Synthesis of novel apionucleosides: A short and concise synthesis of 2-deoxyapio-L-furanosyl acetate from D-lactose

Article abstract of DOI:10.1016/S0008-6215(03)00018-1

A series of 2′-deoxyapio-L-furanosyl pyrimidine nucleosides were efficiently synthesized starting from D-lactose via condensation of lactitor acetates with silylated pyrimidine bases under standard Vorbrueggen conditions. Their structures were determined by 1D and 2D NMR spectroscopy. All the synthesized nucleosides were assayed against several viruses such as HIV-1, HBV, HSV-1, HSV-2, and HCMV. However, none of these compounds had any significant antiviral activity at concentrations up to 100 μM.

Full text of DOI:10.1016/S0008-6215(03)00018-1

Carbohydrate Research 338 (2003) 705–710
www.elsevier.com/locate/carres
Synthesis of novel apionucleosides: a short and concise synthesis
of 2-deoxyapio- -furanosyl acetate from -lactose
L
D
Jihee Kim, Joon Hee Hong*
College of Pharmacy, Chosun Uni6ersity, Kwangju 501-759, Republic of Korea
Received 3 August 2002; received in revised form 5 November 2002; accepted 4 January 2003
Abstract
A series of 2%-deoxyapio-
L
-furanosyl pyrimidine nucleosides were efficiently synthesized starting from D-lactose via condensation
of lactitor acetates with silylated pyrimidine bases under standard Vorbru¨ggen conditions. Their structures were determined by 1D
and 2D NMR spectroscopy. All the synthesized nucleosides were assayed against several viruses such as HIV-1, HBV, HSV-1,
HSV-2, and HCMV. However, none of these compounds had any significant antiviral activity at concentrations up to 100 mM.
© 2003 Elsevier Science Ltd. All rights reserved.
Keywords: Apionucleoside; 2-Deoxyapiose; Vorbru¨ggen condition
1. Introduction
biological activities. In other approaches, more funda-
mental modifications to the pentofuranose moiety, re-
sulting in isonucleosides and apionucleosides, have been
reported to be compatible with antiviral activities.16
The transposition of the base moiety to C-2% or the C-4%
hydroxymethyl group to C-3% leads to isonucleosides
and apionucleosides, respectively. In attempts to dis-
cover new lead compounds with an improved biological
activity, a number of apiosyl-nucleosides with several
kinds of functional groups in the 3%-position were syn-
thesized in previous studies.17 In this paper, a very short
The discovery of novel nucleosides as antiviral and
anticancer agents has been the goal of nucleoside
chemists for decades. In particular, since the emergence
of the HIV pandemic, extensive effort have been con-
centrated on various modifications in the sugar moiety
of nucleosides, resulting in FDA approved anti-HIV
agents such as AZT,1 ddC,2 ddI,3 d4T,4 3TC,5 and
Abacavir.6 In addition, several nucleosides as anti-HBV
agents including DAPD,7
which are being developed at various stages, have been
synthesized. Among these compounds, 3TC
L L
-F-ddC,8 and -FMAU,9
and efficient synthetic route for novel 2%-deoxyapioyl-
L-
nucleosides (Fig. 1) from a very cheap and commer-
(lamivudine) is being clinically used as an anti-HIV as
well as anti-HBV agent.10 Although there has been
considerable interest in modifications at the 2%- and
3%-position of the nucleosides, much less is known about
the 4%-modified compounds.11 However, naturally oc-
cially available
reported.
D-lactose and their antiviral activity is
curring antibiotics, nucleocidin12 possessing
a 4%-
fluorine atom, 4%-azido thymidine (ADRT),13
4%-fluorinated carbocyclic nucleoside,14 and the 3%-fluoro
oxetanosin analogue15 have demonstrated a variety of
* Corresponding author. Tel.: +82-62-2306378; fax: +82-
62-2225414
E-mail address: hongjh@mail.chosun.ac.kr (J.H. Hong).
Fig. 1.
0008-6215/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00018-1

706
J. Kim, J.H. Hong / Carbohydrate Research 338 (2003) 705–710
standard Vorbru¨ggen conditions gave separable
2. Results and discussion
stereoisomers, 6 and 9 (Scheme 2) which were separated
by silica gel chromatography and treated with 80%
acetic acidic solution to give the deprotected uracil
derivatives, 12 and 15, respectively. For the synthesis of
the thymine nucleosides, the glycosyl donor 5 was
condensed with persilylated thymine under similar con-
densation conditions to give the anomeric mixtures, 7
and 10, which were difficult to separate by normal silica
gel column chromatography. Without separation, the
anomeric mixture of 7 and 10 was subjected to similar
acidic hydrolysis conditions as described for uracil to
give the separable nucleosides, 13 and 16, respectively.
For the synthesis of the cytosine nucleosides, the key
intermediate 5 was condensed with silylated N4-benzoyl
cytosine under same conditions as described for the
thymine nucleosides to afford the products, 8 and 11.
The anomeric mixtures were easily separated by silica
gel column chromatography. To remove the isopropyli-
dene protecting groups, nucleosides 8 and 11 were
subjected to similar acidic hydrolysis conditions to fur-
In order to reach the key intermediate 5 for the synthe-
sis of the desired nucleosides, commercially available
D-lactose was used as a carbohydrate chiral template
starting material. a-
could be made from
D
-Isosaccharino-1,4-lactone (1)
D-lactose by the well-known
method.18 Following previously described methodolo-
gies we have synthesized lactol derivative 4 (Scheme
1).19 The vicinal diol 1 was protected in a mixed solvent
of 2,2-dimethoxypropane and acetone with a catalytic
amount of p-TsOH to give an isopropylidene protected
2 in an 86% yield. Treatment of 2 with lithium alu-
minum hydride (LiAlH4) in anhydrous THF furnished
3, of which the vicinal diol moiety was readily cleaved
by sodium metaperiodate (NaIO4) to give compound 4
in the cyclized lactol form in a 64% yield for the two
steps. The lactol derivative 4 was acetylated by acetic
anhydride in an anhydrous pyridine solvent to give a
glycosyl donor 5 in a 85% yield.
Condensation of 5 with silylated uracil under the
Scheme 1. Reagents: (i) DMP, PTSA, acetone, rt, 2 h, 86%; (ii) LiAlH4, THF, reflux, overnight, 80%; (iii) NaIO4, MeOH–H2O,
rt, 2 h, 82%; (iv) Ac2O, DMAP, pyridine, rt, overnight, 91%.
Scheme 2. Reagents: (i) persilylated pyrimidine nucleobase, TMSOTf, CH3CN, rt, 4 h, 50–70%; (ii) 80% AcOH, 80 °C, 2–3 h,
40–60%; (iii) NH3–MeOH, rt, overnight, 85–90%.

J. Kim, J.H. Hong / Carbohydrate Research 338 (2003) 705–710
707
nish 14 and 17, respectively. The free nucleosides 18
and 19 were obtained by treatment under debenzoyla-
tion conditions using saturated methanolic ammonia.
Stereochemical assignments of the synthesized com-
pounds were determined on the basis of 1H NMR
spectroscopy. A cross peak was found in the NOESY
spectrum for 18 between proximal hydrogen atoms
(H-6 and H-3¦b). However, there were no cross peaks
in the spectrum for 19. It should be noted that the
synthetic route of the enantiomers of 12, 13 and 18 has
been previously reported.20 As a result, the structures of
the synthesized nucleosides were readily determined by
a comparisons of the optical rotation values and their
NMR spectra.
MgSO4. Removal of solvent gave a syrup, which was
purified by silica gel column chromatography (1:1.5
hexane–EtOAc) to give compound 2 (24.4 g, 98%) as a
white solid: mp 54.5 °C; [h]2D5 +42.2° (c 1.0, CHCl3)
1
{Lit.19 mp 56 °C; [h]D +43° (c 1.0, CHCl3)}; H NMR
(CDCl3) l 6.71 (m, 1 H, H-4), 4.35 (d, J 9.3 Hz, 1 H,
H-5), 4.13 (d, J 9.0 Hz, 1 H, H-5), 4 00 (d, J 12.3 Hz,
1 H, H-2%), 3. 63 (d, J 17.7, 1 H, H-2%), 2.46 (dd, J 14.1,
7.5 Hz, 1 H, H-3%a), 2.35 (dd, J 13.8, 6.6 Hz, 1 H,
H-3%b), 1.49 (s, 3 H, CH3), 1.45 (s, 3 H, CH3).
3.3. 3-Deoxy-2-C-hydroxymethyl-2,2%-O-isopropylidene-
D-glycero-pentitol (3)
In summary, a very efficient synthetic route for novel
To a solution of 2 (1.0 g, 4.92 mmol) in dry THF (10
mL), LiAlH4 was added in small portions at 0 °C. The
mixture was stirred overnight at rt and an excess of
LiAlH4 was destroyed by the sequential addition of
water (0.4 mL), and 10% NaOH (0.6 mL) and water
(1.2 mL). After filtering the slurry mixture through a
pad of Celite, it was washed several times with MeOH.
The combined filtrate was concentrated under reduced
pressure to give a crude triol 3 as a syrup (0.88 g, 82%),
which was subjected to the subsequent reaction without
further purification. For the purpose of spectroscopic
analyses, a small amount of crude 3 was acetylated
under the standard conditions (Ac2O, DMAP, Py). This
product was described as its tri-O-acetylated derivative
3% as an oil, which was purified by silica gel column
chromatography (2:1 hexane–EtOAc): 3%: [h]2D5 −16.4°
(c 1.0, CHCl3) {Lit.19 syrup; [h]D −16° (c 1.0,
2%-deoxyapio-L-furanosyl nucleosides starting from very
cheap and commercially available
D-lactose was devel-
oped. All the synthesized compounds were tested
against several viruses such as HIV-1 (MT-4 cells),
HBV, HSV-1,2 (CCL18 cells), and HCMV (AD-169
and Davis cells). However, none of these compounds
had any significant antiviral activity up to 100 mM.
3. Experimental
3.1. General
The melting points were determined on a Mel-temp II
laboratory device and were uncorrected. The NMR
spectra were recorded on a Bruker 300 Fourier trans-
form spectrometer; chemical shifts are reported in parts
per million (l) and the signals are quoted as s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet) and dd
(doublet of doublets). The UV spectra were obtained
using a Beckman DU-7 spectrophotometer. The optical
rotations were measured on an Autopol-IV digital po-
larimeter. Elemental analyses were performed in the
Korea Basic Science Institute (KBSI). Thin layer chro-
matography (TLC) was performed on Uniplates (silica
gel) purchased from Analtech Co. Dry 1,2-dichloro-eth-
ane, CH2Cl2, MeCN, C6H6 and Py were distilled from
CaH2 prior to use. Dry THF was obtained by distilla-
tion from Na and benzophenone when the solution
became purple.
1
CHCl3)}; H NMR (CDCl3) l 5.25 (m, 1 H, H-4), 4.34
(dd, J 12.0, 3.5 Hz, 1 H, H-5), 4.14–3.94 (m, 3 H, H-1
and H-2%a), 3 78 (d, J 8.7 Hz, 1 H, H-2%b), 2.19–1.90
(m, 2 H, H-3), 2.09 (s, 3 H, CH3CO), 2.06 (s, 3 H,
acetyl), 2.05 (s, 3 H, acetyl), 1.39 (s, 6 H, 2CH3).
3.4. 3-C-Hydroxymethyl-3,3%-O-isopropylidene-
L-glyc-
ero-tetrose (4)
To a solution of 3 (1.5 g, 7.2 mmol) in MeOH (14 mL),
a solution of sodium periodate (1.87 g, 7.36 mmol) in
water (10 mL) was added slowly at rt. The mixture was
stirred for 1 h and poured into a satd NaHCO3 soln.
The resulting solid was filtered and washed with
MeOH. The combined solution was concentrated, and
the residue was then extracted with EtOAc, washed
with brine, and dried over anhyd magnesium sulfate.
The removal of the solvent gave a syrup, which was
purified by silica gel column chromatography (2:1 hex-
ane–EtOAc) to give a diastereomeric mixture of 4 (1.03
3.2. a-
D-Isosaccharino-1,4-lactone acetonide (2)
a- -Isosaccharino-1,4-lactone (20 g, 0.123 mol) was
D
dissolved in a 1:5 mixture of 2,2%-dimethoxypropane
and acetone (60/300 mL). p-Toluenesulfonic acid
monohydrate (950 mg) was then added to the mixture.
The reaction mixture was stirred 1 h at rt and neutral-
ized with Et3N. The resulting solution was evaporated
under reduced pressure. The residue was extracted with
EtOAc, washed with brine, and dried under anhyd
1
g, 82%) as a syrup: H NMR (CDCl3) l 5.64 (dd, J 4.0,
2.0 Hz, 1 H, H-1), 5.46 (d, J 4.0 Hz, 1 H, H-1),
4.10–3.78 (m, 4 H, H-4 and H-3%), 2.28–2.00 (m, 2 H,
H-2), 1.56 (s, 6 H, 2CH3); Anal. Calcd for C8H14O4: C,
55.16; H, 8.10. Found: C, 54.89; H, 8.36.

708
J. Kim, J.H. Hong / Carbohydrate Research 338 (2003) 705–710
3.5. 1-O-Acetyl-3-C-hydroxymethyl-3,3%-O-isopropyli-
dene- -glycero-tetrose (5)
H, H-4%), 2.76 (dd, J 13.8, 6.3 Hz, 2 H, H-2%), 1.42 (s, 6
H, 2CH3); Anal. Calcd for C12H16N2O5: C, 53.73; H,
6.01; N, 10.44. Found: C, 53.78; H, 6.10; N, 10.45.
L
Compound 4 (1.0 g, 5.74 mmol) was dissolved in anhyd
Py (10 mL). To this solution, DMAP (20 mg) and Ac2O
(0.81 mL, 8.6 mmol) was added drop wise at 0 °C. The
mixture was stirred for 4 h at rt and was added cold
water (1 mL) was then added. The solvent was concen-
trated under reduced pressure and coevaporated with
toluene twice. The residue was extracted with EtOAc,
washed with brine, and dried (MgSO4). Removal of
solvent gave a syrupy residue, which was purified by
silica gel column chromatography (5:1 hexane–EtOAc)
to give diastereomeric mixture of 5 (1.05 g, 85%) as an
3.7. 1-[3-C-Hydroxymethyl-3,3%-O-isopropylidene-b-
glycero-tetrafuranosyl] thymine (7) and 1-[3-C-hydrox-
L-
ymethyl-3,3%-O-isopropylidene-a- -glycero-tetrafuranosyl
L
] thymine (10)
As a diastereomeric mixture, compound 7 and 10 were
prepared by the same procedure as described for 6 and
9: 1H NMR (CDCl3) l 11.28 (br s, 2 H, ꢀ2NH), 7.76 (s,
1 H, H-6), 7.49 (s, 1 H, H-6), 6.18 (t, J 7.5, Hz, 1 H,
H-1%), 6.00 (dd, J 7.0, 4.5 Hz, 1 H, H-1%), 4.19 (d, J 8.7
Hz, 1 H, H-4%), 3.90 (d, J 8.7 Hz, H-4%), 3.78 (d, J 9.0
Hz, 1 H, H-4%), 3.63 (d, J 9.0 Hz, H-4%), 3.42 (s, 2 H,
H-3¦), 3.34 (s, 2 H, H-3¦), 2.48 (m, 2 H, H-2%), 2.04 (m,
2 H, H-2%), 1.45 (s, 6 H, 2CH3), 1.37 (s, 6 H, 2CH3);
Anal. Calcd for C13H18N2O5: C, 55.31; H, 6.43; N, 9.92.
Found: C, 55.49; H, 6.21; N, 9.88.
1
oil: H NMR (CDCl3) l 6.36 (d, J 3.9 Hz, 0.3 H, H-1),
6.26 (t, J 4.2 Hz, 0.7 H, H-1), 4.13–3.86 (m, 4 H, H-4
and H-3%), 2.55 (dd, J 14.4, 6.0 Hz, 0.6 H, H-2), 2.17 (d,
J 4.8 Hz, 1.4 H, H-2), 2.09 (s, 2.1 H, CH3CO), 2.01 (s,
0.9 H, H-2, CH3CO), 1.37 (s, 4.2 H, CH3), 1.29 (s, 1.8
H, CH3); Anal. Calcd for C10H16O5: C, 55.55; H, 7.46.
Found: C, 55.67; H, 7.35.
3.8. N4-Benzoyl-1-[3-C-hydroxymethyl-3,3%-O-isopropy-
3.6. 1-[3-C-Hydroxymethyl-3,3%-O-isopropylidene-b-
L-
lidene-b-L
-glycero-tetrafuranosyl] cytosine (8) and N4-
glycero-tetrafuranosyl] uracil (6) and 1-[3-C-hydrox-
benzoyl-1-[3-C-hydroxymethyl-3,3%-O-isopropylidene-a-
glycero-tetrafuranosyl] cytosine (11)
L-
ymethyl-3,3%-O-isopropylidene-a- -glycero-tetrafuranosyl
L
] uracil (9)
The cytosine derivative 8 and 11 was prepared using the
same method as described for the synthesis of 6 and 9;
The suspension of uracil (233 mg, 2.08 mmol), HMDS
(15 mL), and (NH4)2SO4 (20 mg, catalytic amount) was
refluxed under a nitrogen atmosphere for 4 h and the
excess HMDS was removed under high vacuum. To the
residue, dry MeCN (5 mL), a solution of the acetates 5
(374 mg, 1.73 mmol) in dry MeCN (15 mL), and
Me3SiOTf (0.4 mL, 1.92 mmol) was added at rt and the
resulting reaction mixture was stirred for 1 h at rt.
Saturated NaHCO3 (5 mL) was added to the reaction
mixture and then stirred for another 30 min, which was
extract with methylene chloride (10 mL×2). The com-
bined organic layer was washed with brine and dried
over anhyd MgSO4, filtered, and concentrated under
vacuum. The residue of the anomeric mixture was
separated by silica gel column chromatography (1:3
hexane–EtOAc) to give 6 (136.6 mg, 30%) and 9 (150
mg, 33%), respectively. 6 [h]2D5 +31.4° (c 0.23, MeOH);
1H NMR (CDCl3) l 8.31 (br s, 1 H, ꢀNH), 7.70 (d, J
6.0 Hz, 1 H, H-6), 6.22 (dd, J 7.5, 2.7 Hz, 1 H, H-1%),
5.76 (d, J 8.1 Hz, 1 H, H-5), 4.22 (d, J 9.6 Hz, 2 H,
H-4%), 3.87 (d, J 9.6 Hz, 2 H, H-3¦), 2.57 (dd, J 15.0, 7.5
Hz, 1 H, H-2%), 2.29 (dd, J 12.0, 2.4 Hz, 1 H, H-2%), 1.41
(s, 3 H, CH3), 1.37 (s, 3 H, CH3); Anal. Calcd for
C12H16N2O5: C, 53.73; H, 6.01; N, 10.44. Found: C,
53.69; H, 6.13; N, 10.37; 9 [h]2D5 +11.1° (c 0.27,
1
8: yield: 37%; [h]2D5 −34.8° (c 0.4, MeOH); H NMR
(CDCl3) l 8.09 (d, J 7.5 Hz, 1 H, H-6), 7.91–7.49 (m,
5 H, Ar), 7.54 (d, J 7.5 Hz, 1 H, H-5), 6.22 (dd, J 6.9,
2.1 Hz, 1 H, H-1%), 4.32 (dd, J 9.9, 1.5 Hz, 1 H, H-4%),
4.05 (s, 2 H, H-3¦), 4.01 (d, J 9.9 Hz, 1 H, H-4%), 2.65
(dd, J 14.4, 6.9 Hz, 1 H, H-2%), 2.44 (dd, J 3.6, 1.8 Hz,
1 H, H-2%), 1.39 (s, 3 H, CH3), 2.91 (s, 3 H, CH3); Anal.
Calcd for C19H21N3O5: C, 61.45; H, 5.70; N, 11.31.
Found: C, 61.48; H, 5.61; N, 11.38; 11: yield: 32%; [h]D25
1
+73.2° (c 0.66, MeOH); H NMR (CDCl3) l 7.93–
7.26 (m, 7 H, Ar, H-6 and H-5), 6.1 (t, J 6.3 Hz, 1 H,
H-1%), 4.35 (s, 2 H, H-4%), 4.04 (dd, J 18.0, 9.0 Hz, 2 H,
H-3¦), 3.06 (dd, J 14.1, 6.3 Hz, 1 H, H-2%), 2.20 (dd, J
16.2, 6.0 Hz, 1 H, H-2%), 1.42 (s, 6 H, 2CH3); Anal.
Calcd for C19H21N3O5: C, 61.45; H, 5.70; N, 11.31.
Found: C, 61.64; H, 5.56; N, 11.25.
3.9. 1-[3-C-(Hydroxymethyl)-3-deoxy-3-hydroxy-b-
erythro-tetrafuranosyl] uracil (12)
L-
To the compound 6 (100 mg, 0.37 mmol), 80% AcOH
soln (3 mL) was added, and stirred for 6 h, at 80 °C.
The solvent was concentrated and coevaporated with
toluene twice and the residue was purified by silica gel
column chromatography (10:1 CH2Cl2–MeOH) to give
compound 12 (54.4 mg, 64%) as a white solid: mp
140–143 °C; UV (MeOH) umax 270.5 nm; [h]2D5 −13.2°
(c 0.8, MeOH)) {Lit.20 mp 135–137 °C; [h]2D0 +12.42°
1
MeOH); H NMR (CDCl3) l 8.46 (br s, 1 H, ꢀNH),
7.34 (d, J 8.4 Hz, 1 H, H-6), 6.22 (t, J 6.6 Hz, 1 H,
H-1%), 5.76 (dd, J 8.1, 2.4 Hz, 1 H, H-5), 4.11 (d, J 9.3
Hz, 1 H, H-4%), 4.04 (s, 2 H, H-3¦), 4.01 (d, J 9.3 Hz, 1

J. Kim, J.H. Hong / Carbohydrate Research 338 (2003) 705–710
709
(c 1.30, MeOH) for enantiomer of 12}; 1H NMR
(Me2SO-d6) l 11.21 (br s, 1 H, ꢀNH), 7.73 (d, J 6.1 Hz,
1 H, H-6), 6.25 (dd, J 7.2, 1.8 Hz, 1 H, H-1%), 5.73 (d,
J 8.1 Hz, 1 H, H-5), 3.99 (d, J 9.6 Hz, 2 H, H-4%), 3.87
(d, J 9.6 Hz, 2 H, H-3¦), 2.57 (dd, J 15.0, 7.5 Hz, 1 H,
H-2%), 2.32 (dd, J 12.4, 2.6 Hz, 1 H, H-2%); Anal. Calcd
for C9H12N2O5: C, 47.37; H, 5.30; N, 12.28. Found: C,
47.16; H, 5.32; N, 12.11.
the method described for preparing 12: mp 172–174 °C;
UV (MeOH) umax 267.5 nm; [h]2D5 −23.2° (c 0.7,
MeOH); 1H NMR (Me2SO-d6) l 11.28 (br s, 1 H, ꢀNH,
D2O exchangeable), 7.48 (s, 1 H, H-6), 6.18 (t, J 7.4 Hz,
1 H, H-1%), 5.12–4.96 (br d, 2 H, ꢀOH, D2O exchange-
able), 4.08 (d, J 9.4 Hz, 1 H, H-4%), 3.62 (d, J 9.4 Hz, 1
H, H-4%), 3.34 (m, 2 H, H-3¦), 2.13 (m, 2 H, H-2%), 1.82
(s, 3 H, CH3); Anal. Calcd for C10H14N2O5: C, 49.58;
H, 5.83; N, 11.56. Found: C, 49.36; H, 5.88; N, 11.79.
3.10. 1-[3-C-(Hydroxymethyl)-3-deoxy-3-hydroxy-b-
erythro-tetrafuranosyl] thymine (13)
L-
3.14. N4-Benzoyl-1-[3-C-(hydroxymethyl)-3-deoxy-3-hy-
droxy-a- -erythro-tetrafuranosyl] cytosine (17)
L
The compound 13 was prepared from 7 using the
method described for preparing 12: mp 171–173 °C;
UV (MeOH) umax 266.0 nm; [h]2D5 +7.10° (c 1.0,
MeOH) {Lit.20 mp 169–172 °C; [h]2D0 −6.30° (c 0.09,
The compound 17 was prepared from 11 as described
for the synthesis of 12: mp 167–169 °C; [h]2D5 +26.1° (c
1
0.67, MeOH); H NMR (CDCl3) l 8.15 (d, J 7.2 Hz, 1
1
MeOH) for enantiomer of 13}; H NMR (Me2SO-d6) l
H, H-6), 7.63 (d, J 7.2 Hz, 1 H, H-5), 8.00–7.33 (m, 5
H, Ar), 6.14 (t, J 6.6 Hz, 1 H, H-1%), 4.16 (d, J 9.3 Hz,
1 H, H-4%), 3.76 (d, J 9.0 Hz, 1 H, H-4%), 3.40 (s, 2 H,
H-3¦), 2.47 (dd, J 13.5, 6.0 Hz, 1 H, H-2%), 2.06 (dd, J
14.1, 7.5 Hz, 1 H, H-2%); Anal. Calcd for C16H17N3O5:
C, 48.00; H, 5.17; N, 12.68. Found: C, 47.76; H, 5.31;
N, 12.78.
11.27 (br s, 1 H, ꢀNH, D2O exchangeable), 7.76 (s, 1 H,
H-6), 6.16 (dd, J 7.4, 5.6 Hz, 1 H, H-1%), 5.05 (br s, 2 H,
ꢀOH, D2O exchangeable), 3.89 (d, J 9.6 Hz, 1 H, H-4%),
3.77 (d, J 9.6 Hz, 1 H, H-4%), 3.43 (d, J 7.5 Hz, 2 H,
H-3¦), 2.03 (m, 2 H, H-2%), 1.89 (s, 3 H, CH3); Anal.
Calcd for C10H14N2O5: C, 49.58; H, 5.83; N, 11.56.
Found: C, 49.68; H, 5.69; N, 11.46.
3.15. 1-[3-C-(Hydroxymethyl)-3-deoxy-hydroxy-b-
thro-tetrafuranosyl] cytosine (18)
L-ery-
3.11. N4-Benzoyl-1-[3-C-(Hydroxymethyl)-3-deoxy-3-
hydroxy-b- -erythro-tetrafuranosyl] cytosine (14)
L
Compound 14 (110 mg, 0.33 mmol) was dissolved in 10
mL of a 0.5 M CH3ONa soln and the resulting solution
was stirred 2 h at rt. The reaction mixture was neutral-
ized with cationic amberlite resin (120+) and filtered.
The filtrate was concentrated under reduced pressure
and the residue was purified by column chromatogra-
phy (5:1 CH2Cl2–MeOH) to give 18 as a white solid (61
mg, 82%): mp 170–171 °C; UV (MeOH) umax 271.5 nm;
[h]D25 −37.12° (c 1.6, MeOH) {Lit.20 [h]2D0 +36.23° (c
0.59, MeOH) for enantiomer of 18}; 1H NMR (Me2SO-
d6) l 8.21 (d, J 7.0 Hz, 1 H, H-6), 7.48 (d, J 7.0 Hz, 1
H, H-5), 6.15 (dd, J 7.2, 1.3 Hz, 1 H, H-1%), 4.19 (d, J
9.3 Hz, 1 H, H-4%), 3.83 (d, J 9.1 Hz, 1 H, H-4%), 3.47
(s, 2 H, H-3¦), 2.45 (dd, J 12.7, 6.0 Hz, 1 H, H-2%), 2.11
(dd, J 13.1, 6.1 Hz, 1 H, H-2%); Anal. Calcd for
C9H13N3O4: C, 47.57; H, 5.77; N, 18.49. Found: C,
47.86; H, 5.56; N, 18.73.
Cytosine derivative 14 was prepared using the method
described for preparing 12: mp 176–178 °C; [h]D25
+
1
73.0° (c 1.6, MeOH); H NMR (CDCl3) l 8.17 (d, J 7.2
Hz, 1 H, H-6), 8.00–7.33 (m, 6 H, Ar and H-5), 6.12
(dd, J 7.4, 1.5 Hz, 1 H, H-1%), 4.19 (d, J 9.3 Hz, 1 H,
H-4%), 3.81 (d, J 9.0 Hz, 1 H, H-4%), 3.44 (s, 2 H, H-3¦),
2.49 (dd, J 12.7, 6.0 Hz, 1 H, H-2%), 2.02 (dd, J 14.1, 6.0
Hz, 1 H, H-2%); Anal. Calcd for C16H17N3O5: C, 48.00;
H, 5.17; N, 12.68. Found: C, 47.88; H, 5.09; N, 12.54.
3.12. 1-[3-C-(Hydroxymethyl)-3-deoxy-3-hydroxy-a-
erythro-tetrafuranosyl] uracil (15)
L-
Compound 15 was made from 9 using a similar proce-
dure as described for 12: mp 169–171 °C; UV (MeOH)
1
umax 271.0 nm; [h]2D5 +36.7° (c 0.57, MeOH); H NMR
(Me2SO-d6) l 11.27 (br s, 1 H, ꢀNH), 7.28 (d, J 8.6 Hz,
1 H, H-6), 6.31 (J 6.3 Hz, 1 H, H-1%), 5.79 (dd, J 8.0,
2.6 Hz, 1 H, H-5), 4.10 (d, J 9.7 Hz, 1 H, H-4%), 4.04 (d,
J 9.7 Hz, 1 H, H-4%), 3.98 (d, J 9.5 Hz, 2 H, H-3¦), 2.74
(dd, J 12.6, 6.0 Hz, 2 H, H-2%); Anal. Calcd for
C9H12N2O5: C, 47.37; H, 5.30; N, 12.28. Found: C,
47.55; H, 5.18; N, 12.45.
3.16. 1-[3-C-(Hydroxymethyl)-3-deoxy-3-hydroxy-a-
erythro-tetrafuranosyl] cytosine (19)
L-
Compound 19 was made from 17 using a similar proce-
dure as described for 18: mp 168–170 °C; UV (MeOH)
1
umax 272.5 nm; [h]2D5 +21.7° (c 0.67, MeOH); H NMR
3.13. 1-[3-C-(Hydroxymethyl)-3-deoxy-3-hydroxy-a-
erythro-tetrafuranosyl] thymine (16)
L
-
(Me2SO-d6) l 8.17 (d, J 7.2 Hz, 1 H, H-6), 7.65 (d, J 7.2
Hz, 1 H, H-5), 6.10 (t, J 6.6 Hz, 1 H, H-1%), 4.10 (d, J
9.2 Hz, 1 H, H-4%), 3.77 (d, J 9.2 Hz, 1 H, H-4%), 3.43
(s, 2 H, H-3¦), 2.45 (dd, J 12.0, 6.1 Hz, 1 H, H-2%), 2.06
The thymine derivative 16 was prepared from 10 using

710
J. Kim, J.H. Hong / Carbohydrate Research 338 (2003) 705–710
J.-P.; Cheng, Y.-C. Antimicrob. Agents Chemother. 1995,
39, 979–981.
10. Dienstag, J. L.; Perrillo, R. P.; Schiff, E. R.;
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(dd, J 12.5, 4.2 Hz, 1 H, H-2%); Anal. Calcd for
C9H13N3O4: C, 47.57; H, 5.77; N, 18.49. Found: C,
47.30; H, 5.91; N, 18.22.
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Acknowledgements
This study was supported by a grant of the Ministry
of Health and Welfare, Republic of Korea (01-PJ1-
PG3-21500-0013). We also thank Dr C.-K.L. (Korea
Research Institute of Chemical Technology) for antivi-
ral assays.
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