Novel isonucleoside analogues: synthesis of 2'-deoxy-2'-nucleobase-5'-deoxy-1',4'-anhydro-D-altritol

Article abstract of DOI:10.1016/S0957-4166(00)00136-1

A new class of isonucleoside analogues with branched-sugar 2'-deoxy-2'-nucleobase-5'-deoxy-1',4'-anhydro-D-altritol (21, 23a-c) has been synthesized from D-glucose in 11 steps. The construction of branched-chain sugars has been carried out by hydroboration-oxidation of a double bond in the corresponding hexose. The key intermediate 12 was synthesized from the branched-chain sugar 11 by the reductive cleavage reaction in the presence of TMSOTf and triethylsilane. A strong solvent effect was observed in the intramolecular nucleophilic substitution of 12. The protic solvent is favorable to form the bicyclic compound 18 by double S(N)2 substitution. The opening reaction of epoxide 17 by nucleobases was achieved regioselectively to give the desired isonucleosides in reasonable yield. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00136-1

Tetrahedron: Asymmetry 11 (2000) 1877±1889
Novel isonucleoside analogues: synthesis of 20-deoxy-
20-nucleobase-50-deoxy-10,40-anhydro-d-altritol
X. B. Tian, J. M. Min and L. H. Zhang*
National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
Beijing Medical University, Beijing 100083, People's Republic of China
Received 31 January 2000; accepted 3 April 2000
Abstract
A new class of isonucleoside analogues with branched-sugar 20-deoxy-20-nucleobase-50-deoxy-10,40-anhydro-
d-altritol (21, 23a±c) has been synthesized from d-glucose in 11 steps. The construction of branched-chain
sugars has been carried out by hydroboration±oxidation of a double bond in the corresponding hexose.
The key intermediate 12 was synthesized from the branched-chain sugar 11 by the reductive cleavage
reaction in the presence of TMSOTf and triethylsilane. A strong solvent e€ect was observed in the intra-
molecular nucleophilic substitution of 12. The protic solvent is favorable to form the bicyclic compound 18
by double SN2 substitution. The opening reaction of epoxide 17 by nucleobases was achieved regio-
selectively to give the desired isonucleosides in reasonable yield. # 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
It is well known that compounds such as AZT and carbovir are potent and selective inhibitors
of HIV reverse transcriptase and have been applied to anti-HIV chemotherapy.1 Second generation
antiviral nucleoside analogues has been announced including enantiomeric forms of L-3TC and
L-5F-ddC. These compounds have shown remarkable activity against HIV and HBV with rela-
tively lower toxicity.2 In such a context, isonucleosides, another class of nucleoside analogues
have attracted much attention owing to their chemical and enzymatic stability and potential
antiviral and anticancer activities. It has been reported that both d- and l-isonucleosides exhibit
some activity against a broad spectrum of viruses and some tumor cell lines.3 It should be pointed
out that branched-chain sugar isonucleosides also possess interesting biological activities.4,5 In
this paper we present the synthesis of novel isonucleoside analogues, namely 20-deoxy-20-nucleo-
base-50-deoxy-10,40-anhydro-d-altritols, in which a branched-chain sugar was introduced in the
isonucleoside molecule.
* 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)00136-1

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2. Results and discussion
The synthesis of 5-C-hydroxymethyl branched sugars has been achieved by several methods.6,7
We intended to design a general method to prepare 5-C-(hydroxymethyl)isonucleosides. The
novel isonucleoside with a branched-chain sugar such as 21 was selected as a target molecule. A
versatile approach to the preparation of such compounds would involve the stereo- and regio-
selective ring opening of epoxide 17 which could be obtained from the intermediate 12. Retro-
synthetic analysis suggested that the key intermediate 12 should become available from the
corresponding hexose (Scheme 1).
Scheme 1. Retrosynthetic analysis of target molecule 21
To check the feasibility of this retrosynthetic scheme, compound 3 was prepared from d-glucose
in high yield.6a c Unfortunately, attempts to obtain compound 12 directly from 3 by means of
reductive deoxygenation6b failed. An alternative route to 12 would involve the hydroboration±
oxidation of alkene 5 (Scheme 2).
Several methods for the synthesis of this compound have also been reported.8 In our hands,
compound 1 was treated with trimethyl orthoformate in the presence of p-toluenesulphonic acid
providing orthoformate 4, which was further converted under treatment with acetic anhydride at
140±150ꢀC for 4 h into 5 in 98% yield. Compound 5 was hydroborated with the borane±dimethyl
sulphide complex; treatment of the resulting complex with hydrogen peroxide gave the desired
compound 6 in 54% yield. However, the formation of 6 was accompanied with the appearance of
three other compounds, namely 7, 8 and 9, which were isolated in 10, 5 and 10% yields, respectively
(vide infra). Reaction of 6 with benzoyl chloride in the presence of pyridine (6-C-hydroxy group
protection) followed by triethylsilane/trimethylsilyl tri¯uoromethanesulphonate (TMSOTf) provided
the desired key intermediate 12 in 53% yield. From the reaction mixture, besides the desired 12,
two other compounds were separated and identi®ed as 13 and 14.
Compound 12 was used for the preparation of epoxide 17, which was obtained if a DMF or
THF solution of 12 was treated at ^10ꢀC with t-BuOK for 30 min. The yields were in the range
85±100%. However, we found that the conversion of 12 to 17 is solvent-dependent. If the same

X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
1879
Scheme 2. Reagents and conditions: (i) H2SO4, acetone, CuSO4, 60%; (ii) TsCl, pyridine, 91%; (iii) 98% H2SO4, H2O,
CH3OH, CHCl3, 30±35ꢀC, 98%; (iv) BzCl, pyridine, 81%; (v) PhOCSCl, DMAP, CH2Cl2 85%; (vi) acetic anhydride,
re¯ux, 88%; (vii) BH3±SMe2, THF; 2N NaOH, 30% H2O2, 54%; (viii) BzCl, pyridine, rt, 98%; (ix) Et3SiH, TMSOTf,
CH2Cl2, 0ꢀC to rt, 53%
reaction was carried out in n-butanol or methanol instead of DMF or THF, the formation of
bicyclic compound 18 in the yield 95±100% occurred.
The structure of 18 was established by X-ray analysis of its crystalline derivative 19 (18 is an oil
at room temperature) after its tosylation (Fig. 1).
Figure 1. X-Ray crystal structure of compound 19

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X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
The X-ray analysis of 19 clearly indicated the cis-fusion of two tetrahydrofuran rings both in
an envelope conformation. The con®guration of the new stereogenic center at C-3 is S. Therefore,
stereoselective formation of 18 directly from 12 must involve double intramolecular SN2 nucleo-
philic substitutions, and protic solvents are favorable for the second substitution. As depicted in
Scheme 3, compound 17 under the conditions as used for the 12 to 19 conversion, also gave
compound 19. Therefore, we report here a convenient approach to stereoselective preparation of
5-deoxy-1,4:3,6-dianhydroglucitol in high yield. Preparation of similar bicyclic compounds such
as 3,6-anhydroglucofuranose, 1,4:3,6-dianhydroglucitol, and 3,6-dideoxy-3,6-epithioglucofuranose
derivatives from d-glucose, d-glucitol and d-allose, respectively, have been reported.9 The ®nal
reaction, ring opening of epoxide 17 with nucleobases, was achieved in DMF solution. This process
required the assistance of a strong base such as DBU, temperature 85±110ꢀC, and reaction time
48±72 h. Although this process was regioselective and ring opening occurred exclusively via
attack at the C-2 position with adenine as the nucleophile, in the case of pyrimidines the yields were
moderate, and the desired products were contaminated with small amounts of C-3-regioisomers,
as shown in Scheme 4.
Scheme 3. Solvent-dependent formation of 17 and 18 from 12. Reagents and conditions: (i) t-BuOK, THF or DMF, ice±
salt bath, 30 min, 85±100%; (ii) t-BuOK, t-BuOH or MeOH, ice±salt bath, 30 min, 95±100%; (iii) TsCl, pyridine, 24 h, 86%
Scheme 4. Reactions and conditions: (i) nucleobase, DBU, DMF, 85±110ꢀC, 48±72 h; (ii) K2CO3/CH3OH or
CH3ONa/CH3OH, rt
1
The structure of the novel isonucleosides 21 and 23a±c was established by H±1H COSY or
NOESY NMR spectroscopy.
As mentioned earlier, compounds 8 and 9 were separated from the reaction mixture as side
products of the hydroboration-oxidation of alkene 5. The 5-C-hydroxyl group in compound 9

X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
1881
was protected by the benzoyl group to give derivative 10. A single crystal of 10 suitable for X-ray
analysis was obtained via crystallization from petroleum ether:ethyl acetate (8:1, v/v). The R
con®guration of the new stereogenic center at C-5 of 9 was con®rmed by X-ray analysis of 10
(Fig. 2).
Figure 2. Compounds 7±9 and X-ray crystal structure of compound 10
Scheme 5. Potential mechanism for the formation of 13 and 14 from 11

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The two disaccharides 13 and 14 were the side products isolated from the reaction mixture after
treatment of compound 11 with triethylsilane/TMSOTf. They could not be separated by any
simple means. The mixture of 13/14 was treated with t-BuOK in THF at ^10ꢀC to give epoxides
15 and 16, which could be separated by column chromatography. The stereochemistry of 13 was
assigned by X-ray analysis of its crystalline derivative 15 (Scheme 5 and Fig. 3).
Figure 3. X-Ray crystal structure of compound 15
3. Experimental
3.1. General procedures
All solvents were dried and distilled prior to use. Thin layer chromatography was performed
using DC-Alufolien Kieselgel 60 F254 (Alltech Assoclates, Inc.) plates with detection by UV, or
staining with 5% phosphomolybdic acid hydrate in ethanol. Column chromatography was
performed on silica gel (200±300 mesh, purchased from Qing-Dao Chemical Company, China).
Melting points were determined on an XT-4A melting point apparatus and are uncorrected. UV
spectra were recorded with a Pharmacia LKB Biochrom 4060 spectrophotometer. Optical rotations
were recorded on a Perkin±Elmer 243B polarimeter. ZAB-HS and KYKY-ZHP-5 and BIFLEX
III (Bruker, Inc.) were used for mass spectra. HRMS were recorded on APEX II (Bruker, Inc.)
FTICR MS. NMR spectra were recorded with a Varian VXR-300 or Bruker APE-400 spectrometer
with TMS as internal standard. Elemental analyses were performed by using a PE-240C instrument.
Evaporations were carried out under reduced pressure with a bath temperature below 45ꢀC.
3.2. 1,2-O-Isopropylidene-3-O-tosyl-5,6-dideoxy-ꢀ-d-xylo-hex-5-enofuranose 5
To a solution of 1 (4.7 g, 12.6 mmol) and trimethyl orthoformate (11.8 mL) was added a catalytic
amount of p-toluenesulfonic acid monohydrate (91 mg, 0.48 mmol). The reaction mixture was

X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
1883
stirred for 24 h at room temperature until TLC indicated that the reaction was complete. The
reaction mixture was neutralized with 2N NaOH. Water (20 mL) was poured into the solution,
then the aqueous layer was extracted with CH2Cl2 and dried over Na2SO4. The solution was
concentrated and diastereoisomeric mixture 4 was obtained as a pale yellow syrup. A solution of
4 (0.6 g, 1.47 mmol) in acetic anhydride (5 mL) was re¯uxed for 4 h. The solvent was removed
under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed with saturated
NaHCO3 (50 mL), water (2Â30 mL) and dried over Na2SO4. After removal of ethyl acetate, the
residue was puri®ed by silica gel chromatography, eluting with cyclohexane:AcOEt (5:1) to give 5
(0.49 g, 88%) as a colorless syrup.
22
D
1
Compound 5, ‰ꢀŠ ^34.6 (c=0.14, CH3OH). H NMR (CDCl3): ꢁ 1.30 (s, 3H, CH3), 1.49 (s,
3H, CH3), 2.46 (s, 3H, CH3-Ts), 4.46 (m, 1H, H-2), 4.71±4.75 (dd, 2H, H-6), 5.18 (m, 1H, H-4),
5.32 (m, 1H, H-3), 5.64 (m, 1H, H-5), 5.95 (d, J=2.4, 1H, H-1), 7.34±7.79 (m, 4H, arom H). 13C
NMR (CDCl3): ꢁ 21.7, 26.2, 26.5, 79.8, 83.4, 104.5, 112.3, 120.1, 130.0, 128.0, 129.8, 132.9, 145.3.
FAB-MS: m/z 341 (M+H)+, 363 (M+Na)+. Anal. calcd for C16H20O6S: C, 56.45; H, 5.92. Found:
C, 56.78; H, 6.09.
3.3. 1,2-O-Isopropylidene-3-O-tosyl-5-deoxy-ꢀ-d-glucofuranose 6, 1,2-O-isopropylidene-3-O-tosyl-
5,6-dideoxy-ꢀ-d-glucofuranose 7, 1,2-O-isopropylidene-3-O-tosyl-6-deoxy-ꢀ-d-idofuranose 8, and
1,2-O-isopropylidene-3-O-tosyl-6-deoxy-ꢀ-d-glucofuranose 9
To an ice-cold solution of 5 (13.04 g, 38.35 mmol) in THF (65 mL) was added dropwise a
.
solution of BH3 SMe2 (4.6 mL, 46 mmol) over 20 min and then the mixture was warmed to room
temperature. After 2 h, the reaction was quenched with methanol at 0ꢀC. To the resulting mixture
at 0ꢀC was added dropwise 2 M NaOH (15.34 mL, 30.68 mmol) and then 30% H2O2 (5.22 mL,
46.02 mmol) sequentially. After stirring at room temperature for an additional 2 h, the solvent
was removed and the residue was extracted with ether (2Â100 mL), the combined organic phase
was washed with water, saturated NaHCO3 and water, and dried over Na2SO4. The solvent was
evaporated in vacuo and the products were isolated by means of silica gel chromatography,
eluting system cyclohexane:AcOEt (4:1), to give 6 (7.34 g, 53.5%) as a colorless syrup, 7 (1.39 g,
10%) as a pale yellow syrup, 8 (0.7 g, 5%) as a light yellow foam and 9 (1.0 g, 9.7%) as a colorless
syrup.
22
D
1
Compound 6, ‰ꢀŠ ^4.3 (c=0.175, CH3OH). H NMR (CDCl3): ꢁ 1.28 (s, 3H, CH3), 1.48 (s,
3H, CH3), 1.63 (m, 1H, H-5), 1.81 (br s, 1H, -OH), 1.86 (m, 1H, H-5), 2.47 (s, 3H, CH3-Ts), 3.70
(m, 2H, H-6), 4.38 (m, 1H, H-4), 4.46 (d, J1,2=3.6, 1H, H-2), 4.77 (d, J3,4=2.4, 1H, H-3), 5.89 (d,
J=3.6, 1H, H-1), 7.36±7.83 (dd, 4H, arom H). FAB-MS: m/z 343 (M^CH3)+, 359 (M+H)+, 381
(M+Na)+. Anal. calcd for C16H22O7S: C, 53.62; H, 6.19. Found: C, 53.78; H, 6.57.
22
D
1
Compound 7, ‰ꢀŠ ^13.0 (c=0.15, CH3OH). H NMR (CDCl3): ꢁ 0.80 (t, 3H, H-6), 1.28 (s,
3H, CH3), 1.45 (m, 1H, H-5), 1.48 (s, 3H, CH3), 1.68 (m, 1H, H-5), 2.47 (s, 3H, CH3-Ts), 4.07 (m,
1H, H-4), 4.65 (d, J1,2=2.4, 1H, H-2), 4.73 (d, J3,4=1.8, 1H, H-3), 5.88 (d, J1,2=2.4, 1H, H-1),
7.36±7.82 (dd, 4H, arom H). FAB-MS: m/z 343 (M+H)+, 365 (M+Na)+, 327 (M^CH3)+. Anal.
calcd for C16H22O6S: C, 56.13; H, 6.48. Found: C, 56.13; H, 6.49.
22
D
1
Compound 8, ‰ꢀŠ ^22.4 (c=0.197, CH3OH). H NMR (CDCl3): ꢁ 0.39 (d, J=3.6, 3H, H-6),
1.29 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.86 (br s, 1H, -OH), 2.47 (s, 3H, CH3-TS), 3.90 (m, 1H, H-5),
3.98 (m, 1H, H-4), 4.70 (d, J1,2=3.6, 1H, H-2), 4.70 (d, J3,4=2.4, 1H, H-2), 4.82 (d, J3,4=1.8, 1H,
H-3), 5.92 (d, J=3.3, 1H, H-1), 7.37±7.83 (dd, 4H, arom H). FAB-MS: m/z 359 (M+H)+, 381
(M+Na)+. Anal. calcd for C16H22O7S: C, 53.62; H, 6.19. Found: C, 53.72; H, 6.31.

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22
D
Compound 9, ‰ꢀŠ ^28.8 (c=0.285, CH3OH). 1H NMR (CDCl3): ꢁ 1.26 (s, 3H, CH3), 1.31 (d,
J5,6=3.6, 3H, H-6), 1.48 (s, 3H, CH3), 2.48 (s, 3H, CH3-TS), 3.96 (m, 2H, H-4,5), 4.51 (d,
J1,2=1.8, 1H, H-2), 4.99 (s, 1H, H-3), 5.87 (d, J1,2=1.8, 1H, H-1), 7.39±7.85 (dd, 4H, arom H).
FAB-MS: m/z 359 (M+H)+, 381 (M+Na)+. Anal. calcd for C16H22O7S: C, 53.62; H, 6.19. Found:
C, 53.94; H, 6.37.
3.4. 5-O-Benzoyl-1,2-O-isopropylidene-3-O-tosyl-6-deoxy-ꢀ-d-glucofuranose 10
To an ice-cold solution of 9 (8.52 g, 23.8 mmol) in dry pyridine (50 mL) was added dropwise
benzoyl chloride (5.34 mL, 46.0 mmol) and then the mixture was stirred at room temperature for
20 h. The mixture was concentrated under reduced pressure, the residue was dissolved in CH2Cl2
(100 mL), washed with 1.4 M H2SO4 (50 mL), saturated NaHCO3 (100 mL) and brine, and dried
over Na2SO4. After removal of the solvent, the residue was puri®ed by silica gel chromatography,
eluting system petroleum ether:AcOEt (8:1), to give 10 (8.07 g, 81% yield) as crystalline needles.
A single crystal was prepared by recrystallization from petroleum ether:ethyl acetate (8:1, v/v).
22
Compound 10, m.p. 123±124ꢀC, ‰ꢀŠ ^41.5 (c=0.205, CH3OH). 1H NMR (CDCl3): ꢁ 1.28 (s, 3H,
D
CH3), 1.30 (d, J5,6=6.4, 3H, H-6), 1.47 (s, 3H, CH3), 2.14 (s, 3H, CH3-Ts), 4.32 (dd, J3,4=2.8,
J4,5=8.6, 1H, H-4), 4.77 (d, J1,2=3.6, 1H, H-2), 4.90 (s, J3,4=2.8, 1H, H-3), 4.97 (m, 1H, H-5),
6.04 (d, J1,2=3.6, 1H, H-1), 7.18±7.83 (m, 9H, arom H). FAB-MS: m/z 463 (M+H)+. Anal. calcd
for C23H26O8S: C, 59.73; H, 5.67. Found: C, 59.94; H, 5.60. Crystal data: empirical formula,
C23H26O8S; formula weight, 62.52; crystal system, orthorhombic, space group, P212121, a=8.012
(1), b=10.692(1), c=27.606(1) A, V=2364.8(4) A3, Z=4, Dc=1.304 g/cm3; R=0.054, Rw=0.049.
3.5. 6-Benzoyl-1,2-O-isopropylidene-3-O-tosyl-5-deoxy-ꢀ-d-glucofuranose 11
To an ice-cold solution of 6 (7.34 g, 20.5 mmol) in dry pyridine (30 mL) was dropped benzoyl
chloride (4.76 mL, 41.0 mmol) and then the mixture was stirred at room temperature for 18 h.
The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate
(50 mL), washed with 1.4 M H2SO4 (50 mL), saturated NaHCO3 (100 mL) and water (100 mL),
and dried over Na2SO4. After removal of ethyl acetate, the residue was puri®ed by silica gel
chromatography, eluting system cyclohexane:AcOEt (5:1), providing 11 (9.27 g, 98%) as a colorless
syrup.
22
D
1
Compound 11, ‰ꢀŠ ^3.2 (c=0.14, CH3OH). H NMR (CDCl3): ꢁ 1.29 (s, 3H, CH3), 1.46 (s,
3H, CH3), 1.85 (m, 1H, H-5), 2.10 (m, 1H, H-5), 2.44 (s, 3H, CH3-Ts), 4.28 (m, 2H, H-6), 4.38 (m,
1H, H-4), 4.67 (d, J1,2=3.6, 1H, H-2), 4.77 (d, J=2.7, 1H, H-3), 5.91 (d, J=3.9, 1H, H-1), 7.35±
7.57 (dd, 4H, arom H). FAB-MS: m/z 447 (M^CH3)+, 485 (M+Na)+. Anal. calcd for C23H26O8S:
C, 59.73; H, 5.67. Found: C, 59.75; H, 5.92.
3.6. 6-O-Benzoyl-3-O-tosyl-5-deoxy-1,4-anhydro-d-glucitols 12, 13 and 14
To a solution of 11 (28.7 g, 62 mmol) in dichloromethane (450 mL) at 0ꢀC was added dropwise
TMSOTf (24.24 mL, 124 mmol) and then the solution was stirred under nitrogen at room
temperature for 0.5 h. Et3SiH (50 mL, 310 mmol) was added to the stirred mixture at 0ꢀC and
stirring was continued for an additional 48 h. The reaction was quenched with saturated NaHCO3
(240 mL). The aqueous layer was extracted with CH2Cl2 (2Â100 mL), the combined organic
phase was washed with brine (2Â200 mL) and dried over Na2SO4. The solvent was removed and

X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
1885
the residue was puri®ed on a silica gel column with petroleum ether/ethyl acetate as an eluent, to
give 12 (12.53 g, 53%) as a pale yellow syrup and a mixture of 13 and 14 (3.47 g, 7%).
22
D
1
Compound 12, ‰ꢀŠ ^12.4 (c=0.227, CH3OH). H NMR (CDCl3): ꢁ 1.82 (m, 1H, H-5), 2.00
(m, 1H, H-5), 3.67 (m, 1H, H-1), 4.15 (m, 1H, H-1), 2.38 (s, 3H, CH3-TS), 4.27 (m, 3H, H-4,6),
4.47 (m, 1H, H-2), 4.78 (d, J=3.6, 1H, H-3), 7.30±8.00 (m, 9H, arom H). FAB-MS: m/z 407
(M+H)+, 429 (M+Na)+. Anal. calcd for C20H22O7S: C, 59.10; H, 5.46. Found: C, 58.56; H,
5.76.
3.7. 2-O-(60-O-Benzoyl-50-deoxy-ꢀ-d-20,30-anhydroallofuranosyl)-6-O-benzoyl-3-O-tosyl-5-deoxy-
1,4-anhydro-d-glucitol 15 and 2-O-(60-O-benzoyl-50-deoxy-ꢂ-d-20,30-anhydroallofuranosyl)-6-O-
benzoyl-3-O-tosyl-5-deoxy-1,4-anhydro-d-glucitol 16
To a solution of the mixture of 13 and 14 (1.946 g, 2.40 mmol) in THF (20 mL) at ^10ꢀC was
added t-BuOK (0.296 g, 2.64 mmol). The reaction mixture was stirred for 30 min at ^10ꢀC, then
the reaction neutralized with AcOH. The solvent was removed in vacuo and the residue was
puri®ed on silica gel column with cyclohexane:AcOEt (4:1) as an eluent to give 15 (1.042 g,
67.9%) as a crystalline powder and 16 (0.407 g, 26.5%) as a colorless syrup (15:16=2.5:1).
22
D
Compound 15, m.p. 67±68ꢀC, ‰ꢀŠ ^7.8 (c=0.18, CH3OH). H NMR (DMSO-d6): ꢁ 1.66 (m,
1
1H, H-50), 1.85 (m, 2H, H-5, H-50), 1.97 (m, 1H, H-50), 2.33 (s, 3H, CH3-Ts), 3.63 (dd, 1H, H-1),
3.83 (d, J=6.96, 1H, H-20), 3.86 (d, J=2.90, 1H, H-30), 4.00 (m, 1H, H-4), 4.08 (m, 1H, H-1), 4.15
(m, 02H, H-6), 4.33 (m, 2H, H-2, H-40), 4.42 (m, 2H, H-60), 4.97 (d, J=28, 1H, H-3), 5.19 (s, 1H,
H-1 ), 7.41±7.99 (m, 14H, arom H). 13C NMR (DMSO-d6): ꢁ 21.00, 26.3, 27.5, 55.4, 57.0, 61.0,
61.6, 71.1, 75.1, 75.6, 82.5, 83.9, 101.4, 127.58, 128.67, 128.72, 129.04, 129.13, 129.59, 130.16,
132.4, 133.25, 133.32, 145.3, 165.44, 165.62. MALDI-TOF MS m/z: 661.27 (M+Na)+, 677.25
+
.
(M+K) . Anal. calcd for C33H34O11S 0.5C6H12: C, 63.53, H; 5.93. Found: C, 64.01; H, 6.32.
Crystal data: empirical formula, C33H34O11S; formula weight, 638.68; crystal system, triclinic;
space group, P1, a=9.825(1), b=12.891(1), c=16.621(1) A, V=1859.2(3) A3, Z=2, Dc=1.141
g/cm3; R=0.057, Rw=0.070.
22
D
0
1
Compound 16, ‰ꢀŠ ^16.1 (c=0.25, CH3OH). H NMR (DMSO-d6): ꢁ 1.73 (m, 2H, H-5,5 ),
1.91 (m, 2H, H-5,50), 2.34 (s, 3H, CH3-Ts), 3.51 (dd, J1a,1b=2.8, J1a,2=10.2, 1H, H-1), 3.71 (d,
J=2.8, 1H, H-20), 3.92 (d, J=2.8, 1H, H-30), 4.06 (m, 2H, H-1, H-4), 4.19 (m, 2H, H-6), 4.27 (m,
3H, H-2, H-40, H-60), 4.37 (m, 1H, H-60), 4.91 (s, 1H, H-10), 5.04 (d, J=3.4, 1H, H-3), 7.46 ±7.99
13
(m, 14H, arom H). C NMR (DMSO-d6): ꢁ 21.00, 27.6, 31.5, 55.8, 56.00, 61.3, 61.6, 70.7, 75.5,
75.8, 79.9, 83.4, 99.9, 127.70, 128.67, 128.69, 129.07, 129.62, 130.22, 132.46, 133.26, 145.36,
165.51, 165.57. MALDI-TOF MS m/z: 661.23 (M+Na)+, 677.18 (M+K)+. Anal. calcd for
C33H34O11S: C, 62.06; H, 5.37. Found: C, 62.63; H, 5.46.
3.8. 6-O-Benzoyl-5-deoxy-1,4:2,3-dianhydro-d-allitol 17
To a solution of 12 (2.34 g, 5.76 mmol) in THF (15 mL) at ^10ꢀC was added t-BuOK (0.774 g,
6.91 mmol) and then the mixture was stirred for 30 min at ^10ꢀC. The solvent was removed under
vacuum. The residue was dissolved in ethyl acetate, washed with brine (50Â2 mL) and dried over
Na2SO4. After removing ethyl acetate, the syrupy 17 was obtained (1.28 g, 95%), its cyclohexane±
acetone solution providing colorless needles.
22
Compound 17, m.p. 53±54ꢀC, ‰ꢀŠ +48.0 (c=0.2, CH3OH). 1H NMR (CDCl3): ꢁ 1.84 (m, 1H,
D
H-5), 1.96 (m, 1H, H-5), 3.69 (d, J1a,2=2.8, 1H, H-1a), 3.76 (d, J1b,2=10.7, 1H, H-1b), 3.80 (dd,

1886
X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
J=2.8, 1H, H-2), 4.02 (d, J=10.7, 1H, H-3), 4.33 (q, 1H, H-4), 4.41 (m, 1H, H-6), 4.52 (m, 1H,
H-6), 7.44±8.03 (m, 5H, arom H). 13C NMR (CDCl3): ꢁ 30.2, 55.9, 58.9, 61.2, 66.2, 74.7, 128.4,
129.5, 130.0, 233.1, 166.4. FAB-MS m/z: 235(M+H)+. Anal calcd for C13H14O4: C, 66.66; H: 6.02.
Found: C, 66.33; H: 6.01.
3.9. 5-Deoxy-1,4:3,6-dianhydro-d-glucitol 18
A mixture of 12 (16.59 g, 48.86 mmol), K2CO3 (14.1 g, 102.15 mmol) and methanol (200 mL)
was stirred at room temperature for 2.5 h. Undissolved material was ®ltered o€. Removal of the
solvent in vacuo and column chromatography (SiO2, petroleum ether:acetone, 6:1) yielded 18
22
D
1
(4.82 g, 91%) as a colorless oil. ‰ꢀŠ +6.7 (c=0.06, CH3OH). H NMR (DMSO-d6): ꢁ 1.88 (m,
2H, H-5), 3.58 (m, 2H, H-1, H-6), 3.73 (m, 2H, H-1, H-6), 4.02 (m, 1H, H-2), 4.17 (d, J=4.1, 1H,
H-3), 4.65 (q, 1H, H-4), 5.06 (d, J=3.96, 1H, -OH). 13C NMR (DMSO-d6): ꢁ 35.1, 68.3, 75.4,
76.5, 83.0, 89.7.
3.10. 2-O-Tosyl-5-deoxy-1,4:3,6-dianhydro-d-glucitol 19
To a stirred solution of 18 (3.505 g, 27 mmol) in dry pyridine (30 mL) at 0ꢀC was added TsCl
(8.29 g, 43.5 mmol). The mixture was stirred for 29 h at room temperature and then concentrated
under reduced pressure. The residue was dissolved in CH2Cl2 (40 mL), washed with water (50
mL), 1.4 M H2SO4 (50 mL), saturated NaHCO3 (2Â50 mL) and brine (50 mL), and dried over
Na2SO4. After removal of the solvent, the residue was puri®ed by silica gel chromatography,
eluting system petroleum ether:acetone (7.5:1), providing 19 (6.6 g, 86%) as a crystalline solid.
Recrystallization from ethanol provided a single crystal for X-ray analysis.
22
D
Compound 19, m.p. 60±61ꢀC, ‰ꢀŠ +35.7 (c=0.205, CH3OH). H NMR (CDCl3): ꢁ 1.96 (m,
1
1H, H-5), 1.99 (m, H, 1H, H-5), 2.46 (s, 3H, CH3-Ts), 3.72 (m, 1H, H-6), 3.89 (m, 3H, H-1, H-6),
4.43 (t, 1H, H-3), 4.79 (q, 1H, H-2), 4.85 (d, 1H, H-4), 7.27±7.82 (m, 4H, arom H). FAB-MS m/z:
285 [M+H]+, 113 [M^TsO]+. Anal calcd for C13H16O5S: C, 54.91; H, 5.67. Found: C, 54.84; H,
5.66. Crystal data: empirical formula, C13H16O5S; formula weight, 284.33; crystal system,
orthorhombic; space group, P212121; a=6.313(1), b=7.534(1), c=28.579(1) A, V=1359.3(3) A3,
Z=4, Dc=1.389 g/cm3, R=0.053, Rw=0.060.
3.11. 60-O-Benzoyl-20-deoxy-20-(adenine-9-yl)-50-deoxy-10,40-anhydro-d-altritol 20
To a solution of epoxide 17 (1 g, 4.27 mmol) and adenine (1.15 g, 8.54 mmol) in DMF (30 mL)
was added DBU (1.9 mL, 12.81 mmol), and the solution was heated to 85ꢀC for 48 h. After the
mixture cooled to room temperature, the solvent was removed at reduced pressure and the residue
puri®ed by silica gel column chromatography, eluting system CH2Cl2:MeOH (9:1), providing 20
22
(0.357g, 51%) as a white powder, as well as unreacted epoxide 17 (0.552 g). ‰ꢀŠ ^35.0 (c=0.145,
D
MeOH). UV (MeOH): lmax=261 nm (" 15 663). 1H NMR (DMSO-d6): ꢁ 2.04 (m, 1H, H-50), 2.14
(m, 1H, H-50), 3.85 (m, 1H, H-40), 4.18 (m, 2H, H-10), 4.43 (m, 3H, H-30, H-60), 4.90 (q, 1H, H-20),
5.82 (d, J=5.48, 1H, 30-OH), 7.25 (br s, 2H, -NH2), 7.35±7.57 (m, 5H,Ph), 8.14 (s, 1H, H-2), 8.19
(s, 1H, H-8). 13C NMR (DMSO-d6): ꢁ 31.8, 61.7, 68.7, 78.6, 80.6, 118.9, 128.7, 129.2, 129.7,
133.2, 139.2, 149.4, 152.3, 156.0, 165.6. FAB-MS m/z: 370 [M+H]+, 136 [adenine+H]+ (base
peak). Anal calcd for C18H19N5O4: C, 58.53; H, 5.81; N, 18.96. Found: C, 58.80; H, 5.49; N,
18.45.

X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
1887
3.12. 20-Deoxy-20-(adenine-9-yl)-50-deoxy-10,40-anhydro-d-altritol 21
To a vigorously stirred solution of 20 (0.35 g, 0.948 mmol) in methanol (10 mL) was added
potassium carbonate (0.327 g, 2.37 mmol) and then the mixture was stirred for 2 h. After ®ltration
and concentration, the residue was puri®ed by silica gel column chromatography, eluting with
22
CH2Cl2:MeOH (10:1) to give 21 (0.199 g, 79%) as a white powder. ‰ꢀŠ ^28.5 (c=0.197, MeOH).
D
UV (MeOH): lmax=261 nm (" 13 519). 1H NMR (DMSO-d6): ꢁ 1.70 (m, 1H, H-50), 1.80 (m, 1H, H-50),
2.08 (m, 2H, H-10), 3.54 (m, 2H, H-60), 3.74 (m, 1H, H-40), 4.27 (q, 1H, H-3), 4.49 (t, JH6 ,OH=5.1,
0
1H, 60-OH), 4.85 (q, 1H, H-20), 5.71 (d, JH3 ,OH=5.5, 1H, 30-OH), 7.23 (br s, 2H, -NH2), 8.15 (s, 1H,
0
H-2), 8.16 (s, 1H, H-8). 13C NMR (DMSO-d6): ꢁ 36.1, 57.7, 61.8, 68.6, 78.9, 80.9, 118.9, 139.2, 149.4,
152.3, 155.9. HRMS (FAB) calcd for C11H15N5O3 [M+H]+: 266.1248. Found: 266.1251.
3.13. 20-Deoxy-20-(uracil-1-yl)-50-deoxy-10,40-anhydro-d-altritol 23a and 30-deoxy-30-(uracil-1-yl)-
50-deoxy-10,40-anhydro-d-altritol 24a
Reaction was performed as above. A mixture 22a was obtained (0.215 g, 38%) as a foam. A
mixture of 22a (150 mg, 0.434 mmol) and sodium methoxide (23.44 mg, 0.434 mmol) in methanol
(1.5 mmL) was stirred for 12 h at room temperature. The reaction mixture was neutralized with
anion ion-exchange resin 717#. After ®ltration and concentration, the residue was puri®ed by
column chromatography (CH2Cl2:MeOH, 10:1) to give a mixture of 23a and 24a (98 mg, 93.3%)
as a pale yellow foam. The mixture was separated by reversed phase HPLC (7% CH3OH in
water) to give 23a (tR 22.9 min, 67 mg, 64%) and 24a (tR 22.9 min, 7 mg, 7%), both as a white
hygroscopic powder.
22
D
Compound 23a, ‰ꢀŠ +4.4 (c=0.09, CH3OH). 1H NMR (DMSO-d6): ꢁ 1.69 (m, 1H, H-50), 1.80
(m, 1H, H-50), 3.51 (m, 2H, H-60), 3.60 (m, 1H, H-40), 3.80 (m, 1H, H-10), 3.89 (m, 1H, H-10), 3.97
(m, 1H, H-30), 4.48 (t, J=5.2, 1H, 60-OH, exchangeable in D2O), 4.75 (m, 1H, H-20), 5.60 (m, 1H,
H-5), 5.63 (m, 1H, 30-OH, exchangeable in D2O), 7.57 (d, J=8.0, 1H, H-6), 11.29 (s, 1H, -NH-,
exchangeable in D2O). HRMS (FAB) calcd for C10H14N2O5 [M+H]+: 243.0975. Found: 243.0973.
Compound 24a, 1H NMR (DMSO-d6): ꢁ 1.40 (m, 2H, H-50), 3.40 (m, 3H, H-10, H-60), 4.10 (m,
1H, H-40), 4.29 (m, 1H, H-10), 4.36 (m, 1H, H-20), 4.51 (t, J=5.2, 1H, 60-OH), 4.75 (m, 1H, H-30),
5.58 (d, J=8.0, 1H, H-5), 5.67 (d, J=4.4, 20-OH), 7.23 (d, J=8.0, 1H, H-6), 11.38 (s, 1H, -NH-).
HRMS (FAB) calcd for C10H14N2O5 [M+H]+: 243.0975. Found: 243.0974.
3.14. 20-Deoxy-20-(5-¯uorouracil-1-yl)-50-deoxy-10,40-anhydro-d-altritol 23b and 30-deoxy-30-(5-
¯uorouracil-1-yl)-50-deoxy-10,40-anhydro-d-altritol 24b
The reaction was performed as above. A mixture of 22b was obtained (0.159 g, 46%) as a pale
yellow foam. Debenzoylation was performed as above to yield a mixture of 23b and 24b (88 mg,
80%) as a white foam. The mixture was separated by reversed phase HPLC (8% CH3OH in
water) to give 23b (tR 25.7 min, 56 mg, 50.6%) and 24b (tR 25.7 min, 10 mg, 9%), both as a white
hygroscopic powder.
22
D
Compound 23b, ‰ꢀŠ +6.4 (c=0.14, CH3OH). 1H NMR (DMSO-d6): ꢁ 1.71 (m, 1H, H-50), 1.79
(m, 1H, H-50), 3.52 (m, 2H, H-60), 3.59 (m, 1H, H-4), 3.81 (m, 1H, H-10), 3.96 (m, 2H, H-10, H-30),
4.48 (t, J=5.2, 1H, 60-OH, exchangeable in D2O), 4.73 (m, 1H, H-20), 5.58 (d, J=5.6, 1H, 30-OH,
exchangeable in D2O), 7.92 (d, J=7.2, 1H, H-6), 11.83 (d, J=5.2, 1H, -NH-, exchangeable in
D2O). HRMS (FAB) calcd for C10H13FN2O5 [M+H]+: 261.0881. Found: 261.0880.

1888
X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
22
D
Compound 24b, ‰ꢀŠ +129.2 (c=0.065, CH3OH). H NMR (DMSO-d6): ꢁ 1.43 (m, 2H, H-50),
1
3.35 (m, 1H, H-10), 3.41 (m, 2H, H-60), 4.08 (m, 1H, H-40), 4.34 (m, 2H, H-10, H-20), 4.50 (t,
J=5.2, 1H, 60-OH), 4.74 (d, J=4.9, 1H, H-30), 5.64 (d, 1H, 20-OH), 7.44 (d, J=6.8, 1H, H-6),
11.93 (s, 1H, -NH-). HRMS (FAB) calcd for C10H13FN2O5 [M+H]+: 261.0881. Found: 261.0881.
3.15. 20-Deoxy-20-(thymin-1-yl)-50-deoxy-10,40-anhydro-d-altritol 23c and 30-deoxy-30-(thymin-1-
yl)-50-deoxy-10,40-anhydro-d-glucitol 24c
The reaction was performed as above. A mixture of 22c was obtained (3.178 g, 42%) as a light
yellow foam. Deprotection was performed as above to give 23c as a pale yellow foam (1.656 g, 85%).
The crude product 24c was puri®ed by preparative layer chromatography to give 24c (25 mg, 2%)
as a white powder.
22
D
1
Compound 23c, ‰ꢀŠ ^17.1 (c=0.07, MeOH). UV (MeOH): lmax=271 nm (" 9961). H NMR
(DMSO-d6): ꢁ 1.66 (m, 1H, -50), 1.78 (d, 3H, 5-CH3), 1.79 (m, 1H, H-50), 3.51 (m, 2H, H-60), 3.59
(m, 1H, H-40), 3.77 (m, 1H, H-10), 3.95 (m, 2H, H-10, H-30), 4.49 (t, 1H, 60-OH, exchangeable in
D2O), 4.78 (m, 1H, H-20), 5.56 (d, J=5.6, 1H, 30-OH, exchangeable in D2O), 7.45 (d, J=0.88, 1H,
H-6), 11.28 (s, 1H, -NH-, exchangeable in D2O). 13C NMR (DMSO-d6): ꢁ 12.1, 35.9, 57.8, 62.5,
68.2, 78.8, 80.5, 109.5, 137.7, 151.1, 163.8. HRMS (FAB) calcd for C11H16N2O5 [M+H]+:
257.1132. Found: 257.1129.
22
D
1
Compound 24c, ‰ꢀŠ +170.8 (c=0.065, MeOH). UV (MeOH): lmax=271 nm (" 11722). H
NMR (DMSO-d6): ꢁ 1.40 (m, 2H, H-50), 1.78 (d, J=8.0, 3H, 5-CH3), 3.36 (m, 2H, H-60), 3.44 (m,
1H, H-10a), 4.07 (m, 1H, H-40), 4.34 (m, 2H, H-10b, H-20), 4.49 (br s, 1H, 60-OH, exchangeable in
D2O), 4.75 (d, J=5.0, 1H, H-30), 5.64 (br s, 1H, 30-OH, exchangeable in D2O), 7.06 (d, J=1.2,
1H, H-6), 11.37 (s, 1H, -NH-, exchangeable in D2O). 13C NMR (DMSO-d6): ꢁ 12.0, 32.0, 57.5,
64.0, 73.5, 75.4, 76.5, 109.1, 138.3, 151.1, 163.5. HRMS (FAB) calcd for C11H16N2O5 [M+H]+:
257.1132. Found: 257.1130.
Acknowledgements
This project was supported by the National Natural Science Foundation of China and we
thank Mrs. Yang Lu, Mrs. Fand Guo, Mr. Bin Zhao, Mr. Ren-Wang Jiang and Professor Qi-Tai
Zheng for X-ray analysis.
References
1. (a) Mitsuya, H.; Weinhold, K.; Furman, P. A.; St Clair, M. H.; Nusino€-Lehrman, S.; Gallo, R. C.; Bolognesi, D.;
Barry, D. W.; Browder, S. Proc. Natl. Acad. Sci. USA 1985, 82, 7096±7100. (b) Vince, R.; Hua, M. J. Med. Chem.
1990, 33, 17±21.
2. (a) Beach, J. W.; Jeong, L. S.; Alves, A. J.; Pohl, D.; Kim, H. O.; Chang, C. N.; Doong, S. L.; Schnazi, R. F.;
Cheng, Y. C.; Chu, C. K. J. Org. Chem. 1992, 57, 2217±2219. (b) Hoong, L. K.; Strange, E. S.; Liotta, D. C.
J. Org. Chem. 1992, 57, 5563±5565. (c) Lin, T.-S.; Lou, M.-Z.; Liu, M.-C.; Pai, S. B.; Dutschman, G. E.; Cheng,
Y. D. J. Med. Chem. 1994, 37, 798±803.
3. (a) Nair, V.; Nuesca, Z. M. J. Am. Chem. Soc. 1992, 114, 7951±7953. (b) Soike, K. F.; Whiterock, V. J. Antiviral
Res. 1994, 23, 219±224. (c) Huryn, D. M.; Sluoski, B. C.; Tam, S. Y.; Todaro, L. J.; Weigele, M. Tetrahedron Lett.
1989, 30, 6259±6262. (d) Huryn, D. M.; Broader, S. J. Med. Chem. 1992, 35, 2347±2354. (e) Jones, M. F.; Noble,
S. A.; Roberston, C. A.; Storer, R.; Highcock, R. M.; Lamont, R. B. J. Chem. Soc., Perkin Trans. 1 1992, 1427±
1439. (f) Jung, M. E.; Kretschik, O. J. Org. Chem. 1998, 63, 2975±2981.

X. B. Tian et al. / Tetrahedron: Asymmetry 11 (2000) 1877±1889
1889
4. (a) Kakefuda, A.; Shuto, S.; Nagahada, T.; Seki, J.; Sasaki, T.; Matsuda, A. Tetrahedron 1994, 50, 10 167±10 182.
(b) Tino, J. A.; Clark, J. M.; Field, A. K.; Jacobs, G. A.; Lis, K. A.; Michalik, T. L.; McGeever-Rubin, B.;
Slarsuchyk, W. A.; Spergel, S. H.; Sundeen, J, E.; Tuomari, A. V.; Weaver, E. R.; Young, M. G.; Zahler, R.
J. Med. Chem. 1993, 36, 1221±1229. (c) Jung, M. E.; Nichols, C. J. J. Org. Chem. 1998, 63, 347±355. (d) Kira, T.;
Lakefuda, A.; Shuto, S.; Matsuda, A.; Baba, M.; Shigeta, S. Nucleosides & Nucleotides 1995, 14, 571±574.
5. Yang, Z. J.; Yu, H. W.; Min, J. M.; Ma, L. T.; Zhang, L. H. Tetrahedron: Asymmetry 1997, 8, 2739±2747.
6. (a) Barton, D. H.; Subramanian, R. J. Chem. Soc., Perkin Trans. 1 1977, 1718±1723. (b) Robins, M. J.; Wilson,
J. S.; Hanssake, F. J. Am. Chem. Soc. 1983, 105, 4059±4065. (c) Bolon, P.; Jahnke, T. S.; Nair, V. Tetrahedron
1995, 51, 10 443±10 452. (d) Hennigfelde, K. A.; Arslan, T.; Hecht, S. M. J. Am. Chem. Soc. 1996, 188, 11 701±
11 714.
7. (a) Etzold, G.; Kowollik, G.; Langen, P. Chem. Commun. 1968, 7, 422. (b) Rawson, E. R.; Webb, T. R.
Nucleosides & Nucleotides 1990, 9, 89±96. (b) Kofer, T.; Rasmussen, P. R.; Vekntin-Hansen, P.; Pedersen, E. B.
Acta Chemica Scandinavica 1997, 51, 318±324.
8. (a) Corey, E. J.; Winter, A. E. J. Am. Chem. Soc. 1963, 85, 2677±2678. (b) Grank, G.; Estwood, F. W. Aust. J.
Chem. 1964, 17, 1392±1398. (c) Ando, M.; Oohara, H.; Takase, K. Chem. Lett. 1986, 879±882.
9. (a) Pickering, L.; Nair, V. Nucleosides & Nucleotides 1997, 16, 1435±1438. (b) Marshall, R.; Dalley, N. K.; Savage,
P. B. Tetrahedron Lett. 1998, 39, 3923±3926. (c) Zou, R.; Matteuci, M. D. Tetrahedron Lett. 1996, 37, 941±943.