Efficient Synthesis of Glycosylated Matijin-Su Derivatives via Ultrasonic Irradiation

Article abstract of DOI:10.1002/cjoc.201600468

Matijin-Su (1) is a phenylalanine dipeptide compound with anti-hepatitis B virus (HBV) activity. Previous reports suggest that the synthesis of glycosylated Matijin-Su derivatives needs at least 10 steps. To simplify the synthetic procedure, we have developed a shorter and more efficient method for the preparation via ultrasound irradiation. Two galactopyranosylated (2) and two glucopyranosylated (3) derivatives were synthesized in 6 or 7 steps. The overall yields for the total synthesis of galactopyranosylated derivatives were markedly increased to 39% (2a) or 22% (2b). And the yields for glucopyranosylated derivatives also reached 29% (3a) or 16% (3b).

Full text of DOI:10.1002/cjoc.201600468

FULL PAPER
DOI: 10.1002/cjoc.201600468
Efficient Synthesis of Glycosylated Matijin-Su Derivatives via
Ultrasonic Irradiation
Guangping Liang,a Zhanxing Hu,b Jie Yuan,b Guangyi Liang,*,b and Bixue Xu*,b
a College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
b Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences,
Guiyang, Guizhou 550002, China
Matijin-Su (1) is a phenylalanine dipeptide compound with anti-hepatitis B virus (HBV) activity. Previous re-
ports suggest that the synthesis of glycosylated Matijin-Su derivatives needs at least 10 steps. To simplify the syn-
thetic procedure, we have developed a shorter and more efficient method for the preparation via ultrasound irradia-
tion. Two galactopyranosylated (2) and two glucopyranosylated (3) derivatives were synthesized in 6 or 7 steps. The
overall yields for the total synthesis of galactopyranosylated derivatives were markedly increased to 39% (2a) or
22% (2b). And the yields for glucopyranosylated derivatives also reached 29% (3a) or 16% (3b).
Keywords Matijin-Su, dipeptide, glycosylation, ultrasonic irradiation
Introduction
the literature.[8] And it was difficult to be synthesized
via the traditional classical methods, such as Koenigs-
Knorr-Methode or thioglycosides as glycosyl donors, by
using desacetyl Matijin-Su as the starting material.
These glycosylated derivatives could only be prepared
by using L-phenylalanol (4) as the starting material
(Scheme 1). The synthesis needs 10－11 steps and in-
volves several protection and deprotection steps which
increase the cost and the time to synthesize them. And
the overall yields of synthesis of target compounds 2a－
2b and 13a－13c were only 5.4%－7.3%, which affect
the study of activities for glycosylated Matijin-Su de-
rivatives.
Herein, we report a more effective method for syn-
thesis of glycosylated derivatives 2 and 3. Scheme 2
shows the synthetic route for compounds 2 and 3. This
approach was based on the ultrasound-promoted glyco-
sylation reaction as a key step. All target compounds
could be prepared using L-phenylalanine (14a) or
L-tyrosine (14b) as starting material. After the amino
group was benzoylated with benzoyl chloride in 2 mol/L
KOH to give compounds 11a－11b, the hydroxyl group
of compound 11b was protected with Ac2O in pyridine
to afford 15. Then, compound 11a or 15 reacted with
L-phenylalanol in the presence of isobutyl chlorofor-
mate (IBCF) and N-methylmorpholine (NMM) to give
intermediates 16a and 16b. Glycosylation of intermedi-
ates 16 with tetra-O-acetyl-D-galactopyranosyl bromide
(19a) or tetra-O-acetyl-D-glucopyranosyl bromide (19b)
was achieved in the presence of silver trifluoromethane
sulfonate (AgOTf) under ultrasonic irradiation in dark
Matijin-Su (N-(N-benzoyl-L-phenylalanyl)-O-
acetyl-L-phenylalanol, Figure 1), a dipeptide derivative
with anti-HBV activity, was isolated from Dichondra
repens Forst.[1] The anti-HBV activity of Matijin-Su and
its dipeptide derivatives had been reported in our previ-
ous studies.[2] In addition, one compound was also de-
veloped into a new drug for treatment of Hepatitis B and
entered phase II clinical trial in China.[3]
OH
R'
O
O
HO
O
NH
OH
H
NH
H
N
O
O
N
O
O
O
R
2a: R = H, R' = axial-OH
2b: R = OH, R' = axial-OH
3a: R = H, R' = equatorial-OH
3b: R = OH, R' = equatorial-OH
Matijin-Su (1)
Figure 1 The structures of Matijin-Su and its glycosylated
derivatives 2 and 3.
To date, Matijin-Su derivatives, including heterocy-
clic derivatives,[4] isosteres,[5] nitric oxide-releasing de-
rivatives[6] and general derivatives[7] have been obtained.
For glycosylated Matijin-Su derivatives, only several
galactopyranosylated derivatives have been described in
*
E-mail: bixue_xu@126.com, guangyi_liang@126.com; Tel.: 0086-0851-83807713; Fax: 0086-0851-83807713
Received July 25, 2016; accepted September 20, 2016; published online November 14, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600468 or from the author.
Chin. J. Chem. 2016, 34, 1353—1359
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Scheme 1 Synthetic procedure for galactopyranosylated Matijin-Su derivatives reported by literature
O
OAc
O
OAc
O
O
O
AcO
AcO
HO
AcO
AcO
HO
OAc
O
NH2
NPhth
OAc
OAc
6
NPhth
TEA
Et2O-BF3, DCM
0 oC to r.t.
4
5
95%
7
O
62%
R2 COOH
OCH3
9a/9b +
(i) N2H4-H2O
NH2HCl
(ii) (Boc)2O, TEA
(iii) Ac2O, Pyr.
(iv) TFA, DCM
R
9a: R = H
(i) IBCF-NMM
0 oC to r.t.
9b: R = OH
n-C4H9Br or
9b
K2CO3, DMF
(ii) NaOH, DMF
OAc
n
-C H13Br
6
AcO
AcO
O
O
O
O
(i) IBCF-NMM
0 oC to r.t.
OAc
NH2
+
OH
O
OCH3
NH2HCl
HN
R1
(ii) NaOH, DMF
R'
R2
10a - 10b
8
11a - 11e
26%
(four steps)
52% - 61%
(two steps or three steps)
IBCF-NMM
0 oC to r.t.
OH
O
OAc
OH
HO
AcO
AcO
O
O
O
NH
NH
MeONa
MeOH
OH
OAc
O
O
O
O
NH
R1
NH
R1
R2
2a: R1 = H, R2 = phenyl, 78% (two steps);
R2
12a - 12e
2b: R1 = OH, R2 = phenyl, 69% (two steps);
13a: R1 =OH, R2 = 2-furyl, 64% (two steps);
13b: R1 = n-OC6H13, R2 = phenyl, 68% (two steps);
13c: R1 = n-OC4H9, R2 = 4-Chlorophenyl, 65% (two steps)
But, the yield also decreased when the frequency
reached 4.0×104 Hz by using different promoters (Ta-
ble 1, Entries 3, 7 and 11). And the yield of some reac-
tions was decreased by more than 15%, such as the
glycosylation by using Ag2CO3 as promoter at 2.5×104
Hz and 4.0×104 Hz (Table 1, Entries 2 and 3). It means
that a higher frequency might reduce the stability of the
sugar donor. In addition, compared with the use of
Ag2CO3 or Ag2O as promoter in other equal conditions,
AgOTf has better yield and shorter reaction time.
After that, the relation between yield and accep-
tor/donor ratio under the frequency 2.5×104 Hz and
using AgOTf as promoter was also studied (Table 2).
The reaction time for glycosylation of 16a and 19a was
shortened by increase of acceptor/donor ratio. In the
initial experiment, acceptor 16a was allowed to react
with donor 19a (1.0 equiv.) in CH2Cl2 for 15 min lead-
room to provide the key intermediates 20 and 21. After
that, the acetyl groups were deprotected with MeONa in
MeOH to provide glycosylated target derivatives 2 and
3.
Results and Discussion
As shown in Scheme 2, compared with the previous
synthetic route, four glycosylated Matijin-Su derivatives
2 and 3 were synthesized in higher yields and fewer
steps. Subsequently, the potential factors affecting the
ultrasound-promoted glycosylation reaction of 16a and
19a, such as ultrasonic frequency and promoters, were
discussed.
We found that the glycosylation reaction was per-
formed under ultrasonic irradiation (Table 1). With the
frequency increasing, the reaction time was shortened.
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Chin. J. Chem. 2016, 34, 1353—1359

Efficient Synthesis of Glycosylated Matijin-Su Derivatives via Ultrasonic Irradiation
Scheme 2 Synthetic route for glycosylated Matijin-Su derivatives via ultrasonic irradiation
Table 1 The influence of different ultrasonic wave and promoters for glycosylation of 16a and 19aa
Entry
Frequencyb/Hz
1.6×104
Timed
17 min
13 min
9 min
Promoter
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOTf
Yield/%
74e
Entry
7
Frequencyb/Hz
4.0×104
－
Timed
7 min
45 h
Promoter
AgOTf
AgOTf
Ag2O
Yield/%
58
1
2
3
4
5
6
2.5×104
4.0×104
81
8
－
62
9
1.6×104
2.5×104
4.0×104
－
15 min
11 min
10 min
46 h
71
c
f
－
1.6×104
2.5×104
48 h
－
10
11
12
Ag2O
79%
64
14 min
10 min
77
86
Ag2O
AgOTf
Ag2O
－
a Reagents and conditions: acceptor (20 mg), donor (31 mg, 1.5 equiv.), anhydrous CH2Cl2, 4 Å molecular sieves (50 mg), promoter (Ta-
ble 1, 1.2 equiv. for donor), argon atmosphere, room temperature. b The frequency of ultrasonic wave in the chemical reaction. c General
chemical reaction without ultrasonic wave. d Time for acceptor to be completely consumed by TLC. e Purification by silica gel column
chromatography. f Traces observed by TLC.
Chin. J. Chem. 2016, 34, 1353—1359
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Liang et al.
FULL PAPER
ing to poor yield of 21a (54% yield) (Table 2, Entry 1).
Gratifyingly, the use of 2 equiv. 19a as the donor led to
the best yield of 21a (88% yield) (Table 2, Entries 4).
However, when the reaction was carried out with three
times 19a, the yield of target compound was lower than
that of 2 equiv. (Table 2, Entries 4 and 5). This result
may have been caused by instantaneous excess bromine
ion from the process of formation of carbocation and the
donor 19a was degraded by ultrasonic in the reaction
system with AgOTf (1.2 equiv. for acceptor).
From the results shown in Tables 1－3, the optimal
conditions for ultrasound-promoted glycosylation reac-
tion could be defined as acceptor 16a, glycosyl donor
19a (1.5 equiv.), anhydrous CH2Cl2, 4 Å molecular
sieves (twice the mass of the acceptor), AgOTf (1.2
equiv.), argon atmosphere, room temperature and ultra-
sonic frequency (2.5×104 Hz). Then, target compounds
2b, 3a and 3b were also synthesized under the optimal
conditions. In comparison with the reported method
(Scheme 1), the new synthetic route of galactopyra-
nosylated compounds can be reduced to six steps (2a) or
seven steps (2b) by using ultrasound irradiation to per-
form glycosylation introduced in this paper and the
overall yields were also increased to 39% (2a) or 22%
(2b). Furthermore, the total yields of glucopyranosy-
lated target compounds 3 also reached 29% (3a) or 16%
(3b).
In addition, as described in Scheme 3, the glycosyla-
tion of 16a with 22 in the presence of trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) and N-iodosuccini-
mide (NIS) under ultrasonic irradiationor using 18 as
adonor in the presence of BF3•Et2O under ultrasonic
irradiation according to the equivalent of substrates
from references[9] was also explored. Using thioglyco-
sides 22 as glycosyl donor, the target intermediates 20a
and 21a could be obtained except that the yield (30%
for 20a, 35% for 21a) was lower than those using com-
pound 19 as a donor (86% for 20a, 83% for 21a) in
CH2Cl2. But, the target compound was not formed by
using the same donor in the presence of TMSOTf-NIS
without ultrasonic. As for 18a or 18b employed as
adonor, the reactions did not proceed in the presence of
BF3•Et2O under ultrasonic irradiation for 40 min, and
the acceptor 16a was untouched (TLC analysis). We
firstly guessed that this result may have been caused by
BF3•Et2O volatilization (room temperature) in ultrasonic
and its too few equivalent according to the literature.
Therefore, excess BF3•Et2O has been used for this reac-
tion in subsequent experiments. But, the target com-
pounds were still not formed. And they were not
achieved under BF3•Et2O in the presence of CH2Cl2
without ultrasonic, either. Thus, we thought that
BF3•Et2O did not make the donor 18a or 18b form car-
bocation, it just formed a coordination bond with this
donor. These results could be attributed to the type of
glycosyl donor and the rate of molecular motion.
Table 2 The influence of acceptor/donor molar ratio for glyco-
sylation of 16a and 19aa
Entry Acceptor/donormol ratio Timeb/min
Yield/%
54
1
2
3
4
5
1∶1.0
1∶1.2
1∶1.5
1∶2.0
1∶3.0
15
16
11
9
66
85
88
8
81
a
Reagents and conditions: acceptor (10 mg), donor (Table 2),
anhydrous CH2Cl2, 4 Å molecular sieves (30 mg), AgOTf (8 mg,
1.2 equiv. for acceptor), argon atmosphere, room temperature and
2.5×104 Hz. b Time for acceptor to be completely consumed by
TLC.
According to the results, we also envisaged that the
quantity of promoter can also affect the rate and amount
of the formation process of carbocation. A preliminary
set of experiments employing different equivalent of
AgOTf as promoter with 16a and 19a at 2.5×104 Hz
confirmed the validity of our hypothesis, as the corre-
sponding 21a derived from 19a was obtained in variable
yields depending on the amount of promoter (Table 3).
Acceptor 16a was allowed to react with donor 19a in
CH2Cl2 and promoter AgOTf (0.5 equiv.) for 21 min
leading to poor yield of 21a (57% yield) (Table 3, Entry
1). Fortunately, the use of AgOTf (1.2 equiv. for accep-
tor) led to the best yield of 21a (83% yield) (Table 3,
Entry 3). Moreover, when the reaction was carried out
with the promoter of 1.5 or 2.0 equiv., the yield of target
compound 21a was lower than that of 1.2 equiv. (Table
3, Entry 3－5).
Table 3 The influence of acceptor/promoter molratio for gly-
cosylation of 16a and 19aa
Entry
Acceptor/promotermolratio Timeb/min Yield/%
Conclusions
1
2
3
4
5
1∶0.5
1∶1.0
1∶1.2
1∶1.5
1∶2.0
21
14
12
12
9
57
78
83
74
70
In summary, an efficient procedure for synthesis of
glycosylated Matijin-Su derivatives with substituted
L-phenylalanine and D-glucose or D-galactose under
ultrasonic irradiation is presented in detail. And the
condition of ultrasonic reaction was also optimized. The
present work is superior to the previously reported
methods[8] as follows: (i) mild reaction conditions, (ii)
higher yields, (iii) simpler experimental procedure. Ad-
ditionally, the glycosylation can be scaled up to 100 mg
a Reagents and conditions: acceptor (10 mg), donor (31 mg, 1.5
equiv.), anhydrous CH2Cl2, 4 Å molecular sieves (30 mg), AgOTf
(Table 3), argon atmosphere, room temperature and 2.5×104 Hz.
b Time for acceptor was completely consumed by TLC.
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Efficient Synthesis of Glycosylated Matijin-Su Derivatives via Ultrasonic Irradiation
Scheme 3 Synthetic procedure for glycosylation reaction by using 22 or 18 as a donor
R2
OAc
R1
AcO
O
16a
S
OAc
O
R2
TMSOTf, NIS
DCM, 0 oC to r.t.
30% for 20a
OAc
22a: R1 = H, R2 = OH
22b: R1 = OH, R2 = H
R1
O
AcO
NH
35% for 21a
H
OAc
N
R2
O
OAc
O
R1
AcO
O
16a
OAc
.
BF3 Et2O, DCM
0 oC to r.t.
OAc
20a: R1 = H, R2 = OAc
21a: R1 =OAc, R2 = H
18a: R1 = H, R2 = OH
18b: R1 = OH, R2 = H
scale in good yields. Now, more glycosylated Matijin-
Su derivatives can be synthesized via the developed
chemical approaches in this paper. And the studies of
synthesis for other glycosylated Matijin-Su derivatives
will be reported elsewhere.
and the mixture was adjusted to pH 5 to 6 before being
extracted with ethyl acetate, washed with saturated so-
dium bicarbonate solution and brine, dried over sodium
sulfate and concentrated in vacuo to afford 15. White
1
solid, yield 81%. H NMR (400 MHz, DMSO-d6) δ:
12.51 (s, 1H), 8.76 (d, J＝8.1 Hz, 1H), 7.80 (d, J＝7.3
Hz, 2H), 7.52 (t, J＝7.2 Hz, 1H), 7.43 (t, J＝7.4 Hz,
2H), 7.40 (d, J＝8.4 Hz, 2H), 7.18 (d, J＝8.3 Hz, 2H),
4.69 (m, 1H), 3.22 (dd, J＝13.9, 4.2 Hz, 1H), 3.10 (dd,
J＝13.5, 11.0 Hz, 1H), 2.15 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ: 173.2, 169.8, 166.5, 149.2, 136.0,
133.9, 131.5, 130.2 (C×2), 128.4 (C×2), 127.1 (C×2),
120.8 (C×2), 54.3, 35.7, 19.9. ESI-MS m/z: 350.2 [M
＋Na]＋. Anal. calcd for C18H17NO5: C 66.05, H 5.23, N,
4.28; found C 66.07, H 5.22, N 4.29.
Experimental
General methods
All NMR data were collected on a Varian INOVA
400-MHz spectrometer in CDCl3 or DMSO-d6. Chemi-
cal shifts are given using TMS as internal reference and
coupling constants (J) are given in Hz. High-resolution
mass spectrometry (HRMS) data were recorded on an
Agilent 1100 LC/MS and an STAR Pulsar I system
spectrometer, and LRMS data were acquired on a Mi-
cromass Quatro-LC Electrospray spectrometer using
electrospray ionization (ESI). Optical rotations were
measured using a JASCO P-2000 polarimeter at 22 to
24 ℃ in the specified solvents. The 200－300 and 300
－400 mesh silica gel (Qingdao Ocean Chemical Fac-
tory, P. R. China) was used for TLC and column chro-
matography, respectively. All air- or moisture-sensitive
reactions were operated using dry solvents under argon
atmosphere. Chemicals were purchased from Acros,
Fluka, or Aladdin and used without further purification.
All compounds were prepared as described in
Scheme 2. Benzoyl chloride was treated with substituted
L-phenylalanine or L-tyrosine in 2 mol/L KOH solution
to give compound 11a (86%) and 11b (78%) according
to the standard procedure.[10] Then, the hydroxyl group
of compound 11b was protected by esterification with
Ac2O in pyridine to prepare 15. Finally, compounds 11a
and 15 reacted with L-phenylalanol in the presence of
IBCF and NMM to afford intermediates 16a (79%) and
16b (68%) based on the reference.[11] All spectral data
of intermediates 11 and 16 were consistent with those of
a previous study.[12]
Compounds 18a－18b, 19a－19b and 22a－22b
were synthesized according to literature.[9,13] And the all
spectral data were in agreement with literature.
General synthetic protocol for glycosylation with 16
and 19 in the presence of AgOTf under ultrasonic
irradiation
A solution of compound 16 (50 mg, 1.0 equiv.) and
19 (1.5 equiv.) in anhydrous CH2Cl2 (5 mL) and acti-
vated 4 Å molecular sieves (100 mg) was stirred for 0.5
h under argon atmosphere and dark at ambient tempera-
ture. Then, AgOTf (1.2 equiv.) was added. The mixture
was sonicated at ambient temperature until intermediate
16 was completely consumed by TLC monitor. The re-
action mixture was diluted with CH2Cl2 and filtered
with Celite. The resulted filtrate was concentrated and
purified to afford compounds 20 and 21. (Caution: Be-
cause too long ultrasound reaction (≥10 min) may raise
the temperature inside the reaction vessel, the system
should be cooled after 10 min before the next run if the
reaction needs to continue.)
N-(N-Benzoyl-L-phenylalanyl)-O-(2,3,4,6-tetra-O-
acetyl-β-D-galactopyranosyl)-L-phenylalanol (20a)
Colorless oil, 78.3 mg, yield 86%. 1H NMR (400 MHz,
CDCl3) δ: 7.75－7.72 (m, 2H), 7.52－7.50 (m, 1H),
7.45－7.42 (m, 2H), 7.33－7.28 (m, 5H), 7.21－7.16
(m, 3H), 7.11－7.09 (m, 2H), 6.87 (d, J＝7.8 Hz, 1H),
6.19 (d, J＝8.4 Hz, 1H), 5.40 (dd, J＝3.4, 1.2 Hz, 1H),
N-Benzoyl-O-acetyl-L-tyrosine (15) Acetic an-
hydride (0.41 g, 4.0 mmol) was added dropwise to a
stirred solution of 11b (0.57 g, 2.0 mmol) in pyridine (5
mL) at 0 ℃. After stirring at room temperature over-
night, the reaction solution was poured into cold water,
Chin. J. Chem. 2016, 34, 1353—1359
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5.22 (dd, J＝10.6, 8.0 Hz, 1H), 5.05 (dd, J＝10.4, 3.6
Hz, 1H), 4.80－4.75 (m, 1H), 4.33 (d, J＝8.0 Hz, 1H),
4.20－4.11 (m, 3H), 3.83－3.78 (m, 1H), 3.63 (dd, J＝
10.2, 4.1 Hz, 1H), 3.44 (dd, J＝10.2, 3.2 Hz, 1H), 3.20
(dd, J＝13.7, 5.8 Hz, 1H), 3.14 (dd, J＝13.6, 7.9 Hz,
1H), 2.81－2.74 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H),
2.02 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 170.4, 170.2, 170.1, 169.5 (C×2), 166.9, 137.2,
136.6, 133.7, 131.8, 129.4 (C×2), 129.1 (C×2), 128.7
(C×2), 128.5 (C×4), 127.1, 127.0 (C×2), 126.6,
101.1, 70.6 (C×2), 69.0, 68.8, 66.9, 61.3, 54.8, 50.2,
38.6, 36.6, 20.9, 20.7, 20.6 (C×2). ESI-MS m/z: 733.6
[M＋H]＋. Anal. calcd for C39H44N2O12: C 63.92, H 6.05,
N 3.82; found C 63.91, H 6.06, N 3.83.
tetra-O-acetyl-β-D-glucopyranosyl)-L-phenylalanol
(21b) Colorless oil, 68.7 mg, yield 80%. H NMR
1
(400 MHz, CDCl3) δ: 7.77 (d, J＝6.8 Hz, 2H), 7.51 (t,
J＝5.6 Hz, 1H), 7.43 (t, J＝8.0 Hz, 2H), 7.24－7.10 (m,
7H), 6.94 (d, J＝7.6 Hz, 2H), 6.80 (d, J＝8.4 Hz, 1H),
6.22 (d, J＝8.8 Hz, 1H), 5.41 (dd, J＝4.4, 1.6 Hz, 1H),
5.22 (dd, J＝10.4, 8.0 Hz, 1H), 5.02 (dd, J＝10.4, 3.6
Hz, 1H), 4.72－4.66 (m, 1H), 4.28－4.21 (m, 2H), 4.19
(d, J＝8.0 Hz, 1H), 4.05 (dd, J＝10.4, 6.4 Hz, 1H), 3.77
(t, J＝6.4 Hz, 1H), 3.58 (dd, J＝10.2, 3.6 Hz, 1H), 3.39
(dd, J＝10.4, 3.6 Hz, 1H), 3.10 (dd, J＝10.8, 4.8 Hz,
1H), 3.04－2.96 (m, 1H), 2.80－2.75 (m, 2H), 2.19 (s,
3H), 2.17 (s, 3H), 2.11 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 171.3, 170.5, 170.2 (C
×2), 169.8, 167.1, 166.5, 155.6, 137.1, 133.6, 131.9,
130.7 (C×2), 129.0 (C×2), 128.5 (C×2), 128.4 (C×
2), 127.9, 127.1 (C×2), 126.5, 116.0 (C×2), 102.3,
71.1, 70.7, 69.5, 69.1, 66.8, 61.7, 55.6, 50.3, 38.2, 36.4,
21.1, 20.8, 20.5 (C×2), 19.9. ESI-LRMS m/z: 791.5
[M＋H]＋. Anal. calcd for C41H46N2O14: C, 62.27, H
5.86, N 3.54; found C 62.29, H 5.83, N 3.56.
N-[N-Benzoyl-O-acetyl)-L-tyrosyl]-O-(2,3,4,6-
tetra-O-acetyl-β-D-galactopyranosyl)-L-phenylalanol
1
(20b) Colorless oil, 79.0 mg, yield 92%. H NMR
(400 MHz, CDCl3) δ: 7.76 (d, J＝7.2 Hz, 2H), 7.52 (t,
J＝7.4 Hz, 1H), 7.44 (t, J＝7.6 Hz, 2H), 7.24－7.10 (m,
7H), 6.79 (d, J＝8.4 Hz, 2H), 6.56 (d, J＝10.2 Hz, 1H),
6.22 (d, J＝8.8 Hz, 1H), 5.38 (dd, J＝3.6, 0.8 Hz, 1H),
5.23 (dd, J＝10.6, 8.0 Hz, 1H), 5.03 (dd, J＝10.4, 3.6
Hz, 1H), 4.74－4.67 (m, 1H), 4.29－4.20 (m, 2H), 4.19
(d, J＝8.0 Hz, 1H), 4.04 (dd, J＝11.4, 6.0 Hz, 1H), 3.75
(t, J＝6.4 Hz, 1H), 3.59 (dd, J＝10.2, 3.6 Hz, 1H), 3.42
(dd, J＝10.4, 2.8 Hz, 1H), 3.10 (dd, J＝13.5, 4.8 Hz,
1H), 3.01 (dd, J＝13.5, 4.8 Hz, 1H), 2.82－2.70 (m,
2H), 2.21 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H), 2.02 (s, 3H),
1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.9,
170.4, 170.3 (C×2), 169.6, 167.3, 166.8, 155.3, 137.2,
133.7, 131.8, 130.6 (C×2), 129.1 (C×2), 128.6 (C×2),
128.5 (C×2), 128.1, 127.0 (C×2), 126.6, 115.8 (C×2),
101.2, 70.7, 70.5, 69.6, 68.9, 67.0, 61.6, 55.4, 50.2, 38.3,
36.5, 20.8, 20.7, 20.6 (C×2), 20.5. ESI-LRMS m/z:
791.7 [M＋H]＋. Anal. calcd for C41H46N2O14: C 62.27,
H 5.86, N 3.54; found C 62.27, H 5.85, N 3.55.
N-(N-Benzoyl-L-phenylalanyl)-O-(2,3,4,6-tetra-O-
acetyl-β-D-glucopyranosyl)-L-phenylalanol (21a)
Colorless oil, 75.6 mg, yield 83%. 1H NMR (400 MHz,
CDCl3) δ: 7.80－7.75 (m, 2H), 7.54－7.48 (m, 1H),
7.46－7.42 (m, 2H), 7.36－7.28 (m, 5H), 7.22－7.14
(m, 3H), 7.11－7.07 (m, 2H), 6.56 (d, J＝7.2 Hz, 1H),
6.15 (d, J＝8.0 Hz, 1H), 5.39 (dd, J＝3.6, 1.2 Hz, 1H),
5.18 (dd, J＝10.0, 7.6 Hz, 1H), 5.02 (dd, J＝8.4, 3.6 Hz,
1H), 4.84－4.77 (m, 1H), 4.30 (d, J＝7.6 Hz, 1H), 4.22
－4.09 (m, 3H), 3.85－3.77 (m, 1H), 3.62 (dd, J＝9.9,
3.2 Hz, 1H), 3.43 (dd, J＝10.0, 3.2 Hz, 1H), 3.18 (dd,
J＝13.6, 5.6 Hz, 1H), 3.07 (dd, J＝11.0, 7.6 Hz, 1H),
2.78－2.71 (m, 2H), 2.13 (s, 3H), 2.11 (s, 3H), 2.02 (s,
3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.2,
170.4, 170.2, 170.1, 169.7, 167.0, 137.5, 136.8, 133.6,
131.5, 129.5 (C×2), 128.9 (C×2), 128.6 (C×2), 128.5
(C×2), 128.4 (C×2), 127.0, 126.8 (C×2), 126.5,
102.4, 70.7 (C×2), 69.1, 68.9, 66.7, 61.2, 55.0, 50.1,
38.5, 36.7, 21.1, 20.8, 20.6 (C×2). ESI-MS m/z: 733.3
[M＋H]＋. Anal. calcd for C39H44N2O12: C 63.92, H 6.05,
N 3.82; found C 63.90, H 6.08, N 3.81.
General procedure for target compounds 2 and 3
The methanol solution of MeONa (4.0 equiv.) was
dropwise added to a methanol solution of glycoside 20
or 21 (30 mg, 1.0 equiv.) at room temperature. After
being stirred for 1.0 h, the reaction mixture was diluted
with MeOH and neutralized with dowex H＋ resin to pH
5 to 6. The resin was filtered off and washed with
MeOH. The resulted filtrate was concentrated and puri-
fied to give compounds 2 or 3.
N-(N-Benzoyl-L-phenylalanyl)-O-(β-D-galacto-
pyranosyl)-L-phenylalanol (2a) White powder, 21.5
mg, yield 93%. m.p. 229－231 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 7.70－7.68 (m, 2H), 7.52－7.49 (m, 1H),
7.42 (t, J＝8.0 Hz, 2H), 7.29－7.14 (m, 9H), 7.12－
7.08 (m, 1H), 4.84 (dd, J＝9.0, 6.4 Hz, 1H), 4.25－4.19
(m, 1H), 4.07 (d, J＝8.0 Hz, 1H), 3.81－3.76 (m, 2H),
3.71－3.65 (m, 2H), 3.62－3.54 (m, 2H), 3.44 (dd, J＝
9.6, 3.6 Hz, 1H), 3.38－3.32 (m, 1H), 3.15 (dd, J＝13.8,
6.4 Hz, 1H), 3.01－2.94 (m, 2H), 2.82 (dd, J＝13.6, 7.6
Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 173.3,
169.9, 139.7, 138.7, 135.3, 132.9, 130.5 (C×2), 130.4
(C×2), 129.5 (C×4), 129.3 (C×2), 128.5 (C×2),
127.8, 127.3, 105.5, 76.6, 74.8, 72.5, 71.9, 70.2, 62.6,
56.7, 52.6, 39.0, 38.0; HRMS-ESI m/z: 587.2368 [M＋
Na]＋; calcd for C31H36N2O8Na 587.2364.
N-(N-Benzoyl-L-tyrosyl)-O-(β-D-galactopyrano-
syl)-L-phenylalanol (2b) White powder, 17.0 mg,
1
yield 77%. m.p. 227－229 ℃; H NMR (400 MHz,
DMSO-d6) δ: 9.11 (s, 1H), 8.40 (d, J＝8.4 Hz, 1H), 7.89
(d, J＝8.4 Hz, 1H), 7.80－7.76 (m, 2H), 7.52－7.48 (m,
1H), 7.45－7.41 (m, 2H), 7.24－7.11 (m, 5H), 7.07 (d,
J＝8.4 Hz, 2H), 6.60 (d, J＝8.4 Hz, 2H), 4.85 (d, J＝
4.6 Hz, 1H), 4.72 (d, J＝5.5 Hz, 1H), 4.63 (t, J＝5.5 Hz,
1H), 4.59－4.52 (m, 1H), 4.36 (d, J＝4.5 Hz, 1H), 4.09
－4.04 (m, 2H), 3.61－3.41 (m, 5H), 3.36－3.27 (m,
3H), 2.95 (dd, J＝13.7, 5.2 Hz, 1H), 2.91－2.77 (m,
N-[N-Benzoyl-O-acetyl)-L-tyrosyl]-O-(2,3,4,6-
1358
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 1353—1359

Efficient Synthesis of Glycosylated Matijin-Su Derivatives via Ultrasonic Irradiation
2H), 2.69 (dd, J＝13.5, 8.0 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ: 171.2, 166.1, 155.6, 138.7, 134.1,
131.2, 130.1 (C×2), 129.3 (C×2), 128.4, 128.2 (C×2),
128.0 (C×2), 127.4 (C×2), 125.9, 114.8 (C×2), 103.7,
75.2, 73.4, 70.6, 69.6, 68.1, 60.5, 55.2, 50.3, 36.4, 36.3.
HRMS-ESI m/z: 603.2315 [M ＋ Na] ＋ ; calcd for
C31H36N2O9Na 603.2313.
Na]＋; calcd for C31H36N2O9Na 603.2313.
Acknowledgement
This work was supported by the National Natural
Science Foundation of China (No. 81360472).
References
N-(N-Benzoyl-L-phenylalanyl)-O-(β-D-glucopy-
ranosyl)-L-phenylalanol (3a) White powder, 19.7 mg,
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(in Chinese).
1
yield 85%. m.p. 213－216 ℃; H NMR (400 MHz,
DMSO-d6) δ: 7.77－7.72 (m, 2H), 7.55－7.50 (m, 1H),
7.45－7.41 (m, 2H), 7.31－7.15 (m, 9H), 7.12－7.08
(m, 1H), 4.64 (dd, J＝8.4, 6.0 Hz, 1H), 4.24－4.18 (m,
1H), 4.08 (d, J＝8.0 Hz, 1H), 3.79－3.72 (m, 2H), 3.68
－3.54 (m, 4H), 3.42 (dd, J＝9.6, 3.6 Hz, 1H), 3.36 (dd,
J＝6.8, 5.6 Hz, 1H), 3.16 (dd, J＝13.2, 6.0 Hz, 1H),
2.99－2.93 (m, 2H), 2.81 (dd, J＝13.6, 7.6 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6) δ: 172.9, 168.7, 140.1,
139.3, 135.5, 133.0, 130.7 (C×2), 130.5 (C×2), 129.6
(C×2), 129.4 (C×2), 129.3 (C×2), 128.5 (C×2),
127.9, 127.3, 106.5, 76.7, 75.8, 72.4, 71.8, 69.8, 62.5,
56.5, 52.6, 39.1, 37.9; HRMS-ESI m/z: 587.2353 [M＋
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N-(N-Benzoyl-L-tyrosyl)-O-(β-D-glucopyrano-
syl)-L-phenylalanol (3b) White powder, 16.5 mg,
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1
yield 75%. m.p. 211－214 ℃; H NMR (400 MHz,
DMSO-d6) δ: 8.92 (s, 1H), 8.41 (d, J＝7.6 Hz, 1H), 7.90
(d, J＝6.4 Hz, 1H), 7.82－7.76 (m, 2H), 7.56－7.51 (m,
1H), 7.49－7.41 (m, 2H), 7.24－7.21 (m, 2H), 7.20－
7.06 (5H, m), 6.61 (d, J＝8.4 Hz, 2H), 4.80 (d, J＝4.5
Hz, 1H), 4.71 (d, J＝5.6 Hz, 1H), 4.62 (t, J＝5.4 Hz,
1H), 4.60－4.54 (m, 1H), 4.37 (d, J＝4.5 Hz, 1H), 4.09
－4.04 (2H, m), 3.61－3.41 (m, 5H), 3.35－3.27 (m,
3H), 2.94－2.79 (m, 3H), 2.71 (dd, J＝13.6, 8.0 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ: 172.1, 166.5,
155.3, 139.0, 134.2, 131.4, 129.8 (C×2), 129.2 (C×2),
128.3, 128.2 (C×2), 127.9 (C×2), 127.5 (C×2), 126.0,
115.1 (C×2), 104.2, 75.3, 73.5, 70.8, 70.2, 68.5, 61.1,
55.6, 50.2, 36.5, 36.4. HRMS-ESI m/z: 603.2318 [M＋
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(Lu, Y.)
Chin. J. Chem. 2016, 34, 1353—1359
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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