Synthesis of 5-substituted-3-[(2'S,3'S)-3'-hydroxy-2'-hydroxymethyltetrahydrofuran-3'-yl]-1,2,4-oxadiazoles and their epimers

Article abstract of DOI:10.1016/S0957-4166(00)00095-1

5-Phenyl-3-[(2'R,3'S)-3'-hydroxy-2'-dimethoxymethyltetrahydrofuran-3'-yl]-1,2,4-oxadiazole 10a and its epimer 11a, 5-methyl-3-[(2'R,3'S)-3'-hydroxy-2'-dimethoxymethyltetrahydrofuran-3'-yl]-1,2,4-oxadiazole 10b and its epimer 11b were synthesized from cyan

Full text of DOI:10.1016/S0957-4166(00)00095-1

Tetrahedron: Asymmetry 11 (2000) 1527±1536
Synthesis of 5-substituted-3-[(20S,30S)-30-hydroxy-
20-hydroxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazoles
and their epimers
W. D. Wu,a L. T. Ma,a L. H. Zhang,a,* Y. Lu,b F. Guob and Q. T. Zhengb
aSchool of Pharmaceutical Sciences, Beijing Medical University, Beijing 100083, PR China
bInstitute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, PR China
Received 31 January 2000; accepted 7 March 2000
Abstract
5-Phenyl-3-[(20R,30S)-30-hydroxy-20-dimethoxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole 10a and its
epimer 11a, 5-methyl-3-[(20R,30S)-30-hydroxy-20-dimethoxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole
10b and its epimer 11b were synthesized from cyanohydrin benzoates 8a, 9a and cyanohydrin acetates 8b,
9b, respectively, by treatment with hydroxylamine in methanol via intramolecular transacylation and sub-
sequent cyclization of the corresponding amidoximes. Hydrolysis and reduction of the dimethoxymethyl
groups in the above compounds gave the desired compounds 12a, 13a, 12b and 13b. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
The development of new classes of antiviral and antitumor agents have led, in our laboratory,
to the preparation of isonucleosides1,2 and iso-C-nucleosides.3 5 iso-C-Nucleosides constitute a
class of nucleoside analogues in which the nucleobases are linked via a carbon±carbon bond to
the carbohydrate moiety at a position other than C-10. It is anticipated that iso-C-nucleosides
may have increased chemical and enzymatic stability under physiological conditions and may
alter the biological pro®les including catabolism. Recently a number of nucleosides with the
unnatural l-con®guration have been reported as potent chemotherapeutic agents against HIV,
HBV and certain forms of cancer, and some of them show lower toxicity pro®les than their
d-counterparts.6 10 Previously, 0 we reported the synthesis of an iso-C-nucleoside in which the
oxadiazole ring is linked at the 3 -position of d-xylose.5 In this paper a series of l-con®guration iso-
C-nucleoside analogues bearing oxadiazole derivatives as nucleobases, 5-phenyl-3-[(20S,30S)-30-
hydroxy-20-hydroxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole 12a, 5-methyl-3-[(20S,30S)-30-
* Corresponding author. Tel: 86-10-62091700; fax: 86-10-62015584; e-mail: zdszlh@mail.bjmu.edu.cn
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00095-1

1528
W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
hydroxy-20-hydroxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole 12b and their epimers, 13a,
13b, were synthesized for investigation of their biological activities.
2. Results and discussion
The most frequently encountered route for the synthesis of substituted 1,2,4-oxadiazoles
involves the acylation and subsequent cyclization of amidoximes, which can be obtained by con-
densation of nitriles with hydroxylamine.11,12 For our purposes the key intermediate would be
cyanohydrins 6. Epoxide 2, prepared from 1,2-O-isopropylidene-a-d-xylose 113 in three steps,1,14
was reduced with lithium aluminum hydride in re¯uxing tetrahydrofuran to a€ord a 6:1 mixture
of tetrahydrofuranols 3 and 4 in 58% and 9.3% yields, respectively. The predominance of tetra-
hydrofuranol 3 is probably attributable to the steric hindrance of the 2-dimethoxymethyl group
to the coordinated reducing reagent; since the lithium aluminum hydride reduction takes place in
an SN2 fashion, the epoxide 2 will be opened from the b-face. The hydroxy group in 3 was oxidized
with pyridinium dichromate (PDC) in dichloromethane to give ketone 5 in 92.6% yield. Addition
of hydrogen cyanide (generated in situ from potassium cyanide and acetic acid) to 5 in dichloro-
methane±water gave an epimeric mixture of cyanohydrins 6 (Scheme 1). Due to almost the same
chromatographic mobility of the two cyanohydrin epimers, no attempt was performed to separate
1
them, and H NMR spectroscopic data showed that the two epimers were present in about the
same amount. When 6 was treated with hydroxylamine15 in methanol under re¯ux, instead of the
corresponding amidoximes, only a low yield of 3-oximido derivative 7 was obtained. Obviously,
cyanohydrins 6 could undergo elimination of hydrogen cyanide under the slightly basic reac-
tion conditions at elevated temperature to a€ord 5, which condensed with hydroxylamine to
give oxime 7 (Scheme 2). For this reason cyanohydrins 6 were protected with benzoyl chloride
in pyridine to a€ord cyanohydrin benzoate 8a and its epimer 9a in 24.7% and 34.3% yields,
respectively.
Scheme 1. (i) Refs. 1 and 14; (ii) LiAlH4, THF, re¯ux; (iii) PDC, Ac2O, CH2Cl2, re¯ux; (iv) KCN, HOAc, CH2Cl2±
H2O, 0ꢀC; (v) BzCl, pyridine, rt; or Ac2O, DMAP, CH2Cl2, rt
In general, amidoximes can be isolated during the synthesis of oxadiazoles,11,12 but in our case,
treatment of both cyanohydrin benzoates, 8a and 9a, with hydroxylamine in methanol a€orded
5-phenyl-oxadiazole derivatives 10a and 11a in 42% and 40% yields, respectively, with a small

W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
1529
Scheme 2. Reaction pathway to 7
amount of compound 7 instead of the corresponding amidoximes (Scheme 3). The formation of 7
was not surprising and it can be ascribed to the debenzoylation of 8a or 9a to cyanohydrins 6 (see
Scheme 2). This `one-step cyclization' was possibly through two intermediates; intermediate II
was formed from amidoximes I by intramolecular transacylation of the neighboring benzoyl
group, and cyclization took place as a fast step (Scheme 4). The evidence to support the neighboring-
group participation mechanism is that in the cases of the reaction of 2,3,5-tri-O-benzoyl-b-d-
Scheme 3. (vi) NH2OH, CH3OH, re¯ux; (vii) 1% HCl±dioxane, 100ꢀC; then NaBH4, rt
Scheme 4. Mechanism for neighboring-group participation, transacylation and cyclization

1530
W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
ribofuranosyl cyanide11 and 2,3,4-tri-O-benzoyl-b-d-xylopyranosyl cyanide12 with hydroxylamine
in methanol, the corresponding amidoximes were obtained and no such transacylation and
cyclization products were noted. To demonstrate the generality of the mechanism, cyanohydrin
acetates 8b and 9b were prepared by treatment of cyanohydrins 6 with acetic anhydride and 4-
dimethylaminopyridine (DMAP) in dichloromethane. Treatment of both cyanohydrin acetates
with hydroxylamine in methanol a€orded 5-methyl-oxadiazole derivatives 10b and 11b, respectively,
as expected.
The stereochemistry of 10a was determined by single crystal X-ray analysis (Fig. 1). It was
shown that the oxadiazole moiety of compound 10a was on the same side as the dimethoxymethyl
group. Correspondingly, the cyano group of cyanohydrin benzoate 8a was deduced to be upon
the tetrahydrofuran ring, and compounds 9a and 11a were the C30 epimers of 8a and 10a,
respectively. The stereochemistries of 5-methyl-oxadiazole derivatives 10b and 11b were deter-
mined by comparison of NMR spectra with those of the 5-phenyl-oxadiazole counterparts.
Remarkable shifts were observed in 1H NMR spectra for the protons of methoxy groups and H6
0
between 10a and 11a, where the protons of methoxy groups in 10a (ꢀ 2.87, 3.17) appeared at
0
higher ®eld than those of 11a (ꢀ 3.17, 3.26) and H6 signal of 10a (ꢀ 4.11, overlapped with signals
0
0
of other protons) was at higher ®eld compared with that of 11a (ꢀ 4.52, doublet, J6 ,2 =7.5 Hz),
re¯ecting a steric interaction of the oxadiazole moiety with the dimethoxymethyl group in 10a.
1
Similar shifts in H NMR spectra data between 10b (chemical shifts for the protons of methoxy
0
groups and H6 : ꢀ 2.89, 3.13; ꢀ 3.99, overlapped) and 11b (chemical shifts for the protons of
0
0
0
methoxy groups and H6 : ꢀ 3.15, 3.35; ꢀ 4.47, doublet, J6 ,2 =7.5 Hz) could infer that 10b had the
same con®guration as 10a, and 11b was the C30 epimer of 10b.
Figure 1. Crystal X-ray structure of compound 10a
The dimethoxymethyl groups in compounds 10a, 10b, 11a and 11b were hydrolyzed in 1%
hydrochloric acid±dioxane and reduced with sodium borohydride to a€ord the deoxy l-ribitol
nucleosides 12a and 12b, and the deoxy l-xylitol nucleosides 13a and 13b. Two byproducts, 5-
phenyl-3-(20-hydroxymethyl-40,50-dihydrofuran-30-yl)-1,2,4-oxadiazole 14a and 5-methyl-3-(20-
hydroxymethyl-40,50-dihydrofuran-30-yl)-1,2,4-oxadiazole 14b were also obtained during the
reaction by E1 elimination of water. The structures of 14a and 14b were identi®ed by NMR
spectra; the orientation of the double bond is consistent with the Saytze€ rule.

W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
1531
3. Experimental
3.1. General procedures
Melting points were determined on an XT-4A melting point apparatus and are uncorrected.
Optical rotations were determined with a Perkin±Elmer 243B polarimeter. IR spectra were
recorded on a DE-983G spectrophotometer in KBr pellets. UV spectra were recorded on a Varian
DMS200 UV±visible spectrophotometer. Mass spectra were obtained on either ZAB-HS or
KYKY-ZHP-5 mass spectrometer. NMR spectra were recorded on a Varian-300 or JEOL AL300
spectrometer with TMS as internal standard. Exchangeable protons were detected by addition of
D2O. Column chromatography was performed on silica gel (200±300 mesh) purchased from
Qingdao Chemical Company, China.
3.2. (2R,3R)-3-Hydroxy-2-dimethoxymethyltetrahydrofuran 3 and (2R,4S)-4-hydroxy-2-dimethoxy-
methyltetrahydrofuran 4
To a solution of 21,14 (10 g, 62 mmol) in dry THF (200 ml), LiAlH4 (7.2 g, 190 mmol) was
added and the reaction mixture was re¯uxed until compound 2 was consumed (checked by TLC).
A mixture of THF (200 ml) and water (13 ml) was added dropwise to destroy the excess LiAlH4
at 0ꢀC, then the mixture was ®ltered and the ®ltrate was concentrated in vacuo. Silica gel column
chromatography (petroleum ether±acetone) a€orded compounds 3 (5.85 g, 58%) and 4 (0.94 g,
9.3%), each as a colorless oil.
15
D
1
Compound 3: ‰ꢁŠ ^31.2 (c 0.16, MeOH). EI-MS (m/z): 131 [M^OCH3]+. H NMR (DMSO-
d6) ꢀ 1.68 (m, 1H, H4a), 1.86 (m, 1H, H4b), 3.28, 3.30 (2s, 3H each, >C(OCH3)2), 3.62 (dd, 1H,
J2,6=5.7 Hz, J2,3=1.2 Hz, H2), 3.76 (m, 2H, H5a, H5b), 4.10 (d, 1H, J6,2=5.7 Hz, H6), 4.15 (m,
1H, H3), 4.89 (d, 1H, D2O exchangeable, 3-OH). 13C NMR (DMSO-d6) ꢀ 35.2 (C4), 53.5 (OCH3),
55.0 (OCH3), 66.7 (C5), 71.6 (C2), 85.9 (C3), 104.1 (C6). Anal. calcd for C7H14O4: C, 51.84; H,
8.70. Found: C, 51.59; H, 8.59.
15
Compound 4: ‰ꢁŠ +2.7 (c 0.185, MeOH). EI-MS (m/z): 131 [M^OCH3]+. H NMR (DMSO-
1
D
d6) ꢀ 1.77 (m, 2H, H3a, H3b), 3.29, 3.30 (2s, 3H each, >C(OCH3)2), 3.51 (d, 1H, J5a,5b=8.7 Hz,
H5a), 3.73 (dd, 1H, J5b,5a=8.7 Hz, J5b,4=3.9 Hz, H5b), 4.01 (m, 1H, H2), 4.18 (d, 1H, J6,2=5.4
Hz, H6), 4.27 (m, 1H, H4), 4.85 (d, 1H, D2O exchangeable, 4-OH). 13C NMR (DMSO-d6) ꢀ 36.2
(C3), 53.6 (OCH3), 54.8 (OCH3), 70.3 (C5), 75.0 (C2), 77.3 (C4), 105.6 (C6). Anal. calcd for
C7H14O4: C, 51.84; H, 8.70. Found: C, 51.47; H, 8.76.
3.3. 2-(S)-Dimethoxymethyl-3-keto-tetrahydrofuran 5
To a stirred solution of 3 (11.0 g, 68 mmol) in dry CH2Cl2 (50 ml) were added pyridium dichromate
(PDC, 15.3 g, 40 mmol) and Ac2O (18.8 ml, 200 mmol), and the mixture was re¯uxed for 1 h.
After being cooled to ambient temperature, Et2O ( 200 ml) was added, and the mixture was
applied to a short silica gel column and eluted by Et2O. The combined eluant was concentrated and
coevaporated with toluene (3Â20 ml) to a€ord 5 (10.1 g, 92.6%) as a pale yellow oil. Compound
5 was used without further puri®cation. IR (KBr): 1755 cm^1 (CO). EI-MS (m/z): 129 [M^OCH3]+.
1H NMR (DMSO-d6) ꢀ 2.46 (overlapped, 2H, H4a, H4b), 3.29, 3.33 (2s, 3H each, >C(OCH3)2),
3.89 (d, 1H, J2,6=2.1 Hz, H2), 4.14 (m, 2H, H5a, H5b), 4.42 (d, 1H, J6,2=2.1 Hz, H6). 13C NMR
(DMSO-d6) ꢀ 36.6 (C4), 54.6 (OCH3), 54.9 (OCH3), 64.9 (C5), 78.4 (C2), 103.4 (C6), 213.1 (C3).

1532
W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
3.4. 2-(R)-Dimethoxymethyl-3-oximido-tetrahydrofuran 7
To a mixture of 5 (880 mg, 5.5 mmol), CH2Cl2 (10 ml), water (5 ml) and potassium cyanide
(720 mg, 11 mmol) at 0ꢀC, HOAc (0.5 ml, 8.2 mmol) was added. The mixture was stirred at 0ꢀC
for 2 h, then the organic phase was separated and dried (Na2SO4). After evaporation in vacuo,
the residue was dissolved in methanol (10 ml) containing free base hydroxylamine [from 800 mg
(11 mmol) of the hydrochloride]15 and the mixture was re¯uxed for 2 h. The solvent was then
evaporated and the residue was puri®ed by silica gel column chromatography (petroleum ether±
ethyl acetate) to a€ord 7 (180 mg, 19%) as a syrup. ‰ꢁŠ15 ^102.8 (c 0.105, MeOH). FAB-MS (m/z):
D
1
176 [M+H]+. H NMR (DMSO-d6) ꢀ 2.57 (overlapped, 2H, H4a, H4b), 3.30, 3.33 (2s, 3H each,
>C(OCH3)2), 3.86 (m, 1H, H5a), 4.01 (m, 1H, H5b), 4.28 (d, 1H, J2,6=3.6 Hz, H2), 4.35 (d, 1H,
J6,2=3.6 Hz, H6), 10.88 (s, 1H, D2O exchangeable, N-OH). 13C NMR (DMSO-d6) ꢀ 27.3 (C4),
54.5 (OCH3), 54.8 (OCH3), 66.6 (C5), 76.9 (C2), 104.5 (C6), 159.0 (C3). Anal. calcd for C7H13NO4:
C, 47.99; H, 7.48; N, 7.99. Found: C, 47.59; H, 7.44; N, 7.74.
3.5. (2R,3S)-3-Benzoyloxy-3-cyano-2-dimethoxymethyltetrahydrofuran 8a and (2R,3R)-3-benzoyl-
oxy-3-cyano-2-dimethoxymethyltetrahydrofuran 9a
To a mixture of 5 (3.6 g, 23 mmol), CH2Cl2 (40 ml), water (20 ml) and potassium cyanide (3.0
g, 46 mmol) at 0ꢀC, HOAc (2.0 ml, 34.5 mmol) was added. The mixture was stirred at 0ꢀC for 2 h,
then the organic phase was separated and dried (Na2SO4). After evaporation in vacuo, the residue
was dissolved in dry pyridine (20 ml), BzCl (2.7 ml, 23 mmol) was added and the mixture was
stirred overnight. Most of the solvent was removed and the residue was partitioned between ice-
cold water (20 ml) and CH2Cl2 (2Â20 ml). The organic extracts were washed in sequence with 1 M
H2SO4 (10 ml), saturated NaHCO3 solution (10 ml) and brine (10 ml), and dried over anhydrous
Na2SO4. The solvent was evaporated and the residue was puri®ed by silica gel chromatography
(petroleum ether±acetone) to yield 8a (1.62 g, 24.7%) and 9a (2.25 g, 34.3%), each as a syrup.
15
Compound 8a: ‰ꢁŠ ^62.0 (c 0.15, MeOH). FAB-MS (m/z): 292 [M+H]+. 1H NMR (DMSO-d6)
D
ꢀ 2.76 (m, 2H, H4a, H4b), 3.41, 3.42 (2s, 3H each, >C(OCH3)2), 3.92 (m, 1H, H5a), 4.11 (m, 1H,
H5b), 4.31 (d, 1H, J2,6=5.4 Hz, H2), 4.60 (d, 1H, J6,2=5.4 Hz, H6), 7.59 (t, 2H, arom. H), 7.75 (t,
1H, arom. H), 8.02 (d, 2H, arom H). 13C NMR (DMSO-d6) ꢀ 38.5 (C4), 54.3 (OCH3), 54.9
(OCH3), 66.5 (C5), 76.5 (C2), 83.8 (C3), 102.7 (C6), 116.2 (CN), 128.0, 128.9, 129.6, 134.4 (arom.
C), 164.2 (CO). Anal. calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.80. Found: C, 62.17; H, 5.83;
N, 4.56.
15
D
Compound 9a: ‰ꢁŠ +48.3 (c 0.12, MeOH). FAB-MS (m/z): 292 [M+H]+. 1H NMR (DMSO-d6)
ꢀ 2.79 (m, 2H, H4a, H4b), 3.38, 3.42 (2s, 3H each, >C(OCH3)2), 3.96 (m, 2H, H5a, H5b), 4.19 (d,
1H, J2,6=7.2 Hz, H2), 4.84 (d, 1H, J6,2=7.2 Hz, H6), 7.60 (t, 2H, arom. H), 7.75 (t, 1H, arom. H),
8.02 (d, 2H, arom. H). 13C NMR (DMSO-d6) ꢀ 38.2 (C4), 53.4 (OCH3), 55.3 (OCH3), 66.2 (C5),
74.8 (C2), 83.6 (C3), 101.5 (C6), 116.5 (CN), 128.1, 129.1, 129.5, 134.4 (arom. C), 163.8 (CO).
Anal. calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.80. Found: C, 61.35; H, 5.79; N, 4.86.
3.6. (2R,3S)-3-Acetoxy-3-cyano-2-dimethoxymethyltetrahydrofuran 8b and (2R,3R)-3-acetoxy-
3-cyano-2-dimethoxymethyltetrahydrofuran 9b
To a mixture of 5 (3.4 g, 21 mmol), CH2Cl2 (40 ml), water (20 ml) and potassium cyanide (2.7
g, 42 mmol) at 0ꢀC, HOAc (1.8 ml, 31.5 mmol) was added and the mixture was stirred at 0ꢀC for

W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
1533
2 h. The organic phase was separated and dried over anhydrous Na2SO4. 4-Dimethylaminopyridine
(DMAP, 3.7 g, 30 mmol) and Ac2O (2.3 ml, 26 mmol) were added and the mixture was stirred
overnight. After water (10 ml) was added, the organic phase was separated and washed in sequence
with 1 M H2SO4 (10 ml), saturated NaHCO3 solution (10 ml) and brine (10 ml), and dried (Na2SO4).
The solvent was evaporated and the residue was puri®ed by silica gel column chromatography
(petroleum ether±acetone) to yield 8b (1.65 g, 33.3%) and 9b (1.57 g, 31.7%), each as a syrup.
15
Compound 8b: ‰ꢁŠ ^48.1 (c 0.185, MeOH). FAB-MS (m/z): 230 [M+H]+. 1H NMR
D
(DMSO-d6) ꢀ 2.13 (s, 3H, COCH3), 2.50 (overlapped, 1H, H4a), 2.64 (m, 1H, H4b), 3.36 (s, 6H,
>C(OCH3)2), 3.82 (m, 1H, H5a), 4.04 (overlapped, 2H, H5b, H2), 4.51 (d, 1H, J6,2=5.4 Hz, H6).
13C NMR (DMSO-d6) ꢀ 20.6 (COCH3), 38.4 (C4), 54.2 (OCH3), 54.7 (OCH3), 66.4 (C5), 75.8
(C2), 83.9 (C3), 102.5 (C6), 116.3 (CN), 169.2 (CO). Anal. calcd for C10H15NO5: C, 52.39; H, 6.59;
N, 6.11. Found: C, 52.01; H, 6.54; N, 5.83.
15
Compound 9b: ‰ꢁŠ ^3.5 (c 0.115, MeOH). FAB-MS (m/z): 230 [M+H]+. 1H NMR (DMSO-d6)
D
ꢀ 2.15 (s, 3H, COCH3), 2.57 (m, 1H, H4a), 2.72 (m, 1H, H4b), 3.34, 3.39 (2s, 3H each,
>C(OCH3)2), 3.92 (m, 2H, H5a, H5b), 4.03 (d, 1H, J2,6=7.5 Hz, H2), 4.57 (d, 1H, J6,2=7.5 Hz,
H6). 13C NMR (DMSO-d6) ꢀ 20.5 (COCH3), 38.0 (C4), 53.3 (OCH3), 55.5 (OCH3), 66.0 (C5), 73.9
(C2), 83.2 (C3), 101.5 (C6), 116.6 (CN), 168.8 (CO). Anal. calcd for C10H15NO5: C, 52.39; H, 6.59;
N, 6.11. Found: C, 52.20; H, 6.62; N, 5.90.
3.7. 5-Phenyl-3-[(20R,30S)-30-hydroxy-20-dimethoxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole
10a
A solution of 8a (840 mg, 2.9 mmol) and free base hydroxylamine [from 610 mg (8.7 mmol) of
the hydrochloride] in methanol (10 ml) was re¯uxed for 2 h. The solvent was then evaporated and
the residue was puri®ed by silica gel column chromatography (petroleum ether±ethyl acetate) to
a€ord 7 (42 mg, 8.2%) and 10a (385 mg, 42%). Recrystallization from ethyl acetate±cyclohexane
gave 10a as colorless needles.
15
D
MeOH
max
Compound 10a: mp 101±102ꢀC. ‰ꢁŠ ^26.2 (c 0.145, MeOH). UV l
(lg "): 204.0 (4.31),
+
1
0
251.9 (4.29). FAB-MS (m/z): 307 [M+H] . H NMR (DMSO-d6) ꢀ 2.17 (m, 1H, H4 a), 2.62 (m,
0
1H, H4 b), 2.87, 3.17 (2s, 3H each, >C(OCH3)2), 3.95 (overlapped, 2H, H2 , H5 a), 4.11 (over-
0
0
0
0
0
lapped, 2H, H5 b, H6 ), 6.13 (s, 1H, D2O exchangeable, 3 -OH), 7.69 (m, 3H, arom. H), 8.14 (d,
13
0
0
2H, arom. H). C NMR (DMSO-d6) ꢀ 38.6 (C4 ), 52.3 (OCH3), 53.6 (OCH3), 66.4 (C5 ), 77.8
0
0
0
(C2 ), 86.4 (C3 ), 101.7 (C6 ), 123.4, 127.7, 129.6, 133.2 (arom. C), 172.6 (C3), 174.4 (C5). Anal.
calcd for C15H18N2O5: C, 58.84; H, 5.92; N, 9.15. Found: C, 58.80; H, 5.85; N, 9.18. Crystal data:
empirical formula, C15H18N2O5; formula weight, 306.31; crystal system, monoclinic; space group,
P21; a=10.586(1), b=6.751(1), c=11.348(1) A, ꢂ=109.37(1)ꢀ, V=765.09(15) A3, Z=2,
D=1.330 g/cm3.
3.8. 5-Phenyl-3-[(20R,30R)-30-hydroxy-20-dimethoxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole
11a
The above procedure applied to 9a (1.22 g, 4.0 mmol) with hydroxylamine (840 mg, 12 mmol)
a€orded 7 (80 mg, 11%) and 11a (490 mg, 40%).
15
D
MeOH
max
Compound 11a: mp 76±76ꢀC ‰ꢁŠ ^35.0 (c 0.14, MeOH). UV l
(lg "): 204.0 (4.36), 251.5
+ 1
0
(4.35). FAB-MS (m/z): 307 [M+H] . H NMR (DMSO-d6) ꢀ 2.28 (m, 1H, H4 a), 2.50 (overlapped,
0
1H, H4 b), 3.17, 3.26 (2s, 3H each, >C(OCH3)2), 4.02 (overlapped, 3H, H5 a, H5 b and H2 ), 4.52
0
0
0

1534
W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
0
0
(d, 1H, J6 ,2 =7.5 Hz, H6 ), 6.03 (s, 1H, D2O exchangeable, 3 -OH), 7.68 (m, 3H, arom. H), 8.10
0
0
(d, 2H, arom. H). 13C NMR (DMSO-d6) ꢀ 41.2 (C4 ), 52.8 (OCH3), 55.3 (OCH3), 66.2 (C5 ), 77.2
0
0
0
0
0
(C2 ), 83.9 (C3 ), 102.7 (C6 ), 123.4, 127.7, 129.5, 133.2 (arom. C), 173.7 (C3), 174.6 (C5). Anal.
calcd for C15H18N2O5: C, 58.84; H, 5.92; N, 9.15. Found: C, 58.72; H, 6.14; N, 9.17.
3.9. 5-Methyl-3-[(20R,30S)-30-hydroxy-20-dimethoxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole
10b
The above procedure applied to 8b (890 mg, 3.9 mmol) with hydroxylamine (700 mg, 10 mmol)
a€orded 7 (160 mg, 23.4%) and 10b (360 mg, 37.8%).
15
D
MeOH
max
0
Compound 10b: ‰ꢁŠ ^59.3 (c 0.145, MeOH). UV l
(lg "): 201.4 (3.61). FAB-MS (m/z):
+
1
0
245 [M+H] . H NMR (DMSO-d6) ꢀ 2.05 (m, 1H, H4 a), 2.49 (overlapped, 1H, H4 b), 2.58 (s,
0
3H, 5-CH3), 2.89, 3.13 (2s, 3H each, >C(OCH3)2), 3.87 (overlapped, 2H, H2 , H5 a), 3.99 (over-
0
0
lapped, 2H, H5 b, H6 ), 5.94 (s, 1H, D2O exchangeable, 3 -OH). 13C NMR (DMSO-d6) ꢀ 11.9
0
0
0
0
0
0
0
(5-CH3), 40.6 (C4 ), 52.6 (OCH3), 53.9 (OCH3), 66.7 (C5 ), 77.9 (C2 ), 86.6 (C3 ), 102.0 (C6 ), 172.1
(C3), 176.4 (C5). Anal. calcd for C10H16N2O5: C, 49.18; H, 6.60; N, 11.47. Found: C, 49.26; H,
6.66; N, 11.30.
3.10. 5-Methyl-3-[(20R,30R)-30-hydroxy-20-dimethoxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole
11b
The above procedure applied to 9b (810 mg, 3.5 mmol) with hydroxylamine (620 mg, 8.8
mmol) a€orded 7 (80 mg, 13%) and 11b (344 mg, 40.2%).
15
D
MeOH
max
Compound 11b: ‰ꢁŠ ^10.8 (c 0.12, MeOH). UV l
(lg "): 202.0 (3.68). FAB-MS (m/z):
+
1
0
0
245 [M+H] . H NMR (DMSO-d6) ꢀ 2.18 (m, 1H, H4 a), 2.38 (m, 1H, H4 b), 2.57 (s, 3H, 5-CH3),
0
3.15, 3.35 (2s, 3H each, >C(OCH3)2), 3.96 (overlapped, 3H, H2 , H5 a, H5 b), 4.47 (d, 1H,
0
0
0
J6 ,2 =7.5 Hz, H6 ), 5.89 (s, 1H, D2O exchangeable, 3 -OH). 13C NMR (DMSO-d6) ꢀ 11.9 (5-
0
0
0
0
0
0
0
0
CH3), 41.3 (C4 ), 52.6 (OCH3), 55.4 (OCH3), 66.2 (C5 ), 77.2 (C2 ), 83.6 (C3 ), 102.7 (C6 ), 172.9
(C3), 176.5 (C5). Anal. calcd for C10H16N2O5: C, 49.18; H, 6.60; N, 11.47. Found: C, 48.96; H,
6.64; N, 11.27.
3.11. 5-Phenyl-3-[(20S,30S)-30-hydroxy-20-hydroxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole 12a
A solution of 10a (260 mg, 0.86 mmol) in dioxane (5 ml) and 1% HCl (5 ml) was heated at
100ꢀC for 1.5 h, then cooled to room temperature. After neutralization, the mixture was treated
with NaBH4 (34 mg, 0.86 mmol) for 30 min, then neutralized again. The solvent was evaporated
and the residue was puri®ed by silica gel column chromatography (petroleum ether±acetone) to
a€ord 12a (175 mg, 78.6%) and 5-phenyl-3-(20-hydroxymethyl-40,50-dihydrofuran-30-yl)-1,2,4-
oxadiazole 14a (17 mg, 8.2%).
15
D
MeOH
max
Compound 12a: mp 74±76ꢀC. ‰ꢁŠ ^81.6 (c 0.125, MeOH). UV l
(lg "): 204.3 (4.33),
+
1
0
251.2 (4.31). FAB-MS (m/z): 263 [M+H] . H NMR (DMSO-d6) ꢀ 2.15 (m, 1H, H4 a), 2.62
0
(m, 1H, H4 b), 3.33 (overlapped, 2H, H5 a, H5 b), 3.93 (m, 2H, H6 a, H6 b), 4.07 (t, 1H, J2 ,6 =7.5
0
0
0
0
0
0
0
0
0
Hz, H2 ), 4.49 (s, 1H, D2O exchangeable, 6 -OH), 6.13 (s, 1H, D2O exchangeable, 3 -OH), 7.66
(m, 3H, arom. H), 8.10 (d, 2H, arom. H). 13C NMR (DMSO-d6) ꢀ 38.0 (C4 ), 61.2 (C6 ), 65.9 (C5 ),
0
0
0
0
0
77.1 (C2 ), 88.1 (C3 ), 123.5, 127.8, 129.6, 133.2 (arom. C), 172.4 (C3), 174.6 (C5). Anal. calcd for
C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.39; H, 5.58; N, 10.54.

W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
1535
Compound 14a: mp 118±119ꢀC. UV lmMaexOH (lg "): 203.7 (4.24), 259.1 (4.49). FAB-MS (m/z): 245
[M+H]+. 1H NMR (DMSO-d6) ꢀ 3.01 (t, 2H, J4 ,5 =9.6 Hz, H4 a, H4 b), 4.51 (t, 2H, J5 ,4 =9.6 Hz,
0
0
0
0
0
0
0
0
0
0
0
H5 a, H5 b), 4.60 (d, 2H, J6 ,OH=6.0 Hz, H6 ), 5.20 (t, 1H, JOH,6 =6.0 Hz, D2O exchangeable,
0
13
0
6 -OH), 7.66 (m, 3H, arom. H), 8.09 (d, 2H, arom. H). C NMR (DMSO-d6) ꢀ 29.9 (C4 ), 54.7
0
0
0
0
(C6 ), 69.8 (C5 ), 97.4 (C3 ), 123.4, 127.8, 129.5, 133.2 (arom. C), 163.4 (C2 ), 165.3 (C3), 173.9 (C5).
Anal. calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C, 64.10; H, 4.97; N, 11.53.
3.12. 5-Phenyl-3-[(20S,30R)-30-hydroxy-20-hydroxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole 13a
A solution of 11a (360 mg, 1.2 mmol) in dioxane (10 ml) and 1% HCl (10 ml) was heated at
100ꢀC for 1.5 h, then cooled to room temperature. After neutralization, the mixture was treated
with NaBH4 (45 mg, 1.2 mmol) for 30 min, then neutralized again. The solvent was evaporated
and the residue was puri®ed by silica gel column chromatography (petroleum ether±acetone) to
a€ord 13a (133 mg, 48.0%) and 14a (78 mg, 27.1%).
15
D
MeOH
max
Compound 13a: mp 109±110ꢀC. ‰ꢁŠ ^22.4 (c 0.14, MeOH). UV l
(lg "): 204.3 (4.25),
+
1
0
251.5 (4.27). FAB-MS (m/z): 263 [M+H] . H NMR (DMSO-d6) ꢀ 2.28 (m, 1H, H4 a), 2.56 (m,
0
0
0
0
0
0
1H, H4 b), 3.58 (m, 1H, H5 a), 3.73 (m, 1H, H5 b), 3.90 (m, 1H, H2 ), 4.02 (m, 2H, H6 a, H6 b), 4.60
(s, 1H, D2O exchangeable, 60-OH), 5.98 (s, 1H, D2O exchangeable, 30-OH), 7.68 (m, 3H, arom.
H), 8.12 (d, 2H, arom. H). 13C NMR (DMSO-d6) ꢀ 40.2 (C4 ), 59.9 (C6 ), 65.6 (C5 ), 76.7(C2 ), 85.8
0
0
0
0
0
(C3 ), 123.3, 127.8, 129.6, 133.3 (arom. C), 173.3 (C3), 175.0 (C5). Anal. calcd for C13H14N2O4: C,
59.54; H, 5.38; N, 10.68. Found: C, 59.62; H, 5.38; N, 10.67.
3.13. 5-Methyl-3-[(20S,30S)-30-hydroxy-20-hydroxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole 12b
A solution of 10b (250 mg, 1 mmol) in dioxane (5 ml) and 1% HCl (5 ml) was heated at 100ꢀC
for 1.5 h, then cooled to room temperature. After neutralization, the mixture was treated with
NaBH4 (38 mg, 1 mmol) for 30 min, then neutralized again. The solvent was evaporated and the
residue was puri®ed by silica gel column chromatography (petroleum ether±acetone) to a€ord
12b (154 mg, 75.2%) and 5-methyl-3-(20-hydroxymethyl-40,50-dihydrofuran-30-yl)-1,2,4-oxadiazole
14b (16 mg, 8.6%).
15
D
MeOH
max
0
Compound 12b: ‰ꢁŠ ^105.7 (c 0.105, MeOH). UV l
(lg "): 201.3 (3.39). FAB-MS (m/z):
+
1
0
201 [M+H] . H NMR (DMSO-d6) ꢀ 2.08 (m, 1H, H4 a), 2.51 (overlapped, 1H, H4 b), 2.57 (s,
0
0
0
0
0
3H, 5-CH3), 3.08 (m, 1H, H5 a), 3.20 (m, 1H, H5 b), 3.89 (m, 2H, H6 a, H6 b), 4.00 (m, 1H, H2 ),
4.42 (t, 1H, D2O exchangeable, 60-OH), 5.94 (s, 1H, D2O exchangeable, 30-OH). 13C NMR
0
0
0
0
0
(DMSO-d6) ꢀ 11.9 (5-CH3), 37.8 (C4 ), 61.2 (C6 ), 65.8 (C5 ), 76.9 (C2 ), 88.0 (C3 ), 171.5 (C3), 176.4
(C5). Anal. calcd for C8H12N2O4: C, 48.00; H, 6.04; N, 13.99. Found: C, 48.33; H, 6.62; N, 13.64.
Compound 14b: mp 68±71ꢀC. UV lmMaexOH (lg "): 204.3 (3.81), 260.8 (4.34). FAB-MS (m/z): 183
[M+H]+. H NMR (DMSO-d6) ꢀ 2.56 (s, 3H, 5-CH3), 2.94 (t, 2H, J4 ,5 =9.6 Hz, H4 a, H4 b), 4.46
1
0
0
0
0
(overlapped, 4H, H5 a, H5 b, H6 a, H6 b), 5.13 (s, 1H, D2O exchangeable, 60-OH). 13C NMR
0
0
0
0
0
0
0
0
0
(DMSO-d6) ꢀ 11.9 (5-CH3), 29.9 (C4 ), 54.5 (C6 ), 69.6 (C5 ), 97.5 (C3 ), 162.7 (C2 ), 164.6 (C3), 175.8
(C5). Anal. calcd for C8H10N2O3: C, 52.74; H, 5.56; N, 15.37. Found: C, 52.57; H, 5.53; N, 15.09.
3.14. 5-Methyl-3-[(20S,30R)-30-hydroxy-20-hydroxymethyltetrahydrofuran-30-yl]-1,2,4-oxadiazole 13b
A solution of 11b (250 mg, 1 mmol) in dioxane (5 ml) and 1% HCl (5 ml) was heated at 100ꢀC
for 1.5 h, then cooled to room temperature. After neutralization, the mixture was treated with

1536
W. D. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 1527±1536
NaBH4 (38 mg, 1 mmol) for 30 min, then neutralized again. The solvent was evaporated and the
residue was puri®ed by silica gel column chromatography (petroleum ether±acetone) to a€ord
13b (165 mg, 83.2%) and 14b (5 mg, 3.3%).
15
D
MeOH
max
Compound 13b: ‰ꢁŠ ^20.0 (c 0.125, MeOH). UV l
(lg "): 201.8 (3.47). FAB-MS (m/z):
+
1
0
0
201 [M+H] . H NMR (DMSO-d6) ꢀ 2.18 (m, 1H, H4 a), 2.42 (m, 1H, H4 b), 2.58 (s, 3H, 5-CH3),
0
0
0
0
0
3.54 (m, 1H, H5 a), 3.64 (m, 1H, H5 b), 3.84 (m, 2H, H6 a, H6 b), 3.98 (m, 1H, H2 ), 4.54 (t, 1H,
D2O exchangeable, 60-OH), 5.80 (s, 1H, D2O exchangeable, 30-OH). 13C NMR (DMSO-d6) ꢀ 11.9
0
0
0
0
0
(5-CH3), 40.2 (C4 ), 59.9 (C6 ), 65.2 (C5 ), 76.6 (C2 ), 85.8 (C3 ), 172.5 (C3), 177.0 (C5). Anal. calcd
for C8H12N2O4: C, 48.00; H, 6.04; N, 13.99. Found: C, 47.77; H, 5.83; N, 13.49.
Acknowledgements
This project was supported by the National Natural Science Foundation of China.
References
1. Yu, H.-W.; Zhang, L.-R.; Zhuo, J.-C.; Ma, L.-T.; Zhang, L.-H. Bioorg. Med. Chem. 1996, 4, 609±614.
2. Yang, Z. J.; Yu, H. W.; Min, J. M.; Ma, L. T.; Zhang, L. H. Tetrahedron: Asymmetry 1997, 8, 2739±2747.
3. Zhang, H. Y.; Yu, H. W.; Ma, L. T.; Min, J. M.; Zhang, L. H. Tetrahedron: Asymmetry 1998, 9, 141±149.
4. Zhang, H. Y.; Yang, Z. J.; Yu, H. W.; Piao, Z. S.; Ma, L. T.; Min, J. M.; Zhang, L. H. Synth. Commun. 1999, 29,
4113±4126.
5. Zhang, M. L.; Cui, Y. X.; Ma, L. T.; Zhang, L. H.; Lu, Y.; Zhao, B.; Zheng, Q. T. Chin. Chem. Lett. 1999, 10,
117±120.
6. Doong, S.-L.; Tsai, C. H.; Schinazi, R. F.; Liotta, D. C.; Cheng, Y.-C. Proc. Natl. Acad. Sci. USA 1991, 88, 8495±
8499.
7. Lin, T. S.; Luo, M. Z.; Pai, S. B.; Dutschuman, G. E.; Cheng, Y.-C. J. Med. Chem. 1994, 37, 798±803.
8. Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z.; Chu, C. K.; Cheng, Y.-C. Cancer Res. 1995, 55, 3008±3011.
9. Lin, T. S.; Luo, M. Z.; Liu, M. C.; Zhu, Y. L.; Dutschman, G. E.; Cheng, Y.-C. Nucleosides and Nucleotides 1995,
14, 1759±1783.
10. Ma, T. W.; Pai, S. B.; Zhu, Y. L.; Lin, J. S.; Shanmuganathan, K.; Du, J.; Wang, C. G.; Kim, H.; Newton, M. G.;
Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1996, 39, 2835±2843.
11. Repke, D. B.; Albrecht, H. P.; Mo€att, J. G. J. Org. Chem. 1975, 40, 2481±2487.
12. Dong, L. J.; Li, L.; Ma, L. T.; Zhang, L. H. Chin. Chem. Lett. 1992, 3, 597±600.
13. Moravcova, J.; Capkova, J.; Stanek, J. Carbohydr. Res. 1994, 263, 61±66.
14. Tam, S.; Holman, M.; Huryn, D.; Cislo, A. Nucleosides and Nucleotides 1991, 10, 245±248.
15. Wempen, I.; Miller, N.; Falco, E. A.; Fox, J. J. J. Med. Chem. 1968, 11, 144.