Synthesis of 3-deoxy-3-nucleobase-2,5-anhydro-D-mannitol: A novel class of hydroxymethyl-branched isonucleosides

Article abstract of DOI:10.1016/S0957-4166(00)00246-9

A concise synthesis of 3-deoxy-3-nucleobase-2,5-anhydro-D-mannitol 6(a- d) has been achieved, using the deamination of 2-amino-2-deoxy-D-glucose to construct in one step the sugar skeleton with the desired sense of chirality at each asymmetric center. The selective dibenzoylation of 2,5-anhydro-D- mannitol 9 was investigated, and the key epoxide intermediate 13 was obtained in good yield via an intramolecular Mitsunobu reaction. The process of opening of epoxide 13 by nucleobases appeared to be regioselective. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00246-9

Tetrahedron: Asymmetry 11 (2000) 2899±2906
Synthesis of 3-deoxy-3-nucleobase-2,5-anhydro-d-mannitol:
a novel class of hydroxymethyl-branched isonucleosides
Z. Lei, J. M. Min and L. H. Zhang*
School of Pharmaceutical Sciences, Beijing Medical University, Beijing 100083, China
Received 20 April 2000; accepted 19 June 2000
Abstract
A concise synthesis of 3-deoxy-3-nucleobase-2,5-anhydro-d-mannitol 6(a±d) has been achieved, using the
deamination of 2-amino-2-deoxy-d-glucose to construct in one step the sugar skeleton with the desired
sense of chirality at each asymmetric center. The selective dibenzoylation of 2,5-anhydro-d-mannitol 9 was
investigated, and the key epoxide intermediate 13 was obtained in good yield via an intramolecular
Mitsunobu reaction. The process of opening of epoxide 13 by nucleobases appeared to be regioselective.
# 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Nucleoside analogues play an important role in antiviral and anticancer chemotherapy. Among
numerous nucleoside analogues,1 hydroxymethyl-branched nucleosides such as naturally occurring
Oxetanocin-A 1a2 and its analogues 1b and 2,3 have received much attention owing to their
profound biological activities. It was reported that the two primary hydroxyl groups in these
hydroxymethyl-branched nucleosides could improve their interaction with corresponding kinase
and polymerase.4 Isonucleosides represent another class of nucleoside analogues in which the
nucleobase is linked at various positions of ribose other than C-10, and have attracted great
interest because of their enhanced chemical and enzymatic stability.5 7 Both d- and l-stereomeric
isonucleosides, such as (S,S)-iso-ddA 36 and its enantiomer 4,7 have exhibited some activities
against a broad spectrum of virus and some tumor cell lines (Scheme 1).
In our search for antiviral and anticancer agents, we have synthesized hydroxymethyl-branched
l-isonucleosides 5 starting from d-glucose.8 In further studies on the structure±activity relation-
ship of these types of nucleoside analogues, we aimed to synthesize their enantiomers, 3-deoxy-3-
nucleobase-2,5-anhydro-d-mannitol 6 (Scheme 2).
* 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)00246-9

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Z. Lei et al. / Tetrahedron: Asymmetry 11 (2000) 2899±2906
Scheme 1.
Scheme 2.
2. Results and discussion
In our previous work8 compounds 5 were obtained from d-glucose via nine steps with a ring
reformation process leading to construction of the sugar skeleton with the con®guration related
to l-mannitol (Scheme 3). Similarly, the title compounds 6 might be prepared from l-glucose.
Due to the high expense of l-glucose, however, it was desirable to seek a practical and convenient
synthetic method for the preparation of 6. It was reported that the deamination of 2-amino-2-
deoxy-d-glucose 7 with nitrous acid led to 2,5-anhydro-d-mannose 8 (Scheme 4).9 Compound
8 could be used to construct the whole desired sugar skeleton and all of four stereogenic centers
in 6.
Scheme 3.
Scheme 4.
The nitrous acid deamination of 7 was carried out in aqueous solution at 0ꢀC, followed by
reduction with sodium borohydride to give 2,5-anhydro-d-mannitol 9 (Scheme 5). Compound 9 is
highly water-soluble and extremely dicult to extract from water and isolate from salts. Its
synthesis reported in literature involved time-consuming work-ups in both steps.10 In our case, a
simpli®ed one-pot procedure was developed to a€ord crude 9, which was directly applied to the
next step.

Z. Lei et al. / Tetrahedron: Asymmetry 11 (2000) 2899±2906
2901
Scheme 5. Reagents and conditions: (i) NaNO2, concentrated HCl, H2O, 0ꢀC; (ii) NaBH4, H2O; (iii) BzCl, pyridine,
CH2Cl2 (1:2 v/v)
The selective protection of the two primary hydroxyls in 9 was accomplished by the treatment
of crude 9 with benzoyl chloride under an optimized reaction condition. The desired dibenzoate
10 was obtained in an overall yield of 37% of three steps starting from 7. Two other side-prod-
ucts, tribenzoate 11 and monobenzoate 12, were also isolated from the reaction mixture in 5%
and 1% yields, respectively (Scheme 5).
Compound 10 is a C2-symmetric molecule in which the two secondary hydroxyl groups are
identical. Therefore, under the intramolecular Mitsunobu reaction condition11 compound 10 was
converted to epoxide 13 in 90% yield, irrespective of which of the hydroxyl groups attacked the
phosphonium cation (Scheme 6).
Scheme 6. Reagents and conditions: (iv) PPh3, diethyl azodicarboxylate, 1,4-dioxane, 70ꢀC, 90%; (v) nucleobases,
DBU, DMF, 90±100ꢀC; (vi) NaOCH3, CH3OH. aTotal yield of 14a and 15a (4.0:1 estimated from 1H NMR spectrum);
c
d
btotal yield of 14b and 15b (4.5:1 estimated); total yield of 14c and 15c (4.6:1 estimated); total yield of 14d and 15d
(4.2:1 estimated)
The regioselective opening of epoxide 13 by nucleobases was achieved in reasonable yields in
the presence of DBU. 1H NMR spectra of the partially puri®ed products showed that the desired
and predominant compounds 14 (a±d) were accompanied by a mixture with their C-4 regio-

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Z. Lei et al. / Tetrahedron: Asymmetry 11 (2000) 2899±2906
isomers 15 (a±d). Further separation of the two isomers failed because of their similar chroma-
tographic mobility. However, after the treatment of the mixture with sodium methoxide in
methanol (deprotection), the title molecules 6 (a±d) and their C-4 regioisomers 16 (a±d) were
obtained after column chromatography (Scheme 6). The structures of 6 (a±d) and 16 (a±d) were
identi®ed by 1H NMR and NOESY spectra.
It is worthy to mention that triphenylmethyl chloride was also evaluated as a reagent for
selective protection of the primary hydroxyls in 9. Bis-tritylated derivative 17 was obtained in a
higher overall yield of 45% in three steps from 7, and compound 17 was easily converted to
epoxide 18. However, the nucleophilic epoxide ring opening in 18 by nucleobases failed, most
probably owing to the steric hindrance of trityl groups (Scheme 7). This observation suggested
that benzoyl group was a desirable choice in presented strategy due to its reasonable selectivity
and low steric hindrance.
Scheme 7. Reagents and conditions: (i) NaNO2, concentrated HCl, H2O, 0ꢀC; (ii) NaBH4, H2O; (iii) TrCl, pyridine;
(iv) PPh3, diethyl azodicarboxylate, 1,4-dioxane, 70ꢀC, 80%
3. Conclusion
In this work we reported on a six-step facile synthesis of a novel class of hydroxymethyl-
branched d-isonucleosides 6. The C2-symmetric molecule 10 was constructed from 2-amino-2-
deoxy-d-glucose 7 via deamination. This synthetic strategy o€ers a simple way for the prepara-
tion of branched-chain sugar isonucleosides of desired sense of chirality at each asymmetric
centre.
4. Experimental
4.1. General procedures
Melting points were determined on a XT-4A melting point apparatus and are uncorrected.
Optical rotations were measured with a Perkin±Elmer 243B polarimeter and 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. HRMS were recorded on APEX II
(Bruker, Inc.) FTICR mass spectrometer. NMR spectra were recorded on a Varian-300 or JEOL
AL300 spectrometer with TMS as internal standard. Exchangable protons were detected by
addition of D2O. Elemental analyses were performed using PE-240C analyzer. Column chroma-
tography was performed on silica gel (200±300 mesh) purchased from the Qingdao Chemical
Company, China. Thin layer chromatography was performed using DC-Alufolien 60 F254
(Alltech Associate, Inc.) plate with detection by UV, or charting with 5% ethanolic solution of
phosphomolybdic acid hydrate.

Z. Lei et al. / Tetrahedron: Asymmetry 11 (2000) 2899±2906
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4.2. 1,6-Di-O-benzoyl-2,5-anhydro-d-mannitol 10, 1,3,6-tri-O-benzoyl-2,5-anhydro-d-mannitol 11
and 1-O-benzoyl-2,5-anhydro-d-mannitol 12
A solution of 2-amino-2-deoxy-d-glucose hydrochloride (technical grade, 32.4 g, 0.15 mol) in
water (300 ml) was cooled to 0ꢀC. Sodium nitrite (30.75 g, 0.45 mol) was added in several
portions at 0ꢀC. Concentrated hydrochloric acid (25.5 ml, 0.3 mol) was then added dropwise at a
rate that the temperature did not exceed 2ꢀC. The solution was stirred for an additional 5 h at
0ꢀC, and then was brought to 25ꢀC. Nitrogen was bubbled through the reaction mixture for 30
min to remove an excess of nitrous acid, and then it was neutralized to PH 7 with 10N NaOH.
The solution was cooled to 0ꢀC, sodium borohydride (5.70 g, 0.15 mol) was added in small
portions, and stirring was continued at ambient temperature for 24 h. The solution was
neutralized with 6N HCl and the aqueous solution was concentrated under reduced pressure. The
remaining semisolid material was twice treated with methanol which was then removed by
evaporation. The residue was then extracted with methanol. The extracts were stirred with ion-
exchange resins (Cation 732# and Anion 717#). After removal of methanol, the residue was dried
under high vaccum to give crude 9 (15 g) as a yellow syrup.
A suspension of crude 9 (15 g) in dry pyridine (150 ml) and dry dichloromethane (250 ml) was
cooled to ^10ꢀC, and benzoyl chloride (9.8 ml, 0.92 equiv.) was added dropwise with rigorous
stirring. The solution was kept below 0ꢀC for 2 h, then cooled again to ^10ꢀC, and another portion
of benzoyl chloride (9.8 ml, 0.92 equiv.) was added dropwise. The reaction mixture was kept at
0ꢀC for 4 h and at ambient temperature for an additional 24 h. After removal of the solvents, the
residue was stirred with ice-cooled saturated NaHCO3 solution (240 ml) for 30 min, and extracted
with ethyl acetate (3Â90 ml). The combined organic layer was washed with brine, 2N HCl, brine,
and dried over Na2SO4. After the solution was concentrated, the residue was applied to silica gel
chromatography (ethyl acetate±petroleum ether) to a€ord 10 (20.7 g, 37% from 7, white solid),
11 (3.57 g, 5% from 7, white solid), and 12 (0.4 g, 1% from 7, colorless syrup), respectively.
Compound 10: m.p. 88±92ꢀC. 1H NMR (300 MHz, DMSO-d6) ꢀ: 4.03 (m, 4H, H-1, H-6), 4.38±
4.45 (m, 4H), 5.53 (br s, 2H, 3-OH, 4-OH), 7.53 (m, 4H), 7.67 (m, 2H), 7.98 (m, 4H). FAB-MS m/
z: 373 [M+H]Á. Anal. calcd. for C20H20O7: C, 64.52; H, 5.38. Found: C, 64.09; H, 5.48.
15
D
Compound 11: m.p. 80±84ꢀC. ‰ꢁŠ +54.0 (c 0.100, CHCl3). 1H NMR (300 MHz, DMSO-d6) ꢀ:
4.30±4.58 (m, 7H), 5.36 (m, 1H, H-3), 5.95 (d, J=3.6 Hz, D2O exchangeable, 1H, 4-OH), 7.51 (m,
6H), 7.66 (m, 3H), 7.98 (m, 6H). FAB-MS m/z: 477 [M+H]Á. Anal. calcd. for C27H24O8: C, 68.07;
H, 5.04. Found: C, 67.99; H, 5.20.
15
D
1
Compound 12: ‰ꢁŠ +42.7 (c 0.075, CHCl3). H NMR (300 MHz, DMSO-d6) ꢀ: 3.36±3.97 (m,
6H), 4.30±4.41 (m, 2H, H-1), 4.73(t, J=5.7 Hz, 1H, D2O exchangeable, 6-OH), 5.23 (d, J=5.1
Hz, 1H, D2O exchangeable, 4-OH), 5.34 (d, J=4.8 Hz, 1H, D2O exchangeable, 3-OH), 7.54 (t,
J=7.2 Hz, 2H), 7.67 (t, J=6.9 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H). FAB-MS m/z: 269 [M+H]Á.
HRMS (FAB) calcd. for C13H16O6: [M+H]Á269.1020. Found: 269.1025.
4.3. 1,6-Di-O-benzoyl-2,5:3,4-dianhydro-d-talitol 13
Compound 10 (10.5 g, 28.2 mmol) and triphenylphosphine (11.1 g, 42.3 mmol) were dissolved
in dry 1,4-dioxane (250 ml). A solution of diethyl azodicarboxylate (6.66 ml, 42.3 mmol) in dry
1,4-dioxane (50 ml) was added dropwise to the solution. The reaction mixture was stirred at 70ꢀC
for 2 h. The solvent was removed in vacuo and the residue was applied to silica gel chromatog-
raphy (ethyl acetate±petroleum ether) to a€ord 13 (8.98 g, 90%) as a white solid.

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Z. Lei et al. / Tetrahedron: Asymmetry 11 (2000) 2899±2906
15
D
Compound 13: m.p. 67±70ꢀC. ‰ꢁŠ ^76.8 (c 0.125, CHCl3). H NMR (300 MHz, CDCl3) ꢀ:
1
3.87, 3.94 (d, d, J=2.7 Hz, 2H, H-3, H-4), 4.23 (m, 2H, H-2, H-5), 4.54 (m, 4H, H-1, H-6), 7.46
(m, 4H), 7.57 (m, 2H), 8.04 (m, 4H). 13C NMR (CDCl3) ꢀ: 56.68, 57.32, 63.21, 64.41, 75.57,
128.37, 128.55, 129.59, 129.74, 133.13, 133.37, 166.24. FAB-MS m/z: 355 [M+H]+. Anal. calcd.
for C20H18O6: C, 67.80; H, 5.08. Found: C, 68.00; H, 5.14.
4.4. Procedure for 6 (a±d) and 16 (a±d)
To a stirred suspension of 13 (4 g, 11.3 mmol) and dry nucleobases (1.5 equiv.) in dry DMF (80
ml), DBU (5.1 ml, 34 mmol) was added dropwise. The clear solution was stirred at 90ꢀC for 24 h.
After removal of DMF in vacuo, the resulting brown residue was diluted with dry dichloro-
methane. Silica gel (40 g) was added and the mixture evaporated to dryness. The dry powder was
applied to silica gel chromatography eluting with ethyl acetate±petroleum ether to recover
unreacted 13, then with dichloromethane±methanol to a€ord a mixture of 14 and 15.
The mixture obtained was dissolved in 15 ml of dry methanol and sodium methoxide (1 equiv.)
was added. The solution was stirred for 3 h and then neutralized to PH 7 with cation ion-
exchange resin 732#. After removal of methanol, the residue was applied to silica gel chromato-
graphy (dichloromethane±methanol), to a€ord 6 and 16, respectively.
4.5. 3-Deoxy-3-(adenin-90-yl)-2,5-anhydro-d-mannitol 6a and 4-deoxy-4-(adenin-90-yl)-2,5-anhydro-
d-iditol 16a
The procedure was carried out as described above. A mixture of 14a and 15a was obtained
(60%) as a foam. After debenzoylation, 6a (70%) and 16a (15%) were a€orded, each as a white
hygroscopic solid.
15
D
MeOH
Compound 6a: m.p. 140ꢀC. ‰ꢁŠ ^9.0 (c 0.067, MeOH). UV l
(lg "): 260.4 (4.16). H
1
max
NMR (300 MHz, DMSO-d6) ꢀ: 3.40 (m, 1H), 3.51 (m, 1H), 3.57 (m, 1H), 3.63 (m, 1H), 3.78 (m,
1H), 4.35 (m, 1H), 4.60 (m, t after D2O exchange, 1H, H-4), 4.73 (dd, 1H, H-3), 4.83 (m, 2H, D2O
exchangeable, 1-OH, 6-OH), 5.57 (d, J=5.4 Hz, 1H, D2O exchangeable, 4-OH), 7.22 (s, 2H, D2O
exchangeable, NH2), 8.13 (s, 1H, H-20), 8.18 (s, 1H, H-80). CI-MS m/z: 282 [M+H]+. Anal. calcd.
for C11H15N5O4: C, 46.96; H, 5.38; N, 24.91. Found: C, 47.03; H, 5.54; N, 24.69.
15
D
MeOH
max
Compound 16a: m.p. 136±140ꢀC. ‰ꢁŠ ^16.0 (c 0.100, MeOH). UV l
(lg "): 266.7 (4.08).
1H NMR (300 MHz, DMSO-d6) ꢀ: 3.11 (m, 2H), 3.60 (m, 2H), 4.32 (m, 2H, H-2, H-5), 4.57 (m,
1H, D2O exchangeable), 4.67 (m, 1H, D2O exchangeable), 4.70 (m, 1H, H-3), 5.01 (m, 1H, H-4),
5.65 (d, J=4.8 Hz, 1H, D2O exchangeable, 3-OH), 7.25 (s, 2H, D2O exchangeable, NH2), 8.01 (s,
1H, H-20), 8.13 (s, 1H, H-80). CI-MS m/z: 282 [M+H]+. HRMS (FAB) calcd. for C11H15N5O4:
[M+H]Á 282.1197. Found: 282.1194.
4.6. 3-Deoxy-3-(thymin-10-yl)-2,5-anhydro-d-mannitol 6b and 4-deoxy-4-(thymin-10-yl)-2,5-
anhydro-d-iditol 16b
The procedure was carried out as described above. A mixture of 14b and 15b was obtained
(40%) as a foam. After debenzoylation, 6b (65%) and 16b (10%) were a€orded, each as a white
hygroscopic solid.
15
Compound 6b: m.p. 100±106ꢀC. ‰ꢁŠ +12.2 (c 0.900, MeOH). UV lMmaexOH (lg "): 271.7(4.08). 1H
D
NMR (300 MHz, DMSO-d6) ꢀ: 3.40 (m, 2H), 3.48 (m, 1H), 3.58 (m, 1H), 3.70 (m, 1H), 3.94 (m,

Z. Lei et al. / Tetrahedron: Asymmetry 11 (2000) 2899±2906
2905
1H), 4.20 (m, dd after D2O exchange, J=7.8 Hz, 1H, H-4), 4.65 (t, J=7.8 Hz, 1H, H-3), 4.77
(m, 2H, D2O exchangeable, 1-OH, 6-OH), 5.46 (d, J=5.1 Hz, 1H, D2O exchangeable, 4-OH),
7.55 (s, 1H, H-60), 11.26 (s, 1H, D2O exchangeable, NH). FABMS m/z: 273 [M+H]+, 295
[M+Na]+. Anal. calcd. for C11H16N2O6: C, 48.53; H, 5.88; N, 10.29. Found: C, 48.27; H, 6.01; N,
9.93.
15
D
MeOH
max
Compound 16b: m.p. 134±136ꢀC. ‰ꢁŠ +144.8 (c 0.105, MeOH). UV l
(lg "): 271.0(4.03).
1H NMR (300 MHz, DMSO-d6) ꢀ: 3.28 (m, 2H), 3.54 (m, 2H), 4.15 (m, 2H, H-2, 5), 4.52 (t,
J=5.7 Hz, 1H, D2O exchangeable, 1-OH), 4.59 (m, t after D2O exchange, J=6 Hz, 1H, H-3),
4.75 (t, J=5.1 Hz, 1H, D2O exchangeable, 6-OH), 4.84 (t, J=6 Hz, 1H, H-4), 5.47 (dd, J=5.4 Hz,
1H, D2O exchangeable, 3-OH), 7.34 (s, 1H, H-60), 11.30 (s, 1H, D2O exchangeable, NH). FAB-
MS m/z: 273 [M+H]+, 295 [M+Na]+. Anal. calcd. for C11H16N2O6: C, 48.53; H, 5.88; N, 10.29.
Found: C, 49.00; H, 6.05; N, 9.82.
4.7. 3-Deoxy-3-(uracil-10-yl)-2,5-anhydro-d-mannitol 6c and 4-deoxy-4-(uracil-10-yl)-2,5-anhydro-
d-iditol 16c
The procedure was carried out as described above. A mixture of 14c and 15c was obtained
(38%) as a foam. After debenzoylation, 6c (65%) and 16c (13%) were a€orded, each as a white
hygroscopic solid.
15
Compound 6c: m.p. 100±104ꢀC. ‰ꢁŠ +14.4 (c 0.090, MeOH). UV lMmaexOH (lg "): 267.0 (4.06). 1H
D
NMR (300 MHz, DMSO-d6) ꢀ: 3.45±3.60 (m, 4H, H-1, H-6), 3.70 (m, 1H), 3.93 (m, 1H), 4.23 (m,
t after D2O exchange, J=7.6 Hz, 1H, H-4), 4.67 (t, J=7.6 Hz, 1H, H-3), 4.76±4.80 (broad, 2H,
D2O exchangeable, 1-OH, 6-OH), 5.50 (d, J=4.8 Hz, 1H, D2O exchangeable, 4-OH), 5.62 (d,
J=7.6 Hz, 1H, H-50), 7.66 (d, J=7.6 Hz, 1H, H-60), 11.27 (s, 1H, D2O exchangeable, NH). CI-
MS m/z: 259 [M+H]+. Anal. calcd. for C10H14N2O6: C, 46.51; H, 5.43; N, 10.85. Found: C, 46.11;
H, 5.56; N, 10.50.
15
D
Compound 16c: m.p. 80±83ꢀC. ‰ꢁŠ +180.0 (c 0.075, MeOH). UV lMmaexOH (lg "): 266.4 (4.11). 1H
NMR (300 MHz, DMSO-d6) ꢀ: 3.30±3.53 (m, 4H), 4.10 (m, 1H), 4.17 (m, 1H), 4.53 (broad s, 1H,
D2O exchangeable), 4.57 (m, t after D2O exchange, 1H, H-3), 4.75 (broad s, 1H, D2O exchange-
able), 4.85 (t, J=6 Hz, 1H, H-4), 5.50 (d, J=5.1 Hz, 1H, D2O exchangeable, 3-OH), 5.56 (d,
J=8.1 Hz, 1H, H-50), 7.52 (d, J=8.1 Hz, 1H, H-60), 11.30 (s, 1H, D2O exchangeable, NH). CI-MS
m/z: 259 [M+H]+. Anal. calcd. For C10H14N2O6: C, 46.51; H, 5.43; N, 10.85. Found: C, 46.59; H,
5.72; N, 10.52.
4.8. 3-Deoxy-3-(50-¯uorouracil-10-yl)-2,5-anhydro-d-mannitol 6d and 4-deoxy-4-(50-¯uorouracil-
10-yl)-2,5-anhydro-d-iditol 16d
The procedure was carried out as described above. A mixture of 14d and 15d was obtained
(36%) as a foam. After debenzoylation, 6d (60%) and 16d (10%) were a€orded, each as a white
hygroscopic solid.
15
Compound 6d: m.p. 95±97ꢀC. ‰ꢁŠ +163.0 (c 0.100, MeOH). UV lMmaexOH (lg "): 274.0 (4.04). 1H
D
NMR (300 MHz, DMSO-d6) ꢀ: 3.33±3.70 (m, 4H), 3.73 (m, 1H), 3.94 (m, 1H), 4.19 (m, t after
D2O exchange, 1H, H-4), 4.65 (m, t after D2O exchange, 1H, H-3), 4.71±5.05 (m, 2H, D2O
exchangeable, 1-OH, 6-OH), 5.50 (d, J=5.1 Hz, 1H, D2O exchangeable, 4-OH), 8.12 (d, J=7.2
Hz, 1H, H-60), 11.81 (d, J=4.8 Hz, 1H, D2O exchangeable, NH). CI-MS m/z: 277 [M+H]+.
HRMS (FAB) calcd. for C10H13N2O6F: [M+H]Á277.0830. Found: 277.0824.

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Z. Lei et al. / Tetrahedron: Asymmetry 11 (2000) 2899±2906
15
Compound 16d: m.p. 104±106ꢀC. ‰ꢁŠ +124.0 (c 0.075, MeOH). UV lMmaexOH (lg "): 272.7 (4.03).
D
1H NMR (300 MHz, DMSO-d6) ꢀ: 3.36 (m, 2H), 3.53 (m, 2H), 4.13 (m, 2H), 4.53 (m, D2O
exchangeable, 1H), 4.65 (m, t after D2O exchange, 1H, H-3), 4.85 (overlapped, 2H, H-4, OH),
5.48 (d, J=5.1 Hz, 1H, D2O exchangeable, 3-OH), 7.88 (d, J=7.8 Hz, 1H, H-60), 11.85 (d, J=5.1
Hz, 1H, D2O exchangeable, NH). CI-MS m/z: 277 [M+H]+. HRMS (FAB) calcd. for
C10H13N2O6F: [M+H]Á277.0830. Found: 277.0821.
Acknowledgements
This work was supported by the National Natural Science Foundation of China and by a grant
(G 1998051103) from the Ministry of Science and Technology of China.
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