Synthesis of 3-C-(methyl β-D-xylofuranosid-3-yl)-5-phenyl-1,2,4-oxadiazole

Article abstract of DOI:10.1016/S0008-6215(99)00106-8

Nucleophilic addition of KCN to 5-O-benzoyl-1,2-O-isopropylidene-α-D-erythro-pentofuranos-3-ulose gave the xylo cyanohydrin stereoselectively. Several xylos-3-yl-1,2,4-oxadiazole derivatives were synthesized from this cyanohydrin and were converted into 3-C-(methyl β-D-xylofuranosid-3-yl)-5-phenyl-1,2,4-oxadiazole. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00106-8

www.elsevier.nl/locate/carres
Carbohydrate Research 318 (1999) 157–161
Note
Synthesis of 3-C-(methyl
-xylofuranosid-3-yl)-5-phenyl-1,2,4-oxadiazole
b-
D
Minglong Zhang, Huyi Zhang, Zhenjun Yang, Lingtai Ma, Jimei Min, Lihe Zhang *
National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
Beijing Medical Uni6ersity, Beijing 100083, People’s Republic of China
Received 30 November 1998; accepted 30 March 1999
Abstract
Nucleophilic addition of KCN to 5-O-benzoyl-1,2-O-isopropylidene-a-
D-erythro-pentofuranos-3-ulose gave the
xylo cyanohydrin stereoselectively. Several xylos-3-yl-1,2,4-oxadiazole derivatives were synthesized from this
cyanohydrin and were converted into 3-C-(methyl b-D-xylofuranosid-3-yl)-5-phenyl-1,2,4-oxadiazole. © 1999 El-
sevier Science Ltd. All rights reserved.
Keywords: Xylosyl 1,2,4-oxadiazole derivatives; Neighboring-group participation effect; Asymmetric synthesis; Isocarbonucleoside
HIV activity [9]. In this paper, we describe the
1. Introduction
stereoselective synthesis of isocarbonucleoside,
3-C-(methyl b- -xylosid-3-yl)-5-phenyl-1,2,4-
D
The synthesis of isonucleosides and isocar-
bonucleosides has been carried out in a search
for compounds having anticancer and antivi-
ral activities [1–3]. Isocarbonucleosides consti-
tute a class of nucleoside analogues in which
the nucleobase is linked by a carbon–carbon
bond to a ribose carbon other than C-1. It is
anticipated that isocarbonucleosides may have
increased chemical and enzymatic stability un-
der physiological conditions. The synthesis of
carbonucleosides has been reported by several
laboratories [4–6]. We have described the syn-
oxadiazole (10) (see Scheme 1) for a study of
its biological activities.
2. Results and discussion
5-O-Benzoyl-1,2-O-isopropylidene-a-
D
-ery-
thro-pentos-3-ulose (1) was prepared from
D
-
xylose [10,11]. Addition of cyanide ion to the
carbonyl group in ketose 1 took place
stereoselectively to give only one isomer, 2.
The stereoselectivity was probably because of
the steric hindrance by the 5-substituent on
the upper face of the furanose ring to the
approaching cyanide ion. Benzoylation of 2
gave the dibenzoate 3, which was converted
into the key intermediate, the amidoxime 4,
with hydroxylamine in methanol. Compound
4 was then condensed with acetic anhydride,
thesis of
D
-xylopyranosyl-1,2,4-oxadiazoles
-xylopyranosyl car-
and have found that
D
bonucleosides have potent biological activities
[7,8]. Recently, a number of 5-aryl-1,2,4-oxa-
diazolines have been shown to possess anti-
* Corresponding author. Fax: +86-10-6201-5584.
E-mail address: zdszlh@mail.bjmu.edu.cn (L. Zhang)
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00106-8

158
M. Zhang et al. / Carbohydrate Research 318 (1999) 157–161
Scheme 1. (i) KCN–Et2O–H2O; (ii) BzCl–Py; (iii) NH2OH–CH3OH; (iv) Ac2O, (CH3CH2CO)2O or benzoyl chloride, respec-
tively; (v) MeOH–NaOMe, pH 7–8, 1 h; and (vi) 1% anhydrous HCl–MeOH.
propanoic anhydride, and benzoyl chloride to
give the 1,2,4-oxadiazole derivatives 5, 6, and
7, respectively. Interestingly, when compounds
5, 6, and 7 were treated with sodium methox-
ide in methanol at pH 7–8 and at room
temperature (rt) for 1 h, only one product, the
5-phenyloxadiazole 8, was obtained in yields
of 72–95%. In contrast, after 10 min, the
intermediate 11 was isolated. In general, a
5-O-benzoyl group on a furanose ring can be
debenzoylated more readily than a 3-O-ben-
zoyl group. However, no 5-O-debenzoyl-3-O-
benzoyl intermediates were found in the
foregoing reactions. The 3-benzoyl group
probably undergoes intramolecular replace-
ment through neighboring participation
(Scheme 2). Witanowski et al. reported that an
increase of solvent polarity favors delocaliza-
tion of electrons from oxygen to nitrogen with
concomitant accumulation of charge on N-4
more than on N-2 in oxadiazole systems [12].
Conjugations between the benzene and oxadi-
azole rings make the system more stable. The
intramolecular replacements of 5, 6, and 7
result in the same product, 8, by way of 11.
The structures of 8 and 11 have been estab-
lished by X-ray crystallographic analysis (Fig.
1).
When 8 was treated under reflux in 1%
hydrochloric acid in methanol, a 1:1 mixture
of a and b methyl xylosides 9 and 10 was
obtained. To modify this ratio, 8 was treated
with 1% anhydrous HCl–anhydrous methanol
at rt, giving 9 and 10 in 1:10 ratio. Moreover,
when the reaction temperature was kept at
−10 °C, only a trace of the isomer 9 was
formed. The isomer can be easily isolated by
column chromatography or recrystallization.
It is suggested that in aqueous methanol and
at high temperature, the glycosylation pro-
ceeds by an SN1 process to afford the 1:1
anomeric mixture. However, with anhydrous
methanol and low temperature, the reaction
proceeds more by SN2 nucleophilic attack,
which results in a high ratio of the b isomer
1
10. The H NMR spectra of 9 and 10 confi-
Scheme 2. A possible mechanism for intramolecular replacement in 5, 6, and 7.

M. Zhang et al. / Carbohydrate Research 318 (1999) 157–161
159
Fig. 1. The X-ray crystal structures of 8 and 11.
rmed the cis and trans configurations of H-1
Bz–H-p), 8.04 (q, 2 H, Bz–H-o); FABMS: m/z
320 [M+1]+. Anal. Calcd for C16H18O6N2: C,
60.18; H, 5.36; N, 4.39. Found: C, 60.12; H,
5.37; N, 4.28.
and H-2 of 9 and 10, respectively.
3. Experimental
1,2-O-Isopropylidene-3,5-di-O-benzoyl-3-C-
cyano-h- -xylofuranose (3).—Compound 2
D
General methods.—Melting points were de-
termined on an X4 melting-point apparatus and
the thermometers were uncorrected. Optical
rotations were determined with a Perkin–
Elmer 243B polarimeter. Mass spectra were
obtained on either ZAB-HS or KYKY-ZHP-5
mass spectrometers. NMR spectra were
recorded on Varian VXR-300 or INOVA-500
spectrometers with Me4Si as the internal stan-
dard. Exchangeable protons were detected by
addition of D2O. Microanalyses were obtained
using a Perkin–Elmer 240C elemental analyzer.
Column chromatography was performed on
silica gel (200–300 mesh) and Silica Gel GF254
was used for TLC and was purchased from the
Qingdao Chemical Company, China.
(1.0 g, 3.1 mmol) was dissolved in a solution of
CH2Cl2 (10 mL) and pyridine (3 mL), and BzCl
(1.1 mL) was added at 0 °C and the mixture was
stirred for 4 days. Water (10 mL) and CH2Cl2
(20 mL) were then added and the organic layer
was separated, washed with 1 M H2SO4 and
water, and dried (Na2SO4) to yield white crys-
tals (1.3 g, 98%), mp 154–156 °C, [h]1D8 −9.34°
1
(c 2.0, EtOAc); H NMR (Me2SO-d6): 1.35 (s,
3 H, CH3), 1.58 (s, 3 H, CH3), 4.79 (d, J5,4 =6.0
Hz, 2 H, H-5), 4.90 (t, J4,5 =6.0 Hz, 1 H, H-4),
5.19 (d, J2,1=3.6 Hz, 1 H, H-2), 6.09 (d,
J1,2=3.6 Hz, 1 H, H-1), 7.54 (q, 2 H, Bz–H-m),
7.73 (t, 1 H, Bz–H-p), 8.01 (q, 2 H, Bz–H-o);
FABMS: m/z 424 [M+1]+. Anal. Calcd for
C23H21NO7: C, 65.24; H, 5.00; N, 3.31. Found:
C, 65.24; H, 5.00; N, 3.31.
1,2 - O - Isopropylidene - 5 - O - benzoyl - 3 - C-
cyano-h-
D
-xylofuranose (2).—A mixture of 1
3-C-Amidoximino-3,5-di-O-benzoyl-1,2-O-
(10 g, 29 mmol), ether (60 mL), water (30 mL)
and KCN (5.66 g, 87 mmol) was stirred vigor-
ously at rt overnight. The organic phase was
separated and dried (Na2SO4). After distilla-
tion, white crystals (9.8 g, 90%) were obtained.
mp 155–157 °C, [h]1D8 +75° (c 2.1, EtOAc); 1H
NMR (Me2SO-d6): 1.32 (s, 3 H, CH3), 1.50 (s,
3 H, CH3), 4.10 (m, 1 H, H-5a), 4.49 (dd, 1 H,
H-4), 4.52 (m, 1 H, H-5a), 4.68 (d, 1 H,
J2,1 =3.5 Hz, H-2), 6.02 (d, 1 H, J1,2=3.5 Hz,
H-1), 7.54 (q, 2 H, Bz–H-m), 7.70 (t, 1 H,
isopropylidene-h- -xylofuranose (4).—Com-
D
pound 3 (10 g, 42 mmol) was treated with
hydroxylamine (90 mmol) to afford the white
crystals [7,8] (6.36 g, 59%), mp 100–104 °C,
[h]1D8 +52.5° (c 1.2, EtOAc); 1H NMR (Me2SO-
d6): 1.25 (s, 3 H, CH3), 1.40 (s, 3 H, CH3), 4.56
(d, J5,4 =6.0 Hz, 2 H, H-5), 4.78 (d, J2,1 =3.6
Hz, 1 H, H-2), 5.00 (t, J4,5 =6.0 Hz, 1 H, H-4),
6.10 (d, J1,2=3.6 Hz, 1 H, H-1), 6.90 (s, 1 H,
–OH, exchangeable), 6.88 (s, 1 H, –OH, ex-
changeable), 8.11–7.41 (m, 10 H, Bz–H), 12.99

160
M. Zhang et al. / Carbohydrate Research 318 (1999) 157–161
3-C-(1,2-O-Isopropylidene-h-
D
-xylofuranos-
(8).—Com-
(s, 2 H, –NH2, exchangeable); FABMS: m/z
457 [M+1]+.
3-yl)-5-phenyl-1,2,4-oxadiazole
pounds 5, 6 or 7 were treated with NaOMe in
MeOH at pH 7–8 for 1 h at rt, to give the
same product 8 in yields of 72–95%, mp
156–157 °C, [h]1D8 +126.2° (c 0.96, EtOAc);
1H NMR (Me2SO-d6): 1.20 (s, 3 H, CH3), 1.33
(s, 3 H, CH3), 3.64 (m, 1 H, H-5b%), 3.77 (m, 1
3-C-(3,5-Di-O-benzoyl-1,2-O-isopropylidene-
h- -xylofuranos-3-yl)-5-methyl-1,2,4-oxadia-
D
zole (5).—A solution of 4 (1.24 g, 2.7 mmol) in
Ac2O (10 mL) was heated at 80 °C under
nitrogen for 20 h. The solvent was distilled off
and the resultant brown syrup was purified on
a column of silica gel chromatography using
petroleum–EtOAc as eluent to give white crys-
H, H-5a%), 4.58 (dd, 1 H, H-4%), 4.67 (d, J2%,1%
=
3.5 Hz, 1 H, H-2%), 4.88 (t, 1 H, exchangeable,
OH-3%), 6.00 (d, J1%,2%=3.5 Hz, 1 H, H-1%), 6.43
(s, 1 H, exchangeable, OH-5%), 7.63 (q, 2 H,
Bz–H-m), 7.72 (t, 1 H, Bz–H-p), 8.12 (q, 2 H,
Bz–H-o). 13C NMR (Me2SO-d6): 26.5 (–CH3),
26.6 (–CH3), 60.0 (C-5%), 78.0 (C-4%), 81.8
(C-2%), 86.0 (C-3%), 104.3 (–C[CH3]2), 111.6
(1%-C), 123.2 (Ph), 127.8 (Ph-m), 129.7 (Ph-o),
133.4 (Ph-p), 169.4 (C-3) 174.8 (C-5); FABMS:
m/z 335 [M+1]+. The crystal system is
orthorhombic, space group P22121, crystal
data: formula (C16H18O6N2)2, unit-cell vol-
ume V=3356.7(3) [3]. The details of unit-
cell parameters are: a=6.732(2), b=15.729
tals (1.06 g, 81%), mp 114–116 °C, [h]D18
+
1
72.95° (c 1.5, EtOAc); H NMR (Me2SO-d6):
1.29 (s, 3 H, –CH3), 1.41 (s, 3 H, –CH3), 2.14
(s, 3 H, –CH3), 4.45 (m, 1 H, H-5%b), 4.76 (dd,
1 H, H-4%), 5.10 (m, 1 H, H-5%a), 5.12 (d,
J2%,1%=3.5 Hz, 1 H, H-2%), 6.20 (d, J1%,2%=3.5
Hz, 1 H, H-1%), 8.11–7.50 (m, 10 H, Bz–H);
FABMS: m/z 481 [M+1]+. Anal. Calcd for
C25H24N2O8: C, 62.50; H, 5.03; N, 5.83.
Found: C, 62.68; H, 5.07; N, 5.69.
3-C-(3,5-Di-O-benzoyl-1,2-O-isopropylidene-
h- -xylofuranos-3-yl)-5-ethyl-1,2,4-oxadiaz-
D
ole (6).—Compound 4 (740 mg, 1.6 mmol)
was treated with propanoic anhydride (5 mL),
as in the procedure just described for the
preparation of 5, to give 6 (720 mg, 90%), mp
,
(1), c=31.701(1) A. Four molecules are con-
tained in one unit cell Z=4.
3-C-(Methyl h- -xylofuranosid-3-yl)-5-phe-
D
1
109–110, [h]1D8 +61.25° (c 0.8, EtOAc); H
nyl-1,2,4-oxadiazole (9) and 3-C-(methyl i- -
D
NMR (Me2SO-d6): 0.97 (t, 3 H, J=7.5 Hz,
–CH3), 1.28 (s, 3 H, –CH3), 1.42 (s, 3 H,
–CH3), 2.45 (q, 2 H, J=7.5 Hz, –CH2), 4.44
(m, 1 H, H-5%), 4.74 (dd, 1 H, H-4%), 5.09 (m,
1 H, H-5%%), 5.12 (d, J2%,1%=3.5 Hz, 1 H, H-2%),
6.18 (d, J1%,2=3.5 Hz, 1 H, H-1%), 8.10–7.47
(m, 10 H, Bz–H); FABMS: m/z 495 [M+1]+.
Anal. Calcd for C26H26N2O8: C, 63.15; H,5.30;
N, 5.66. Found: C, 63.25; H, 5.29; N, 5.61.
3-C-(3,5-Di-O-benzoyl-1,2-O-isopropylidene-
xylofuranosid-3-yl)-5-phenyl-1,2,4-oxadiazole
(10).—Compound 8 (470 mg, 1.4 mmol) was
treated with 1% anhydrous HCl–MeOH at rt
to give 9 (33 mg, 7.6%) and 10 (335 mg, 77%),
isolated by column chromatography using
petroleum–EtOAc as eluent. Compound 9 was
colorless crystals: mp 146–147 °C, [h]D18
+
1
25.7° (c 0.93, EtOAc); H NMR (Me2SO-d6):
3.42 (s, 3 H, OCH3-1%), 3.86 (dd, 1 H, H-4%),
3.96 (m, 2 H, H-5), 4.03 (d, 1 H, H-2%), 4.70 (d,
J1%,2%=0.0 Hz, 1 H, H-1%), 5.08 (1 H, OH-5%,
exchangeable), 5.09 (1 H, OH-2%, exchange-
able), 6.38 (1 H, OH-3%, exchangeable), 7.64
(m, 2 H, Ph–H), 7.70 (m, 1 H, Ph–H), 8.11 (d,
2 H, Ph–H); 13C NMR (Me2SO-d6): 56.0
(OCH3), 66.3 (C-4%), 69.0 (C-5%), 70.7 (C-2%),
99.7 (1%-C), 123.5 (Ph), 127.7 (Ph-m), 129.6
(Ph-o), 133.1 (Ph-p), 171.6 (C-3), 174.2 (C-5);
FABMS: m/z 309 [M+1]+. Anal. Calcd for
C14H16N2O6: C, 54.54; H, 5.23; N, 9.08.
Found: C, 54.59; H, 5.26; N, 9.10. Com-
pound 10 was colorless crystals: mp 181–
h - - xylofuranos-3-yl)-5-phenyl-1,2,4-oxadia-
D
zole (7).—Compound 4 (640 mg, 1.4 mmol)
was treated with BzCl (480 mg), as described
for the preparation of 5, to give 7 (660 mg,
85%), mp 154–155 °C, [h]1D8 +95.22° (c 0.77,
1
EtOAc); H NMR (Me2SO-d6): 1.33 (s, 3 H,
–CH3), 1.47 (s, 3 H, –CH3), 4.55 (m, 1 H,
H-5b%), 4.91 (dd, 1 H, H-4%), 5.22 (m, 1 H,
H-5a%), 5.38 (d, 1 H, J2,1=3.6 Hz, H-2%), 6.32
(d, J1,2 =3.6 Hz, 1 H, H-1%) 8.08–7.30 (m, 15
H, Bz–H, Ph–H); FABMS: m/z 557 [M+
1]+. Anal. Calcd for C31H28N2O8: C, 66.90; H,
5.07; N, 5.03. Found: C, 66.97; H, 5.32; N,
4.96.
1
82 °C, [h]1D8 −46.9° (c 1.6, EtOAc); H NMR
(Me2SO-d6): 3.40 (1 H, H-2%), 3.41 (s, 3 H,

M. Zhang et al. / Carbohydrate Research 318 (1999) 157–161
161
OCH3-1%), 3.71 (dd, 1 H, H-4%), 3.79 (m, 1 H,
H-5b%), 3.96 (m, 1 H, H-5a%), 4.92 (d, J1%,2%
Found: C, 62.97; H, 5.10; N, 6.40. The crys-
tals belong to the orthorhombic system, space
group P212121, unit-cell parameters: a=
=
8.0 Hz, 1 H, H-1%), 5.30 (1 H, OH-5%, ex-
changeable), 5.44 (1 H, OH-2%, exchangeable),
5.74 (1 H, OH-3%, exchangeable), 7.65 (m, 2 H,
Ph–H), 7.71 (m, 1H, Ph–H), 8.13 (d, 2 H,
Ph–H); 13C NMR (Me2SO-d6): 55.9 (OCH3),
63.9 (C-5%), 72.2 (C-4%), 75.4 (C-3%), 78.2 (C-2%),
102.2 (C-1%), 123.6 (Bz), 127.7 (Bz-m), 129.6
(Bz-o), 133.1 (Bz-p), 171.0 (C-3), 173.4 (C-5);
FABMS: m/z 309 [M+1]+. Anal. Calcd for
C14H16N2O6 (308.29): C, 54.54; H, 5.23; N,
9.08. Found: C, 54.43; H, 5.32; N, 9.07.
,
10.839(4), b=12.016(3), c=16.230(7) A, unit-
cell volume V=2113.8(13) [3]. The number of
molecules in one unit cell Z=4.
Acknowledgements
The authors appreciate the financial support
of the National Natural Science Foundation
of China and thank Professor Y.Z. Ling for
helpful discussions.
3-C-(5-O-Benzoyl-1,2-O-isopropylidene-h- -
D
xylofuranos - 3 - yl) - 5 - phenyl - 1,2,4-oxadiazole
(11).—Compounds 5, 6, or 7 were treated
with NaOMe in MeOH at pH 7–8 for 10 min
at rt. The mixture was extracted with EtOAc,
the organic phase was separated and dried
(Na2SO4). Evaporation afforded colorless
crystals of 11, isolated by column chromatog-
raphy eluting with petroleum–EtOAc, mp
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1
130–131 °C, [h]1D8 +49.4° (c 1.13, EtOAc); H
NMR (Me2SO-d6): 1.25 (s, 3 H, CH3), 1.40 (s,
3 H, CH3), 4.56 (m, 2 H, H-5%), 4.77 (d,
J2%,1%=3.5 Hz, 1 H, H-2%), 4.98 (m, 1 H, ex-
changeable, OH-4%), 6.09 (d, J1%,2=3.5 Hz, 1
H, H-1%), 6.87 (s, 1 H, exchangeable, OH-3%),
8.11–7.42 (m, 10 H, Bz–H, Ph–H); 13C NMR
(Me2SO-d6): 26.5 (–CH3), 26.6 (–CH3), 62.5
(C-5%), 78.0 (C-4%), 78.4 (C-2%), 86.0 (C-3%),
104.6 (CꢀO), 112.1 (1%-C), 123.0 (Bz-p), 127.8
(Bz-m), 128.6 (Bz-m), 129.1 (Bz-o), 129.3 (Bz-
p), 129.6 (Bz-o), 133.4 (Bz-3, 3%), 165.4 (–
C[CH3]2), 169.3 (C-3), 174.9 (C-5); FABMS:
m/z 439 [M+1]+. Anal. Calcd for
C23H22N2O7: C, 63.01; H, 5.06; N, 6.39.
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.