A facile and stereoselective synthesis of 3,4,6-tri-O-acetyl-2-deoxy-2- phthalimido-β-D-glucopyranosyl chloride

Article abstract of DOI:10.3184/174751913X13728407114482

Acetylation of D-glucosamine catalysed by sulfuric acid and N-phthaloylation of the glucosyl acetate yielded 1,3,4,6- tetra-O-acetyl-2- deoxy-2-phthalimido-α-D-glucopyranose. This gave the corresponding pure β-glucosyl chloride upon treatment with PCl₅-BF₃. An anomeric chlorination with thionyl chloride combined with the Lewis acids (ZnCl₂, SnCl₄ and BiCl₃) resulted in an α/β anomer mixture.

Full text of DOI:10.3184/174751913X13728407114482

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 467
AUGUST, 467–469
A facile and stereoselective synthesis of 3,4,6-tri-O-acetyl-2-deoxy-2-
phthalimido-β-D-glucopyranosyl chloride
Zhiling Caoa,b*, Wenjie Liua, Yingying Qua, Guowei Yaoc, Dachao Gaoa and Weiwei Liua
aJiangsu Key Laboratory of Marine Biotechnology, Huaihai Institute ofTechnology, Lianyungang 222005, P. R. China
bJiangsu Marine Resources Development Research Institute, Lianyungang 222001, P. R. China
cSchool of Life Science, Beijing Institute ofTechnology, Beijing 100081, P. R. China
Acetylation of D-glucosamine catalysed by sulfuric acid and N-phthaloylation of the glucosyl acetate yielded 1,3,4,6-
tetra-O-acetyl-2-deoxy-2-phthalimido-α-D-glucopyranose. This gave the corresponding pure β-glucosyl chloride upon
treatment with PCl5-BF3. An anomeric chlorination with thionyl chloride combined with the Lewis acids (ZnCl2, SnCl4
and BiCl3) resulted in an α/β anomer mixture.
Keywords: 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl chloride, anomeric chlorination, glucosyl chloride,
stereoselective synthesis
2-Deoxy-2-amino glucosides and other amino sugar glycosides
are common structural units found in various oligosaccha-
rides.1,2 N-Phthalimido-protected glycosyl donors have been
extensively studied, and their use has become a method of
choice for the synthesis of 1,2-trans glycosides and oligosac-
charides of the 2-amino-2-deoxysugar(1).3–5 Phthalimido-pro-
tecting groups play a key role in the stereoselective synthesis
of 1,2-trans glycoside through neighbouring-group participa-
tion.6 However, phthaloylation of 1 with phthalic anhydride
followed by acetylation with acetic anhydride resulted in low
yields of mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-
α-D-glucopyranose (3) and its β anomer.7 Kochetkov8 even
developed a method of preparation 3 from the anomeric
mixtures via fractional crystallisation. Subsequent treatment
of 3 with HCl or AlCl3 gave the corresponding β-glucosyl
halides (4b).9,10 However, this method is time-consuming and
results in a very low yield.
Compound 3 and 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-
β-D-glucopyranosyl chloride (4b) are important glycosyl
donors.11–14 In this study, we used a facile, two-step method
to synthesise pure α-anomeric 3 directly from 1, which gave
the corresponding pure β-glucosyl chloride 4b upon treatment
with PCl5-BF3 in high yield. The effect of the chlorination
reagent on stereoselective chlorination of the anomeric center
of 3 was also investigated.
was used to catalyse acetylation and facilitate the conversion
of the glucosamine hydrochloride salt into its hemisulfate (2).
α-Glucosyl acetate 2 was preferentially formed because of its
higher thermodynamic stability. Ethanol was subsequently
added to the reaction solvent to decompose the excess acetic
anhydride and precipitate the product. Compound 2 was
identified as an α-anomer because of the small J1,2 anomeric
1
coupling constant (3.3 Hz) in its H NMR spectra.16,21 The
amino proton signals were observed at δ (H) 8.72 ppm. The
hemisulfate 2 is very sensitive to moisture and it must be stored
under anhydrous conditions.
The synthesis of the N-phthalimido derivative from the
α-tetraacetate 2 was accomplished using a modified method.7
Acetylation of the anomeric hydroxyl group makes phtha-
loylation of the 2-amino group difficult by decreasing the
nucleophilicity of the amino group. In this study, 3 was
efficiently prepared using 4-dimethylaminopyridine (DMAP)
as a powerful catalyst for N-acylation by neutralisation of the
hemisulfate 2 with triethylamine and then phthaloylation
with phthalic anhydride. Data from 1H NMR showed that the
α-configuration was maintained at the anomeric center during
N-phthaloylation.
Results and discussion
Our strategy is based on acetylation of all of the hydroxyl
groups of 1 before phthaloylation of the 2-amino group. Pure
compound 3 can be easily synthesised from 1,3,4,6-tetra-
O-acetyl-2-amino-2-deoxy-α-D-glucopyranose (Scheme 1).
Previous methods for the synthesis of 1,3,4,6-tetra-O-acetyl-2-
amino-2-deoxy-α-D-glucopyranose included N-protection of 1
with propargyloxycarbonyl15 or diethyl ethoxymethylene
malonate16,17 and hydrolysis of N-acetyl-D-glucosamine oxazo-
line.18 However, these methods are multistep processes involv-
ing lengthy protection and deprotection steps. Therefore, in
this study, we used a simple and efficient method for synthesis-
ing 1,3,4,6-tetra-O-acetyl-2-deoxy-α-D-glucopyranose hemis-
ulfate (2) directly from 1 by acetylation with sulfuric acid as a
catalyst.
Sulfuric acid is commonly used in the synthesis of sugar
acetates19 and in the catalysis of the anomerisation of glucose
pentacetates into α-anomer.20 Selective acetylation of the
hydroxyl group of glucosamine 1 was achieved by sulfuric
acid catalysis, which blocks the amino group by salt forma-
tion. In our experiment, 1.0 equiv of concentrated sulfuric acid
Scheme 1 Reagent and condition: (a) Ac2O, concentrated
sulfuric acid, rt; (b) (i) phthalic anhydride, triethylamine,
DMAP, CH2Cl2 rt; (ii) Ac2O, rt; (c) PCl5/BF3.
* Correspondent. E-mail: zhiling_cao@126.com

468 JOURNAL OF CHEMICAL RESEARCH 2013
Table 1 Yelds and α/β rations of chlorination product of
N-phthalimido derivativesa
In conclusion, we have developed a new procedure for the
efficientsynthesisof3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-
β-D-glucopyranosyl chloride (4b) from the 2-amino-2-deoxy-
sugar D-glucosamine in 61% yield over three steps. Key inter-
mediates, 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-α-Dgluco-
pyranose hemisulfate and its N-phthalimido derivative, were
also stereoselectively synthesised. PCl5–BF3 was shown to be
an effective chlorination reagent for the β-stereoselective chlo-
rination of the anomeric centre of N-phthalimido glucosamine
acetate.
Entry
Chlorination agentb
Time/h
Yield/% α/β ratioc
Experimental
1
2
3
4
SOCl2/BiCl3
SOCl2/SnCl4
SOCl2/ZnCl2
PCl5/BF3
12
4
86
90
81
95
41:59
55:45
44:56
β only
Melting points were determined using a Tianjin Skylight XT4A micro
melting point apparatus and are reported uncorrected. NMR spectra
were measured using a Bruker Avance (300 MHz) spectrometer with
tetramethylsilane as the internal standard. Microanalysis was carried
out using a Perkin Elmer 2400 analyser. Optical rotation measurements
were carried out on a WZZ-2S automatic polarimeter at 589.4 nm
(Na D-line). A silica gel GF254 plate (Qingdao Haiyang Chemical
Plant, Qingdao, China) was used for TLC under UV light (λ 254 nm).
All other chemicals for synthesis were purchased from TCI (Tokyo,
Japan) unless otherwise specified.
2
0.5
a All reactions performed in CH2Cl2 at room temperature. b SOCl2
(2.0 equiv.), BiCl3 (0.1 equiv.).26 SOCl2 (2.0 equiv.), SnCl4
(2.0 equiv.).25 SOCl2 (2.0 equiv.), ZnCl2 (4.0 equiv.).24 PCl5
(1.2 equiv.), BF3 (0.1 equiv.).23 c 1H NMR ratio.
1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-α-Dglucopyranose hemi-
sulfate (2): D-Glucosamine hydrochloride (5.0 g, 23.2 mmol) was dis-
solved into acetic anhydride (18.0 mL, 190 mmol). The mixture was
cooled in an ice-salt bath and stirred for 10 min. Then, concentrated
sulfuric acid (1.3 mL, 23.2 mmol) was carefully added into the mix-
ture. The cooling bath was removed, and the mixture was again stirred
at room temperature for 12 h, during which time the reaction solution
became clear. Ethanol (30 mL) was added to the solution, causing the
formation of a white precipitate. The solution containing the precipi-
tate was vigorously stirred for another 30 min. Then, the precipitate
was filtered, washed with ethyl acetate, and dried to yield 7.98 g
(86.8%) of 2. M.p. 186–188 °C; [a]2D4 + 116.2° (c 0.2, H2O); IR (KBr)
(vmax, cm−1): 3442, 3291, 1702, 1644, 1562, 1412, 1331, 1166, 1021,
795, 642; 1H NMR (300 MHz, DMSO) δ 8.72 (bs, 3H, -NH3SO4), 6.22
(d, J1,2 = 3.3 Hz, 1H, H-1), 5.25 (t, 1H, J3,4 = J2,3 9.6 Hz, H-3), 5.01 (t,
J4,5 = J3,4 9.6 Hz, 1H, H-4), 4.23–4.08 (m, 2H, H-6a, H-5), 3.99 (d,
J6a,6b 10.7 Hz, 1H, H-6b), 3.83 (dd, J2,3 10.7 Hz, J1,2 3.0 Hz, 1H, H-2),
2.19, 2.05, 2.00, 1.98 (4s, 12H, OCOCH3); 13C NMR (75 MHz,
DMSO) δ 169.93, 169.17, 168.64 (C=O), 88.23 (C-1), 68.97 (C-2),
68.81 (C-5), 67.41 (C-3), 61.04 (C-4), 50.22 (C-6), 20.81, 20.71,
20.44, 20.26 (CH3). Anal. Calcd for C28H44N2O22S: C, 42.42; H, 5.59;
N, 3.53. Found: C, 42.70; H, 5.66; N, 3.59%.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-phthalimido-a-D-glucopyranose
(3): Phthalic anhydride (1.00 g, 6.75 mmol), triethylamine (1 mL),
and DMAP (88.8 mg, 0.73 mmol) were added to a stirred solution of
2 (1.8 g, 4.54 mmol) in CH2Cl2 (20 mL). The mixture was stirred for
1 h at room temperature. Then acetic anhydride (1 mL) was added and
the mixture was again stirred for 24 h. The progress of the reaction
was monitored by TLC (silica, ethyl acetate: petroleum ether 2:3), and
ethanol (4 mL) was added after completion. The solvents evaporated
after 20 min of stirring. The residue was extracted with ethyl acetate
(10 mL), washed with water, dried (MgSO4). After complete evapora-
tion of the ethyl acetate, the residue was recrystallised from ethanol to
Shoda22 has reviewed the glycosyl chloride synthesis.
Phosphorus pentachloride (PCl5) or thionyl chloride combined
with Lewis acids, such as BF3,23 ZnCl2,24 SnCl4,25 and BiCl3,26
are excellent chlorinating reagents which have been widely
used for the preparation of anomerically pure α or β-glucosyl
chlorides. However, there are few studies on the chlorination
of D-glucosamine using these reagents. Hence, we investigated
the chlorination reaction of N-phthalimido glucosamine
acetate based on the previously studied methods. The anomeric
composition of the chloride products was then determined by
1H NMR spectroscopy.
Table 1 shows that treatment of 3 with PCl5 or thionyl
chloride combined with Lewis acids provided good yields of
glucosyl chlorides. Among the reagents that were screened,
only PCl5 gave the pure β-anomeric product 4b. Chlorination
with thionyl chloride/Lewis acid resulted in an α/β anomer
mixture with ratios ranging from 4:6 to 6:4.
The proposed mechanism for the β-selective chlorination
with PCl5 involves the formation of a bicyclic N-acyloxonium
ion intermediate (Scheme 2).23 Although it had been demon-
strated earlier the chlorination was limited to 1,2-trans acetate,
the α-glucosyl acetate 3 can also readily react with PCl5.
Thionyl chloride-mediated chlorination of N-phthalimido
glucosamine acetates exhibited poorer α-stereoselectivity
compared with the glycosyl acetates. This result demonstrates
that the stereoselective chlorination of the anomeric group is
greatly affected by the phthaloyl group on the nitrogen atom
regardless of whether the reaction proceeds via the SN1 or SN2
mechanism.
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2013 469
yield 1.65 g (76.1%) of 3. M.p. 128–129 °C (lit.8 128–131 °C); [a]2D4 +
115.5° (c 0.5, CHCl3); H NMR (300 MHz, CDCl3) δ 7.80–7.87 (m,
Received 23 April 2013; accepted 20 May 2013
Paper 1301910 doi: 10.3184/174751913X13728407114482
Published online: 9 August 2013
1
2H), 7.77–7.71 (m, 2H), 6.56 (dd, J2,3 11.5, J3,4 9.2 Hz, 1H, H-3), 6.28
(d, J1,2 3.3 Hz, 1H, H-1), 5.16 (t, J3,4 = J4,5 9.6 Hz, 1H, H-4), 4.71 (dd,
J2,3 11.6, J1,2 3.3 Hz, 1H, H-2), 4.41–4.25 (m, 2H, H-6a, H-5), 4.17–
4.09 (m, 1H, H-6b), 2.12, 2.08, 2.05, 1.87 (4s, 12H, OCOCH3); 13C
NMR (75 MHz, CDCl3) δ 170.82, 169.92, 169.68, 169.47 (O–C=O),
167.54 (2C=O), 134.60 (2C-arom), 123.87 (2C-arom), 90.65 (C-1),
70.30 (C-5), 69.50 (C-3), 67.12 (C-4), 61.64 (C-6), 52.93 (C-2), 21.11,
20.87, 20.78 (CH3).
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We thank the PAPD Program (A Project Funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions) and the Open-ended Funds of Jiangsu
Key Laboratory of Marine Biotechnology, Huaihai Institute of
Technology (No. 2011HS001) and Jiangsu Marine Resources
Development Research Institute (No. JSIMR201204) for
support.

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