Synthesis of azide-armed α-1-C-alkyl-imino-d-xylitol derivatives as key building blocks for the preparation of iminosugar click conjugates

Article abstract of DOI:10.1080/07328303.2011.610544

Azide-armed α-1-C-alkyl-imino-d-xylitol derivatives have been efficiently prepared by way of olefin cross-metathesis in eight to nine steps and in an overall yield of 19% to 26% from 2,3,4-tri-O-benzyl-d-xylopyranose. Optimization of cleavage conditions of N-NAP-protected tertiary amines using DDQ in CH₂Cl₂-H₂O (18:1) is also reported. The iminosugars synthesized will be used as key building blocks in the synthesis of multivalent iminosugars of biological interest by way of Cu(I)-catalyzed azide-alkyne cycloaddition reaction.

Full text of DOI:10.1080/07328303.2011.610544

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Synthesis of Azide-armed α-1-C-Alkyl-
imino-d-xylitol Derivatives as Key
Building Blocks for the Preparation of
Iminosugar Click Conjugates
Camille Decroocq a , Laura Mamani Laparra a , David Rodríguez-
Lucena a & Philippe Compain a
a Laboratoire de Synthèse Organique et Molécules Bioactives,
Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne
de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087,
Strasbourg, France
Published online: 14 Dec 2011.
To cite this article: Camille Decroocq , Laura Mamani Laparra , David Rodríguez-Lucena & Philippe
Compain (2011): Synthesis of Azide-armed α-1-C-Alkyl-imino-d-xylitol Derivatives as Key Building
Blocks for the Preparation of Iminosugar Click Conjugates, Journal of Carbohydrate Chemistry, 30:7-9,
559-574
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Journal of Carbohydrate Chemistry, 30:559–574, 2011
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C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2011.610544
Synthesis of Azide-armed
α-1-C-Alkyl-imino-D-xylitol
Derivatives as Key Building
Blocks for the Preparation of
Iminosugar Click Conjugates
Camille Decroocq, Laura Mamani Laparra,
David Rodr´ıguez-Lucena, and Philippe Compain
Laboratoire de Synthe`se Organique et Mole´cules Bioactives, Universite´ de Strasbourg
et CNRS (UMR 7509), Ecole Europe´enne de Chimie, Polyme`res et Mate´riaux, 25 rue
Becquerel, 67087 Strasbourg, France
Azide-armed α-1-C-alkyl-imino-D-xylitol derivatives have been efficiently prepared by
way of olefin cross-metathesis in eight to nine steps and in an overall yield of 19%
to 26% from 2,3,4-tri-O-benzyl-D-xylopyranose. Optimization of cleavage conditions of
N-NAP-protected tertiary amines using DDQ in CH2Cl2-H2O (18:1) is also reported.
The iminosugars synthesized will be used as key building blocks in the synthesis of
multivalent iminosugars of biological interest by way of Cu(I)-catalyzed azide-alkyne
cycloaddition reaction.
Keywords Iminosugars; Olefin cross-metathesis; Pharmacological chaperones;
Gaucher disease; C-glycosides
INTRODUCTION
Thousands of iminosugars have been synthesized or isolated since the discov-
ery of this famous class of glycosidase inhibitors in the 1960s.[1,2] Quite surpris-
ingly, there are still very few examples of multivalent iminosugars[3,4] in the
literature, whereas numerous analogs of multimeric carbohydrates have been
reported to date.[5,6] In addition, prior glycosidase inhibition studies performed
Received June 6, 2011; accepted July 31, 2011.
Address correspondence to Philippe Compain, Laboratoire de Synthe`se Organique
et Mole´cules Bioactives, Universite´ de Strasbourg et CNRS (UMR 7509), Ecole Eu-
rope´enne de Chimie, Polyme`res et Mate´riaux, 25 rue Becquerel, 67087 Strasbourg,
France. E-mail: philippe.compain@unistra.fr
559

C. Decroocq et al.
560
N
N
N
R
R
OH
N
R =
( )5
HO
HO
R
R
O
O
OH
O
O
O
O
O
O
H
N
O
O
R
R
R
R
O
O
( )6
O
O
O
O
OH
HO
OH
2
O
O
O
O
O
O
H
N
( )n
N3
O
O
R
R
OH
HO
R
R
OH
3
1
Figure 1: Iminosugar click cluster 1 and iminoxylitol derivatives 2 and 3.
with di- to tetravalent analogs of 1-deoxynojirimycin (DNJ), a famous glycosi-
dase inhibitor, generally displayed comparable if not decreased inhibition over
their monomeric counterparts.[3] Very recently, we reported the synthesis of do-
decavalent iminosugar 1 by way of Cu(I)-catalyzed 1,3-cycloaddition of organic
azides with terminal alkynes, a so-called “click” reaction (Fig. 1).[4] Evaluation
toward a panel of glycosidases led to the first evidence of a significant multiva-
lent effect in glycosidase inhibition with binding enhancement of up to three
orders of magnitude over the corresponding monovalent ligand for Jack bean
α-mannosidase. These results have been further confirmed with multivalent
iminosugars based on a β-cyclodextrin core.[7]
In our first exploration study,[4] N-alkyl analogs of DNJ were selected as
the peripheral ligands. This class of compounds is known to consist of poorly
selective glycosidase inhibitors and therefore was used as a model for examin-
ing the influence of multivalency on inhibition selectivity. In a second step, our
aim was to prepare multivalent systems based on potent and specific inhibitors
of glycosidases of therapeutic interest. In connection with our studies on phar-
macological therapy for lysosomal diseases,[8,9] we have recently disclosed that
α-1-C-alkyl-imino-D-xylitol derivatives (α-1-C-alkyl-DIX) were highly potent
inhibitors of human β-glucocerebrosidase (GCase) with Ki values in the nM
range.[8c,9] GCase is the enzyme involved in Gaucher disease, which is one of
the most prevalent lysosomal storage disorders.[10] The lead compound of the
DIX family, α-1-C-nonyl-imino-D-xylitol (2), acts as a pharmacological chaper-
one[10b] and is able to partially restore the residual cellular activity of GCase
in N370S fibroblasts from Gaucher patients at nanomolar subinhibitory con-
centration.[9] The preparation of multivalent systems presenting potent GCase

Preparation of Azide-armed Iminosugars
561
inhibitors in multiple copies by way of azide-alkyne cycloaddition reaction re-
quires an efficient access to azide-armed α-1-C-alkyl-iminoxylitol derivatives
such as 3. This is quite a challenging task; in our initial strategy, α-1-C-alkyl-
imino-D-xylitol derivatives were obtained in 10 steps from L-xylose in low over-
all yields, the two key steps of the process (imine-chain extension and one-pot
acetal deprotection/intramolecular reductive amination) proceeding in low and
unreliable yields (ca. 5% to 35%).[9] Our synthetic strategy hinges on two key
steps: the stereoselective addition of allyl Grignard reagents to xylopyranosy-
lamine 5 and the olefin cross-metathesis reaction of α-1-C-allyl-imino-D-xylitol
derivatives 11 (Sch. 1 and 2). Structural diversity may then be easily intro-
duced by means of the second key step to access α-1-C-substituted iminoxylitol
derivatives containing linkers of different lengths and structures.
OBn NHNAP
OH
b
a
O
O
BnO
BnO
BnO
BnO
OH
NHNAP
BnO
BnO
OBn OBn
5
6
4
c
NNAP
NNAP
BnO
BnO
BnO
BnO
+
BnO
7a
BnO
7b
Scheme 1: Reagent: (a) 8, Et3N, molecular sieves 4Å, DMSO, 60◦C; (b) allylMgBr, THF, 0◦C to
rt, 70% over two steps (c) MsCl, molecular sieves 4Å, Py, 100◦C, 4 h, 76%.
RESULTS AND DISCUSSION
α-1-C-Allyl-imino-D-xylitol derivatives 14 and 15 were prepared by modifi-
cation of the chain extension methodology using glycosylamine substrates
reported by the groups of Nicotra[11] and Martin[8c,12,13] for the synthesis
of imino-C-glycosides (Sch. 1). The synthetic strategy was applied to 2-
naphthalenemethyl (NAP)-protected xylopyranosylamine 5 instead of the cor-
responding N-benzyl derivative. The N-NAP group can be cleaved very selec-
tively under mild conditions using DDQ in the presence of benzyloxy groups.[14]
Our synthetic strategy based on a cross-metathesis reaction indeed re-
quires replacement of the endocyclic amine with a less coordinating group
to avoid chelation with the catalyst metal center and thus the formation of
unproductive complexes.[15] The readily available tri-O-benzyl-D-xylopyranose
4 [16] was dissolved in DMSO and reacted with 2-naphthylmethylamine
hydrochloride (8)[17] in the presence of TEA at 60◦C. The corresponding N-
NAP glycosylamine 5 obtained was submitted to the next step without purifi-
cation. Addition of three equivalents of allylmagnesium bromide to 5 in THF

C. Decroocq et al.
562
d
b or c
NBoc
a
BnO
BnO
NR
BnO
NH
BnO
BnO
BnO
BnO
BnO
7b
BnO
12
10
11a R= Boc
11b R= Troc
H
N
OTs
N3
f
e
NBoc
NBoc
OH
g
HO
HO
HO
HO
( )5
OH
13
OH
15
HO
OTs
N3
( )5
( )5
14
OH
CN
Mes N
Cl
N
Mes
Mes N
N
Cl
Mes
Cl
Ph
N
BnO
BnO
Ru
Ru
Cl
BnO
PCy3
O
17
16
9
Scheme 2: Reagent: (a) DDQ, CH2Cl2/H2O, 0◦C to rt, 86%; (b) Boc2O, Et3N, CH2Cl2, 0◦C to rt,
97% (11a); (c) TrocCl, Py, rt, 98% (11b); (d) 1-tosyloxy-4-pentene, 17 cat., CH2Cl2, 40◦C, 67%;
(e) H2, Pd/C, HCl 2M, THF/MeOH, rt, 88%; (f) NaN3, DMSO, rt, quant.; (g) TFA/H2O, rt, 53%.
afforded the expected δ-amino alcohols 6 as a mixture of diastereoisomers (de
60%) and in a good yield (70% from 4). Diastereoisomers 6 were efficiently
cyclized using mesyl chloride in pyridine at 100◦C via an intramolecular SN2
mechanism.[8c,18] This efficient process afforded α-1-C-allyl-iminoxylitol 7b in
76% yield after purification on silica gel, the minor β-epimer 7a being obtained
in 13% yield. The 1,2-cis configuration of the major epimer 7b, which adopted
4
predominantly the C1 conformation (J2,3 = 8.9 Hz, axial-axial coupling con-
stant), was established unambiguously by JH,H coupling constants (J1,2
=
5.6 Hz, axial-equatorial coupling constant). Quite unexpectedly, the removal
of the N-naphthalenemethyl protective group proved difficult. Under typical
deprotection conditions (1.5 equiv. of DDQ in CH2Cl2-MeOH),[14] the expected
amine 10 was obtained along with compound 9 in 28% and 23% yield, respec-
tively (Sch. 2). This side reaction was never observed in our previous investiga-
tions of the scope of the oxidative cleavage of the N-NAP-protecting group.[14]
After various attempts, the best results were obtained using a smaller quantity
of DDQ (2 equiv.) in the presence of water instead of MeOH as the nucleophilic
co-solvent. Under these conditions, the secondary amine 10 was obtained in
86% yield and protected with a Boc group or a Troc group to provide α-1-C-
allyl-iminoxylitol derivatives 11 (Sch. 2). The direct introduction of the azide
function by reacting 5-azido pentene[19] and α-1-C-allyl-iminoxylitol 11b in the
presence of 5 to 10 mol% of Grubbs catalyst (16) was found to be unsuccessful
under various experimental conditions.[20,21] The reaction was then performed

Preparation of Azide-armed Iminosugars
563
with 1-tosyloxy-4-pentene to obtain a versatile intermediate allowing the di-
rect introduction of an azide function or more elaborated moieties by SN2-type
reactions. A solution of α-1-C-allyl-iminoxylitol derivative 11a was refluxed in
the presence of 6 equiv. of 1-tosyloxy-4-pentene[19a] and 20 mol% of Grubbs cat-
alyst (16) or Grubbs-Hoveyda catalyst (17). The best results were obtained for
this latter catalyst and the desired cross-metathesis product 12 was isolated
in 67% yield. Not surprisingly, attempts to perform the same reaction using 7b
failed under various experimental conditions. The selective one-step removal
of the benzyl-protecting groups and reduction of the double bond in 12 was
conducted with 10% palladium on carbon to provide the piperidinol 13 in 88%
yield. The displacement of the tosylate group with sodium azide was achieved
in quantitative yield in DMSO to afford the desired N-Boc-protected substrate
14 for azide-alkyne cycloaddition reaction. The fully deprotected azide-armed
α-1-C-alkyl-iminoxylitol derivative 15 was obtained by treatment of 14 with
TFA. The same synthetic sequence applied to 11b, the N-Troc analog of 11a,
was found to be much less efficient as lower yields were obtained for every syn-
thetic step. In addition, the final removal of the N-Troc-protecting group using
Zn in AcOH/ether[21] led to degradation products.
CONCLUSION
In conclusion, we have developed a practical and efficient access to azide-
armed α-1-C-alkyl-imino-D-xylitol derivatives by way of olefin cross-metathesis
in eight to nine steps and in an overall yield of 19% to 26% from xylopyranose
4.[16] The synthetic versatility of key advanced intermediates such as 11 or 12
may be further exploited to access α-1-C-substituted iminoxylitol derivatives
containing linkers of different lengths and structures. Optimization of cleav-
age conditions of N-NAP-protected tertiary amines using DDQ in CH2Cl2-H2O
(18:1) has also been achieved. Azide-armed α-1-C-alkyl-imino-D-xylitol deriva-
tives synthesized will be used as key building blocks in the synthesis of original
multivalent iminosugars by way of Cu(I)-catalyzed azide-alkyne cycloaddition
reaction. It is noteworthy that despite the tremendous surge of interest in so-
called “click” methodologies for functional molecule synthesis, [22] this concept
has been poorly exploited in the field of iminosugars to date.[3a,4,23] The syn-
thesis and biological evaluation of the iminosugar click clusters designed as
human β-glucocerebrosidase inhibitors will be reported in due course. Azide-
armed iminosugars prepared in this study may also find application in the
preparation of other relevant iminosugar conjugates or in the design of li-
braries of biologically active compounds.
General Methods
Dichloromethane (CH2Cl2) was distilled over CaH2 under Ar; dimethylsul-
foxide (DMSO) was distilled over CaH2 under reduced pressure. Tetrahydrofu-
ran (THF) was dried by passage through an activated alumina column under

C. Decroocq et al.
564
Ar. Pyridine was distilled over KOH under reduced pressure and stored over
KOH. All reactions were performed in standard glassware. Column chromatog-
raphy: silica gel 60 (230–400 mesh, 0.040–0.063 mm) was purchased from E.
Merck. Flash chromatography was carried out in a Grace Reveleris flash sys-
tem equipped with UV/Vis and ELSD detectors. Thin layer chromatography
(TLC) was performed on aluminum sheets coated with silica gel 60 F254 pur-
chased from E. Merck. IR spectra (cm−1) were recorded on a Perkin–Elmer
Spectrum One Spectrophotometer. NMR spectra were recorded on a Bruker AC
300 or AC 400 with solvent peaks as reference. Carbon multiplicities were as-
signed by distortionless enhancement by polarization transfer (DEPT) experi-
ments. The 1H signals were assigned by COSY, HSQC. ESI-HRMS mass spec-
tra were carried out on a Bruker MicroTOF spectrometer. Specific rotations
were determined at rt (20◦C) in a Perkin–Elmer 241 polarimeter for sodium
(λ = 589 nm).
2-Naphthylmethylamine Hydrochloride (8)[17]
Naphthalene-2-carbonitrile (3.0 g, 19.58 mmol) was dissolved in abso-
lute ethanol (112 mL); 10% wt. palladium supported on carbon (1.041 g,
0.979 mmol, 0.05 eq. Pd) was added followed by concentrated hydrochloric
acid (1.98 mL, 19.58 mmol, 1.0 eq.). Argon was bubbled into the solution fol-
lowed by hydrogen gas. The mixture was stirred at rt, under H2 atmosphere,
for 20 h. It was then filtered through a pad of celite and washed thoroughly
with ethanol, and the filtrate concentrated under reduced pressure and finally
dried under vacuum. The desired product 8 was obtained as white powder
(3.670 g, 97% yield). Analytical data were consistent with the literature:[17b] Rf
1
0.46 (CH3CN/H2O/NH4OH 10:1:1); H NMR (MeOD, 300 MHz): δ 4.32 (s, 2H,
CH2N), 7.53–7.62 (m, 3H), 7.88–8.03 (m, 4H); 13C NMR (MeOD, 75.5 MHz):
δ 45.4 (CH2N), 127.8, 128.7, 128.8, 129.7, 129.9, 130.3, 131.0 (CHAr), 132.6,
135.6, 135.7 (CAr); MS (ESI): m/z 158.1 (calcd. for [C11H12N]+ 158.1).
1-C-Allyl-2,3,4-tri-O-Benzyl-1-Methylnaphthylamino-1-
Deoxy-D-Xylitol (6)
Under anhydrous conditions, compound 4 (1.95 g, 4.64 mmol) was dis-
solved in DMSO (12 mL). 2-Naphthylmethylamine hydrochloride (8) (1.35 g,
6.96 mmol, 1.5 eq.), triethylamine (0.97 mL, 6.96 mmol, 1.5 eq.), and molec-
◦
˚
ular sieves 4 A (0.4 g) were added to the mixture, which was stirred at 60 C
for 22 h. The latter was filtered through celite and washed thoroughly with
diethyl ether. Water (100 mL) was added to the filtrate and phases were sep-
arated. The aqueous layer was extracted using diethyl ether (3 × 120 mL).
The combined extracts were dried over Na2SO4, filtered, and concentrated

Preparation of Azide-armed Iminosugars
565
under reduced pressure to provide N-methylnaphthyl-2,3,4-tri-O-benzyl-D-
xylopyranosylamines (5) as an orange solid. Rf 0.45 (AcOEt/petroleum ether
1:3 + 1% Et3N).
Under anhydrous conditions, the crude compounds 5 were dissolved in
THF. At 0◦C, allylmagnesium bromide (13.9 mL of 1.0 M solution in Et2O,
13.9 mmol, 3 eq.) was added dropwise. After 15 hours, 2 more equivalents of
allylmagnesium bromide were added at 0◦C and the reaction was stirred at rt
for another 15 hours. After cooling down to 0◦C, the mixture was hydrolyzed
using a few milliliters of water. The mixture was concentrated under reduced
pressure, the residue dissolved in diethyl ether (250 mL), and water was added
to allow the phases to separate. The organic layer was washed with water (3
× 150 mL) and brine (100 mL), dried over Na2SO4, filtered, and finally con-
centrated under reduced pressure. The yellow solid residue was purified by
column chromatography on silica gel (AcOEt/petroleum ether + 0.5% Et3N
1:5 to 1:3). The diastereoisomers 6 were obtained as colorless oil (1.95 g, 70%
yield over two steps). Rf 0.27 (AcOEt/petroleum ether 1:3 + 1% Et3N). IR: νmax
(neat) 3461 (OH, NH) cm−1; HRMS (ESI): m/z 602.326 ([M+H]+, calcd. for
C40H44NO4: 602.326).
A pure analytical sample of the major diastereoisomer, (1R)-1-C-allyl-2,3,4-
tri-O-benzyl-1-methylnaphthylamino-1-deoxy-D-xylitol, has been isolated and
characterized by NMR 1H and 13C: 1H NMR (CDCl3, 300 MHz) δ 2.23–2.38 (m,
1H, -CH2a-CH ), 2.41–2.54 (m, 1H, -CH2b-CH ), 2.61–2.71 (m, 1H, H-1), 3.35
(q, J = 4.4 Hz, 1H, H-4), 3.61 (dd, J = 11.7 and 4.2 Hz, 1H, H-5a), 3.70 (dd, J =
11.7 and 5.2 Hz, 1H, H-5b), 3.77 (d, J = 13.2 Hz, 1H, CH2Ar), 3.81 (dd, J = 7.2
and 2.4 Hz, 1H, H-2), 4.07 (d, J = 13.0 Hz, 1H, CH2Ar), 4.10–4.17 (m, 1H, H-3),
4.30 (d, J = 11.7 Hz, 1H, CH2Ph), 4.48 (d, J = 11.8 Hz, 1H, CH2Ph), 4.59 (d, J
= 11.4 Hz, 1H, CH2Ph), 4.72 (d, J = 11.4 Hz, 1H, CH2Ph), 4.81 (d, J = 11.4 Hz,
1H, CH2Ph), 4.87 (d, J = 11.4 Hz, 1H, CH2Ph), 4.97–5.07 (m, 2H, CH CH2),
5.56–5.75 (m, 1H, CH CH2), 7.14–7.21 (m, 2H, CHAr), 7.22–7.37 (m, 13H,
CHAr), 7.41–7.51 (m, 3H, CHAr), 7.62–7.87 (m, 4H, CHAr). 13C NMR (CDCl3,
75.5 MHz) δ 35.4 (-CH2-CH ), 51.2 (CH2Ar), 56.4 (C-1), 61.8 (C-5), 72.0, 74.4,
74.7 (3 CH2Ph), 78.3 (C-4), 80.08 (C-3), 80.14 (C-2), 117.2 ( CH CH2), 125.7,
126.1, 126.8, 127.2, 127.6, 127.7, 127.8, 127.9, 128.1, 128.3, 128.38, 128.44,
128.6 (22 CHAr), 132.7, 133.4 (2 CAr), 136.1 ( CH CH2), 138.19, 138.24, 138.4,
138.9 (4 CAr).
1-C-Allyl-N-Methylnaphthyl-2,3,4-Tri-O-Benzyl-
1,5-Dideoxy-1,5-Imino-D-Xylitol (7a and 7b)
Under anhydrous conditions, compound 6 (1.804 g, 3.00 mmol) was dis-
solved in pyridine (45 mL). Methanesulfonyl chloride (0.58 mL, 7.49 mmol,
˚
2.5 eq.) was then added followed by molecular sieves 4 A (1.9 g). The re-
action mixture was stirred at 100◦C for 4 h. It was then filtered through

C. Decroocq et al.
566
celite and washed thoroughly with AcOEt (200 mL). The organic layer was
then washed with water (4 × 150 mL), dried over MgSO4, filtered, and con-
centrated under reduced pressure. Toluene was added and the mixture was
concentrated; this operation was repeated three times to remove residual pyri-
dine. The resulting brown oil was purified by column chromatography on silica
gel (AcOEt/petroleum ether: 1:5 to 1:3) to afford 1.325 g of diastereoisomer 7b
(76% yield) and 0.220 g of diastereoisomer 7a (13% yield).
Major diastereomer 7b
20
1
R = 0.48 (AcOEt/petroleum ether 1:4); α +21.1 (c 1, CHCl3). H NMR
f
[ ]D
(300 MHz, Acetone-d6): δ 2.46 (bt, J = 7 Hz, 2H, -CH2-CH ), 2.53–2.66 (m,
1H, H-5a), 2.87 (dd, J = 12.4 and 4.5 Hz, 1H, H-5b), 3.33 (q, J = 6.0 Hz, 1H,
H-1), 3.59–3.70 (m, 2H, H-3 and H-4), 3.79 (dd, J = 8.9 and 5.6 Hz, 1H, H-2),
3.92 (d, J = 13.9 Hz, 1H, CH2Ar), 4.06 (d, J = 13.8 Hz, 1H, CH2Ar), 4.55–4.69
(m, 4H, CH2Ph), 4.87 (d, J = 11.3 Hz, 1H, CH2Ph), 4.92 (d, J = 11.2 Hz, 1H,
CH2Ph), 4.99 (d, J = 10.1 Hz, 1H, CH CH2a), 5.13 (d, J = 17.3 and 1.7 Hz,
1H, CH CH2b), 5.90–6.03 (m, 1H, CH CH2), 7.13–7.36 (m, 13H, CHAr),
7.37–7.43 (m, 2H, CHAr), 7.45–7.53 (m, 3H, CHAr), 7.76 (s, 1H, CHAr), 7.81–7.92
(m, 3H, CHAr). 13C NMR (75.5 MHz, CDCl3) δ 28.8 ( CH2 CH ), 48.2 (CH2Ar
or C-5), 59.2 (CH2Ar or C-5), 60.2 (C-1), 72.7, 73.1, 75.7 (3 CH2Ph), 78.7, 80.8,
82.9 (C-2, C-3 and C-4), 115.8 ( CH CH2), 125.7, 126.1, 126.7, 126.8, 127.56,
127.63, 127.7, 127.8, 127.9, 128.1, 128.42, 128.43 (22 CHAr), 133.0, 133.5, 137.1
(3 CAr), 138.5 ( CH CH2), 138.6, 138.7, 139.3 (3 CAr). HRMS (ESI): m/z
584.312 ([M+H]+, calcd. for C40H42NO3: 584.316).
Minor diastereomer 7a
20
1
R = 0,37 (AcOEt/petroleum ether 1:4); α
[ ]D
f
−1.8 (c 1, CHCl3). H NMR
(300 MHz, CDCl3): δ 1.87–2.01 (m, 1H, H-5a), 2.43–2.59 (m, 1H, H-1), 2.65–2.81
(m, 2H, CH2 CH ), 2.97 (dd, J = 11.5 and 3.2 Hz, 1H, H-5b), 3.28 (d, J =
13.2 Hz, 1H, CH2Ar), 3.47–3.62 (m, 3H, H-2, H-3 and H-4), 4.28 (d, J = 13.2
Hz, 1H, CH2Ar), 4.43 (d, J = 11.7 Hz, 1H, CH2Ph), 4.52 (d, J = 11.7 Hz, 1H,
CH2Ph), 4.69 (d, J = 10.9 Hz, 1H, CH2Ph), 4.82 (d, J = 10.9 Hz, 1H, CH2Ph),
4.99 (d, J = 11.0 Hz, 1H, CH2Ph), 5.02 (d, J = 10.8 Hz, 1H, CH2Ph), 5.17 (d,
J = 11.5 Hz, 2H, CH CH2), 5.96–6.15 (m, 1H, CH CH2), 7.05–7.18 (m, 4H,
CHAr), 7.20–7.39 (m, 11H, CHAr), 7.40–7.57 (m, 3H, CHAr), 7.67 (s, 1H, CHAr),
7.74–7.91 (m, 3H, CHAr). 13C NMR (75.5 MHz, CDCl3) δ 32.2 ( CH2 CH ),
54.0 (CH2Ar or C-5), 59.2 (CH2Ar or C-5), 64.6 (C-1), 72.7, 75.3, 75.5 (3 CH2Ph),
78.4, 80.2, 87.6 (C-2, C-3 and C-4), 117.7 ( CH CH2), 125.7, 126.1, 127.0,
127.3, 127.6, 127.77, 127.80, 127.86, 127.89, 127.94, 128.0, 128.2, 128.3, 128.4,
128.5, 128.6 (22 CHAr), 133.0, 133.5 (2 CAr), 134.4 ( CH CH2), 136.5, 138.4,
138.8, 139.0 (4 CAr).

Preparation of Azide-armed Iminosugars
567
α-1-C-Allyl-N-(Cyano-Naphthalen-2-yl-Methyl)-2,3,4-Tri-O-Benzyl-
1,5-Dideoxy-1,5-Imino-D-Xylitol (9)
Compound 9 was obtained as a by-product in the reaction of deprotection
of the 2-naphthalenemethyl group using DDQ in CH2Cl2/MeOH. Rf = 0,75
20
1
(AcOEt/petroleum ether + 1% Et N 1:1); α
+20.4 (c 1, CHCl3). H NMR
[ ]D
3
(400 MHz, CHCl3) δ 2.52–2.62 (m, 2H, CH2 CH ), 2.69–2.84 (m, 2H, H-5),
3.31 (q, J = 5.6 Hz, 1H, H-1), 3.68–3.79 (m, 3H, H-2, H-3 and H-4), 4.47–4.68
(m, 4H, CH2Ph), 4.82 (d, J = 11.2 Hz, 1H, CH2Ph), 4.87 (d, J = 11.1 Hz,
1H, CH2Ph), 5.05 (s, 1H, CHCN), 5.11 (d, J = 10Hz, 1H, CH CH2a), 5.17
(dd, J = 17.0 and 1.7 Hz, 1H, CH CH2b), 5.84–5.98 (m, 1H, CH CH2),
7.15–7.25 (m, 5H, CHAr), 7.25–7.40 (m, 10H, CHAr), 7.51 (dd, J = 8.4 and 1.9
Hz, 1H, CHAr), 7.54–7.61 (m, 2H, CHAr), 7.81–7.94 (m, 4H, CHAr). 13C NMR
(75.5 MHz, MeOD) δ 29.5 ( CH2 CH ), 46.2 (C-5), 58.8 (C-1 or CH C N),
59.2 (C-1 or CH C N), 72.88, 72.93, 75.1 (CH2Ph), 77.4, 79.7, 81.3, 117.0
( CH CH2), 118.3 (C≡N), 125.0, 126.8, 127.0, 127.5, 127.6, 127.7, 127.8,
127.9, 127.99, 128.00, 128.36, 128.42, 129.2 (22 CHAr), 131.4, 133.1, 133.7
(3 CAr), 136.9 ( CH CH2), 138.36, 138.42, 139.0 (3 CAr); HRMS (ESI): m/z
631.291 ([M+Na]+, calcd. for C41H40N2Na1O3: 631.293).
α-1-C-Allyl-2,3,4-Tri-O-Benzyl-1,5-Dideoxy-1,5-Imino-D-Xylitol (10)
Compound 7b (308 mg, 0.53 mmol) was dissolved in a CH2Cl2/H2O mix-
ture 18:1 (12 mL) and stirred at 0◦C. DDQ (180 mg, 0.79 mmol, 1.5 eq.) was
added and the mixture was stirred at rt for 1.5 h; 0.5 eq. of DDQ was added
to complete the reaction and the mixture was stirred at rt for another 15 min.
The mixture was concentrated to dryness and the residues were taken up in
DCM. This organic phase was washed five times with a saturated solution of
sodium bicarbonate, dried over Na2SO4, and filtered. Solvent was evaporated
off and the residual brown liquid was purified by flash chromatography (SiO2,
AcOEt/petroleum ether + 1% Et3N 1:9 to 1:1) to afford 10 as a brown viscous
oil (202 mg, 86% yield).
20
R 0.28 (AcOEt/petroleum ether 1:1 + 1% Et N); α
f
−5.0 (c 1, CHCl3).
[ ]D
3
1H NMR (300 MHz, CDCl3) δ 1.91 (bs, 1H, NH), 2.34 (t, J = 7.5 Hz, 2H,
CH2 CH ), 2.89 (dd, J = 13.2 and 6.1 Hz, 1H, H-5a), 3.00 (dd, J = 13.3
and 4.0 Hz, 1H, H-5b), 3.07 (td, J = 7.3 and 3.8 Hz, 1H, H-1), 3.43 (q, J = 5.3
Hz, 1H, H-4), 3.49 (dd, J = 6.1 and 4.0 Hz, 1H, H-2), 3.73 (t, J = 6.1 Hz, 1H,
H-3), 4.52 (d, J = 11.5 Hz, 1H, CH2Ph), 4.59 (s, 2H, CH2Ph), 4.65 (d, J = 11.5
Hz, 1H, CH2Ph), 4.67 (s, 2H, CH2Ph), 5.02–5.13 (m, 2H, CH CH2), 5.67–5.83
(m, 1H, CH CH2), 7.19–7.42 (m, 15H, CHAr). 13C NMR (75.5 MHz, CDCl3)
δ 33.0 ( CH2 CH ), 44.4 (C-5), 54.8 (C-1), 72.2, 72.5, 74.1 (3 CH2Ph), 76.7
(C-4), 77.3 (C-3), 78.1 (C-2), 117.2 ( CH CH2), 127.70, 127.73, 127.8, 127.96,
128.00, 128.44, 128.50, 128.51 (15 CHAr), 136.1 ( CH CH2), 138.68, 138.70,
138.71 (3 CAr). HRMS (ESI): m/z 444.253 ([M+H]+, calcd. for C29H34N1O3:
444.253).

C. Decroocq et al.
568
α-1-C-Allyl-N-(tert-Butoxycarbonyl)-2,3,4-Tri-O-Benzyl-
1,5-Dideoxy-1,5-Imino-D-Xylitol (11a)
Compound 10 (202 mg, 0.46 mmol) was dissolved in CH2Cl2 (3.5 mL). Et3N
(70 µL, 0.50 mmol, 1.1 eq.) and Boc2O (109 mg, 0.50 mmol, 1.1 eq.) were added
at 0◦C. The reaction mixture was allowed to raise rt and stirred for 3 h 30 min
until the starting material was completely consumed. Solvent was evaporated
off. The residue was purified by flash chromatography (SiO2, AcOEt/petroleum
ether 1:20 to 1:8) to afford a colorless oil 11a as a mixture of rotamers, accord-
ing to NMR data (240 mg, 97% yield).
20
1
R = 0.63 (AcOEt/petroleum ether 1:3); α −15.0 (c 1, CHCl3). H NMR
[ ]D
f
(300 MHz, CDCl3) δ 1.48 (s, 9H, C(CH3)3), 2.23–2.45 (m, 1H, CH2a CH ),
2.53–2.68 (m, 1H, CH2b CH ), 2.76 (q, J = 11.6 Hz, 1H, H-5a), 3.39–3.67 (m,
2H, H-2 and H-4), 3.75 (t, J = 9.2 Hz, 1H, H-3), 4.12 (dd, J = 13.5 and 5.6 Hz,
0.5H, H-5b), 4.34–4.45 (m, 0.5H, H-1), 4.49 (dd, J = 13.5 and 5.7 Hz, 0.5H, H-
5b), 4.63–4.86 (m, 4.5H, H-1 and CH2Ph), 4.86–5.02 (m, 2H, CH2Ph), 5.03–5.19
(m, 2H, CH CH2), 5.62–5.90 (m, 1H, CH CH2), 7.27–7.48 (m, 15H, CHAr).
13C NMR (75.5 MHz, CDCl3) δ 28.3 (CH3), 29.7 ( CH2 CH ), 39.9 and 41.3
(C-5), 51.2 and 53.1 (C-1), 72.6, 73.0, 73.1, 73.2, 75.7, 75.8 (3 CH2Ph), 78.3 and
78.5 (C-2, C-3 or C-4), 79.7 and 79.9 (C-2, C-3 or C-4), 80.1 and 80.3 ( C(CH3)3),
82.1 and 82.3 (C-2, C-3 or C-4), 116.9 and 117.3 ( CH CH2), 127.6, 127.7,
127.8, 127.89, 127.92, 128.0, 128.3, 128.4,2, 128.45, 128.48 (15 CHAr), 134.7
and 134.8 ( CH CH2), 138.2, 138.26, 138.28, 138.32, 138.9 (3 CAr), 154.9 (C =
O). 1H NMR (400 MHz, 70◦C, DMSO-D6) δ 1.38 (s, 9H, C(CH3)3), 2.26–2.40 (m,
1H, CH2a CH ), 2.41–2.48 (m, 1H, CH2b CH ), 2.67 (t, J = 12.2 Hz, 1H,
H-5a), 3.31–3.41 (m, 1H, H-4), 3.45 (dd, J = 9.1 and 6 Hz, 1H, H-2), 3.66 (t, J =
9.1 Hz, 1H, H-3), 4.03–4.21 (m, 1H, H-1), 4.37–4.54 (m, 1H, H-5), 4.66 (bs, 4H,
CH2Ph), 4.80 (bs, 2H, CH2Ph), 4.98 (d, J = 10 Hz, 1H, CH CH2a), 5.09 (d,
J = 17 Hz, 1H, CH CH2b), 5.62–5.78 (m, 1H, CH CH2), 7.19–7.43
(m, 15H, CHAr). 13C NMR (100 MHz, 70◦C, DMSO-D6) δ 27.5 (CH3), 28.8
( CH2 CH ), 40.7 (C-5), 51.7 (C-1), 71.4, 71.6, 73.9 (3 CH2Ph), 77.5, 78.8, 78.9
(C-2, C-3, C-4), 81.0 (-C(CH3)3), 116.1 ( CH CH2), 126.7, 126.9, 127.0, 127.08,
127.13, 127.5, 127.66, 127.68 (15 CHAr), 134.7 ( CH CH2), 137.9, 138.1, 138.6
(3 CAr), 153.6 (C O); IR (neat): 1693 (C O) cm−1. HRMS (ESI): m/z 566.285
([M+Na]+, calcd. for C34H41N1Na1O5: 566.288).
α-1-C-Allyl-N-(2,2,2-Trichloro-Ethoxycarbonyl)-2,3,4-Tri-O-
Benzyl-1,5-Dideoxy-1,5-Imino-D-Xylitol (11b)
Under anhydrous conditions, compound 11b (101 mg, 0.228 mmol) was dis-
solved in pyridine (3 mL). 2,2,2-Trichloroethyl chloroformate (0.047 mL, 0.342
mmol, 1.5 eq.) was added and the mixture was stirred at rt for 4 h. TrocCl was
added again (1.0 eq.) and the mixture was stirred at rt for another 3 h. Solvent

Preparation of Azide-armed Iminosugars
569
was evaporated under reduced pressure. A few milliliters of toluene was added
and evaporated off to help removal of pyridine. This operation was repeated
three times. Residual viscous solid was taken up in CH2Cl2 (10 mL). This or-
ganic solution was washed with a saturated solution of sodium bicarbonate,
dried over MgSO4, and filtered. Solvent was evaporated off and the crude
product was purified by chromatography (SiO2, AcOEt/petroleum ether +
1% Et3N 1:9 to 1:8) to afford a white viscous solid 11b as a mixture of rotamers,
according to NMR data (0.138 g, 98% yield).
20
R 0.64 (AcOEt/petroleum ether 1:4 + 1% Et N); α −11.0 (c 1, CHCl3).
f
[ ]D
3
1H NMR (300 MHz, CDCl3) δ 2.25–2.43 (m, 1H, CH2a CH ), 2.56–2.72 (m,
1H, CH2b CH ), 2.83 (q, 1H, J = 11.7 Hz, H-5a), 3.43–3.64 (m, 2H, H-
2 and H-4), 3.72 (td, J = 9.1 and 2.7 Hz, 1H, H-3), 4.34 (td, J = 13.8 and
5.7 Hz, 1H, H-5b), 4.52–4.78 (m, 6.5H, CH2Ph, H-1 and CH2CCl3), 4.79–4.90
(m, 2.5H, CH2Ph and CH2CCl3) 5.04 (bd, J = 11.7 Hz, 1H, CH CH2a), 5.10
(bd, J = 18.3 Hz, 1H, CH CH2b), 5.62–5.81 (m, 1H, CH CH2), 7.27–7.40
(m, 15H, CHAr). 13C NMR (75.5 MHz, CDCl3) δ 29.7 and 29.8 ( CH2 CH ),
41.1 (C-5), 52.8 and 53.3 (C-1), 73.06, 73.15, 73.36, 73.39, 75.2, 75.3, 75.9, 76.0
(CH2Ph and CH2CCl3), 78.1, 78.3, 79.6, 79.7, 81.9, 82.0 (C-2, C-3 and C-4), 95.6
and 95.8 ( CCl3), 117.8 and 118.0 ( CH CH2), 127.7, 127.86, 127.93, 128.0,
128.08, 128.11, 128.5, 128.58, 128.61, 128.64 (15 CHAr), 134.10 and 134.14
( CH CH2), 138.07, 138.11, 138.81, 138.83 (3 CAr), 153.8 and 153.9 (C O). IR
(neat) : 1673, 1717 (C O) cm−1; HRMS (ESI): m/z 640.138 ([M+Na]+, calcd.
for C32H34Cl3N1NaO5: 640.139).
N-(tert-Butoxycarbonyl)-α-1-C-[6-(Toluene-4-Sulfonyloxy)-Hex-
2-Enyl]-2,3,4-Tri-O-Benzyl-1,5-Dideoxy-1,5-Imino-D-Xylitol (12)
Under anhydrous conditions, compound 11a (244 mg, 0.449 mmol) was dis-
solved in distilled and degassed CH2Cl2 (8 mL). 1-Tosyloxy-4-pentene[19] (431
mg, 1.80 mmol, 4 eq.) was added to the reaction mixture and then the cata-
lyst 17 (42 mg, 0,07 mmol, 15 mol%). The mixture was refluxed for 5 h and
another 0.05 eq. of catalyst and 2 eq. of tosylated compound were added. The
mixture was refluxed again for 18 h. The reaction was then filtered through
silica gel and the solvent was evaporated. The residue was purified by flash
chromatography (SiO2, AcOEt/petroleum ether 1:20 to 1:3) to afford a color-
less oil 12 as a mixture of rotamers, according to NMR data (228 mg, 67%
20
yield). R = 0,63 (AcOEt/petroleum ether 1:3); α −4.2 (c 1, CHCl3). 1H NMR
[ ]D
f
(400 MHz, CDCl3) δ 1.39 (s, 9H, C(CH3)3), 1.62–1.75 (m, 2H), 1.94–2.05 (m,
2H), 2.12–2.32 (m, 1H, C1 CH2a CH ), 2.38–2.50 (m, 1H, C1 CH2b CH ),
2.43 (s, 3H, PhCH3), 2.62 (q, J = 13.5 Hz, 1H, H-5a), 3.32–3.59 (m, 2H, H-
2 and H-4), 3.65 (t, J = 9.0 Hz, 1H, H-3), 3.93–4.09 (m, 2.5H, CH2OTs and
H-5b), 4.21–4.31 (m, 0.5H, H-1), 4.38 (dd, J = 13.3 and 5.9 Hz, 0.5H, H-5b),

C. Decroocq et al.
570
4.58–4.78 (m, 4.5H, CH2Ph and H-1), 4.80–4.93 (m, 2H, CH2Ph), 5.18–5.41
(m, 2H, CH CH ), 7.27–7.42 (m, 17H, CHAr), 7.79 (d, J = 8.4 Hz, 2H,
CHAr). 13C NMR (75.5 MHz, CDCl3) δ 21.7 (PhCH3), 23.0, 23.1, 28.39, 28.41
and 28.45 (C(CH3)3), 28.75 and 28.81 ( CH2 CH ), 40.0 and 41.4 (C-5), 51.4
and 53.3 (C-1), 69.96 and 70.04 (CH2OTs), 72.6, 73.1, 73.2, 73.3, 75.77, 75.83
(3 CH2Ph), 78.4 and 78.6 (C-4), 79.8 and 80.0 (C-2), 80.2 ( C(CH3)3), 82.2 and
82.3 (C-3), 127.56, 127.64, 127.71, 127.75, 127.8, 127.9, 127.99, 128.00, 128.04,
128.4, 128.50, 128.53, 128.6, 129.3, 129.8, 129.9, 130.0, 130.7, 130.9, (19 CHAr
and CH CH ), 133.30, 133.34, 138.27, 138.30, 138.4, 139.0, 144.8, 144.9
(5 CAr), 154.86 and 154.90 (C O); IR (neat) : 1690 (C O), 1363 (SO2), 1176
(SO2) cm−1. HRMS (ESI): m/z 756.356 ([M+H]+, calcd. for C44H54N1O8S1: 756.
356).
N-(tert-Butoxycarbonyl)-α-1-C-[6-(Toluene-4-Sulfonyloxy)-
Hexyl]-1,5-Dideoxy-1,5-Imino-D-Xylitol (13)
Compound 12 (228 mg, 0.30 mmol) was dissolved in THF/MeOH (3:1, 12
mL); 4 drops of HCl 2M were added as well as Pd/C (32 mg of 10% Pd, 0,1
eq.). Three cycles of vacuum/argon were made in the flask followed by two
cycles vacuum/H2. The reaction mixture was stirred under H2 atmosphere
for 5.5 h. The reaction was then filtered through a pad of celite and the sol-
vent was evaporated. The residue was purified by flash chromatography (SiO2,
MeOH/CH2Cl2 1:99 → 5:95) to afford a colorless oil 13 as a mixture of ro-
tamers, according to NMR data (129 mg, 88% yield). Rf = 0.29 (MeOH/CH2Cl2
20
5:95); α +2.9 (c 1, CHCl3). 1H NMR (300 MHz, MeOD) δ 1.14–1.35 (m, 6H),
[ ]D
1.45 (bs, 10H, C(CH3)3 and C1 CH2a), 1.55–1.66 (m, 2H, H-10), 1.66–1.82
(m, 1H, C1 CH2b), 2.46 (s, 3H, PhCH3), 2.50–2.72 (m, 1H, H-5a), 3.23–3.34 (m,
1H, H-4), 3.35–3.46 (m, 2H, H-2 and H-3), 4.02 (t, J = 6.3 Hz, 2H, CH2OTs),
4.05–4.17 (m, 1H, H-5b), 4.18–4.35 (m, 1H, H-1), 7.45 (d, J = 8.1 Hz, 2H, CHAr)
7.78 (d, J = 8.4 Hz, 2H, CHAr). 13C NMR (75.5 MHz, MeOD) δ 21.6 (PhCH3),
24.7 and 24.8 (C1 CH2), 26.4 and 26.6, 26.8, 28.6 ( C(CH3)3), 29.6, 29.8, 43.0
and 44.2 (C-5), 55.8 and 57.1 (C-1), 71.6 (C-4), 71.9 (-CH2OTs), 72.7 and 73.0
(C-2 or C-3), 75.91 and 76.92 (C-2 or C-3), 81.5 ( C(CH3)3), 128.9 (CHAr), 131.0
(CHAr), 134.6 (CAr), 146.4 (CAr), 156.7 and 156.8 (C=O); IR (neat): 3382 (O H),
1692, 1664 (C O), 1365 (SO2), 1176 (SO2) cm−1. HRMS (ESI): m/z 510.215
([M+Na]+, calcd. for C23H37N1Na1O8S1: 510.213).
α-1-C-(6-Azido-Hexyl)-N-(Tert-Butoxycarbonyl)-1,5-Dideoxy-1,5-
Imino-D-Xylitol (14)
Compound 13 (129 mg, 0.26 mmol) was dissolved in DMSO (1.8 mL),
sodium azide (22 mg, 0.33 mmol, 1.25 eq.) was added, and the reaction mix-
ture was stirred under argon atmosphere for 24 h. Water was added slowly to

Preparation of Azide-armed Iminosugars
571
quench the reaction. The aqueous phase was extracted with Et2O (3 × 7 mL).
The organic phases were washed with water (5 mL) and dried over Na2SO4.
The residue was purified by flash chromatography (SiO2, MeOH/CH2Cl2 1:20
to 1:9) to afford a colorless oil 14 as a mixture of rotamers, according to
20
NMR data (94.5 mg, quant.). Rf = 0,5 (MeOH/CH2Cl2 1:9);
α
+2.4 (c
[ ]D
1
1, MeOD). H NMR (300 MHz, MeOD) δ 1.18–1.45 (m, 6H), 1.44–1.49 (m,
9H, C(CH3)3), 1.50–1.67 (m, 3H, Halkyl and C1 CH2a), 1.68–1.86 (m, 1H,
C 1 CH2b), 2.52–2.74 (m, 1H, H-5a), 3.22–3.36 (m, 3H, H-4 and CH2OTs),
3.35–3.47 (m, 2H, H-2 and H-3), 4.06 (bt, J = 4 Hz, 1H, H-5b), 4.21–4.37 (m,
1H, H-1). 13C NMR (75.5 MHz, MeOD) δ 24.7, 24.8, 26.7, 27.0, 27.78, 27.82,
28.6 ( C(CH3)3), 29.9, 43.1 and 44.3 (C-5), 52.4 ( CH2OTs), 55.9 and 57.1 (C-
1), 71.6 and 71.9 (C-2, C-3 or C-4), 72.8 and 73.0 (C-2, C-3 or C-4), 75.9 (C-2, C-3
or C-4), 81.4 ( C(CH3)3), 156.7 (C O); IR (neat): 3376 (O H), 2095 (N3) 1683
(C O) cm−1. HRMS (ESI): m/z 381.216 ([M+Na]+, calcd. for C16H30N4Na1O5:
381.211).
α-1-C-(6-Azido-Hexyl)-1,5-Dideoxy-1,5-Amino-D-Xylitol (15)
Compound 14 (26 mg, 0.07 mmol) was dissolved in H2O (0.6 mL). TFA
(0.3 mL) was added dropwise at 0◦C; the reaction mixture was allowed to raise
to rt and was stirred under Ar atmosphere for 4 h. The solvent was evapo-
rated. The product was taken up in water and Dowex 50 × 8 (H+) ion-exchange
resin was added. The resin was washed with MeOH and H2O. The product was
eluted with aqueous ammonia (7% NH4OH) and the eluted fractions were con-
centrated under vacuum. The product was then dissolved in water again and
Ambersep 800 (OH−) ion-exchange resin was added. The resin was filtered off
and the filtrate solvent was removed to afford 15 as a white solid (10 mg, 53%).
Rf = 0.48 (MeOH/CH2Cl2 2:8); [α]2D0 +8.2 (c 0.5, H2O). H NMR (300 MHz,
1
D2O) δ 1.20–1.55 (m, 8H), 1.56–1.67 (m, 2H), 2.64 (dd, J = 13.0 and 8.1 Hz,
1H, H-5a), 2.88 (dd, J = 13.0 and 4.4 Hz, 1H, H-5b), 2.92–3.00 (m, 1H, H-1),
3.33 (t, J = 6.9 Hz, 2H, CH2OTs), 3.46–3.55 (m, 1H, H-3), 3.55–3.64 (m, 2H,
H-2 and H-4). 13C NMR (75.5 MHz, MeOD) δ 25.2, 25.4, 25.8, 27.9, 28.1, 43.8
(C-5), 51.2 (C-11), 54.8 (C-1), 70.6 (C-3), 72.1 (C-4), 72.6 (C-2); IR (neat) : 3319
(O H, N H), 2094 (N3) cm−1. HRMS (ESI): m/z 259,177 ([M+H]+, calcd. for
C11H23N4O3: 259,176).
ACKNOWLEDGEMENTS
This work was supported by the CNRS, the University of Strasbourg, the
Agence National de la Recherche (ANR, grant number 08JC-0094-01), and a
doctoral fellowship from the French Department of Research to C.D. We fur-
ther thank M. Schmitt for NMR measurements.

C. Decroocq et al.
572
REFERENCES
1. Iminosugars: From Synthesis to Therapeutic Applications; Compain, P., Martin,
O.R., Eds.; Wiley-VCH, Weinheim, 2007.
2. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Stu¨tz, A.E., Ed.,
Wiley-VCH, New York, 1999.
3. (a) For the first systematic biological evaluation of multivalent iminosugars as
glycosidase inhibitors see: Diot, J.; Garcia-Moreno, M.I.; Gouin, S.G.; Ortiz Mellet,
C.; Haupt, K.; Kovensky, J. Multivalent iminosugars to modulate affinity and selec-
tivity for glycosidases. Org. Biomol. Chem. 2009, 7, 357–363; (b) Wennekes, T.; van
der Berg, R.J.B.H.N.; Bonger, K.M.; Donker-Koopman, W.E.; Ghisaidoobe, A.; van der
Marel, G.A.; Strijland, A.; Aerts, J.M.F.G.; Overkleeft, H.S. Synthesis and evalua-
tion of dimeric lipophilic iminosugars as inhibitors of glucosylceramide metabolism.
Tetrahedron Asymm. 2009, 20, 836–846; (c) Johns, B.A.; Johnson, C.R. Scaffolded bis-
azasugars: a dual warhead approach to glycosidase inhibition. Tetrahedron Lett. 1998,
39, 749–752; (d) Lohse, A.; Jensen, K.B.; Lundgren, K.; Bols, M. Synthesis and decon-
volution of the first combinatorial library of glycosidase inhibitors. Bioorg. Med. Chem.
1999, 7, 1965–1971.
4. Compain, P.; Decroocq, C.; Iehl, J.; Holler, M.; Hazelard, D.; Mena Barraga´n, T.;
Ortiz Mellet, C.; Nierengarten, J.-F. Glycosidase inhibition with fullerene iminosugar
balls: a dramatic multivalent effect. Angew. Chem. Int. Ed. 2010, 49, 5753–5756.
5. See for example: (a) Lahman, M. Architectures of multivalent glycomimetics for
probing carbohydrate–lectin interactions. Top. Curr. Chem. 2009, 288, 17–65; (b) Dam,
T.K.; Brewer, C.F. Multivalent lectin-carbohydrate interactions: energetics and mech-
anisms of binding. Adv. Carbohydr. Chem. Biochem. 2010, 63, 139–164; (c) Imberty,
A.; Chabre, Y.; Roy, R. Glycomimetics and glycodendrimers as high affinity microbial
anti-adhesins. Chem. Eur. J. 2008, 14, 7490–7499.
6. Choi, S.-K. Synthetic Multivalent Molecules: Concepts and Biomedical Applica-
tions, Wiley & Sons, New Jersey, 2004.
7. Decroocq, C.; Rodr´ıguez-Lucena, D.; Russo, V.; Mena Barraga´n, T.; Ortiz Mellet,
C.; Compain, P. The multivalent effect in glycosidase inhibition: Probing the influence
of architectural parameters with cyclodextrin-based iminosugar click clusters. Chem.
Eur. J. 2011, in press (DOI 10.1002/chem.201102266).
8. See for example: (a) Yu, L.; Ikeda, K.; Kato, A.; Adachi, I.; Godin, G.; Com-
pain, P.; Martin, O.R.; Asano, N. α-1-C-Octyl-1-deoxynojirimycin as a pharmaco-
logical chaperone for Gaucher disease. Bioorg. Med. Chem. 2006, 14, 7736–7744;
(b) Boucheron, C.; Toumieux, S.; Compain, P.; Martin, O.R.; Ikeda, K.; Asano, N. Syn-
thesis of 4-O-glycosylated 1-deoxynojirimycin derivatives as disaccharide mimic-based
inhibitors of human β-glucocerebrosidase. Carbohydr. Res. 2007, 342, 1960–1965; (c)
Scho¨nemann, W.; Gallienne, E.; Compain, P.; Ikeda, K.; Asano, N.; Martin, O.R. Syn-
thesis of new β-1-C-alkylated imino-L-iditols: a comparative study of their activity as
β-glucocerebrosidase inhibitors. Bioorg. Med. Chem. 2010, 18, 2645–2650; (d) Oula¨ıdi,
F.; Front-Deschamps, S.; Gallienne, E.; Lesellier, E.; Ikeda, K.; Asano, N.; Compain, P.;
Martin, O.R. Second-generation iminoxylitol-based pharmacological chaperones for the
treatment of Gaucher disease. ChemMedChem 2011, 6, 353–361.
9. Compain, P.; Martin, O.R.; Boucheron, C.; Godin, G.; Yu, L.; Ikeda, K.; Asano, N.
Design and synthesis of highly potent and selective pharmacological chaperones for the
treatment of Gaucher’s disease. ChemBioChem, 2006, 7, 1356–1359.
10. (a) Zimran, A. Gaucher’s Disease. Balliere Tindall, 1997; (b) Fan, J.-Q. Iminosugars
as active-site-specific chaperones for the treatment of lysosomal storage disorders. In

Preparation of Azide-armed Iminosugars
573
Iminosugars: From Synthesis to Therapeutic Applications; Compain, P.; Martin, O.R.,
Eds. Wiley-VCH, Weinheim, 2007, pp. 225–247.
11. (a) Cipolla, L.; Lay, L.; Nicotra, F.; Pangrazio, C.; Panza, L. Synthesis of azasugars
by Grignard reaction on glycosylamines. Tetrahedron 1995, 51, 4679–4690; (b) Cipolla,
L.; Palma, A.; La Ferla, B.; Nicotra, F. Synthesis of nojirimycin C-glycosides. J. Chem.
Soc. Perkin Trans I. 2002, 2161–2165.
12. For a review on imino-C-glycoside synthesis see: Compain, P.; Chagnault, V.;
Martin, O.R. Tactics and strategies for the synthesis of iminosugar-C-glycosides: a re-
view. Tetrahedron: Asymm. 2009, 20, 672–711.
13. Liautard, V.; Desvergnes, V.; Itoh, K.; Liu, H.-W.; Martin, O.R. Convergent and
stereoselective synthesis of iminosugar-containing Galf and UDP-Galf mimicks: evalu-
ation as inhibitors of UDP-Gal Mutase. J. Org. Chem. 2008, 73, 3103–3115.
14. Godin, G.; Compain, P.; Martin, P. 2-Naphtylmethyl (NAP) as a versatile
amino protecting group, chemoselective removal under mild conditions. Synlett. 2003,
2065–2067.
15. For a review on olefin metathesis of amine-containing systems see: Compain, P.
Olefin metathesis of amine-containing systems: beyond the current consensus. Adv.
Synth. Catal. 2007, 349, 1829–1846.
16. Nadein, O.N.; Kornienko, A. An approach to pancratistatins via ring-closing
metathesis: efficient synthesis of novel 1-Aryl-1-deoxyconduritols F. Org. Lett. 2004,
6, 831–834.
17. (a) Hartung, W.H. Catalytic reduction of nitriles and oximes. J. Am. Chem. Soc.
1928, 50, 3370–3374; (b) Lehmann, F.; Scobie, M. Rapid and convenient microwave-
assisted synthesis of primary amines via reductive N-alkylation of methyl carbamate
with aldehydes. Synthesis 2008, 11, 1679–1682.
18. Dondoni, A.; Perrone, D. A convenient synthesis of iminosugar-C-glycosides via
organometallic addition to N-benzyl-N-glycosylhydroxylamines. Tetrahedron 2003, 59,
4261–4273.
19. For the synthesis of 5-azido pentene and 1-tosyloxy-4-pentene see: (a) Smejkal,
T.; Breit, B. A supramolecular catalyst for regioselective hydroformylation of unsatu-
rated carboxylic acids. Angew. Chem. Int. Ed. 2008, 47, 311–315; (b) Montevecchi, P.C.;
Navacchia, M.L.; Spagnolo, P. A study of vinyl radical cyclization onto the azido group
by addition of sulfanyl, stannyl, and silyl radicals to alkynyl azides. Eur. J. Org. Chem.
1998, 1219–1226.
20. For examples of olefin cross-metathesis performed with azide-containing sub-
strates see: (a) Chaudhari, V.D.; Ajish Kumar, K.S.; Dhavale, D.D. An efficient syn-
thesis of D-erythro- and D-threo-sphingosine from D-glucose: olefin cross-metathesis
approach. Org. Lett. 2005, 7, 5805–5807; (b) Rai, A.N.; Basu, A. Sphingolipid synthesis
via olefin cross metathesis: preparation of a differentially protected building block and
application to the synthesis of D-erythro-ceramide. Org. Lett. 2004, 6, 2861–2863.
21. For the first examples of olefin cross-metathesis reaction performed with imi-
nosugar substrates see: Godin, G.; Compain, P.; Martin, O.R. General access to imi-
nosugar C-Glycoside building blocks by means of cross-metathesis: a gateway to glyco-
conjugate mimetics. Org Lett. 2003, 5, 3269–3272.
22. See for example: (a) Moses, J.E.; Moorhouse, A.D. The growing applications of
click chemistry. Chem. Soc. Rev. 2007, 36, 1249–1262; (b) Kolb, H.C.; Sharpless, K.B.
The growing impact of click chemistry on drug discovery. Drug Discovery Today 2003, 8,
1128–1137; (c) Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click chemistry: diverse chemical
function from a few good reactions. Angew. Chem. Int. Ed. Engl. 2001, 40, 2004–2021.

C. Decroocq et al.
574
23. (a) Diaz, L.; Bujons, J.; Casas, J.; Llebaria, A.; Delgado, A.J. Click chemistry ap-
proach to new N-substituted aminocyclitols as potential pharmacological chaperones
for Gaucher disease. J. Med. Chem. 2010, 53, 5248–5255; (b) Ardes-Guisot, N.; Alonzi,
D.S.; Reinkensmeier, G.; Butters, T.D.; Norez, C.; Becq, F.; Shimada, Y.; Nakagawa, S.;
Kato, A.; Ble´riot, Y.; Sollogoub, M.; Vauzeilles, B. Selection of the biological activity
of DNJ neoglycoconjugates through click length variation of the side chain. Org. Bio.
Chem. 2011, 9, 5373–5388; (c) Diot J.D.; Garcia Moreno, I.; Twigg G.; Ortiz Mellet,
C.; Haupt K.; Butters, T.D.; Kovensky, J.; Gouin, S.G., Amphiphilic 1-deoxynojirimycin
derivatives through click strategies for chemical chaperoning in N370S Gaucher cells.
J. Org. Chem. 2011, 76, 7757–7768.