Synthesis, separation and configuration determination of diastereoisomers of (R,S)-1-methyl-3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propyl 2,3-dideoxy-α- D-erythro-hex-2-enopyranosides

Article abstract of DOI:10.1016/j.tet.2004.08.075

For synthesizing title compounds, first we carried out the Ferrier's rearrangement involving tri-O-acetyl-d-glucal 1 and alcohols 2a-e using Montmorillonite K-10 as a catalyst. This reaction gave diastereoisomeric mixture of 3a-e and 4a-e. Basic hydrolysi

Full text of DOI:10.1016/j.tet.2004.08.075

Tetrahedron 60 (2004) 10761–10769
Synthesis, separation and configuration determination of
diastereoisomers of
(R,S)-1-methyl-3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propyl
2,3-dideoxy-a-D-erythro-hex-2-enopyranosides
a
Rajendra M. Srivastava,a, Joa˜o R. de Freitas Filho, Maria Jose da Silva,
a,†
*
´
Suzana C. de Melo Souto,a Gene B. Carpenterb and W. M. Faustinoa
a
´ ´
Departamento de Quımica Fundamental, Universidade Federal de Pernambuco, Cidade Universitaria, 50.740-540 Recife, PE, Brazil
bDepartment of Chemistry, Brown University, Providence, RI 02912, USA
Received 9 August 2004; accepted 16 August 2004
Available online 25 September 2004
Abstract—For synthesizing title compounds, first we carried out the Ferrier’s rearrangement involving tri-O-acetyl-D-glucal 1 and alcohols
2a–e using Montmorillonite K-10 as a catalyst. This reaction gave diastereoisomeric mixture of 3a–e and 4a–e. Basic hydrolysis of each pair
of diastereoisomeric mixture furnished title compounds 5a–e and 6a–e, which were separated very carefully over a silica gel column yielding
all diastereoisomers in the pure form. One of them 5d was subjected to a single crystal X-ray analysis to determine the correct configuration at
the asymmetric carbon atom of the aglycone. The methyl signals of the diastereomers helped to assign the configuration of each
diastereoisomer. Molecular orbital calculations of 5d using the semi-empirical method (AM1) has been performed to compare its results with
the crystallographic data. We have also determined the rotational barrier of C(8) and O(9) bond in both (R) and (S) enantiomers of
compounds 5a and 6a.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
to combine an oxadiazole moiety with a sugar frame-
work.9,11–14 Further, no work appeared in the literature
which describes the synthesis of unsaturated glycosides
having an 1,2,4-oxadiazole part as an aglycone. Therefore,
this paper gives a detailed account of the preparation,
separation and configuration differentiation of the dia-
stereomers of 5a–e and 6a–e. Overall, there are 10 new
unsaturated glycosides having a stereocenter in the aglycone
moiety also. To the best of our knowledge, these have not
yet been recorded in the literature.
The incorporation of heterocyclic moieties in carbohydrates
has been gaining impetus.1–3 Because of our interest in the
synthesis 1,2,4-oxadiazoles and 4,5-dihydro-1,2,4-oxa-
diazoles, we wished to unite the oxadiazole part with the
carbohydrate framework. One of the reasons to undertake
such program was that 1,2,4-oxadiazole derivatives
manifest a wide range of biological activities4–6 including
antiinflammatory property.7 In 1996, various 4,5-dihydro-
1,2,4-oxadiazoles (D2-1,2,4-oxadiazolines) have been found
to possess anti-HIV activity.8 Yu and co-workers have
reported the preparation, spectroscopic and X-ray
diffraction studies of two diastereoisomeric spirohetero-
cyclic D2-1,2,4-oxadiazolines having a spiral junction at
C-3 of fructopyranose.9 The spiroheterocyclic compounds
have extensive applications as drugs as well.10 A literature
search revealed that only a few attempts have been made
2. Results and discussion
Racemic 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-2-butanols 2a–e
were used to carry out Ferrier’s rearrangement.15 Reaction of
these alcohols individually with tri-O-acetyl-D-glucal 1 gave
diastereomers 3a–e and 4a–e, respectively (Scheme 1). Each
diastereomeric pair showed only one spot on a thin-layer
chromatogram. However, the 1H NMR spectrum of each set
presented two methyl doublets in the region d 1.21–1.40 ppm
in the ratio of 2:3 indicating the presence of diastereomers.
Each methyl doublet has another overlapping doublet of
smaller intensity (w40%) suggesting them as a mixture of
Keywords: Diastereoisomers; X-ray crystallography; Configuration; Tor-
sion angles.
* Corresponding author. Tel.: C55-81-2126-8440; fax: C55-81-2126-
8442; e-mail: rms@ufpe.br
† Taken in part from the Ph.D. thesis (2001) of J. R. de Freitas Filho.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.075

10762
R. M. Srivastava et al. / Tetrahedron 60 (2004) 10761–10769
Scheme 1.
conformational isomers. This observation requires some
clarifications. Since the reaction has been carried out in
methylene chloride, each diastereoisomer formed confor-
mational isomer as shown below for 5d and 5d0. The two
conformational isomers of each diastereoisomer are visible
when the temperature is not higher. There is a small barrier to
rotation between C(8) and O(9) which causes this to happen
(see the section dealing with M.O. calculations). When the
compound is deacetylated, separated and purified, only
one conformational isomer is observed for 5a and 6a.
Apparently, during the work-up rotation along the C(8) and
O(9) bond occurred to provide the most stable conformation
which shows only one doublet for the methyl group for each
diastereoisomer.
crystallized. All of them gave the methyl doublet at d
1.35 ppm, and the anomeric proton appeared at d 5.13 ppm.
The other set of diastereoisomers (larger quantity) are
liquids and it was not possible to crystallize them. All five of
them produced a methyl doublet at d 1.25 ppm, and the
anomeric proton absorbed at d 5.16 ppm. One of the
diastereoisomers (either 5d or 6d) which had better crystals
was subjected to X-ray crystallography. It turned out that it
has the configuration (R) at the carbon atom containing the
methyl group in the aglycone moiety. This diastereoisomer
is designated as 5d. Therefore the other diastereoisomer
must possess configuration (S) for the same carbon atom
(C-8) in 6d. It is presumed that, all compounds 6a–e possess
configuration (S) at the asymmetric carbon atom of the
Next, we hydrolyzed the diacetylated sugars using the
method of Fraser-Reid and collaborators,16 which furnished
diols 5a–e and 6a–e again as a mixture of diastereoisomers.
Thin-layer chromatography displayed two spots of very
close Rf values. However, it was possible to separate them
by a very careful liquid chromatography over silica gel. The
diastereoisomer which is in smaller proportion, in each case,
aglycone while 5a–e have configuration (R) at the same
stereocenter.
Pure 5a and 6a were reacetylated individually and their
spectra recorded. This was done just to make correct
assignments of their chemical shifts in the 1H NMR spectra,
which are give in Section 4.

R. M. Srivastava et al. / Tetrahedron 60 (2004) 10761–10769
10763
Figure 1. Ortep diagram of compound 1-(R)-methy-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]lpropryl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside 5d.
2.1. Structure, configuration and conformation of 5d
mol. A comparison of some selected dihedral angles of 5d
with its crystallographic data are given in Table 1, which
shows that the experimental and calculated values are
somewhat closer. The calculations further demonstrate that
the p-tolyl ring and the 1,2,4-oxadiazole rings are coplanar
(torsion angle N(2)–C(3)–C(16)–C(17)Z10.618). The bond
distances between C(13)–C(12) and C(12)–O(11) are
The crystallographic data provided the precise information
regarding the configuration (at C-8) and also about the
molecular conformation of 5d. As expected, the configur-
ations at C(10), C(12) and C(13) are (S), (R) and (S),
respectively. It is interesting to know that the C(8)–H bond
is found approximately parallel to those on C(10) and C(13),
and antiparallel to the one on C(12). The ortep diagram is
shown in Figure 1.
˚
˚
1.54 A and 1.43 A, respectively.
Figure 4 depicts the most stable conformation of 5d
obtained by the AM1 level of calculation.
There is another feature which needs comment. This
concerns the hydrogen bonding between the molecules.
Each hydroxyl oxygen atom, O(25) and O(26), is involved
in two hydrogen bonds, one as a donor and one as acceptor.
O(25) donates a hydrogen bond to O(26) of a parallel
molecular in an adjacent cell, O(26) donates a hydrogen
bond to O(25) of a molecule generated by a two-fold screw
rotation in the [010] direction. The result is that molecules
are linked into slabs normal to the [010] direction; the two
slabs that pass through one unit cell are not linked together.
The other oxygen and nitrogen atoms are not involved in
hydrogen bond (see Figs. 2 and 3).
Next, we examined the stable conformation of 6d using
the same method as described for 5d. The dihedral angle
H(15)–C(15)–C(10)–H(10) is K46.208 which clearly
indicates the disposition of H-10 equatorially. The other
interesting feature is that C(23)–C(8)–C(7) and C(6) form
an angle of K165.98. The heterocyclic and the p-tolyl rings
are at the lower level of the pyranose ring as exhibited in
Figure 5. In this case also, the p-tolyl ring and 1,2,4-
oxadiazole ring are almost coplanar. Selected bond lengths,
bond angles and torsion angles of 5d and 6d are given in
Table 2.
In order to determine the rotational barrier of the C(8) and
O(9) bond, diastereoisomers 5a and 6a were chosen.
2.2. Semi-empirical molecular orbital calculations of
compounds 5d and 6d
The rotational impediment along the C(8) and O(9) bond in
5a is approximately 4.0 kcal/mol, whereas in 6a it
approximates about 8.0 kcal/mol. Although the semi-
empirical method is less sophisticated, the barrier seems
reasonable. Figure 6 represents the structures of 5a and 6a.
The numbering of the atoms of these molecules here has
been slightly modified.
The semi-empirical calculations (AM1) showed that
compound 5d has a torsion angle H(15)–C(15)–C(10)–
H(10) of K43.28 which clearly shows that the anomeric
proton is disposed equatorially. The ring oxygen atom is a
little above the plane of C(10)-C(15)-C(14)-C(13). The
C(12) atom is slightly below the plane just described. The
enthalpy of formation of this compounds is K112.04 kcal/
Figure 2. Compound 1-(R)-methyl-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]propryl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside 5d showing the hydrogen bonds
between O(25A) and H-26, H(25B) and O(26), O(26A) and H(25), and O(25) and H(26B).

Figure 3. Unit cell depicting the packing of 1-(R)-methyl-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]propryl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside 5d molecules in the crystal.

R. M. Srivastava et al. / Tetrahedron 60 (2004) 10761–10769
10765
Table 1. Comparison of the calculated and experimental torsion angles
of 5d
Point Apparatus, series IA-9100, Electrothermal Ltd.,
England. IR spectra were recorded as KBr films on a
Brucker IFFS66 series Fourier transform spectro-
Torsion angle (8C)
X-ray
67.70
AM1 method
1
photometer. The 300 MHz H NMR spectra were recorded
C(10)–O(11)–C(12)–C(13)
C(10)–C(15)–C(14)–C(13)
C(15)–C(14)–C(13)–C(12)
C(14)–C(13)–C(12)–O(11)
C(10)–O(11)–C(12)–C(24)
O(26)–C(13)–C(14)–C(15)
O(9)–C(10)–O(11)–C(12)
O(9)–C(10)–C(15)–C(14)
62.07
1.48
10.25
with a Varian Unity Plus spectrophotometer or a Brucker
DRX 300 using CDCl3 as solvent and TMS as an internal
standard. Elemental analyses were performed in the
Department of Fundamental Chemistry, Federal University
of Pernambuco, Recife (Brazil). Thin-layer chromatography
(TLC) was carried out on plates coated with silica gel 60
2.10
19.0
K52.1
K170.3
140.7
77.3
K115.6
K40.16
K177.67
128.64
71.62
K97.12
Figure 4. Stable conformation of (1R)-1-methyl-3-[(p-tolyl)-1,2-4-oxadiazol-5-yl]propyl 2,3-didesoxy-a-D-erythro-hex-2-enopyranoside 5d obtained by the
AM1 method.
Figure 5. Stable conformation of (1S)-1-methyl-3-[(p-tolyl)-1,2-4-oxadiazol-5-yl]propyl 2,3-didesoxy-a-D-erythro-hex-2-enopyranoside 6d obtained by the
AM1 method.
3. Conclusion
followed by the exposure of the plates in a chamber
containing iodine vapors, which revealed the spots. The
solvent system for running the TLC plates was a mixture of
0.5:9.5 ethyl acetate–dichlromethane. For compounds 5e
and 6e, the solvent system for the development of the plate
was CHCl3/AcOEt/MeOH, 8.5:1.0:0.5. Optical rotaions
were measured with a Prkin–Elmer 141 and 241 polari-
In summary, the glycosides 5a–e and 6a–e have been
synthesized and diastereoisomers have been separated by
chromatography. Also the configuration of compound 5d
was proved by X-ray crystallography.
´
meters at the Universite Claude Bernard Lyon 1, Villeur-
4. Experimental
banne (France), and at the University of Sa˜o Carlos, Sa˜o
Carlos, Sa˜o Paulo (Brazil), respectively.
Melting points were determined with a Digital Melting

10766
R. M. Srivastava et al. / Tetrahedron 60 (2004) 10761–10769
Table 2. Selected bond lengths, bond angles and torsion angles of 5d and 6d obtained by AM1 calculations
Atoms AM1
Configuration at
C(8) (R)
Configuration at
C(8) (S)
˚
Bond length (A)
C(10)–O(9)
C(10)–O(11)
C(10)–O(15)
C(14)–O(15)
O(9)–C(8)
C(5)–C(6)
C(5)–N(4)
C(5)–O(1)
N(2)–C(3)
1.42
1.41
1.50
1.33
1.43
1.48
1.33
1.43
1.36
1.31
1.46
1.42
1.42
1.50
1.33
1.43
1.48
1.33
1.43
1.36
1.31
1.46
O(1)–C(2)
C(3)–C(16)
Bond angle (8)
H(15)–C(15)–C(10)
C(10)–O(11)–C(12)
H(10)–C(10)–O(11)
O(9)–C(10)–H(10)
C(10)–O(9)–C(8)
O(9)–C(8)–C(23)
C(23)–C(8)–C(7)
C(6)–C(5)–N(4)
C(6)–C(5)–O(1)
115.8
113.7
105.4
111.1
115.6
106.8
112.3
134.1
116.4
115.3
114.4
104.7
113.4
117.0
113.5
111.2
133.6
116.9
Torsion angle (8)
O(9)–C(10)–O(11)–C(12)
C(10)–O(11)–C(12)–C(13)
C(10)–O(9)–C(8)–C(23)
C(23)–C(8)–C(7)–C(6)
H(10)–C(10)–C(15)–H(15)
C(10)–O(9)–C(8)–C(7)
71.6
62.1
K131.8
K75.3
K43.2
106.4
71.2
60.6
K44.5
K165.9
K46.2
81.3
Figure 6. Structures of 5a and 6a.
AM1 method: Semi-empirical molecular orbital calcu-
lations were carried out employing the AM1 method.17
The MOPAC 93 program18,19 was used for the calculations.
Geometry optimization could be achieved in all cases, the
gradient norm being %0.2.
chromatography over silica gel using hexane–ethyl acetate
(9:1) gave chromatographically pure 2a–e.22
4.2. General procedure for the preparation of (R e S)-1-
methyl-3-[3-(aryl)-1,2,4-oxadiazol-5-yl]propyl 4,6-di-O-
acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranosides
3a–e and 4a–e
4.1. General procedure for the preparation of 4-[3-aryl-
1,2,4-oxadiazol-5-yl]-2-butanol 2a–e
The reaction of 2a–e with compound 1 were conducted
according to the method of Toshima et al.20 The details are
given below.
Sodium borhydride (7.66 mmol) was added to a solution of
4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-2-butanones21 (16.15 mmol)
dissolved in methanol (57 mL) under stirring at room
temperature. After an hour of agitation, thin layer
chromatography showed the disappearance of the starting
material and the formation of a new product. Later, most of
the solvent was evaporated and the residue was treated with
a saturated aqueous sodium chloride solution and extracted
with ethyl acetate (3!30 mL). Drying (Na2SO4) and
solvent evaporation afforded of the crude product. Liquid
4.2.1. (R e S)-1-Methyl-3-[3-(phenyl)-1,2,4-oxadiazol-5-
yl] propyl-4,6-di-O-acetyl-2,3-dideoxy-a-D-eryhtro-hex-
2-enopyranoside 3a and 4a. Yield 68%, RfZ0.58 (dichro-
methane–ethyl acetate, 9:1); IR nmax (KBr): 1743, 1368,
1231, 1034, 722 cmK1 1H NMR (CDCl3): d 8.12–8.02
;
(m, 2H, H-17 and H-21), 7.54–7.42 (m, 3H, H-18, H-19 and
H-20), 6.00–5.72 (m, 2H, H-14 and H-15), 5.23 (dd, 1H,

R. M. Srivastava et al. / Tetrahedron 60 (2004) 10761–10769
10767
JZ9.6 Hz, 3.0 Hz, H-13), 5.16 and 5.13 (20bs, each 1H,
H-10), 4.30–4.16 (m, 2H, H-23 and H-23 ), 4.16–3.84
(m, 0 2H, H-12 and H-8), 3.20–3.00 (m, 2H, H-6 and
H-6 ), 2.18–2.02 (m, 2H, H-7 and H-70), 2.09 (s, 3H,
OAc), 2.08 (s, 3H, OAc), 1.36 and 1.34 (2d, each 3H,
JZ6.3 Hz, H-22), 1.25 and 1.24 (2d, each 3H, JZ
6.0 Hz, H-22).
4.3. General procedure for the preparation of (R and S)-
1-methyl-3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propyl2,3-
´
dideoxy-a-D-erythro-hex-2-enopyranosıde 5a–e and 6a–e
The hydrolysis of 3a–e and 4a–e were conducted according
to the method of Fraser-Reid et al.16 The products were
purified by chromatography using dichlromethane–ethyl
acetate (9.5:0.5) to give 5a–e as a crystalline solids and 6a–e
as a syrup.
4.2.2. 1-(R and S)-Methyl-[3-(o-tolyl)-1,2,4-oxadiazol-5-
yl] propyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-
2-enopyranoside (3b and 4b). Yield 53%; IR nmax (KBr):
4.3.1. 1-(R)-Methyl-[3-(phenyl)-1,2,4-oxadiazol-5-yl]pro-
pyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside (5a).
RfZ0.12, yield 45%; mp 105.3–106.5 8C; [a]2D7ZC10G18
1
1743, 1370, 1223, 1053, 741 cmK1; H NMR (CDCl3): d
7.94–7.80 (m, 1H, H-21), 7.38–7.15 (m, 3H,0 H-18, H-19
and H-20), 5.86–5.60 (m, 2H, H-14 and H-15 ), 5.25 (dd,
1H, JZ9.6 and 2.7 Hz, H-13), 5.15 and 5.12 (2s, each 1H,
H-10), 4.24 (m, 2H, H-24 and H-240), 4.10–3.78 (m, 2H,
H-12 and H-8), 3.18–3.01 (m, 2H, H-6 and H-600), 2.60
(s, 3H, Ar-CH3), 2.09–2.04 (m, 2H, H-7 and H-7 ), 2.08
(s, 3H, OAc), 2.07 (s, 3H, OAc), 1.38 (2d, each 3H,
JZ6.3 Hz, H-23), 1.24 (2d, each 3H, JZ6.0 Hz, H-23).
(cZ1.5, CH2Cl2); IR nmax (KBr): 3407, 1594, 1025 cmK1
;
1H NMR (CDCl3): H NMR (300 MHz, CDCl3): d 8.10–
8.04 (ddd, 2H, JZ1.8, 5.4, 10.2 Hz, H-17 and H-21), 7.48
(dd, 3H, JZ1.8, 10.2 Hz, H-18, H-19 and H-20), 5.94 (d,
1H, JZ10.5 Hz, H-14), 5.74 (ddd, 1H, JZ10.5, 2.4, 2.1 Hz,
H-15), 5.08 (s, 1H, H-10), 4.22 (dd, 1H, JZ3.6, 7.5 Hz, H-
13), 3.91–3.71 (m, 4H, H-12, H-23, H-230 and H-8), 3.04
(m, 2H, H-6 and H-60), 2.10–2.02 (m, 2H, H-7 and H-70),
1.97 (s, 1H, OH), 1.90 (s, 1H, OH), 1.32 (d, 3H, JZ6.3 Hz,
H-22). Anal. Calcd for (C18H22O5N2$3/4H2O): C, 60.07; H,
6.58; N, 7.78. Found: C, 60.32; H, 6.39; N, 7.46.
1
4.2.3. 1-(R and S)-Methyl-[3-(m-tolyl)-1,2,4-oxadiazol-5-
yl] propyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-
2-enopyranoside (3c and 4c). Yield 83%; IR nmax (KBr):
1
1744, 1575, 1369, 1034, 738 cmK1; H NMR (CDCl3): d
4.3.2. 1-(S)-Methyl-[3-(phenyl)-1,2,4-oxadiazol-5-yl]-
propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(6a). RfZ0.15, colorless thick liq., yield 53%; [a]2D7Z
C57G18 (cZ1.5, CH2Cl2); IR nmax (KBr): 3353, 1594,
3.00–7.81 (m, 2H, H-17 and H-21), 7.41–7.24 (m, 2H, H-19
and H-20), 6.00–5.78 (m, 2H, H-14 and H-15), 5.36–5.20
(m, 1H, H-13), 5.16 and 5.12 (2d, each 1H, H-10), 4.36–4.18
(m, 2H, H-24 and H-240), 4.18–4.10 (m, 1H, H-12)0, 4.06–
3.80 (m, 1H, H-8), 3.22–2.90 (m, 2H, H-6 and H-60), 2.42
(bs, 3H, Ar-CH3), 2.15–2.02 (m, 2H, H-7 and H-7 ), 2.08
(s, 3H, OAc), 2.07 (s, 3H, OAc), 1.35 (d, 3H, JZ6.3 Hz,
H-23), 1.25 (d, 3H, JZ6.3 Hz, H-23).
1025 cmK1 1H NMR (CDCl3): 1H NMR (300 MHz,
;
CDCl3): d 8.10–8.04 (ddd, 2H, JZ1.8, 5.1, 10.2 Hz, H-17
and H-21), 7.51–7.46 (dd, 3H, JZ1.8, 10.2 Hz, H-18, H-19
and H-20), 5.95 (dd, 1H, JZ1.5, 10.2 Hz, H-14), 5.70 (ddd,
1H, JZ10.2, 2.1, 1.5 Hz, H-15), 5.04 (d, 1H, JZ1.5 Hz,
H-10), 4.10 (d, 1H, JZ7.2 Hz, H-13), 3.94–3.74 (m,
4H, 0H-12, H-23, H-230 and H-8), 3.31–3.01 (m, 2H, H-6 and
H-6 ), 2.58 (s, 1H, OH), 2.12–2.04 (m, 2H, H-7 and H-70),
1.97 (s, 1H, OH), 1.20 (d, 3H, JZ6.0 Hz, H-22). Anal.
Calcd for (C18H22O5N2$3/4H2O): C, 60.07; H, 6.58; N,
7.78. Found: C, 60.32; H, 6.39; N, 7.46.
4.2.4. 1-(R and S)-Methyl-[3-(p-tolyl)-1,2,4-oxadiazol-5-
yl] propyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-
2-enopyranoside (3d and 4d). Yield 92%; IR nmax (KBr):
1744, 1370, 1034, 756 cmK1; 1H NMR (CDCl3): d 7.97 and
7.94 (2d, each 2H, JZ8.4 Hz, H-17 and H-21), 7.29 and
7.28 (2d, each 2H, JZ8.4 Hz, H-18 and H-20), 6.00–5.54
(m, 2H, H-14 and H-15), 5.28 and 5.25 (2bd, each 1H,
JZ9.9 and 9.0 Hz, H-13), 5.16 and 5.13 (2bs, each 1H,
H-10), 4.40–4.20 (m, 2H, H-24 and H-240), 4.20–3.85
(m, 2H, H-12 and H-8), 3.28–2.95 (m, 2H, H-6 and0 H-60),
2.41 (s, 3H, Ar-CH3), 2.22–2.02 (m, 2H, H-7 and H-7 ), 2.08
and 2.07 (2s, 3H, OAc), 1.35 (d, 3H, JZ6.0 Hz, H-23), 1.23
(d, 3H, JZ6.0 Hz, H-23).
4.3.3. 1-(R)-Methyl-[3-(o-tolyl)-1,2,4-oxadiazol-5-yl]-
propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(5b). RfZ0.08, yield 33%; mp 124.3–125 8C; [a]2D8Z
C19.88 (cZ0.5, CHCl3); IR nmax (KBr): 3400, 1595, 1365,
1059, 738 cmK1; 1H NMR (300 MHz, CDCl3): d 7.96–7.93
(d, 1H, JZ7.5 Hz, H-21), 7.41–7.27 (dd, 3H, JZ1.8,
7.8 Hz, H-18, H-19 and H-20), 5.97 (dd, 1H, JZ10.5,
1.8 Hz H-14), 5.68 (tt, 1H, JZ10.5, 1.8, 2.1 Hz, H-15), 5.25
(td, 1H, JZ1.8 Hz, H-13), 5.08 (bs, 1H, H-10), 4.22–3.72
(m, 4H,0 H-12, H-24, H-240 and H-8), 3.07 (m, 2H, H-6
and H-6 ), 2.61 (s, 3H. ArCH3), 2.12–2.04 (m, 2H, H-7 and
H-70), 1.98 (s, 2H, OH), 1.33 (d, 3H, JZ6.3 Hz, H-23).
Anal. Calcd for (C19H24O5N2): C, 63.31; H, 6.71; N, 7.77.
Found: C, 62.93; H, 6.71; N, 7.40.
4.2.5. 1-(R and S)-Methyl-[3-(p-chlorophenyl)-1,2,4-oxa-
diazol-5-yl] propyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-
erythro-hex-2-enopyranoside (3e and 4e). Yield 58%; IR
nmax (KBr): 1744, 1475, 1035, 748 cmK1 1H NMR
;
(CDCl3): d 8.00–7.99 (2d, each 2H, JZ8.7 Hz, H-17 and
H-21), 7.45–7.44 (2d, each 2H, JZ8.7 Hz, H-18 and H-20),
5.97–5.73 (m, 2H, H-14 and H-15), 5.28 and 5.21 (2ddd,
each 1H, JZ9.5 Hz, 3.3 Hz, 1.5 Hz, H-13), 5.15 and 5.11
(2bs, each 1H, H-10), 4.25–4.16 (m, 2H, H-24 and H-240),
4.15–3.82 (m, 2H, H-12 and H-8), 3.20–3.10 (m, 2H, H-6
and H-60), 2.10–2.02 (m, 2H, H-7 and H-70), 2.08 (s, 3H,
OAc), 2.07 (s, 3H, OAc), 1.35 (d, 3H, JZ6.3 Hz, H-23),
1.23 (d, 3H, JZ6.0 Hz, H-23).
4.3.4. 1-(S)-Methyl-[3-(o-tolyl)-1,2,4-oxadiazol-5-yl]-
propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(6b). RfZ0.08, colorless syrup, yield 33%; [a]2D7ZC188
(cZ0.4, CHCl3); IR nmax (KBr): 3350, 1594, 1026, 1370,
1
738 cmK1; H NMR (300 MHz, CDCl3): d 7.96–7.93 (d,
1H, JZ7.2 Hz, H-21), 7.41–7.30 (m, 3H, H-18, H-19
and H-20), 5.96 (d, 1H, JZ10.2 Hz, H-14), 5.68 (tt, 1H, JZ

10768
R. M. Srivastava et al. / Tetrahedron 60 (2004) 10761–10769
10.2, 1.5 Hz, H-15), 5.18 (td, 1H, JZ3.0 Hz, H-13), 5.06 (s,
1H, H-10), 4.10–3.75 (m, 4H, H-12, H-24, H-240 and H-8),
3.07 (m, 2H, H-6 and H-60), 2.61 (s, 3H. ArCH3), 2.23 (s,
2H, OH), 2.10–1.97 (m, 2H, H-7 and H-70), 1.23 (d, 3H, JZ
6.0 Hz, H-23). Anal. Calcd for (C19H24O5N2): C, 63.31; H,
6.71; N, 7.77. Found: C, 62.95; H, 6.65; N, 7.43.
CH3), 2.12–2.04 (m, 2H, H-7 and H-70), 1.22 (d, 3H, JZ
6.0 Hz, H-23). Anal. Calcd for (C19H24O5N2): C, 63.31; H,
6.71; N, 7.77. Found: C, 63.89; H, 7.24; N, 7.56.
4.3.9. 1-(R)-Methyl-[3-(p-chlorophenyl)-1,2,4-oxadiazol-
5-yl]propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyrano-
side (5e). RfZ0.27, yield 30%; mp 132.7–133.8 8C;
[a]2D5ZC13.148 (cZ0.7, CHCl3); IR nmax (KBr): 3404
4.3.5.
1-(R)-Methyl-[3-(m-tolyl)-1,2,4-oxadiazol-5-
(OH), 1589, 1474, 1449 cmK1 1H NMR (300 MHz,
;
yl]propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(5c). RfZ0.09, yield 43%; mp 127.3–128.9 8C;
[a]2D7ZC17.68 (cZ0.8, CHCl3); IR nmax (KBr): 3352
(OH), 1574, 1351, 1027, 738 cmK1; H NMR (300 MHz,
CDCl3) d: 7.88–7.84 (dd, 2H, JZ1.5, 9.6 Hz, H-17 and H-
21), 7.39–7.30 (d, 2H, JZ7.8 Hz, H-19 and H-20), 5.95 (d,
1H, JZ9.9 Hz, H-14), 5.75 (ddd, 1H, JZ9.9, 3.0, 1.2 Hz,
H-15), 5.08 (s, 1H, H-10), 4.23 (sl, 1H, H-13), 4.01–3.77 (m,
4H, 0H-12, H-24, H-240and H-8), 3.01–3.10 (m, 2H, H-6 and
H-6 ), 2.62 (s, 1H, OH), 2.42 (s, 3H, Ar-CH3), 2.10–2.02 (m,
2H, H-7 and H-70), 1.32 (d, 3H, JZ6.0 Hz, H-10). Anal.
Calcd for (C19H24O5N2): C, 63.31; H, 6.71; N, 7.77. Found:
C, 62.98; H, 6.77; N, 7.48.
CDCl3): d 8.02–7.99 (dd, 2H, JZ8.4, 3.0 Hz, H-17 and
H-21), 7.47–7.44 (dd, 2H, JZ7.8, 1.2 Hz, H-18 and H-20),
5.90 (d, 1H, JZ10.5 Hz, H-14), 5.74 (ddd, 1H, JZ10, 5 Hz,
e JZ1.8, 1.5 Hz, H-15), 5.07 (s, 1H, H-10), 4.22 (d, 1H,0JZ
7.5 Hz, H-13), 3.95–3.67 (m, 4H, H-12, H-24, H-24 and
H-8), 3.09–3.01 (m, 2H, H-6 and H-60), 2.09–2.02 (m, 2H,
H-7 and H-70), 1.70 (bs, 2H, OH), 1.32 (d, 3H, JZ6.3 Hz,
H-23). Anal. Calcd for (C18H24O5N2Cl): C, 56.77; H, 5.56;
N, 7.36. Found: C, 56.88; H, 5.78; N, 7.14.
4.3.10. 1-(S)-Methyl-3-(p-chlorophenyl)-1,2,4-oxadiazol-
5-yl]propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyrano-
side (6e). RfZ0.40, colorless syrup, yield 35%; [a]2D5ZC
33.78 (cZ0.6, CHCl3); IR nmax (KBr): 3404 (OH), 1589,
4.3.6. 1-(S)-Methyl-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]-
propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(6c). Colorless syrup, RfZ0.14, yield 48%; [a]2D7Z
C18.58 (cZ1.2, CHCl3); IR nmax (KBr): 3406 (OH), 1596,
1
1564, 1474, 1449 cmK1; H NMR (300 MHz, CDCl3): d
8.02–7.98 (dd, 2H, JZ1.5, 8.1 Hz, H-17 and H-21), 7.47–
7.38 (dd, 2H, JZ8.4, 2.1 Hz, H-18 and H-20), 6.34 (dd, 1H,
JZ9.8, 1.8 Hz, H-14), 5.90 (dd, 1H, JZ9.8 Hz, e JZ
3.3 Hz, H-15), 5.06 (s, 1H, H-10), 4.12 (d,0 1H, JZ6.9 Hz,
H-13), 3.98–3.65 (m, 4H,0H-12, H-24, H-24 and H-8), 3.13–
303 (m, 2H, H-6 a0nd H-6 ), 2.96 (s, 2H, OH), 2.10–1.92 (m,
2H, H-7 and H-7 ), 1.28 (d, 3H, JZ6.0 Hz, H-23). Anal.
Calcd for (C18H24O5N2Cl): C, 56.77; H, 5.56; N, 7.36.
Found: C, 56.31; H, 5.70; N, 6.96.
1366, 1059, 738 cmK1 1H NMR (300 MHz, CDCl3) d:
;
7.92–7.84 (dd, 2H, JZ4.5, 10.8 Hz, H-17 and H-21), 7.40–
7.30 (d, 3H, JZ7.8 Hz, H-19 and H-20), 5.95 (d, 1H, JZ
10.2 Hz, H-15), 5.69 (dd, 1H, JZ10.2, 2.7 Hz, H-14), 5.05
(s, 1H, H-10), 4.11 (sl, 1H, H-14), 3.93–3.80 (m, 4H, H-102,
H-24, H-240and H-8), 3.00–3.16 (m, 2H, H-6 and H-6 ),
2.85 (s, 1H, OH), 2.42 (s, 3H, Ar-CH3), 2.18–1.97 (m, 2H,
H-7 and H-70), 1.24 (d, 3H, JZ6.0 Hz, H-23). Anal. Calcd
for (C19H24O5N2): C, 63.31; H, 6.71; N, 7.77. Found: C,
62.94; H, 6.88; N, 7.45.
4.4. General procedure for the acetylation of (R) and (S)-
1-methyl-3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propyl-2,3-
dideoxy-a-D-erythro-hex-2-enopyranoside (5a and 6a)
4.3.7. 1-(R)-Methyl-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]-
propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(5d). RfZ0.19, yield 42%; mp 128.9–129.5 8C; [a]2D7Z
C14G18 (cZ0.7, CH2Cl2); IR nmax (KBr): 3335 (OH),
1588, 1365, 1026, 744 cmK1; 1H NMR (300 MHz, CDCl3):
d 7.95 (d, 2H, JZ8.1 Hz, H-17 and H-21), 7.30 (dd, 2H, JZ
8.7 Hz, H-18 and H-20), 5.92 (d, 1H, JZ10.2 Hz, H-14),
5.72 (ddd, 1H, JZ10, 2 Hz, e JZ2, 7, 2.1 Hz, H-15), 5.22
(d, 1H, JZ7.5 Hz, H-13), 5.07 (s, 1H, H-10), 3.96–3.71 (m,
4H, H-12, H-24, H-240 and H-8), 3.03 (m, 2H, H-6 and H-60)
2.41 (s, 3H, Ar-CH3), 2.09–2.02 (m, 2H, H-7 and H-70), 1.32
(d, 3H, JZ6.3 Hz, H-23). Anal. Calcd for (C19H24O5N2):
C, 63.31; H, 6.71; N, 7.77. Found: C, 62.89; H, 6.68; N,
7.71.
To the pure dihydroxy compounds 5a or 6a (0.07 g,
0.21 mmol) in dry pyridine (2.0 mL), in a 10 mL round-
bottom flask and cooled to 0 8C was added Ac2O (1.0 mL).
Stirring at rt overnight gave mixture of 4,6-di-O-acetyl-2,3-
dideoxy-a-D-erythro-hex-2-enopyranosides 3a and 4a. Puri-
fication was achieved by column chromatography over
silica gel. Elution with 1:9 EtOAc–n-hexane gave 5a or 6a
in pure forms.
4.4.1. 1-(R)-Methyl-[3-(phenyl)-1,2,4-oxadiazol-5-yl]-
propyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-
enopyranoside (3a). RfZ0.61, liq., yield 90%; [a]2D5Z438
(cZ0.49, CHCl3); IR nmax (KBr): 1743, 1571, 1368, 1231,
1
4.3.8. 1-(S)-Methyl-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]-
propyl 2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(6d). RfZ0.22, colorless syrup, yield 30%; [a]2D5ZC798
(cZ0.7, CH2Cl2); IR nmax (KBr): 3414 (OH), 1590, 1365,
1026, 757 cmK1; 1H NMR (300 MHz, CDCl3): d 7.95–7.92
(d, 2H, JZ8.4 Hz,0H0 -200 and H-21), 7.29–7.26 (dd, 2H, JZ
7.8, 2.1 Hz, H-18 and H-2000), 5.95 (dd, 1H, JZ10.2,
1.8 Hz, H-14), 5.68 (dd, 1H, JZ10, 2 Hz, e JZ2, 7 Hz,
H-15), 5.05 (s, 1H, H-10), 4.10 (d, 1H, JZ9.3 Hz, H-13),
3.92–3.73 (m, 4H, H-12, H-24, H-240and H-8), 3.20–3.00
(m, 2H, H-6 and H-60), 2.96 (s, 2H, OH), 2.41 (s, 3H, Ar-
1034, 722 cmK1; H NMR (CDCl3): d 8.09–8.06 (dd, 2H,
JZ3.3, 9.6 Hz, H-17 and H-21), 7.53–7.49 (m, 3H, H-18,
H-19 and H-20), 5.80 (d, 1H, JZ10.2 Hz, H-14), 5.85 (ddd,
1H, JZ10.2, 2.7, 2.0 Hz, H-15), 5.31 (dd, 1H, JZ9.6,
1.5 Hz, H-13) 5.14 (bs, 1H, H-10), 4.60–4.40 (m, 2H, H-23
or H-230), 4.35 (m, 1H, H-8), 3.82 (dd, 1H, JZ9.7, 5.4 Hz,
H-12), 3.06 (t, 2H, JZ7.5 Hz, H-6 and H-60), 2.15–2.00 (m,
2H, H-7 and H-70), 2.10 (s, 3H, OAc), 2.09 (s, 3H, OAc),
1.36 (d, 3H, JZ6.3 Hz, H-22). Anal. Calcd for
(C22H26O7N2): C, 61.39 H, 6.09 N, 6.51. Found: C, 61.37
H, 6.07 N, 6.28.

R. M. Srivastava et al. / Tetrahedron 60 (2004) 10761–10769
10769
4.4.2. 1-(S)-Methyl-[3-(phenyl)-1,2,4-oxadiazol-5-yl]-
propyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-
enopyranoside (4a). RfZ0.65, mp 63.6 8C (from
n-hexane–ether), 96%; [a]2D5Z698 (cZ0.91, CHCl3); IR
found, in the online version, at doi:10.1016/j.tet.2004.08.
075
References and notes
1
nmax (KBr): 1744, 1571, 1369, 1232, 1034, 722 cmK1; H
NMR (CDCl3): d 8.10–8.06 (m, 2H, H-17 and H-21), 7.54–
7.46 (m, 3H, H-18, H-19 and H-20), 5.90 (d, 1H, JZ
10.2 Hz, H-14), 5.80 (ddd, 1H, JZ10.2, 2.7, 2.2 Hz, H-15),
5.30 (dd, 1H, JZ9.7, 1.5 Hz, H-13) 5.18 (sl, 1H, H-10), 4.28
(dd, 1H, JZ13.1, 5.4 Hz, H-23 or0H-230), 4.20 (dd, 1H, JZ
13.1 Hz, J%1.0 Hz, H-23 or H-23 ), 4.15 (m, 1H, H-8), 4.04
(dd,01H, JZ9.7, 5.4 Hz, H-12), 3.01–3.20 (m, 2H, H-6 and
H-6 ), 2.20–2.06 (m, 2H, H-7 and H-70), 2.10 (s, 3H, OAc),
2.09 (s, 3H, OAc), 1.26 (d, 3H, JZ6.0 Hz, H-22). Anal.
Calcd for (C22H26O7N2): C, 61.39 H, 6.09 N, 6.51. Found:
C, 61.58 H, 6.14 N, 6.26.
1. Sheban, M. A. E. Adv. Heterocycl. Chem. 1998, 70, 163–337.
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Details of the crystallographic data (CCDC) for compound
5d has been deposited with the Cambridge Crystallographic
Data Center. These data may be acquired from the
Director of CCDC, 12 Union Road, Cambridge CB2
1DEZ, UK (Tel.: C44-1223-336408, fax: C44-1223-33-
6033; e-mail: deposit@ccdc.cam.ac.uk or www: http//www.
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´
Our thanks are also due to Dr. L. Cottier, Universite Claude
Bernard Lyon 1, Villeurbanne, France, for measuring the
specific rotation of compounds 5e and 6e, and to Prof.
Timothy Brocksom, Universidade Federal de Sa˜o Carlos,
Sa˜o Paulo, for obtaining the specific rotation of compounds
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The X-ray equipment was purchased with assistance from
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Supplementary data
21. Kimura, G. Y. V.; Srivastava, R. M. Unpublished work.
22. De Freitas Filho, J. R.; Ph.D. Thesis, Federal University of
Pernambuco, Recife, 2001.
Supplementary data associated with this article can be