Convenient approaches to synthesis of furanoid sugar-aza-crown ethers from C-ribosyl azido aldehyde via a reductive amination/amidation

Article abstract of DOI:10.1016/j.carres.2009.03.008

A short and highly efficient route to the α-anomer of a furanoid sugar-aza-crown ether was developed by a one-pot reductive amination of an α-anomer C-ribosyl azido aldehyde. In addition, the β-anomer furanoid sugar-aza-crown ether was synthesized from a

Full text of DOI:10.1016/j.carres.2009.03.008

Carbohydrate Research 344 (2009) 1020–1023
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Note
Convenient approaches to synthesis of furanoid sugar-aza-crown ethers from
C-ribosyl azido aldehyde via a reductive amination/amidation
Yu-Chi Hsieh a, Jiun-Ly Chir b, Wei Zou c, Hsiu-Han Wu a, An-Tai Wu a,
*
a Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
b Biotechnology Center in Southern Taiwan, Academia Sinica, 2F., No. 22, Lane 31, Sec. 1, Huandong Road, Sinshih Township, Tainan County 744, Taiwan
c Institute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario, Canada K1A 0R6
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and highly efficient route to the
a
-anomer of a furanoid sugar-aza-crown ether was developed by
Received 11 February 2009
Received in revised form 2 March 2009
Accepted 7 March 2009
a one-pot reductive amination of an
a-anomer C-ribosyl azido aldehyde. In addition, the b-anomer fura-
noid sugar-aza-crown ether was synthesized from a linear disaccharide precursor via amidation and then
followed by microwave-assisted amide reduction.
Available online 12 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Furanoid
Sugar-aza-crown ether
Amination
Amidation
In recent years, new sugar-based molecular receptors such as
sugar-aza-crown (SAC)1 ethers have received attention, especially
pyranoid-based SAC ethers, because of applicable functions such
as metal chelation, host–guest recognition, and chemosensors.
They are easily obtained by reducing the amide bond in cyclic
pyranoid sugar amino acids (SAAs), which have been extensively
synthesized by many groups.2–8 Xie et al. reported a short and
highly efficient route to pyranoid SAC ethers through the one-pot
Staudinger/aza-Wittig reaction of azido aldehydes for macrocycli-
zation.9 In addition, modified pyranoid SAC ethers with bispyrenyl
have also been synthesized and applied to sensing and recognizing
Cu2+ cation.10 Therefore, we are interested in the synthesis of fura-
noid SAC ethers. In this paper, we adopt two strategies to synthe-
lyzed hydrogenation, the b-anomer C-riboside favored
intramolecular cyclization leading to the formation of the tricyclic
lactam12 3 in 65% yield. Because the cyclodimerization was based
on the anomeric configuration, the epimerization of the b-anomer
to the
a
-anomer of C-riboside for dimercyclization should be
HN
N3
CHO
(b)
N3
CO2Me
(a)
O
O
O
O
O
O
O
O
O
size
approach involves converting a C-ribosyl azido aldehyde monomer
directly into -anomer SAC ether by one-pot reductive amination;
the other is the conversion of a linear disaccharide precursor to the
SAA by intramolecular amidation and reduction of the amide
bonds to obtain the b-anomer furanoid SAC ether.
The preparation of furanoid SAC ethers, starting from the
readily available aza-C-riboside 1,11 is outlined in Scheme 1. The
reaction of 1 with DIBAL-H at À78 °C produced the b-anomer
C-ribosyl azido aldehyde 2 in 64% yield. We intended to use the
reductive amination strategy for this cyclodimerization. Unfortu-
nately, when treating the azido aldehyde 2 under palladium-cata-
a- and b-anomer furanoid SAC ethers, respectively. One
1
2
3
a
(c)
O
O
O
H
CHO
N3
N
O
O
O
(b)
N
H
O
O
O
4
5
* Corresponding author. Fax: +1 886 4 7211 190.
E-mail address: antai@cc.ncue.edu.tw (A.-T. Wu).
Scheme 1. Reagents and conditions: (a) DIBAL-H, À78 °C, CH2Cl2; (b) H2, Pd/C,
MeOH; (c) Zn(OAc)2, NaOMe, MeOH.
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.03.008

Y.-C. Hsieh et al. / Carbohydrate Research 344 (2009) 1020–1023
1021
NH2
CO2Me
O
O
O
O
O
O
O
O
O
O
H
H
(a)
(b)
O
O
N
N
CO2Me
(a), (d)
NH
O
O
O
O
O
1
N3
O
O
6
O
(e)
(c)
N
N
N3
CO2H
H
H
8
O
O
O
O
O
O
O
9
10
Scheme 2. Reagents and conditions: (a) H2, Pd/C, MeOH; (b) NaOH, THF, H2O; (c) DEPC, Et3N, DMF; (d) K2CO3, MeOH; (e) LAH, THF, microwave.
performed. Accordingly, 2 was treated overnight with 4% NaOMe
H-5 was observed as a broad doublet at d 3.68 (J = 9.9 Hz). Two
H-7 protons were observed at different field strengths as multi-
plets at d 3.08 and 2.47. On the other hand, H-1 of the b-anomer
furanoid SAC 10 was observed at more downfield strengths as a
13
and Zn(OAc)2 to obtain the
a-anomer C-ribosyl azido aldehyde
4 in 75% yield with about 15% starting material remaining. Further-
more, following reduction of the C-ribosyl azido aldehyde 4, under
palladium-catalyzed hydrogenation, the compound spontaneously
underwent intermolecular reductive amination. We observed the
multiplet at d 2.62–2.88 than that of
a-anomer. H-2 and H-5 of
the b-anomer overlap and were observed as a multiplet at d
3.97–4.02. The H-5 in both cases showed an obvious shift differ-
ence of 0.31 ppm. The 13C NMR spectra further supported the shift
desired dimer
a-anomer furanoid SAC ether 5 in 80% yield and
no imine intermediate or remaining polymers were observed dur-
ing the reaction. Interestingly, the results of our study are inconsis-
tent with the study performed by Xie et al.9 They performed
reduction of the C-glucosyl azido aldehydes bearing different pro-
tection groups under palladium-catalyzed hydrogenation, but
imine intermediates (pyranoid derivatives) were the major prod-
ucts with a trace of amine products. This dissimilarity probably
arises from the steric hindrance derived from backbone-based
groups (protecting groups or sugar rings) applied during the
difference with the carbon (C-5) signals of the
a- and b-anomer
furanoid SAC (5 and 10) at around d 79.4 and d 85.5, respectively.
The structures of all the products were in accord with spectro-
scopic data and analyses.
In summary, we described an efficient method for the synthesis
of
a- and b-anomer furanoid SAC ethers from aza-C-riboside via
reductive amination and amidation, respectively. The resulting
furanoid-based SAC ethers, a new class of molecular receptors,
probably can lead to easy access for applications in chemosensors.
We consider the fluorescent derivatives of furanoid-based SACs to
hydrogenation process. The
a-anomer furanoid SAC ether 5 was
characterized by NMR and mass spectra.
The requisite b-anomer furanoid SAC ether, however, can be
synthesized from its linear disaccharide, which is the conventional
process for synthesizing similar cyclic homooligomers,1 as shown
in Scheme 2. Accordingly, the aza-C-riboside 1 was subjected to
reduction by hydrogenation and hydrolysis, respectively, to pro-
duce the corresponding amino ester 6 in 92% yield and the azido
acid 7 in 90% yield. With these two C-ribosides in hand, the cou-
pling of the amino ester 6 and the azido acid 7 was carried out with
diethyl phosphoryl cyanide (DEPC) and Et3N in DMF to obtain the
linear disaccharide 8 in 81% yield. The azido group in the linear
disaccharide 8 was reduced by catalytic hydrogenation, which pro-
duced an amino ester intermediate. After filtration and removal of
the solvent, the intermediate was treated with K2CO3 in MeOH,
which resulted in intramolecular amidation with the ester leading
to the desired b-anomer furanoid SAA 9 as a major product in 76%
yield, and a trace amount of the starting material 8. Furthermore,
we tried to synthesize the more flexible amine-linked b-anomer
furanoid SAC ether 10 by reducing the amide bonds. Next, we used
classical reduction conditions such as BH3ÁTHF or LAH under reflux
after a long reaction time, but they were totally inert to reduction.
This is probably due to the intramolecular hydrogen bond interac-
tion between the NH groups and oxygen atoms of the SAC ether 9.
Finally, reducing the amide bonds of 9 with microwave irradiation
and excess LAH was found to be successful for obtaining the
desired b-anomer furanoid SAC ether 10 in 67% yield.
A comparison of the 1H NMR spectra in CDCl3 of the
furanoid SAC ether 5 and the b-anomer furanoid SAC ether 10 is
shown in Figure 1. In the 1H NMR spectra, the H-1 of the
-anomer
a-anomer
a
furanoid SAC ether 5 appears as a multiplet at d 2.41–2.66, H-2 was
observed as a doublet of a doublet at d 4.27 (J = 12.6, 3.9 Hz), and
Figure 1. 1H NMR spectra of
SAC ether 10 (CDCl3; 298 K).
a-anomer furanoid SAC ether 5 and b-anomer furanoid

1022
Y.-C. Hsieh et al. / Carbohydrate Research 344 (2009) 1020–1023
be synthesized and further examined with ligands such as cation
metals to demonstrate their application.
3.68 (d, J = 9.9 Hz, 2H), 3.11–3.05(m, 3H), 2.63 (dd, J = 12.0,
3.9 Hz, 2H), 2.49–2.47 (m, 4H), 2.04–1.99 (m, 3H), 1.83–1.78 (m,
2H), 1.43 (s, 6H), 1.24 (s, 6H); 13C NMR (75 MHz, CDCl3) d: 112.6,
83.5, 82.7, 81.8, 79.4, 48.7, 48.4, 27.7, 26.2, 25.3; HRMS (FAB): calcd
for C20H34N2O6 (M+H), m/z 398.2417; found m/z 399.2501.
1. Experimental
1.1. General methods
1.5. Methyl 2-C-(5-amino-5-deoxy-2,3-di-O-isopropylidene-b-
D
-ribofuranosyl)acetate (6)
All reagents were obtained from commercial suppliers and were
used without further purification. DCM was distilled over CaH2.
MeOH was distilled over magnesium and iodine. Analytical thin-
layer chromatography was performed using silica gel 60 F254
plates (Merck). The 1H and 13C NMR spectra were recorded with
a Bruker AM 300 spectrometer. Chemical shifts are given in ppm
with residual CHCl3 or CD3OD as reference. Mass spectra were
recorded under fast atom bombardment (FAB) or electron spray
interface (ESI) conditions. Microwave reactions were carried out
in a Milestone Start S with a maximum power of 300 W and
50 mL process flask.
A mixture of 1 (1.72 g, 6.34 mmol) and 10% Pd–C (0.17 g) in
methanol (20 mL) was stirred under H2 atmosphere (balloon pres-
sure) for 40 min when the starting material was completely con-
sumed. The reaction mixture was filtered and the filtrate was
concentrated. Purification by chromatography (DCM–MeOH 10:1)
gave 6 (1.43 g, 92%) as a yellow oil; Rf 0.2 (DCM–MeOH 10:1); 1H
NMR (300 MHz, CDCl3) d: 4.52–4.43 (m, 2H), 4.23–4.18 (m, 1H),
3.88 (m, 1H), 3.66 (s, 3H, CO2Me), 2.91–2.73 (m, 2H), 2.64–2.52
(m, 2H), 1.50 (s, 3H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3) d:
170.9, 114.7, 85.5, 84.2, 82.4, 80.3, 51.8, 44.0, 38.1, 27.4, 25.5;
HRMS (FAB): calcd for C11H20NO5 (M+H), m/z 246.1341; found m/
z 246.1343.
1.2. Methyl 2-C-(5-azido-5-deoxy-2,3-di-O-isopropylidene-b-D-
ribofuranosyl) acetaldehyde (2)
1.6. Methyl 2-C-(5-azido-5-deoxy-2,3-di-O-isopropylidene-b-D-
ribofuranosyl)acetic acid (7)
To a solution of 1 (3.58 g, 13 mmol) in dry CH2Cl2 (100 mL) was
added 1 M solution of DIBALH (30 mL, 2.5 equiv) at À78 °C. The
reaction mixture was stirred at the temperature for 1 h. MeOH
(16 mL) was added and stirred for 10 min at À78 °C. Saturated NaCl
(2 mL), Et2O (50 mL) and MgSO4 (1.07 g) were subsequently added.
The mixture was stirred at room temperature for 1 h and then was
filtered through Celite. The solvent was removed and the crude
product was purified by chromatography (hexanes–EtOAc 5:1) to
give 2 (2.01 g, 64%) as a colorless oil; Rf 0.34 (EtOAc–hexanes
1:2.5); 1H NMR (300 MHz, CDCl3) d: 9.71 (t, J = 1.5 Hz, 1H), 4.54
(dd, J = 6.9, 4.5 Hz, 1H), 4.40 (dd, J = 6.6, 5.1 Hz, 1H), 4.30–4.25
(m, 1H), 4.03 (q, J = 4.2 Hz, 1H), 3.49 (dd, J = 13.2, 3.6 Hz, 1H),
3.28 (dd, J = 13.2, 4.5 Hz, 1H), 2.74–2.69 (m, 2H), 1.47 (s, 3H),
1.27 (s, 3H); 13C NMR (75 MHz, CDCl3) d: 199.3, 115.1, 84.2, 82.9,
81.8, 79.4, 52.0, 46.8, 27.2, 25.3; HRMS (FAB): calcd for
C10H16N3O4 (M+H), m/z 242.1141; found m/z 242.1138.
To a solution of 1 (5.32 g, 0.02 mol) in THF (10 mL) was added
1 M aqueous NaOH(aq) (5 mL). The mixture was stirred overnight,
then AmberliteÒ IR-120 (H+) was added to neutralize, and the mix-
ture was filtered and concentrated. The resulting residue was puri-
fied by silica chromatography (hexanes–EtOAc 3:1) to give 7
(4.65 g, 90%) as a colorless oil; Rf 0.31 (hexanes–EtOAc 1:2); 1H
NMR (300 MHz, CDCl3) d: 4.57–4.52 (m, 2H), 4.28–4.26 (m, 1H),
4.08–4.07 (m, 1H), 3.52 (dd, J = 12.9, 3.6 Hz, 1H), 3.33 (dd,
J = 12.9, 4.5 Hz, 1H), 2.73–2.70 (m, 2H), 1.52 (s, 3H), 1.32 (s, 3H);
13C NMR (75 MHz, CDCl3) d: 174.8, 115.0, 84.1, 83.0, 81.9, 80.6,
52.2, 37.9, 27.3, 25.4; HRMS (FAB): calcd for C10H16N3O5 (M+H),
m/z 258.1090; found m/z 258.1086.
1.7. Linear furanoid sugar amino acid (8)
1.3. Methyl 2-C-(5-azido-5-deoxy-2,3-di-O-isopropylidene-a-D-
ribofuranosyl) acetaldehyde (4)
To a solution of amine 6 (1.90 g, 7.75 mmol) and acid 7 (2.00 g,
7.77 mmol) in DMF (20 mL) under nitrogen atmosphere, DEPC
(1.7 mL, 1.5 equiv) and Et3N (3 mL, 3 equiv) were added at 0 °C.
The solution was allowed to warm to room temperature and stir-
red for two days. Then, the mixture was partitioned in EtOAc–
H2O (1:1), the organic layer was washed with brine, and the
aqueous layers were combined and extracted with EtOAc. The
organic layers were combined, dried, filtered, and concentrated.
The resulting residue was purified by silica column chromatogra-
phy (hexanes–EtOAc 3:1) to give 8 (3.03 g, 81%) as a brown oil;
Rf 0.33 (hexanes–EtOAc 1:2); 1H NMR (300 MHz, CDCl3) d: 4.54–
4.46 (m, 4H), 4.16 (d, J = 4.5 Hz, 2H), 4.07–4.00 (m, 2H), 3.67 (s,
3H), 3.57–3.52 (m, 2H), 3.40–3.32 (m, 2H), 2.69–2.52 (m, 4H),
1.48 (s, 3H), 1.44 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H); 13C NMR
(75 MHz, CDCl3) d: 171.1, 169.8, 115.0, 114.7, 84.2, 83.9, 83.0,
82.8, 82.4, 81.9, 81.3, 80.4, 52.1, 51.8, 40.9, 40.1, 37.3, 27.4,
27.3,25.4; HRMS (ESI): calcd for C21H32N4O9 (M+), m/z 484.2169;
found m/z 484.2176.
To a solution of 2 (1.04 g, 4.32 mmol) and Zn(OAc)2 (4.7 g,
6.0 equiv) was added 0.7 M solution of NaOMe in MeOH (15 mL).
The mixture was stirred overnight, and then neutralized by adding
HOAc. The mixture was extracted with EtOAc, filtered, and concen-
trated. The resulting residue was purified by silica column chroma-
tography (hexanes–EtOAc 5:1) to give 4 (0.78 g, 75%) as a colorless
oil; Rf 0.34 (hexanes–EtOAc 2.5:1); 1H NMR (300 MHz, CDCl3) d:
9.78 (d, J = 1.2 Hz, 1H), 4.77–4.60 (m, 2H), 4.42–4.16 (m, 2H),
3.39–3.28 (m, 2H), 2.86–2.83 (m, 2H), 1.44 (s, 3H), 1.30 (s, 3H);
13C NMR (75 MHz, CDCl3) d: 199.9, 112.9, 83.2, 82.6, 81.2, 76.2,
51.6, 43.6, 26.1, 24.7; HRMS (FAB): calcd for C10H16N3O4 (M+H),
m/z 242.1141; found m/z 242.1137.
1.4. Furanoid sugar-aza-crown (5)
A mixture of 4 (0.95 g, 3.94 mmol) and 10% Pd–C (0.1 g) in
methanol (20 mL) was stirred under H2 atmosphere (balloon pres-
sure) for 24 h until the starting material was completely con-
sumed. The reaction mixture was filtered and the filtrate was
concentrated. Purification by chromatography (EtOAc–MeOH 3:1)
gave 5 (0.63 g, 80%) as a pale yellow solid; mp: 182 °C; Rf 0.21
(EtOAc–MeOH 1:2); 1H NMR (300 MHz, CDCl3) d: 4.57 (dd, J = 6.0,
5.7 Hz, 2H), 4.38 (d, J = 6.0 Hz, 2H), 4.27 (dd, J = 12.6, 3.9 Hz, 2H),
1.8. Cyclic furanoid sugar amino acid (9)
A mixture of 8 (1.72 g, 3.57 mmol) and 10% Pd–C (0.17 g) in
methanol (20 mL) was stirred under H2 atmosphere (balloon pres-
sure) for 40 min when the starting material was completely
consumed. The reaction mixture was filtered and the filtrate was

Y.-C. Hsieh et al. / Carbohydrate Research 344 (2009) 1020–1023
1023
concentrated. The crude product was dissolved in MeOH and
Acknowledgment
K2CO3 (0.74 g, 5.35 mmol) was added. The mixture was stirred at
room temperature for 24 h. Then AmberliteÒ IR-120 (H+) was
added to neutralize, and the mixture was filtered and concen-
trated. Purification by chromatography (EtOAc–MeOH 20:1) gave
9 (1.32 g, 87%) as a yellow solid. Mp 234 °C (decomp.); Rf 0.57
(EtOAc–MeOH 5:1); 1H NMR (300 MHz, CDCl3) d: 6.62 (s, 1H),
6.60 (s, 1H), 4.67 (dd, J = 4.2, 7.2 Hz, 2H), 4.41 (dd, J = 7.2, 5.4 Hz,
2H), 4.12–4.07 (m, 2H), 3.93–3.82 (m, 5H), 3.19–3.13 (m, 2H),
2.56 (t, J = 3.9 Hz, 3H), 1.45 (s, 6H), 1.26 (s, 6H); 13C NMR
(75 MHz, CDCl3) d: 170.3, 115.1, 83.7, 83.1, 81.3, 81.1, 40.2, 39.4,
27.2, 25.3; HRMS (ESI): calcd for C20H30N2O8 (M+), m/z 426.2002;
found m/z 426.2007.
This work was supported by the National Science Council of
Taiwan.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2009.03.008.
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1.9. Furanoid sugar-aza-crown (10)
To a solution of 9 (0.127 g, 0.30 mmol) in dry THF (35 mL) was
added LAH (68 mg, 6 equiv) at 0 °C. After stirring for 5 min, the
mixture was stirred at 70 °C under 300 W microwave irradiation
for 6 h. Then the mixture was filtered, concentrated, and extracted
with EtOAc. The solvent was removed and the crude was purified
by chromatography (EtOAc–MeOH 3:1) to give 10 (0.08 g, 67%)
as a yellow solid. Mp 143 °C; Rf 0.09 (EtOAc–MeOH 1:2); 1H NMR
(300 MHz, CDCl3) d: 4.75 (s, 1H), 4.49 (dd, J = 6.9, 4.5 Hz, 2H),
4.37 (dd, J = 6.9, 4.8 Hz, 2H), 4.02–3.97 (m, 3H), 2.88–2.77 (m,
5H), 2.66 (dd, J = 11.7, 7.5 Hz, 2H), 1.96–1.77 (m, 7H), 1.49 (s,
6H), 1.30 (s, 6H); 13C NMR (75 MHz, CDCl3) d: 114.9, 85.5, 84.7,
83.0, 82.5, 51.0, 47.2, 30.6, 27.3, 25.4; HRMS (FAB): calcd for
C20H35N2O6 (M+H), m/z 399.2495; found m/z 399.2499.