Stereoselective synthesis, structural characterization, and properties of 1,2-O-isopropylidene-3-C-(5-phenyl-1,2,4-oxadiazol-3-yl)-β-D-psicopyranose

Article abstract of DOI:10.1016/j.bmc.2004.10.023

1,2:4,5-Di-O-isopropylidene-3-C-(5-phenyl-1,2,4-oxadiazol-3-yl) -β-d-psicopyranose 14 was synthesized stereoselectively from 1,2:4,5-di-O-isopropylidene-3-C-amidoximino-3-O-benzoyl-β-d-psicopyranose 8 using a novel procedure. Treatment of 8 with acetic an

Full text of DOI:10.1016/j.bmc.2004.10.023

Bioorganic & Medicinal Chemistry 13 (2005) 353–361
Stereoselective synthesis, structural characterization, and
properties of 1,2-O-isopropylidene-3-C-(5-phenyl-1,2,4-
oxadiazol-3-yl)-b-D-psicopyranose
Jianxin Yu,a,* Suna Zhang,b Zhongjun Li,c Wenjie Lud and Mengshen Caic
aAdvanced Radiological Sciences, Department of Radiology, The University of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines Blvd., Dallas, TX 75390-9058, USA
bDepartment of Chemistry, Xinjiang University, Wulumqi 830046, China
cNational Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking Medical University,
Beijing 100083, China
dDepartment of Chemistry, Wuyi University, Jiangmen 529020, China
Received 17 March 2003; revised 7 October 2004; accepted 9 October 2004
Available online 2 November 2004
Abstract—1,2:4,5-Di-O-isopropylidene-3-C-(5-phenyl-1,2,4-oxadiazol-3-yl)-b-D-psicopyranose 14 was synthesized stereoselectively
from 1,2:4,5-di-O-isopropylidene-3-C-amidoximino-3-O-benzoyl-b-D-psicopyranose 8 using a novel procedure. Treatment of 8 with
acetic anhydride, chloroacetyl chloride, propanic anhydride, or benzoyl chloride causes the 3-O-benzoyl group to undergo an intra-
molecular replacement reaction with neighboring group participation and transfer resulting in a more stable conjugation system of
the 1,2,4-oxadiazol ring. A possible mechanism, as well as structural analysis and bioactivity are described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The synthesis of branched-chain sugars has attracted
considerable attention1 because of their biological
importance. In addition, the incorporation of heterocy-
clic moieties in the carbohydrate framework has gained
much importance.2–4 Recently, a number of oxadiazol-
ines have been reported to possess anti-HIV activity5
prompting us to synthesize heterocyclic moieties as
branched-chain links to carbohydrate fragments.6 We
report here the stereospecific synthesis of 1,2:4,5-di-O-
isopropylidene-3-C-(5-phenyl-1,2,4-oxadiazol-3-yl)-b-D-
psicopyranose (14) from the key intermediate 1,2:4,5-di-
O-isopropylidene-3-C-amidoximino-3-O-benzoyl-b-D-
psicopyranose (8) using a novel approach, as well as a
possible mechanism and the structural confirmation by
spectroscopic data and X-ray crystallographic analysis
(Scheme 1).
Since cyano group can be easily transformed into other
functional groups, cyano branched carbohydrates offer
useful, versatile intermediates in the syntheses of
branched sugars.7–12 Our syntheses started with the
reaction of 1,2:4,5-di-O-isopropylidene-b-D-erythro-2-
hexulopyranose-3-ulose (1), which was prepared in two
steps with high yields.13 Application of the phase trans-
fer catalysis method yielded 1,2:4,5-di-O-isopropylidene-
3-C-cyano-b-D-psicopyranose (2) with complete stereo-
selectivity in nearly quantitative yield.14
Initially, we assumed that reaction of 1 with NaCN in
CH2Cl2–H2O in the presence of tetrabutylammonium
bromide (TBAB) as catalyst possibly would give 2 and
its epimer 1,2:4,5-di-O-isopropylidene-3-C-cyano-b-D-
fructopyranose (3). We expected one of epimer be pre-
dominant due to the attack of cyanide anion on the
carbonyl group from the less hindered side of the
asymmetric
1,2:4,5-di-O-isopropylidene-b-D-erythro-
Keywords: Branched-chain sugars; Oxadiazoles; Synthesis; X-ray;
Bioactivity.
2,3-hexodiulo-2,6-pyranose (1). However, the 13C
NMR spectrum showed a single isomer (2 or 3) was
formed in the synthesis of the cyano branched sugar,
*
Corresponding author. Tel.: +1 214 648 8872; fax: +1 214 648
4538; e-mail: jian-xin.yu@utsouthwestern.edu
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.10.023

354
J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
Ph
R1
O
O
N
HO
N
N
CH3
CH3
N
N
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H2N C
O
O
O
O
R1
O
O
O
O
O
O
v
iv
CH3
vi
i
HO
O
O
O
O
O
O
O
O
CH3
O
O
OH
OR2
OH
O
CH3
OR
CH3
R2
O
O
CH3
O
CH3
CH3
2 R1 = CN, R2 = OH
3 R1 = OH, R 2 = CN
4 R1 = CN, R2 = OAc
CH3
18
10 R1 = Me, R 2 = Bz
8 R = Bz
9 R = H
1
}
}
11 R1 = ClCH2, R2 = Bz
12 R1 = Et, R 2 = Bz
13 R1 = Ph, R 2 = Bz
14 R1 = Ph, R 2 = H
15 R1 = Me, R 2 = Ac
ii
iii
5 R1 = OAc, R 2 = CN
6 R1 = CN, R2 = OBz
7 R1 = OBz, R 2 = CN
}
16 R1 = ClCH2, R2 = ClCH2CO
17 R1 = Et, R 2 = EtCO
Scheme 1. Reagents and conditions: (i) NaCN, TBAB, rt, CH2Cl2–H2O; (ii) Ac2O–Py, rt; (iii) BzCl–Py, 0ꢁC–rt; (iv) NH2OH–CH3OH, reflux;
(v) Ac2O, ClCH2COCl, (CH3CH2CO)2O or benzoyl chloride, respectively, N2, 80 or 120–130ꢁC; (vi) CF3CO2H (90%)–CH2Cl2, reflux, 24h, 80%.
which indicates that the new asymmetric center was
formed with total stereoselectivity.
Table 1. Crystal data and structure refinement for 4
Empirical formula
Formula weight
Temperature
C15H21NO7
327.13
296(2)K
Configuration of 2 or 3 was confirmed by comparison of
the reduced derivative with a known compound.14 Be-
cause 2 or 3 were key intermediates for further syntheses
of heterocyclic branched carbohydrates, an absolute
determination of its structure was deemed to be of value.
At first, we intended to determine the specific configura-
tion of 2 or 3 through the NOESY spectrum of the acet-
ylated derivative 4 or 5 by use of the correlations
between H-1,10 or H-4, H-5, H-6, H-60 and the methyl
protons of acetyl group. Molecular modeling studies
of 4 and 5 showed that the distances between H-1,10
or H-4, H-5, H-6, H-60 and the methyl protons of acetyl
˚
Wavelength
0.71073A
Orthorhombic
P212121
Crystal system
Space group
Unit cell dimensions
˚
a = 7.879(1)A, a = 90ꢁ
b = 14.111(1)A, b = 90ꢁ
c = 15.256(1)A, v = 90ꢁ
1696.2(3)A , 4
1.282mg/m3
0.096mmꢀ1
888
˚
˚
3
˚
Volume, Z
Dcalcd
Absorption coefficient
F(000)
Crystal size
0.10 · 0.20 · 0.20mm
0–180.0ꢁ
h Range for data collection
Limiting indices
˚
0 6 h 6 11, 0 6 k 6 13,
group are all above 2.5A, rendering the NOESY ap-
ꢀ1 6 l 6 24
proach impractical. Fortunately, we obtained suitable
crystals of 4 or 5 from AcOEt–cyclohexane (1:1) for
X-ray crystallographic analysis. X-ray diffraction clearly
indicated that the specific configuration of the 1,2:4,5-di-
O-isopropylidene-3-C-cyano-hex-2-ulopyranose is the
Reflections collected
Independent reflections
Absorption correction
Refinement method
1712
2570 (Rint = 0.0092)
None
Full-matrix least-squares on F2
2570/0/277
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices
structure 2. The pyranoid ring adopts a C1 chair con-
4
3.506
R1 = 0.0700, WR2 = 0.0640
R1 = 0.0490, WR2 = 0.0780
ꢀ1.9(12)
formation. Crystallographic data, and details on data
collection and structure refinement are summarized in
Table 1. The coordinates of the nonhydrogen atoms
are listed in Table 2. The bond lengths and bond angles
are listed in Tables 3 and 4, respectively. The ORTEP
plot for compound 4 is shown in Figure 1, and the pack-
ing arrangement of the molecules is shown in Figure 2.
The stereoselectivity is probably because the steric hin-
drance by the 4,5-O-isopropylidene group limits the
approaching cyanide anion from the upper face of the
pyranose ring, and the addition reaction of NaCN to 1
proceeds in kinetic control manner.15–17
Absolute structure parameter
Extinction coefficient
Largest diff. peak and hole
0.089(10)
ꢀ3
˚
0.270 and ꢀ0.240eA
ation in pyridine. Furthermore, the results are very dif-
ferent from those of 2 in acetylation and benzoylation.
Presumably this happened by pyridine-promoted forma-
tion of 1 followed by attack of the cyanide anion onto
the carbonyl carbon under thermodynamic control
affording 3, which was then benzoylated to form 7.
The structures of 2, 4, 6, and 7 were based on analytical
and spectroscopic data, the IR spectrum of 2 has
absorption for the –OH group at 3389.5cmꢀ1 and 4, 6
and 7 have absorption for the carbonyl groups at
ꢁ1740cmꢀ1, but none had a band for the C„N group
in accord with those reported previously for cyano
branched-chain sugars and glycosyl cyanides.14,19 The
presence of the C„N group was confirmed by the crys-
tallographic data and supported by the 13C resonances
at 115–118ppm. Epimerization of 6 to 7 caused the
Treatment of 2 with benzoyl chloride in pyridine from
0ꢁC to room temperature overnight gave 1,2:4,5-di-O-
isopropylidene-3-C-cyano-3-O-benzoyl-b-D-psicopyra-
nose (6) in a yield of 60% and 1,2:4,5-di-O-isopropylid-
ene-3-C-cyano-3-O-benzoyl-b-D-fructopyranose (7) in a
yield of 30%. Perez-Perez et al.18 have demonstrated that
cyanohydrins could be epimerized to the thermodynam-
ically more stable forms by treatment with 1,8-diazabi-
cyclo[5.4.0]undec-7-ene in acetonitrile. But, there is no
previous report so far of this phenomenon during acyl-

J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
Table 2. Fractional atomic coordinates (· 104) and equivalent thermal
parameters of 4
355
Atom
x
y
z
U(equiv) · 10
O-1
O-2
O-3
O-4
O-5
O-6
O-7
N-1
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-11
C-12
C-13
C-14
C-15
1679(6)
1478 (4)
6524(3)
6003(2)
5977(3)
6796(3)
6108(2)
7708(3)
8934(3)
8098(3)
6609(3)
7144(3)
6375(4)
5592(3)
5329(4)
7187(4)
5987(4)
6454(5)
4983(5)
6361(5)
5604(6)
7132(6)
8577(3)
9021(4)
7727(4)
4715(2)
3298(2)
1822(2)
1092(2)
3668(2)
2646(3)
3425(3)
2088(4)
3452(3)
2576(3)
1844(3)
2116(3)
3086(4)
4258(3)
4077(3)
3818(4)
4397(4)
976(4)
4.9(2)
3.3(1)
3.9(1)
4.4(2)
3.6(1)
4.9(2)
4.6(2)
5.2(3)
3.2(2)
2.9(2)
3.2(2)
3.5(2)
4.1(2)
4.2(2)
4.1(2)
5.4(3)
5.8(3)
4.6(3)
6.4(4)
6.3(4)
3.4(1)
4.4(3)
3.7(2)
ꢀ3339(5)
ꢀ1278(5)
ꢀ1414(5)
ꢀ1839(6)
ꢀ677(5)
2411(7)
80(7)
ꢀ279(6)
ꢀ523(7)
ꢀ1757(7)
ꢀ1754(8)
618(8)
2565(8)
4240(8)
2761(10)
ꢀ2964(8)
ꢀ2816(10)
ꢀ4235(10)
ꢀ1909(7)
ꢀ3642(8)
1232(7)
265(4)
758(4)
Figure 1. The ORTEP plot for structure 4.
3083(3)
3089(4)
2319(3)
˚
Table 3. The bond lengths (A) for 4
O(1)–C(6)
O(1)–C(7)
O(2)–C(1)
O(2)–C(7)
O(3)–C(4)
O(3)–C(10)
O(4)–C(3)
C(1)–C(2)
C(1)–C(6)
C(2)–C(3)
C(2)–C(15)
C(3)–C(4)
C(4)–C(5)
1.435(7)
1.418(7)
1.414(6)
1.464(6)
1.431(7)
1.431(7)
1.423(6)
1.561(7)
1.534(7)
1.568(7)
1.500(7)
1.529(7)
1.526(8)
O(4)–C(10)
O(5)–C(1)
O(5)–C(5)
O(6)–C(2)
O(6)–C(13)
O(7)–C(13)
N(1)–C(15)
C(7)–C(8)
1.474(7)
1.412(6)
1.438(7)
1.469(6)
1.396(6)
1.212(7)
1.123(8)
1.527(9)
1.506(9)
1.526(9)
1.516(9)
1.502(8)
C(7)–C(9)
C(10)–C(11)
C(10)–C(12)
C(13)–C(14)
Table 4. The bond angles (ꢁ) for 4
Figure 2. The arrangement of the molecules in the unit cell.
C(6)–O(1)–C(7)
C(1)–O(2)–C(7)
C(4)–O(3)–C(10)
C(3)–O(4)–C(10)
C(1)–O(5)–C(5)
C(2)–O(6)–C(13)
O(2)–C(1)–O(5)
O(2)–C(1)–C(2)
O(2)–C(1)–C(6)
O(5)–C(1)–C(2)
O(5)–C(1)–C(6)
C(2)–C(1)–C(6)
O(6)–C(2)–C(1)
O(6)–C(2)–C(3)
O(6)–C(2)–C(15)
C(1)–C(2)–C(3)
C(1)–C(2)–C(15)
C(3)–C(2)–C(15)
O(4)–C(3)–C(2)
O(4)–C(3)–C(4)
C(2)–C(3)–C(4)
107.5(4)
109.2(4)
104.3(4)
107.5(4)
113.2(4)
122.9(4)
112.7(4)
106.9(4)
103.9(4)
106.9(4)
108.1(4)
118.6(4)
110.6(4)
108.9(4)
112.7(4)
107.3(4)
110.2(4)
106.9(4)
109.7(4)
104.7(4)
112.6(4)
O(3)–C(10)–C(11)
O(3)–C(10)–C(12)
O(4)–C(10)–C(11)
O(3)–C(10)–C(12)
113.1(5)
109.4(5)
107.9(5)
108.8(5)
neighboring H-4 chemical shift to move from dH-4
=
5.09ppm in 6 to dH-4 = 4.64ppm in 7, almost overlaping
with H-5,6 due to the benzoyl group linked to the
C-3 from the above of sugar ring providing a shielding
effect.
C(11)–C(10)–C(12)
C(3)–C(4)–C(5)
O(5)–C(5)–C(4)
O(1)–C(6)–C(1)
O(1)–C(7)–O(2)
O(1)–C(7)–C(8)
O(6)–C(13)–O(7)
O(6)–C(13)–C(14)
O(7)–C(13)–C(14)
N(1)–C(15)–C(2)
O(3)–C(4)–C(3)
O(3)–C(4)–C(5)
O(1)–C(7)–C(9)
O(2)–C(7)–C(8)
O(2)–C(7)–C(9)
C(8)–C(7)–C(9)
O(3)–C(10)–O(4)
113.4(5)
115.9(4)
114.4(5)
101.8(4)
105.2(4)
111.9(5)
122.7(4)
113.9(5)
123.5(5)
174.1(6)
101.2(4)
113.4(4)
109.3(5)
106.8(4)
109.7(5)
113.6(5)
103.6(5)
Moffatt and co-workers20 reported that the reaction of
2,3,5-tri-O-benzoyl-b-D-ribofuranosyl cyanide with hy-
droxylamine in methanol at 50ꢁC produced 2,5-anhydro-
3,4,6-tri-O-benzoyl-b-D-allonamidoxime in only 34%
yield, and presumed the rather low yield was due to
the several more polar by-products arising from partial
debenzoylation. Dong and co-workers21,22 found that
the yields of amidoximes through the condensation of
nitriles with hydroxylamine were dependent on the
pH of the reaction mixtures. By controlling the pH
between 7 and 8, the best result, 48% yield of the key

356
J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
Table 5. Crystal data and structure refinement for 14
intermediate amidoxime 8 was obtained through reflux-
ing of 6 with hydroxylamine in anhydrous methanol, but
unsuccessful through refluxing of 4 under the same reac-
tion conditions because the reaction proceeded in a
more-complex manner to give the key intermediate ami-
doxime 8 in very low yield (<5%). Comparing the prod-
uct 9 from the condensation of 2 and hydroxylamine or
debenzoylation of 8 with the several more polar unsepa-
rated by-products by TLC, we verified that 9 and the
more polar by-products are different from each other,
so the low yield of amidoxime seems not only due to
the debenzoylation.
Empirical formula
Formula weight
Temperature
C20H24N2O7
404.41
291(2)K
˚
Wavelength
0.71073A
Orthorhomic
P212121
Crystal system
Space group
Unit cell dimensions
˚
a = 10.309(1)A, a = 90ꢁ
b = 10.474(1)A, b = 90ꢁ
˚
˚
c = 18.646(3)A, v = 90ꢁ
2013.3(4)A , 4
3
˚
Volume, Z
Dcalcd
1.334mg/m3
0.102mmꢀ1
856
Absorption coefficient
F(000)
Crystal size
0.56 · 0.50 · 0.42mm
2.18–26.99ꢁ
0 6 h 6 13, 0 6 k 6 13, 1 6 l 6 23
2766
The identities of 8, 9 were established unequivocally
from their analytical and spectroscopic data, both of
them showed the strong characteristic IR absorptions
of –NH2 and –OH functions at ꢁ3400cmꢀ1 and the ex-
pected quasimolecular ion at m/z 445 [M+Na], 341
[M+Na] in the FAB-MS. The –NH2, –OH groups of
8, 9 were also found with characteristics in the 1H
NMR spectra. On the other hand, in the 13C NMR spec-
tra displayed the absence of the cyano signal at 115–
118ppm instead of the formed C@N signal at
ꢁ152ppm.
h range for data collection
Limiting indices
Reflections collected
Independent reflections
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices
2625 (Rint = 0.0180)
None
Full-matrix least-squares on F2
2625/0/268
0.914
R1 = 0.0334, WR2 = 0.0662
R1 = 0.0526, WR2 = 0.0711
Absolute structure parameter 2.0(11)
Extinction coefficient
Largest diff. peak and hole
0.0283(13)
0.147 and 0.137eA
ꢀ3
˚
The amidoxime 8 was then treated with acetic anhy-
dride, propanoic anhydride, chloroacetyl chloride, and
benzoyl chloride expectantly giving the 1,2,4-oxadiazole
derivatives 10, 11, 12, and 13, respectively. First, it was
treated with acetic anhydride at 80ꢁC under nitrogen
atmosphere for 18h, presumably giving 1,2:4,5-di-O-
isopropylidene-3-C-(5-methyl-1,2,4-oxadiazol-3-yl)-3-O-
benzoyl-b-D-psicopyranose 10. The FAB-MS and
ESI-MS at m/z 427 [M+Na]+, 443 [M+K]+, and
405 [M+1]+ with the elemental analysis indicated the
molecular formula to be C20H24N2O7 (14) but not
C22H26N2O8 as the substituted 1,2,4-oxadiazole deriva-
tive 10 we desired. The characteristics from the NMR
spectra by comparison of 1,2:4,5-di-O-isopropylidene-
3-C-cyano-b-D-psicopyranose, 1,2:4,5-di-O-isopropylid-
ene-3-C-cyano-3-O-acetyl-b-D-psicopyranose, 1,2:4,5-
di-O-isopropylidene-3-C-cyano-3-O-benzoyl-b-D-psico-
pyranose, 1,2:4,5-di-O-isopropylidene-3-C-cyano-3-O-
benzoyl-b-D-fructopyranose with 1,2:4,5-di-O-isopropyl-
idene-3-C-amidoximino-3-O-benzoyl-b-D-psicopyranose
1 showed that the 1,2:4,5-di-O-isopropylidene-D-pyra-
nose fragment still remained in 14. Another remainder
was C8H6N2O2, in which two parts composed as 5-phen-
yl-1,2,4-oxadiazol-3-yl [C8H5N2O] on the basis of NMR
Table 6. Fractional atomic coordinates (· 104) and equivalent thermal
parameters of 14
Atom
x
y
z
U(equiv) · 10
O-1
O-2
O-3
O-4
O-5
O-6
O-7
N-1
N-2
C-1
1189(2)
2332(1)
4526(1)
5169(1)
6471(1)
4311(2)
1023(2)
2061(2)
1986(2)
2480(2)
3212(2)
3693(2)
4373(2)
5328(2)
4974(2)
1234(2)
1461(2)
34(2)
2036(1)
1450(1)
4018(1)
3804(1)
2452(2)
1385(1)
5103(2)
4232(2)
4946(2)
2403(2)
2123(2)
3302(2)
2835(2)
1758(2)
830(2)
287(1)
1262(1)
802(1)
52(1)
43(1)
43(1)
50(1)
52(1)
46(1)
61(1)
59(1)
40(1)
47(1)
39(1)
35(1)
39(1)
46(1)
52(1)
45(1)
58(1)
68(1)
38(1)
40(1)
41(1)
49(1)
57(1)
60(1)
60(1)
51(1)
57(1)
91(1)
88(1)
2248(1)
1620(1)
638(1)
1974(1)
2059(1)
926(1)
136(1)
828(1)
C-2
C-3
1253(1)
1943(1)
1809(1)
1233(1)
828(1)
C-4
C-5
C-6
C-7
1083(2)
218(2)
C-8
C-9
503(1)
1181(3)
4178(2)
5475(2)
6396(2)
7115(2)
7985(2)
8144(2)
7432(3)
6553(2)
3502(2)
3129(3)
4612(3)
1273(2)
1426(1)
1287(1)
1037(1)
1509(1)
1253(1)
528(2)
spectral data, and hydroxyl group –OH at 3397.0cmꢀ1
.
C-10
C-11
C-12
C-13
C-14
C-15
C-16
C-17
C-18
C-19
C-20
2573(2)
1059(2)
85(2)
We tried to determine the configuration of C-3 by
NOESY, but there were no correlations between HO-3
or the benzene hydrogens and H-2, -4, -5, and -6 of
sugar ring. However, the crystals of 14 from acetone–
cyclohexane (1:1) were suitable for X-ray crystallo-
graphic analysis.
650(2)
1539(2)
1693(2)
974(2)
55(1)
308(1)
89(2)
6508(2)
7175(3)
7151(3)
2099(1)
2789(2)
1739(2)
Crystallographic data, and details on data collection
and structure refinement are summarized in Table 5.
The coordinates of the non-hydrogen atoms are listed
in Table 6. The bond lengths and bond angles are listed
in Tables 7 and 8, respectively. The ORTEP plot for
compound 14 is shown in Figure 3 together with the
numbering scheme, and the packing arrangement of
the molecules is shown in Figure 4. The pyranoid ring

J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
357
˚
Table 7. The bond lengths (A) for 14
O(1)–C(1)
O(1)–C(7)
O(2)–C(2)
O(2)–C(7)
O(3)–C(3)
O(4)–C(4)
O(4)–C(18)
O(5)–C(18)
O(5)–C(5)
O(6)–C(2)
O(6)–C(6)
O(7)–C(11)
O(7)–N(1)
N(1)–C(10)
N(2)–C(11)
N(2)–C(10)
C(1)–C(2)
1.414(3)
1.420(2)
1.405(2)
1.443(2)
1.417(2)
1.424(2)
1.444(3)
1.417(3)
1.430(3)
1.416(2)
1.427(3)
1.339(2)
1.415(2)
1.293(3)
1.293(3)
1.372(3)
1.525(3)
C(2)–C(3)
1.549(3)
1.510(3)
1.544(3)
1.518(3)
1.493(3)
1.468(3)
1.381(3)
1.385(3)
1.378(3)
1.372(3)
1.372(3)
1.379(3)
1.492(3)
1.510(3)
1.497(4)
1.511(4)
C(3)–C(10)
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
C(11)–C(12)
C(12)–C(17)
C(12)–C(13)
C(13)–C(14)
C(14)–C(15)
C(15)–C(16)
C(16)–C(17)
C(7)–C(9)
C(7)–C(8)
C(18)–C(20)
C(18)–C(19)
Table 8. The bond angles (ꢁ) for 14
C(2)–O(6)–C(6)
C(1)–O(1)–C(7)
C(2)–O(2)–C(7)
C(4)–O(4)–C(18)
C(18)–O(5)–C(5)
C(11)–O(7)–N(1)
C(10)–N(1)–O(7)
114.21(16) O(1)–C(1)–C(2)
107.59(16) O(2)–C(2)–O(6)
108.57(15) O(2)–C(2)–C(1)
108.53(16) O(6)–C(2)–C(1)
105.15(17) O(2)–C(2)–C(3)
105.81(16) O(6)–C(2)–C(3)
103.64(17) C(1)–C(2)–C(3)
104.15(18)
112.79(16)
105.30(16)
106.76(17)
108.22(16)
107.91(15)
116.00(17)
105.60(15)
122.26(19)
123.29(18)
113.19(19)
Figure 3. The ORTEP plot for compound 14.
C(11)–N(2)–C(10) 102.94(17) O(3)–C(3)–C(10)
O(3)–C(3)–C(4)
C(10)–C(3)–C(4)
O(3)–C(3)–C(2)
C(10)–C(3)–C(2)
C(4)–C(3)–C(2)
O(4)–C(4)–C(5)
O(4)–C(4)–C(3)
C(5)–C(4)–C(3)
O(5)–C(5)–C(6)
O(5)–C(5)–C(4)
C(6)–C(5)–C(4)
O(6)–C(6)–C(5)
112.80(16) N(1)–C(10)–C(3)
111.21(16) N(2)–C(10)–C(3)
108.18(15) N(2)–C(11)–O(7)
110.40(16) N(2)–C(11)–C(12) 128.40(2)
108.58(15) O(7)–C(11)–C(12) 118.42(19)
102.82(16) C(17)–C(12)–C(13) 119.40(2)
111.63(16) C(17)–C(12)–C(11) 118.70(2)
113.11(17) C(13)–C(12)–C(11) 121.90(2)
110.81(19) C(14)–C(13)–C(12) 120.20(2)
101.38(16) C(15)–C(14)–C(13) 120.00(2)
116.31(18) C(14)–C(15)–C(16) 120.30(2)
114.31(18) C(15)–C(16)–C(17) 120.10(2)
N(1)–C(10)–N(2) 114.42(19) C(16)–C(17)–C(12) 120.10(2)
O(1)–C(7)–O(2)
O(1)–C(7)–C(9)
O(2)–C(7)–C(9)
O(1)–C(7)–C(8)
O(2)–C(7)–C(8)
C(9)–C(7)–C(8)
103.69(16) O(5)–C(18)–O(4)
108.60(2) O(5)–C(18)–C(20)
105.43(17)
109.40(2)
109.90(2)
110.40(2)
109.10(2)
108.70(17) O(4)–C(18)–C(20)
110.73(18) O(5)–C(18)–C(19)
110.13(19) O(4)–C(18)–C(19)
114.40(2)
C(20)–C(18)–C(19) 112.40(2)
Figure 4. The arrangement of the molecules in the unit cell.
retains a C1 chair conformation, 5-phenyl-1,2,4-oxadi-
4
azole and 3-OH groups are bonded to C-3 in equatorial
and axial positions, respectively. The X-ray diffraction
analysis also indicates that the crystal has molecular
stacking along a one-dimensional chain. Figure 4 exhib-
its the interaction among the molecules in the columnar
stacking. The molecules assemble through 3-OHꢂ ꢂ ꢂO-1
were homogeneous by TLC and had the same sharp
melting point as well as the elemental analyses, IR,
1
MS, and H, 13C NMR spectral data.
Taking these facts into account, we believe that the 3-O-
benzoyl group undergoes an intramolecular replacement
reaction through neighbor participation and a more sta-
ble conjugation system is formed in compound 14 dur-
˚
intermolecular hydrogen bonds (2.88A; 157.1ꢁ).
In order to confirm the unexpected reaction and study
the mechanism, we explored the reactions of 8 with chlo-
roacetyl chloride, propanic anhydride, or benzoyl chlo-
ride instead of acetic anhydride, at 120–130ꢁC under
nitrogen for 22h. Only one product, the 5-phenyloxadi-
azole 14, but not 11–13, was obtained in yields 81–83%
from each of the above three reactions. The products
ing the cyclization of 8 with acetic anhydride,
chloroacetyl chloride, propanic anhydride, or benzoyl
chloride. As shown in Scheme 2, the novel procedure
proceeds as follows: acetylation of amidoxime 8 takes
place first at the hydroxyl group to form 1,2:4,5-di-
O-isopropylidene-3-(C-carbamoacetylhydromoyl)-3-O-
benzoyl-b-D-psicopyranose A.23 The lone electron pair

358
J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
Ph
O
R-C-O
O
O
O
N
C
RCO
H2N
N
C
HO
N
C
N
N
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph-C-N
H2N
O
O
O
O
O
O
O
O
O
H
O
O
O
O
O
O
O
O
OH
14
OH
O
CH3
CH3
OBz
O
CH3
O
O
CH3
CH3
PhC
CH3
CH3
CH3
O
B
8
A
R = CH3, ClCH2, CH3CH2, Ph
R = CH3, ClCH2, CH3CH2, Ph
Scheme 2. The possible mechanism for the intramolecular replacement reaction to form 14.
on NH2 with high density attacks the carbon of C@O
group in 3-O-benzoyl group to produce the intramole-
cular replacement reaction through neighboring group
participation and transfer. The resulting intermediate
B undergoes ring closure reactions with the action of
anhydrides or benzoyl chloride under reflux to remove
the hydrogen from NH2 and give rise to the compound
14.
containing the tested chemicals 14 and 18. Cells were
incubated for 48h with molecules 14, 18 (0.1–10lM),
followed by MTT or SRB Cell Inhibition Assay
(Promega, Madison, WI, USA) (Table 9). The absorb-
ance of each well was measured using a microculture
plate reader at 570nm (MTT) and 540nm (SRB).
3. Experimental
The 3-benzoyl group undergoing intramolecular
replacement through neighboring participation has
been found24 previously on treatment of 3-C-(3,5-di-
O-benzoyl-1,2-O-isopropylidene-a-D-xylofuranos-3-yl)-
5-methyl or ethyl, phenyl-1,2,4-oxadiazoles with sodium
meth- oxide in methanol at pH7–8. Apparently, these
intramolecular replacements took place under different
reaction conditions and in diverse mechanisms.
General procedures: Melting points were determined
using an X4 micromelting-piont apparatus and are
uncorrected. Optical rotations were determined with a
Perkin–Elmer Model 241MC polarimeter. IR spectra
were recorded with a Biorad FT-40 spectrophotometer
(KBr pellets). All NMR spectra were recorded on a Var-
ian MERCURY 400 spectrometer (400MHz for 1H,
100MHz for 13C) with CDCl3 as solvent, Me4Si as an
internal standard. Mass spectra were obtained on either
ZAB-HS or HP 1100-MSD mass spectrometers. Col-
umn chromatography was performed on silica gel
(200–300mesh) and silica gel GF254 for TLC was pur-
chased from the Qingdao Chemical Company (China).
Detection was effected by spraying the plates with 5%
ethanolic H2SO4 (followed by heating at 110ꢁC for
10min) or by direct UV irradiation of the plate. All
the crystallographic measurements were carried out on
a KUMA KM-4 diffractometer with graphite-mono-
chromated MoKa radiation in a h/2h scan mode. The
unit cell parameters were determined from least-squares
refinement based on the setting angles of 25 reflections.
The stability of conditions was controlled by three con-
trol measurements every 100 reflections. The structures
were solved by direct methods using the SHELXS (1990)
program from the SHELX-97 package. Anisotropic dis-
placement coefficients were applied to all nonhydrogen
atoms. Refinement of all hydrogen atoms was done with
idealized positions using isotropic temperature factors
set to 1.2 times of the equivalent isotropic temperature
factor of the neighboring C or O atoms. The structure
refinements were performed using the SHELXL program.
With the aim of preparing 1,2,4-oxadiazole derivatives
13, 15–17, many efforts through the cyclization of 9 with
acetic anhydride, chloroacetyl chloride, propanic anhy-
dride, and benzoyl chloride under refluxing temperature,
however, gave complex inseparable mixtures.
Deprotection with 80% AcOH, 1% HCl/MeOH, or
CF3CO2H/CH2Cl2, only CF3CO2H/CH2Cl2 under re-
flux temperature for 1day did successfully cleave up
4,5-O-isopropylidene group of 14 to afford the 1,2-O-
isopropylidene derivative 18.
In vitro antitumor activities of 14 and 18 against tumor
cells HL-60, Bel-7402, KB and Hela were evaluated by
MTT and SRB assays.25,26 Assays were performed using
96-well plates (Falcon, Becton Dickinson, Mountain
View, CA, USA) seeded with 103 cells per well in
200lL RPMI 1640 without phenol red and supple-
mented with 10% FCS. After 24h incubation, the med-
ium was replaced with fresh RPMI 1640 medium
Table 9. Inhibition ratio (%) of 14, 18 on tumor cells
Compound 14
Compound 18
0.1 (lM) 1 (lM) 10 (lM) 0.1 (lM) 1 (lM) 10 (lM)
3.1. 1,2:4,5-Di-O-isopropylidene-3-C-cyano-b-D-psico-
pyranose (2)
A
B
C
D
22.78
1.64
31.59 29.94
9.92
17.68
ꢀ17.29
ꢀ19.51
ꢀ13.04
27.96
ꢀ8.64
23.79
ꢀ2.91
ꢀ1.46
ꢀ16.69
ꢀ10.85
ꢀ15.36 ꢀ7.28
ꢀ7.54 ꢀ0.97
ꢀ17.01 ꢀ12.40
A solution of 1,2:4,5-di-O-isopropylidene-b-D-erythro-2-
hexulopyranose-3-ulose (1) (1.29g, 5mmol) and tetrabu-
tyl-ammonium bromide (0.48g, 1.5mmol) in CH2Cl2
(15mL) was vigorously stirred at room temperature with
the solution of NaCN (0.98g, 20mmol) in H2O (15mL)
ꢀ16.19
ꢀ6.85
A: HL-60a, B: Bel-7402b, C: KBb, D: Helab.
a Detected by the standard MTT method.
b Detected by the standard SRB method.

J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
359
until TLC (95:5 benzene–MeOH) showed reaction
complete. The organic layer was separated, washed,
dried (Na2SO4), evaporated under reduced pressure to
give a syrup, which was recrystallized from EtOH to
idene-3-C-cyano-3-O-benzoyl-b-D-psicopyranose 6 and
1,2:4,5-di-O-isopropylidene-3-C-cyano-3-O-benzoyl-b-
D-fructopyranose 7.
yield white crystalline 2 (95–97%), mp 119–120ꢁC,
1,2:4,5-Di-O-isopropylidene-3-C-cyano-3-O-benzoyl-b-
D-psicopyranose 6 (0.82g, 60%) as white needle crystals,
22
Rf 0.31 (9:1:1 benzene–MeOH–ether), ½aꢃ ꢀ162.5
D
(c 1.01, CH2Cl2), mmax: 3389.5 (m, OH) cmꢀ1. Like many
other cyanosugars, the IR spectrum of 2 showed the
mp 124–125ꢁC, Rf 0.62 (3:2 cyclohexane–EtOAc),
22
½aꢃ ꢀ148.5 (c 1.0, CH2Cl2). mmax: 1741.0 (vs, PhCO)
D
absence of a CN band.11,12 dH: 4.33 (1H, d, J1,1
=
cmꢀ1; dH: 8.10–7.46 (5H, m, Ph–H), 4.58 (1H, d, J1,1
=
0
0
9.8Hz, H-1), 4.04 (1H, d, H-10), 4.78 (1H, d,
J4,5 = 2.9Hz, H-4), 4.43 (1H, d, J5,6 = 14.2Hz, H-5),
4.15 (2H, s, H-6,60), 3.33 (1H, s, OH-3), 1.62, 1.53,
1.49, 1.43 (12H, 4s, 4 · CH3) ppm; dC: 118.67 (C„N),
114.24, 103.62 (2 · CMe2), 73.15 (C-1), 110.25 (C-2),
74.04 (C-3), 70.13 (C-4), 69.74 (C-5), 59.91 (C-6),
26.44, 25.93, 25.62, 24.81 (4 · CH3) ppm.
12.8Hz, H-1), 4.03 (1H, d, H-10), 5.09 (1H, d,
J4,5 = 9.2Hz, H-4), 4.43 (1H, m, H-5), 4.34 (1H, dd,
J5,6 = 4.0Hz, J6,6 = 13.0Hz, H-6), 4.04 (1H, d, H-60),
0
2.17, 1.55, 1.53, 1.35 (12H, 4s, 4 · CH3) ppm; dC:
163.96 (CO), 134.04, 130.24, 128.68 (Ph–C), 115.29
(C„N), 113.00, 103.92 (2 · CMe2), 73.04 (C-1), 110.55
(C-2), 71.98 (C-3), 74.09 (C-4), 70.83 (C-5), 61.75 (C-
6), 26.06, 25.86, 25.69, 24.89 (4 · CH3) ppm; ESI-MS
(%): m/z 390 [M+1]+ (100), 374 [MꢀCH3]+ (90), 332
(85), 185, 105, 77, 59, 43.
Anal. Calcd for C13H19NO6: C, 54.74, H, 6.67, N, 4.91.
Found: C, 55.09, H, 6.81, N, 4.61.
3.2. 1,2:4,5-Di-O-isopropylidene-3-C-cyano-3-O-acetyl-b-
D-psicopyranose (4)
Anal. Calcd for C20H23NO7: C, 61.69, H, 5.91, N, 3.59.
Found: C, 61.63, H, 6.04, N, 3.62.
A solution of 1,2:4,5-di-O-isopropylidene-3-C-cyano-b-
D-psicopyranose (2) (0.29g, 1mmol) in Ac2O–pyridine
(1:2, 5mL) was stirred at room temperature until TLC
(9:1:1 benzene–MeOH–ether) showed that the reaction
completed, then poured onto ice water, extracted with
CH2Cl2 (3 · 20mL), the organic extracts were washed
with water, dried (Na2SO4), and evaporated under
reduced pressure to give the syrup, which was chroma-
tographed on a short silica gel column to afford white
crystalline 4 (0.31g, 96%) [1:1 AcOEt–cyclohexane],
1,2:4,5-Di-O-isopropylidene-3-C-cyano-3-O-benzoyl-b-
D-fructopyranose 7 (0.41g, 30%) as white prism crystals,
mp 118–119ꢁC, Rf 0.55 (3:2 cyclohexane–EtOAc),
22
½aꢃ 65.5 (c 1.0, CH2Cl2). mmax: 1734.0 (vs, PhCO)
D
cmꢀ1; dH: 8.09–7.44 (5H, m, Ph–H), 4.62 (1H, d, J1,1
=
0
12.8Hz, H-1), 4.28 (1H, d, H-10), 4.64 (1H, d,
J4,5 = 7.6Hz, H-4), 4.44 (1H, m, H-5), 4.30 (1H, dd,
J5,6 = 4.0Hz, J6,6 = 13.2Hz, H-6), 4.25 (1H, d, H-60),
0
1.82, 1.54, 1.49, 1.43 (12H, 4s, 4 · CH3) ppm; dC:
163.40 (C@O), 133.92, 130.03, 128.62 (Ph–C), 115.23
(C„N), 113.92, 104.05 (2 · CMe2), 74.61 (C-1), 110.61
(C-2), 73.02 (C-3), 77.48 (C-4), 72.23 (C-5), 61.32 (C-
6), 26.21, 26.08, 25.57, 24.99 (4 · CH3) ppm; ESI-MS
(%): m/z 390 [M+1]+ (100), 374 [MꢀCH3]+ (94), 332
(88), 185, 105, 77, 59, 43.
mp 149–150ꢁC, Rf 0.47 (9:1:1 benzene–MeOH–
22
ether), ½aꢃ ꢀ195.8 (c 1.01, CH2Cl2), mmax: 1735.6 (vs,
D
CO) cmꢀ1; dH: 4.53 (1H, d, J1,1 = 9.9Hz, H-1), 3.96
0
(1H, d, H-10), 4.78 (1H, d, J4,5 = 5.7Hz, H-4), 4.33
0
(1H, dd, J5,6 = 3.9Hz, J5,6 = 6.0Hz, H-5), 4.24 (1H,
0
dd, J6,6 = 13.5Hz, H-6), 4.13 (1H, d, H-60), 2.04 (3H,
s, CH3CO), 1.58, 1.50, 1.49, 1.39 (12H, 4s, 4 · CH3)
ppm; dC: 168.71 (CO), 116.12 (C„N), 113.41, 104.32
(2 · CMe2), 72.90 (C-1), 109.55 (C-2), 54.61 (C-3),
75.03 (C-4), 70.55 (C-5), 60.12 (C-6), 26.71, 26.07,
25.13, 24.65, 23.69 (5 · CH3) ppm; ESI-MS (%): m/z
328 [M+1]+ (100).
Anal. Calcd for C20H23NO7: C, 61.69, H, 5.91, N, 3.59.
Found: C, 61.58, H, 6.05, N, 3.54.
3.4. 1,2:4,5-Di-O-isopropylidene-3-C-amidoximino-3-O-
benzoyl-b-D-psicopyranose (8)
A solution of 6 (1.20g, 3.08mmol) and hydroxylamine
(6.5mmol) in anhydrous MeOH (15mL) (pH = 7–8)
was refluxed with stirring for 8h, After the reaction
was complete (TLC 1:2 cyclohexane–EtOAc), the sol-
vent was removed by distillation, the residue was puri-
fied by silica gel column chromatography with 2:3
cyclohexane–EtOAc affording 8 (0.75g, 58%) as white
Anal. Calcd for C15H21NO7: C, 55.02, H, 6.47, N, 4.28.
Found: C, 55.04, H, 6.50, N, 4.30.
3.3. 1,2:4,5-Di-O-isopropylidene-3-C-cyano-3-O-benzoyl-
b-D-psicopyranose (6) and 1,2:4,5-di-O-isopropylidene-3-
C-cyano-3-O-benzoyl-b-D-fructopyranose (7)
crystals, mp 109–112ꢁC, Rf 0.62 (1:2 cyclohexane–
22
Cyanohydrins 2 (1.0g, 3.51mmol) was dissolved in a
solution of CH2Cl2 (5mL) and pyridine (4mL), BzCl
(1.6mL, 14mmol) was then added dropwise to the
well-stirred reaction mixture at 0ꢁC and the stirring con-
tinued for an overnight from 0ꢁC to room temperature
until TLC showed the compound 2 disappear, the mix-
ture was poured onto ice water, extracted with CH2Cl2
(3 · 30mL), washed, dried (Na2SO4), concentrated,
and purified by column chromatography on silica gel
(3:1 cyclohexane–EtOAc) to give 1,2:4,5-di-O-isopropyl-
EtOAc), ½aꢃ ꢀ102.3 (c 1.0, CH2Cl2). mmax: 3394.0
D
(vs, OH, NH2), 1687.0 (m, CO) cmꢀ1; dH: 9.85 (1H, br
s, OH, exchangeable with D2O), 8.11–7.45 (5H, m,
Ph–H), 5.23 (2H, s, NH2, exchangeable with D2O)
4.81 (1H, d, J1,1 = 7.5Hz, H-1), 3.82 (1H, d, H-10),
0
5.61 (1H, d, J4,5 = 7.8Hz, H-4), 4.43 (1H, ddd,
0
J5,6 = 2.7Hz, J5,6 = 6.0Hz, H-5), 4.18 (1H, dd,
J6,6 = 10.8Hz, H-6), 3.86 (1H, d, H-60), 1.55, 1.53,
0
1.50, 1.41 (12H, 4s, 4 · CH3) ppm; dC: 170.71 (C@O),
151.86 (C@N), 133.59, 130.19, 128.42 (Ph–C), 111.86,

360
J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
103.30 (2 · CMe2), 73.92 (C-1), 110.97 (C-2), 73.45 (C-
3), 75.73 (C-4), 65.04 (C-5), 63.04 (C-6), 26.63, 26.19,
25.96, 25.01 (4 · CH3) ppm; ESI-MS (%): m/z 445
[M+Na]+ (100).
109.58 (C-2), 71.89 (C-3), 73.83 (C-4), 71.01 (C-5),
60.03 (C-6), 25.04, 25.79, 25.64, 25.21 (4 · CH3) ppm;
FABMS (%): m/z 443 [M+K]+ (90), 427 [M+Na]+
(100); ESI-MS (%): m/z 405 [M+1]+ (100).
Anal. Calcd for C20H26N2O8: C, 56.80, H, 6.16, N, 6.64.
Found: C, 56.76, H, 6.18, N, 6.70.
Anal. Calcd for C20H24N2O7: C, 59.40, H, 5.94, N, 6.93.
Found: C, 59.38, H, 5.96, N, 6.91.
3.5. 1,2:4,5-Di-O-isopropylidene-3-C-amidoximino-b-D-
psicopyranose (9)
Treatment of 8 (0.20g, 0.47mmol) with chloroacetyl
chloride, propanic anhydride and benzoyl chloride
(10mL), respectively, at 120–130ꢁC under nitrogen at-
mosphere for 22h until the TLC (1:2 acetone–cyclohex-
ane) showed the reaction complete, the mixture was
poured onto ice water, extracted with CH2Cl2
(3 · 20mL), washed, dried (Na2SO4), concentrated,
and purified by column chromatography on silica gel
to give compound 14 (81–83%) as white crystals, which
is consistent with the product obtained in the above pro-
cedure in all physical and spectral data.
The procedure described for the preparation of 8 was
followed starting from 2 (0.50g, 1.75mmol), hydroxyl-
amine (3.7mmol) in anhydrous MeOH (10mL), TLC
(1:3 cyclohexane–EtOAc) of the reaction showed com-
plete conversion of the cyanohydrins 2 to the amidoxime
9, the purification by silicon gel column chromatogra-
phy with 1:3 cyclohexane–EtOAc afforded the com-
pound 9 (0.26g, 46%) as white crystals, mp 148–
22
D
149ꢁC, Rf 0.42 (1:3 cyclohexane–EtOAc), ½aꢃ ꢀ85.3 (c
1.1, CH2Cl2). mmax: 3470.4, 3440.0, 3387.0 (vs, OH,
NH2) cmꢀ1; dH: 9.00 (2H, br s, NH2), 8.78 (1H, br s,
OH, exchangeable with D2O), 4.73 (1H, d,
3.7. 1,2-O-Isopropylidene-3-C-(5-phenyl-1,2,4-oxadiazol-
3-yl)-b-D-psicopyranose (18)
J1,1 = 7.5Hz, H-1), 4.02 (1H, d, H-10), 5.48 (1H, d,
Compound 14 (0.40g, 1mmol) was dissolved in a solu-
tion of CH2Cl2 (10mL), CF3CO2H (0.5mL, 90%) was
added, the reaction mixture was stirred for 24h at reflux
temperature until TLC showed the compound 14 disap-
pear, cooled to 0ꢁC, and neutralized with NaHCO3, the
mixture was evaporated, and the residue was purified by
silica gel column chromatography (10:1 CHCl3–MeOH)
0
J4,5 = 7.5Hz, H-4), 4.34 (1H, ddd, J5,6 = 3.0Hz,
0
0
J5,6 = 8.7Hz, H-5), 4.12 (1H, dd, J6,6 = 12.0Hz, H-6),
3.86 (1H, d, H-60), 2.11 (1H, s, OH-3), 1.48, 1.45, 1.39,
1.30 (12H, 4s, 4 · CH3) ppm; ESI-MS (%): m/z 341
[M+Na]+ (100), 319 [M+1]+ (90).
Anal. Calcd for C13H22N2O7: C, 49.05, H, 6.97, N, 8.80.
Found: C, 49.07, H, 6.80, N, 8.82.
to give compound 18 (0.29g, 80%) as white crystals, mp
22
D
149–151ꢁC, Rf 0.53 (9:1 CHCl3–MeOH), ½aꢃ ꢀ166.5 (c,
1.0 CH2Cl2). mmax: 3485.1, 3433.2, 3377.1 (vs, OH),
1612.5 (s, C@N), 1566.2 (s, C–N) cmꢀ1; dH: 8.15–7.50
(5H, m, Ph–H), 4.57 (2H, br s, OH-4,5), 4.20 (1H, d,
An alternative synthesis from 8 (100mg, 0.24mmol) by
treatment with methanolic NaOMe (1M, 10mL) at
room temperature for 18h gave 9 (72mg, 96%), which
is identical in all respects to the product obtained in
the above procedure.
J1,1 = 12.0Hz, H-1), 4.00 (1H, d, H-10), 4.52 (1H, d,
0
J4,5 = 9.6Hz, H-4), 4.02 (1H, m, H-5), 4.07 (1H, dd,
J5,6 = 4.8Hz, J6,6 = 14.7Hz, H-6), 3.98 (1H, d, H-60),
0
3.40 (1H, br s, HO-3), 1.45, 1.07 (6H, 2s, 2 · CH3)
ppm; dC: 175.84 (C-30), 169.97 (C-50), 133.02, 129.12,
128.26, 123.76 (Ph–C), 113.00 (CMe2), 69.04 (C-1),
106.18 (C-2), 69.03 (C-3), 72.21 (C-4), 67.87 (C-5),
64.60 (C-6), 26.06, 25.68 (2 · CH3) ppm; ESI-MS (%):
m/z 403 [M+K]+ (42), 387 [M+Na]+ (98), 307 (100).
3.6. 1,2:4,5-Di-O-isopropylidene-3-C-(5-phenyl-1,2,4-
oxadiazol-3-yl)-b-D-psicopyranose (14)
A solution of 8 (0.20g, 0.47mmol) in redistilled Ac2O
(8mL) was heated at 80ꢁC under nitrogen atomosphere
for 18h until the TLC (1:2 acetone–cyclohexane)
showed the reaction complete. Anhydrous EtOH
(10mL) was added and stirred for 30min. Then the sol-
vent was distilled off and further co-evaporated with tol-
uene, the resultant brown syrup was purified on a
column of silica gel chromatography using acetone–
cyclohexane (1:3) as eluent to give white crystals 14
Anal. Calcd for C17H20N2O7: C, 56.04, H, 5.49, N, 7.69.
Found: C, 55.94, H, 5.60, N, 7.59.
4. Supplementary data
(0.17g, 88%), mp 116–117ꢁC, Rf 0.26 (1:2 acetone–cyc-
CCDC contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033; or deposit@ccdc.cam.ac.uk).
22
lohexane), ½aꢃ ꢀ148.5 (c, 1.0 CH2Cl2). mmax: 3397.0 (s,
D
OH), 1603.0 (s, C@N), 1555.0 (s, C–N) cmꢀ1; dH: 8.16
(2H, dd, J2,3 = J5,6 = 6.0Hz, J2,4 = J4,6 = 1.8Hz, ArH-
2,6), 7.57 (1H, dd, J3,4 = J4,5 = 4.8Hz, ArH-4), 4.60
(1H, d, J1,1 = 9.5Hz, H-1), 4.03 (1H, d, H-10), 5.23
0
(1H, d, J4,5 = 5.5Hz, H-4), 4.41 (1H, m, H-5), 4.37
0
(1H, dd, J5,6 = 3.0Hz, J6,6 = 12.5Hz, H-6), 4.30 (1H,
d, H-60), 3.33 (1H, s, HO-3, exchangeable with D2O),
1.63, 1.48, 1.43, 1.11 (12H, 4s, 4 · CH3) ppm; dC:
175.84 (C-30), 170.89 (C-50), 132.83, 129.05, 128.23,
124.01 (Ph–C), 112.97, 105.36 (2 · CMe2), 72.18 (C-1),
Acknowledgements
This work was supported by the financial support of the
National Natural Science Foundation of China (No.

J. Yu et al. / Bioorg. Med. Chem. 13 (2005) 353–361
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361
29862006) and in part by the National Laboratory of
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Southwestern Medical Center at Dallas) for editorial
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