An improved methodology for the synthesis of 1-C-allyl imino-d-xylitol and -l-arabinitol and their rapid functionalization

Article abstract of DOI:10.1016/j.tet.2012.12.082

As part of our research program dedicated to the design and synthesis of new iminosugars as pharmacological chaperones for the treatment of lysosomal storage disorders, we developed a rapid and efficient methodology for the access to functionalized and no

Full text of DOI:10.1016/j.tet.2012.12.082

Tetrahedron 69 (2013) 3348e3354
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journal homepage: www.elsevier.com/locate/tet
An improved methodology for the synthesis of 1-C-allyl
imino-
D
-xylitol and -
L
-arabinitol and their rapid functionalization
a
a
a
b
b
ꢀ
Anna Biela , Farah Oulaïdi , Estelle Gallienne , Marcin Gorecki , Jadwiga Frelek ,
Olivier R. Martin a
,
*
a
ꢀ
ꢀ
ꢀ
Institut de Chimie Organique et Analytique, UMR 7311, Universite d’Orleans & CNRS, rue de Chartres, BP 6759, 45067 Orleans cedex 2, France
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 October 2012
Received in revised form 7 December 2012
Accepted 13 December 2012
Available online 9 January 2013
As part of our research program dedicated to the design and synthesis of new iminosugars as pharmaco-
logical chaperones for the treatment of lysosomal storage disorders, we developed a rapid and efficient
methodology for the access to functionalized and non-functionalized 1-C-alkylated derivatives in the
D
-xylo and
inhibitors of, respectively,
responsible for Krabbe disease. The key step of the synthesis is the diastereoselective addition of allyl-
trimethylsilane to the -xylo or -arabino N-benzyloxycarbonyl protected glycopyranosylamine. This pro-
L
-arabino series. These compounds, as gluco and galacto mimics, were designed to be potent
b
-glucocerebrosidase, involved in Gaucher disease, and -galactocerebrosidase,
b
Keywords:
Iminosugars
Pharmacological chaperones
Lysosomal storage disorders
Cross metathesis
D
L
tective group allows the direct functionalization of the obtained iminosugars using metathesis or oxidation
reactions. For determination of the absolute configuration of dihydroxylation reaction products the in situ
dimolybdenum methodology of electronic circular dichroism spectroscopy was successfully used.
Ó 2013 Elsevier Ltd. All rights reserved.
Circular dichroism
1. Introduction
inhibitors, were found to be active at low concentrations as good
chaperone molecules for lysosomal enzymes as they strongly in-
Lysosomal storage disorders (LSD) are inherited and rare diseases
caused by an impaired catabolism of glycolipids in the lysosome.1
Mutations in the glycosidases responsible for the hydrolysis of
these macromolecules promote their elimination from cells by the
protein quality control mechanisms, leading to the accumulation of
their undegraded substrates. Gaucher disease, the most prevalent
teract with their active site.5 Our group first focused its investigations
on the design and synthesis of new iminosugars as potential phar-
macological chaperones for GCase.6
a-1-C-Nonyl imino-D-xylitol 1
(a-C9-DIX, Fig.1) was found to be a powerful inhibitor of this enzyme
(IC50¼7 nM) and a good chaperone molecule with a 1.8-fold increase
of N370S mutant enzyme activity at 10 nM concentration.6b This
LSD, is due to the deficiency of
hydrolase responsible for the cleavage of glucosylceramide
b
-glucocerebrosidase (GCase), the
compound was synthesized in ten steps and 6% overall yield from L-
b-gly-
xylose.6b As this synthesis lacks reproducibility, we recently de-
veloped a different methodology to these iminosugars using the
cosidic bond.2 Two strategies are currently approved for the treat-
ment of Gaucher disease, namely Enzyme Replacement Therapy
(ERT) and Substrate Reduction Therapy (SRT).3 ERT consists of the
injection of recombinant GCase, while SRT uses small molecules
acting as inhibitors of the glucosylceramide biosynthesis. A third
strategy, Pharmacological Chaperone Therapy (PCT) is currently
under clinical trials for several LSD. Small molecules acting as
pharmacological chaperones are believed to stabilize the confor-
mation of the deficient, but still active enzyme and allow it to bypass
the quality control barriers and to be transported to the lysosome;
the activity of the deficient enzyme is thus increased and excess
glucosylceramide can be hydrolyzed, leading to a significant de-
crease of disease symptoms.4 Iminosugars, as potent glycosidase
nucleophilic addition of Grignard reagents to the
tert-butanesulfinyl imine.7 However this ten-step synthesis leads to
-1-C-hexylimino- -xylitol 2 ( -C6-DIX, Fig. 1) with 4% overall yield
and requires the use of expensive tert-butanesulfinamide.
L-xylose-derived N-
a
D
a
HO
H O
H
N
H
N
8
( )
5
( )
OH
OH
OH
OH
2
1
Fig. 1.
a-1-C-Alkyl imino-D-xylitol derivatives.
We describe here a more rapid and efficient methodology for
the synthesis of -1-C-alkyl-DIX, such as 1 and 2, wherein the key
step is the diastereoselective addition of allyltrimethylsilane to the
a
* Corresponding author. Tel.: þ33 238 494 581; fax: þ33 238 417 281; e-mail
address: olivier.martin@univ-orleans.fr (O.R. Martin).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.082

A. Biela et al. / Tetrahedron 69 (2013) 3348e3354
3349
O
O
N-benzyloxycarbonyl protected glycopyranosylamine derivative;
a, b, c
d, e
BnO
BnO
BnO
BnO
D
-xylose
we have already used this methodology for the synthesis of UDP-
galactofuranose mimics.8 While the synthesis of related iminosu-
gar derivatives was reported to be successful by way of the addition
of the allyl Grignard reagent to N-benzyl glycosylamines,6e,9,y
a methodology originally pioneered by Nicotra and co-workers,10
our approach has the definite advantage of avoiding N-protecting
group replacement as the addition of AllylTMS to NeZ glycosyl-
amines provides directly amino alditols derivatives in which ni-
trogen carries a deactivating protecting group. After cyclization, the
allyl group can be rapidly functionalized by cross-metathesis, oxi-
dation or other reactions with electrophilic reagents without fur-
ther manipulation at the nitrogen atom. Moreover this synthetic
strategy is also convenient for the preparation of functionalized 1-
OH
NHZ
OBn
OBn
3
4
OBn NHZ
OH
NZ
g, h
BnO
BnO
f
BnO
OBn OBn
6
5
ds > 90%
HO
H
N
NZ
i
j
BnO
BnO
n
( )
BnO
OH
OH
2 n = 2
n
( )
7a n = 2
7b n = 5
1 n = 5
C-alkylated iminosugars in the
analogy with the xylo series, potential pharmacological chaperones
for mutant -galactocerebrosidase (GALC). This enzyme hydrolyzes
L-arabino series, which might be, by
Scheme 1. Reagents and conditions: (a) MeOH, HCl (from SOCl2), reflux (b) NaH, BnBr,
TBAI, anhyd DMF, RT (c) 1 M H2SO4, AcOH, dioxane, reflux, 64% (3 steps) (d) Ac2O,
b
ꢁ
pyridine, RT (e) NH2CO2Bn, TMSOTf, anhyd CH2Cl2, 4 A MS, RT, 85% (2 steps) (f) AllTMS,
the glycosidic bond of galactosylceramide and psychosine (Fig. 2).
t
TMSOTf, anhyd CH3CN, ꢀ20 ꢁC, 81% (g) MsCl, NEt3, anhyd CH2Cl2, 4 A MS, RT (h) BuOK,
ꢁ
anhyd THF, RT, 59% (2 steps) (i) pent-1-ene (n¼2), oct-1-ene (n¼5), HoveydaeGrubbs
i
catalyst, anhyd CH2Cl2, RT, 41% (7a), 78% (7b) (j) H2, Pd/C, 1 N HCl, PrOH, RT, quant.
OH
HO
NHR
O
This methodology was found to be efficient also for the synthesis
C
H
O
13 27
H O
of iminosugars in the
lacking the C5-CH2OH group. 2,3,4-Tri-O-benzyl-
8 was synthesized from -arabinose using the same strategy as for
L-arabino series, which are galactoside mimics
OH
L-arabinopyranose
OH
L
xylose.14 The N-protected arabinopyranosylamine derivative 9 was
obtained by acetylation of the anomeric position followed by ad-
dition of benzyl carbamate in the presence of TMSOTf. Addition of
AllylTMS gave the open-chain derivative 10 (mostly syn-di-
astereoisomer). Traces of the other diastereoisomer (around 10%)
could be observed on 1H and 13C NMR spectra, but could not be
separated from the desired compound at that stage of the synthesis.
The mixture was then submitted to mesylation and cyclization
under the same conditions as in xylo series, leading to a separable
Fig. 2. Structures of galactosylceramide (R]COC15H31) and psychosine (R¼H).
GALC deficiency is responsible for Krabbe disease, another LSD,
which has currently no treatment available.11 It has been shown
very recently that PCT may also be a promising strategy for the
treatment of this disease.12
2. Results and discussion
2,3,4-Tri-O-benzyl-
D-xylopyranose 3 was easily synthesized
mixture of the two anomers 11b and 11a. The major one 11b was
thus obtained in eight steps and 13% overall yield (Scheme 2), which
can be compared to the 26% overall yield obtained in the xylo series.
from
D
-xylose in three steps and excellent overall yield.13 Acetyla-
tion of the anomeric position followed by addition of benzyl car-
bamate in the presence of TMSOTf provided efficiently the N-
protected xylopyranosylamine 4. Using the conditions we de-
veloped for the synthesis of UDP-Galf mimics,8 this compound was
then submitted to the addition of AllylTMS in the presence of
OBn
OBn
O
O
a, b, c
d, e
L-arabinose
NHZ
BnO
BnO
OBn
OH
TMSOTf leading to the open-chain amino -iditol derivative 5, in
D
OBn
9
OBn
8
good yield (81%) and with very good syn-diastereoselectivity.
Traces of two unseparable compounds (around 15%), one of which
might be the other diastereoisomer, could be observed on the 1H
and 13C NMR spectra. Fortunately these impurities were easily
eliminated during the cyclization, which was efficiently achieved
by mesylation of the free alcohol function, followed by a base-
NZ
BnO
BnO
OH
OBn NHZ
g, h
f
11β
+
OBn
promoted ring closure giving the
a
-1-C-allyl imino-
D
-xylitol 6. Its
Z
OBn OBn
4C1 conformation was unambiguously established by the high 1H
N
BnO
10
NMR coupling constants between H3 and H2/H4 (J¼9.3 Hz). The
syn major
OBn
a
configuration was also demonstrated by the J1,2 coupling constant
11α
(J1,2¼5.9 Hz), although more definitive evidence comes from the
NMR data of the final products 1 and 2. Metathesis using second
generation HoveydaeGrubbs catalyst allowed chain elongation in
moderate yield for (highly volatile) pentene and in good yield for
octene. The iminosugars 6, 7a, and 7b exist as mixtures of rotamers
due to the presence of the benzyloxycarbonyl protective group. A
last step of deprotection by hydrogenolysis provided quantitatively
Scheme 2. Reagents and conditions: (a) MeOH, HCl (from AcCl), reflux, 59% (b) NaH,
BnBr, anhyd DMF, RT (c) 3 N HCl, 80% aq AcOH, 90 ꢁC, 56% (2 steps) (d) Ac2O, pyridine,
ꢁ
RT (e) NH2CO2Bn, TMSOTf, anhyd CH2Cl2, 4 A MS, RT, 81% (2 steps) (f) AllTMS, TMSOTf,
anhyd CH3CN, ꢀ25 C, 71% (g) MsCl, NEt3, anhyd CH2Cl2, 4 A MS, RT (h) tBuOK, anhyd
ꢁ
ꢁ
THF, RT, 66% (11b), 8% (11a) (2 steps).
The low quality of 1H NMR spectra due to the presence of
rotamers did not allow the direct determination of the pseudo
a
-C6-DIX 2 and a-C9-DIX 1. These iminosugars acting as potent
anomeric configurations of 11
on the nitrogen-deprotected iminosugars. For this purpose, com-
pounds 12 and 12 were obtained by hydrogenolysis under basic
b and 11a. This was easily achieved
GCase inhibitors were thus synthesized efficiently and reproducibly
in ten steps and 11% and 20% overall yields, respectively, from
a simple aldose (Scheme 1).
b
a
conditions, in order to avoid O-debenzylation (Scheme 3). The
pseudo anomeric configurations were assigned according to the
small 1H NMR coupling constants measured in 12
J2,3¼J3,4¼2.8 Hz), compared to the high ones measured in 12
b
(J1,2¼1.9 Hz,
y
Successful addition of allylindium to unprotected glycosylamines was recently
reported.9d
a

3350
A. Biela et al. / Tetrahedron 69 (2013) 3348e3354
remaining acetate ligands still coordinated to the metal atoms.
OBn
OBn
H
Thus, this reduction or restriction of the conformational freedom
makes an absolute configurational assignment possible on the basis
of the chiroptical data alone. As can be seen in Fig. 3, a positive
helicity of the diol 13a correlates with positive CEs at 310 and
380 nm whilst the inverse correlation of helicity of the diol subunit
and sign of CEs takes place for diol 13b. Thus, provided the relative
configuration of vic-diol after ligation to the Mo2-core to be gauche
with preferred antiperiplanar orientation of the hydroxyl group
versus bulky substituent, the absolute configuration of the newly
formed stereogenic center in 13a is (R) and in 13b (S).
NZ
N
BnO
BnO
BnO
11β
OBn
12β
OBn
OBn
Z
H
N
N
BnO
BnO
BnO
OBn
11α
12α
i
Scheme 3. Reagents and conditions: H2, Pd/C, NEt3, PrOH, RT, quant.
(J1,2¼J2,3¼9.3 Hz). Inversion of conformation from 11
b b
(4C1) to 12
(1C4) is consistent with the cleavage of the N-protecting group.
N-Acyl-protected piperidines favor indeed a conformation in which
the substituent
a
to nitrogen is in axial disposition.15
In order to prepare potential GALC inhibitors with a structure
mimicking the functions present in psychosine (Fig. 2), we envisaged
the synthesis of derivatives carrying a functionalized aglycone. So the
allyl iminosugar 11b was submitted to dihydroxylation on one hand
and on the other, to hydroboration/oxidation reactions (Scheme 4).
Fig. 3. ECD spectra of in situ formed Mo-complexes of 13a (red line) and 13b (blue
line) recorded in DMSO. The preferred conformation of the diols in the chiral Mo-
complexes is shown on the right.
b
a
14a R1 = H, R = OH
Hydroboration/oxidation reaction was found to be more diffi-
cult. Using catecholborane and Wilkinson’s catalyst,17 compound
15 could be isolated only in moderate yield. Due to the presence of
the benzyloxycarbonyl protective group, the iminosugars 13a, 13b,
and 15 exist as mixtures of rotamers, which leads to broad signals
on the 1H NMR spectra. Finally, these compounds were submitted
14b R1 = OH, 2R = H
2
13a R1 = H, R = OH
13b R1 = OH, 2R = H
2
11
β
c, d
to hydrogenolysis leading to the
sugars 14a, 14b, and 16. Evaluation of these compounds as in-
hibitors of lysosomal -galactosidase, -galactosidase and b-
L-arabino functionalized imino-
b
a
b
galactocerebrosidase is in progress to determine their activity and
selectivity as potential pharmacological chaperones.
15
16
Scheme 4. Reagents and conditions: (a) OsO4, NMO, THF, tBuOH, H2O, RT, 51% (13a),
22% (13b) (b) H2, Pd/C, 1 N HCl, iPrOH, RT, 96% (14a), 57% (14b), quant. (16) (c) cat-
echolborane, Wilkinson’s catalyst, THF, 40 ꢁC (d) NaOH, H2O2, RT, 46%.
3. Conclusion
We improved the synthesis of 1-C-alkylated iminosugars in the
xylopyranose series and demonstrated that this is also applicable in
the -arabinopyranose series. These compounds are potential phar-
macological chaperones for the treatment of, respectively, Gaucher
and Krabbe diseases. The key step is the diastereoselective addition
of AllylTMS to N-Z-protected glycopyranosylamines, which is thus
shown to be applicable not only to glycofuranosylamines.8,18 This
strategy allows the direct functionalization of the allyl substituent
using metathesis or oxidation reactions, leading to a diversity of non-
functionalized or functionalized 1-C-alkylated iminosugars.
D-
Dihydroxylation was efficiently realized using the OsO4/NMO
system leading to a separable mixture of the two diastereoisomers
13a and 13b. Configuration of the secondary alcohol was de-
termined by circular dichroism analysis. To assign the absolute
configuration of the newly formed stereogenic center in com-
pounds 13a and 13b, the in situ dimolybdenum methodology of
electronic circular dichroism spectroscopy (ECD) has been applied.
This straightforward, simple, and reliable approach consists of
mixing a nonracemic transparent vic-diol with dimolybdenum
tetraacetate acting as an auxiliary chromophore.16 The transition
metal ions, when complexed to an optically active ligand, become
involved in the symmetry of the ligand. Thus, the Cotton Effects
(CEs) related to electronic transitions of the metal atom are ob-
tained and they are characteristic for the absolute configuration of
the compound acting as ligand (in this case 1,2-diol). In general, an
application of the helicity rule relating the sign of the OeCeCeO
torsional angle with the sign of the CEs arising in the 300e400 nm
spectral range allows an unequivocal assignment of the stereo-
structure of investigated diol units. This is due to the fact that in the
chiral Mo-complexes formed in situ the conformational mobility of
diols is very much reduced due to the restricted rotations of the
L
4. Experimental section
4.1. General
All reactions requiring anhydrous conditions were carried out
using oven-dried glassware under an atmosphere of dry Ar. THF was
distilled from Na/benzophenone. CH2Cl2 was distilled from CaH2.
ꢁ
CH3CN was dried using activated 3 A molecular sieves. All reagent-
grade chemicals were obtained from commercial suppliers and
were used as received. Infrared spectra were recorded using neat
compounds on a Nicolet iS10 FT-IR spectrometer. Low-resolution

A. Biela et al. / Tetrahedron 69 (2013) 3348e3354
3351
mass spectra were recorded on a PerkineElmer Sciex API 3000. High
resolution mass spectra were recorded on a Bruker Q-TOF MaXis
CH3CN (120 mL) under Ar at ꢀ20 ꢁC was added AllylTMS (13 mL,
81.8 mmol, 6.8 equiv). After stirring for 15 min, TMSOTf (2.2 mL,
12.1 mmol,1 equiv) was added and the reaction mixture was stirred
for 20 h at ꢀ20 ꢁC. At 0 ꢁC, saturated NaHCO3 (60 mL) was added.
The mixture was diluted with EtOAc (300 mL) and H2O (100 mL).
The organic phase was washed with brine (100 mL), dried over
MgSO4 and concentrated under vacuum. The residue was purified
twice by flash chromatography on silica gel (pet. ether/EtOAc 8:2)
to afford 5 (5.78 g, 81%) as a colorless oil. 1H NMR of the major
ꢀ
spectrometer in Orleans or on a WatersQ-TOF micro spectrometer in
Clermont-Ferrand.1H and 13C NMR spectra were recorded on Bruker
Avance DPX 250 or Bruker Avance 400 spectrometers. Chemical
shifts are given inparts per million and are referenced tothe residual
solvent signal or to TMS as internal standard. Carbon multiplicities
were assigned by distortionless enhancement by polarization
transfer (DEPT) experiments. 1H and 13C signals were attributed on
the basis of HeH and CeH correlations. Specific optical rotations
were measured at 20 ꢁC in a 1-dm cell with a PerkineElmer 341
polarimeter. ECD spectra were acquired between 650 and 280 nm at
room temperature with a Jasco J-815 spectropolarimeter using
DMSO solutions in cells of 0.2 and 1 cm path length (spectral band
diastereoisomer (400 MHz, CDCl3):
d
¼7.34e7.28 (m, 20H, HAr),
5.63e5.52 (m, 1H, eCH]), 5.14 (d, 1H, J¼10.0 Hz, NH), 5.06 (s, 2H,
CO2CH2Ph), 4.99e4.93 (m, 2H, ]CH2), 4.88 (d, 1H, J¼11.1 Hz,
OCH2Ph), 4.77 (d, 1H, J¼11.2 Hz, OCH2Ph), 4.68 (d, 1H, J¼11.7 Hz,
OCH2Ph), 4.58 (d, 1H, J¼11.2 Hz, OCH2Ph), 4.52 (d, 1H, J¼11.1 Hz,
OCH2Ph), 4.51 (d, 1H, J¼11.7 Hz, OCH2Ph), 3.82e3.65 (m, 6H, H1, H2,
H3, H4, H5), 2.27e2.07 (m, 3H, eCH2eCH], OH). 13C NMR of the
width 2 nm, high sensitivity). Depending on the S/N-ratio the l-scan
speed was 200 nm/min. For ECD measurements the solid chiral diol
(4.5e5 mg) was dissolved in a solution of the stock [Mo2(OAc)4]
complex (7e8 mg) in DMSO (10 mL) so that the molar ratio of the
stock complex to diol was about 1:1.5. As the true concentrations of
the individual optically active complexes are not known, apparent
major diastereoisomer (100 MHz, CDCl3):
d
¼156.29 (C]O),
138.29e136.56 (CAr), 134.55 (eCH]), 128.64e127.82 (CHAr), 117.86
(]CH2), 80.26, 79.80, 77.73 (C2, C3, C4), 75.23, 72.28 (OCH2Ph),
66.86 (CO2CH2Ph), 61.41 (C5), 51.58 (C1), 38.05 (eCH2eCH]). IR
D
ε0 values are given, calculated from the total stock complex con-
n
¼3434, 3064, 3031, 2931, 2874, 1713, 1498, 1210, 1049, 1026, 734,
centration and assuming 100% complexation. [Mo2(OAc)4] and
DMSO (Uvasol) were commercially available from Fluka AG and E.
Merck, respectively, and were used without further purification.
Analytical thin layer chromatography was performed using Silica
Gel 60F254 precoated plates (Merck) with visualization by ultraviolet
light and phosphomolybdic acid or ceric sulfate/ammonium mo-
lybdate solutions. Flash chromatography was performed on Silica
Gel 60 (230e400 mesh).
696. MS (ESI) m/z 618.5 [MþNa]þ. HRMS (ESI) [MþNa]þ calcd for
C37H41NNaO6 m/z 618.2832; found m/z 618.2831.
4.2.3. (1R)-1-C-Allyl-2,3,4-tri-O-benzyl-N-benzyloxycarbonyl-1,5-
dideoxy-1,5-imino- -xylitol (6). To a solution of 5 (5.78 g,
D
9.70 mmol) in dry CH2Cl2 (100 mL) under Ar were added NEt3
ꢁ
(3 mL, 21.5 mmol, 2.2 equiv) and 4 A molecular sieves. The mixture
was stirred for 10 min and MsCl (1.6 mL, 20.7 mmol, 2.1 equiv) was
added. The reaction mixture was stirred for 23 h at room temper-
ature. The solid was filtered, washed with CH2Cl2 (200 mL) and the
filtrate was treated with saturated NH4Cl (200 mL). The organic
phase was washed with brine (200 mL), dried over MgSO4 and
concentrated under vacuum. The residue was dissolved in dry THF
4.2. Synthesis of 1-C-alkyl imino-D-xylitol derivatives
4.2.1. N-Benzyloxycarbonyl 2,3,4-tri-O-benzyl- -xylopyranosyl-
a,
b-
D
amine (4). To a solution of 2,3,4-tri-O-benzyl-a,b-D-xylofuranose 3
t
(6.0 g, 14.3 mmol) in pyridine (30 mL) was added Ac2O (6.5 mL,
69.2 mmol, 4.8 equiv). The reaction mixture was stirred for 18 h at
room temperature. CH2Cl2 was added (300 mL). The organic phase
was washed with H2O (3ꢂ400 mL) and dried over MgSO4. After
concentration under vacuum and coevaporation with toluene, the
crude product was obtained as a colorless oil, which was used in the
next step without further purification. 1-O-Acetyl 2,3,4-tri-O-ben-
(90 mL) under Ar and BuOK (3.23 g, 28.8 mmol, 3 equiv) was
added. The reaction mixture was stirred for 25 h at room temper-
ature. Saturated NH4Cl (200 mL) and EtOAc (300 mL) were added.
The organic phase was washed with brine (200 mL), dried over
MgSO4 and concentrated under vacuum. Flash chromatography on
silica gel (toluene/EtOAc 98:2) afforded 6 (3.33 g, 59%) as a colorless
oil and as a mixture of rotamers (A/B 1:1). [
a
]
D ꢀ15.1 (c¼1.1, CHCl3).
zyl-
a
,
b
-
D
-xylopyranose was dissolved in dry CH2Cl2 (30 mL) and
1H NMR (400 MHz, CDCl3):
d
¼7.37e7.25 (m, 20H, HAr), 5.76e5.66
ꢁ
stirred for 10 min under Ar in the presence of 4 A molecular sieves
and benzyl carbamate (4.3 g, 28.4 mmol, 2 equiv). TMSOTf (2.6 mL,
14.4 mmol, 1 equiv) was added and the mixture was stirred at room
temperature for 1.5 h. NEt3 (2.5 mL) was then added. The solid was
filtered over Celite, washed with CH2Cl2 and the filtrate was con-
centrated under vacuum. Flash chromatography on silica gel (tolu-
(m, 0.5H, eCH]B), 5.61e5.50 (m, 0.5H, eCH]A), 5.14e4.92 (m, 4H,
CO2CH2Ph, ]CH2), 4.89e4.81 (m, 2H, OCH2Ph), 4.72e4.61 (m, 4.5H,
OCH2Ph, H1B), 4.45e4.41 (m, 0.5H, H1A), 4.41 (dd, 0.5H, J¼5.7,
13.5 Hz, H5eqA or B), 4.17 (dd, 0.5H, J¼5.7, 13.5 Hz, H5eqA or B), 3.68 (t,
1H, J¼9.3 Hz, H3), 3.56 (dd, 0.5H, J¼5.9, 9.3 Hz, H2B), 3.50 (dd, 0.5H,
J¼5.9, 9.3 Hz, H2A), 3.49e3.46 (m, 0.5H, H4A or B), 3.41 (ddd, 0.5H,
J¼5.7, 9.3, 11.1 Hz, H4A or B), 2.76 (dd, 0.5H, J¼11.1, 13.5 Hz, H5axA or
ene/EtOAc 9:1) afforded the mixture of anomers (
a
d
/
b
3:7) 4 (6.76 g,
85%) as a white solid. 1H NMR (400 MHz, CDCl3):
¼7.32e7.24 (m,
B), 2.74 (dd, 0.5H, J¼11.1, 13.5 Hz, H5axA
B), 2.62e2.51 (m, 1H,
or
20H, HAr), 5.80 (d, 0.3H, J¼8.0 Hz, NHa), 5.34 (dd, 0.3H, J¼3.6, 8.0 Hz,
H1a), 5.20 (br s, 0.7H, NHb), 5.14e5.11 (m, 1.4H, CO2CH2Phb),
5.06e5.03 (m, 0.6H, CO2CH2Pha), 4.91e4.48 (m, 6.7H, OCH2Ph, H1b),
3.90 (dd, 0.7H, J¼5.1, 11.6 Hz, H5bb), 3.78 (dd, 0.3H, J¼3.9, 12.2 Hz,
H5ba), 3.72e3.61 (m, 1.3H, H3, H5aa), 3.59e3.53 (m, 1H, H2a, H4b),
3.45e3.41 (m, 0.3H, H4a), 3.32e3.22 (m, 1.4H, H2b, H5ab). 13C NMR
CH2eCH]), 2.35e2.25 (m, 1H, CH2eCH]). 13C NMR (100 MHz,
CDCl3):
d¼155.69, 155.60 (C]O), 138.93e136.56 (CAr), 134.54,
134.35 (eCH]),128.63e127.69 (CHAr),117.66,117.41 (]CH2), 82.20,
82.06 (C3), 79.81 (C2), 78.38, 78.34 (C4), 75.86e72.86 (OCH2Ph),
67.60, 67.50 (CO2CH2Ph), 53.00, 52.28 (C1), 41.09, 40.81 (C5), 29.77,
29.73 (eCH2eCH]). IR
n
¼3064, 3031, 2901, 2871, 1699, 1454, 1423,
(100 MHz, CDCl3):
d
¼155.92, 155.63 (C]O), 138.46e136.14 (CAr),
1314, 1209, 1094, 734, 695. MS (ESI) m/z 600.5 [MþNa]þ. HRMS
(ESI) [MþNa]þ calcd for C37H39NNaO5 m/z 600.2726; found m/z
600.2707.
128.57e127.79 (CHAr), 84.57 (C3b), 82.17 (C1b), 79.65 (C2b), 77.83
(C4b), 77.45 (C1a), 76.81 (C3a), 76.07 (C2a), 74.85 (C4a), 75.59e72.42
(OCH2Ph), 67.15, 67.12 (CO2CH2Ph), 65.31 (C5b), 62.50 (C5a). IR
n
¼3355, 3063, 3032, 2868, 1700, 1531, 1453, 1281, 1232, 1090, 1073,
4.2.4. (1R)-2,3,4-Tri-O-benzyl-N-benzyloxycarbonyl-1-C-hex-2-enyl-
1,5-dideoxy-1,5-imino-D-xylitol (7a). To a solution of 6 (294 mg,
0.509 mmol) in dry CH2Cl2 (2 mL) under Ar were added second
1042, 731, 694. MS (ESI) m/z 576.5 [MþNa]þ. HRMS (ESI) [MþNa]þ
calcd for C34H35NNaO6 m/z 576.2362; found m/z 576.2357.
generation HoveydaeGrubbs catalyst (20 mg, 0.032 mmol,
4.2.2. 1-C-Allyl-2,3,4-tri-O-benzyl-1-(N-benzyloxycarbonyl)amino-
0.06 equiv) and pentene (720
mL, 6.57 mmol, 13 equiv). The reaction
1-deoxy- -xylitol (5). To a solution of 4 (6.67 g, 12.0 mmol) in dry
D
mixture was stirred for 30 h at 20 ꢁC. The solvent was evaporated

3352
A. Biela et al. / Tetrahedron 69 (2013) 3348e3354
and the crude product was purified twice by flash chromatography
on silica gel (pet. ether/EtOAc 95:5) to afford 7a (129 mg, 41%) as
1.58e1.51 (m, 1H, eCHeCH2eCH2), 1.37e1.32 (m, 8H, CH2), 0.91 (t,
3H, J¼7.0 Hz, CH3). 13C NMR (100 MHz, MeOD):
¼70.56 (C2), 69.56
d
a colorless oil and as a mixture of rotamers (A/B 1:1). [
a
]
D ꢀ11.2 (c
(C3), 69.36 (C4), 55.93 (C1), 47.36 (C5), 32.80, 30.31 (CH2), 30.19
1.1, CHCl3). 1H NMR (400 MHz, CDCl3):
d¼7.38e7.24 (m, 20H, HAr),
(CHeCH2eCH2), 26.42, 23.60 (CH2), 14.41 (CH3). IR
n
¼3363, 3281,
5.47e5.36 (m, 1H, eCHeCH2eCH]CH), 5.33e5.26 (m, 0.5H,
eCHeCH2eCH]CHB), 5.21e5.16 (m, 0.5H, eCHeCH2eCH]CHA),
5.13e5.01 (m, 2H, CO2CH2Ph), 4.89e4.81 (m, 2H, OCH2Ph),
4.72e4.61 (m, 4.5H, OCH2Ph, H1B), 4.43e4.36 (m, 1H, H1A, H5eqA or
B), 4.16 (dd, 0.5H, J¼5.9, 13.6 Hz, H5eqA or B), 3.72e3.65 (m, 1H, H3),
3.56 (dd, 0.5H, J¼5.9, 9.5 Hz, H2B), 3.50 (dd, 0.5H, J¼5.9, 9.5 Hz,
3091, 3018, 2925, 2856, 1539, 1460, 1416, 1292, 1054, 990, 723.
HRMS (ESI) [MþH]þ calcd for C11H24NO3 m/z 218.1756; found m/z
218.1767.
4.2.7. (1R)-1-C-Nonyl-1,5-dideoxy-1,5-imino- -xylitol (1). To a solu-
D
tion of 7b (53 mg, 0.080 mmol) in EtOH (2 mL) were added 1 N HCl
(0.4 mL, 5 equiv) and 10% Pd/C (30 mg). The reaction mixture was
stirred at room temperature under a H2 atmosphere for 20 h. The
catalyst was filtered through a membrane, washed with EtOH and
the filtrate was concentrated under vacuum. The residue was
treated with AmberliteÒ IRA400 resin ðOHꢀÞ in water to give 1
(21 mg, quant.) as a white solid. Analytical data are in accordance
with the literature data.6b
H2A), 3.49e3.46 (m, 0.5H, H4A
B), 3.41 (ddd, 0.5H, J¼5.9, 8.8,
or
11.2 Hz, H4A
B), 2.78e2.70 (m, 1H, H5ax), 2.55e2.45 (m, 1H,
or
eCHeCH2eCH]), 2.29e2.19 (m, 1H, eCHeCH2eCH]), 2.01e1.83
(m, 2H, eCH]CHeCH2), 1.38e1.23 (m, 2H, eCH]CHeCH2eCH2),
0.83 (t, 3H, J¼7.3 Hz, CH3). 13C NMR (100 MHz, CDCl3):
¼155.70,
d
155.55 (C]O), 138.95e136.66 (CAr), 133.63, 133.38 (eCH]CHe),
128.62e127.65 (CHAr), 125.72, 125.54 (eCH]CHe), 82.22, 82.07
(C3), 79.89 (C2), 78.41, 78.37 (C4), 75.83e72.73 (OCH2Ph), 67.49,
67.42 (CO2CH2Ph), 53.29, 52.39 (C1), 41.04, 40.76 (C5), 34.75, 34.66
(]CHeCH2e), 28.55, 28.42 (CHeCH2eCH]), 22.64, 22.60 (]
4.3. Synthesis of 1-C-alkyl imino-L-arabinitol derivatives
CHeCH2eCH2e), 13.76, 13.67 (CH3). IR
n
¼3063, 3031, 2955, 2927,
4.3.1. N-Benzyloxycarbonyl -arabinopyr-
anosylamine (9). To a solution of 2,3,4-tri-O-benzyl-a,b-L-arabino-
2,3,4-tri-O-benzyl-
a
,
b
-
L
2870, 1699, 1453, 1423, 1313, 1198, 1095, 733, 695. HRMS (ESI)
[MþNa]þ calcd for C40H45NNaO5 m/z 642.3195; found m/z
642.3194.
pyranose 8 (1.0 g, 2.38 mmol) in pyridine (4.8 mL) was added Ac2O
(1.2 mL, 12.8 mmol, 5.4 equiv). The reaction mixture was stirred for
3 h at room temperature. CH2Cl2 (48 mL) was added. The organic
phase was washed with H2O (3ꢂ18 mL) and dried over MgSO4.
After concentration under vacuum and coevaporation with toluene,
the crude product was obtained as a colorless oil, which was used in
the next step without further purification. 1-O-Acetyl 2,3,4-tri-O-
4.2.5. (1R)-2,3,4-Tri-O-benzyl-N-benzyloxycarbonyl-1-C-non-2-enyl-
1,5-dideoxy-1,5-imino- -xylitol (7b). To a solution of 6 (89 mg,
D
0.154 mmol) in dry CH2Cl2 (4 mL) under Ar were added second
generation HoveydaeGrubbs catalyst (39 mg, 0.062 mmol,
0.4 equiv) and 1-octene (91
m
L, 0.580 mmol, 3.8 equiv). The reaction
benzyl-a,b-L-arabinopyranose was dissolved in dry CH2Cl2 (2.4 mL)
mixture was stirred for 41 h at 40 ꢁC. The solvent was evaporated
and the crude product was purified by flash chromatography on
silica gel (pet. ether/EtOAc 9:1) to afford 7b (80 mg, 78%) as a col-
orless oil and as a mixture of rotamers (A/B 1:1). 1H NMR (400 MHz,
containing 4 A molecular sieves under Ar. After 5 min of stirring,
benzyl carbamate (0.72 g, 4.76 mmol, 2 equiv), then TMSOTf
(0.44 mL, 2.43 mmol, 1.0 equiv) were added. The mixture was
stirred at room temperature for 2 h. NEt3 (0.33 mL) was then added.
The solid was filtered over Celite, washed with CH2Cl2 and the fil-
trate was concentrated under vacuum. Flash chromatography on
silica gel (toluene/acetone 95:5) afforded the mixture of anomers
ꢁ
CDCl3):
d
¼7.38e7.24 (m, 20H, HAr), 5.48e5.39 (m, 1H,
eCHeCH2eCH]CH), 5.33e5.27 (m, 0.5H, eCHeCH2eCH]CHB),
5.21e5.15 (m, 0.5H, eCHeCH2eCH]CHA), 5.14e5.02 (m, 2H,
CO2CH2Ph), 4.89e4.81 (m, 2H, OCH2Ph), 4.72e4.61 (m, 4.5H,
OCH2Ph, H1B), 4.42e4.36 (m, 1H, H1A, H5eqA or B), 4.16 (dd, 0.5H,
J¼5.6, 13.6 Hz, H5eqA or B), 3.72e3.65 (m, 1H, H3), 3.56 (dd, 0.5H,
J¼6.0, 9.6 Hz, H2B), 3.50 (dd, 0.5H, J¼6.0, 9.6 Hz, H2A), 3.47e3.37 (m,
1H, H4), 2.78e2.70 (m, 1H, H5ax), 2.54e2.45 (m, 1H,
eCHeCH2eCH]), 2.29e2.19 (m, 1H, eCHeCH2eCH]), 2.04e1.85
(m, 2H, eCH]CHeCH2), 1.26e1.21 (m, 8H, CH2), 0.90e0.85 (m, 3H,
(a/b
4:6) 9 (1.07 g, 81%) as a colorless oil. 1H NMR (400 MHz, CDCl3):
d
¼7.31e7.21 (m, 20H, HAr), 6.30 (d, 0.4H, J¼6.7 Hz, NHa), 5.68
(d, 0.6H, J¼9.4 Hz, NHb), 5.32 (d, 0.6H, J¼9.4 Hz, H1b), 5.18e5.15
(m, 0.4H, H1a), 5.15e5.03 (m, 2H, CO2CH2Ph), 4.73e4.34 (m, 6H,
OCH2Ph), 3.95e3.87 (m, 1H, H5b), 3.83e3.75 (m, 2.6H, H3, H4,
H5ab), 3.59 (t, 0.4H, J¼5.3 Hz, H2a), 3.52 (dd, 0.4H, J¼2.2, 11.6 Hz,
H5aa), 3.47 (dd, 0.6H, J¼1.9, 3.5 Hz, H2b). 13C NMR (100 MHz,
CH3). 13C NMR (100 MHz, CDCl3):
d
¼155.78, 155.65 (C]O),
CDCl3):
d
¼155.48 (C]O), 138.16e138.11 (CAr), 128.59e127.56
139.04e136.76 (CAr), 133.98, 133.75 (eCH]CHe), 128.70e127.72
(CHAr), 125.51, 125.36 (eCH]CHe), 82.30, 82.15 (C3), 79.98 (C2),
78.50 (C4), 75.90e72.80 (OCH2Ph), 67.56, 67.49 (CO2CH2Ph), 53.38,
52.49 (C1), 41.14, 40.86 (C5), 32.79, 32.73 (]CHeCH2e),
31.94e29.00 (CH2), 28.63, 28.51 (CHeCH2eCH]), 22.83 (CH2),
(CHAr), 79.04 (C1a), 77.60 (C3a), 76.98 (C1b), 76.58 (C2b), 76.20 (C2a),
73.10e72.93 (OCH2Ph), 72.29e72.22 (C3b, C4), 71.41, 71.39
(OCH2Ph), 66.91, 66.79 (CO2CH2Ph), 62.57 (C5b), 60.69 (C5a). IR
n
¼3320, 3063, 3031, 2902, 1732, 1689, 1534, 1292, 1250, 1081, 1045,
772, 730. MS (ESI) m/z 576.5 [MþNa]þ. HRMS (ESI) [MþNa]þ calcd
14.33 (CH3). IR
n
¼3031, 2924, 2855, 1700, 1453, 1423, 1313, 1202,
for C34H35NNaO6 m/z 576.2362; found m/z 576.2357.
1096, 968, 733, 695. HRMS (ESI) [MþH]þ calcd for C43H52NO5 m/z
662.384000; found m/z 662.383684.
4.3.2. 1-C-Allyl-2,3,4-tri-O-benzyl-1-(N-benzyloxycarbonyl)amino-
1-deoxy- -arabinitol (10). To a solution of 9 (1.07 g, 1.92 mmol) in
L
4.2.6. (1R)-1-C-Hexyl-1,5-dideoxy-1,5-imino-
D
-xylitol (2). To a solu-
dry CH3CN (19 mL) under Ar at ꢀ20 ꢁC was added AllylTMS
(2.15 mL, 13.5 mmol; 7.0 equiv). After stirring for 10 min, TMSOTf
(0.36 mL, 1.98 mmol; 1 equiv) was added and the reaction mixture
was stirred overnight at ꢀ20 ꢁC. At 0 ꢁC, saturated NaHCO3 (33 mL)
was added. The mixture was diluted with EtOAc (200 mL). The
organic phase was washed with brine (2ꢂ70 mL), dried over MgSO4
and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (toluene/acetone 95:5) to afford 10
(0.82 g, 71%) as a colorless oil. 1H NMR of the major diastereoisomer
tion of 7a (731 mg, 1.18 mmol) in iPrOH (10 mL) were added 1 N HCl
(1.2 mL, 1 equiv) and 10% Pd/C (350 mg). The reaction mixture was
stirred at room temperature under a H2 atmosphere for 22 h. The
catalyst was filtered through a membrane, washed with iPrOH and
the filtrate was concentrated under vacuum. The residue was
treated with AmberliteÒ IRA400 resin ðOHꢀÞ in water to give 2
(256 mg, quant.) as a white solid. [
a
]
ꢀ21.3 (c 0.96, MeOH). Mp
D
>145 ꢁC (decomp.). 1H NMR (400 MHz, MeOD):
d¼3.87 (t, 1H,
J¼3.8 Hz, H3), 3.75e3.72 (m, 1H, H4), 3.69 (br s, 1H, H2), 3.21 (dd,
1H, J¼2.2, 13.4 Hz, H5b), 3.12 (ddd, 1H, J¼2.0, 6.2, 8.2 Hz, H1), 2.99
(dd, 1H, J¼2.8, 13.4 Hz, H5a), 1.75e1.66 (m, 1H, eCHeCH2eCH2),
(400 MHz, CDCl3):
d
¼7.32e7.23 (m, 20H, HAr), 5.73e5.63 (m, 1H,
eCH]), 5.20 (d, 1H, J¼9.8 Hz, NH), 5.13e5.05 (m, 4H, CO2CH2Ph, ]
CH2), 4.87e4.44 (m, 6H, OCH2Ph), 3.90e3.61 (m, 6H, H1, H2, H3, H4,

A. Biela et al. / Tetrahedron 69 (2013) 3348e3354
3353
H5), 2.35e2.22 (m, 3H, CH2eCH], OH). 13C NMR of the major di-
astereoisomer (100 MHz, CDCl3):
(CAr), 134.51 (eCH]), 128.55e127.83 (CHAr), 118.21 (]CH2), 80.81,
J¼2.9, 14.3 Hz, H5b), 2.48e2.44 (m, 2H, H1, H5a), 2.00 (br s, 1H, NH),
1.88e1.81 (m, 1H, CH2eCH2eCH3), 1.58e1.47 (m, 1H,
CH2eCH2eCH3), 1.36e1.23 (m, 2H, CH2eCH2eCH3), 0.91 (t, 3H,
d
¼156.28 (C]O), 138.44e136.62
80.28, 79.42 (C2, C3, C4), 75.42, 75.27, 71.86 (OCH2Ph), 66.97
J¼7.1 Hz, CH3). 13C NMR (100 MHz, CDCl3):
¼138.98, 138.73, 138.71
d
(CO2CH2Ph), 61.34 (C5), 52.29 (C1), 38.21 (eCH2eCH]). IR
n
¼3031,
(CAr), 128.49e127.63 (CHAr), 84.36, 81.14 (C2, C3), 75.60 (OCH2Ph),
73.83 (C4), 71.81, 71.51 (OCH2Ph), 60.23 (C1), 47.06 (C5), 34.62
(CH2eCH2eCH3), 19.22 (CH2eCH2eCH3), 14.44 (CH3). 1H NMR
2875, 1714.5, 1498, 1454, 1210, 1057, 1026.5, 734, 696. MS (ESI) m/z
618.0 [MþNa]þ. HRMS (ESI) [MþNa]þ calcd for C37H41NNaO6 m/z
618.2832; found m/z 618.2838.
(400 MHz, acetone-d6):
d
¼7.31e7.09 (m, 15H, HAr), 4.82 (d, 1H,
J¼11.2 Hz, OCH2Ph), 4.60e4.53 (m, 3H, OCH2Ph) 4.47 (d, 1H,
J¼11.2 Hz, OCH2Ph), 4.46 (1H, J¼11.8 Hz, OCH2Ph), 3.81e3.80 (m,
1H, H4), 3.43 (dd, 1H, J¼2.8, 9.3 Hz, H3), 3.29 (t, 1H, J¼9.3 Hz, H2),
3.01 (dd, 1H, J¼2.9, 14.4 Hz, H5b), 2.52 (br s, 1H, NH), 2.37 (dd, 1H,
J¼1.1, 14.4 Hz, H5a), 2.25 (dt, 1H, J¼2.8, 9.3, 9.3 Hz, H1), 1.74e1.66
(m, 1H, CH2eCH2eCH3), 1.48e1.37 (m, 1H, CH2eCH2eCH3),
4.3.3. (1R)- and (1S)-1-C-Allyl-2,3,4-tri-O-benzyl-N-benzyloxycar-
bonyl-1,5-dideoxy-1,5-imino- -arabinitol (11b) and (11a). To a solu-
L
tion of 10 (0.82 g, 1.37 mmol) in dry CH2Cl2 (14 mL) under Ar were
ꢁ
added NEt3 (0.42 mL, 3.02 mmol, 2.2 equiv) and 4 A molecular sieves.
Then MsCl (0.22 mL, 2.84 mmol, 2.1 equiv) was added. The reaction
mixture was stirred for 35 min at room temperature. The solid was
filtered, washed with CH2Cl2 (150 mL) and the filtrate was treated
with saturated NH4Cl (27 mL). The organic phase was washed with
brine (2ꢂ50 mL), dried over MgSO4 and concentrated under vacuum.
1.28e1.05 (m, 2H, CH2eCH2eCH3), 0.84 (t, 2H, J¼7.3 Hz, CH3). 13
C
NMR (100 MHz, acetone-d6):
d
¼140.52, 140.40, 140.20 (CAr),
129.00e127.96 (CHAr), 85.50 (C3), 82.03 (C2), 75.55 (OCH2Ph),
75.39 (C4), 71.95, 71.73 (OCH2Ph), 60.74 (C1), 47.61 (C5), 35.36
(CH2eCH2eCH3), 19.94 (CH2eCH2eCH3), 14.60 (CH3). HRMS (ESI)
[MþH]þ calcd for C29H36NO3 m/z 446.26897; found m/z 446.26941.
t
The residue was dissolved in dry THF (14 mL) under Ar and BuOK
(0.31 g, 2.76 mmol, 2 equiv) was added. The reaction mixture was
stirred for 2.5 h at room temperature. Saturated NH4Cl (27 mL) and
EtOAc (150 mL) were added. The organic phase was washed with
brine (150 mL), dried over MgSO4 and concentrated under vacuum.
Flash chromatography on silica gel (pet. ether/EtOAc 9:1) afforded
4.3.5. (1R)-2,3,4-Tri-O-benzyl-N-benzyloxycarbonyl-1-C-(2,3-
dihydroxypropyl)-1,5-dideoxy-1,5-imino-
L
-arabinitol (13). To a solu-
tion of 11
b
(465 mg, 0.805 mmol) in a mixture of THF (3 mL), tBuOH
11
found to exist as a mixture of rotamers (A/B 1:1): 1H NMR (400 MHz,
CDCl3):
b
(503 mg, 66%) and 11
a
(61 mg, 8%) as colorless oils. 11
b
was
(9 mL) and H2O (1.6 mL) was added NMO (113 mg, 0.965 mmol,
1.2 equiv). After 5 min of stirring, a 2.5% solution of OsO4 in tBuOH
(0.82 mL, 0.062 mmol, 0.08 equiv) was added. The reaction was
stirred at room temperature for 16 h. The mixture was then treated
with a 0.1 N Na2S2O5 solution (5 mL) and stirred for 30 min. CH2Cl2
(20 mL) and H2O (10 mL) were added. The aqueous phase was
extracted with CH2Cl2 (20 mL). The combined organic phases were
dried over MgSO4 and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel (CH2Cl2/acetone 9:1)
to give a separable mixture of the two diastereoisomers 13a
(252 mg, 51%) and 13b (106 mg, 22%) as colorless oils. 13a: 1H NMR
d¼7.38e7.00 (m, 20H, HAr), 5.74 (br s, 0.5H, eCH]B), 5.60 (br
s, 0.5H, eCH]A), 5.14e5.07 (m, 2H, CO2CH2Ph), 5.03e4.91 (m, 2H, ]
CH2), 4.85e4.46 (m, 7.5H, OCH2Ph, H1, H5bA or B), 4.31e4.20 (m, 0.5H,
H5bA or B), 4.12e4.07 (m,1H, H2), 3.74e3.69 (m,1H, H4), 3.55 (dd,1H,
J¼3.3, 10.1 Hz, H3), 2.71 (br s, 1H, H5a), 2.58 (br s, 1H, CH2eCH]),
2.22e2.13 (m, 1H, CH2eCH]). 13C NMR (100 MHz, CDCl3):
(C]O), 138.77e136.77 (CAr), 135.09 (eCH]), 128.41e127.57 (CHAr),
117.12 (]CH2), 78.26 (C3), 76.46 (C2), 73.27 (OCH2Ph), 72.57 (C4),
72.31, 70.82 (OCH2Ph), 67.45 (CO2CH2Ph), 53.63, 52.98 (C1), 40.03,
d¼156.23
39.35 (C5), 29.37 (eCH2eCH]). IR
n
¼3064, 3031, 2868, 1695, 1496,
(400 MHz, CDCl3):
d
¼7.40e7.24 (m, 20H, HAr), 5.19 (d,1H, J¼12.2 Hz,
1453, 1422, 1346, 1232, 1090, 1072, 1027, 967, 734, 695. MS (ESI) m/z
CO2CH2Ph), 5.09 (d, 1H, J¼12.2 Hz, CO2CH2Ph), 4.92e4.90 (m, 1H,
H1), 4.73e4.55 (m, 6H, OCH2Ph), 4.27 (d, 1H, J¼14.6 Hz, H5b), 4.19
(dd, 1H, J¼6.5, 10.0 Hz, H2), 3.97 (s, 1H, OH), 3.69 (s, 1H, H4),
3.53e3.49 (m, 4H, H3, CHOH, CH2OH), 2.68 (d, 1H, J¼14.6 Hz, H5a),
2.34e2.33 (m, 1H, OH), 1.89e1.82 (m, 1H, CH2eCHOHe), 1.48 (t, 1H,
600.5 [MþNa]þ. HRMS (ESI) [MþNa]þ calcd for C37H39NNaO5 m/z
600.2726; found m/z 600.2712. 11
a
: HRMS (ESI) [MþH]þ calcd for
C37H40NO5 m/z 578.29010; found m/z 578.29032.
4.3.4. (1R)- and (1S)-2,3,4-Tri-O-benzyl-1-C-propyl-1,5-dideoxy-1,5-
J¼13.1 Hz, CH2eCHOHe). 13C NMR (100 MHz, CDCl3):
¼157.32 (C]
d
imino-
L
-arabinitol (12
b
) and (12
a
). To a solution of 11
b
or 11
a
O), 138.65e136.11 (CAr), 128.73e127.64 (CHAr), 78.40 (C3), 75.80
(C2), 73.31, 72.76 (OCH2Ph), 72.48 (C4), 71.25 (OCH2Ph), 68.28
(CO2CH2Ph), 68.25 (CHOH), 66.73 (CH2OH), 50.41 (C1), 40.71 (C5),
27.85 (CH2eCHOHe). HRMS (ESI) [MþH]þ calcd for C37H42NO7 m/z
612.29558; found m/z 612.29541. 13b: 1H NMR (400 MHz, CDCl3):
i
(60 mg, 0.104 mmol) in PrOH (1 mL) were added NEt3 (3.5
mL,
0.024 mmol, 0.24 equiv) and 10% Pd/C (15.6 mg). The reaction
mixture was stirred at room temperature under a H2 atmosphere
for 2 h. The catalyst was filtered through a membrane, washed with
CH2Cl2 and the filtrate was concentrated under vacuum to give,
d
¼7.34e7.24 (m, 20H, HAr), 5.16e5.06 (m, 2H, CO2CH2Ph), 4.80 (d,
respectively, 12
b
and 12
a
(46 mg, quant.) as colorless oils. 12
b
: 1H
1H, J¼11.4 Hz, OCH2Ph), 4.73e4.49 (m, 6H, H1, OCH2Ph), 4.28e4.25
(m, 1H, H5b), 4.12e4.09 (m, 1H, H2), 3.76e3.64 (m, 3H, CHOH, H4,
CH2OH), 3.51e3.44 (m, 2H, H3, CH2OH), 2.86 (d,1H, J¼15.0 Hz, H5a),
2.04e2.00 (m, 1H, CH2eCHOHe), 1.60e1.52 (m, 1H, CH2eCHOHe).
NMR (400 MHz, CDCl3):
d
¼7.36e7.17 (m, 15H, HAr), 4.78 (d, 1H,
J¼12.3 Hz, OCH2Ph), 4.56 (d, 1H, J¼12.3 Hz, OCH2Ph), 4.55 (d, 1H,
J¼12.2 Hz, OCH2Ph), 4.49 (d, 1H, J¼12.2 Hz, OCH2Ph), 4.43 (d, 1H,
J¼11.8 Hz, OCH2Ph), 4.36 (d, 1H, J¼11.8 Hz, OCH2Ph), 3.86 (t, 1H,
J¼2.8 Hz, H3), 3.71 (ddd, 1H, J¼2.8, 6.3, 9.3 Hz, H4), 3.37 (br d, 1H,
J¼2.8 Hz, H2), 3.04e2.97 (m, 2H, H5), 2.93 (dt, 1H, J¼1.9, 6.9, 6.9 Hz,
H1), 1.98 (br s,1H, NH), 1.43e1.26 (m, 3H, CH2eCH2eCH3), 1.20e1.10
(m, 1H, CH2eCH2eCH3), 0.86 (t, 3H, J¼7.3 Hz, CH3). 13C NMR
13C NMR (100 MHz, CDCl3):
d¼156.76 (C]O), 138.63e136.28 (CAr),
128.70e127.68 (CHAr), 78.42 (C3), 76.32 (C2), 73.61 (OCH2Ph), 72.64,
72.61 (C4, CHOH), 71.44, 71.12 (OCH2Ph), 68.02 (CO2CH2Ph), 66.29
(CH2OH), 52.29 (C1), 40.79 (C5), 28.51 (CH2eCHOHe). HRMS (ESI)
[MþH]þ calcd for C37H42NO7 m/z 612.29558; found m/z 612.29569.
(100 MHz, CDCl3):
(CHAr), 77.18 (C2), 75.11 (C4), 73.49 (C3), 73.13, 72.66, 71.05
d
¼139.05, 138.84, 138.36 (CAr), 128.46e127.65
4.3.6. (1R)-1-C-((2R)-2,3-Dihydroxypropyl)-1,5-dideoxy-1,5-imino-
(OCH2Ph), 53.71 (C1), 44.58 (C5), 33.33 (CH2eCH2eCH3), 19.72
L
-arabinitol (14a). To a solution of 13a (213 mg, 0.348 mmol) in iPrOH
(CH2eCH2eCH3), 14.34 (CH3). IR
n
¼3029, 2926, 2867, 1604, 1495,
(3.5 mL) were added 1 N HCl (0.7 mL, 2 equiv) and 10% Pd/C (52.5 mg).
The reaction mixture was stirred at room temperature under a H2
atmosphere overnight. The catalyst was filteredthrough a membrane,
washed with MeOH and the filtrate was concentrated under vacuum.
This procedure was repeated once to afford fully deprotected com-
pound. The residue was treated with AmberliteÒ IRA400 resin ðOHꢀÞ
1454, 1356, 1206, 1091, 1027, 909, 816, 733, 696. HRMS (ESI)
[MþH]þ calcd for C29H36NO3 m/z 446.26897; found m/z 446.26937.
12a
: 1H NMR (400 MHz, CDCl3):
d
¼7.40e7.26 (m, 15H, HAr), 4.97 (d,
1H, J¼10.8 Hz, OCH2Ph), 4.70 (s, 2H, OCH2Ph), 4.64e4.57 (m, 3H,
OCH2Ph), 3.77 (s, 1H, H4), 3.49e3.47 (m, 2H, H2, H3), 3.13 (dd, 1H,

3354
A. Biela et al. / Tetrahedron 69 (2013) 3348e3354
in water to give 14a (69 mg, 96%) as a brown solid. [
a
]
D þ10.3 (c 1.0,
71.49 (C2), 66.53 (C3 or C4), 62.91 (CH2OH), 54.43 (C1), 46.39 (C5),
30.44, 28.20 (CH2eCH2eCH2OH). HRMS (ESI) [MþH]þ calcd for
C8H18NO4 m/z 192.12303; found m/z 192.12315.
MeOH). 1H NMR (400 MHz, MeOD):
d¼3.87e3.85 (m, 1H, H3), 3.82
(dd, 1H, J¼2.9, 7.9 Hz, H4), 3.78e3.72 (m, 1H, CHOH), 3.66 (dd, 1H,
J¼1.5, 3.9 Hz, H2), 3.50e3.43 (m, 2H, CH2OH), 3.10e3.07 (m, 1H, H1),
2.76 (d, 2H, J¼7.9 Hz, H5), 1.64e1.49 (m, 2H, CH2eCHOHe). 13C NMR
Acknowledgements
(100 MHz, MeOD):
d
¼73.67 (C2), 72.60 (C3), 71.08 (CHOH), 67.71
(CH2OH), 67.19 (C4), 51.67 (C1), 46.72 (C5), 36.46 (CH2eCHOHe).
HRMS (ESI) [MþH]þ calcd for C8H18NO5 m/z 208.11795; found m/z
208.11799.
Financial support of this study by grants from ANR (07MRAR-
015-01), VML and the French Department of Research is gratefully
ꢂ
acknowledged. A.B. thanks the ‘Ministere de l’Enseignement
ꢀ
ꢀ
Superieur et de la Recherche’, O.F. thanks the CNRS and Region
4.3.7. (1R)-1-C-((2S)-2,3-Dihydroxypropyl)-1,5-dideoxy-1,5-imino-L-
€
Centre for PhD fellowships. We also thank Wojciech Schonemann
for the synthesis of compounds 7b and 1.
arabinitol (14b). To a solution of 13b (103 mg, 0.168 mmol) in iPrOH
(1.7 mL) were added 1 N HCl (0.34 mL, 2 equiv) and 10% Pd/C
(25.5 mg). The reaction mixture was stirred at room temperature
under a H2 atmosphere overnight. The catalyst was filtered through
a membrane, washed with MeOH and the filtrate was concentrated
under vacuum. This procedure was repeated twice to afford fully
deprotected compound. The residue was treated with AmberliteÒ
IRA400 resin ðOHꢀÞ in water to give 14b (20 mg, 57%) as a light
References and notes
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Meer, G. Nat. Rev. Mol. Cell Biol. 2004, 5, 554e565; (c) Kolter, T.; Sandhoff, K.
Biochim. Biophys. Acta 2006, 1758, 2057e2079; (d) Wennekes, T.; van den Berg,
R. J. B. H. N.; Boot, R. G.; van der Marel, G. A.; Overkleeft, H. S.; Aerts, J. M. F. G.
Angew. Chem., Int. Ed. Engl. 2009, 48, 8848e8869.
yellow oil. [
a
]
ꢀ11.3 (c 1.0, MeOH). 1H NMR (400 MHz, MeOD):
D
2. (a) Butters, T. D. Curr. Opin. Chem. Biol. 2007, 11, 412e418; (b) Grabowski, G. A.
Lancet 2008, 372, 1263e1271.
d
¼3.89e3.86 (m, 1H, H3), 3.84 (dd, 1H, J¼2.9, 7.9 Hz, H4), 3.81e3.75
3. (a) Futerman, A. H.; Sussman, J. L.; Horowitz, M.; Silman, I.; Zimran, A. Trends
Pharmacol. Sci. 2004, 25, 147e151; (b) Beck, M. Hum. Genet. 2007, 121, 1e22; (c)
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4. (a) Fan, J.-Q. Trends Pharmacol. Sci. 2003, 24, 355e360; (b) Fan, J.-Q. Biol. Chem.
2008, 389, 1e11; (c) Yu, Z.; Sawkar, A. R.; Kelly, J. W. FEBS J. 2007, 274,
4944e4950; (d) Parenti, G. EMBO Mol. Med. 2009, 1, 268e279; (e) Valenzano,
K. J.; Khanna, R.; Powe, A. C.; Boyd, R.; Lee, G.; Flanagan, J. J.; Benjamin, E. R.
Assay Drug Dev. Technol. 2011, 9, 213e235.
5. See for example: (a) Fan, J.-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nat. Med. 1999, 5,
112e115; (b) Fan, J.-Q. In Iminosugars, from Synthesis to Therapeutic Applications;
Compain, P., Martin, O. R., Eds.; Wiley-VCH: Weinheim, Germany, 2007;
pp 225e247; (c) Sawkar, A. R.; Cheng, W.-C.; Beutler, E.; Wong, C.-H.; Balch, W.
E.; Kelly, J. W. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15428e15433; (d) Chang, H.-
H.; Asano, N.; Ishii, S.; Ichikawa, Y.; Fan, J.-Q. FEBS J. 2006, 273, 4082e4092; (e)
Kornhaber, G. J.; Tropak, M. B.; Maegawa, G. H.; Tuske, S. J.; Coales, S. J.; Ma-
huran, D. J.; Hamuro, Y. ChemBioChem 2008, 9, 2643e2649.
6. (a) Yu, L.; Ikeda, K.; Kato, A.; Adachi, I.; Godin, G.; Compain, P.; Martin, O.;
Asano, N. Bioorg. Med. Chem. 2006, 14, 7736e7744; (b) Compain, P.; Martin, O.
R.; Boucheron, C.; Godin, G.; Yu, L.; Ikeda, K.; Asano, N. ChemBioChem 2006, 7,
1356e1359; (c) Boucheron, C.; Toumieux, S.; Compain, P.; Martin, O. R.; Ikeda,
K.; Asano, N. Carbohydr. Res. 2007, 342, 1960e1965; (d) Chagnault, V.; Compain,
P.; Lewinski, K.; Ikeda, K.; Asano, N.; Martin, O. R. J. Org. Chem. 2009, 74,
(m, 1H, CHOH), 3.72e3.71 (m, 1H, H2), 3.51e3.43 (m, 2H, CH2OH),
3.15e3.12 (m, 1H, H1), 2.79 (d, 2H, J¼7.9 Hz, H5), 1.66 (ddd, 1H,
J¼3.3, 5.9, 14.2 Hz, CH2eCHOHe), 1.53e1.46 (m, 1H, CH2eCHOHe).
13C NMR (100 MHz, MeOD):
d
¼72.53 (C3), 72.39 (C2), 71.91 (CHOH),
67.54 (CH2OH), 67.16 (C4), 52.88 (C1), 46.79 (C5), 34.85
(CH2eCHOHe). HRMS (ESI) [MþH]þ calcd for C8H18NO5 m/z
208.11795; found m/z 208.11787.
4.3.8. (1R)-2,3,4-Tri-O-benzyl-N-benzyloxycarbonyl-1-C-
(3-hydroxypropyl)-1,5-dideoxy-1,5-imino-
L
-arabinitol
(15). 11b
(208 mg, 0.360 mmol), catecholborane (1 N in THF, 0.72 mL,
2 equiv) and Wilkinson’s catalyst (6.5 mg, 0.007 mmol, 0.02 equiv)
were mixed under Ar. The reaction was heated at 40 ꢁC for 4 days,
then cooled down to room temperature and diluted with EtOH
(0.72 mL). 2 N NaOH (0.72 mL) and 30% H2O2 (0.72 mL) were added.
The reaction mixture was stirred at room temperature for 2.5 d. The
aqueous phase was extracted with Et2O (2ꢂ10 mL). The combined
organic phases were washed with 0.1 N Na2S2O3 (2ꢂ10 mL), 2 N
NaOH (2ꢂ10 mL), H2O (10 mL), saturated NH4Cl (10 mL) and dried
over MgSO4. After concentration, the crude product was purified by
flash chromatography on silica gel (pet. ether/EtOAc 8:2, then 5:5)
to afford 15 (98 mg, 46%) as a colorless oil. 1H NMR (400 MHz,
€
3179e3182; (e) Schonemann, W.; Gallienne, E.; Compain, P.; Ikeda, K.; Asano,
N.; Martin, O. R. Bioorg. Med. Chem. 2010, 18, 2645e2650; (f) Oulaïdi, F.; Front-
Deschamps, S.; Gallienne, E.; Lesellier, E.; Ikeda, K.; Asano, N.; Compain, P.;
Martin, O. R. ChemMedChem 2011, 6, 353e361.
7. Oulaïdi, F.; Gallienne, E.; Compain, P.; Martin, O. R. Tetrahedron: Asymmetry
2011, 22, 609e612.
8. Liautard, V.; Desvergnes, V.; Itoh, K.; Liu, H.-w.; Martin, O. R. J. Org. Chem. 2008,
73, 3103e3115.
CDCl3):
d
¼7.34e7.24 (m, 20H, HAr), 5.10 (br s, 2H, CO2CH2Ph),
9. (a) Wennekes, T.; van den Berg, R. J. B. H. N.; Boltje, T. J.; Donker-Koopman, W.
E.; Kuijper, B.; van der Marel, G. A.; Strijland, A.; Verhagen, C. P.; Aerts, J. M. F. G.;
Overkleeft, H. S. Eur. J. Org. Chem. 2010, 1258e1283; (b) Decroocq, C.; Laparra, L.
M.; Rodriguez-Lucena, D.; Compain, P. J. Carbohydr. Chem. 2011, 30, 559e574;
(c) Goddard-Borger, E. D.; Tropak, M. B.; Yonekawa, S.; Tysoe, C.; Mahuran, D. J.;
Withers, S. G. J. Med. Chem. 2012, 55, 2737e2745; (d) Behr, J.-B.; Hottin, A.;
Ndoye, A. Org. Lett. 2012, 14, 1536e1539; (e) Hottin, A.; Dubar, F.; Steenackers,
A.; Delannoy, P.; Biot, C.; Behr, J.-B. Org. Biomol. Chem. 2012, 10, 5592e5597.
10. Cipolla, L.; Lay, L.; Nicotra, F.; Pangrazio, C.; Panza, L. Tetrahedron 1995, 51,
4679e4690.
11. (a) Suzuki, K.; Suzuki, Y. Proc. Natl. Acad. Sci. U.S.A. 1970, 66, 302e309; (b)
Svennerholm, L.; Vanier, M. T.; Mansson, J. E. J. Lipid Res. 1980, 21, 53e64; (c)
Wenger, D. A.; Rafi, M. A.; Luzi, P.; Datto, J.; Costantino-Ceccarini, E. Mol. Genet.
Metab. 2000, 70, 1e9.
12. Lee, W. C.; Kang, D.; Causevic, E.; Herdt, A. R.; Eckman, E. A.; Eckman, C. B. J.
Neurosci. 2010, 30, 5489e5497.
13. Nadein, O. N.; Kornienko, A. Org. Lett. 2004, 6, 831e834.
4.79e4.24 (m, 8H, OCH2Ph, H1, H5b), 4.09 (br s, 1H, H2), 3.73e3.53
(m, 3H, H4, CH2OH), 3.55 (dd, 1H, J¼2.8, 10.1 Hz, H3), 2.76e2.73 (m,
1H, H5a), 1.86e1.15 (m, 4H, CH2eCH2eCH2OH). 13C NMR (100 MHz,
CDCl3):
d
¼156.46 (C]O), 138.81e136.57 (CAr), 128.61e127.55
(CHAr), 78.30 (C3), 76.65 (C2), 73.29 (OCH2Ph), 72.62 (C4), 72.26,
70.91 (OCH2Ph), 67.70 (CO2CH2Ph), 62.62 (CH2OH), 53.32 (C1),
40.00 (C5), 29.10, 20.58 (CH2eCH2eCH2OH). HRMS (ESI) [MþH]þ
calcd for C37H42NO6 m/z 596.30066; found m/z 596.30055.
4.3.9. (1R)-1-C-(3-Hydroxypropyl)-1,5-dideoxy-1,5-imino-L-arabini-
tol (16). To a solution of 15 (135 mg, 0.227 mmol) in iPrOH
(0.44 mL) were added 1 N HCl (0.44 mL, 2 equiv) and 10% Pd/C
(35 mg). The reaction mixture was stirred at room temperature
under a H2 atmosphere overnight. The catalyst was filtered through
a membrane, washed with MeOH and the filtrate was concentrated
under vacuum. This procedure was repeated once to afford fully
deprotected compound. The residue was treated with AmberliteÒ
IRA400 resin ðOHꢀÞ in water to give 16 (43 mg, quant.) as a light
14. (a) Zhao, G.-L.; Yu, Z.-Y.; Li, Y.; Pang, L.-N.; Wang, J.-W. Chin. J. Chem. 2008, 26,
158e164; (b) Tejima, S.; Fletcher, H. G. J. Org. Chem. 1963, 28, 2999e3004.
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H. Chem. Ber. 1968, 101, 3365e3376.
16. (a) Frelek, J.; Snatzke, G. Fresenius Z. Anal. Chem.1983, 316, 261e264; (b) Frelek, J.;
Geiger, M.; Voelter, W. Curr. Org. Chem.1998, 2,197e226; (c) Frelek, J.; Klimek, A.;
ꢀ
Ruskowska, P. Curr. Org. Chem. 2003, 7, 1081e1104; (d) Frelek, J.; Gerards, M.;
yellow oil. 1H NMR (400 MHz, MeOD):
d
¼3.91e3.88 (m, 2H, H3,
ꢀ
ꢀ
ꢀ
Gorecki, M.; Jab1onska, E.; Kruszewska, A.; Urbanczyk-Lipkowska, Z.; Morzycki, J.
ꢀ
W.; Suszczynska, A.; Szczepek, W. J. J. Org. Chem. 2007, 72, 2906e2916.
H4), 3.73e3.72 (m, 1H, H2), 3.58e3.56 (m, 2H, CH2OH), 2.90 (t, 1H,
J¼6.3 Hz, H1), 2.81 (d, 2H, J¼7.8 Hz, H5), 1.66e1.47 (m, 4H,
17. Burgess, K.; Ohlmeyer, M. J. Chem. Rev. 1991, 91, 1179e1191.
18. Chronowska, A.; Gallienne, E.; Nicolas, C.; Kato, A.; Adachi, I.; Martin, O. R.
Tetrahedron Lett. 2011, 52, 6399e6402.
CH2eCH2eCH2OH). 13C NMR (100 MHz, MeOD):
d¼72.16 (C3 or C4),