An efficient and simple method for stereoselective synthesis of N-substituted iminosugars from D-xylose derivative

Article abstract of DOI:10.1002/cjoc.201400070

A series of new N-substituted iminosugars were successfully synthesized through a general synthetic route from D-xylose derivative. This approach provided a convenient access to the synthesis of N-alkylated iminosugars as potential glucosidase inhibitors, which included a reaction of reductive amination. Various N-alkylated iminosugars were prepared in good yields with high stereoselectivity. Copyright

Full text of DOI:10.1002/cjoc.201400070

NOTE
DOI: 10.1002/cjoc.201400070
An Efficient and Simple Method for Stereoselective Synthesis
of N-Substituted Iminosugars from D-Xylose Derivative
Jichao Zhang,a,b Wen Yuan,a,b Xiaofeng Ma,a,b Haibo Wang,a,b and Huawu Shao*,a
a Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu, Sichuan 610041, China
b University of Chinese Academy of Sciences, Beijing 100049, China
A series of new N-substituted iminosugars were successfully synthesized through a general synthetic route from
D-xylose derivative. This approach provided a convenient access to the synthesis of N-alkylated iminosugars as po-
tential glucosidase inhibitors, which included a reaction of reductive amination. Various N-alkylated iminosugars
were prepared in good yields with high stereoselectivity.
Keywords iminosugars, stereoselective synthesis, N-alkylation, reductive amination, Michael addition
Introduction
1), which are beneficial to the construction of imino-
sugar library. Notably, this approach is particularly
convenient for the synthesis of N-substituted 1-C-
branched iminosugars.
Polyhydroxypiperidines, also named iminosugars (or
azasugars)[1,2] are carbohydrate mimetics, where nitro-
gen atom replaces the oxygen in the ring system tem-
plate. The most attractive properties of iminosugars are
their potential biological activities toward glycosidase[3]
and glycosyl transferases inhibitors.[4] They also have
great potential as drugs to treat various diseases such as
diabetes,[5] Gaucher′s disease,[6] HIV infection[7] and
other diseases. For example, iminosugar derivatives
(Miglitol[8] and Miglustat[6,9]) have been the listed
medicines in the treatment of type 2 diabetes and
Gaucher′s disease. Attracted by the interesting activity,
a number of excellent works have been done to study
the synthesis and biological activity associated with
iminosugars.[10] Furthermore, many examples indicate
that as enzyme inhibitors, the ability and selectivity of
iminosugars are highly dependent on the 1-C-branch
and the substituted group on nitrogen atom.[11] The ini-
tial therapeutic application promoted the further explo-
ration of N-substituted iminosugars.[9,12] Thus, it is very
significant to establish a general approach to synthesize
various substrates for their biological activity study.
Previously, started from D-ribose, we have reported
the synthesis of N-substituted iminosugars from 5-al-
kylamine-1-C-(2'-oxoalkyl)-glycosides by subsequent
base-mediated β-elimination and intramolecular Mi-
chael addition. As our continued interests in the stereo-
selective synthesis of substituted sugars,[13] herein, we
report an efficient approach for the preparation of a se-
ries of new N-substituted iminosugars through a general
synthetic route starting from D-xylose derivate (Scheme
Scheme 1 Synthesis of N-substituted iminosugars starting from
D-xylose derivative
O
N3
O
(1) Pd/C, H2, MeOH
NH2
OBn
OBn
(2) NaOMe/MeOH
HO
OBn
BnO
(β-elimination)
1
O
OBn
OBn
HO
RCHO
Michael addition
O
MeOH, NaBH(AcO)3
0 oC - r.t.
N
H
2
OBn
OBn
HO
O
R = C2H5, n-propyl, iso-propyl, C6H13, p-Cl-phenyl,
N
phenyl, o-Cl-phenyl, m-Cl-phenyl, p-OCH3-phenyl,
p-NO2-phenyl, p-CH3-phenyl, furyl
R
3a - 3l
Experimental
The procedure for the preparation of the starting
material 1 in Scheme 1 and all the final products listed
in Scheme 2 are included in the supporting information.
Synthesis of compound 2: To a solution of 1 (500
mg, 1.3 mmol) in methanol (8 mL) was added 10%
Pd/C (250 mg) under hydrogen atmosphere. After the
*
E-mail: shaohw@cib.ac.cn; Fax: 0086-028-82890288
Received February 5, 2014; accepted March 20, 2014; published online April 4, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400070 or from the author.
Chin. J. Chem. 2014, 32, 361—364
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
361

Zhang et al.
NOTE
Scheme 2 Synthesis of various N-substituted iminosugars 3a－3l (a Yield based on the corresponding major substrate)
OBn
OBn
OBn
OBn
OBn
OBn
N
OBn
HO
OBn
OBn
OBn
OBn
HO
HO
HO
HO
O
OBn
O
HO
O
O
O
O
N
N
N
N
N
O
2
5
3c (79%)a
3a (86%)a
3b (68%)a
3d (73%)a
3e (65%)a
3f (53%)a
OBn
3'
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
4'
OBn
OBn
HO
HO
HO
HO
HO
O
O
O
O
HO
5'
6'
O
2'
O
2
N1'
N
N
N
N
1
3
N
Cl
Cl
Cl
OCH3
NO2
3l (54%)a
3g (60%)a
3h (75%)a
3i (65%)a
3j (74%)a
3k (56%)a
reaction was completed as detected by TLC, the reac-
tion mixture was filtered and then concentrated. 6 mL of
NaOMe/MeOH with concentration of 10 mg/mL was
added immediately. The resulting mixture was stirred
for 8 h at 0 ℃ to room temperature. The reaction mix-
ture was concentrated in vacuo and purified by chroma-
tography (dichloromethane/MeOH, 15∶1) to give 2 as
a mixture of two anomers (major/minor＝5∶1) in 73%
yield. For major product: [α]2D0 −31.8 (c 0.4, CHCl3);
1H NMR (400 MHz, CD3OD) δ: 7.42－7.24 (m, 11H),
4.71 (s, 2H), 4.63 (d, J＝11.4 Hz, 1H), 4.46 (d, J＝11.4
Hz, 1H), 3.75－3.60 (m, 3H), 3.59－3.52 (m, 1H), 3.05
(dd, J＝13.4, 2.8 Hz, 1H), 2.86－2.71 (m, 2H), 2.65 (dd,
J＝17.5, 7.1 Hz, 1H), 2.10 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ: 208.0, 137.9, 137.7, 128.2, 128.1, 127.8,
127.6, 127.5, 58.0, 82.5, 80.2, 79.9, 71.6, 71.4, 50.0,
29.2. ESI-HRMS: m/z calcd for C29H33ClNO4 [M＋H]＋
370.2013, found 370.2010.
1H, H-3’), 2.78 (dd, J6’a,6’b＝16.5 Hz, J6’a,5’＝6.1 Hz,
1H, H-6’a), 2.71 (dd, J＝11.9, 5.1 Hz, 1H, H-1a), 2.60
(dd, J6’b,6’a＝16.5 Hz, J6’b,5’＝5.1 Hz, 1H), 2.32 (d, J＝
10.8 Hz, 1H, H-1b), 2.17 (s, 3H, H-3); 13C NMR (100
MHz, CDCl3) δ: 207.3, 138.7, 137.8, 137.3, 132.8,
129.7, 128.6, 128.5, 128.4, 128.2, 127.9, 127.8, 82.0,
80.2, 72.5, 69.9, 57.9, 56.8, 49.8, 36.8, 31.1. ESI-HRMS:
m/z calcd for C29H33ClNO4 [M＋H]＋ 494.2093, found
494.2096.
Results and Discussion
To investigate the influence of bases on the synthesis
of iminosugar intermediate 2, we carried out the reac-
tion in various bases and solvents. As shown in Table 1,
1% NaOMe/MeOH was selected as the optimal reaction
conditions (Table 1, Entry 4). Other bases, such as
K2CO3 and KOH were found to be less satisfactory in
terms of the stereoselectivity (Table 1, Entries 2 and 3).
Other conditions, such as Na2CO3/H2O and NaOH/H2O
gave lower yield (Table 1, Entries 8 and 9), while only
trace amount of desired product was obtained in NaOMe/
THF and NaHCO3/H2O (Table 1, Entries 6 and 7).
General synthetic procedures for the N-substituted
iminosugars 3a－3l: Compound 2 (37.0 mg, 0.1 mmol)
was dissolved in methanol (2 mL) containing fresh ac-
tivated 4 Å molecular sieves (75 mg). After cooling to 0
℃, aldehyde (0.3 mmol, 3 equiv.) was added. The reac-
tion mixture was stirred for 30 min under argon atmos-
phere, NaBH(OAc)3 (63.6 mg, 0.3 mmol) was added.
The resulting mixture was then warmed to room tem-
perature. When the starting material completely disap-
peared as detected by TLC, the reaction mixture was
concentrated in vacuo and purified by flash column
chromatography (petroleum ether/ethyl acetate, 6 ∶
1→2∶1) to give 3a－3l as syrups. 3g was selected as
an example. Yield 60%, colourless syrup. [α]2D0 ＋12.0
Table 1 The influence of different bases and solvents
Entry Base/Solventa
Isomer ratio (major/minor)b Yieldc/%
1
2
3
4
5
6
TEA/MeOH
－
trace
71
K2CO3/MeOH
KOH/MeOH
NaOMe/MeOH
NaOMe/MeCN
NaOMe/THF
4∶1
1∶1
5∶1
1∶1
－
68
73
67
1
(c 0.2, CHCl3); H NMR (400 MHz, CDCl3) δ: 7.43－
trace
7.29 (m, 11H, Ar), 7.22 (d, J＝8.2 Hz, 2H, Ar), 5.00 (d,
J＝11.5 Hz, 1H, PhCH2), 4.69 (d, J＝11.5 Hz, 1H,
PhCH2), 4.54 (s, 2H, PhCH2), 3.98 (dd, J＝10.8, 5.4 Hz,
1H, H-5’), 3.75 (dd, J＝8.8, 5.2 Hz, 1H, H-4’), 3.69 (d,
J＝13.7 Hz, 1H, N-CH2-Ar), 3.67－3.58 (m, 1H, H-2’),
3.45 (d, J＝16.9 Hz, 1H, N-CH2-Ar), 3.41 (t, J＝8.7 Hz,
－
7
8
9
NaHCO3/H2O
Na2CO3/H2O
NaOH/H2O
trace
45
1∶1
1∶1
47
a 10 mg/mL basic solution. Isolated overall yield. b The ratio of
c
isomer based on 1H NMR.
362
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 361—364

Stereoselective Synthesis of N-Substituted Iminosugars from D-Xylose Derivative
In order to obtain various N-substituted iminosugars
conveniently, alkyl was introduced by reductive amina-
tion of 2 with RCHO (R＝C2H5, C3H7, C6H13, and Ar).
As the model substrate, propionaldehyde was selected to
investigate the influence of reductive reagents, solvent
and temperature on the yield of final product. The result
was summarized in Table 2.
moderate yield. Obviously, heteroaromatic aldehyde (3b)
was also a suitable substrate for the reductive amination,
which offered product in 68% yield.
The stereochemistry of the major product was de-
1
termined by the H-1H-COSY and coupling constant.
Taking compound 3g as an example, the coupling con-
stants between H2’ and H3’ (JH2’, H3’＝8.7 Hz), showed
convincingly the trans-configuration between C1 and
3’-OBn. Meanwhile the result was further supported by
Table 2 Optimization of reductive amination conditionsa
Temperature Yieldb/%
the coupling constants between H3’ and H4’ (JH3’, H4’
＝
Entry
Reagent
Solvent
8.7 Hz), which was the known trans-configuration.
1
2
3
4
5
6
7
8
NaBH(OAc)3 DCM/HOAc
NaBH(OAc)3 DCM/HOAc
NaBH(OAc)3 MeOH
0 ℃－r.t.
reflux
15
trace
54
Conclusions
−20 ℃
In summary, we described an efficient approach for
the synthesis of various N-substituted iminosugars from
D-xylose derivative. A series of N-alkyl substituted
iminosugars C-glycosides were synthesized in good
yields with high stereoselectivity. Meanwhile, the
method is applied to the synthesis of other analogues.
The assessment to the biological activities of these
compounds is in progress.
NaBH(OAc)3 MeOH/4 Å M.S.c
65
−20 ℃
NaBH(OAc)3 MeOH
NaBH(OAc)3 MeOH/4 Å M.S.c 0 ℃－r.t.
0 ℃－r.t.
77
86
NaBH3CN
NaBH3CN
MeOH
0 ℃－r.t.
0 ℃－r.t.
trace
trace
MeOH/HOAc
a
Reaction condition: substrate 2 (0.1 mmol), solvent (2 mL),
reductive reagent (0.3 mmol). b Isolated yield. c Fresh activated.
Acknowledgement
As showed in Table 2, NaBH(OAc)3 in DCM/HOAc
was selected as reaction system preferentially due to
their excellent performance, during our research on
double reductive amination between glycosyl-1,4-di-
carbonyl compounds and amines.[14,15] However, the
desired product was only obtained in 15% isolated yield
at 0 ℃to r.t., while only trace amount of the product
was obtained when the reaction was carried out in reflux
condition (Table 2, Entries 1 and 2). Encouragingly,
when MeOH was employed as a solvent, and the reac-
tion was carried out at −20 ℃, the reductive amination
product was obtained in 54% yield (Table 2, Entry 3).
The yield was further improved to 65% when 4 Å M.S.
was added to the reaction mixture (Table 2, Entry 4).
However, when NaBH3CN was used, only trace amount
of the product was detected (Table 2, Entry 7). Finally,
it was found that the desired product can be obtained in
86% yield when the reaction was performed at 0 ℃ to
r.t. (Table 2, Entry 6).
With the optimal reaction conditions in hand, reduc-
tive amination was further investigated with different
kinds of aliphatic and aromatic aldehydes (Scheme 1). It
must be mentioned that, the starting material compound
2, which contains a pair of anomers, is very hard to be
separated by flash chromatograph, therefore, we used
the anomeric mixture (major/minor＝5∶1) as the start-
ing material to evaluate the scope of the reaction.
This work was supported by the National Natural
Science Foundation of China (Nos. 21372215 and
20972151).
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Chin. J. Chem. 2014, 32, 361—364