1-C-Alkyl imino-d-xylitol and -l-arabinitol derivatives obtained via nucleophilic addition to pentose-derived N-tert-butanesulfinyl imines: Sugar- versus chiral auxiliary-induced stereoselectivity

Article abstract of DOI:10.1016/j.tetasy.2011.02.024

The stereoselective synthesis of 1-C-alkyl iminosugars in the d-xylo and l-arabino series as potential drugs for the treatment of lysosomal diseases has been achieved. The key step involves nucleophilic addition to pentodialdofuranose-derived imines gener

Full text of DOI:10.1016/j.tetasy.2011.02.024

Tetrahedron: Asymmetry 22 (2011) 609–612
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Tetrahedron: Asymmetry
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1-C-Alkyl imino-D-xylitol and -L-arabinitol derivatives obtained via
nucleophilic addition to pentose-derived N-tert-butanesulfinyl imines:
sugar- versus chiral auxiliary-induced stereoselectivity
Farah Oulaïdi a, Estelle Gallienne a, Philippe Compain b, , Olivier R. Martin a,
⇑
⇑
a Institut de Chimie Organique et Analytique, UMR 6005, Université d’Orléans & CNRS, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
b Laboratoire de Synthèse Organique et Molécules Bioactives, UMR 7509, Université de Strasbourg & CNRS, ECPM, 25 rue Becquerel, 67087 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of 1-C-alkyl iminosugars in the D-xylo and L-arabino series as potential drugs
Received 14 February 2011
Accepted 28 February 2011
Available online 12 April 2011
for the treatment of lysosomal diseases has been achieved. The key step involves nucleophilic addition to
pentodialdofuranose-derived imines generated using enantiopure tert-butanesulfinamide. Depending on
the pentofuranose configuration and structure, the stereoselectivity of this reaction was found to be con-
trolled either by the sugar moiety or by the stereogenic sulfur center.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
from Gaucher patients at a nanomolar sub-inhibitory concentra-
tion (10 nM).7 Moreover,
a
-C9-DIX 2 is highly selective and dis-
plays no inhibition toward -glucosidases, including lysosomal
and intestinal -glucosidases.
Recently, pharmacological chaperone therapy (PCT)1 has
emerged as a promising therapeutic option for the treatment of
glycosphingolipid lysosomal storage disorders.2,3 This small group
of a dozen inherited diseases, also known as glycosphingolipidoses,
are characterized by the deficiency of glycosidases involved in the
catabolism of glycosphingolipids in the lysosome. The chaperone
therapy is based on the ability of competitive inhibitors to enhance
the residual hydrolytic activity of the mutant enzyme at sub-inhib-
itory concentrations.1 Reversible competitive inhibitors are be-
lieved to induce or stabilize the proper conformation of the
defective enzyme, thus preventing its degradation by the ‘quality
control’ mechanism in the endoplasmic reticulum.4 The normal
trafficking to lysosomes of the mutant enzyme, which is still
catalytically active, is restored and the residual enzyme activity
is consequently enhanced in these organelles. Most of the pharma-
cological chaperones identified, to date, for the treatment of gly-
cosphingolipidoses are iminosugars. Isofagomine (Plicera™) and
1-deoxygalactonojirimycin (Amigal™) 1 are currently being evalu-
ated in clinical trials for the treatment of Gaucher and Fabry dis-
eases, respectively (Fig. 1).5 In a search for a chaperone-based
therapy for glycosphingolipidoses,6,7 we have recently identified
a
a
2. Results and discussion
The identification of -1-C-alkyl-iminoxylitol was reached by
a
way of structure–activity relationship studies taking N-alkyl-1-
deoxynojirimycin (DNJ) derivatives, such as 3, as a starting point
for optimization (Fig. 1). This provided the basis for a new para-
digm in the design of highly selective glycolipid hydrolases inhib-
itors: removal of the 5-CH2OH group of N-butyl-DNJ and a shift of
the alkyl chain from the endocyclic nitrogen atom to C-1 in the a-
position lead to selective nM inhibitors of human GCase. Based on
these results, our first objective was to extend the scope of this
structural modification to inhibitors of other lysosomal glycosi-
dases. Our prime target was b-galactocerebrosidase, which cleaves
bGalCer, and the mutations of which are at the origin of Krabbe’s
disease (globoid cell leukodystrophy).8
a-1-C-Alkyl-imino-L-
arabinitols mimic the galacto configuration of the substrate and
could therefore be powerful inhibitors of this enzyme and thus
be useful as pharmacological chaperones.9 In addition, this family
of compounds could also have a favorable effect on other lyso-
a-1-C-nonyl-iminoxylitol 2 (a-C9-DIX, Fig. 1), as an efficient phar-
macological chaperone for the treatment of Gaucher disease: this
compound is able to increase, by a factor of ꢀ2, the residual cellu-
lar activity of b-glucocerebrosidase (GCase) in N370S fibroblasts
somal glycosidases such as
a-galactosidase A (Fabry disease) or
b-galactosidase (GM1-gangliosidosis). It is important to note that no
treatment is currently available for Krabbe’s disease. In this context,
we designed synthetic strategies toward 1-C-alkyl-iminosugars in
the L-arabino series to target Krabbe’s disease, and in the D-xylo
⇑
Corresponding authors. Tel.: +33 238 494 581; fax: +33 238 417 281.
E-mail addresses: philippe.compain@unistra.fr (P. Compain), olivier.martin@
series to improve our initial synthetic sequence.7 These syntheses
hinged on nucleophilic addition to pentodialdofuranose-derived
univ-orleans.fr (O.R. Martin).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.024

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F. Oulaïdi et al. / Tetrahedron: Asymmetry 22 (2011) 609–612
N-tert-butanesulfinyl imines (Ellman’s imines). Ellman’s chiral
using methanolic HCl. Hydrolysis of the glycosidic bond, intramo-
lecular reductive amination and cleavage of the benzyl groups
were performed in a one-pot process by treatment of 8 with aque-
ous HCl in 1,4-dioxane followed by hydrogenolysis. Following this
auxiliary10 was expected to provide stereocontrol in the key imine
chain extension step, which controls the a- versus b-configuration
at the pseudo-anomeric center in the final product. Furthermore,
the addition of Grignard reagents to N-tert-butanesulfinyl imines
proceeds generally very efficiently in good yields and high
diastereoselectivity.10,11
procedure,
a-C6-DIX 9 was obtained in 28% overall yield from 8.
The one-pot process was particularly difficult to optimize, which
was in contrast to our observations in the sorbofuranose series.14
This may be explained by the relative instability of the intermedi-
ate cyclic hemiaminal under aqueous acidic conditions.15 The
influence of Ellman’s chiral auxiliary on the stereochemical out-
come of the imine chain extension step was evaluated by perform-
ing the same synthetic sequence using (S)-tert-butanesulfinamide
(Scheme 2). The addition of hexylmagnesium bromide to 10, the
epimer of imine 7, was again found to proceed in good yield and
high diastereoselectivity from the re face of the imine 10. This indi-
cated that the stereoselectivity of the addition step is likely to be
controlled by the sugar moiety and is independent of the configu-
ration at the stereogenic sulfur center.
R
H
N
H
N
N
8
HO
4
OH
HO
OH
HO
OH
OH
OH
OH
OH
1 R = H, (4S)
isofagomine
3 R = n-Butyl, (4R)
2 Ki = 2.2 nM (GCase)
Ki = 116 μm (GCase)
The high stereoselectivity of the addition of the organometallic
species to the re face of imines 7 and 10 can be rationalized by
the chelated intermediate A involving as ligands the nitrogen
atom of the N-sulfinyl imine and the ring oxygen atom of the
xylofuranose moiety (Scheme 2).16 In furanoid systems, it is well
established that the endocyclic oxygen acts as a coordinating
Lewis base in the additions of organometallic reagents to pentodi-
aldo-furanose derivatives.17 Such chelation seems to counterbal-
ance the possible chair-transition state intermediate B (Fig. 2)
proposed by Ellman in which the magnesium atom of the
Grignard reagent is chelated to the oxygen atom of the sulfinyl
imine.10 Based on these results, we decided to extend the synthe-
sis to the 1-C-alkyl-imino-L-arabinitols using racemic tert-butane-
sulfinamide (Scheme 3).
In addition, the L-lyxo precursor 14 was designed to carry a ben-
zyl glycoside to facilitate the cleavage of this group during the one-
pot intramolecular reductive amination step. The synthesis of this
Figure 1.
The synthesis of the C-alkylated iminoxylitols began with the
improved preparation of aldehyde 6, by furanoside formation,12
tritylation at the primary position, benzylation, detritylation and
Dess–Martin oxidation (Scheme 1).13 At the stage of 5, the anomers
were separated and the synthesis continued with the major one 5b.
Condensation of 6 with (R)-tert-butanesulfinamide in dry dichloro-
methane in the presence of anhydrous CuSO4 afforded imine 7. The
nucleophilic addition of hexylmagnesium bromide to this imine
provided the expected amine 8 as a single diastereoisomer in
73% yield. It is noteworthy that similar reactions performed with
less reactive L-xylose-derived N-benzyl imines led to much lower
yields.7 The configuration of the newly created stereocenter was
unambiguously established to be (R) at the stage of the piperidine
products. The formation of the piperidine ring via intramolecular
reductive amination of the unmasked aminoxylose derived from
8 proved more difficult. Removal of the sulfinyl group was realized
intermediate from commercially available
based on the optimization of known reaction sequences
(Scheme 3).18 The reaction of
-gulonolactone with an excess of
D-gulono-c-lactone is
D
acetone under acidic conditions followed by treatment with DI-
BAL-H afforded hemiacetal 12 which was converted into a separa-
ble mixture of the two anomers of benzyl furanosides 13. The
synthetic sequence was continued with the major anomer 13b.
Regioselective deprotection of the 5,6-O-isopropylidene acetal
and subsequent oxidative cleavage19 of the resulting diol provided
OH
OBn
O
O
c, d
a, b
OMe
OMe
L-xylose
TrO
HO
OH
OBn
4
5
OBn
OBn
OBn
OBn
O
O
f
g
e
O
5β
O
b
H
a
6
O
N
tBu
N
tBu
HN
S
tBu
OMe
OMe
S
OMe
OBn
OBn
OMe
S
R OBn
OBn
10
O
O
O
7
6
11 R = Hex de > 98%
H
N
OBn
O
R
( )4
h, i, j
H
H
C2
Mg
Br
H
HO
OH
HN
S
N
tBu
R'N
OMe
O
O
( )4
c,d,e
R
OBn
OH
re face
O
addition
HO
OH
9
8 R = Hex de > 98%
OH
9
RMgBr
H
H
Scheme 1. Reagents and conditions: (a) HCl (33 mM), MeOH, reflux; (b) TrCl
(1.2 equiv), pyridine, reflux, 68%; (c) NaH (4 equiv), BnBr (4 equiv), DMF, 0 °C to rt,
69%; (d) 80% AcOH, 70 °C, 80%; (e) Dess–Martin periodinane (1.2 equiv), CH2Cl2, 0 °C
to rt, quant.; (f) (R)-tert-butanesulfinamide (1.2 equiv), anhyd CuSO4, CH2Cl2, 48%;
(g) hexylmagnesium bromide (4 equiv), toluene, À78 °C to rt, 73%; (h) HCl (3 mM),
MeOH, rt, quant.; (i) 0.4 M HCl/dioxane (1/1), 75 °C; (j) H2, 10% Pd/C, rt, 28% (two
steps).
A
R' = t-BuS(O)
Scheme 2. Reagents and conditions: (a) (S)-tert-butanesulfinamide (1.2 equiv),
anhyd CuSO4, CH2Cl2, 66%; (b) hexylmagnesium bromide (4 equiv), toluene, À78 °C
to rt, 53%; (c) HCl (3 mM), MeOH, rt, quant.; (d) 0.4 M HCl/dioxane (1/1), 75 °C; (e)
H2, 10% Pd/C, rt, 30% (two steps).

F. Oulaïdi et al. / Tetrahedron: Asymmetry 22 (2011) 609–612
611
dium on carbon under mild acidic conditions (Scheme 3). This
one-pot process was found to be quite efficient as 1-C-alkyl imino-
sugars 17 and 18 were obtained in 57–69% yields (for 17 and 18).
H
O
O
tBu
H
S
S
R'
O
N
N
tBu
The pseudo-
raphy and deprotected in quantitative yields to afford 1-C-alkyl-
imino- -arabinitols 19 and 20. Having optimized the key one-pot
a- and -b-epimers were separated by flash chromatog-
Mg
R
O
O
H
Br
L
OBn
B
process of our strategy, we attempted to rationalize the low diaste-
reoselectivity observed for the addition to sulfinyl imine 15. The
loss of stereocontrol observed at C5 suggested that, contrary to
C
Figure 2.
the
D-xylo series, the stereoselectivity of the addition step was
not controlled by the sugar moiety, but might be dependent on
the configuration at the stereogenic sulfur center. To validate this
hypothesis, we studied the nucleophilic addition to the (SR)- and
(SS)-epimers of sulfinyl imines 15a and 15b (Scheme 4). The reac-
tion performed with 4 equiv of butylmagnesium bromide was
found to be highly diastereoselective; the stereoselectivity was
thus controlled by the configuration at the sulfur center. Sulfinyl
O
OH
a, b
c
O
O
D-gulono-γ-lactone
O
O
12
OBn
O
O
amines 21 and 22 were converted to
arabinitols 20a and 19a, respectively, according to the synthetic se-
quence described in Scheme 4. The marked difference of stereocon-
trol in the L-xylo and L-lyxo series may be explained as follows: the
results obtained with xylofuranose-derived imines 8 and 10 clearly
indicated that the chelation of the magnesium ions to the nitrogen
atom of the imine and the endocyclic ring oxygen atom as in inter-
mediate A is favored over the chair-transition state intermediate B
involving the oxygen atom of the sulfinyl imine as the ligand
(Fig. 2).
a- and b-1-C-butyl-imino-L-
O
O
+
OBn
O
O
O
O
O
O
13β
13α
d,e
OBn
OBn
O
O
g
f
O
tBu
N
S
O
O
O
O
O
a
b
14
15
14
OBn
OBn
H
H
( )n
O
( )n
O
OBn
N
N
O
+
tBu
N
tBu
N
H
N
h, i
tBu
S
S
OH
OH
(S)
(R) O
S
O
O
O
c
O
O
c
O
O
( )n
O
O
O
O
O
15b
15a
17a n=3; 17b n=5
17c n=8
18a n=3; 18b n=5
18c n=8
16a n=3; 16b n=5
16c n=8
OBn
OBn
O
O
H
H
j
j
H
N
H
tBu
tBu
N
S
S
O
O
O
O
H
H
O
( )2
O
( )2
( )n
N
( )n
N
22
21
OH
OH
d,e,f
HO
HO
d,e,f
19a
OH
OH
20a
20a n=3; 20b n=5
20c n=8
19a n=3; 19b n=5
19c n=8
Scheme 4. Reagents and conditions: (a) (R)-tert-butanesulfinamide (1.2 equiv),
anhyd CuSO4, CH2Cl2, 74%; (b) (S)-tert-butanesulfinamide (1.2 equiv), anhyd CuSO4,
CH2Cl2, 77%; (c) butylmagnesium bromide (4 equiv), toluene, À78 °C to rt, 66% 21,
78% 22; (d) HCl (3 mM), MeOH, rt; (e) H2, 10% Pd/C, iPrOH/AcOH (100/1), rt; (f)
Dowex 50WX8 (H+), dioxane/H2O (1/1), rt, 83% 19a, 69% 20a for the three steps.
Scheme 3. Reagents and conditions: (a) acetone, H2SO4, anhyd CuSO4, rt, 97%; (b)
DIBAL-H (3 equiv), CH2Cl2, À78 °C, 86%; (c) NaH (2 equiv), BnBr (2 equiv), TBAI
(cat.), DMF, 76% (13b), 16% (13a); (d) 70% AcOH, rt, 94%; (e) NaIO4 on SiO2, CH2Cl2,
0 °C, quant.; (f) tert-butanesulfinamide (1.2 equiv), anhyd CuSO4, CH2Cl2, 80%; (g)
alkylmagnesium bromide (4 equiv), toluene, À78 °C to rt, 76% (16a), 73% (16b), 64%
(16c); (h) HCl (3 mM), MeOH, rt; (i) H2, 10% Pd/C, iPrOH–AcOH (100/1), rt, 46%
(17a), 19% (18a), 39% (17b), 18% (18b), 49% (17c), 20% (18c) (two steps); (j) Dowex
50WX8 (H+), dioxane/H2O (1/1), rt, quant.
In the L-lyxo series, the 2,3-O-isopropylidene acetal induces
strong conformational constraints and steric effects. As a result,
the conformation of the imine around the sp2–sp3 bond required
for chelation becomes less favorable, and the system adopts an
‘open’ conformation such as C, which favors sulfinyl imine-induced
stereocontrol by a transition state as illustrated in B.
aldehyde 14 in 94% yield over two steps. Condensation of 14 with
racemic tert-butanesulfinamide afforded the key imine intermedi-
ate 15. The nucleophilic addition of various organomagnesium re-
agents to sulfinyl imine 15 proceeded with acceptable to good
yields. However, in contrast to the results obtained with sulfinyl
imines 7 and 10, a significant loss in stereoselectivity was ob-
served.20 The one-pot deprotection (tert-butanesulfinyl and benzyl
groups) and intramolecular reductive amination were performed
on a mixture of diastereoisomers 16 using hydrogen over palla-
3. Conclusion
In conclusion, we have developed an efficient, stereocontrolled
access to
a- or b-1-C-alkyl-imino-L-arabinitols. The key step in-
volves the nucleophilic addition to pentose-derived imines gener-
ated from enantiopure tert-butanesulfinamide. A comparison with
results obtained in the D-xylo series indicated that, depending on

612
F. Oulaïdi et al. / Tetrahedron: Asymmetry 22 (2011) 609–612
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the pentose structure, the stereoselectivity of the addition step was
controlled either by the sugar moiety or by the configuration at the
stereogenic sulfur center. The evaluation of these iminosugars as
chaperones for the treatment of glycosphingolipidoses is currently
in progress.
Acknowledgments
Financial support of this study by grants from ANR (07MRAR-
015-01), CNRS and the French Department of Research is gratefully
acknowledged. One of us (F.O.) thanks the CNRS and Région Centre
for a fellowship.
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