3′-Selective modification of a 4′,5′-didehydro-5′- deoxy-2′,3′-epoxyuridine using nucleophiles

Article abstract of DOI:10.1016/j.tet.2005.06.053

1-(2,3-Anhydro-5-deoxy-4,5-didehydro-α-l-erythro-pent-4-enofuranosyl) uracil 4 was obtained by the treatment of 5′-iodo-2′,3′- epoxyuridine 5 with LiHMDS in excellent yield. The pyrimidine nucleoside 4 possesses quite unique vinyl epoxide moiety within th

Full text of DOI:10.1016/j.tet.2005.06.053

Tetrahedron 61 (2005) 8499–8504
30-Selective modification of a 40,50-didehydro-50-deoxy-20,30-
epoxyuridine using nucleophiles
b,
Hideki Takasu,a Yoshie Tsuji,b Hironao Sajikib, and Kosaku Hirota
*
*
aMedicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd, 463-10 Kagasuno, Kawauchi, Tokushima 771-0192, Japan
bLaboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
Received 18 May 2005; accepted 13 June 2005
Available online 11 July 2005
Abstract—1-(2,3-Anhydro-5-deoxy-4,5-didehydro-a-L-erythro-pent-4-enofuranosyl)uracil 4 was obtained by the treatment of 50-iodo-20,30-
epoxyuridine 5 with LiHMDS in excellent yield. The pyrimidine nucleoside 4 possesses quite unique vinyl epoxide moiety within the
molecules. The reactions of 4 with a variety of nucleophiles gave 30-substituted pyrimidine nucleosides without the formation of the
corresponding 20-substituted isomers. In the case of NaN3 or PhSH, the corresponding 50-adduct was obtained as a minor product together
with the expected 30-adduct.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In order to develop an entirely regioselective nucleophilic
attack toward the epoxide moiety of 20,30-anhydro nucleo-
sides, we expected the use of a conjugated epoxide with a
double bond such as 4 would lead to a better result. Here we
would like to report the synthesis of 1-(2,3-anhydro-5-
deoxy-4,5-didehydro-a-L-erythro-pent-4-enofuranosyl)ura-
cil (4) and its application to the regioselective synthesis of
30-adducts (2).7
Chemical modification of nucleosides has been very
important for the synthesis of biologically active com-
pounds such as anti-viral agents1 and synthetic oligonucleo-
tide probes.2 A number of modifications of the sugar moiety
in nucleosides have been carried out up to now. Especially,
a wide variety of attempts have been made to devise novel
methodologies to functionalize the 20- and 30-sites of
nucleosides in connection with AZT, a potent anti-HIV
agent. 20,30-Anhydro-b-D-lyxofuranosyl pyrimidine nucleo-
sides (1) first synthesized by Fox et al.,3 are useful key
intermediates for the 20- or 30-modified pyrimidine nucleo-
side analogues. A large number of reactions of 1 with a
variety of nucleophiles have been investigated.4,5 However,
a limitation to these methods is the poor regio-control of 20-
or 30-addition of nucleophiles. Usually, 30-adducts (2) were
obtained as major products together with minor 20-adducts
(3). Although a few reports indicated that 30-adducts (2)
were obtained selectively5, the yields of the 30-adducts were
very low and the existence of unisolable 20-adducts (3) was
suspected. Previously, we have reported the reaction of 1
(RZOH, or OR0) with AlMe3 with a view to the
regioselective 20-attack of the methyl group by the cyclic
coordination effect of AlMe3 between 50- and epoxide-
oxygen, while a mixture of the 30- and 20-adduct (2 and 3)
was obtained6 as well as other reported results.4
2. Results and discussion
The synthesis of 40,50-didehydro-50-deoxy-20,30-epoxyuri-
dine (4) was achieved by treatment of 50-iodo-20,30-
epoxyuridine (5)3c with t-BuOK, an appropriate non-
nucleophilic base, at room temperature (64%), while the
use of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) as a base
gave a complex mixture. After optimization of the reaction
conditions, we finally found the use of LiHMDS, a bulky
and totally non-nucleophilic base, in DMF at 0 8C gave 4 in
92% yield (Scheme 1).
Keywords: Nucleophile; Nucleoside; Adduct.
*
Therefore, the reaction of 4 using a variety of nucleophiles
was investigated. We first carried out the reaction of 4 with
Corresponding authors. Tel.: C81 58 237 3931; fax: C81 58 237 5979;
e-mail: sajiki@gifu-pu.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.053

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H. Takasu et al. / Tetrahedron 61 (2005) 8499–8504
Next, we investigated the reaction of 4 with NaN3 in DMF at
room te0mperature. Similar to the other reactions (entries
1–6), 3 -adduct (6g) was afforded as a major product
together with 50-adduct (8g),8 formed by the nucleophilic
addition onto the 50-position of 4 as a side product (3%)
(Scheme 3 and Table 1, en0try 7). When this reaction was
carried out at 120 8C, the 5 -adduct (8g) was afforded as a
major product (28%) along with 30-adduct (6g) as a minor
product (4%) (Scheme 3). In addition, a similar tendency
was observed in the reaction of 4 with PhSH (Scheme 3
and Table 1, entry 8). In these reactions, formation of a
20-adduct (7) was never observed as well as in other
reactions of 4 with nucleophiles (entries 1–6). Usually, the
30-cation is more stable than the 20-cation owing to the
electron-withdrawing effect of the 10-uracil moiety of
20,30-epoxyuridine derivatives (1) and the formation of
30-adduct (2) was superior to the formation of 20-adduct (3),
although the effect is not enough to perform the
regioselective 30-nucleophilic addition. On the other hand,
the 30-pos0ition of 4 is the allylic position and it is obvious
that the 3 -cation is strongly stabilized by the conjugation
with the 40,50-double bond as an allylic cation (Fig. 1).
Therefore, regioselective nucleophilic addition onto the
30-position occurred readily and the 30-adduct (6) was
obtained regioselectively. In the reaction with a compara-
tively soft nucleophile such as NaN3 or PhSH, 50-adduct (8)
was also formed as a by-product.9,10
Scheme 1. Synthesis of 1-(2,3-anhydro-5-deoxy-4,5-didehydro-a-L-ery-
thro-pent-4-enofuranosyl)uracil 4 from 5. Reactant and condition: (a) t-
BuOK, DMF, rt (64%) or (b) LiHMDS, DMF, 0 8C, Ar (92%).
5 equiv of AlMe3 in CH2Cl2 under reflux conditions. The
regioselective nucleophilic addition of a methyl group to
epoxide proceeded on the 30-position and the 30-adduct (6a)
was obtained as the sole product in 81% isolated yield and
the isomeric 20-adduct (7a) and other by-products were not
detected in the reaction mixture (Scheme 2). To ascertain
the generality of this regioselective reaction, treatment of 4
with various nucleophiles was investigated. The results are
summarized in Table 1. When MeONa was used as a
nucleophile, reflux conditions were required for completion
of the reaction. On the other hand, all other additions were
achieved at room temperature (entries 3–8). Reactions using
BnNH2, AlMe3, MeONa and NaN3 proceeded without an
additional base (entries 1–3, and 7). In the case of BzOH,
BzSH and PhSH, Et3N was employed as a base (entries 5, 6,
and 9). When NaH was employed as a base instead of Et3N
for the reaction of BzOH, a lowering of the yield of 6e and a
remaining of the starting material 4 were observed. The
reaction of BzOH was very slow (168 h) and the
corresponding arabinofuranosyl derivative (6e0) was formed
as a by-product based upon the hydrolysis of (6e), although
the 30-addition of BzSH was completed within 48 h because
of the high nucleophilicity.
Scheme 2. Reaction of 4 with AlMe3.
Table 1. Nucleophilic addition to 4
Scheme 3. Reaction of 4 with NaN3 or PhSH.
Entry
Nucleophile
Additional
base
Solvent
Tempera-
ture
T (h)
R
Yield (%)a
Product
6
8
1
2
3
4
5
6
7
8
AlMe3
—
—
—
MeONa
Et3N
Et3N
—
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
DMF
reflux
reflux
12
6
Me
a
b
c
d
e
f
81
80
81
69
61
52
63
80
ndb
ndb
ndb
ndb
ndb
ndb
3
MeONa
BnNH2
CH2(CO2Me)2
BzOH
BzSH
NaN3
PhSH
OMe
NHBn
CH(CO2Me)2
OBz
SBz
N3
rt
rt
rt
rt
rt
rt
24
12
168
48
3
g
h
Et3N
—
1
SPh
11
a Isolated yield after chromatographic separation.
b Not detectable.

H. Takasu et al. / Tetrahedron 61 (2005) 8499–8504
8501
simplicity of this method makes it an attractive new tool for
synthesis of various sugar modified pyrimidine nucleosides.
4. Experimental
4.1. General
Figure 1.
It was noteworthy that the use of Et2AlCN as a nucleophile
provided 30,40-unsaturated-30-adduct (9) as the sole product
via isomerization of the 30-adduct (10) because of the
efficient activation of 30-hydrogen of 10 by the strong
electron-withdrawing cyano group after regular nucleophi-
lic attack of the cyano anion onto the 30-position of 4
(Scheme 4).
1H and 13C NMR spectra were recorded on a JEOL EX 400
spectrometer or a JEOL GX 270 spectrometer (1H: 400 or
270 MHz, 13C: 100 MHz). Chemical shifts (d) are given in
ppm relative to residual solvent or tetramethylsilane as an
internal standard. Low and high-resolution mass spectra
were taken on a JEOL JMS-SX 102 or JMS-D300 machine.
Melting points were determined on a Yanagimoto micro-
melting-point apparatus and were corrected. IR spectra were
recorded on a Perkin Elmer model 1600 FT-IR spectropho-
tometer. UV spectra were obtained from EtOH solution on a
Shimazu UV-260 spectrophotometer. All reagents were
commercially available and used without further purifi-
cation. Compounds known in the literature were character-
ized by comparison of their 1H NMR data with the
previously reported data.
4.1.1. 1-(2,3-Anhydro-5-deoxy-4,5-didehydro-a-L-ery-
thro-pent-4-enofuranosyl)uracil (4). To a stirred solution
of 53c (336 mg, 1.0 mmol) in dry DMF (20 ml) was added
1.0 M THF solution of LiN[(CH3)3Si]2 (2.2 ml, 2.2 mmol)
at 0 8C under argon atmosphere. The reaction mixture was
stirred for 4 h at 0 8C and the mixture was evaporated in
vacuo at room temperature. The residue was diluted with
water and neutralized with saturated NH4Cl and extracted
with AcOEt. The organic solution was evaporated in vacuo
and the residue was subjected to silica gel column
Scheme 4. Reaction of 4 with Et2AlCN.
Usually, the 50-hydroxy group of nucleosides is supposed to
be important for biological activity, while 30-adducts (6) do
not possess the 50-hydroxy group. So we investigated the
conversion method of the olefin of 6 to a hydroxymethyl
group. The hydroboration reaction of 6b should be
applicable to the introduction of the 50-hydroxy group.
The reaction of 6b with BH3–THF at room temperature,
followed by H2O2–NaOH treatment, gave only undesirable
a-isomer (11). When the reaction was heated at reflux
temperature, the desired b-isomer (12) was afforded as a
minor product (17%) together with corresponding a-isomer
(11) (53%) (Scheme 5). As the reason for this isomer ratio,
it was indicated that the steric hindrance effect of the
30-methoxy group was more effective than that of the uracil
ring. At present, we are unable to determine the underlying
cause of this stereoselectivity.
chromatography (benzene/AcOEt 3:1) to afford
(192 mg, 92%) as a white foam.
4
MASS m/z (relative intensity): 208 (MC, 43%), 112 (BCC1,
18%), 97 (SC, 100%). 1H NMR (CDCl3) d: 8.71 (1H, br s,
N3–H), 7.50 (1H, d, JZ8.3 Hz, 6-H), 6.39 (1H, s, 10-H), 5.
76 (1H, d, JZ8.3 Hz, 5-H),0 4.74 (1H, d, JZ2.4 Hz, 50-Ha),
4.59 (1H, d, JZ2.4 Hz, 5 -Hb), 4.23 (1H, d, JZ2.9 Hz,
20-H), 4.05 (1H, d, JZ2.9 Hz, 30-H). 13C NMR (CDCl3) d:
162.84 (4-C), 154.34 0(40-C), 150.30 (2-C), 140.75 (6-C),
102.80 (5-C), 95.95 (5 -C), 81.79 (10-C), 56.52 (20-C), 54.56
(30-C). HRMS m/z calcd for C9H8N2O4: 208.0484. Found:
208.0473.
4.1.2. 1-(3,5-Dideoxy-3-methyl-b-D-threo-pent-4-enofur-
anosyl)uracil (6a). To a stirred solution of 4 (48 mg,
0.23 mmol) in dry CH2Cl2 (10 ml) was added 1.0 M hexane
solution of AlMe3 (1.20 ml, 1.20 mmol) at room tempera-
ture under argon atmosphere. The reaction mixture was
refluxed for 12 h and the mixture was partitioned between
CHCl3 (30 ml) and water (30 ml). The aqueous layer was
filtered using a Celite cake and the filtrate was concentrated
in vacuo. The residue was subjected to silica gel column
chromatography (CHCl3/MeOH 10:1) to afford 6a (42 mg,
81%) as a white foam.
Scheme 5. 50-Hydroxylation reaction of 6b: (i) BF3–THF, THF, reflux (ii)
H2O2, NaOH.
3. Conclusion
We have shown a simple synthetic method of 1-(2,3-
anhydro-5-deoxy-4,5-didehydro-b-D-erythro-pent-4-eno-
furanosyl)uracil (4) and mild and efficient regioselective
method for the conversion of 4 to 30-substituted pyrimidine
nucleosides (6), (9), (11) and (12) without the formation
of the corresponding 20-substituted derivatives. The
reaction is general for a variety of nucleophiles and the
MASS m/z (relative intensity): 224 (MC, 2%), 113 (SC and
1
BCC2, 14%), 112 (BCC1, 14%), 95 (100%). H NMR
(DMSO-d6) d: 11.35 (1H, br s, N3–H), 7.31 (1H, d, JZ8.

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H. Takasu et al. / Tetrahedron 61 (2005) 8499–8504
3 Hz, 6-H), 6.26 (1H, d, JZ4.9 Hz, 10-H), 5.77 (1H, d, JZ4.
9 Hz, 20-OH), 5.58 (1H, d, JZ8.3 Hz, 5-H), 4.32 (1H, d, JZ
1.5 Hz, 50-Ha), 4.03 (1H, t, JZ4.9 Hz, 20-H0), 4.01 (1H, d,
JZ1.5 Hz, 50-Hb), 2.68 (1H, q, JZ6.8 Hz, 3 -H), 1.15 (3H,
d, JZ6.8 Hz, 30-CH3). 13C NMR (DMSO-d6) d: 163.93 (4-
C), 163.15 (40-C), 1500.47 (2-C), 141.47 (6-C), 100.86 (5-C),
85.17 (50-C), 82.40 (1 -C), 74.36 (20-C), 41.99 (30-C), 16.60
(30-CH3). Anal. Calcd for C10H12N2O4 (MwZ224.21): C,
53.57; H, 5.39; N, 12.49. Found: C, 53.30; H, 5.42; N, 12.23.
room temperature under argon atmosphere. The reaction
mixture was stirred for 12 h and the mixture was neutralized
with AcOH. The solvent was evaporated in vacuo and the
residue was diluted with water and extracted with AcOEt.
The organic solution was dried over MgSO4 and the solvent
was evaporated in vacuo and residue was subjected to silica
gel column chromatography (CHCl3/MeOH 30:1) to afford
6d (331 mg, 69%) as a white foam.
MASS m/z (relative intensity): 340 (MC, 5%), 322 (MCK
H2O, 100%), 228 (SCK1, 38%), 211 (MCKCH(CO2Me)2
C2, 80%). 1H NMR (CDCl3) d: 9.01 (1H, br s, N3–H), 7.33
(1H, d, JZ8.3 Hz, 6-H), 6.39 (1H, d, JZ4.8 Hz, 100-H), 5.69
(1H, d, JZ8.3 Hz, 50-H), 4.86 (1H, d, JZ4.8 Hz, 2 -0H), 4.60
(1H, d, JZ2.4 Hz, 5 -Ha), 4.10 (1H, d, JZ2.4 Hz, 5 -Hb), 3.
79 (6H, s, CH3!2), 3.74 (1H, br s, 30-H), 3.71 (1H, br s,
20-OH), 3.35–3.43 (1H, m, 30-CH(CO2Me)2). HRMS m/z
calcd for C14H16N2O8: 340.0897. Found: 340.0907.
4.1.3. 1-(5-Deoxy-3-O-methyl-b-D-threo-pent-4-enofura-
nosyl)uracil (6b). To a stirred solution of 4 (13 mg,
0.06 mmol) in dry MeOH (5 ml) was added 28% MeOH
solution of sodium methoxide (0.06 ml, 0.30 mmol) at room
temperature under argon atmosphere. The reaction mixture
was refluxed for 6 h and the mixture was neutralized with
AcOH. The solvent was evaporated in vacuo. The residue
was subjected to silica gel column chromatography (CHCl3/
MeOH 20:1) to afford 6b (12 mg, 80%). Residue was
recrystallized from MeOH (colorless solid).
4.1.6. 1-(3-O-Benzoyl-5-deoxy-b-D-threo-pent-4-enofura-
nosyl)uracil (6e). To a stirred solution of 4 (107 mg,
0.51 mmol) in dry CH2Cl2 (5 ml) was added benzoic acid
(188 mg, 1.54 mmol) and Et3N (0.21 ml, 1.54 mmol) at
room temperature under argon atmosphere. The reaction
mixture was stirred for 168 h at room temperature and the
solvent was evaporated in vacuo. The residue was diluted
with water and extracted with AcOEt and the organic
solution was dried over MgSO4 and the solvent was
evaporated in vacuo. The residue was subjected to silica
gel column chromatography (CHCl3/MeOH 50:1) to afford
6e (103 mg, 61%) (white foam) and 6e0 (12 mg, 10%)
(white foam), respectively.
Mp: 166–167 8C. MASS m/z (relative intensity): 240 (MC,
1
1%), 111 (BC, 100%). H NMR (DMSO-d6) d: 11.47 (1H,
br s, N3–H), 7.41 (1H, d, JZ8.0 Hz, 6-H0), 6.29 (1H, d, JZ3.
4 Hz, 10-H), 6.07 (1H, d, JZ2.9 Hz, 2 -OH), 5.74 (1H, d,
JZ8.0 Hz, 5-H), 4.67 (1H, s, 50-Ha), 4.43 (1H, s, 50-Hb), 4.
21 (1H, br s, 20-H), 4.13 (1H, br s, 30-H), 3.42 (3H, s, 30-
OCH3). 13C NMR (DMSO-d6) d: 163.16 (4-C), 157.49 (40-
C), 150.31 (2-C), 141.60 (6-C), 100.062 (5-C), 88.07 (50-C),
86.70 (10-C), 83.96 (30-C), 72.15 (2 -C), 55.76 (30-OCH3).
Anal. Calcd for C10H12N2O5 (MwZ240.21): C, 50.00;
H, 5.04; N, 11.66. Found: C, 50.07; H, 5.04; N, 11.52.
Compound 6e. MASS m/z (relative intensity): 330 (MC,
0.7%), 312 (MCKH2O, 13%), 218 (SCK1, 18%), 208
(MCKOCOPhC1, 19%), 201 (SCKH2O, 7%), 105
4.1.4. 1-(3-Benzylamino-3,5-dideoxy-b-D-threo-pent-4-
enofuranosyl)uracil (6c). To a stirred solution of 4
(137 mg, 0.66 mmol) in dry CH2Cl2 (5 ml) was added
benzylamine (3.60 ml, 32.9 mmol) at room temperature
under argon atmosphere. The reaction mixture was stirred
for 24 h and the mixture was concentrated in vacuo. The
residue was subjected to silica gel column chromatography
(CHCl3/MeOH 30:1) to afford 6c (169 mg, 81%). Residue
was recrystallized from AcOEt (colorless solid).
1
(PhCO, 100%). IR (KBr) cmK1: 3424.3, 1686.7. H NMR
(CDCl3) d: 10.46 (1H, br s, N3–H), 7.98 (2H, d, JZ7.3 Hz,
Ph-o), 7.32–7.51 (4H, m, Ph-m and p and 6-H), 6.51 (1H, d,
JZ3.4 Hz, 10-H), 5.75 (1H, br s, 30-H), 5.62 (1H,0 d, JZ
8.3 Hz, 5-H), 5.17 (1H, br s, 20-OH), 4.80 (2H, br s, 2 -H and
50-Ha), 4.66 (1H, d, JZ2.4 Hz, 50-Hb). HRMS m/z calcd for
C16H14N2O6: 330.0852. Found: 330.0843.
Mp: 153–155 8C. MASS m/z (relative intensity): 315 (MC,
5%), 297 (MCKH2O, 4%), 224 (MCKCH2Ph, 6%), 203
(SCC1, 12%), 186 (SCKH2O, 58%), 91 (PhCHC2 , 100%).
IR (KBr) cmK1: 3395.9, 1685.7. 1H NMR (DMSO-d6) d: 11.
41 (1H, br s, N3–H),07.27–7.42 (6H, m, Ph-H and 6-H), 6.48
(1H, d, JZ3.4 Hz, 1 -H), 5.80 (1H, d, JZ4.3 Hz, 20-OH), 5.
65 (1H, d, JZ7.8 Hz, 5-H), 4.52 (1H, s, 50-Ha), 4.21 (1H, br
s, 20-H), 4.19 (1H, s, 50-Hb), 3.88 (1H, d, JZ10 Hz, 30-
NHCH2), 3.78 (1H, d, JZ10 Hz, 30-NHCH2), 3.54 (1H, br s,
30-H), 2.80 (1H, br s, 30-NH). Anal. Calcd for C16H17N3O4
(MwZ315.33): C, 60.94; H, 5.43; N, 13.33. Found: C,
60.94; H, 5.46; N, 13.17.
Compound 6e0. MASS m/z (relative intensity): 226 (MC,
51%), 208 (MCKH2O, 13%), 115 (SC, 100%). IR (KBr)
cmK1: 3383.9, 1686.8. 1H NMR (CDCl3) d: 10.83 (1H, br s,
N3–H), 7.98 (1H, d, JZ8.1 Hz, 6-H), 6.62 (1H, d, JZ
2.9 Hz, 10-H), 5.58 (1H, d, JZ8.1 Hz, 5-H), 4.81 (1H, 0br s,
20-H), 4.72 (1H, d, JZ2.7 0Hz, 50-Ha), 4.63 (1H, br s, 3 -H),
4.55 (1H, d, JZ2.7 Hz, 5 -Hb). FABHRMS m/z calcd for
C9H11N2O5: 227.0668. Found: 227.0664.
4.1.7. 1-(3-Benzoylthio-3,5-dideoxy-b-D-threo-pent-4-
enofuranosyl)uracil (6f). To a stirred solution of 4
(169 mg, 0.81 mmol) in dry CH2Cl2 (5 ml) was added
thiobenzoic acid (0.29 ml, 2.44 mmol) and Et3N (0.34 ml,
2.44 mmol) at room temperature under argon atmosphere.
The reaction mixture was stirred for 2 days at room
temperature and the solvent was evaporated in vacuo. The
residue was subjected to silica gel column chromatography
(CHCl3/MeOH 45:1) to afford 6f (145 mg, 52%) as a white
foam.
4.1.5. 1-(3,5-Dideoxy-3-di(methoxycarbonyl)methyl-b-D-
threo-pent-4-enofuranosyl)uracil (6d). To a stirred sol-
ution of dimethyl malonate (1.28 ml, 11.19 mmol) in dry
MeOH (5 ml) was added 28% MeOH solution of sodium
methoxide (1.08 ml, 5.60 mmol) at room temperature under
argon atmosphere. The mixture was added to a stirred
solution of 4 (291 mg, 1.40 mmol) in dry MeOH (5 ml) at

H. Takasu et al. / Tetrahedron 61 (2005) 8499–8504
8503
MASS m/z (relative intensity): 346 (MC, 4%), 328 (MCK
H2O, 3%), 209 (MCKSCH2Ph, 5%), 105 (PhCO, 100%),
8.3 Hz, 5-H), 5.38 (1H, d, JZ4.4 Hz, 20-OH), 4.80–4.82
(1H, m, 20-H), 4.61 (1H, d, JZ2.0 Hz, 50-Ha), 4.23 (1H, br
s, 30-H), 4.21 (1H, d, JZ2.0 Hz, 50-Hb). 13C NMR (CDCl3)
d: 165.99 (4-C), 157.96 (40-C), 149.91 (2-C), 142.95 (6-C),
132.63 (SPh-C), 129.25 (SPh-C), 128.17 (SPh-C), 1000.41
(5-C), 88.06 (10-C), 87.41 (50-C), 74.24 (20-C), 53.50 (3 -C).
Anal. Calcd for C15H14N2O4S1 (MwZ318.35): C, 56.59; H,
4.43; N, 8.80. Found: C, 56.34; H, 4.49; N, 8.78.
1
77 (Ph, 48%). IR (KBr) cmK1: 3425.2, 1683.6. H NMR
(CDCl3) d: 9.64 (1H, br s, N3–H), 7.93 (2H, d, JZ7.3 Hz,
Ph-o), 7.58–7.64 (1H, m, Ph-p), 7.44–7.49 (3H, m, Ph-m and
6-H), 6.40 (1H, d, JZ3.4 Hz, 10-H), 5.65 (1H, d, JZ7.8 Hz,
5-H), 4.71 (1H, d, JZ1.9 Hz, 50-Ha), 4.60–4.67 (3H, m,
30-H, 20-H and 20-OH), 4.44 (1H, d, JZ2.4 Hz, 50-Hb).
HRMS m/z calcd for C16H14N2O5S1: 346.0623. Found: 346.
0610.
Compound 8h. MASS m/z (relative intensity): 318 (MC,
33%), 209 (MCKSPh, 50%), 206 (SCK1, 7%), 123
(PhSCHC2 , 100%), 112 (BCC1, 9%). H NMR (CDCl3)
1
4.1.8. 1-(3-Azido-3,5-dideoxy-b-D-threo-pent-4-enofura-
nosyl)uracil (6g) and 1-(5-azido-3,5-dideoxy-b-D-glycero-
pent-4-enofuranosyl)uracil (8g). To a stirred solution of 4
(122 mg, 0.59 mmol) in dry DMF (10 ml) was added
sodium azido (57 mg, 0.88 mmol) at room temperature
under argon atmosphere. The reaction mixture was stirred
for 3 h at room temperature and the mixture was
concentrated in vacuo. The residue was subjected to silica
gel column chromatography (benzene/AcOEt 2:1) to give
6g (93 mg, 63%) as the first fraction (white foam) and 8g
(5 mg, 3%) as the second fraction (white foam).
d: 10.75 (1H, br s, N3–H), 7.23–7.47 (6H, m, 6-H and
30-SPh), 6.46 (1H, d, JZ6.4 Hz, 10-H), 5.51 (1H, d, JZ
8.3 Hz, 5-H), 5.16 (2H, br s, 20-H and 30-H), 4.58 (1H, d, JZ
3.9 Hz, 20-OH), 3.66 (2H, s, 50-H!2). 13C NMR (CDCl3) d:
165.22 (4-C), 156.88 (40-C), 150.48 (2-C), 143.00 (6-C),
134.83 (SPh-C), 130.53 (SPh-C), 129.07 (SPh-0C), 127.15
(SPh-C), 102.27 (30-C), 100.74 (5-C), 86.91 (1 -C), 71.88
(20-C), 31.46 (50-C). Anal. Calcd for C15H14N2O4S1 (MwZ
318.35): C, 56.59; H, 4.43; N, 8.80. Found: C, 56.30; H,
4.40; N, 8.72.
Compound 6g. IR (KBr) cmK1: 2104 (N3). MASS m/z
(relative intensity): 251 (MC, 2%), 209 (MCKN3, 14%),
4.1.10. 1-(3-Cyano-3,5-dideoxy-b-D-glycero-pent-3-eno-
furanosyl)uracil (9). To a stirred solution of 4 (296 mg,
1.42 mmol) in dry THF (10 ml) was added 1.0 M toluene
solution of Et2AlCN (14 ml, 14 mmol) under argon
atmosphere. The reaction mixture was refluxed for 2 h.
EtOH was added and the mixture was stirred for 30 min and
the solvent was evaporated in vacuo. The residue was
diluted with water and extracted with AcOEt and the
organic solution was dried over MgSO4 and the solvent was
evaporated in vacuo. The residue was subjected to silica gel
column chromatography (CHCl3/MeOH 30:1) to afford 9
(193 mg, 58%). Residue was recrystallized from acetone
and AcOEt (colorless solid).
1
167 (100%), 112 (BCC1, 39%). H NMR (DMSO-d6) d:
11.44 (1H, br s, N3–H), 7.36 (1H, d, JZ8.3 Hz, 6-H), 06.29
(1H, d, JZ4.4 Hz, 20-OH), 6.24 (1H, d, JZ4.4 Hz, 1 -H),
5.61 (1H, d, JZ8.3 H0z, 5-H), 4.69 (1H, d, JZ2.4 Hz, 50-
Ha), 4.63 (1H, br0s, 3 -H) 4.41 (1H, d, JZ2.4 Hz, 50-Hb),
4.09 (1H, br s, 2 -H). Anal. Calcd for C9H9N5O4 (MwZ
251.20): C, 43.03; H, 3.61; N, 27.88. Found: C, 43.13; H,
3.67; N, 27.64.
Compound 8g. IR (KBr) cmK1: 2105 (N3). MASS m/z
(relative intensity): 251 (MC, 12%), 209 (MCKN3, 4%),
1
167 (100%), 113 (BCC2, 44%). H NMR (DMSO-d6) d:
11.42 (1H, br s, N3–H), 7.32 (1H, d, JZ8.0 Hz, 6-H), 6.42
(1H, d, JZ6.8 Hz, 10-H), 5.62 (1H, d, JZ8.0 Hz, 5-H),05.57
(1H, d, JZ4.9 Hz, 20-OH), 5.29 (1H, d, JZ1.5 Hz, 3 -H),
4.88–4.91 (1H, m, 20-H), 4.09 (2H, s, 500-H!2). 13C NMR
(DMSO-d6) d: 163.32 (4-C), 154.29 (4 -C), 150.53 (2-C),
142.37 (6-C), 103.890 (50-C), 100.82 (5-C), 86.02 (10-C),
70.68 (30-C), 46.45 (2 -C). HRMS m/z calcd for C9H9N5O4:
251.0662. Found: 251.0655.
Mp: 219–222 8C. MASS m/z (relative intensity): 235 (MC,
29%), 217 (MCKH2O, 9%), 192 (MCKH2O–CNC1, 6%),
123 (SCK1, 38%), 113 (BCC2, 100%). IR (KBr) cmK1
:
1
3426.6, 3196.6, 2218.0 (CN), 1697.9, 1671.7, 1653.5. H
NMR (DMSO-d6) d: 11.53 (1H, br s, N3–H), 7.44 (1H, d,
JZ7.8 Hz, 6-H), 6.66 (1H, d, JZ7.3 Hz, 10-H), 6.23 (1H, d,
JZ5.9 Hz, 020-OH), 5.65 (1H, d, JZ7.8 Hz, 5-H), 5.07–5.11
(1H, m, 2 -H), 2.15 (3H, s, 50-CH3). Anal. Calcd for
C10H9N3O4 (MwZ235.20): C, 51.07; H, 3.86; N, 17.87.
Found: C, 51.27; H, 3.93; N, 17.68.
4.1.9. 1-(3,5-Dideoxy-3-phenylthio-b-D-threo-pent-4-eno-
furanosyl)uracil (6h) and 1-(3,5-dideoxy-5-phenylthio-b-
D-glycero-pent-4-enofuranosyl)uracil (8h). To a stirred
solution of 4 (110 mg, 0.53 mmol) in Et3N (10 ml) was
added thiophenol (82 ml, 0.80 mmol) at room temperature
under argon atmosphere. The reaction mixture was stirred
for 1 h at room temperature and the solvent was evaporated
in vacuo and a small amount of the remaining Et3N was
removed as the toluene azetrope. The residue was subjected
to silica gel column chromatography (CHCl3/MeOH 150:1)
to give 6h (134 mg, 80%) as the first fraction (white foam)
and 8h (19 mg, 11%) as the second fraction (white foam).
4.1.11. 1-(3-O-Methyl-a-L-xylo-furanosyl)uracil (11) and
1-(3-O-methyl-b-D-arabino-furanosyl)uracil (12). To a
stirred solution of 6b (30 mg, 0.125 mmol) in dry THF
(10 ml) was added 1 M THF solution of BH3–THF
(0.625 ml, 0.625 mmol) at 0 8C under argon atmosphere
and the reaction mixture was stirred for 1 h at 0 8C. One
molar THF solution of BH3–THF (1.625 ml, 1.625 mmol)
was added to the reaction mixture and the reaction mixture
was refluxed for 17 h. After cooling to room temperature,
H2O and 3 N NaOH (0.125 ml, 0.375 mmol) and 30% H2O2
(0.12 ml, 1.25 mmol) was added to the reaction mixture.
The reaction mixture was stirred for 6 h at room
temperature. After acidification with AcOH, the reaction
mixture was washed with saturated NaCl and the aqueous
layer was extracted with THF. The organic solution was
Compound 6h. MASS m/z (relative intensity): 318 (MC,
1
58%), 206 (SCK1, 100%), 112 (BCC1, 16%). H NMR
(CDCl3) d: 11.04 (1H, br s, N3–H), 7.23–7.50 (6H, m, 6-H
and 30-SPh), 6.37 (1H, d, JZ2.9 Hz, 10-H), 5.46 (1H, d, JZ

8504
H. Takasu et al. / Tetrahedron 61 (2005) 8499–8504
4. (a) Doerr, I. L.; Codington, J. F.; Fox, J. J. J. Org. Chem. 1965,
30, 467. (b) Kowollik, G.; Langen, P. Z. Chem. 1975, 15, 147.
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combined and dried over Na2SO4. The solvent was removed
in vacuo and the mixture was analyzed by the H NMR
(17% of the 12 was detected). The crude mixture was
purified by silica gel column chromatography (CHCl3/
MeOH 15:1) to give 11 (53%).
1
¨
J. Heterocycl. Chem. 1984, 21, 773. (e) Habich, D.; Barth, W.
Synthesis 1988, 943. (f) Wu, J.-C.; Pathak, T.; Tong, W.; Vial,
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Balzarini, J.; De Clercq, E.; Herdewijn, P. J. Med. Chem. 1990,
33, 868. (k) Haung, J.-T.; Chen, L.-C.; Wang, L.; Kim, M.-H.;
Warshaw, J. A.; Armstrong, D.; Zhu, Q.-Y.; Chou, T.-C.;
Watanabe, K. A.; Matulic-Adamic, J.; Su, T.-L.; Fox, J. J.;
Polsky, B.; Baron, P. A.; Gold, J. W. M.; Hardy, W. D.;
Zuckerman, E. J. Med. Chem. 1991, 34, 1640. (l) Haraguchi,
K.; Tanaka, H.; Maeda, H.; Itoh, Y.; Saito, S.; Miyasaka, T. J.
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Compound 11. FABMASS m/z (relative intensity): 259
1
(MCC1, 7%), 154 (100%). H NMR (DMSO-d6) d: 11.25
(1H, br s,0N3–H), 7.41 (d, JZ8.2 Hz, 6-H), 5.92 (1H, d, JZ
3.6 Hz, 1 -H), 5.76 (1H, d, JZ4.5 Hz, 20-OH), 5.55 (1H, d,
JZ8.2 Hz, 5-H), 4.72 (1H, t, JZ5.5 Hz, 50-OH), 4.28–4.34
(1H, m, 30-H), 4.21–4.25 (1H, m, 20-H), 3.74–3.76 (1H, m,
40-H), 3.48–3.63 (2H, m, 50-H!2), 3.36 (3H, s, 30-OCH3).
NOE experiment, 40-H/030-H 0(7.3%), 40-H/20-OH (1.2%),
30-H/6-H (6.2%) and 1 -H/2 -H (6.4%). FABHRMS m/z
calcd for C10H15N2O6: 259.0930. Found: 259.0938.
Compound 12. 1H NMR (DMSO-d6) d: 11.28 (1H, br s, N3–
H), 7.60 (d, JZ8.2 Hz, 6-H), 5.90 (1H, d, JZ4.5 Hz, 10-H),
5.76 (1H, d, JZ5.1 Hz, 20-OH)0, 5.57 (1H, d, JZ8.2 Hz,
5-H), 5.08 (1H, t, JZ5.7 Hz, 5 -OH), 4.12–4.16 (1H, m,
20-H), 3.79–3.84 (1H, m, 30-H), 3.66–3.68 (1H, m, 40-H),
3.58–3.61 (2H, m, 50-H!2), 3.34 (3H, s, 30-OCH3).
FABHRMS m/z calcd for C10H15N2O6: 259.0930. Found:
259.0943.
¨
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References and notes
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R. M.; McRobert, M. J.; Crawford-Ruth, D.; Verheyden, J. P.
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San-Felix, A.; Balzarini, J.; De Clercq, E.; Camarasa, M.-J.
J. Med. Chem. 1992, 35, 2988.
2. Ruth, T. L. Oligonucleotides and Their Analogues; IRL:
London, 1991. Giese, B.; Imwinkelried, P.; Petretta, M. Synlett
1994, 1003 and references therein.
3. (a) Codington, J. F.; Fecher, R.; Fox, J. J. J. Am. Chem. Soc.
1960, 82, 2794. (b) Chang, N. C.; Burchannel, J. H.; Fecher,
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1962, 27, 163.
8. Dalla, V.; Pale, P. Tetrahedron Lett. 1996, 37, 2781.
9. Marshall, J. A. Chem. Rev. 1989, 89, 1503.
10. Detailed results for the reaction mechanism will be reported in
due course.