One step stereoselective synthesis of oxazoline-fused saccharides and their conversion into the corresponding 1,2-cisglycosylamines bearing various protected groups

Article abstract of DOI:10.1039/d0ob02477e

Herein we disclosed a straightforward synthesis of oxazoline-fused saccharides (oxazolinoses) from peracetylated saccharides and benzonitriles under acidic conditions with stoichiometric amounts of water. The density functional theory (DFT) calculations have revealed the origin of the stereoselectivity and the key role of water in promoting the departure of the acetyl group at C-2. The resulting oxazolinoses can be concisely converted into the corresponding 1,2-cisglycosylamines bearing various protected groups, allowing the access to schisandrin derivatives.

Full text of DOI:10.1039/d0ob02477e

Organic &
Biomolecular Chemistry
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PAPER
One step stereoselective synthesis of oxazoline-
fused saccharides and their conversion into the
corresponding 1,2-cis glycosylamines bearing
various protected groups†
Cite this: Org. Biomol. Chem., 2021,
9, 1580
1
a,b
a,b
b,c
b,c
Sanfeng Dong,‡ Yitian Zhao,‡ Yulong Shi,‡ Zhijian Xu,
Jingshan Shen,
Weiliang Zhu
b,c
a
a
a,b,c
b,c
Qi Jia,* Yiming Li, Kaixian Chen,
Bo Li
*
and
a,b,c
*
Herein we disclosed a straightforward synthesis of oxazoline-fused saccharides (oxazolinoses) from pera-
cetylated saccharides and benzonitriles under acidic conditions with stoichiometric amounts of water.
The density functional theory (DFT) calculations have revealed the origin of the stereoselectivity and the
key role of water in promoting the departure of the acetyl group at C-2. The resulting oxazolinoses can
be concisely converted into the corresponding 1,2-cis glycosylamines bearing various protected groups,
allowing the access to schisandrin derivatives.
Received 11th December 2020,
Accepted 20th January 2021
DOI: 10.1039/d0ob02477e
rsc.li/obc
hydrates but also essential to the development of carbohydrate
drugs. In particular, glycosylamines not only exist widely in
Introduction
4
Carbohydrates are one of the four major types of essential bio- organisms, but also can be used as saccharide mimics for bio-
logical macromolecules, along with nucleic acids, proteins, function studies and the intermediates for the synthesis of
and lipids. In organisms, carbohydrates are often conjugated heterocyclic rings. Accordingly, the synthesis and multi-site
with amino acid residues to form glycopeptides and glyco- modification of glycosylamines are becoming more and more
1
5
proteins so as to perform biological functions. For example, important.
glycopeptides are widely found in structurally diverse natural The usual method for preparing 1-glycosylamines is
6
products such as the metabolites produced by bacteria (e.g. through the reduction of 1-azide saccharides. However, it is
2
vancomycin). In addition, some glycoproteins that exist more convenient to convert oxazoline-fused saccharides (oxa-
7
widely in organisms with the bio-recognition function are zolinoses) into 1-glycosylamines by acid hydrolysis.
N-glycosides which generally contain the core pentasacchar- Oxazolinoses are commonly prepared from 1-azide saccharides
8
ides and aspartic acid residues (e.g. erythropoietin and chloro- and triphenylphosphine. In addition, the saccharides are
3
virus N-glycans) (Scheme S1, ESI†).
firstly converted into enoses under acidic conditions, which
Due to the limited availability of natural-derived carbo- then react with amides and halogenated reagents such as NIS
9
hydrates, chemical synthesis and modification to produce a to produce oxazolinoses. Meanwhile, Mong used perbenzyl
richer variety of natural carbohydrates and non-natural thioglucoside and nitrile by treating them with triflic anhy-
1
0
analogs are not only conducive to the research of carbo- dride (Tf
2
O) and NIS to form oxazolinoses. The use of special
1
1
reagents such as the Burgess reagent or new methods such
1
2
as thiourea/halogen bond donor co-catalysis to obtain substi-
tuted glycosylamines was also reported. In general, the existing
methods synthesize glycosylamines via many synthesis steps
by using halogen, metal or hazardous reagents. Therefore,
more convenient and effective methods for the synthesis of
oxazolinoses need to be developed. It is best to achieve both
selective modification of the 2 and 3 hydroxyl groups on the
saccharide ring and the construction of 1,2-cis glycosidic
bonds (Scheme 1a).
a
Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai
01203, China. E-mail: q_jia@126.com
2
b
CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, China. E-mail: boli@simm.ac.cn, wlzhu@simm.ac.cn
c
School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan
Road, Beijing 100049, China. E-mail: boli@simm.ac.cn, wlzhu@simm.ac.cn
†
Electronic supplementary information (ESI) available. CCDC 2036191. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ob02477e
1
3
Starting from the structural optimization of berberine, we
previously developed a facile method to prepare 4-alkoxy-2-oxa-
‡
These authors contributed equally to this manuscript.
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methanesulfonic acid and then the carbocation is attacked by
benzonitrile 2 to perform a stereoselective ring-closure reac-
tion controlled by the stability of the intermediate and low free
energy barrier. The existence of water in the environment pro-
moted the departure of the acetyl group at C-2 to generate
target product 3 (Scheme 1c). Oxazolinose 3 can be easily con-
verted into the corresponding 1,2-cis glycosylamine 12 bearing
various protected groups at the 2,3-positions on the saccharide
2
ring in a few steps and then 1-NH can further be transformed
into 1-OH in one step. Saccharide screening has shown that
oxazolinoses can be synthesized from various six- or five-mem-
bered monosaccharides and oligosaccharides. Therefore, 1-α
and 1-β glycosylamines can be obtained from different sacchar-
ides. This provides a general strategy for synthesizing multi-
site modified saccharides from oxazolinoses. In addition, oxa-
zolinoses can be directly used to synthesize complex chiral
molecules such as schisandrins.
Table 2 Screening of the benzonitriles
Scheme 1 Glycosylamines: objectives and obstacles.
zoline derivatives from nitriles and β-hydroxyacetals
1
4
(
Scheme 1b). Herein we disclose that peracetylated sacchar-
ide 1 generates a carbocation under the action of trifluoro-
R
R
R
Table 1 Optimization of the reaction conditions
3
A
B
3G
3H
3M
3N
3
a
Entry
Acid
Additive
Solvent
Time
Temp.
Yield
3
3
C
D
3I
3O
1
2
3
4
5
6
7
8
9
TsOH
HCl
TFA
—
—
—
—
Al(OTf)
Fe(OTf)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
EA
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
12 h
2 h
6 h
12 h
2 h
2 h
2 h
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0 °C
40 °C
rt
rt
rt
rt
rt
0
0
0
0
0
0
0
35%
40%
33%
38%
40%
21%
28%
74%
51%
57%
20%
75%
9%
0
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
3
3J
3P
3
CuSO
CuSO
4
4
·5H
2
O
H
2
O
b
c
3E
3F
3K
3L
3Q
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1.0
0.1
0.5
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
Acetone
EtOH
0
0
a
b
c
2
HPLC yield. The equivalent of TfOH. The equivalent of H O. rt:
a
b
room temperature.
Yield. 1,2-cis : 1,2-trans.
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which is probably due to the protonation of nitrogen atoms
under acidic conditions (3P and 3Q). This also shows that the
Results and discussion
In the process of screening the reaction conditions, we found nucleophilicity of the cyano group is closely related to the reac-
that compound 3A can be obtained by using trifluoromethane- tion yields. In order to determine the structure of the products,
sulfonic acid and water in the dichloromethane solvent (entry we removed the acetyl protecting group of compound 3D to
9
1
, Table 1). By investigating the amount of water (entries obtain 3S, and then determined the X-ray single crystal struc-
0–13), we found that one equivalent of water gave the highest ture of 3S.
yield of 3A (40% yield, entry 12). Then the amounts of tri-
Based on the above results, we selected the benzonitrile
fluoromethanesulfonic acid were screened (entries 14–16) and substrates with good stereoselectivity of products and contin-
two equivalents of the acid were found to give 3A in the ued to screen various saccharides (Scheme 2). Different six-
highest yield of 74% (entry 15). In addition, changing the membered ring saccharides can successfully obtain the corres-
temperature (entries 17 and 18) and reaction time (entries 19 ponding products (3Da, 3Db, 3Ra). The C–N configuration at
and 20) did not afford a higher yield of 3A. Several other sol- the 1-position of the product is controlled by the configuration
vents were also screened but no product of 3A was observed of the ortho group at the 2-position on the saccharide ring. For
(entries 21–23).
example, glucose gives 1-alpha product 3D, while mannose
According to the optimized reaction conditions, different gives 1-beta products 3Db and 3Ra, which indicated that we
benzonitrile substrates were then investigated for exploring the can further obtain 1-α or 1-β glycosylamines from different sac-
stereoselectivity of the reaction (Table 2). The yields of the charides. Moreover, both disaccharide and trisaccharide sub-
compounds with electron-donating substituents are between strates can give the corresponding products (3Dc and 3Dd). In
5
7% and 90% (3B–3D), while those with electron-withdrawing addition, five-membered ring saccharides can also generate
substituents dropped significantly to <40% (3E). The stereo- oxazolinoses in high yields and with good stereoselectivity (3a–
1
selectivity of product 3D with the electron-donating substitu- g). We have compared the H-NMR spectra of several oxazoli-
ent is much better than those of other products, similar to the noses and found visible differences of the chemical shifts of
unsubstituted 3A. The yields and stereoselectivities of com- the hydrogen atom at the 1-position between 1-α and 1-β C–N
pounds 3G–3I with the halogen substituent at the para posi- configurations (Fig. S1, ESI†). The chemical shifts of the hydro-
tion of the benzene ring are obviously weaker than those of gen atom on C-1 for 1-α oxazolinoses are around at 6.10 ppm.
compound 3F with the halogen substituent at the ortho posi- Electron-donating or electron-withdrawing substituents can
tion of the benzene ring. When adding other electron-donating make the chemical shifts fluctuate slightly. Meanwhile, the
substituents to the benzene ring substituted by the ortho- chemical shifts of the hydrogen atom on C-1 for 1-β oxazoli-
halogen, there is no rule to follow in the yields and configur- noses are at around 6.40 ppm. Therefore, the difference
1
ation control (3J–3O). Finally, we also tried cyanide substrates between the two isomers can be recognized via H-NMR
with basic nitrogen groups, but no product was obtained, spectra.
a
b
c
Scheme 2 Screening of the saccharides. ( : HPLC yield; : 1,2-cis : 1,2-trans; : isolated yield.)
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Scheme 3 Computational study of two different proposed intramolecular cyclization mechanisms for intermediates A1 and A2. All energies are in
−1
kcal mol
.
The reaction mechanism is proposed in Scheme 3a. Acetyl However, the experimental results mainly gave 1,2-cis product
glucose 1A generates carbocation compound T under the 3A (C1). In order to gain a further insight into the intra-
action of trifluoromethanesulfonic acid. Then T is attacked by molecular cyclization mechanism and the preference of stereo-
benzonitrile 2A, which might give 1-S and 1-R products. selectivity for the oxazoline ring of target product C1 (3A), a
Scheme 4 Conversion and application of oxazolinoses (reaction conditions of 10a–c. 10a: succinic anhydride, TEA, THF, yield 92%; 10b: N-tert-
butoxycarbonyl-L-aspartic acid 1-methyl ester, HATU, TEA, DCM, yield 73%; 10c: p-tolylboronic acid, cupric acetate monohydrate, TEA, DCM, yield
25%).
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computational study using the density functional theory (DFT) through 3–4 steps of simple transformations, oxazolinoses can
method at the M06-2X/6-311G(d) level was performed using be used to prepare the corresponding 1,2-cis glycosylamine
1
5,16
Gaussian 16 B.01
2
for geometry optimization, frequency bearing various protected groups. In addition, the 1-NH of
analysis and transition state search. The solvent effects of di- the saccharide can also be easily converted to a hydroxyl group
chloromethane (DCM) were taken into consideration by using via a diazotization reaction. Moreover, oxazolinoses can also
1
7
a solvation model based on density (SMD) during the be directly used for the asymmetric synthesis of complex chiral
calculations.
molecules such as schisandrins.
As shown in Scheme 3b, intermediate A1 was predicted to
−1
be more stable than A2 by 5.0 kcal mol , indicating that A1 is
the dominant configuration produced from the nucleophilic
attack of benzonitrile. A1 could undergo intramolecular
nucleophilic addition of its oxygen atom of the acetoxy group
Experimental section
Materials and methods
attacking the carbon atom of the imide bond to afford B1, via All starting materials were purchased from commercial suppli-
transition state TS1 with a free energy barrier of 18.8 kcal ers, and all super-dry solvents were used as supplied from J&K
−
1
mol . On the other hand, A2 might proceed through a similar Scientific. All solvents and materials were used without further
reaction pathway via transition state TS2 to afford B2 with a purification. NMR spectra were recorded using a Bruker
−
1
−1
free energy barrier of 23.4 kcal mol , 4.6 kcal mol higher Avance 600, 500 or 400 NMR spectrometer and a Varian
than TS1, which is consistent with the experimental obser- Mercury Plus 600 or 400 NMR spectrometer operating at
1
vation that C2 almost cannot be detected at room temperature. 600 MHz, 500 MHz or 400 MHz for H NMR and 150 MHz,
1
3
The water existing in the environment promoted the departure 125 MHz or 100 MHz for C NMR, using TMS as the internal
1
3
of the B1 acetyl group to generate target product C1, which is standard and CDCl
1
3
or DMSO-d6 as the solvent. C NMR
4.1 kcal mol− more stable than C2, suggesting again that C1 spectra were recorded with complete proton decoupling.
1
should be the main product of the reaction (section 5, ESI†).
ESI-MS and EI-MS were performed on a Finnigan LCQ/DECA
We further investigated the potential application of oxazoli- system and a Thermo-DFS system, respectively. HRMS spectra
noses in organic synthesis (Scheme 4A). For example, 3A can were obtained using a Micromass Ultra Q-TOF (ESI) or
undergo a ring-opening reaction under acidic conditions to Thermo-DFS (EI) spectrometer. Flash column chromatography
give 1-α-amino compound 4A with the benzoate group at the was carried out using silica gel (200–400 mesh). Thin layer
2
-position. On the other hand, the acetyl protecting groups of chromatography (TLC) was performed using F254 fluorescent
3
A can be removed to generate 5. Then the benzyl protecting treated silica gel, which was visualised under UV light
groups were introduced to give 6 which can be treated with (254 nm). The optical rotation was recorded using an Autopol
acid to produce 4B. After diazotization treatment, the 1- VI system.
α-amino group of 4B can be converted into a 1-β-hydroxyl
group to obtain 7 with a selective protecting group at the
2
-position. 1-α-Amino carbohydrate 4B can smoothly syn-
Experimental procedure
thesize glycosylamines 10a–c. Compound 5 can also undergo
simple conversion of the protective group on the saccharide
ring through 8 and 9 to obtain glycosylamine 10d with differ-
(
3aS,5R,6R,7S,7aR)-5-(Acetoxymethyl)-2-phenyl-3a,6,7,7a-
tetrahydro-5H-pyrano[2,3-d]oxazole-6,7-diyl diacetate (3A)
entially protected polyhydroxyl groups at the 2,3-positions on To a solution of β-D-glucose pentaacetate (195 mg, 0.5 mmol)
the saccharide ring. Thus, the N-glycoside derivatives similar and benzonitrile (50 μL, 0.5 mmol) in dry DCM (dichloro-
to 10a–c can be further prepared via 10d. In addition, methane), water (10 μL) was added. After stirring the above
2
-bromo-3,4,5-methoxybenzonitrile and β-D-glucose pentaace- mixture for 10 minutes, TfOH (90 μL, 1 mmol) was added and
tate can undergo two steps of oxazolinose synthesis and stirred for 2 hours at room temperature. Then the mixture was
Ullmann-coupling reactions to generate the axial chiral com- poured into water (20 mL) and extracted with ethyl acetate
pound 11 with a P configuration (Scheme 4B). This shows that (20 mL) three times. The organic layers were combined and
oxazolinoses have the potential to act as chiral blocks in washed with water and brine, dried over anhydrous sodium
organic synthesis.
sulfate, and concentrated in vacuo to give a crude product
which was purified using a silica gel column (petroleum ether/
ethyl acetate 2 : 1) to give product 3A (144.3 mg, yield 74%) as a
1
yellow oil. H NMR (500 MHz, chloroform-d) δ 8.07–7.99 (m,
Conclusions
2H), 7.59–7.53 (m, 1H), 7.46 (dd, J = 8.4, 7.1 Hz, 2H), 6.09 (d, J
In summary, we have developed a convenient method through = 7.7 Hz, 1H, H-1), 5.33–5.29 (m, 1H, H-3), 4.98 (ddd, J = 8.4,
peracetylated saccharides and benzonitriles by using trifluoro- 4.5, 0.9 Hz, 1H, H-4), 4.63 (ddd, J = 7.7, 3.6, 0.9 Hz, 1H, H-2),
methanesulfonic acid and water to synthesize oxazolinoses 4.31 (dd, J = 12.1, 5.2 Hz, 1H, H-6), 4.19 (dd, J = 12.1, 2.9 Hz,
that can be directly converted into 1,2-cis glycosylamines with 1H, H-6), 3.75 (ddd, J = 8.2, 5.1, 2.9 Hz, 1H, H-5), 2.16 (s, 3H),
1
3
a benzoate group at the 2-position. Thus, 1-α and 1-β glycosyl- 2.09 (s, 3H), 1.94 (s, 3H). C NMR (125 MHz, chloroform-d) δ
amines can be obtained from different saccharides. Meanwhile, 170.68, 169.54, 169.47, 166.59, 132.68, 128.90, 128.59, 126.21,
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9
3.22, 75.82, 70.55, 68.07, 67.30, 63.28, 20.87, 20.78, 20.61. Hz, 1H), 7.41 (d, J = 1.5 Hz, 2H), 7.38–7.34 (m, 5H), 7.33–7.29 (m,
+
HRMS (ESI): C H NO [M + H] , calculated: 392.134, found: 5H), 7.29–7.24 (m, 5H), 7.18–7.16 (m, 1H), 6.09 (d, J = 7.6 Hz, 1H),
3
1
9
22
8
2
0
92.1351. [α]D = 33.5 (c = 0.064, MeOH).
4.85 (d, J = 11.8 Hz, 1H), 4.77–4.69 (m, 3H), 4.67 (dd, J = 7.5, 4.6
Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.50 (dd, J = 11.7, 7.1 Hz, 2H),
(3aS,5R,6R,7S,7aR)-5-(Acetoxymethyl)-2-(benzo[d][1,3]dioxol-5-
3
=
.89 (dd, J = 6.9, 4.7 Hz, 1H), 3.82 (dd, J = 8.9, 6.9 Hz, 1H), 3.72 (d, J
2.9 Hz, 1H), 3.63 (d, J = 9.0 Hz, 1H). C NMR (150 MHz, chloro-
yl)-3a,6,7,7a-tetrahydro-5H-pyrano[2,3-d]oxazole-6,7-diyl
diacetate (3D)
13
form-d) δ 165.9, 138.1, 137.9, 132.3, 128.7, 128.5, 128.4, 128.4,
Piperonylonitrile (73.5 mg, 0.5 mmol) and β-D-glucose penta- 128.3, 128.0, 127.9, 127.9, 127.9, 127.7, 127.6, 126.9, 94.1, 81.2,
acetate (195 mg, 0.5 mmol) were used as described for 3A to 80.2, 74.6, 73.8, 73.5, 72.7, 71.8, 69.4. HRMS (ESI): C34 [M +
H34NO
5
1
+
give compound 3D (135.5 mg, yield 62%) as a yellow oil. H H] , calculated: 536.2431, found: 536.2438.
NMR (600 MHz, chloroform-d) δ 7.59 (dd, J = 8.1, 1.7 Hz, 1H), To a solution of 6 (1 g, 1.86 mmol) in acetone (30 mL),
.47 (d, J = 1.6 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.05 (m, 3H, hydrochloric acid (1 mL, 0.2 mmol, 2.0 M in diethyl ether) and
7
2
H-1 and CH ), 5.28 (m, 1H, H-3), 4.97 (ddd, J = 8.6, 4.6, 0.9 Hz, water (250 µL) were added. After stirring the above mixture for
1
1
8
H, H-4), 4.60 (ddd, J = 7.7, 3.8, 0.9 Hz, 1H, H-2), 4.30 (dd, J = 12 h at room temperature, the product was formed as a white
2.1, 5.1 Hz, 1H, H-6), 4.22–4.16 (m, 1H, H-6), 3.74 (ddd, J = precipitate, which was filtered to give a white solid product 4B
1
6
.2, 5.0, 2.8 Hz, 1H, H-5), 2.16 (s, 3H), 2.09 (s, 3H), 1.97 (s, 3H). (0.857 g, yield 83%). H NMR (500 MHz, DMSO-d ) δ 9.06 (s,
1
3
C NMR (125 MHz, chloroform-d) δ 170.68, 169.54, 169.46, 2H), 8.01–7.95 (m, 2H), 7.71–7.65 (m, 1H), 7.54 (t, J = 7.8 Hz,
66.14, 151.43, 147.88, 124.35, 119.98, 108.80, 108.29, 101.82, 2H), 7.35 (d, J = 4.3 Hz, 4H), 7.33–7.25 (m, 4H), 7.20 (dd, J =
1
9
3.16, 75.91, 70.62, 67.98, 67.31, 63.26, 20.85, 20.77, 20.64. 7.6, 1.9 Hz, 2H), 7.17–7.06 (m, 3H), 7.04–6.95 (m, 2H), 5.13 (t, J
+
HRMS (ESI): C H NO [M + H] , calculated: 436.1238, = 9.2 Hz, 1H), 4.94 (d, J = 9.0 Hz, 1H), 4.71 (dd, J = 11.0, 6.9 Hz,
found: 436.1248. [α]D = 97.5 (c = 0.002, MeOH).
2
0
22
10
2
0
2H), 4.61–4.48 (m, 4H), 4.04 (t, J = 9.2 Hz, 1H), 3.90 (m, 1H),
1
3
3
1
1
6
.75–3.61 (m, 3H). C NMR (125 MHz, DMSO-d ) δ 138.18,
37.96, 134.04, 130.04, 129.82, 129.05, 128.75, 128.73, 128.65,
28.60, 128.53, 128.34, 128.31, 128.24, 128.20, 128.08, 128.07,
(2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-amino-5-(benzoyloxy)
tetrahydro-2H-pyran-3,4-diyl diacetate (4A)
To a solution of 3A (39 mg, 0.1 mmol) in acetone (5 mL), 128.01, 81.99, 79.24, 77.59, 76.84, 75.07, 74.61, 72.78, 72.61,
+
hydrochloric acid (100 μL, 0.2 mmol, 2.0 M in diethyl ether) 68.38. HRMS (ESI): C H NO [M + H] , calculated: 554.2537,
3
0
4
36
6
2
and water (25 µL) were added. After stirring the above mixture found: 554.2549. [α] = 59.3 (c = 0.054, MeOH).
D
for 12 h at room temperature, the product was formed as a
white precipitate, which was filtered to give a white solid 4A
(
3R,4S,5R,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-2-
1
hydroxytetrahydro-2H-pyran-3-yl benzoate (7)
(
(
27.5 mg, yield 67%). H NMR (400 MHz, chloroform-d) δ 8.03
dd, J = 8.3, 1.4 Hz, 2H), 7.65–7.56 (m, 1H), 7.47 (t, J = 7.7 Hz, To a solution of 4B (55.3 mg, 0.1 mmol) in acetone (5 mL), concen-
2
1
1
H), 5.48 (t, J = 9.7 Hz, 1H), 5.13 (m, 2H), 4.36 (d, J = 8.7 Hz, trated hydrochloric acid (250 µL) and sodium nitrite (13 mg,
H), 4.29 (dd, J = 12.3, 4.9 Hz, 1H), 4.17 (dd, J = 12.3, 2.3 Hz, 0.2 mmol) were added. After stirring at room temperature for 12 h,
H), 3.85–3.75 (m, 1H), 2.14 (d, J = 1.0 Hz, 3H), 2.07 (d, J = 0.9 the mixture was poured into water (20 mL) and extracted with ethyl
1
3
Hz, 3H), 1.95 (d, J = 0.9 Hz, 3H). C NMR (150 MHz, metha- acetate (20 mL) three times. The organic layers were combined and
nol-d ) δ 170.63, 169.87, 169.68, 164.86, 132.16, 129.94, 129.59, washed with water and brine, dried over anhydrous sodium
28.14, 79.31, 74.51, 71.91, 71.20, 67.30, 61.22, 19.18, 19.09, sulfate, and concentrated in vacuo to give a crude product which
4
1
1
+
8.96. HRMS (ESI): C H NO [M + H] , calculated: 410.1446, was purified using a silica gel column (petroleum ether/ethyl
1
0
9
24
9
2
1
found: 410.1441. [α]D = 38.6 (c = 0.067 MeOH).
acetate 3 : 1) to give 7 (45.1 mg, yield 81%) as a white solid. H
NMR (500 MHz, chloroform-d) δ 8.13–8.01 (m, 2H), 7.59 (t, J = 7.4
Hz, 1H), 7.47 (d, J = 7.8 Hz, 2H), 7.40–7.29 (m, 11H), 7.21–7.17 (m,
(
2S,3R,4S,5R,6R)-2-Amino-4,5-bis(benzyloxy)-6-((benzyloxy)
methyl)tetrahydro-2H-pyran-3-yl benzoate (4B)
4
H), 5.58 (t, J = 3.3 Hz, 1H), 5.16 (dd, J = 10.0, 3.5 Hz, 1H),
To a solution of compound 3A (3.0 g, 7.67 mmol) in MeOH, TEA 4.90–4.82 (m, 3H), 4.64 (d, J = 12.4 Hz, 1H), 4.59–4.55 (m, 2H), 4.27
5.3 mL, 5 eq.) was added. The reaction mixture was stirred at (t, J = 9.5 Hz, 1H), 4.18 (dt, J = 10.2, 3.5 Hz, 1H), 3.76–3.70 (m, 3H),
(
13
room temperature for 2 d, and then MeOH and TEA were removed 3.11 (d, J = 3.5 Hz, 1H). C NMR (125 MHz, chloroform-d) δ
under reduced pressure to give a black oil 5 (2.2 g). The residue 165.87, 149.85, 138.13, 138.01, 137.81, 133.25, 129.87, 129.82,
was dissolved in dry DMF (30 mL). Then benzyl bromide (4.87 mL, 129.68, 128.46, 128.42, 128.41, 128.32, 128.00, 127.95, 127.90,
5
eq.) and sodium hydride (1.6 g, 5 eq.) were added under a nitro- 127.79, 127.76, 127.65, 90.64, 79.69, 78.14, 75.56, 75.12, 74.20,
+
7 4
gen atmosphere and stirred at room temperature for 30 min. Then 73.54, 70.43, 68.78. HRMS (ESI): C34H38NO [M + NH ] , calculated:
the mixture was poured into water (50 mL) and extracted with ethyl 572.2643, found: 572.2628. [α] = −68.3 (c = 0.112, MeOH).
2
0
D
acetate (50 mL) three times. The organic layers were combined and
washed with water and brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo to give a crude product which
(
3
3aS,4aR,7S,8aR,9S,9aR)-9-(Benzyloxy)-2,7-diphenyl-
a,4a,5,8a,9,9a-hexahydro-[1,3]dioxino[4′,5′:5,6]pyrano[2,3-d]
oxazole (9)
was purified using a silica gel column (petroleum ether/ethyl
1
acetate 5 : 1) to give 6 (2.53 g, yield 62%) as a yellow solid. 6: H To a solution of 3A (1.5 g, 3.83 mmol) in MeOH, TEA (2.5 mL,
NMR (600 MHz, chloroform-d) δ 7.97–7.95 (m, 1H), 7.51 (t, J = 7.4 5 eq.) was added. The reaction mixture was stirred at room
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temperature for two days, and after that, MeOH and TEA were (2S,3R,4S,5R,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-
removed under reduced pressure to give a black oil (2.2 g) ((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutanamido)
which was then dissolved in dry acetonitrile (30 mL). tetrahydro-2H-pyran-3-yl benzoate (10b)
Benzaldehyde (2 mL, 2eq) and PTSA (3.5 g, 2 eq.) were added
under a nitrogen atmosphere. After stirring at room tempera-
To a solution of 4B (55.3 mg, 0.1 mmol) in DCM (5 mL), TEA
(3.2 μL, 0.3 mmol), N-tert-butoxycarbonyl-L-aspartic acid 1-methyl
ture for 6 hours, the mixture was poured into water (50 mL)
and extracted with ethyl acetate (50 mL) three times. The
organic layers were combined and washed with water and
brine, dried over anhydrous sodium sulfate, and concentrated
in vacuo to give a crude product which was purified using a
silica gel column (petroleum ether/ethyl acetate 5 : 1) to give
intermediate 8 (1.06 g, yield 79%) as a yellow oil.
To a solution of 8 (45 mg, 1 mmol) in dry DMF, benzyl
bromide (30 μL, 2 eq.) and sodium hydride (12 mg, 2 eq.) were
added under a nitrogen atmosphere. After stirring at room
temperature for 30 min, the mixture was poured into water
ester (36 mg, 0.15 mmol) and HATU (76 mg, 0.2 mmol) were
added. After stirring at room temperature for 6 h, the mixture was
poured into water (20 mL) and extracted with ethyl acetate
(20 mL) three times. The organic layers were combined and
washed with water and brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo to give a crude product which
was purified using a silica gel column (petroleum ether/ethyl
1
acetate 1 : 1) to give 10b (57.1 mg, yield 73%) as a white solid. H
NMR (500 MHz, chloroform-d) δ 8.0–8.0 (m, 2H), 7.6 (ddt, J = 8.7,
7
8
.1, 1.3 Hz, 1H), 7.5–7.4 (m, 2H), 7.4–7.3 (m, 10H), 7.2–7.1 (m,
H), 6.7 (d, J = 9.2 Hz, 1H), 5.7 (d, J = 8.9 Hz, 1H), 5.3 (t, J = 9.3
(20 mL) and extracted with ethyl acetate (20 mL) three times.
Hz, 1H), 5.2 (t, J = 9.3 Hz, 1H), 4.9–4.8 (m, 2H), 4.7 (d, J = 11.1 Hz,
The organic layers were combined and washed with water and
brine, dried over anhydrous sodium sulfate, and concentrated
in vacuo to give a crude product which was purified using a
1
4
3
H), 4.7 (s, 1H), 4.6 (d, J = 10.8 Hz, 1H), 4.5 (d, J = 12.0 Hz, 1H),
.5–4.4 (m, 1H), 3.9 (dt, J = 29.3, 9.1 Hz, 2H), 3.8–3.8 (m, 2H),
.6–3.6 (m, 1H), 3.3 (s, 3H), 2.8–2.8 (m, 1H), 2.7 (dd, J = 16.5, 4.4
silica gel column (petroleum ether/ethyl acetate 10 : 1) to give
13
Hz, 1H), 1.4 (s, 9H). C NMR (125 MHz, chloroform-d) δ 171.4,
1
9
7
7
4
1
1
1
1
7
(42.1 mg, yield 95%). H NMR (500 MHz, chloroform-d) δ
.98–7.91 (m, 2H), 7.59–7.52 (m, 1H), 7.51–7.42 (m, 5H),
.42–7.27 (m, 7H), 6.06 (d, J = 8.1 Hz, 1H), 5.64 (s, 1H),
.94–4.84 (m, 2H), 4.77 (dd, J = 8.1, 4.6 Hz, 1H), 4.44 (dd, J =
0.6, 5.2 Hz, 1H), 3.86–3.73 (m, 3H), 3.66 (td, J = 9.6, 5.1 Hz,
1
1
7
70.7, 166.7, 155.6, 137.8, 137.7, 137.7, 133.6, 129.9, 129.1, 128.5,
28.4, 128.3, 128.0, 127.9, 127.9, 127.8, 127.8, 83.0, 80.0, 78.3,
7.5, 76.7, 75.5, 75.1, 73.6, 73.6, 68.0, 52.1, 50.8, 49.8, 37.8, 28.3.
+
HRMS (ESI): C H N O [M + H] , calculated: 783.3487, found:
44 51 2 11
20
783.3499. [α]D = 250.0 (c = 0.011, MeOH).
1
3
H). C NMR (125 MHz, chloroform-d) δ 164.83, 137.80,
37.31, 132.39, 128.99, 128.62, 128.47, 128.41, 128.20, 128.03,
27.82, 126.72, 126.07, 101.34, 95.35, 80.74, 80.62, 78.85,
3.20, 68.83, 62.85. HRMS (ESI): C27
(
2S,3R,4S,5R,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-2-(p-
tolylamino) tetrahydro-2H-pyran-3-yl benzoate (10c)
+
H
26NO
5
[M + H] , calcu-
To a solution of 4B (55.3 mg, 0.1 mmol) in DCM (5 mL), TEA (3
drops), cupric acetate monohydrate (18.2 mg, 0.1 mmol) and
p-tolylboronic acid (39 mg, 0.3 mmol) were added. After stirring at
room temperature for two days, the mixture was poured into water
(20 mL) and extracted with ethyl acetate (20 mL) three times. The
organic layers were combined and washed with water and brine,
dried over anhydrous sodium sulfate, and concentrated in vacuo to
give a crude product which was purified using a silica gel column
lated: 444.1805, found: 444.1815.
4
-(((2S,3R,4S,5R,6R)-3-(Benzoyloxy)-4,5-bis(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)amino)-4-
oxobutanoic acid (10a)
To a solution of 4B (55.3 mg, 0.1 mmol) in THF (5 mL), TEA
(3.2 μL, 0.3 mmol) and succinic anhydride (15 mg, 0.15 mmol)
were added. After stirring at room temperature for 3 h, the
mixture was poured into water (20 mL) and extracted with
ethyl acetate (20 mL) three times. The organic layers were com-
bined and washed with water and brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo to give a crude
product which was purified using a silica gel column (pet-
(
petroleum ether/ethyl acetate 3 : 1) to give 10c (16.8 mg, yield
1
2
5%) as a white solid. H NMR (600 MHz, acetone-d
8.4, 1.4 Hz, 2H), 7.66–7.61 (m, 1H), 7.50 (dd, J = 8.3, 7.4 Hz, 2H),
.36–7.28 (m, 10H), 7.16 (m, 5H), 6.93–6.90 (m, 2H), 6.74–6.70 (m,
H), 5.36 (d, J = 9.9 Hz, 1H), 5.22 (t, J = 9.2 Hz, 1H), 5.07 (dd, J =
.9, 9.0 Hz, 1H), 4.91–4.86 (m, 2H), 4.75 (dd, J = 27.2, 11.1 Hz, 2H),
4.62–4.53 (m, 2H), 4.13 (dd, J = 9.3, 8.6 Hz, 1H), 3.84–3.78 (m, 3H),
6
) δ 8.06 (dd, J
=
7
2
9
roleum ether/ethyl acetate 1 : 1) to give 10a (60.3 mg, yield
1
9
8
2
1
=
2%) as a white solid. H NMR (400 MHz, chloroform-d) δ
.04–7.94 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz,
H), 7.39–7.29 (m, 8H), 7.22–7.08 (m, 7H), 6.74 (d, J = 9.1 Hz,
H), 5.29 (t, J = 9.3 Hz, 1H), 5.18 (t, J = 9.2 Hz, 1H), 4.81 (dd, J
10.9, 8.0 Hz, 2H), 4.77–4.63 (m, 2H), 4.52 (dd, J = 17.7, 11.4
1
3
2
1
1
1
.16 (s, 3H). C NMR (150 MHz, acetone-d
38.31, 138.27, 138.07, 132.85, 129.10, 128.87, 128.13, 127.77,
27.70, 127.61, 127.39, 127.23, 127.22, 127.05, 126.93, 126.84,
13.94, 83.34, 83.28, 78.17, 75.29, 74.51, 74.07, 73.68, 72.44, 68.65,
6
) δ 165.32, 143.42,
+
1
9.14. HRMS (ESI): C41
H
42NO
6
[M + H] , calculated: 644.3007,
Hz, 2H), 3.91 (m, 2H), 3.78 (s, 1H), 3.68–3.63 (m, 1H),
20
1
3
found: 644.3010. [α] = 400.0 (c = 0.061, MeOH).
D
2
1
1
8
2
6
.61–2.31 (m, 4H). C NMR (125 MHz, chloroform-d) δ 175.25,
72.24, 166.81, 137.81, 137.63, 137.62, 133.63, 129.81, 128.92,
28.53, 128.38, 128.27, 128.02, 127.86, 127.81, 127.77, 127.71,
(
(
2S,3R,4S,5R,6R)-2-Amino-4-(benzyloxy)-5-hydroxy-6-
hydroxymethyl)tetrahydro-2H-pyran-3-yl benzoate (10d)
2.99, 78.38, 77.51, 76.56, 75.43, 75.06, 73.55, 67.95, 30.71,
9.66. HRMS (ESI): C38
76.2517, found: 676.2520. [α] = 59.8 (c = 0.075, MeOH).
+
H
39NNaO
9
[M + Na] , calculated: To a solution of 9 (45 mg, 0.1 mmol) in acetone (3 mL),
2
0
−1
0.25 mL HCl–Et O (2 M L ) and water (25 µL) were added.
D
2
1586 | Org. Biomol. Chem., 2021, 19, 1580–1588
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Paper
After stirring overnight, the reaction mixture was evaporated exploratory experiments. S. D. and Y. Z. contributed to the syn-
under reduced pressure. The residue was washed with di- thetic experiments for reaction condition optimization, sub-
chloromethane three times and then filtered to give 10d strate screening and application of oxazolinoses. Y. S. and
1
(
35.2 mg, yield 94%) as a yellow solid. H NMR (500 MHz, Z. X. contributed to the quantum chemistry calculation of the
DMSO-d ) δ 8.97 (s, 2H), 7.97 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.3 reaction mechanism. J. S., Y. L. and K. C. contributed to the
6
Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.18–7.12 (m, 1H), 7.12–7.03 frequent discussions of the experiments.
(m, 4H), 5.80 (s, 1H), 5.06 (t, J = 9.2 Hz, 1H), 4.87 (d, J = 9.0 Hz,
1
3
H), 4.81 (d, J = 11.5 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H),
1
3
.83–3.74 (m, 2H), 3.62–3.49 (m, 5H). C NMR (125 MHz, Conflicts of interest
DMSO-d
1
6
6
) δ 164.98, 138.17, 133.52, 129.61, 129.57, 128.57,
There are no conflicts to declare.
27.93, 127.45, 127.35, 81.75, 79.48, 78.96, 73.98, 71.90, 69.53,
+
6
0.01. HRMS (ESI): C20H24NO [M + H] , calculated: 374.1598,
found: 374.1596.
Acknowledgements
(
3aS,3a′S,5R,5′R,6R,6′R,7S,7aR,7′S,7a′R)-((S)-4,4′,5,5′,6,6′-
Hexamethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(5-(acetoxymethyl)-
a,6,7,7a-tetrahydro-5H-pyrano[2,3-d]oxazole-2,6,7-triyl)
tetraacetate (11)
-Bromo-3,4,5-methoxybenzonitrile (135.5 mg, 0.5 mmol) and
Financial support from the National Natural Science
Foundation of China (22077131; 81872797), the National
Science & Technology Major Project “Key New Drug Creation
and Manufacturing Program”, China (2018ZX09711002), and
the Natural Science Foundation of Shanghai, China
3
2
β-D-glucose pentaacetate (195 mg, 0.5 mmol) were used as
described for 3A to give compound 3R (131.4 mg, yield 44%)
as a yellow oil. H NMR (500 MHz, chloroform-d) δ 7.17 (s,
(
19ZR1467800) is gratefully acknowledged.
1
1
9
2
2
1
1
6
H), 6.10 (d, J = 7.7 Hz, 1H), 5.37–5.35 (m, 1H), 5.00 (dd, J =
.2, 4.8 Hz, 1H), 4.63 (dd, J = 7.8, 4.0 Hz, 1H), 4.36–4.29 (m,
H), 4.23–4.19 (m, 1H), 3.94 (s, 3H), 3.90 (s, 6H), 2.15 (s, 3H),
.10 (s, 3H), 2.02 (s, 3H). C NMR (125 MHz, chloroform-d) δ
70.20, 169.07, 168.97, 165.31, 152.08, 151.20, 145.62, 122.64,
10.06, 109.49, 92.96, 75.85, 70.63, 67.62, 66.83, 62.52, 60.72,
Notes and references
1
2
3
4
5
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1
3
(
4
b) U. Carlo and K. Yasuhiro, Curr. Opin. Chem. Biol., 2018,
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+
20
2
[M + H] , calculated: 560.0762, found: 560.0761. [α] = 45.775
D
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c = 0.142, MeOH).
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1
(38.0 mg, yield 40%) as a yellow oil. H NMR (500 MHz, chloro-
(a) B. Ghosh and S. S. Kulkarni, Chem. – Asian J., 2020, 15,
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4
2
50; (b) W. Li, J. B. McArthur and X. Chen, Carbohydr. Res.,
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4
13
(s, 6H), 2.09 (s, 6H), 2.08 (s, 6H), 1.99 (s, 6H). C NMR
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(
1
6
125 MHz, chloroform-d) δ 170.63, 169.52, 169.24, 166.93,
52.88, 151.96, 121.16, 108.46, 92.58, 71.78, 67.53, 67.47,
2.73, 60.88, 60.56, 56.21, 20.74, 20.59. HRMS (ESI):
+
(
f) V. K. Madduluri and A. K. Sah, Carbohydr. Res., 2019,
C
44
2
H
53
N
2
O
22 [M + H] , calculated: 961.3084, found: 961.3092.
0
485, 107798.
[α] = −139.4 (c = 0.061, MeOH).
D
6
7
J. Zheng, K. B. Urkalan and S. B. Herzon, Angew. Chem., Int.
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