Synthesis of D- and L-apio nucleoside analogues with 2′-hydroxyl group as potential anti-HIV agents

Article abstract of DOI:10.1016/j.bmc.2003.12.002

The present work describes the asymmetric synthesis of D- and L-apio-2′,3′-dideoxynucleoside analogues, 4 and 5 with 2′-hydroxyl group via a common intermediate 9, starting from D-galactose. Stereoselective dihydroxylation and deoxygenation through radica

Full text of DOI:10.1016/j.bmc.2003.12.002

Bioorganic & Medicinal Chemistry 12 (2004) 1101–1109
Synthesis of D- and L-apio nucleoside analogues with 20-hydroxyl
group as potential anti-HIV agents
Dong Zhe Jin,a Sung Hee Kwon,b Hyung Ryong Moon,c Prashantha Gunaga,b
Hea Ok Kim,b Dae-Kee Kim,b Moon Woo Chuna,* and Lak Shin Jeongb
aCollege of Pharmacy, Seoul National University, Seoul 151-742, South Korea
bCollege of Pharmacy, Ewha Womans University, Seoul 120-750, South Korea
cCollege of Pharmacy, Pusan National University, Pusan 609-735, South Korea
Received 13 October 2003; accepted 4 December 2003
Abstract—The present work describes the asymmetric synthesis of d- and l-apio-20,30-dideoxynucleoside analogues, 4 and 5 with
20-hydroxyl group via a common intermediate 9, starting from d-galactose. Stereoselective dihydroxylation and deoxygenation
through radical inversion were successfully employed to synthesize the key intermediate 12 with d-apio structure, while stereo-
selecetive hydroboration-oxidation was used for the synthesis of another key intermediate 18 with l-apio structure.
# 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Therefore, in order to increase anti-HIV activity of
apio-ddNs 3, we designed and synthesized d- and l-
apio cytidines, 4 and 5 with 20-hydroxyl group in the
hope that the 20-hydroxyl group might play an impor-
tant role in binding affinity to their target enzyme,
reverse transcriptase and kinases required for their acti-
vation into triphosphates as 30-hydroxyl group of nor-
mal substrate, 20-deoxycytidine does. For the synthesis
of the desired d- and l-apio nucleosides 4 and 5, we
employed highly stereoselective dihydroxylation, deoxy-
genation of tert-hydroxyl group, and hydroboration-
oxidation as key steps, starting from carbohydrate tem-
plate, d-galactose and evaluated them for anti-HIV
activity. Here, we wish to report the asymmetric synth-
A number of nucleoside derivatives have been designed,
synthesized and evaluated for the development of anti-
viral and antitumor agents. Particularly, 20,30-unsub-
stituted-20,30-dideoxynucleosides (ddNs) have exhibited
potent antiviral activity against human immunodefi-
ciency virus (HIV), among which 20,30-dideoxycytidine
(1, ddC, zalcitabine)1 is one of the most potent anti-HIV
agent and is being clinically used for the treatment of
AIDS patients (Fig. 1).
However, ddC( 1) has side effects such as peripheral
neuropathy resulting from the inhibition of mitochon-
drial DNA2 and appearance of the resistant strains.
Thus, as a part of worldwide efforts to look for antiviral
agents with more potent anti-HIV activity and less side
effects than ddC, iso- and apio-dideoxynucleosides (iso-
ddNs 2 and apio-ddNs 3) in which base and 40-hydroxyl
group are moved to 20 and 30 position, respectively have
been designed and synthesized by several groups
including our laboratory.3,4a,4dꢀ4g However, these
nucleosides were less potent than ddC( 1), although they
were not reported to show peripheral neuropathy.4a,5
Keywords: Apio nucleotides; Antiviral; Stereoselective.
* Corresponding author. Tel.: +82-2-880-7847; fax: +82-2-888-0649;
e-mail: mwchun@snu.ac.kr
Figure 1. The rationale for the design of the target nucleosides.
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.12.002

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D. Z. Jin et al. / Bioorg. Med. Chem. 12 (2004) 1101–1109
esis of d- and l-apio ddCanalogues 4 and 5 and their
anti-HIV activity.
d-Apio ddCanalogue 4 was synthesized starting from
d-galactose, as shown in Scheme 2. The apio sugar 7
was prepared from d-galactose according to the known
method.6 Oxidation of 7 with PCC followed by treat-
ment of the resulting ketone 8 with methyl triphenyl-
phosphonium bromide in the presence of NaH and
t-amyl alcohol gave the olefin 9, which can be utilized
for the synthesis of both d- and l-apio ddNs. Stereo-
selective cis-dihydroxylation of 9 with catalytic amount
of OsO4 and NMO was occurred due to the steric effect
of 1,2-isopropylidene group to yield diol 10. Primary
hydroxyl group of compound 10 was regioselectively
benzylated using organotin chemistry to afford mono-
benzyl ether 11. Treatment of 11 with NaH, CS2 and
MeI gave the xanthate, which was subjected to the
deoxygenation (Et3B and Bu3SnH)7 to give 12 with
d-apio skeleton through inversion of stereochemistry at
2. Results and discussion
A strategy for the synthesis of d- and l-apio ddCana-
logues 4 and 5 is illustrated in Scheme 1.
It was envisioned that the olefin 6 could be an appro-
priate common key intermediate to give access to the
target nucleosides 4 and 5. Starting from the olefin 6
which can be prepared from d-galactose, stereoselective
dihydroxylation followed by stereoselective deoxygena-
tion would produce d-apio sugar intermediate, while
regio- and stereoselective hydroboration-oxidation
would afford l-apio sugar intermediate.
Scheme 1. Retrosynthetic analysis of the target nucleosides 4 and 5.
Scheme 2. Reagents: (a) PCC, 4A MS, CH2Cl2, rt, overnight, 68%; (b) CH3PPh3Br, NaH, t-amyl alcohol, THF, rt, 2 h, 80%; (c) OsO4, NMO,
acetone: H2O (4:1), rt, 4 h, 98%; (d) n-Bu2SnO, toluene, 140 ꢁC, 2 h and then, n-Bu4NBr, BnBr, 90–100 ꢁC, overnight, 73%; (e) (i) NaH, THF, rt, 1 h
and then, CS2, MeI, rt, 1 h; (ii) n-Bu3SnH, Et3B, benzene, rt, 3 h, 70% from 11; (f) p-TsOH, MeOH, rt, overnight, 75%; (g) Ac2O, DMAP, pyridine,
rt, 1 h, 86%; (h) silylated N4-benzoylcytosine, TMSOTf, CH3CN, rt, overnight; (i) BCl3, C HCl2, ꢀ78 ꢁC, 2 h; (j) Ac2O, pyridine, rt, overnight, 52%
2
from 15a; (k) K2CO3, MeOH, CH2Cl2, ꢀ5 ꢁC, 40 min, 70%; (l) NaOMe, MeOH, rt, overnight, 92%.

D. Z. Jin et al. / Bioorg. Med. Chem. 12 (2004) 1101–1109
1103
C3-position. Acid-catalyzed methanolysis of 12 using
p-TsOH in methanol produced methyl glycosides 13,
which were acetylated to give the glycosyl donor 14.
Condensation of 14 with silylated N4-benzoylcytosine in
the presence of TMSOTf afforded b-anomer 15a (71%)
and a-anomer 15b (12%) after silica gel column chro-
matography. As in our previous report,8 the neighbor-
ing group effect by 2-acetoxy group in compound 14
was not large, when compared to that in 3-deoxy-2-
ribosyl acetate, because of the repulsive effect between
exomethylene group and incoming silylated N4-ben-
zoylcytosine nucleophile. Anomeric configurations were
was successively oxidized with NaBO3 to give 18 with l-
apio skeleton. Benzyl protection of 18 as benzyl ether 19
followed by methanolysis under acid conditions gave
20. The secondary hydroxyl group of 20 was protected
with benzyl chloride to give methyl glycosides 21, which
were ready for the condensation with N4-benzoylcyto-
sine. Unfortunately, coupling of 21 with N4-benzoylcy-
tosine in the presence of TMSOTf produced very small
amounts of the desired nucleoside and two other major
1
UV absorbing spots on TLC. H NMR spectra of the
two major spots showed the presence of methoxy group
and cytosine, indicating that condensation was occurred
with ring-opened intermediate 21a generated from the
binding of Lewis acid (TMSOTf) to the ring oxygen of
21, giving a diastereomeric mixture of ring-opened pro-
duct 21b (Scheme 4).
1
assigned on the basis of H NOE experiments between
10-H and exomethylene’s H on the protected nucleo-
sides, 15a and 15b. A NOE (0.65%) of b-anomer 15a
was smaller than that (2.25%) of a-anomer 15b. Treat-
ment of 15a with BCl3 at ꢀ78 ꢁCproduced the mixture
of monoacetate 16a and diol 16b, which without further
purification was acetylated with acetic anhydride in
pyridine to give diacetate 16c. The diacetate 16c was
chemoselectively deblocked in the presence of benza-
mide, using K2CO3 in a solution of methanol and
methylene chloride at ꢀ5 ꢁCto give the diol 17 (70%).
d-b-Apio ddCanalogue 49 was finally obtained after the
removal of benzoyl group of 17 with NaOMe.
It is worthy to note that condensation of methyl glyco-
sides 14 afforded the desired cyclic nucleoside 15a with-
out giving a ring-opened nucleoside, probably due to
electron withdrawing effect by 2-acetoxy group. Thus,
to remove the formation of 21b, electron-donating
methoxy group of 21 was converted to the electron-
withdrawing acetoxy group in two steps to give the
acetate 23. As expected, coupling of 23 with N4-
benzoylcytosine afforded a mixture of the desired
nucleosides, 24a (22%) and 24b (43%). Higher yield of
a-anomer over b-anomer appears to be due to the steric
hindrance by 2-O-benzyl group. Anomeric configur-
The synthesis of l-apio ddCanalogues 5 and its
a-anomer 5a is depicted in Scheme 3. The same inter-
mediate 9 used for the synthesis of d-apio ddCanalogue
4 was treated with 9-BBN. Hydroboration was regio-
and stereoselectively occurred at the opposite side to the
1,2-isopropylidene group of 9 to afford borate, which
1
ations were assigned based on the H NOE experiments
between 10-H and 30-H on the protected nucleosides, 24a
and 24b. A NOE (2.05%) of b-anomer 24a was larger
Scheme 3. Reagents: (a) 9-BBN, THF, 0 ꢁC, 3 h and then, NaBO3, H2O, rt, overnight, 70%; (b) BnBr, NaH, n-Bu4NI, THF, rt, overnight, 90%;
(c) p-TsOH, MeOH, rt, 2 d, 97%; (d) BnBr, NaH, n-Bu4NI, THF, rt, overnight, 98%; (e) 8 N HCl, H2O:1,4-dioxane (1:2), rt, 2 d, 95%; (f) Ac2O,
pyridine, rt, overnight, 93%; (g) silylated N4-benzoylcytosine, TMSOTf, ClCH2CH2Cl, ꢀ35 ꢁC, 1 h; (h) BCl3, C HCl2, ꢀ78 ꢁC, 30 min, 68% for 25a,
2
70% for 25b; (i) NaOMe, MeOH, rt, overnight, 97% for 5, 81% for 5a.

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D. Z. Jin et al. / Bioorg. Med. Chem. 12 (2004) 1101–1109
Scheme 4. Ring-opened product 21b formed during condensation of 21 with cytosine.
3.2.
furo[2,3-d][1,3]dioxole (9)
(3aR,6aR)-2,2-Dimethyl-6-methylene-tetrahydro-
than that (0.36%) of a-anomer 24b. Removal of benzyl
group of 24a and 24b with BCl3 at ꢀ78ꢁCfollowed by
debenzoylation with NaOMe produced l-b-apio ddC
analogue 5 and its a-anomer 5a,9a respectively.
To a suspension of methyltriphenylphosphonium bro-
mide (24.4 g, 68.28 mmol) and t-amyl alcohol (8.2 mL,
75.10 mmol) in dry THF (200 mL) was added NaH (3.1
g, 77.38 mmol, 60% in mineral oil) at 0 ꢁCand the
reaction mixture was stirred at room temperature for 2
h. To this yellow ylide was added a solution of 8 (3.6 g,
22.76 mmol) in dry THF (20 mL) dropwise at 0 ꢁCand
the reaction mixture was stirred at room temperature
for 3 h. The reaction mixture was quenched with satu-
rated aqueous NH4Cl solution and extracted with
EtOAc. The organic layer was washed with water, dried
over anhydrous MgSO4, filtered, and evaporated. The
residue was purified by silica gel column chromato-
graphy (hexane:ethyl acetate=7:1) to give 9 (2.84 g,
80%) as a colorless oil: 1H NMR (CDCl3) d 1.37 (s, 3H,
CH3), 1.52 (s, 3H, CH3), 4.31 (m, 1H, 5-Ha), 4.64 (m,
1H, 5-Hb), 4.84 (m, 1H, 6a-H), 5.19 (m, 1H, vinylic Ha),
5.38 (m, 1H, vinylic Hb), 5.86 (d, 1H, J=10 Hz, 3a-H).
Anal. calcd for C8H12O3: C, 61.52; H, 7.74. Found: C,
61.66; H, 7.59.
The antiviral activity of d- and l-apio ddCanalogues 4,
5 and 5a was evaluated against HIV-1 in MT-4 cells.
However, all compounds showed neither significant
anti-HIV activity nor cytotoxicity up to 100 mM. Lack
of antiviral activity of the synthesized nucleosides may
be attributed to the poor affinity to cellular kinases, not
being converted into their triphosphates.
In summary, asymmetric synthesis of d- and l-apio
ddCanalogues 4 and 5 was achieved, using three
stereoselective dihydroxylation, deoxygenation, and
hydroboration-oxidation as key steps from the common
intermediate 9. These stereoselective reactions may be
widely applied in the nucleoside chemistry. Chemo-
selective deprotection of acetyl group in the presence of
the benzoyl group, poor neighboring group effect by
2-acetoxy group of apio-sugar and generation of ring-
opened nucleosides may also provide nucleoside chem-
ists with useful information.
3.3. (ꢀ)-(3aR,6S,6aR)-6-Hydroxymethyl-2,2-dimethyl-
tetrahydro-furo[2,3-d][1,3]dioxol-6-ol (10)
3. Experimental
To a solution of 9 (2.5g, 16.04 mmol) in acetone (86
mL) and water (21 mL) were added osmium tetroxide (2
mL, 0.16 mmol, 2.5 wt%) and N-methyl morpholine-N-
oxide (19 mL, 97.31 mmol, 60 w/v%) at 0 ꢁCand the
reaction mixture was stirred at room temperature for 4
h and then quenched with saturated aqueous Na2S2O3
solution. The reaction mixture was extracted with
EtOAc and the organic layer was washed with water,
dried over ahnhydrous MgSO4, filtered, and evapo-
rated. The residue was purified by silica gel column
chromatography (methylene chloride:methanol=10:1)
to give 10 (2.99 g, 98%) as a white solid: mp 125 ꢁC ; a[ ]
3.1. (3aR,6aS)-2,2-Dimethyl-dihydro-furo[2,3-d][1,3]di-
oxol-6-one (8)
To a suspension of PCC (21.6 g, 100.2 mmol) and 4 A
molecular sieves (16.7 g, 0.5 g/1.0 mmol) in CH2Cl2 (330
mL) was added a solution of 7 (5.35 g, 33.4 mmol) in
CH2Cl2 (40 mL) at 0 ꢁCand the mixture was stirred at
room temperature overnight. Diethyl ether and Celite
were added to the mixture and stirred for 1 h. The
whole mixture was filtered through a short pad of silica
gel and Celite and evaporated. The residue was purified
by silica gel column chromatography (hexane:ethyl ace-
tate=2:1) to give 8 (3.6 g, 68%) as a hygroscopic white
solid: H NMR (CDCl3) d 1.37 (s, 3H, CH3), 1.46 (s,
3H, CH3), 4.06 (d, 1H, J=17.2 Hz, 5-Ha), 4.31 (dd, 1H,
J=0.8, 4.4 Hz, 6a-H), 4.34 (dd, 1H, J=0.8, 17.2 Hz, 5-
Hb), 6.05 (d, 1H, J=4.4 Hz, 3a-H); 13CNMR (CDCl
d 27.2, 27.5, 69.1, 75.9, 104.2, 114.4, 209.1. Anal. calcd for
C7H10O4: C, 53.16; H, 6.37. Found: C, 52.84; H, 6.39.
2D5=ꢀ37.4ꢁ (c 0.91, MeOH); H NMR (CD3OD) d 1.30
1
(s, 3H, CH3), 1.46(s, 3H, CH3), 3.63 (d, 1H, J=11.2 Hz,
HOCHH), 3.73 (d, 1H, J=9.6 Hz, 5-Ha), 3.78 (d, 1H,
J=11.2 Hz, HOCHH), 3.88 (d, 1H, J=9.6 Hz, 5-Hb),
4.32 (d, 1H, J=3.6 Hz, 3-H), 5.90 (d, 1H, J=3.6 Hz, 2-
H); 13CNMR (CD 3OD) d 26.6, 27.4, 63.4, 74.9, 83.5,
85.6, 107.9, 113.7. Anal. calcd for C8H14O5: C, 50.52; H,
7.42. Found: C, 50.79; H, 7.71.
1
)
3

D. Z. Jin et al. / Bioorg. Med. Chem. 12 (2004) 1101–1109
1105
3.4. (ꢀ)-(3aR,6S,6aR)-6-Benzyloxymethyl-2,2-dimethyl-
tetrahydro-furo[2,3-d][1,3]dioxol-6-ol (11)
room temperature overnight, neutralized with triethyla-
mine and evaporated. The residue was purified by silica
gel column chromatography (hexane:ethyl acetate=
1
To a solution of 10 (2.58 g, 13.56 mmol) in toluene (100
mL) was added n-Bu2SnO (5.5 g, 22.09 mmol) and the
reaction mixture was heated at 140–150 ꢁCfor 2 h. After
the oil bath was cooled to 90–100 ꢁC, n-Bu4NBr (2.2 g,
6.82 mmol) and benzyl bromide (2.5 mL, 21.01 mmol)
were added to the reaction mixture. The reaction mix-
ture was heated at 90–100 ꢁCovernight and evaporated
to give the residue, which was purified by silica gel col-
umn chromatography (hexane:ethyl acetate=2:1) to
give 11 (2.77 g, 73%) as a white solid: mp 62 ꢁC;
[a]D25=ꢀ29.4ꢁ (c 1.26, CHCl3); 1H NMR (CDCl3) d 1.29
(s, 3H, CH3),1.45 (s, 3H, CH3), 2.74 (br s, 1H, OH),
3.51 (d, 1H, J=9.6 Hz, BnOCHH), 3.77 (d, 1H, J=9.6
Hz, BnOCHH), 3.80 (d, 1H, J=9.6 Hz, 5-Ha), 3.85 (d,
1H, J=9.6 Hz, 5-Hb), 4.32 (d, 1H, J=3.6 Hz, 3-H), 4.55
(d, 1H, J=12.0 Hz, benzylic Ha), 4.61 (d, 1H, J=12.0
Hz, benzylic Hb), 5.95 (d, 1H, J=3.6 Hz, 2-H), 7.28–
7.34 (m, 5H, Ph); 13C NMR (CDCl3) d 26.6, 27.2, 69.5,
73.9, 74.0, 81.5, 84.5, 106.4, 112.7, 127.9, 128.1, 128.7,
137.7. Anal. calcd for C15H20O5: C, 64.27; H, 7.19.
Found: C, 64.10; H, 7.15.
1.5:1) to give 13 (1.22 g, 75%) as a colorless oil: H
NMR (CDCl3) d 2.67–2.75 (m, 1H, 4-H), 3.32 (s, 3H,
OCH3), 3.71 (d, 2H, J=5.6 Hz, BnOCH2), 3.87 (t, 1H,
J=8.4 Hz, 5-Ha), 4.00 (t, 1H, J=8.4 Hz, 5-Hb), 4.21 (d,
1H, J=4.8 Hz, 3-H), 4.49 (d, 1H, J=12.0 Hz, benzylic
Ha), 4.54 (d, 1H, J=12.0 Hz, benzylic Hb), 4.81 (s, 1H,
2-H), 7.28–7.34 (m, 5H, Ph). Anal. calcd for C13H18O4:
C, 65.53; H, 7.61. Found: C, 65.52; H, 7.91.
3.7. Acetic acid (2RS,3R,4S)-4-benzyloxymethyl-2-meth-
oxy-tetrahydro-furan-3-yl ester (14)
To a solution of 13 (1.36 g, 5.39 mmol) in pyridine (10
mL) were added acetic anhydride (1.53 g, 16.17 mmol)
and 4-(dimethylamino)pyridine (100 mg) at 0 ꢁCand the
reaction mixture was stirred at room temperature for 1
h. The reaction mixture was evaporated, and parti-
tioned between ethyl acetate and dilute HCl. The
organic layer was dried over anhydrous MgSO4, filtered
and evaporated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=5:1) to
give 14 (1.38 g, 86%) as a colorless oil: 1H NMR
(CDCl3) d 1.99 (s, 3H, OCOCH3), 2.91–2.98 (m, 1H, 4-
H), 3.33 (s, 3H, OCH3), 3.44 (dd, 1H, J=7.6, 9.6 Hz,
BnOCHH), 3.60 (dd, 1H, J=7.6, 9.6 Hz, BnOCHH),
3.77 (t, 1H, J=8.4 Hz, 5-Ha), 4.13 (t, 1H, J=8.4 Hz, 5-
Hb), 4.45 (d, 1H, J=12.0 Hz, benzylic Ha), 4.50 (d, 1H,
J=12.0 Hz, benzylic Hb), 4.82 (s, 1H, 2-H), 5.14 (d, 1H,
J=3.2 Hz, 3-H), 7.27–7.35 (m, 5H, Ph). Anal. calcd for
C15H20O5: C, 64.27; H, 7.19. Found: C, 64.41; H, 7.27.
3.5. (ꢀ)-(3aR,6S,6aR)-6-Benzyloxymethyl-2,2-dimethyl-
tetrahydro-furo[2,3-d][1,3]dioxole (12)
To a solution of 11 (2.77 g, 9.88 mmol) in dry THF
(60 mL) was added 60% NaH (1.18 g, 29.64 mmol) at
ꢀ5 ꢁCand the reaction mixture was stirred at room
temperature for 1 h. To this mixture were added CS2
(8.8 mL, 148.2 mmol) and MeI (19 mL, 296.4 mmol)
and the reaction mixture was stirred at room temper-
ature for 1 h. The reaction mixture was evaporated to
give crude xanthate, which was used for the next step
without further purification. To a solution of the xan-
thate in dry benzene (60 mL) were added triethylborane
(14.8 mL, 14.80 mmol, 1.0 M solution in hexane) and
n-Bu3SnH (4 mL, 14.8 mmol) at room temperature and
the mixture was stirred at the same temperature for 3 h.
The reaction mixture was quenched with water, extrac-
ted with EtOAc, dried over anhydrous MgSO4, filtered,
and evaporated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=7.5:1ꢁ)
to give 12 (1.82 g, 70%) as a colorless oil: [a]2D5=ꢀ4.2
3.8. Acetic acid (2R,3R,4S)- and (2S,3R,4S)-2-(4-ben-
zoylamino-2-oxo-2H-pyrimidin-1-yl)-4-benzyloxymethyl-
tetrahydro-furan-3-yl ester (15a and 15b)
A suspension of N4-benzoylcytosine (1.18 g, 5.50 mmol)
and ammonium sulfate (catalytic amount) in hexam-
ethyldisilazane (HMDS, 15 mL) was heated at 150–
160 ꢁCovernight to give a clear solution. The reaction
mixture was cooled to room temperature and HMDS
was removed under anhydrous condition in vacuo. To a
solution of the residue in dry acetonitrile (15 mL) were
added a solution of 15 (1.03 g, 3.67 mmol) in dry ace-
tonitrile (5 mL) and TMSOTf (1 mL, 5.5 mmol) at 0 ꢁC
and the reaction mixture was stirred at room temper-
ature overnight. After quenched with saturated aqueous
NaHCO3 solution, the reaction mixture was filtered
through a Celite and the filtrate was partitioned between
methylene chloride and water. The organic layer was
dried over anhydrous MgSO4, filtered and evaporated.
The residue was purified by silica gel column chroma-
tography (methylene chloride:methanol=40:1) to give
b-isomer 15a (1.2 g, 71%) as a white solid and a-isomer
15b (0.2 g, 12%) as a white solid.
1
(c 1.9, CHCl3); H NMR (CDCl3) d 1.29 (s, 3H, CH3),
1.45 (s, 3H, CH3), 2.39–2.46 (m, 1H, 4-H), 3.50 (dd, 1H,
J=7.6, 9.2 Hz, BnOCHH), 3.67 (dd, 1H, J=8.4, 10.8
Hz, 5-Ha), 3.76 (dd, 1H, J=6.8, 9.2 Hz, BnOCHH),
3.99 (dd, 1H, J=7.2, 8.4 Hz, 5-Hb), 4.48 (d, 1H, J=12.0
Hz, benzylic Ha), 4.53 (d, 1H, J=12.0 Hz, benzylic Hb),
4.63 (t, 1H, J=4.0 Hz, 3-H), 5.81 (d, 1H, J=4.0 Hz, 2-
H), 7.26–7.32 (m, 5H, Ph); 13CNMR (CDCl 3) d 26.4,
26.6, 44.8, 66.6, 69.3, 73.4, 80.2, 106.4, 111.9, 127.7,
127.8, 128.5, 138.3. Anal. calcd for C15H20O4: C, 68.16;
H, 7.63. Found: C, 67.97; H, 7.67.
b-isomer 15a: UV (C HCl2) lmax 259 nm; 1H NMR
2
3.6. (2RS,3R,4S)-4-Benzyloxymethyl-2-methoxy-tetra-
hydro-furan-3-ol (13)
(CDCl3) d 2.08 (s, 3H, OCOCH3), 2.69–2.75 (m, 1H, 4-
H), 3.45 (dd, 1H, J=8.0, 8.8 Hz, BnOCHH), 3.66 (dd,
1H, J=5.6, 8.8 Hz, BnOCHH), 4.08 (t, 1H, J=9.2 Hz,
5-Ha), 4.47 (s, 2H, benzylic CH2), 4.52 (t, 1H, J=9.2
A solution of 12 (1.8 g, 6.80 mmol) and p-TsOH (647
mg, 3.40 mmol) in methanol (40 mL) was stirred at

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D. Z. Jin et al. / Bioorg. Med. Chem. 12 (2004) 1101–1109
Hz, 5-Hb), 5.60 (d, 1H, J=5.6 Hz, 3-H), 5.93 (dd, 1H,
J=1.6, 5.6 Hz, 2-H), 7.28–8.02 (m, 12H, 2*Ph, H-5, H-
6). Anal. calcd for C25H25N3O6: C, 64.79; H, 5.44; N,
9.07. Found: C, 64.65; H, 5.60; N, 9.02.
Hb), 5.79 (s, 1H, 2-H), 7.53–7.99 (m, 6H, Ph, H-5), 8.10
(d, 1H, J=7.6 Hz, H-6). To a solution of 17 (27 mg,
0.08 mmol) in methanol (3 mL) was added 0.1 M
NaOMe solution (0.08 mL, 0.008 mmol) and the reac-
tion mixture was stirred at room temperature overnight.
After neutralized with acetic acid, the reaction mixture
was evaporated and the residue was purified by silica gel
column chromatography (methylene chloride:meth-
anol=4:1) to give 4 (17 mg, 92%) as a white solid after
crystallizaton from diethyl ether and methanol. The
spectroscopic data was identical with those of authentic
sample.9c Anal. calcd for C9H13N3O4: C, 47.57; H, 5.77;
N, 18.49. Found: C, 47.48; H, 5.89; N, 18.46
a-isomer 15b: 1H NMR (CDCl3) d 2.07 (s, 3H,
OCOCH3), 2.69–2.75 (m, 1H, 4-H), 3.45 (dd, 1H,
J=7.2, 9.2 Hz, BnOCHH), 3.64 (dd, 1H, J=6.0, 9.2
Hz, BnOCHH), 4.05 (t, 1H, J=9.2 Hz, 5-Ha), 4.47 (s,
2H, benzylic CH2), 4.53 (t, 1H, J=9.2 Hz, 5-Hb), 5.64
(dd, 1H, J=0.8, 5.2 Hz, 3-H), 5.83 (d, 1H, J=0.8 Hz, 2-
H), 7.26–8.12 (m, 12H, 2*Ph, H-5, H-6). Anal. calcd for
C25H25N3O6: C, 64.79; H, 5.44; N, 9.07. Found: C,
64.52; H, 5.73; N, 8.86.
3.11. (ꢀ)-((3aR,6R,6aR)-2,2-Dimethyl-tetrahydro-furo[2,3-
d][1,3]dioxol-6-yl)-methanol (18)
3.9. Acetic acid (2R,3R,4S)-4-acetoxymethyl-2-(4-benz-
oylamino-2-oxo-2H-pyrimidin-1-yl)-tetrahydro-furan-3-
yl ester (16c)
To a solution of 9 (10.0 g, 64.02 mmol) in dry THF (400
mL) was added 9-BBN (512 mL, 256 mmol, 0.5 M
solution in THF) dropwise at 0 ꢁCand the reaction
mixture was stirred at the same temperature for 3 h. A
solution of sodium perborate (59.0 g, 384.12 mmol) in
water (170 mL) were added to the mixture and this
mixture was stirred at room temperature overnight,
extracted with EtOAc, dried over anhydrous MgSO4,
filtered, and evaporated. The residue was purified by
silica gel column chromatography (hexane:ethyl ace-
tate=2:1) to give 18 (7.8 g, 70%) as a white solid:
[a]D25=ꢀ34.2ꢁ (c 1.11, CHCl3); 1H NMR (CDCl3) d 1.34
(s, 3H, CH3), 1.53 (s, 3H, CH3), 2.09 (t, 1H, J=5.6 Hz,
OH), 2.30–2.36 (m, 1H, 6-H), 3.85–3.90 (m, 3H, 5-Ha,
HOCH2), 4.96 (t, 1H, J=8.0 Hz, 5-Hb), 4.73 (t, 1H,
J=4.0 Hz, 6a-H), 5.87 (d, 1H, J=3.6 Hz, 3a-H); 13C
NMR (CDCl3) d 26.4, 26.7, 46.1, 59.1, 68.0, 81.2, 106.5,
122.2. Anal. calcd for C8H14O4: C, 55.16; H, 8.10.
Found: C, 55.20; H, 8.23.
To a solution of 15a (0.96 g, 2.08 mmol) in anhydrous
methylene chloride (15 mL) was added boron trichloride
(20 mL, 20.0 mmol, 1.0 M solution in methylene chlo-
ride) at ꢀ78 ꢁCand the mixture was stirred at the same
temperature for 2 h. The reaction mixture was quenched
with methanol, neutralized with pyridine and evapo-
rated. Without further purification, the residue was dis-
solved in pyridine (15 mL) and acetic anhydride (4 mL,
41.6 mmol) at 0 ꢁCand the reaction mixture was stirred
at room temperature overnight and evaporated. The
residue was partitioned between methylene chloride and
water, and the organic layer was washed with dilute
HCl, dried over anhydrous MgSO4, filtered, and eva-
porated. The residue was purified by silica gel column
chromatography (methylene chloride:methanol=40:1)
to give 16c (0.45 g, 52%) as a white solid: UV (CH2Cl2)
lmax 259 nm; 1H NMR (CDCl3) d 1.99 (s, 3H,
OCOCH3), 2.09 (s, 3H, OCOCH3), 2.77–2.84 (m, 1H, 4-
H), 3.96 (t, 1H, J=9.2 Hz, 5-Ha), 4.01 (dd, 1H, J=7.2,
11.2 Hz, AcOCHH), 4.21 (dd, 1H, J=7.2, 11.2 Hz,
AcOCHH), 4.45 (t, 1H, J=8.4 Hz, 5-Hb), 5.66 (dd, 1H,
J=1.6, 5.6 Hz, 3-H), 5.82 (d, 1H, J=1.6 Hz, 2-H), 7.45
(br t, 2H, J=7.2, meta’s H), 7.54–7.56 (m, 2H, para’s H,
H-5), 7.74 (d, 1H, J=7.6 Hz, H-6), 7.90 (br d, 2H, J=8.0
Hz, ortho’s H). Anal. calcd for C20H21N3O7: C, 57.83;
H, 5.10; N, 10.12. Found: C, 58.00; H, 5.12; N, 9.99.
3.12. (ꢀ)-(3aR,6R,6aR)-6-Benzyloxymethyl-2,2-dimethyl-
tetrahydro-furo[2,3-d][1,3] dioxole (19)
To a suspension of 60% NaH (273 mg, 6.82 mmol) and
n-Bu4NI (140 mg, 0.37 mmol) in anhydrous THF (20
mL) was added a solution of 18 (645 mg, 3.79 mmol) in
anhydrous THF (5 mL) slowly at 0 ꢁCand the reaction
mixture was stirred 0 ꢁCfor 20 min and then at room
temperature for 30 min. After cooled to 0 ꢁC, the reac-
tion mixture was treated with benzyl bromide (0.49 mL,
4.16 mmol). The reaction mixture was stirred at room
temperature overnight and partitioned between EtOAc
and water. The organic layer was dried over anhydrous
MgSO4, filtered, and evaporated. The residue was pur-
ified by silica gel column chromatography (hexane:ethyl
acetate=4:1) to give 19 (880 mg, 90%) as a yellowish
3.10. (ꢀ)-4-Amino-1-((2R,3R,4S)-3-hydroxy-4-hydroxy-
methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (4)
To a solution of 16c (450 mg, 1.08 mmol) in methanol
(20 mL) and methylene chloride (5 mL) was added
potassium carbonate (600 mg, 4.33 mmol) at ꢀ5 ꢁCand
the reaction mixture was stirred at the same temperature
for 40 min. After neutralized with acetic acid, the reac-
tion mixture was filtered through a short pad of silica
gel and Celite, and evaporated. The residue was purified
by silica gel column chromatography (methylene chlor-
ide:methanol=30:1) to give 17 (250 mg, 70%) as a
white solid: UV (MeOH) lmax 258 nm; 1H NMR
(CD3OD) d 2.32–2.38 (m, 1H, 4-H), 3.70 (dd, 1H,
J=6.8, 10.8 Hz, HOCHH), 3.88 (dd, 1H, J=6.8, 10.8
Hz, HOCHH), 4.03 (dd, 1H, J=8.4, 10.8 Hz, 5-Ha),
4.38 (d, 1H, J=4.4 Hz, 3-H), 4.49 (t, 1H, J=8.4 Hz, 5-
oil: [a]2D5=ꢀ27.9ꢁ (c 2.26, CHCl3); H NMR (CDCl3) d
1
1.31 (s, 3H, CH3), 1.48 (s, 3H, CH3), 2.41–2.46 (m, 1H,
6-H), 3.51 (dd, 1H, J=7.6, 9.2 Hz, BnOCHH), 3.69 (dd,
1H, J=8.0, 11.2 Hz, 5-Ha), 3.78 (dd, 1H, J=7.2, 9.2
Hz, BnOCHH), 4.01 (dd, 1H, J=7.2, 8.4 Hz, 5-Hb),
4.50 (d, 1H, J=12.0 Hz, benzylic Ha), 4.54 (d, 1H,
J=12.0 Hz, benzylic Hb), 4.64 (t, 1H, J=3.6 Hz, 6a-H),
5.83 (d, 1H, J=3.6 Hz, 3a-H), 7.28–7.34 (m, 5H, Ph).
Anal. calcd for C15H20O4: C, 68.16; H, 7.63. Found: C,
68.40; H, 7.74.

D. Z. Jin et al. / Bioorg. Med. Chem. 12 (2004) 1101–1109
1107
3.13. (2RS,3R,4R)-4-Benzyloxymethyl-2-methoxy-tetra-
hydro-furan-3-ol (20)
room temperature for 2 d. After the reaction mixture
was partitioned between water and EtOAc, the organic
layer was washed with saturated aqueous NaHCO3
solution, dried, filtered, and evaporated. The residue
was purified by silica gel column chromatography (hex-
ane:ethyl acetate=2:1) to give 22 (5.3 g, recovery yield:
A solution of 19 (880 mg, 3.33 mmol) and p-TsOH (317
mg, 1.66 mmol) in methanol (30 mL) was stirred at room
temperature for 2 d. The reaction mixture was neu-
tralized with triethylamine and evaporated. The residue
was purified by silica gel column chromatography (hex-
ane:ethyl acetate=3:1) to give 20 (770 mg, 97%) as a
1
95%) as a colorless oil: H NMR (CDCl3) d 2.55–2.62
(m, 1H, major’s 4-H), 2.83–2.91 (m, 1H, minor’s 4-H),
3.45 (dd, 1H, J=4.4, 9.2 Hz, major’s BnOCHH), 3.53
(dd, 1H, J=7.6, 9.2 Hz, minor’s BnOCHH), 3.65 (dd,
1H, J=4.0, 9.2 Hz, major BnOCHH), 3.74–3.80 (m,
2H, minor’s BnOCHH, 5-Ha), 3.89 (dd, 1H, J=6.4, 8.8
Hz, major’s 5-Ha), 3.93–3.98 (m, 2H, major’s 5-Hb,
minor’s 5-Hb), 4.04 (dd, 1H, J=4.0, 8.4 Hz, major’s 3-
H), 4.17 (t, 1H, J=8.0 Hz, minor’s 3-H), 4.50–4.56 (m,
6H, major’s benzylic Ha, Hb, Hc, minor’s Ha, Hb, Hc),
4.62 (d, 1H, J=12.0 Hz, minor’s benzylic Hd), 4.69 (d,
1H, J=12.0 Hz, major’s benzylic Hd), 5.28 (br d, 1H,
J=3.2 Hz, major’s 2-H), 5.38 (s, 1H, minor’s 2-H),
7.24–7.34 (m, 20H, major’s 2*Ph, minor’s 2*Ph). Anal.
calcd for C19H22O4: C, 72.59; H, 7.05. Found: C, 72.44;
H, 7.23.
1
colorless oil: H NMR (CDCl3) d 2.68–2.75 (m, 1H, 3-
H), 3.32 (s, 3H, OCH3), 3.68–3.71 (m, 2H, BnOCH2),
3.86 (t, 1H, J=8.4 Hz, 5-Ha), 4.01 (t, 1H, J=8.8 Hz, 5-
Hb), 4.21 (t, 1H, J=4.8 Hz, 3-H), 4.50 (d, 1H, J=12.0
Hz, benzylic Ha), 4.55 (d, 1H, J=12.0 Hz, benzylic Hb),
4.81 (s, 1H, 2-H), 7.28–7.34 (m, 5H, Ph). Anal. calcd for
C13H18O4: C, 65.53; H, 7.61. Found: C, 65.85; H, 7.71.
3.14. (2RS,3R,4R)-3-Benzyloxy-4-benzyloxymethyl-2-
methoxy-tetrahydro-furan (21)
To a suspension of 60% NaH (1.36 g, 34.0 mmol) and
n-Bu4NI (0.7 g, 1.89 mmol) in anhydrous THF (35 mL)
was added a solution of 20 (4.5 g, 18.89 mmol) in
anhydrous THF (15 mL) slowly at 0 ꢁCand the reaction
mixture was stirred 0 ꢁCfor 20 min and then at room
temperature for 30 min. After cooled to 0 ꢁC, the reac-
tion mixture was treated with benzyl bromide (0.49 mL,
4.16 mmol). The reaction mixture was stirred at room
temperature overnight and partitioned between EtOAc
and water. The organic layer was dried over anhydrous
MgSO4, filtered, and evaporated. The residue was pur-
ified by silica gel column chromatography (hexane:ethyl
acetate=6:1) to give 21 (6.1 g, 98%) as a colorless oil.
3.18. (2RS,3R,4R)-3-Benzyloxy-4-benzyloxymethyl-
tetrahydro-furan-2-yl ester (23)
To a solution of 22 (5.3 g, 16.86 mmol) in pyridine (25
mL) was added acetic anhydride (5.2 mL, 50.58 mmol)
at 0ꢁCand the reaction mixture was stirred at room
temperature overnight, and evaporated. The residue was
purified by silica gel column chromatography (hex-
ane:ethyl acetate=4:1) to give 23 (5.6 g, 93%) as a col-
1
orless oil: H NMR (CDCl3) d 2.01 (s, 3H, OCOCH3),
2.55–2.65 (m, 1H, 4-H), 3.54 (dd, 1H, J=7.2, 8.8 Hz,
BnOCHH), 3.75 (dd, 1H, J=7.2, 8.8 Hz, BnOCHH),
3.82 (dd, 1H, J=8.0, 9.6 Hz, 5-Ha), 4.01 (d, 1H, J=5.2
Hz, 3-H), 4.20 (t, 1H, J=8.0 Hz, 5-Hb), 4.49 (d, 2H,
J=1.6 Hz, benzylic CH2), 4.53 (d, 1H, J=12.4 Hz,
benzylic Ha), 4.71 (d, 1H, J=12.4 Hz, benzylic Hb), 6.22
(s, 1H, 2-H), 7.27–7.32 (m, 10H, 2*Ph). Anal. calcd for
C21H24O5: C, 70.77; H, 6.79. Found: C, 70.47; H, 6.81.
3.15. Major isomer
1H NMR (CDCl3) d 2.79–2.86 (m, 1H, 4-H), 3.32 (s,
3H, OCH3), 3.55 (dd, 1H, J=7.6, 9.2 Hz, BnOCHH),
3.77 (dd, 1H, J=6.8, 9.2 Hz, BnOCHH), 3.82 (t, 1H,
J=8.4 Hz, 5-Ha), 3.96 (d, 1H, J=5.2 Hz, 3-H), 4.08 (t,
1H, J=8.4 Hz, 5-Hb), 4.51 (s, 2H, benzylic CH2), 4.53
(d, 1H, J=12.0 Hz, benzylic Ha), 4.63 (d, 1H, J=12.0
Hz, benzylic Hb), 4.92 (s, 1H, 2-H), 7.28–7.34 (m, 10H,
2*Ph). Anal. calcd for C20H24O4: C, 73.15; H, 7.37.
Found: C, 73.10; H, 7.73.
3.19. (+)-N-[1-((2S,3R,4R)-3-Benzyloxy-4-benzyloxy-
methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyr-
imidin-4-yl]-benzamide (24a) and (ꢀ)-N-[1-((2R,3R,4R)-
3-Benzyloxy-4-benzyloxymethyl-tetrahydro-furan-2-yl)-
2-oxo-1,2-dihydro-pyrimidin-4-yl]-benzamide (24b)
3.16. Minor isomer
1H NMR (CDCl3) d 2.58–2.67 (m, 1H, 4-H), 3.36 (s,
3H, OCH3), 3.63 (dd, 1H, J=9.2, 9.6 Hz, BnOCHH),
3.78 (dd, 1H, J=4.8, 9.2 Hz, BnOCHH), 3.90 (dd, 1H,
J=4.8, 9.2 Hz, 5-Ha), 3.95 (dd, 1H, J=4.8, 8.8 Hz, 3-
H), 4.00 (t, 1H, J=8.8 Hz, 5-Hb), 4.47 (s, 2H, benzylic
CH2), 4.55 (d, 1H, J=12.4 Hz, benzylic Ha), 4.60 (d,
1H, J=12.4 Hz, benzylic Hb), 4.76 (d, 1H, J=4.4 Hz, 2-
H), 7.25–7.31 (m, 10H, 2*Ph). Anal. calcd for
C20H24O4: C, 73.15; H, 7.37. Found: C, 73.29; H, 7.11.
A suspension of N4-benzoylcytosine (6.0 g, 27.88 mmol)
and ammonium sulfate (catalytic amount) in hexa-
methyldisilazane (HMDS, 40 mL) was heated at 150–
160 ꢁCovernight to give a clear solution. The reaction
mixture was cooled to room temperature and HMDS
was removed under anhydrous condition in vacuo. To a
solution of the residue in dry dichloroethane (40 mL)
was added a solution of 23 (5.6 g, 15.71 mmol) in dry
dichloroethane (10 mL) and TMSOTf (5.7 mL, 31.42
mmol) at ꢀ30 ꢁCand the reaction mixture was stirred at
the same temperature for 1 h. After quenched with
saturated aqueous NaHCO3 solution, the reaction mix-
ture was filtered through a pad of Celite and the filtrate
was partitioned between methylene chloride and water.
The organic layer was dried over anhydrous MgSO4,
3.17. (2RS,3R,4R)-3-Benzyloxy-4-benzyloxymethyl-
tetrahydro-furan-2-ol (22)
A solution of 21 (6.4 g, 19.48 mmol) in aqueous 8 N
HCl (22mL) and 1,4-dioxane (44 mL) was stirred at

1108
D. Z. Jin et al. / Bioorg. Med. Chem. 12 (2004) 1101–1109
filtered, and evaporated. The residue was purified by
silica gel column chromatography (methylene chlor-
ide:methanol=20:1) to give b-isomer 24a (1.8 g, 22%)
as a white solid and a-isomer 24b (3.4 g, 43%) as a
white solid.
3.60 (dd, 1H, J=7.2, 10.8 Hz, BnOCHH), 3.78 (dd, 1H,
J=7.2, 10.8 Hz, BnOCHH), 3.94 (dd, 1H, J=8.0, 10.4
Hz, 5-Ha), 4.28 (d, 1H, J=4.8 Hz, 3-H), 4.39 (t, 1H,
J=8.0 Hz, 5-Hb), 5.69 (s, 1H, 2-H), 7.43–7.89 (m, 6H,
Ph, H-5). 8.00 (d, 1H, J=7.6 Hz, H-6). Anal. calcd for
C16H17N3O5: C, 58.00; H, 5.17; N, 12.68. Found: C,
57.82; H, 5.46; N, 12.81.
b-isomer 24a: mp 127 ꢁC ; UV (C HCl2) lmax 258 nm;
2
[a]2D5=+89.1o (c 0.92, CHCl3); 1H NMR (CDCl3) d
2.78–2.87 (m, 1H, 4-H), 3.49 (dd, 1H, J=6.8, 9.2 Hz,
BnOCHH), 3.66 (dd, 1H, J=8.0, 9.2 Hz, BnOCHH),
3.88 (dd, 1H, J=8.0, 11.2 Hz, 5-Ha), 4.16 (t, 1H, J=8.0
Hz, 5-Hb), 4.22 (d, 1H, J=11.6 Hz, benzylic Ha), 4.34
(d, 1H, J=11.6 Hz, benzylic Hb), 4.46 (s, 2H, benzylic
CH2), 4.47 (t, 1H, J=4.0 Hz, 3-H), 6.15 (d, 1H, J=3.2
Hz, 2-H), 7.01–7.53 (m, 15H, 3*Ph), 7.60 (d, 1H, J=7.2
Hz, H-5), 7.88 (d, 1H, J=7.2 Hz, H-6). Anal. calcd for
C30H29N3O5: C, 70.43; H, 5.71; N, 8.21. Found: C,
70.26; H, 5.99; N, 8.04.
3.22. (+)-4-Amino-1-((2S,3R,4R)-3-hydroxy-4-hydroxy-
methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (5)
To a solution of 25a (36 mg, 0.10 mmol) in methanol (2
mL) was added 0.1 M NaOMe solution (0.2 mL, 0.02
mmol) and the reaction mixture was stirred at room
temperature overnight. After neutralized with acetic
acid, the reaction mixture was evaporated and the resi-
due was purified by silica gel column chromatography
(methylene chloride:MeOH=3:1) to give 5 (24 mg,
97%) as a white solid followed after crystallization from
diethyl ether and methanol: mp 228 ꢁC ; MSm/z 228
(M++1); UV (MeOH) lmax 273 nm; [a]2D5=+120.0ꢁ (c
0.2, MeOH); 1H NMR (CD3OD) d 2.61–2.68 (m, 1H, 4-
H), 3.66 (dd, 1H, J=6.8, 10.8 Hz, HOCHH), 3.87 (dd
1H, J=6.8, 10.8 Hz, HOCHH), 3.93 (dd, 1H, J=7.6,
11.2 Hz, 5-Ha), 4.12 (t, 1H, J=7.6 Hz, 5-Hb), 4.40 (dd,
1H, J=2.8, 4.8 Hz, 3-H), 5.86 (d, 1H, J=7.2 Hz, H-5),
6.00 (d, 1H, J=2.8 Hz, 2-H), 7.63 (d, 1H, J=7.2 Hz, H-
6); 13CNMR (CD 3OD) d 47.7, 59.9, 71.0, 71.3, 91.0,
94.6, 144.5, 158.4, 167.8. Anal. calcd for C9H13N3O4: C ,
47.57; H, 5.77; N, 18.49. Found: C, 47.56; H, 5.90; N,
18.31.
a-isomer 24b: UV (C HCl2) lmax 258 nm; [a]25=ꢀ62.8ꢁ
2
D
1
(c 0.35, CHCl3); H NMR (CDCl3) d 2.35–2.42 (m, 1H,
4-H), 3.56 (dd, 1H, J=7.2, 8.8 Hz, BnOCHH), 3.68 (dd,
1H, J=6.8, 8.8 Hz, BnOCHH), 4.05 (dd, 1H, J=4.4,
11.6 Hz, 5-Ha), 4.17 (d, 1H, J=4.8 Hz, 3-H), 4.42 (s,
2H, benzylic CH2), 4.44 (t, 1H, J=8.8 Hz, 5-Hb), 4.79
(d, 1H, J=12.0 Hz, benzylic Ha), 4.97 (d, 1H, J=12.0
Hz, benzylic Hb), 6.05 (s, 1H, 2-H), 7.22–7.92 (m, 17H,
3*Ph, H-5, H-6). Anal. calcd for C30H29N3O5: C, 70.43;
H, 5.71; N, 8.21. Found: C, 70.38; H, 5.60; N, 8.34.
3.20.
(+)-N-[1-((2S,3R,4R)-3-Hydroxy-4-hydroxy-
methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyr-
imidin-4-yl]-benzamide (25a)
3.23. (ꢀ)-4-Amino-1-((2R,3R,4R)-3-hydroxy-4-hydroxy-
methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (5a)9a
To a solution of 24a (82 mg, 0.15 mmol) in anhydrous
methylene chloride (5 mL) was added boron trichloride
(1.6 mL, 1.6 mmol, 1.0 M solution in methylene chlo-
ride) at ꢀ78 ꢁCand the reaction mixture was stirred at
the same temperature for 30 min. After quenched with
methanol and neutralized with pyridine, the volatile
materials were evaporated. The resulting residue was
purified by silica gel column chromatography (methyl-
ene chloride:MeOH=15:1) to give 25a (36 mg, 68%) as
a white solid: mp 202 ꢁC; UV (MeOH) lmax 257 nm;
Compound 25b (19 mg, 0.05 mmol) was converted to
compound 5a (11 mg, 81%) as a white solid according
to the same procedure used in the preparation of 5: MS
m/z 228 (M++1); UV (MeOH) lmax 273 nm;
[a]2D5=ꢀ87.5ꢁ (c 0.08, MeOH); H NMR (CD3OD) d
1
2.25–2.33 (m, 1H, 4-H), 3.65 (dd, 1H, J=7.2, 10.8 Hz,
HOCHH), 3.83 (dd, 1H, J=7.2, 10.8 Hz, HOCHH),
3.93 (dd, 1H, J=8.0, 10.8 Hz, 5-Ha), 4.25 (d, 1H, J=4.8
Hz, 3-H), 4.35 (t, 1H, J=2.8, 8.0 Hz, 5-Hb), 5.66 (s, 1H,
2-H), 5.87 (d, 1H, J=7.6 Hz, H-5), 8.00 (d, 1H, J=7.6
Hz, H-6); 13CNMR (CD 3OD) d 44.6, 59.4, 73.0, 76.8,
95.7, 96.1, 141.7, 158.4, 168.0. Anal. calcd for
C9H13N3O4: C, 47.57; H, 5.77; N, 18.49. Found: C,
47.35; H, 5.92; N, 18.27.
[a]2D5=+91.9ꢁ (c 0.37, CHCl3); H NMR (CD3OD) d
1
2.61–2.68 (m, 1H, 4-H), 3.64 (dd, 1H, J=6.8, 10.8 Hz,
BnOCHH), 3.85 (dd, 1H, J=6.8, 10.8 Hz, BnOCHH),
3.96 (dd, 1H, J=8.0, 11.2 Hz, 5-Ha), 4.14 (t, 1H, J=8.0
Hz, 5-Hb), 4.47 (t, 1H, J=4.0 Hz, 3-H), 6.03 (d, 1H,
J=2.8 Hz, 2-H), 7.47–7.93 (m, 5H, Ph), 7.54 (d, 1H,
J=7.2 Hz, H-5), 8.04 (d, 1H, J=7.2 Hz, H-6). Anal.
calcd for C16H17N3O5: C, 58.00; H, 5.17; N, 12.68.
Found: C, 57.78; H, 5.53; N, 12.64.
References and notes
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