Facile synthesis of urea-and thiocarbamate-tethered glycosyl beta-amino acids

Article abstract of DOI:10.1039/c5ra10622b

We describe here an efficient way to synthesize series of new urea- and thiocarbamate-tethered glycosyl β-amino acids under mild conditions. These glycosyl β-amino acids are elaborately designed on the basis of natural N-linked glycosides. They have the same side chain length as natural N-glycosyl amino acid while the main chain is replaced with β-amino acid chain. The linkage is an isostere of natural N-linked bond but exhibits competitive stability to chemical and enzymatic hydrolysis. This facile route is benefit from the choice of the commercially available l-aspartic acid as starting material, which not only provides a β-amino acid moiety, but also the α-carboxy group could be transformed to active isocyanate conveniently and economically. The prospective glycosyl β-amino acids are obtained readily by the reaction of isocyanate with appropriately protected glycosylamines and glycosylthiols.

Full text of DOI:10.1039/c5ra10622b

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Facile synthesis of urea-and thiocarbamate-
tethered glycosyl beta-amino acids†
Cite this: RSC Adv., 2015, 5, 71868
ab
a
a
a
a
a
Hanbing Teng,* Zengwei Zhang, Yifan Zhou, Zhiyong Chen, Qi Chen, Yang Liu
and Wenjin Xu
a
We describe here an efficient way to synthesize series of new urea- and thiocarbamate-tethered glycosyl
b-amino acids under mild conditions. These glycosyl b-amino acids are elaborately designed on the basis of
natural N-linked glycosides. They have the same side chain length as natural N-glycosyl amino acid while
the main chain is replaced with b-amino acid chain. The linkage is an isostere of natural N-linked bond but
exhibits competitive stability to chemical and enzymatic hydrolysis. This facile route is benefit from the
choice of the commercially available L-aspartic acid as starting material, which not only provides a
b-amino acid moiety, but also the a-carboxy group could be transformed to active isocyanate
conveniently and economically. The prospective glycosyl b-amino acids are obtained readily by the
reaction of isocyanate with appropriately protected glycosylamines and glycosylthiols.
Received 4th June 2015
Accepted 17th August 2015
DOI: 10.1039/c5ra10622b
www.rsc.org/advances
a-amino acids, in which a-amino acid moiety could be directly
originated from the library of natural a-amino acid conve-
Introduction
7
–12
Glycopeptides have gained considerable synthetic attention due niently,
to their applications in diverse biochemical processes, such as involves the construction of a b-amino acid moiety, which
the synthesis of glycosyl b-amino acids always
15
1
cellular recognition, adhesion and signaling. To develop makes the synthetic route more complicated.
homogeneous, stable and readily accessible glycopeptides
L-aspartic acid is commercially available natural a-amino
analogues for biological studies and therapeutic applications, acid containing b-amino acid moiety. To the best of our
2
–6
particular attention have been paid to glycopeptide mimics,
in which natural O- and N-glycosidic linkages were replaced by synthesize glycosyl b-amino acid until recently. Herein, we show
knowledge, it has not been used as starting materials to
7
2,8
non-natural linkages, like carbon–carbon, carbon–sulfur,
a facile route to the design and synthesis of various kinds of
glycosyl b-amino acids by the use of L-aspartic acid as starting
9
10
9a,9d,11
12
urea, thiourea, carbamate
and N-heterocycle.
In the past decade, b-amino acids have become an inter- materials. The prominent advantage of the route is that it
esting synthetic target because the presence of a methylene signicantly avoids the additional construction of a b-amino
could provide higher conformational exibility compared to acid moiety at later steps.
a-amino analogues, which strongly affects the structural and
biological properties of b-peptides, such as secondary structure highly similar to natural N-linked glycosides in structure, could
The simplest way to prepare glycosyl b-amino acids, which is
13
and the rate of enzymatic degradation. Furthermore, b-amino directly form amide by the condensation reactions of the gly-
16
acid-containing peptides exhibit greater stability and higher cosylamines with a-carboxyl group of L-aspartic acid. The
14
biological activity than their parent a-peptides.
obtained glycosyl b-amino acids have a shorter side chain than
Currently, considerable research efforts have been devoted natural N-linked glycosides. Moreover, they display the same
to the design and synthesis of glycosyl b-amino acids, which drawback of the linkage as the natural N-linked glycosides,
9a,17
could be utilized into neoglycopeptide syntheses for the which is unstable to chemical and enzymatic hydrolysis.
formation of hybrid peptides or oligomers in a dened
As an interesting candidate for replacing the natural
15
sequence. Different from the prevalent synthesis of glycosyl N-glycosidic linkage, the urea linkage is capable of increasing
resistance to chemical and enzymatic degradation while main-
taining the characteristic properties of the natural
compounds. Furthermore, the urea motif is well known as its
a
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of
Technology, 122 Luoshi Road, Wuhan 430070, People's Republic of China. E-mail:
wdthb@163.com
18
strong hydrogen bonding capacity, which makes the neo-
19
b
glycopeptides more water soluble than natural glycopeptides.
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing,
Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, People's Republic We are aiming to synthesize urea-tethered glycosyl b-amino
of China
acids based on natural N-linked glycosyl amino acid building
blocks. The target compound II is shown in Scheme 1. From a
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c5ra10622b
1
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Scheme 4 The synthesis of urea-tethered glycosyl b-amino acids.
Table 1 List of the synthesis of urea-tethered glycosyl b-amino
Scheme 1 Natural N-linked glycosides and target urea-tethered and
thiocarbamate-tethered glycosyl b-amino acids.
a,b
acids
c
Entry
1
Glycosylamines
Time
Yield
Product
45 min
91
2
30 min
87
Scheme 2 Two routes to prepared the target urea-tethered glycosyl
b-amino acids.
3
4
1 h
90
88
structure aspect, it is very similar to the natural N-linked
1.5 h
glycosides I, regardless of the factor of the main chain. Only
the methylene (–CH –) unit is replaced by imino group (–NH–)
2
in the side chain. Namely, besides displacing the a-amino acid
chain with b-amino acid chain, we chose a more stable isostere-
urea linkage to replace the natural N-linked bond while main-
taining the same side chain length. These elaborately modied
glycosyl b-amino acids would be attractive building blocks to
replace the natural N-glycosyl amino acid in the design of
neoglycopeptide.
5
1.5 h
85
a
b
All the solvent were dichloromethane. All reactions were conducted
c
at room temperature. Isolated yield.
There are two synthetic routes to prepare the target urea-
tethered glycosyl b-amino acids (Scheme 2). Route A shows
obvious advantageous over Route B, since amine 2 is oen
synthesized by the active intermediate isocyanate 1. Further-
more, Route A avoids the preparation of various glycosyl isocy-
ꢀ1
absorption at 2141 cm in IR) by the mixed anhydride reacting
23
ꢁ
with NaN3. Heating acyl azide 6 in toluene at 85 C in situ
provided isocyanate 7 (strong absorption at 2249 cm in IR) in
ca. 71% yield from compound 5. The crude product was used
directly without purication for next transformation.
ꢀ1
3
20
anates R NCO, which could be extremely unstable.
The glycosylamines was prepared according to the literature
24,25
method.
All the glycosylamines were reacted with isocyanate
7
to provide the corresponding target urea-tethered glycosyl
Results and discussion
b-amino acids readily (Scheme 4, Table 1).
As outlined in Route A, our synthetic route mainly involves
converting the a-carboxyl group of L-aspartic acid to isocyanate
and binding the glycosylamines with isocyanate by urea. The
synthesis of isocyanate 7 is shown in Scheme 3, the a-amino of
L-aspartic acid was protected by Boc aer the b-carboxy group
We found that the glycosylthiols could also react with
isocyanate 7 to provide the corresponding thiocarbamate-
tethered glycosyl b-amino acids, a new class in the library of
glycosyl b-amino acid (Scheme 5, Table 2). The glycosylthiols
26
was prepared according to the reported method.
21,22
was esteried selectively.
The a-carboxy group of compound
The reaction of isocyanate 7 with acetylated 1-hydroxy glucose
or galactose afforded too much unexpected by-products. We
couldn't obtain carbamate-tethered glycosyl b-amino acids even
5
was then converted to corresponding acyl azide 6 (strong
9a
though adding NEt3 or DMAP. The a-carboxy group of
Scheme 3 The synthesis of b-amino acid bearing active isocyanate in Scheme 5 The synthesis of thiocarbamate-tethered glycosyl b-amino
the side chain.
acid.
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Table 2 List of the synthesis of thiocarbamate-tethered glycosyl b- glycosyl b-amino acids can be easily obtained in good yield,
a,b
amino acids
respectively, by isocyanate reacting with glycosylamines or gly-
c
cosylthiols. The rout is concise and no costly reagent is used.
These new glycosyl b-amino acids can be used as prospective
building blocks for the synthesis of neoglycopeptides.
Entry
1
Glycosylthiols
Time
2 h
Yield
92
Product
Experimental section
General remarks
2
3
2 h
89
86
All starting materials and solvents were obtained from commer-
cial suppliers and were used without further purication unless
1
13
otherwise stated. Reagents were used as purchased. H and
NMR spectra were recorded on a Bruker Avance 400 MHz
instrument, using Me
MS spectra were measured by MicrOTOF-Q III UltiMate 3000.
Infrared (IR) spectra were measured by Bruker VERTEX80v FTIR
vacuum spectrometer. Thin-layer chromatography (TLC) was
performed on precoated plates silica gel GF254 with detection by
UV light, Iodine or 0.2% ninhydrin in ethanol followed by heating.
C
2.5 h
2.5 h
4
Si as an internal standard (d ¼ 0 ppm). ESI-
4
83
a
b
All the solvent were dichloromethane. All reactions were conducted
c
at room temperature. Isolated yield.
General procedure for compound 7
Compound 7. Compound 5 (2.5 g, 10 mmol) was dissolved in
compound 5 can be easily converted to isocyanate 7 by two steps
ꢁ
dry THF (30 mL) and cooled to ꢀ15 C. Aer addition of EtO-
27
without used expensive reagent such as DPPA. The infrared (IR)
spectra of crude product acyl azide 6 showed that it oen con-
tained rearrangement compound 7. We have attempted to
characterize the active intermediate acyl azide 6 and isocyanate
COCl (1 mL, 11 mmol) and Et N (1.7 mL, 12 mmol), the mixture
3
was stirred for 20 min. A solution of NaN (1.6 g, 25 mmol) in
3
ꢁ
H O (5 mL) was added and stirred for 1 h at ꢀ10 C. The solution
2
2
was then diluted with H O and extracted with EtOAc (150 mL).
7
with Electrospray ionization mass spectrometry (ESI-MS), only
the signal peak of acyl azide 6 was observed at m/z ¼ 295.1010
M + Na], no signal of isocyanate 7 was detected. The reaction of
The organic layers were washed with brine (2 ꢂ 10 mL), dried
over Na SO and concentrated under reduced pressure to give
2
4
[
crude acyl azide 6. The crude acyl azide 6 was dissolved in
isocyanate 7 with the glycosylamines showed faster reaction rate
than that of 7 with glycosylthiols. In these cases, the mono-
saccharides react faster than the corresponding disaccharides.
The representative compound 9a was choosed to research the
epimerization at C-1 position. The crude reaction mixture was
ꢁ
toluene (35 mL) and heated to 85 C under stirring for 3 h. The
toluene was removed under reduced pressure to afford isocya-
nate 7 as clear oil 1.73 g (yield ca. 71%). This isocyanate 7 was
directly used in the next step without further purication.
1
detected directly by HNMR aer removing solvent in vacuum
1
The synthesis of compound 9a was described as a
representative example
when the reaction was completed. In order to get a clear HNMR
of crude reaction mixture, the isocyanate was elaborately prepared
and it was excessive to avoid the interference from the glucosyl- To a solution of compound 7 (0.24 g, 1 mmol) in dry CH
amine 8a. The result showed that no epimerized product was (8 mL), 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosylamine (0.35 g,
found. The product 9a was b-anomer (d ¼ 5.19, J
¼ 9.2) and its 1 mmol) was added. The mixture was stirred at room tempera-
Cl
2
2
H1,2
conguration was the same as the raw material glucosylamine 8a. ture for 45 min until the disappearance of the starting material
from the TLC plate (CH Cl –EtOAc, 1 : 1), and the solvents were
evaporated. The residue was puried by silica gel column chro-
matography (CH Cl –EtOAc, 1 : 1) to get the desired compound.
2
2
Conclusions
2
2
We have described a facile method for the preparation of series
of new urea- and thiocarbamate-tethered glycosyl b-amino acids
Spectroscopic data for compound 9a
based on natural N-linked glycosides under mild conditions. Column chromatography: 1 : 1 CH
2
Cl
2
–EtOAc; white solid;
ꢀ
1
These glycosyl b-amino acids display very distinctive structural yield: 91%. IR: n (cm ) 3354 (br), 2968 (br), 1740, 1545, 1508,
ꢀ
1 1
3
features. The natural-N-linkage-based isostere is more stable to 1369, 1221, 1032 cm . HNMR (400 MHz, CDCl ): d (ppm) 6.43
chemical and enzymatic hydrolysis while the side chain length (br, 1H, NHCONH), 6.20 (br, 1H, NHCONH), 5.92 (br, 1H,
is the same as natural N-linked glycoside residues. The advan- NHCOO), 5.45 (br, 1H, NHCHNH), 5.30 (t, J ¼ 9.6 Hz, 1H, H-3),
tage of our method is the employment of commercially avail- 5.19 (t, J ¼ 9.2 Hz, 1H, H-1), 5.05 (t, J ¼ 9.6 Hz, 1H, H-4), 4.91
able L-aspartic acid as starting material, which can provide a (t, J ¼ 9.6 Hz, 1H, H-2), 4.29 (dd, J ¼ 12.4, 4.0 Hz, 1H, H-6a), 4.07
b-amino acid moiety, and the a-carboxy group of which can be (d, J ¼ 12.4 Hz, 1H, H-6b), 3.86 (d, J ¼ 8.4 Hz, 1H, H-5), 3.67
transformed to the active isocyanate conveniently and (s, 3H, COOCH
3
), 2.89 (br, 2H, COCH
2
), 2.18–1.98 (m, 12H, 4 ꢂ
1
3
economically. The desired urea- and thiocarbamate-tethered COCH ), 1.40 (s, 9H, C(CH
3
3
)
3
). C NMR (100 MHz, CDCl ):
3
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ꢀ1 1
d (ppm) 171.41, 170.70, 170.61, 170.00, 169.64, 155.88, 154.92, 1229, 1040 cm . H NMR (400 MHz, CDCl
3
): d (ppm) 6.27 (br,
8
3
0.14, 79.70, 73.22, 73.09, 70.59, 68.28, 61.88, 55.90, 51.99, 1H, NHCONH), 6.05–5.87 (m, 2H, NHCONH, NHCOO), 5.47 (br,
0
9.18, 28.27, 20.67, 20.63, 20.55 ppm. ESI-Q-TOF MS (m/z): calcd 1H, NHCHNH), 5.36 (br, 1H, H-1 ), 5.28 (t, J ¼ 9.2 Hz, 1H, H-1),
+
0
0
for C H N O Na: 614.2168 ([M + Na] ), found: 614.2536.
5.14–5.08 (m, 2H, H-2 , H-3), 4.95 (dd, J ¼ 10.4, 2.8 Hz, 1H, H-4 ),
2
4
37 3 14
0
4
1
.84 (t, J ¼ 9.2 Hz, 1H, H-2), 4.49 (d, J ¼ 7.6, 1H, H-3 ), 4.45 (d, J ¼
0
2 Hz, 1H, H-4), 4.16–4.05 (m, 3H, H-6a,b, H-6 a), 3.90 (t, J ¼ 6.8
Spectroscopic data for compound 9b
0
0
Hz, 1H, H-6 b), 3.81–3.73 (m, 2H, H-5, H-5 ), 3.69–3.70 (m, 3H,
An equivalent mole triethylamine was used in the reaction.
Column chromatography: 1 : 1 CH Cl –EtOAc; white solid; yield:
OCH
COCH
d (ppm) 171.35, 170.91, 170.48, 170.37, 170.21, 170.13, 169.51,
3
), 2.89–2.89 (br, 2H, CH
2
CO), 2.16–1.96 (m, 21H, 7 ꢂ
2
2
13
3 3 3 3
), 1.43 (s, 9H, C(CH ) ). C NMR (100 MHz, CDCl ):
ꢀ
1
87%. IR: n (cm ) 3358 (br), 2922 (br), 1734, 1551, 1369, 1229, 1036
ꢀ
1 1
cm . H NMR (400 MHz, CDCl
3
): d (ppm) 6.10 (d, J ¼ 3.6 Hz, 1H,
1
7
2
69.05, 155.69, 154.95, 100.93, 80.15, 79.72, 76.06, 74.13, 72.96,
1.03, 70.91, 70.60, 69.01, 66.62, 62.15, 60.76, 55.92, 51.96, 39.22,
NHCOO), 5.68–5.63 (m, 3H, NHCONH, H-1), 5.28–5.11 (m, 3H,
NHCHNH, H-3, H-4), 4.20 (td, J ¼ 7.2, J ¼ 4 Hz, 1H, H-2), 4.18 (dd,
J ¼ 12.4, J ¼ 4 Hz, 1H, H-6a), 4.01–3.93 (m, 2H, H-5, H-6b), 3.64
8.30, 20.87, 20.78, 20.67, 20.64, 20.59, 20.5. ESI-Q-TOF MS (m/z):
+
calcd for C36
H
53
N
3
O
22Na: 902.3013 ([M + Na] ), found: 902.3423.
(
1
s, 3H, COOCH ), 2.76 (t, J ¼ 4.8 Hz, 2H, COCH ), 2.14–1.97 (m,
3
2
1
3
2H, 4 ꢂ COCH ), 1.34 (s, 9H C(CH ) ). C NMR (100 MHz,
3
3 3
Spectroscopic data for compound 11a
CDCl ): d (ppm) 171.35, 171.12, 170.77, 169.21, 168.86, 156.21,
3
Column chromatography: 1 : 2 petroleum ether–EtOAc; white
1
55.35, 91.15, 80.41, 71.56, 69.65, 67.78, 61.70, 55.99, 52.08, 51.57,
ꢀ1
solid; yield: 92%. IR: n (cm ) 3333 (br), 2966 (br), 1740, 1695,
39.29, 28.24, 21.04, 20.73, 20.70, 20.59. ESI-Q-TOF MS (m/z): calcd
ꢀ
1 1
+
1
495, 1369, 1042 cm . H NMR (400 MHz, CDCl
3
): d (ppm) 6.77
for C24
37 3
H N O
14Na: 614.2168 ([M + Na] ), found: 614.2464.
(
br, 1H, SCONH), 5.68 (br, 2H, OCONH, CH(NH) ), 5.29–5.25 (m,
2
2
1
H, H-1, H-3), 5.16–5.11 (m, 2H, H-2, H-4), 4.31 (d, J ¼ 12.4 Hz,
H, H-6a), 4.11 (d, J ¼ 12.8 Hz, 1H, H-6b), 3.83 (d, J ¼ 9.6 Hz, 1H,
Spectroscopic data for compound 9c
Column chromatography: 1 : 1 CH Cl
0%. IR: n (cm ) 3356 (br), 2976 (br), 1740, 1542, 1367, 1223,
2
2
–EtOAc; white solid; yield:
H-5), 3.73 (s, 3H, COOCH ), 2.90 (br, 2H, COCH ), 2.09, 2.03, 2.01
3
2
ꢀ
1
9
1
13
(
3s, 12H, 4 ꢂ COCH
3
3 3
), 1.44 (s, 9H, C(CH ) ). C NMR (100 MHz,
ꢀ
1 1
043 cm . H NMR (400 MHz, CDCl
Hz, 1H, NHCONH), 5.80–5.74 (m, 2H, NHCONH, NHCOO), 5.36–
3
): d (ppm) 6.13 (d, J ¼ 8.0
3
CDCl ): d (ppm) 171.18, 170.69, 170.02, 169.44, 169.40, 162.89,
8
2
2.04, 80.68, 76.21, 73.92, 69.02, 67.84, 61.66, 56.26, 52.18, 38.65,
8.26, 20.72, 20.62, 20.57. ESI-Q-TOF MS (m/z): calcd for C24
5
4
.37 (m, 2H, NHCHNH, H-3), 5.02–5.09 (m, 3H, H-1, H-2, H-4),
.08–4.03 (m, 2H, H-6a,b), 4.01–3.97 (m, 1H, H-5), 3.63 (s, 3H,
-
+
36 2
H N O14SNa: 631.1779 ([M + Na] ), found: 631.1746.
COOCH ), 2.85 (br, 2H, COCH ), 2.08–1.92 (m, 12H, 4 ꢂ COCH ),
3
2
3
1
3
1
1
7
2
.37 (s, 9H, C(CH
)
3 3
). C NMR (100 MHz, CDCl
3
): d (ppm)
Spectroscopic data for compound 11b
Column chromatography: 1 : 2 petroleum ether–EtOAc; white
solid; yield: 89%. IR: n (cm ) 3333 (br), 2957 (br), 1736, 1695,
1499, 1367, 1221, 1045 cm . H NMR (400 MHz, CDCl ): d (ppm)
3
71.37, 170.99, 170.44, 170.13, 169.89, 155.61, 154.95, 80.26,
1.90, 71.17, 68.28, 67.26, 61.11, 60.42, 56.02, 51.98, 39.09, 28.30,
ꢀ1
0.75, 20.67, 20.59, 20.55. ESI-Q-TOF MS (m/z): calcd for
ꢀ
1 1
+
C
24
H
37
N
3
O
14Na: 614.2168 ([M + Na] ), found: 614.2527.
7
.19 (br, 1H, SCONH), 5.95–5.93 (m, 1H, NHCOO), 5.66 (br, 1H,
CH(NH) ), 5.47 (br, 1H, H-1), 5.30 (br, 2H, H-3, H-2), 5.16 (br, 1H,
2
Spectroscopic data for compound 9d
Column chromatography: 1 : 1 CH Cl
8%. IR: n (cm ) 3362 (br), 2966 (br), 1738, 1510, 1367, 1225,
H-4), 4.15–4.13 (m, 3H, H-5, H-6), 3.72 (s, 3H, COOCH
H, CH ), 1.44 (s, 9H,
CO), 2.16, 2.05, 1.99 (3s, 12H, 4 ꢂ COCH
C(CH ): d (ppm) 171.14, 170.36,
70.18, 169.86, 169.64, 163.16, 154.42, 82.26, 80.42, 74.73, 71.83,
3
), 2.92 (br,
2
2
–EtOAc; white solid; yield:
2
2
3
ꢀ
1
1
3
8
1
3 3 3
) ). C NMR (100 MHz, CDCl
ꢀ
1 1
3
034 cm . H NMR (400 MHz, CDCl ): d (ppm) 6.30 (br, 1H,
1
6
2
NHCONH), 6.04–5.88 (m, 2H, NHCONH, NHCOO), 5.39 (br, 1H,
7.26, 66.53, 61.18, 56.47, 52.03, 38.69, 28.20, 20.64, 20.57, 20.55,
0
0
NHCHNH), 5.38–5.33 (m, 3H, H-1, H-1 , H-3 ), 5.19 (t, J ¼ 9.2 Hz,
0.48. ESI-Q-TOF MS (m/z): calcd for C H N O SNa: 631.1779
2
4
36 2 14
+
H-3), 5.06 (td, J ¼ 2.0, 10.0 Hz, 1H, H-2), 4.87 (ddd, J ¼ 2.0, 5.6,
([M + Na] ), found: 631.1756.
0
0
1
4.4 Hz, 1H, H-2 ), 4.77 (t, J ¼ 9.2 Hz, 1H, H-4 ), 4.44 (d, J ¼ 12.4
0
Hz, 1H, H-4), 4.23 (m, 2H, H-6a, H-6 a), 4.06–3.93 (m, 3H, H-6b,
Spectroscopic data for compound 11c
Column chromatography: 1 : 1 CH Cl –EtOAc; white solid;
0
H-5), 3.84–3.81 (m, 1H, H-5 ), 3.69 (d, J ¼ 2.8 Hz, 3H, COOCH
3
),
), 1.42 (s,
): d (ppm) 171.36,
2
2
2
9
1
1
6
2
.89 (br, 2H, CH
2
CO), 2.13–2.00 (m, 21H, 7 ꢂ COCH
3
ꢀ
1
yield: 86%. IR: n (cm ) 3339 (br), 2968 (br), 1740, 1501, 1369,
219, 1034 cm . H NMR (400 MHz, CDCl ): d (ppm) 6.95 (br,
3
H, SCONH), 5.78 (br, 1H, NHCOO), 5.65 (br, 1H, CH(NH)
1
3
H, C(CH
)
3 3
). C NMR (100 MHz, CDCl
3
ꢀ
1 1
1
1
(
1
2
4
70.77, 170.65, 170.58, 170.55, 169.86, 169.84, 169.49, 155.77,
54.97, 95.58, 80.21, 79.40, 75.59, 73.50, 72.80, 71.34, 69.98,
9.32, 68.45, 67.97, 62.98, 61.43, 55.94, 51.98, 39.17, 28.33, 28.28,
2
), 5.40
0
br, 1H, H-1 ), 5.34 (d, J ¼ 9.6 Hz, 1H, H-1), 5.29 (d, J ¼ 12.0 Hz,
0
H, H-3 ), 5.06 (t, J ¼ 9.6 Hz, 1H, H-3), 4.98 (t, J ¼ 9.6 Hz, 1H, H-
0.87, 20.82, 20.66, 20.60, 20.57. ESI-Q-TOF MS (m/z): calcd for
0
0
), 4.86 (d, J ¼ 10.8 Hz, 1H, H-2 ), 4.46 (d, J ¼ 12.4 Hz, 1H, H-4 ),
+
C
36 53 3
H N O
22Na: 902.3013 ([M + Na] ), found: 902.3429.
0
.26–4.23 (m, 2H, H-6a, H-6 a), 4.12 (dd, J ¼ 6.4, 13.6 Hz, 1H,
0
H-4), 4.05–4.02 (m, 2H, H-6b, H-6 b), 3.94 (d, J ¼ 9.6 Hz, 1H, H-
Spectroscopic data for compound 9e
Column chromatography: 1 : 1 CH Cl
5%. IR: n (cm ) 3333 (br), 2972 (br), 1738, 1691, 1504, 1366, C(CH
0
5
), 3.82 (d, J ¼ 8.4 Hz, 1H, H-5), 3.72 (s, 3H, COOCH ), 2.91
3
2
2
–EtOAc; white solid; yield: (br, 2H, CH
2
CO), 2.16–2.00 (m, 21H, 7 ꢂ COCH
3
), 1.44 (s, 9H,
): d (ppm) 171.14, 171.02,
ꢀ
1
13
8
3
)
3
). C NMR (100 MHz, CDCl
3
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1
9
6
2
70.57, 170.51, 169.92, 169.84, 169.65, 169.45, 162.84, 154.37,
5.64, 81.56, 80.57, 76.39, 76.18, 72.57, 70.01, 69.30, 68.50,
7.97, 62.76, 61.46, 60.36, 56.39, 52.10, 38.63, 28.22, 20.99,
0.82, 20.78, 20.63, 20.54. ESI-Q-TOF MS (m/z): calcd for C -
S. Pacico, A. Marra and A. Dondoni, Tetrahedron Lett.,
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5009–5012; (b) V. V. Sureshbabu and Basavaprabhu, Synlett,
3
6
+
H
52 2
N O22SNa: 919.2624 ([M + Na] ), found: 919.2585.
2011, 1160–1164; (c) Y. Ichikawa, T. Minami, S. Kusaba and
Spectroscopic data for compound 11d
Column chromatography: 1 : 1 CH Cl
yield: 83%. IR: n (cm ) 3337 (br), 2978 (br), 1740, 1501, 1369,
N. Saeki, Org. Biomol. Chem., 2014, 12, 3924–3931; (d)
Y. Ichikawa, S. Kusaba, T. Minami and Y. Tomita, Synlett,
2011, 1462–1466.
2
2
–EtOAc; white solid;
ꢀ
1
1
10 (a) R. F. Barghash, A. Massi and A. Dondoni, Org. Biomol.
Chem., 2009, 7, 3319–3330; (b) V. V. Sureshbabu,
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2010, 715–720.
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K. U. Gunther and T. Ziegler, Synthesis, 2014, 2362–2370;
1
219, 1043. H NMR (400 MHz, CDCl
3
): d (ppm) 6.64 (br, 1H,
), 5.28 (d, J ¼ 2.7 Hz,
H, H-3 ), 5.20–5.12 (m, 2H, H1, H-1 ), 5.06–4.95 (m, 2H, H-3,
SCONH), 5.58 (br, 2H, NHCOO, CH(NH)
1
2
0
0
0
0
H-2 ), 4.87 (dd, J ¼ 10.4, 3.2 Hz, 1H, H-4 ), 4.41–4.38 (m, 2H,
0
0
H-2, H-4 ), 4.09–3.99 (m, 4H, H-6 a,b, H-6a,b), 3.82–3.75 (m, 2H,
0
H-5, H-5 ), 3.66 (s, 3H, COOCH
3
), 2.83 (br, 2H, CH
2
CO), 2.08–
1
3
1
.90 (m, 21H, 7 ꢂ COCH
3 3 3
), 1.36 (s, 9H, C(CH ) ). C NMR
(100 MHz, CDCl ): d (ppm) 171.17, 170.39, 170.38, 170.17,
3
(
c) W. Tang and M. L. Becker, Chem. Soc. Rev., 2014, 43,
013–7039.
3 V. D. Pinho, B. Gutmann and C. O. Kappe, RSC Adv., 2014, 4,
7419–37422.
14 F. Kudo, A. Miyanagaa and T. Eguchi, Nat. Prod. Rep., 2014,
1, 1056–1073.
1
8
6
2
70.08, 169.68, 169.57, 169.01, 162.88, 154.33, 100.94, 81.85,
0.64, 75.69, 73.65, 71.01, 70.72, 69.36, 69.00, 66.64, 61.96,
0.88, 60.40, 56.27, 52.15, 38.61, 28.25, 21.05, 20.99, 20.87,
0.76, 20.64, 20.61, 20.51. ESI-Q-TOF MS (m/z): calcd for C -
7
1
3
3
6
+
H N O SNa: 919.2624 ([M + Na] ), found: 919.2681.
5
2 2 22
3
1
5 (a) M. Andreini, C. Taillefumier, B. Fernette and Y. Chapleur,
Lett. Org. Chem., 2008, 5, 360–364; (b) Y. Inaba, S. Yano and
Y. Mikata, Bull. Chem. Soc. Jpn., 2008, 81, 606–616; (c)
M. Andreini, A. S. Felten, H. T. T. Thien, C. Taillefumier,
N. Pellegrini-Moise and Y. Chapleur, Tetrahedron Lett.,
Acknowledgements
We are grateful for nancially supported by self-determined and
innovative research funds of WUT (No. 2014-IV-098; No.
145220004) and National Training Programs of Innovation and
2
012, 53, 2702–2705; (d) A. S. Felten, N. Pellegrini-Moise,
K. Selmeczi, B. Henry and Y. Chapleur, Eur. J. Org. Chem.,
013, 5645–5654.
Entrepreneurship for Undergraduates (No. 20141049720003).
2
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71872 | RSC Adv., 2015, 5, 71868–71872
This journal is © The Royal Society of Chemistry 2015