Design, synthesis and bioactivity evaluation of Galf mimics as antitubercular agents

Article abstract of DOI:10.1016/j.carres.2015.11.002

A series of novel Galf mimics has been synthesized and characterized by IR, ¹H NMR, ¹³C NMR, mass spectral and element analysis. All the newly prepared compounds were screened for their antitubercular activities. Bioactivity assays manifested that most of Galf mimics exhibited good antitubercular activities. Especially compound 4d and 4e displayed remarkable antitubercular efficacies, which were comparable to ethambutol.

Full text of DOI:10.1016/j.carres.2015.11.002

Accepted Manuscript
Title: Design, synthesis and bioactivity evaluation of galf mimics as
antitubercular agents
Author: Chunyan Liu, Linyu Hou, Aiguo Meng, Gang Han, Weiguo Zhang,
Shende Jiang
PII:
S0008-6215(15)00346-8
DOI:
Reference:
http://dx.doi.org/doi: 10.1016/j.carres.2015.11.002
CAR 7092
To appear in:
Carbohydrate Research
Received date: 4-8-2015
Revised date: 31-10-2015
Accepted date: 2-11-2015
Please cite this article as: Chunyan Liu, Linyu Hou, Aiguo Meng, Gang Han, Weiguo Zhang,
Shende Jiang, Design, synthesis and bioactivity evaluation of galf mimics as antitubercular agents,
Carbohydrate Research (2015), http://dx.doi.org/doi: 10.1016/j.carres.2015.11.002.
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Carbohydrate Research
journal homepage: www.elsevier.com
Design, synthesis and bioactivity evaluation of Galf mimics as antitubercular agents
a,
b
c
a
a
d
Chunyan Liu , Linyu Hou , Aiguo Meng , Gang Han , Weiguo Zhang and Shende Jiang
a
School of Pharmacy, North China University of Science and Technology, Tangshan 063000, P. R. China
School of Public Health, North China University of Science and Technology, Tangshan 063000, P. R. China
Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, P. R. China
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. China
b
c
b
Highlights
Figure. Chemical Structures of DMDG and Glaf mimics
—
——

Corresponding author. School of Pharmacy, North China University of Science and Technology,
Tangshan 063000, P.R. China. e-mail: chunyanliu@ncst.edu.cn
Page 1 of 9

Graphical Abstract
A series of novel Galf mimics have been synthesized
1
13
and characterized by IR, H NMR, C NMR, mass
spectral and element analysis. All the newly prepared
compounds were screened for their antitubercular
activities. Bioactivity assays manifested that most of
Galf mimics exhibited good antitubercular activities.
Especially compound 4d and 4e displayed remarkable
antitubercular efficacies, which were comparable to
ethambutol.
Design, synthesis and docking studies of Galf mimics as
antitubercular agents
a,
b
c
a
Chunyan Liu , Linyu Hou , Aiguo Meng , Gang Han ,
a
e
Weiguo Zhang and Shende Jiang
a
School of Pharmacy, North China University of Science and Technology , Tangshan 063000, P.R. China
School of Public Health, North China University of Science and Technology, Tangshan 063000, P. R. China
Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, P.R. China
School of Pharmacy, Xuzhou Medical College, Xuzhou, Jiansu 221004, China
b
c
b
e
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. China
Page 2 of 9

ARTICLE INFO
ABSTRACT
A series of novel Galf mimics have been synthesized and characterized by IR, H
NMR, C NMR, mass spectral and element analysis. All the newly prepared
compounds were screened for their antitubercular activities. Bioactivity assays
manifested that most of Galf mimics exhibited good antitubercular activities.
Especially compound 4d and 4e displayed remarkable antitubercular efficacies, which
were comparable to ethambutol.
1
Article history:
Received
Received in revised form
Accepted
13
Available online
kerds:
Mycobacterium tuberculosis
UDP-galactopyranose mutase
Galf mimics
2
009 Elsevier Ltd. All rights reserved.
antimycobacterial activity
1
. Introduction
galactitol (DMDG) is the Galf mimic and possesses inhibitory
13
activity on the growth of TB, thus the Galf mimic may have
Tuberculosis (TB), caused by infection with the bacterium M.
14
therapeutic potential. A few of DMDG derivatives designed to
tuberculosis, remains a major global health problem, responsible
for ill health among millions of people each year. The current
treatment for susceptible strains requires long treatment periods
with multiple antibiotics, as no new TB drugs have been
introduced into clinical use in the past 4 decades. The emergence
of multi-drug and extensively-drug resistant strains of M.
tuberculosis has further contributed to the urgent need for the
development of anti-tubercular agents with novel modes of
inhibit UGM have been reported, however, only some have
shown weak inhibition of the activity towards UGM. In the
previous study, we also described the synthesis of a Galf
disaccharide by nucleophilic addition of L-arabinofurano-alkyne
1
2
15
to iminogalactitol-derived nitrone.
Recent contributions by various leaders in the field seemed to
suggest that C1-alkyl, vinyl, and aryl-substituted pyrrolidine and
piperidine iminosugars be more selective inhibitors of
glycosidases through stronger interactions with the aglycon
binding site or with lipophilic pockets around the enzymes’
3
action.
The structure of the mycobacterial cell wall serves as a
significant permeability barrier to the passage of antibiotics into
the organism. Galactofuranose (Galf) residues are present in the
mycolyl-arabinogalactan-peptidoglycan (mAGP) complex, the
major structural element of the cell wall, and play a pivotal role
in the virulence and the viability of TB. The biosynthetic
precursor of Galf-containing glycoconjugates is uridine 5’-
diphosphate (UDP) Galf, which is generated by the enzyme
UDP-galactopyranose mutase (UGM). UGM is a flavoenzyme
that catalyzes the isomerization of UDP-galactopyranose (UDP-
Galp) to UDP-galactofuranose (UDP-Galf) and then the
production of the biosynthetic glycosyl donor UDP-Galf is used
by galactofuranosyl transferases. Absence of UGM and Galf in
mammals, along with the fact that biosynthesis of Galf residues
are essential for cell wall biosynthesis and the viability of
mycobacteria, makes UGM a potential selective target for
therapeutic intervention. There have been significant efforts
directed towards the development of different substrate
analogues and transition state mimics of Galf residues, which
have been synthesized and screened against UGM in the recent
16
active sites. We thus reasoned that C1-alkyl and aryl substituted
4
Galf mimic may generate an original scaffold for biological
evaluation. These guiding results, in line with our interest in
designing Galf mimics (Figure 1) as UGM inhibitors, we now
describe the synthesis of C1-alkyl and aryl-substituted Galf
mimics and evaluated for their anti-tubercular activity.
5
2. Results and discussion
2
.1. Chemistry
Recent work conducted in our laboratory has shown the
6
utilization of cyclic nitrone toward the synthesis of iminosugars
7
17
and their biological evaluation. Thus, in continuation of our
research interest for the synthesis of DMDG and novel
iminosugars based on the cyclic nitrone 1 as an important
intermediate, the synthetic pathways are illustrated in Figure 2.
Our synthetic approach of DMDG depended on the
iminogalactitol-derived nitrone 1 on N-O bond reductive
cleavage followed by deprotection of benzyl functionality, which
8
9
past.
18
is different from the reported synthetic methods. While the
Many pyranoses and furanoses with the ring oxygen replaced
by an imino group are natural products and useful as potent
synthesis of C1--alkylated or C1--arylated pyrrolidine
iminosugar 4 is based on the coupling of the sugar entities by a
1,3-dipolar cycloaddition process between nitrone 1 and an alkyl-
or aryl- group as a dipolarophile followed by deprotection of
benzyl functionality. A major advantage of this methodology is
the very high -stereoselectivity of the cycloadditions onto
1
0
glycosidase inhibitors. Recently these iminosugars, both natural
and unnatural, have been of intense interest due to their
promising chemotherapeutic properties against diabetes, cancer,
1
1
tuberculosis and viral infections. Amongst iminosugars, five-
membered pyrrolidine compounds such as 2,5-dideoxy-2,5-
imino-D-mannitol (DMDP) and 2,5-dideoxy-2,5-imino-D-
glycero-D-manno-heptitol (homo DMDP) are selective inhibitors
1
7
19
nitrone 1, as shown in our previous studies and other groups.
For the synthesis of the iminogalactitol-derived nitrone 1, we
employed D-galactose as a chiral building block to afford 2,3,5,6-
1
2
of - and -glucosidases.
The 1,4-dideoxy-1,4-imino-D-
tetra-O-benzyl-D-galactofuranose 5. The lactol
5
was
Page 3 of 9

sequentially reacted with hydroxylamine hydrochloride and then
selectively silylated by tert-butyldimethylsilyl chloride to afford
an inseparable mixture of E/Z-oxime derivatives 6. The synthesis
of nitrone 1 was obtained from oxime derivatives 6, based on
3. Conclusions
In summary, Galf mimics have been synthesized. The
structures proposed for all synthesized compounds were
confirmed by spectroscopic data and elemental analysis, and they
were evaluated for their antibacterial properties. Both synthesized
compounds (4d and 4e) showed moderate to good anti-tubercular
activity compare to antibacterial drug (ethambutol). Galf mimics
can be considered as an initial leads for the development of better
anti-tubercular agents.
intramolecular S 2 reactions carried out by oximate anion, which
N
occurred with inversion of configuration at the attacked carbon
atom. The methodology involved the intramolecular alkylation of
20
an oxime have been successfully adopted by other groups.
The utility of nitrone 1 was demonstrated in the synthesis of
the known pyrrolidine iminosugar DMDG (Scheme 2). Thus,
reduction of C=N in nitrone 1 with sodium borohydride afforded
compound 2 in good yield, but 2 was not very stable to storage.
In the next step, one pot N－O bond by catalytic hydrogenation
gave the targeted compound. The spectral and analytical data of
4
4
. Experimental
.1. General methods
Chemicals purchased from commercial vendors were used
1
3
DMDG were found to be in consonance with those reported.
without purification. Infrared spectra were recorded using a
Shimadu FTIR-8400s Fourier Transform spectrometer as a thin
film on KBr plates. NMR spectra were recorded on a Bruker AV-
Acetylation of DMDG was taken place in acetic anhydride and
pyridine with N,N-dimethylaminopyridine as a catalysis and
dichloromethane as solvent to afford compound 8.
1
13
3
6
00 at 300MHz ( H) and 75 MHz ( C), or a Bruker AV-600 at
00MHz ( H) and 150 MHz ( C) and were referenced to the
1 13
Targeting toward pyrrolidine iminosugar C-glycosides, we
explored the 1,3-addition of Grignard to nitrone 1 (Scheme 3).
This reaction in diethyl ether at 0C was highly diastereo-
selective and then afforded C1--alkylated or C1--arylated N-
hydroxy pyrrolidine iminosugar 3 and its C1-epimer in the ratio
internal standard tetramethylsilane, in the respective deuterated
solvents. Coupling constants (J) are reported in Hertz. CDCl was
empolyed for protected compounds and D O or CD OH for free
sugar. Mass spectra were recorded on a mass spectrometer.
Elemental analyses were performed by the analytical services at
Nankai University (Tianjin). Flash chromatography was
performed on silica gel (300-400 mesh). TLC was run on pre-
coated aluminium plates (Merck Kieselgel 60 F254) and the
spots were visualized with UV light and basic aqueous potassium
permanganate followed by heating.
3
2
3
4
:1, respectively. The spectral and analytical data of 3 were in
agreement with the proposed structure’s. Hydrogenolysis of
compound 3 using hydrogen with Pd/C as catalysis gave 4.
Acetylation of iminosugar 4 was the same as that of DMDG to
afford compound 9.
This procedure was used to synthesize some distinct
pyrrolidines (Figure 3), including DMDG in high yields and high
purities. Next, biological evaluation of this focused library
against tubercular activity was conducted.
4
.1.1 1-deoxy-2,3,4,5-tetra-O-benzyl-1,4-hydroxyl-amino-D-
galactofuranose (2)
To a solution of nitrone 1 (1g, 1.86mmol) in dry methanol (15mL)
was added dropwise HCl (2N in methanol, 0.92ml) at 0ºC. The
reaction mixture was vigorously stirred for 5 min, followed by
slow addition of sodium borohydride (0.1g, 1.86mmol). After 4h
stirring, the reaction was quenched with saturated sodium
bicarbonate solution (20 mL) and extracted with ethyl acetate (3x
2
.2. Biological evaluation
The synthetic compounds were evaluated for their in vitro
antimycobacterial activity against M. tuberculosis H37Rv strains
2
0
by the broth microdilution assay method. The minimum
inhibition concentrations are showed in Table 1.
2
0 mL). The combined organic layers were dried over sodium
sulfate, filtered and concentrated in vacuo to give an oil. The
crude residue was purified by flash chromatography (petroleum
ether/AcOEt=5/2) to afford 2 (0.93g, 93%) as a colourless oil.
IR( KBr, cm ): 3387, 3086, 3063, 3031, 2869, 1604, 1496, 1454,
1
It’s demonstrated that protected sugars showed excellent
inhibitory potential as compared to partially or completely
2
1
unprotected ones. Surprisingly, Galf mimics bearing benzyl or
acetyl groups displayed no significant improvement in activity
against M. tuberculosis, and acetylation of iminosugar seemed to
show higher activity than benzylation of ones. DMDG with a
MIC value of 12.5µg/mL was much more effective than
protected compound 2 and 8. Compound 4a and 4b showed also
a MIC value of 12.5µg/mL. The MIC value was higher than or
similar to that of benzyled ones 3a or 3b, and superior to that of
acetyled ones 9a and 9b. Compound 4c with a MIC value of
-
1
1
363, 1251, 1073, 1027; H NMR (300 MHz, CDCl ) δ 8.19 (s,
3
1
H, N-OH), 7.27 －7.37 (m, 20H, H ), 4.69 －4.71 (d, 1H,
Ar
J=11.8Hz, OCH Ph), 4.55－4.58 (d, 1H, J=11.8Hz, OCH Ph),
4.50－4.53 (d, 1H, J=11.9Hz, OCH
OCH Ph), 3.95－3.96 (q, 1H, J=5.1Hz, H-3), 3.85 (br q, 2H, H-2
and H-5), 3.77－3.79 (dd, 1H, J=1.8Hz and J=8.5Hz, H-6a), 3.63
2
2
Ph), 4.37－4.47 (m, 5H,
2
2
－
3.68 (dd, 1H, J=2.3Hz and J=7.8Hz, H-6b), 3.22－3.25 (d, 1H,
6
.25µg/mL showed a good activity, which was more effective
J=10.6Hz, H-4), 3.01 (brq, 1H, H-1a), 2.88 － 2.92 (dd, 1H,
J=5.7Hz and J=5.0Hz, H-1b); C-NMR (75 MHz, CDCl ) δ 61.9
than compound 3c bearing benzyl groups and as effective as
compound 9c bearing acetyl groups. In contrast, compounds 4d
and 4e exhibited promising activity with MIC values of
13
3
(
C1), 67.8 (C4), 71.9, 72.6 and 73.3 (OCH
OCH Ph), 78.6 (C5), 85.1 (C2), 85.7 (C3), 127.5－128.4 (CHAr),
36.9, 137.1, 137.2 and 137.9 (CqAr); MS-EI (m/z): 562 (M +Na);
Anal. Calc. For C H NO : C, 75.67; H, 6.91; N, 2.60; found: C,
2Ph), 73.5 (C6), 73.7
(
1
2
3
.13µg/mL, which showed significantly higher activity than the
+
protected compound. Despite these two Galf mimics were less
active than the main drug isoniazid, whose MIC values were
close to that of the “second-line” drug in clinical use as
ethambutol. The results revealed that pyrroles carrying a aryl-
substituent at the 2-position were optimal for antimycobacterial
activity.
3
4
37
5
7
5.58; H, 6.95; N, 2.58.
4.1.2 1-deoxy-1,4-imino-D-galactofuranose (DMDG)
To a stirred solution of 2 (1g, 1.85 mmol) in 5:1 MeOH: EtOAc
(20 mL) was added Pearlman’s catalyst (20% Pd(OH) /C,
2
Degussa type, 1g) and acetic acid (10 drops). The flask was
purged under vacuum and H (3 bar) introduced. This process
2
was repeated 5 times and the reaction allowed to stir vigorourly
under H2 (3 bar) overnight. The catalyst was removed by
Page 4 of 9

1
3
filtration and washed thoroughly with hot MeOH. The combined
filtrates were then evaporated in vacuo to give a colourless oil.
The oil was filtered through Amberlite OH resin to give DMDG
1.38－1.40 (d, 3H, J=6.24, CH3); C-NMR (150 MHz, CD OD)
3
δ 28.8 (CH ), 61.1 (C1), 62.3 (C4), 68.9 (C6), 70.2 (C5), 75.9 (C2),
77.1 (C3); MS-EI (m/z): 200 (M +Na); Anal. Calc. For C H NO :
C, 47.45; H, 8.53; N, 7.90; found: C, 47.48; H, 8.56; N, 7.89.
3
+
7
15
4
2
0
[12]
20
(
0.19g, 63%). [α] +2.7 (c 1.8, H O); lit. , [α] +3.0 (c 2.4,
D
2
D
1
H O); H NMR(300 MHz, D O) δ 4.01(dt, 1H, H-3), 3.93–3.96
2
2
4
.1.6 N-acetyl-1-methyl-1-deoxy-2,3,4,5-tetra-O-acetyl-1,4-
(m, 1H, H-2), 3.62–3.66 (m, 1H, H-5), 3.58 (dd, 1H, J=3.5Hz
imino-D-galactofuranose (9a)
and J=11.8Hz, H-6b), 3.45 (dd, 1H, J=6.6Hz and J=12.0Hz, H-
6
1
a), 3.19 (s, 1H, NH), 2.99 (dd, 1H, J=4.9Hz and J=12.4Hz, H-
b), 2.85–2.83 (m, 1H, H-4), 2.79 (dd, 1H, J=2.8Hz and
Following the same procedure as 8, compound 9a was obtained
1
as a colourless oil, yield 81%, H-NMR (600 MHz, CD Cl)
3
1
3
J=12.5Hz, H-1a); C-NMR (75 MHz, D O) δ 60.9 (C1), 61.8
2
5.17－5.20 (m, 1H, , H-3), 5.14－5.17 (m, 1H, H-2), 4.93－
(C4), 68.3 (C6), 69.4 (C5), 75.6 (C2), 76.8 (C3); MS-EI (m/z): 186
4
.94 (m, 1H, H-5), 4.52－4.56 (m, 1H, H-6b), 4.11－4.12(m, 1H,
H-6a), 3.95－4.08 (m, 1H, H-4), 3.24－3.25(m, 1H, H-1), 2.14 (s,
H, N(O)CMe), 1.96－2.05 (m, 12H, OCMe), 1.48－1.53 (d, 3H,
+
(M +Na); Anal. Calc. for C H NO : C, 44.16; H, 8.03; N, 8.58.
6 13 4
Found: C, 44.08; H, 8.11; N, 8.53.
3
1
3
4
.1.3 N-acetyl-1-deoxy-2,3,4,5-tetra-O-acetyl-1,4-imino-D-
J=6.39, CH3); C-NMR (150 MHz, CDCl ) δ 20.6, 20.7, 20.7,
3
galactofuranose (8)
20.9 (OCMe), 22.7 (NOCMe), 29.8 (CH ), 63.9 (C1), 64.1 (C4),
3
6
1
9.9 (C6), 71.3 (C5), 77.2 (C2), 78.4 (C3), 169.1, 169.3, 169.4,
70.0, 170.1 (C=O); MS-EI (m/z): 410 (M +Na); Anal. Calc. For
To a stirred solution of DMDG (0.19g, 1.17 mmol) in dry
pyridine (20 mL) was added acetic anhydride (5 mL, 53mmol)
and 4-dimethylaminopyridine (0.1g, 0.82 mmol) at r.t. overnight.
The reaction mixture was concentrated in vacuo and the residue
was purified via flash column chromatography (petroleum
+
C H NO : C, 52.71; H, 6.50; N, 3.62; found: C, 52.80; H, 6.46;
N, 3.58.
1
7
25
9
4.1.7
1-ethyl-1-deoxy-2,3,4,5-tetra-O-benzyl-1,4-hydroxyl-
ether/AcOEt=7/1) to give product 8 (0.32g, 73%) as a colourless
amino-D-galactofuranose (3b)
1
oil. H NMR (600 MHz, CDCl ) δ 5.20-5.23 (m, 1H, H-3), 5.16-
3
Following the same procedure as 3a, compound 3b was obtained
as a colourless oil, yield 92%, IR(KBr, cm ): 3383, 3089, 3063,
5
4
1
2
.18 (d, 1H, J=4.2Hz, H-2), 4.96-4.99 (t, 1H, J=10.8Hz, H-5),
.57-4.60 (dd, 1H, J=5.3Hz and J=10.6Hz, H-6b), 4.12-4.15 (m,
H, H-6a), 3.07-3.09 (dd, 1H, J=4.7Hz and J=10.3Hz, H-4),
.95-3.02 (m, 2H, H-1), 2.13-2.14 (s, 3H, N(O)CMe), 2.01-2.09
-1
3
031, 2867, 1605, 1496, 1453, 1363, 1308, 1251, 1073, 1027;
1
H-NMR (600 MHz, CDCl ) δ 7.21－7.35 (m, 20H, H ), 5.59 (s,
3
Ar
1
3
1H, N-OH), 4.77－4.79 (d, 1H, J=11.63, OCH Ph), 4.53－4.56
2
(m, 12H, OCMe); C-NMR (150 MHz, CDCl ) δ 20.6, 20.7,
3
(
d, 2H, J=11.59, OCH Ph), 4.48－4.53 (m, 3H, OCH Ph), 4.33－
2
0.7, 20.8 (OCMe), 22.7 (NOCMe), 62.9 (C1), 65.5(C4), 69.8
2
2
(
1
C6), 71.3 (C5), 78.4 (C2), 80.1 (C3), 169.0, 169.4, 169.7, 169.9,
70.1 (C=O); MS-EI (m/z): 396 (M +Na); Anal. Calc. For
4.35 (dd, 2H, J=12.51, J=11.89, OCH
2 and H-3), 3.77－3.79 (m, 2H, H-5 and H-6b), 3.73-3.75 (m, 1H,
H-6a), 3.51-3.53 (t, 1H, H-4), 3.41 (t, 1H, H-1), 1.36-1.38 (d, 2H,
2
Ph), 3.85－3.87 (m, 2HH-
+
C H NO : C, 51.47; H, 6.21; N, 3.75; found: C, 51.49; H, 6.15;
N, 3.78.
1
6
23
9
1
3
J=5.83, CH ), 0.96-0.98 (m, 3H, CH ); C-NMR (150 MHz,
2
3
CDCl ) δ 29.9 (CH ), 21.6 (CH ), 62.1 (C1), 68.0 (C4), 72.3, 72.9
3
2
3
4
.1.4 1-methyl-1-deoxy-2,3,4,5-tetra-O-benzyl-1,4-hydroxyl-
and 73.8 (OCH
2
Ph), 74.1 (C6), 74.4 (OCH Ph), 78.9 (C5), 85.3 (C2),
2
amino-D-galactofuranose (3a)
8
5.9 (C3), 127.3－129.0 (CHAr), 137.3, 137.5, 137.5, and 138.1
To a solution of nitrone 1 (1g, 1.86mmol) in dry diethyl ether
+
(
CqAr); MS-EI (m/z): 590 (M +Na); Anal. Calc. For C H NO :
36 41 5
(15mL) was added dropwise methylmagnesium bromide (1M in
C, 76.16; H, 7.28; N, 2.47; found: C, 76.18; H, 7.33; N, 2.48.
diethyl ether, 2mL) under nitrogen at 0ºC. The reaction mixture
was stirred for 30min at room temperature, quenched with
saturated ammonium chloride solution and then extracted with
ethyl acetate (3 x 20 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated in vacuo to
give an oil. The crude residue was purified by flash
4.1.8 1-ethyl-1-deoxy-1,4-imino-D-galactofuranose (4b)
Following the same procedure as DMDG, compound 4b was
1
obtained as a colourless oil, yield 83%, H-NMR (600 MHz,
CD OD,  ppm): 4.95 (s, 4H), 3.99－4.03 (t, 1H, J=6.42, H-3),
3
3
.87－3.89 (m, 1H, H-2), 3.62－3.67 (m, 3H, H-6 and H-5), 3.38
chromatography (petroleum ether/AcOEt=5/1) to afford
a
-
1
(m, 1H, H-4), 3.29－3.31 (m, 1H, H-1), 1.92 (s, 1H, N-OH), 1.35
colourless oil 3a (0.81g, 78%). IR (KBr, cm ): 3385, 3088, 3063,
030, 2866, 1605, 1496, 1454, 1363, 1308, 1251, 1073, 1027;
1
3
－
1.38 (m, 2H, CH ), 0.92－0.95 (d, 3H, J=5.86, CH ); C-NMR
2 3
3
1
(
150 MHz, CD OD) δ 29.6 (CH ), 20.8(CH ), 61.5 (C1), 62.6
H-NMR (600 MHz, CDCl ) δ 7.20－7.32 (m, 20H, H ), 5.62 (s,
3 2 3
3
Ar
(
(
C4), 68.8 (C6), 71.3 (C5), 76.0 (C2), 77.4 (C3); MS-EI (m/z): 214
1
2
H, N-OH), 4.76－4.78 (d, 1H, J=11.6, OCH Ph), 4.54－4.58 (d,
2
+
M +Na); Anal. Calc. For C H NO : C, 50.25; H, 8.96; N, 7.32;
8 17 4
H, J=11.9, OCH Ph), 4.47－4.52 (m, 3H, OCH Ph), 4.32－4.38
2
2
found: C, 50.31; H, 8.97; N, 7.29.
(dd, 2H, J=14.69 and J=11.60, OCH Ph), 3.84－3.85 (m, 2H, H-
2
4
.1.9 N-acetyl-1-ethyl-1-deoxy-2,3,4,5-tetra-O-acetyl-1,4-
2
1
1
and H-3), 3.76－3.77 (m, 2H, H-5 and H-6b), 3.73－3.74 (m,
H, H-6a ), 3.50－3.52 (t, 1H, H-4), 3.42 (t, 1H, H-1), 1.21－
imino-D-galactofuranose (9b)
1
3
.22 (d, 3H, J=6.48, CH3); C-NMR (150 MHz, CDCl ) δ 28.7
Following the same procedure as 8, compound 9b was obtained
3
1
(
CH ), 62.7 (C1), 68.9 (C4), 72.1, 72.8 and 73.9 (OCH
2
Ph), 74.2
Ph), 79.1 (C5), 85.7 (C2), 86.0 (C3), 127.7－128.9
CHAr), 137.4, 137.5, 137.6, and 138.0 (CqAr); MS-EI (m/z): 576
as a colourless oil, yield 88%, H-NMR (600 MHz, CD
Cl)
3
3
(C6), 74.5 (OCH
2
5.12－5.15 (1H, m, H-3), 5.04－5.06 (m, 1H, H-2), 4.92－4.93
(m, 1H, H-5), 4.52－5.55 (m, 2H, H-6), 3.96－4.09 (m, 2H, H-1
(
+
(M +Na); Anal. Calc. For C H NO : C, 75.92; H, 7.10; N, 2.53;
35 39 5
and H-4), 2.13 (s, 3H, N(O)CMe), 1.95－2.03 (m, 12H, OCMe),
found: C, 75.89; H, 7.12; N, 2.48.
13
1
.41－1.50 (m, 2H, CH ), 0.96－0.99 (m, 3H, CH ); C-NMR
2
3
4
.1.5 1-methyl-1-deoxy-1,4-imino-D-galactofuranose (4a)
(150 MHz, CDCl ) δ 20.6, 20.7, 20.7, 20.9 (OCMe), 22.6
3
(
NOCMe), 29.1 (CH ), 21.3 (CH ), 62.7 (C1), 63.3 (C4), 67.9
2 3
Following the same procedure as DMDG, compound 4a was
obtained as a colourless oil, yield 76%. H-NMR (600 MHz,
CD OD) 4.93 (s, 4H, OH), 3.99－4.01 (t, 1H, J=6.4, H-3), 3.86
－
(
1
C6), 70.2 (C5), 76.1 (C2), 77.7 (C3), 169.0, 169.3, 169.3, 169.6,
70.0 (C=O); MS-EI (m/z): 424 (M +Na); Anal. Calc. For
1
+
3
C H NO : C, 53.86; H, 6.78; N, 3.49; found: C, 53.83; H, 6.81;
1
8
27
9
3.88 (d, 1H, J=3.2, H-2), 3.63－3.68 (m, 3H, H-6 and H-5),
N, 3.44.
3
.37 (m, 1H, H-4), 3.26－3.28 (m, 1H, H-1), 1.91 (s, 1H, N-OH),
Page 5 of 9

4
.1.10 1-phenyl-1-deoxy-2,3,4,5-tetra-O-benzyl-1,4-hydroxyl-
(C3), 114.8, 127.5－129.8 (CHAr), 137.0, 137.6, 137.9, 138.0,
+
amino-D-galactofuranose (3c)
1
38.1 and 156.5 (CqAr); MS-EI (m/z): 744 (M +Na); Anal. Calc.
For C H NO : C, 78.20; H, 6.56; N, 1.94; found: C, 78.18; H,
Following the same procedure as 3a, compound 3c was obtained
47 47
6
-
1
6
.59; N, 1.95.
as a colourless oil, yield 89%, IR(KBr, cm ): 3343, 3106, 3087,
1
3
063, 3031, 2869, 1604, 1496, 1454, 1365, 1076, 1028; H-NMR
4
.1.14
1-ρ-hydroxyphenyl-1-deoxy-1,4-imino-D-
(
300 MHz, CDCl ) δ 7.07－7.46(m, 25H, H ), 4.96 (s, 1H, N-
galactofuranose (4d)
3
Ar
OH), 4.56－4.58 (d, 2H, J=12.1, OCH Ph), 4.53－4.55 (d, 2H,
2
Following the same procedure as DMDG, compound 4b was
-
1
J=12.0, OCH Ph), 4.36－4.39 (d, 2H, J=11.8, OCH Ph), 4.32－
2
2
obtained as a colourless oil, yield 83%, IR (KBr, cm ): 3198,
1
4
.35(d, 2H, J=11.60, OCH Ph), 4.23 (d, 1H, J=7.2 Hz, H-3), 4.11
2
1617, 1512, 1401, 1262, 1179, 1124, 1074; H-NMR (300 MHz,
(dd , 1H, J=2.7 and 3.2 Hz, H-2), 4.06 (dd, 1H, J=3.4 and 7.1 Hz,
D O) 7.26－7.28 (d, 2H, J=8.7Hz, H ), 6.86－6.87 (d, 2H,
2
Ar
H-5), 3.89 (dd, 1H , J= 3.7 and 8.7 Hz, H-6a), 3.78 (t, 1H, J=6.9
J=8.8Hz, H ), 4.12－4.13 (dd, 1H, J=7.3 and J=9.1Hz, H-3),
Ar
Hz, H-6b), 3.69－3.75 (m, 1H, H-4), 3.49－3.51 (t, 1H, H-1);
3
.93－3.94 (t, 1H, J=7.2Hz, H-2), 3.90－3.91 (d, 1H, J=9.5Hz,
13
C-NMR (75 MHz, CDCl ) δ 66.7 (C1), 68.9 (C4), 71.6, 72.0,
3
H-5), 3.88－3.89 (t, 1H, J=7.5Hz, H-6a), 3.67－3.74 (m, 2H, H-
7
8
1
3.5 (OCH
2
Ph), 74.0 (C6), 74.3 (OCH Ph), 78.6 (C5), 83.7 (C2),
2
1
3
6
a and H-1), 3.28－3.22 (m, 1H, H-4); C-NMR (75 MHz, DO2)
δ 61.6 (C1), 62.0 (C4), 63.3 (C6), 69.7 (C5), 76.9 (C2), 81.3 (C3),
15.8, 125.8－130.4 (CHAr), 153.7 (CqAr); MS-EI (m/z): 278
7.1 (C3), 127.2－128.7 (CHAr), 137.8, 138.1, 138.2, 138.4 and
39.4 (CqAr); MS-EI (m/z): 638 (M +Na); Anal. Calc. For
+
1
(
C H NO : C, 78.02; H, 6.71; N, 2.27; found: C, 78.05; H, 6.73;
4
0
41
5
+
M +Na); Anal. Calc. For C H NO : C, 56.46; H, 6.71; N, 5.49;
12 17 5
N, 2.23.
found: C, 56.43; H, 6.69; N 5.48.
4
.1.11 1-phenyl-1-deoxy-1,4-imino-D-galactofuranose (4c)
4
.1.15 N-acetyl-1-ρ-acetyloxyphenyl-1-deoxy-2,3,4,5-tetra-O-
Following the same procedure as DMDG, compound 4c was
acetyl-1,4-imino-D-galactofuranose (9d)
1
obtained as a colourless oil, yield 81%, H-NMR (300 MHz,
Following the same procedure as 8, compound 9d was obtained
D O)  7.32－7.41 (m, 5H, H ), 4.09 (dd, 1H, J=7.5 and 8.8Hz,
-1
2
Ar
as a colourless oil, yield 92%, IR (KBr, cm ): 3133, 1741, 1650,
H-3), 3.93 (t, 2H, H-2 and H-1a), 3.72 (dd, 1H, J=4.7 and 11.2Hz,
H-5 and H-1b), 3.68 (dd, 1H, J=4.9 and 10.7Hz, H-6a), 3.63 (dd,
1
1
601, 1497, 1454, 1401, 1365, 1225, 1076, 1107, 1027; H-NMR
(
300 MHz, CDCl ) δ 7.24－7.25 (d, 2H, J=9.4Hz, H ), 6.80－
3
A
r
1
H, J=6.3 and 11.6Hz, H-1), 3.19 (dd, 1H, J=2.5 and 6.8Hz, H-4);
1
3
6.81 (d, 2H, J=9.1Hz, H ), 5.06 (m, 1H, H-3), 4.96-4.97 (m, 1H,
Ar
C-NMR (75 MHz, DO ) δ 61.8 (C1), 62.4 (C4), 64.0 (C6), 71.3
2
H-2), 4.23－7.25 (d, 1H, J=6.6Hz, H-5), 4.10－4.11 (dd, 1H,
J=2.9 and 4.9Hz, H-6a), 4.07－4.08 (dd, 1H, J=3.7 and 7.8Hz,
H-6b), 3.90－3.92 (dd, 1H, J=4.1 and 8.4 Hz, H-1), 3.65－3.66
(dd, 1H, J=6.2 and 10.7 Hz, H-4), 2.14(s, 3H, N(O)CMe), 1.97－
(
1
C5), 77.5 (C2), 82.2 (C3), 127.3, 128.2, 128.9, 129.0 (CHAr),
39.7 (CqAr); MS-EI (m/z): 262 (M +Na); Anal. Calc. For
+
C H NO : C, 60.24; H, 7.16; N, 5.85; found: C, 60.27; H, 7.19;
1
2
17
4
N, 5.81.
1
3
2
2
6
.06 (m, 15H, OCMe); C-NMR (75 MHz, CDCl ) δ 20.1, 20.7,
3
4
.1.12 N-acetyl-1-phenyl-1-deoxy-2,3,4,5-tetra-O-acetyl-1,4-
0.8, 20.8, 20.9 (OCMe), 22.9 (NOCMe), 62.6 (C1), 63.4 (C4),
5.0 (C6), 70.8 (C5), 79.0 (C2), 83.1 (C3), 116.0, 125.7－130.1
imino-D-galactofuranose (9c)
Following the same procedure as 8, compound 9c was obtained
(
CHAr), 155.7 (CqAr), 168.1, 169.0, 169.2, 169.4, 169.8, 170.0
-
1
as a colourless oil, yield 91%, IR(KBr, cm ): 2938, 1743, 1653,
+
(C=O) ; MS-EI (m/z): 530 (M +Na); Anal. Calc. For C H NO :
1
24 29
11
1
604, 1496, 1454, 1372, 1365, 1225, 1076, 1107, 1028; H-NMR
C, 56.80; H, 5.76; N, 2.76; found: C, 56.77; H, 5.79; N, 2.75.
(
300 MHz, CDCl ) δ 7.35－7.43 (m, 5H, H ), 5.08 (m, 1H, H-3),
3
Ar
4
.1.16 1-(3’-methoxy-4’-benzyloxy)-phenyl-1-deoxy-2,3,4,5-
4
.99 (m, 1H, H-2), 4.26 (d, 1H, J=7.3Hz, H-5), 4.12 (dd, 1H,
tetra-O-benzyl-1,4-hydroxyl-amino-D-galactofuranose (3e)
J=3.1 and 4.5Hz, H-6a), 4.08 (dd, 1H, J=3.4 and 7.2 Hz, H-6b),
3
1
.91 (dd, 1H, J=4.2 and 8.6 Hz, H-4), 3.65 (dd, 1H, J=6.3 and
Following the same procedure as 3a, compound 3e was obtained
-
1
1.6 Hz, H-1), 2.14(s, 3H, N(O)CMe), 1.98－2.06 (m, 12H,
as a colourless oil, yield 84%, IR (KBr，cm ): 3136, 1615, 1518,
1
3
1
OCMe); C-NMR (75 MHz, CDCl ) δ 20.7, 20.7, 20.8, 20.9
1454, 1403, 1247, 1121, 1024; H NMR (300 MHz, CDCl ): δ
3
3
(OCMe), 22.6 (NOCMe), 62.7 (C1), 63.1 (C4), 64.6 (C6), 71.9
7
.25-7.45 (m, 25 H, H ), 7.08－7.09 (d, 1H, J=3.2Hz, H ),
Ar Ar
(C5), 79.1 (C2), 82.6 (C3), 127.1, 128.2, 128.8, 128.8 (CHAr),
6
.99-7.00 (dd, 1H, J=3.2 and 7.8Hz, H ), 6.93－6.94 (d, 1H,
Ar
1
4
3
39.8 (CqAr), 169.0, 169.3, 169.4, 169.9, 170.1 (C=O); MS-EI (m/z):
J=8.4Hz, H ), 5.06 (s, 1H, N-OH), 4.75 (m, 2H, OCH Ph), 4.69
+
Ar
2
72 (M +Na); Anal. Calc. For C H NO : C, 58.79; H, 6.06; N,
2
2
27
9
－
4.71 (d, 2H, J=11.3Hz, OCH Ph), 4.56 － 4.57 (d, 2H,
2
.12; found: C, 58.72; H, 6.09; N, 3.11.
J=12.0Hz, OCH Ph), 4.52－4.53 (d, 2H, J=12.0Hz, OCH Ph),
2
2
4
1
.1.13 1-ρ-benzyloxyphenyl-1-deoxy-2,3,4,5-tetra-O-benzyl-
,4-hydroxyl-amino-D-galactofuranose (3d)
4
.34－4.35 (d, 2H, J=11.8, OCH Ph), 4.19－4.20 (d, 1H, J=7.0
2
Hz, H-3), 4.06－4.11 (m, 2H, H-2 and H-5), 3.91(s, 3H, OCH3),
3.89－3.90 (m, 1H, H-6a), 3.84－3.85 (dd, 1H, J=3.9 and 9.0 Hz,
Following the same procedure as 3a, compound 3d was obtained
as a colourless oil, yield 91%, IR (KBr, cm ): 3136, 1615, 1516,
-
1
H-6b), 3.75－3.76 (dd, 1H, J=7.0 and 9.0Hz, H-4), 3.66－3.71
1
1
7
6
2
4
454, 1401, 1247, 1124, 1027; H-NMR (300 MHz, CDCl ) δ
13
3
(
m, 1H, H-1); C-NMR (75 MHz, CDCl ) δ 56.1 (OCH ), 67.0
3
3
.28－7.45(m, 25H, H ), 7.08 (dd, 2H, J=3.6 and 7.3Hz, H ),
Ar
Ar
(C1), 68.7 (C4), 71.7, 72.0, 73.5 (OCH Ph), 73.7, (C6), 78.0 (C5),
2
.93 (d, 2H, J=8.7Hz, H ), 5.03 (s, 1H, N-OH), 4.72－4.73 (d,
Ar
83.5 (C2), 87.2 (C3), 111.6, 113.7, 121.5 (CHAr), 127.5－128.5
H, J=10.5, OCH Ph), 4.54－4.56 (d, 2H, J=12.0, OCH Ph),
(CHAr), 131.8, 137.1, 137.9, 138.1, 138.2, 148.1 and 148.4 (CqAr);
2
2
+
.52－4.53 (d, 2H, J=11.8, OCH Ph), 4.34－4.36 (d, 2H, J=11.6,
MS-EI (m/z): 774 (M +Na); Anal. Calc. For C48
H49NO
7
: C,
2
7
6.67; H, 6.57; N, 1.86; found: C, 76.66; H, 6.54; N, 1.83.
OCH Ph), 4.30－4.32(d, 2H, J=11.6, OCH Ph), 4.19－4.20 (d,
2
2
1
4
H, J=7.2Hz, H-3) , 4.08－4.11 (m, 2H, H-2 and H-5), 4.05－
.05 (dd, 1H, J=3.2 and 6.7Hz, H-6a), 3.83－3.85 (dd, 1H , J=3.9
4
.1.17 1-(3’-methoxy-4’-hydroxy)-phenyl-1-deoxy-1,4-imino-
D-galactofuranose (4e)
and 8.7Hz, H-6b), 3.76－3.78 (t, 1H, J=7.1Hz, H-4), 3.69－3.75
Following the same procedure as DMDG, compound 4e was
1
3
(
m, 1H, H-1); C-NMR (75 MHz, CDCl ) δ 66.8 (C1), 68.9 (C4),
-1
3
obtained as a colourless oil, yield 77%, IR(KBr，cm ): 3209,
7
1.7, 72.0, 73.4 (OCH2Ph), 73.7 (C6), 78.1 (C5), 83.4 (C2), 87.1
1
1
637, 1401, 1276, 1252, 1132, 1038; H-NMR (D O, 300 MHz)
2
Page 6 of 9

2
.
Haddad, S.; Boudriga, S.; Porzio, F.; Soldera, A.; Askri, M.;
Sriram, D.; Yogeeswari, P.; Knorr, M.; Rousselin, Y.; Kubicki, M.
M. RSC. Adv. 2014, 4, 59462.
δ 6.99－7.01 (d, 1H, J=8.3Hz, H ), 6.91 (s, 1H, H ), 6.87－6.88
Ar
Ar
(
d, 1H, J=5.2Hz, H ), 4.05－4.06 (dd, 1H, J=7.5 and 8.7Hz, H-
Ar
3
3
), 3.90－3.91 (t, 1H, J=7.3Hz, H-2), 3.81 (s, 3H, OCH ), 3.79－
.80 (d, 1H, J=9.4Hz, H-5), 3.71－3.72 (m, 2H, H-6), 3.65－3.66
3. (a) Barot, K. P.; Jain, S. V.; Gupta, N.; Gupta, N.; Kremer, L.;
Singh, S.; Takale, V. B.; Joshi, K.; Ghate, M. D. Eur. J. Med.
Chem. 2014, 83, 245. (b) Kumar, K.; Singh, P.; Kremer, L.;
Guerardel, Y.; Biot, C.; Kumar, V. Dalton.Trans. 2012, 41, 5778.
(c) Moustafa, G. A. I.; Nojima, S.; Yamano, Y.; Aono, A.; Arai,
M.; Mitarai, S.; Tanaka, T.; Yoshimitsu, T. Med. Chem. Commun.
3
(dd, 1H, J=6.4 and 11.6Hz, H-4), 3.20－3.21 (dd, 1H, J=6.4 and
13
1
1.1Hz, H-1); C-NMR (75 MHz, DO ) δ 56.1 (OCH ), 61.7
2
3
(C1), 62.4 (C4), 63.5 (C6), 69.3 (C5), 77.4 (C2), 81.9 (C3), 112.7,
2
013, 4,720.
1
14.4 and 119.6 (CHAr), 132.6, 145.4 and 147.4 (CqAr); MS-EI
+
4. Brennan, P. J. Tuberculosis 2003, 83, 91.
(m/z): 308 (M +Na); Anal. Calc. For C H NO : C, 54.73; H,
13 19 6
5
6
.
.
(a) Lederkremer, R. M.; Colli, W. Glycobiology 1995, 5, 547; (b)
Houseknecht, J. B.; Lowary, T. L. Curr. Opin. Chem. Biol. 2003,
6
.71; N, 4.91; found: C, 54.71; H, 6.74; N 4.90.
7
6
, 677; (c) Pedersen, L. L.; Turco, S. J. Cell. Mol. Life Sci. 2003,
0, 259; (d) Peltier, P.; Euzen, R.; Daniellou, R.; Nugier-Chauvin,
4
1
.1.18 N-acetyl-1-(3’-methoxy-4’-acetyloxy)-acetyloxyphenyl-
-deoxy-2,3,4,5-tetra-O-acetyl-1,4-imino-D-galactofuranose
C.; Ferrières, V. Carbohydr. Res. 2008, 343, 1897.
(9e)
(a) Soltero-Higgin, M.; Carlson, E. E.; Gruber, T. D.; Kiessling, L.
L. Nat. Struct. Mol. Biol. 2004, 11, 539; (b) Bela´nˇova´, M.;
Dianisˇkova´, P.; Brennan, P. J.; Completo, G. C.; Rose, N. L.;
Lowary, T. L.; Mikusˇova´, K. J. Bacteriol. 2008, 190, 1441; (c)
Rose N.L.; Completo, G.C.; Lin, S-L; McNeil M.; Palcic M.M.;
Lowary, T. L. J. Am. Chem. Soc. 2006, 128, 6721.
Following the same procedure as 8, compound 9e was obtained
as a colourless oil, yield 93%, IR (KBr, cm ): 3142, 1745, 1651,
1
-
1
1
601, 1496, 1454, 1403, 1365, 1225, 1076, 1107, 1027; H-NMR
(300 MHz, CDCl ) δ 7.03－7.04 (d, 1H, J=8.7Hz, H ), 6.95-
3
Ar
7
.
Tefsen, B.; Ram, A. F. J.; van Die, I.; Routier, F. H. Glycobiology
6
.97 (dd, 1H, J=2.3 and 8.6Hz, H ), 6.88－6.90 (d, 1H, J=2.4Hz,
Ar
2
012, 22, 456.
H ), 5.05 (m, 1H, H-3), 4.88－4.89 (m, 1H, H-2), 4.26－4.27 (d,
Ar
8. Pan, F.; Jackson, M.; Ma, Y. F.; McNeil, M. J. Bacteriol. 2001,
183, 3991.
1
4
1
1
H, J=7.2Hz, H-5), 4.12－4.13 (dd, 1H, J=3.3 and 5.2Hz, H-6a),
.07－4.08 (dd, 1H, J=3.5 and 7.1 Hz, H-6b), 3.90－3.91 (dd,
9
.
(a) van Straaten, K.E.; Kuttiyatveetil, J. R.A.; Sevrain C.M.;
Villaume, S.A.; Jiménez-Barbero, J.; Linclau, B.; Vincent, S.P.;
Sanders, D. A. R. J. Am. Chem. Soc. 2015, 137, 1230; (b)
Dykhuizen, E. C.; May, J. F.; Tongpenyai, A.; Kiessling, L. L. J.
Am. Chem. Soc. 2008, 130, 6706; (c) Sadeghi-Khomami, A.;
Forcada, T. J.; Wilson, C.; Sanders, D. A. R.; Thomas, N. R. Org.
Biomol. Chem. 2010, 8, 1596; (d) Partha, S. K.; Sadeghi-
Khomami, A.; Cren, S.; Robinson, R. I.; Woodward, S.; Slowski,
K.; Berast, L.; Zheng, B.; Thomas, N. R.; Sanders, D. A. R. Mol.
Inf. 2011, 30, 873; (e) Carlson, E. E.; May, J. F.; Kiessling, L. L.
Chem. Biol. 2006, 13, 825; (f) Borrelli, S.; Zandberg, W. F.;
Mohan, S.; Ko, M.; Martinez-Gutierrez, F.; Partha, S. K.; Sanders,
D. A. R.; Av-Gay, Y.; Pinto, B. M. Int. J. Antimicrob. Agents.
H, J=3.7 and 7.9Hz, H-4), 3.83 (s, 3H, OCH ), 3.63－3.64 (dd,
3
H, J=6.1 and 11.2Hz, H-1), 2.14 (s, 3H, N(O)CMe), 1.95-2.04
1
3
(m, 15H, OCMe); C-NMR (75 MHz, CDCl ) δ 20.1, 20.6, 20.8,
3
2
0.8, 20.9 (OCMe), 22.9 (NOCMe), 56.1 (OCH ), 62.6 (C1), 63.7
3
(C4), 64.9 (C6), 69.9 (C5), 79.1 (C2), 82.2 (C3), 112.8, 114.6 and
1
1
19.7 (CHAr), 131.8, 144.4 and 147.1 (CqAr), 168.0, 169.1, 169.3,
+
69.3, 169.8, 170.1 (C=O); MS-EI (m/z): 560 (M +Na); Anal.
Calc. For C H NO : C, 58.86; H, 5.81; N, 2.61; found: C,
5
2
5
31
12
8.82; H, 5.81; N, 2.60.
2
010, 36, 364; (g) El Bkassiny, S.; N’Go, I.; Sevrain, C. M.; Tikad,
4
.2. Biological evaluation
A.; Vincent, S. P. Org. Lett. 2014, 16, 2462; (h) Soltero-Higgin,
M.; Carlson, E.E.; Phillips, J. H.; Kiessling, L.L. J. Am. Chem. Soc.
2
2
Thomas, N. R. Org. Lett. 2005, 7, 4891; (h) Caravano, A.; Vincent,
S. P.; Sinaÿ, P. Chem. Comm. 2004, 1216.
The mycobacterial strains, which were cultivated on
004, 126, 10532; (i) Itoh, K.; Huang, Z. S.; Liu, H. W. Org. Lett.
007, 9, 879; (g) Sadeghi-Khomami, A.; Blake, A. J.; Wilson, C.;
Middlebrook 7H9 Broth supplemented with oleic acid-albumin-
dextrose-catalase (OADC) enrichment and prepared in 0.9%
NaCl solution to get inoculum density of 5×10 cells/mL, were
5
dispensed into each well, except the blank. 125 mL of each test
material solution and the standard drug isoniazid and ethambutol,
prepared by dissolving in DMSO and further dilution in
Middlebrook 7H9 Broth, was added to well 1 of the lane in
duplicate followed by serial double dilutions to well 14 of the
lane, 100 µg/mL at well 1 to 0.012 µg/mL at well 14. The last
two wells in the lane were used as a sterile and growth control
respectively. Growth inhibition was determined after 3 days of
incubation at 37 °C and the MIC values were determined as
minimum concentration inhibiting the growth of tested
tuberculosis strains in relation to the probe with no tested
compound. Tests were carried out three times in duplicate and
isoniazid and ethambutol were used as positive controls.
10. Bande O.P.; Jadhav V.H.; Puranik V.G.; Dhavale D.D. ;
Lombardo M. Tetrahedron Lett. 2009, 50, 6906.
1
1
1. Chandrasekhar B.; Madhan A.; Venkateswara R. B. Tetrahedron.
007, 63, 8746.
2. Yamashita, T. ; Yasuda, K. ; Kizu, H. ; Kameda, Y. ; Watson, A.
A. ; Nash, R. J. ;Fleet, G. W. J. ; Asano, N. J. Nat. Prod. 2002, 65,
1875.
2
1
1
3. Leea R. E. ; Smith M. D. ; Nash R. J. ; Griffiths R. C. ; McNeil
M. ; Grewal R. K. ; Yan W, Besrac G. S. ; Brennanc P.J. ; Fleet G.
W. J. Tetrahedron Lett. 1997, 38, 6733.
4. (a) Desvergnes, S; Desvergnes, V; Martin, R.T.; Itoh, K.; Liu, H.;
Py, S. Bioorg. Med. Chem. 2007, 15, 6443; (b) Veerpen, N.; Yuan,
Y.; Sanders, D. A.R.; Pinto, B. M. Carbohydr. Res. 2004, 339,
2205; (c) Liautard, V.; Desvergnes, V.; Itoh, K.; Liu, H.; Martin,
R.T. J. Org. Chem. 2008, 73, 3013-3115.
1
1
5. Liu, C.Y.; Kan, H.; Wightman, R. H.; Jiang S.D. Tetrahedron Lett.
2
013, 54, 1192.
Acknowledgments
6. Compain, P.; Chagnault, V.; Martin, O. R. Tetrahedron:
Asymmetry 2009, 20, 672.
This work was supported by grants from the National Natural
Science Foundation of China (No. 21302040), National Natural
Science Foundation of Hebei Province, China (No.
H2014209272), and Foundation of Hebei Province’s University,
China (No. Q2012147).
17. (a) Liu, C.Y.; Gao, J.C.; Yang, G.; Wightman, R. H.; Jiang S.D.
Lett. Org. Chem.; 2007, 4, 556; (b) Liu, C.Y.; Meng, A.G.
Chemical Research and Application; 2010, 22, 911; (c) Liu, C.Y.;
Meng, A.G.; Zhan, H. Chemical Research and Application 2010,
1
8, 462; (d) Liu, C.Y.; Meng, A.G.; Zhan, H. Acta Academiae
Medicinae Militaris Tertiae 2010, 32, 369; (e) Meng, A.G.; Liu,
C.Y.; Ma, H. C. Chinese Journal of Experimental Traditional
Medical Formulae, 2011, 17, 217.
References and notes
1
8. (a) Bernotas C.R. Tetrahedron Lett. 1990, 31, 469; (b) Lundt I.,
Madsen R. Synthesis. 1993, 720; (c) Paulsen H., Steinert K.,
Heyns K. Chem. Ber. 1970, 103, 1599; (d) Lombardo M.,
Fabbroni S., Trombini C. J. Org. Chem. 2001, 66, 1264; (e) Pham-
Huu D-P., Gizaw Y., BeMiller J.N., Petrus L. Tetrahedron. 2003,
1
.
WHO, Global Tuberculosis Report 2014 [M], World Heatlh
Organization, 2014, 17.
5
9, 9413.
Page 7 of 9

1
9. (a) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003,
5; (b) Goti, A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.;
20. (a) Gurjar, M. K.; Borhade, R.G.; Puranik, V. G.; Ramana, C. V.
Tetrahedron Lett. 2006, 47, 6979; (b) Cardona, F.; Faggi, E.;
Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003, 44,
2315; (b) Carmona, A. T.; Whigtman, R. H.; Robina, I.; Vogel, P.
Helv. Chim. Acta 2003, 86, 3066; (c) Desvergnes, S.; Py, S.;
Valle′e, Y. J. Org. Chem. 2005, 70, 1459.
3
Merino, P.; Tejero, T. Org. Lett. 2003, 5, 4235; (c) Cardona, F.;
Valenza, S.; Goti, A.; Brandi, A. Tetrahedron Lett. 1997, 38, 8097;
(
d) Cardona,F.; Valenza, S.; Picasso, S.; Goti, A.; Brandi, A. J.
Org. Chem. 1998, 63, 7311; (d) Yu. C.Y.; Huang, M.H. Org. Lett.
006, 8, 3021; (e) Duff, F. J.; Vivien, V.; Wightman, R. H. Chem.
Commun. 2000, 2127; (e) Lombardo, M.; Trombini, C. Synthesis
2
21. Franzblau S.G., Witzig R.S., McLaughlin J.C., Torres P., Madico
G., Hernandez A., Degnan M.T., Cook M.B., Quenzer V.K.,
Ferguson R.M., Gilman R.H. J. Clin. Microbiol. 1998, 36, 362.
22. Mugunthan G., Sriram D., Yogeeswari P., Kartha R. Carbohydr.
Res. 2011, 346, 2401.
2
1
000, 759; (f) Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48,
337; (g) Peer, A.; Vasella, A. Helv. Chim. Acta 1999, 82, 1044;
(h) Tamura, O.;Toyao, A.; Ishibashi, H. Synlett 2002, 1344.
OH
OH
H
Ac
N
BnO
OAc
N
N
OH
BnO
OAc
HO
OH
HO
OH
OH
DMDG
OH
OH
OAc
OAc
OH
BnO
OBn
OH
OH
OH
N
2
8
N
H
H
OH
Ac
OH
N
OAc
BnO
H
N
N
homo DMDP
DMDP
OH
OAc
BnO
OH
4a
OH
OAc
OAc
BnO
3a
OBn
9
a
HO
OH
HO
OH
Ac
N
OH
OAc
OH
H
OH
BnO
OH
N
N
H
R
N
OAc
OH
N
BnO
OH
H
OH
OH
4b
OH
OAc
OAc
BnO
3b
OBn
9
b
DMDG
Glaf mimics
Ac
N
OH
OAc
H
OH
N
Figure 1. Chemical Structures of iminosugars and Galf mimics
BnO
N
OH
OAc
BnO
OH
OH
OAc
9c
OAc
OH
OH
N
H
BnO
BnO
OBn
N
4c
OH
3c
BnO
O
N
BnO
OH
OH
Ac
BnO
OBn
OH
OAc
OAC
OH
N
H
OH
BnO
OBn
N
BnO
DMDG
N
2
OH
OAc
BnO
OH
N
BnO
OBn
BnO
OAc
OAc
OH
OH
OH
H
BnO
OBn
N
R
R
1
BnO
OH
4
d
3
d
9d
BnO
OBn
OH
OH
Ac
N
OAc
OCH3
OH
N
OH
H
OCH3
BnO
OCH3
N
OAc
3
4
OH
BnO
OAc
OH
OBn
OH
OH
OAc
OAc
Figure 2. Synthetic pathways of DMDG and Galf mimics
BnO
OBn
3
e
4e
9e
Figure 3. Chemical Structures of Galf mimics
N
BnO
OH
OTBDMS
O
b
a
OH
BnO
BnO
OBn
D-galactose
OBn OBn
BnO
OBn
6
5
N
O
I
OTBDMS
BnO
c
N
d
BnO
OBn
BnO
OBn OBn
BnO
OBn
7
1
Scheme 1 Reagents and conditions: (a) i. TsOH.H
NaH, DMF, 0C, Bu NI, BnBr, rt; iii. MeCN:H O:TFA = 5:3:1, reflux; (b) i.
NH OH.HCl, MeOH, NaOMe, reflux; ii. TBDMSCl, pyridine; (c) I , PPh
imidazole, toluene, reflux; (d) TBAF, toluene, reflux.
2
O, methanol, reflux; ii.
4
2
2
2
3
,
Page 8 of 9

OH
N
BnO
O
N
BnO
NaBH4
20%Pd(OH)2/C
BnO
BnO
2N HCl,
methanol
H2, MeOH:EtOAc=5:1
BnO
OBn
BnO
OBn
2
1
Ac
OAc
OH
H
N
N
Ac O, DMAP
2
OAc
OH
DCM, pyridine
OAc
OAc
OH
OH
5
DMDG
Scheme 2. Synthesis of DMDG
OH
BnO
O
N
BnO
2
20%Pd(OH) /C
Grignard
Diethyl ether, 0℃
N
R
BnO
BnO
2
H , MeOH:EtOAc=5:1
BnO
OBn
BnO
OBn
3
1
Ac
OH
OAc
H
N
N
R
R
2
Ac O, DMAP
OH
OAc
DCM, pyridine
OH
OH
OAc
OAc
4
6
Scheme 3. Synthesis of novel iminosugars
Table 1 MIC value (µg/mL) of antimycobacterial activity of synthesized
compounds and reference drug
MIC
µg/mL)
MIC
(µg/mL)
compound
compound
(
2
DMDG
8
>25
12.5
>25
>25
12.5
6.25
12.5
12.5
6.25
3c
4c
9c
3d
4d
9d
3e
4e
9e
12.5
6.25
6.25
12.5
3.13
6.25
>25
3a
4a
9a
3b
4b
9b
3.13
6.25
isoniazid
0.024
ethambutol
1.56
Page 9 of 9