were determined
from 24 reflections (20.28° \ h \ 24.88°). 6,505 Reflec-
tions were recorded for h \ 75°. All the Friedel pairs were
not collected since no heavy atom was suspected to be part
of the structure. The two standard reflections for intensity
showed a significant decay of 27.54%. The data were
corrected for this decay and for the Lorenz and polarization
effects. Crystal data are summarized in Table 1.
Results and Discussion
Since compound 8 crystallized in the P1 space group, the
cell and the asymmetric unit are identical; the cell dis-
plays two molecules 8-I and 8-II which are chemically
identical even though there is no symmetry link between
them. The secondary structure results from two intermo-
lecular hydrogen bonds based on the N-hydroxyl groups
(Table 2) and from phenyl group p-stackings. Whilst
N(36) of 8-II is the acceptor of H–bond from H(1) of 8-I,
the acceptor of H-bond from H(38) of 8-II is O(2) of the
molecule 8-I.
Structure Determination and Refinement
The structure was solved using SIR-92, [39] and refined
using TeXsan. [40] C, N and O atoms were refined
anisotropically by the full matrix least-squares method. H
atoms were generally set geometrically and recalculated
before the last refinement cycle, however the hydrogen
atoms from the hydroxyl groups were located from the
Fourier Map. Figures were created using ORTEP [41] and
Insight II [42].
Table 2 Hydrogen bonds between molecules 8-I and 8-II
A
H
B
B-adc A_B
A–H H_B A–H_B
O(1) H(1)
N(36) 55401 2.845(4) 1.02 1.85
55601 2.917(3) 1.13 1.96
161.8
139.3
O(6) H(38) O(2)
123

J Chem Crystallogr (2009) 39:494–499
497
Fig. 4 Ortep drawing for
conformer II of compound 8
(10% probability for thermal
ellipsoids)
Each of the two molecules from the cell are composed
of saturated six-membered rings containing a nitrogen
atom (piperidinic rings) on which positions 3, 4 and 5 are
functionalized by benzyloxy groups, position 2 by a ben-
zyloxymethyl (Fig. 4). The nitrogen atoms are
functionalized with a hydroxy group, with N–O bond
˚
lengths of 1.444 A in both molecules. The nitrogen atoms
are pyramidal as demonstrated by the bond angles around
the nitrogen atom (for example, in molecule 8-II: O(6)–
N(36)–C(37) = 106.7(2); O(6)–N(36)–C(41) = 105.3(2)°;
C(37)–N(36)–C(41) = 111.2(2)°). The observed bond
lengths and bond angles are within the regular range
observed for organic compounds [43].
The conformations of the piperidinic rings in 8-I and 8-
II display very slight differences which can be analyzed
with the Cremer and Pople parameters [44] which are
˚
Q = 0.590(4) A, U2 = 201,4(3)°, H = 175.7(3)° and
˚
Q = 0.576(4) A, U2 = 135.3(3)°, H = 177.0(3)°, respec-
tively. These indicate that the piperidinic rings are very
close to a perfect chair conformation. Direct superposition
of the six-membered rings of the two molecules using
Insight II evidences that the main differences between the
conformations consist in the folding of the benzyloxy
groups (Fig. 5). This superposition of the two conformers
8-I and 8-II shows also two main orientations of the phenyl
groups for p-stacking.
Fig. 5 Insight II drawing of the superposition of conformers 8-I
(blue) and 8-II (pink) [Refer online version for color figure]
The X-ray structure displays unambiguously the relative
configuration of the molecule, compound 8 exhibiting a
trans, trans relationship of the substituents on N-1 and C-3
compared to the benzyloxymethyl group at C-2. Since there
123

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J Chem Crystallogr (2009) 39:494–499
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is no heavy atom and since all the Friedel pairs have not been
measured, it was not possible to deduce the absolute con-
figuration from the data: the calculated Flackparameters [45]
are meaningless and there is no significative change in R
values for both possible structures. However the correct
configuration (2R, 3R, 4R, 5R)-3,4,5-tris-benzyloxy-2-ben-
zyloxymethyl-piperidin-1-ol 8 was assigned from the
starting material with the chiral centers at C-3, C-4 and C-5 in
D-fructose left unchanged by the chemical reactions used to
prepare nitrone 9 and thus, N-hydroxypiperidine 8. Inter-
estingly, the equatorial orientation of the N-hydroxy group is
also noticeable in the solid state preferred conformations of 8
(4C1 chair conformations by analogy with carbohydrates).
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Conclusion
The 2,3,4,6-tetra-O-benzyl protected derivative 8 of N-
hydroxy-1-deoxymannojirimycin (N-OH-DMJ, 7) was
prepared for the first time from a D-fructose-derived nit-
rone. Using L-selectride as the reductant, the N-hydroxy
piperidine 8 was isolated in a good yield (86%) and as a
single diastereomer. Its crystallographic data, and in par-
ticular the evidence for the equatorial orientation of its N-
hydroxy substituent, should be useful for future molecular
modeling studies and for designing novel inhibitors of
specific glycoprocessing enzymes.
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Supplementary Material
Crystallographic data (CIF) for (2R, 3R, 4R, 5R)-3,4,5-tris-
benzyloxy-2-benzyloxymethyl-piperidin-1-ol have been
deposited with the Cambridge Crystallographic Data Center
as supplementary publication number CCDC-683365. This
material is available free of charge via www.ccdc.can.
ac.uk/conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK. Fax: ?44-1223-336033. E-mail: deposit@ccdc.
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Acknowledgments We thank Mrs Marie-Louise Dheu-Andries for
her helpful support. E. R. is grateful to the French Ministry of Edu-
cation, Research and Technology (MENRT) for a doctoral fellowship.
´
This work was supported by the CNRS, the Universite Joseph Fourier
and the Agence Nationale pour la Recherche (Grant No. ANR-05-
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