Synthesis of 2S-(2-hydroxyethyl)-3R-hydroxy-4S-(thymin-1-yl or adenin-9-yl)-tetrahydrofuran

Article abstract of DOI:10.1016/j.tet.2008.07.039

Two synthetic strategies were developed to obtain isonucleosides 2a and 2b. Starting from the known compound 4, an extension of one carbon unit at sugar 6-terminal was achieved by Wittig reaction and Stannyl-desulfonylation reaction. After oxidation of th

Full text of DOI:10.1016/j.tet.2008.07.039

Tetrahedron 64 (2008) 9630–9635
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2S-(2-hydroxyethyl)-3R-hydroxy-4S-(thymin-1-yl or adenin-9-yl)-
tetrahydrofuran
y
y
*
Ying-Chun Liu , Jun Zhang , Lei Xing, Zhen-Jun Yang , Liang-Ren Zhang, Li-He Zhang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two synthetic strategies were developed to obtain isonucleosides 2a and 2b. Starting from the known
compound 4, an extension of one carbon unit at sugar 6-terminal was achieved by Wittig reaction and
Stannyl-desulfonylation reaction. After oxidation of the double bond, the isonucleosides with elongated
side chain 2a and 2b were synthesized. For the synthesis of isonucleosides containing different bases, an
epoxide intermediate approach was developed. Isonucleosides 2a and 2b were synthesized by re-
gioselective epoxide opening reaction of 18 in good yield.
Received 22 January 2008
Received in revised form 5 July 2008
Accepted 11 July 2008
Available online 16 July 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Isonucleoside
Wittig reaction
Epoxide
Stannyl-desulfonylation
1. Introduction
from 10- to 20-position, the chemical and enzymatic stabilities of the
nucleosides increase. Previous studies in our group showed that
As a class of potential therapeutic agents, antisense oligonu-
cleotides have been developed for the treatment of diseases such as
cancer, inflammation, and virus infection.1–4 However, several
drawbacks that have emerged negatively affect their therapeutic
efficacy. For example, natural oligodeoxynucleotides are readily
degraded in the serum or in vivo and show poor uptake by the cell
membrane. To improve the biostability of oligonucleotides, chem-
ically modified oligonucleotides are widely used. Though phos-
phorothioate oligodeoxynucleotides are currently used as the
standard choice of chemically modified oligodeoxynucleotides, its
non-sequence-specific protein binding leads to significant side ef-
fects, including complement activation, thrombocytopenia, in-
hibition of cell–matrix interaction, and reduction of cell
proliferation.5 To overcome these limitations, intensive efforts were
focused on the development of other kinds of chemically modified
oligonucleotides, which were named as the second generation of
oligonucleotides. For example, modifications of the 2-position of
ribose with electronegative substituents such as the 20-O-(2-
methoxy)ethyl (MOE) group6 or a 20-O,40-C-methylene bridge
(locked nucleic acid; LNA) were performed.7
homo-oligoisonucleotides antagonized the hydrolysis of snake
venom phosphodiesterase. Furthermore, some kinds of homo-oli-
goisonucleotides also showed strong binding abilities to their
complementary sequences though they were a little weaker than
the native counterpart8–12 (Fig. 1, I and II). The results suggested
that antisense oligonucleotides constructed from isonucleotides
could antagonize the hydrolysis of nuclease and showed acceptable
binding abilities, maintained the inhibitory abilities to decrease
mRNA transcription and functional protein translation.12 The fur-
ther modification of compound II (R¼CH2OH, Fig. 1) gave amino-
isonucleosides, which were successfully incorporated into siRNA
and increased the gene silencing efficiency of siRNA when they
were incorporated at sense strand of siRNA.13
To investigate whether the extension of phosphodiester linkage
could improve the hybridization properties, we reported previously
the synthesis of 10,40-anhydro-20,50-dideoxy-20-nucleobase-
D-altri-
tol (1) in which an additional methylene group was introduced at
the 6-position of sugar moiety of compound I (R¼H).14 (Fig. 1) It
was found that oligomers containing 1 could form duplexes with
both DNA and RNA complementary strands, which indicated that
the extended phosphodiester linkage in these oligomers rendered
the sugar moiety more flexible to fit the required A or B confor-
mation of the duplex.15 In order to investigate the hybridization
properties of oligonucleotides consisting of the isonucleosides with
elongated side chain, we report here the synthesis of 2S-(2-
hydroxyethyl)-3R-hydroxy-4S-(thymin-1-yl or adenin-9-yl)-tetra-
hydrofuran (2), the enantiomer of 1.
Isonucleosides represent a novel class of nucleoside analogues
in which the nucleobase is linked to various positions of ribose
other than C-1 (Fig. 1). Because of the shift of N-glycosidic bond
* Corresponding author. Tel.: þ86 10 82802503.
E-mail address: yangzj@bjmu.edu.cn (Z.-J. Yang).
y
Authors contributed equally to this paper.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.039

Y.-C. Liu et al. / Tetrahedron 64 (2008) 9630–9635
9631
OH
3
OH
O
OH
OH
O
OH
6
B
B
B
B
OH HO
HO
2
4
OH
OH HO
7
5
O
O
O
B
R
R
2
1
II
I
Ribonucleoside
2a: B=T; 2b: B =A
1: B = A, T
I,II: R = H, CH2OH, B = A, T, C, G et al
Figure 1. Structures of ribonucleoside and isonucleosides.
2. Results and discussion
(E-isomer and minor Z-isomer, without separation) in 71.0% yield.
Stannyl-desulfonylation of 13 with Bu3SnH in toluene, followed by
treatment with NH4F in EtOH at 90 ꢀC, afforded compound 15 in
60.0% yield.
In our reported works, compound 1 was synthesized from
-glucose by 11 synthetic steps.13 Compound 2 could be obtained
D
from
material. In this paper we present the synthesis of isonucleoside 2
from -xylose by two concise approaches. According to the retro-
L
-glucose. However,
L
-glucose is not a convenient starting
Compound 15 was hydroborated using 9-BBN (1 M solution in
THF) and subsequently oxidized by H2O2 to give compound 16. In
this reaction, 0.5 M NaOH was used to ensure the benzoate stable.
Crude 16 was protected by tert-butyldimethylsilyl group. The key
intermediate epoxide 18 was successfully obtained by intra-
molecular nucleophilic attack under basic condition.
The regioselective attack of epoxide 18 by thymine or adenine
was accomplished using DBU as a basic catalyst. The desired and
predominant compound 19a (35.5% yield) and 19b (46.8% yield)
was obtained along with a small amount of regioisomer 20a (about
4.0% yield) and 20b (about 5.0% yield), respectively. Compound 19a
or 19b was deprotected using 1 M TBAF solution in THF to obtain 2a
(65.5% yield) or 2b (61.4% yield), respectively.
D
synthesis analysis, compound 2 could be obtained from compound
II (Fig. 1, R¼H) by extension of one carbon unit at 6-terminal.
Therefore, the known compound 5a16 was oxidized and followed
by Wittig reaction and stannyl-desulfonylation17 to yield the key
intermediate 7a. However, it was found that the key intermediate 7
could be yielded directly from compound 4a, which was prepared
from compound 3a.16 The acetal group in compound 4a was hy-
drolyzed by 1% HCl and reacted with Wittig reagent in one-pot to
give compound 6a in 85.0% yield. Compound 6a was then reacted
with Bu3SnH and AIBN to yield compound 7a (Scheme 1).
There were no differences for the general data (NMR, optical
rotation, MS, and UV) of compound 2a or 2b obtained from two
different methods, respectively. The structure of 2b was charac-
terized further by 1H NMR, 1H–1H COSY, and NOESY spectra. The
strong NOE effect of 3-OH with 2-H and 4-H in sugar moiety con-
firms that adenine and 2-(2-hydroxyethyl) group are on the same
side of the sugar ring, and adenin-9-yl is connected at 4-position of
sugar moiety (Fig. 2).19
In conclusion, two synthetic strategies were developed to syn-
thesize isonucleosides 2a and 2b. Starting from the known com-
pound 4, an extension of one carbon unit at sugar 6-terminal was
achieved by Wittig reaction and Stannyl-desulfonylation reaction.
After oxidation of the double bond, the isonucleosides with elon-
gated side chain 2a and 2b were synthesized. For the synthesis of
isonucleosides containing different bases, an approach with epox-
ide intermediate 18 was designed. Isonucleosides 2a and 2b were
synthesized by regioselective epoxide opening reaction in good
yield. The preliminary results showed that compound 2a or 2b
incorporated antisense oligonucleotides (single incorporation at 30-
end, 50-end or middle of single strand) kept almost same affinity to
complementary strand as that of II (R¼H, B¼A, T), and all were
lower than that of natural one. The further results will be reported
elsewhere.20
OCH
OBz
OCH
3 OBz
3 OH
i
HO
H3CO
H3CO
T
T
T
78.4%
O
O
O
3a
4a
5a
iii
85%
ii
OBz
OBz
3
6
R
7
v
2
O
T
T
4
5
95.2%
O
6a. R = Ts
iv
8a
7a. R = SnBu3
78.5%
Scheme 1. Reagents and conditions: (i) BzCl, Py; (ii) (a) DCC, DMSO, Cl2CHCOOH; (b)
TsCH]PPh3; (iii) (a) 1% HCl, THF, 70–90 ꢀC; (b) DMSO, TsCH]PPh3; (iv) Bu3SnH, AIBN,
toluene, reflux; (v) NH4F, EtOH, reflux.
Destannylation of 7a with ammonium fluoride in ethanol at
80 ꢀC gave compound 8a. Compound 8a or 8b17 was hydroborated
first by borane-dimethyl sulfide complex then reacted with hy-
drogen peroxide to give compound 9a or 9b in 42.0 or 50.5% yield
and some debenzoylated product 2a or 2b in w17.0% yield. Com-
pound 9a or 9b can be converted completely to 2a or 2b using
NaOCH3 in 91.4 or 90.0% yield, respectively (Scheme 2).
OBz
OBz
OH
HO
HO
i
ii
3. Experimental
3.1. General
B
B
T
O
O
O
2a. B = T, 91.4%
2b. B = A, 90.0%
9a. B = T, 42.0%
9b. B = A, 50.5%
8a. B = T
8b. B = A[17]
Scheme 2. Reagents and conditions: (i) (a) BH3-SMe2, THF, 2 N NaOH, 30% H2O2; (ii)
NaOCH3, MeOH.
All solvents were dried and distilled prior to use. Chemical re-
agents were purchased from Acros and Sigma Co., and were used
without further purification. Thin layer chromatography was per-
formed on silica gel GF254 (Qin-Dao Chemical Co., China) plates
with detection by UV or by heating. Silica gel (200–300 mesh; Qin-
Dao Chemical Co.) was used for short column chromatography.
NMR spectra were recorded on JEOL JNM-AL300 or Varian INOVA-
500 instrument. 1H NMR and 13C NMR spectra were referenced
using DMSO-d6 or CDCl3 as a solvent with internal standard TMS.
Elemental analyses were performed by using a Vario EL III in-
strument. High-resolution ESI mass spectra were obtained at MDS
In another approach, the formation of N-glycoside was post-
poned to the later synthetic step. By this strategy, an epoxide in-
termediate 18 was synthesized. From this intermediate, various
base substituted isonucleosides can be prepared more easily. As
shown in Scheme 3, compound 1018 was protected to give benzoate
11 in which the acetal group was hydrolyzed by trifluoroacetic acid
in water to yield aldehyde 12 quickly and completely. Without
purification, crude 12 was reacted with Wittig reagent [(p-toly-
lsulfonyl)methylene]triphenylphosphorane to give compound 13

9632
Y.-C. Liu et al. / Tetrahedron 64 (2008) 9630–9635
OTs
OTs
OTs
O
H3CO
H3CO
O
R
iii
71.3%
v
ii
D-Xylose
OR
OBz
RO
OBz
67.6%
BzO
O
O
12
O
OTs
15
10. R = H;
13. R = Ts
14. R = SnBu3
i. 98.1%
iv. 88.1%
11. R = Bz
OH
B
O
O
TBDMSO
ix
vi
viii
+
OH
B
OR
89.6%
OTBDMS
O
O
OTs
O
18
BzO
vii
19a. B = T, R = TBDMS, 35.5%
19b. B = A, R = TBDMS, 46.8%
2a. R = H, 65.5%
20a. 4.0%
20b. 5.0%
16. R = H
x
17. R = TBDMS
60.6% from 15
2b. R = H, 61.4%
Scheme 3. Reagents and conditions: (i) BzCl, DMAP, Py; (ii) TFA/H2O (v/v¼7:1), rt; (iii) Ph3P]CHTs, THF; (iv) Bu3SnH, AIBN, PhCH3; (v) NH4F, EtOH; (vi) (a) BH3-THF; (b) 0.5 N NaOH,
30% H2O2; (vii) TBDMSCl, DMF, imidazole; (viii) K2CO3, MeOH; (ix) adenine, DBU, DMF; (x) TBAF, THF.
Figure 2. NOE spectrum of compound 2b. The NOE exist between 2-H, 3-OH, and 4-H, respectively.
SCIEX QSTAR and Bruker DALTONICS APEX IV 70e instruments, and
the data are reported in m/e (intensity to 100%). Optical rotations
were recorded on Perkin–Elmer 243B Polarimeter.
by silica gel column chromatography (petroleum ether/EtOAc) to
yield 4a (1.5 g, 78.4%).
1H NMR (300 MHz, CDCl3):
d 1.85 (s, 3H, T-CH3), 3.42 (s, 3H,
–OCH3), 3.45 (s, 3H, –OCH3), 4.01 (dd, 1H, J5a,4¼2.7 Hz,
J5a,5b¼10.5 Hz, 5a-H), 4.08 (dd, 1H, J2,6¼3.3 Hz, 2-H), 4.17 (dd, 1H,
J5b,4¼6.9 Hz, 5b-H), 4.65 (d, 1H, 6-H), 5.25 (t, 1H, J2,3¼3.0 Hz, 3-H),
5.49 (d, 1H, J3,4¼3.0 Hz, 4-H), 7.32–7.60 (m, 3H, Bz), 7.49 (s, 1H, 6-H
in thymine), 7.94 (d, 2H, Bz-H), 10.02 (br s, 1H, NH); 13C NMR
3.1.1. [2R-Dimethoxymethyl-3R-benzoxy-4S-(thymin-1-yl)]-
tetrahydrofuran (4a)
To a solution of 3a15 (1.4 g, 4.9 mmol) in dry pyridine, BzCl
(0.84 mL, 7.35 mmol) was added and the mixture was stirred for 4 h
at room temperature. After evaporation, the residue was dissolved
in EtOAc, washed with satd NaHCO3 solution and brine, dried over
anhydrous Na2SO4, and then evaporated. The residue was purified
(75 MHz, CDCl3): d 12.6, 56.0, 56.8, 60.9, 71.5, 78.8, 83.5, 104.1, 111.4,
128.4, 129.8, 128.9, 133.5, 137.4, 150.8, 163.8, 165.6; HRMS (TOF)
calcd for C19H23N2O7 (MþH)þ: 391.1499, found: 391.1489.

Y.-C. Liu et al. / Tetrahedron 64 (2008) 9630–9635
9633
3.1.2. {2S-[2(E)-p-Tolunenesulfonylethylene]}-3R-benzoxy-4S-
3.1.5. [2S-(1-Vinyl)-3R-benzoxy-4S-(adenin-9-yl)]-tetra-
(thymin-10-yl)}-tetrahydrofuran (6a)
hydrofuran (8b)
Compound 4a (400 mg, 1.02 mmol) was dissolved in the mix-
ture of THF (7 mL) and 1% HCl solution (7 mL), and the solution was
stirred for 2 days at 70 ꢀC. NaOH (2 N) was used to neutralize the
solution to pH¼7 and the mixture was extracted with CH2Cl2. The
organic layer was washed with satd NaHCO3 solution, brine, dried
over anhydrous Na2SO4 and CuSO4, and then concentrated to
yellow syrup. The crude syrup was dissolved in DMSO (3.5 mL)
under an inert atmosphere and [(p-tolylsulfonyl)methylene]-
triphenylphosphorane (620 mg, 1.45 mmol) was added. The mix-
ture was stirred overnight at room temperature. MeOH (8 mL) was
added and stirred for 30 min at room temperature, the resulting
mixture was filtered and washed with cold MeOH, and the com-
bined filtrates were evaporated. The residue was partitioned
(EtOAc/H2O), the organic layer was washed with H2O (three times),
NaHCO3 solution, and brine, dried over Na2SO4, and evaporated.
The residue was purified by silica gel column chromatography
(petroleum ether/EtOAc) to give 6a (453 mg, 80.0%).
Compound 8b was synthesized by the reported method.17
1H NMR (300 MHz, CDCl3):
d
4.32 (d, 1H, J5,4¼2.7 Hz, 5b-H), 4.43
(dd, 1H, J5,4¼5.7, 10.5 Hz, 5a-H), 4.59 (d, 1H, J3,2¼4.5 Hz, 3-H), 5.20–
5.39 (m, 2H, 7-H), 5.33 (d, 1H, J4,3¼7.8 Hz, 4-H), 5.48 (d, 1H,
J2,3¼4.5 Hz, 2-H), 5.70 (6-NH2 in adenine), 6.25 (s, 1H, 6-H), 7.55–
8.06 (m, 5H, Bz), 8.01(s, 1H, H-2 in adenine), 8.39 (s, 1H, H-8 in
adenine).
3.1.6. [2S-(2-Hydroxyethyl)-3R-benzoxy-4S-(thymin-1-yl)]-
tetrahydrofuran (9a)
To a solution of 8a (90 mg, 0.26 mmol) in anhydrous THF
(10 mL), BH3-SMe2 complex (1 M solution in THF, 0.47 mL,
0.46 mmol) was added under an inert atmosphere. The reaction
was stirred for 2 h at room temperature and then cooled to 0 ꢀC, 2 N
NaOH (1.54 mL, 0.304 mmol) and 30% H2O2 (0.55 mL, 0.456 mmol)
were added. After stirring for another 2 h at room temperature, the
mixture was concentrated. The complex was dissolved in CHCl3 and
washed with water and satd NaHCO3, dried over anhydrous
Na2SO4, and then evaporated. The residue was purified by silica gel
column chromatography (cyclohexane/EtOAc) to give 9a (39 mg,
42%) and 2a (11 mg, 17%).
1H NMR (300 MHz, CDCl3):
d 1.80 (s, 3H, T-CH3), 2.44 (s, 3H, Ts-
CH3), 4.17 (dd, 1H, J5a,4¼3.3 Hz, J5a,5b¼10.5 Hz, 5a-H), 4.32 (dd, 1H,
J5b,4¼6.6 Hz, 5b-H), 5.22 (dd, 1H, J2,3¼5.7 Hz, 3-H), 4.65 (dt,
1H, J2,6¼2.1 Hz, 2-H), 5.34 (dt, 1H, J3,4¼3.0 Hz, 4-H), 6.77 (dd, 1H,
J6,7¼15.0 Hz, 6-H), 7.01 (s, 1H, 6-H in thymine), 7.27 (d, 1H,
J6,7¼15.0 Hz 7-H), 7.43–7.71 (m, 5H, Bz), 7.79 (d, 2H, Ts), 8.02 (d, 2H,
1H NMR (300 MHz, CDCl3):
d 1.80 (d, 3H, thymine-CH3), 1.83–
1.99 (m, 2H, 6-H), 3.97–4.02 (m, 2H, 7-H), 4.04 (dd, J5a,4¼4.5 Hz,
J5a,5b¼10.0 Hz, 1H, 5a-H), 4.07–4.11 (m, 1H, 2-H), 4.13 (dd,
J5b,4¼2.5 Hz, 1H, 5b-H), 4.52 (br s, 1H, –OH), 5.06–5.11 (m, 1H, 3-H),
5.28–5.32 (m, 1H, 4-H), 7.52 (d, J¼1.0 Hz, 1H, 6-H in thymine), 7.54–
7.57 (m, 2H, Bz-H), 7.65–7.75 (m, 3H, Bz-H), 11.30 (br s, 1H, –NH–);
Ts), 8.32 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3):
d 12.4, 21.6, 60.9,
70.8, 81.5, 82.0, 112.5, 127.9, 128.4, 128.5, 128.6, 129.9, 130.1, 131.9,
132.0,132.1,132.8,134.1,135.8,139.7,144.9,150.3,162.9,165.7; HRMS
(TOF) calcd for C25H23N2O7S (MꢁH)þ: 495.1231, found: 495.1208.
13C NMR (75 MHz, CDCl3):
d 12.2, 35.2, 57.3, 61.5, 68.6, 79.2, 81.3,
3.1.3. {2S-[2(E)-Tributylstannylvinyl]}-3R-benzoxy-4S-(thymin-
1-yl)}-tetrahydrofuran (7a)
109.6, 128.8, 129.4, 131.5, 134.0, 137.7, 150.8, 163.8; HRMS (TOF)
calcd for C18H21N2O6 (MþH)þ: 361.1394, found: 361.1397.
To a solution of 6a (130 mg, 0.262 mmol) in toluene (10 mL),
Bu3SnH (0.25 mL, 0.825 mmol) was added under the atmosphere of
argon. After 15 min, AIBN (11 mg, 0.052 mmol) was added. The
solution was refluxed for 4 h, evaporated, and the residue was
purified by silica gel column chromatography (petroleum ether/
EtOAc) to yield 7a (130 mg, 78.5%).
3.1.7. [2S-(2-Hydroxyethyl)-3R-benzoxy-4S-(adenin-9-yl)]-
tetrahydrofuran (9b)
By the same method as that for 9a, 9b was obtained from 8b in
50.5% yield.
1H NMR (300 MHz, CDCl3):
d 1.84–2.01 (m, 2H, 6-H), 3.98–4.02
1H NMR (300 MHz, CDCl3):
d
0.86 (t, 9H, butyl–CH2–CH3), 0.91
(m, 2H, 7-H), 4.03 (dd, J5a,4¼4.5 Hz, J5a,5b¼10.0 Hz, 1H, 5a-H), 4.05–
4.09 (m, 1H, 2-H), 4.14 (dd, J5b,4¼2.5 Hz, 1H, 5b-H), 4.53 (br s, 1H, 3-
OH), 5.06–5.10 (m, 1H, 3-H), 5.30–5.35 (m, 1H, 4-H), 5.71 (6-NH2 in
adenine), 7.54–7.58 (m, 2H, Bz-H), 7.65–7.9 (m, 3H, Bz-H), 8.01 (s,
1H, H-2 in adenine), 8.28 (s, 1H, H-8 in adenine).
(t, 6H, butyl–CH2–), 1.20–1.31 (m, 6H, butyl–CH2–), 1.42–1.54 (m,
6H, butyl–CH2–), 1.94 (s, 3H, T-CH3), 4.07 (dd, 1H, J5a,4¼3.0 Hz,
J5a,5b¼10.5 Hz, 5a-H), 4.31 (dd, 1H, J5b,4¼7.0 Hz, 5b-H), 4.40–4.43
(m,1H, J2,6¼5.0 Hz, 2-H), 5.20 (dd,1H, J2,3¼6.0 Hz, 3-H), 5.33 (m,1H,
J3,4¼3.0 Hz, 4-H), 6.21 (dd, 1H, J6,7¼19.0 Hz, 6-H), 6.52 (d, 1H, 7-H),
7.27 (s, 1H, 6-H in thymine), 7.47 (t, 2H, Bz), 7.60 (t, 1H, Bz), 8.02 (d,
3.1.8. {2S-[2-Hydroxyethyl]-3R-hydroxyl-4S-(thymin-1-yl)}-
tetrahydrofuran (2a)
2H, Bz), 8.06 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3):
d 9.5, 12.6,
13.6, 27.2, 29.0, 30.9, 60.8, 70.7, 82.3, 85.8, 112.0, 128.5, 128.9, 129.8,
133.6, 133.8, 136.4, 142.3, 150.4, 163.0, 165.4; HRMS (TOF) calcd for
C
To the solution of 9 (20 mg, 0.055 mmol) in anhydrous MeOH
(10 mL), 30% NaOMe in MeOH (0.15 mL) was added. The mixture
was stirred at room temperature for 1 h and evaporated. The resi-
due was purified by silica gel chromatography (CH2Cl2/MeOH) to
30H45N2O5Sn (MþH)þ: 633.2344, found: 633.2373.
3.1.4. [2S-(1-Vinyl)-3R-benzoxy-4S-(thymin-1-yl)]-tetra-
hydrofuran (8a)
give 2a (13 mg, 91.4%) as a white solid.
20
[a
]
þ8.39 (c 0.155, MeOH); UV (MeOH): lmax¼271 nm (
3
8600).
D
To a solution of 7a (250 mg, 0.395 mmol) in dry EtOH (50 mL),
NH4F (650 mg, 19.7 mmol) was added and the resulting solution
was refluxed for 3 days, and then evaporated. The residue was
purified by silica gel column chromatography (petroleum ether/
EtOAc) to give 8a (129 mg, 95.2%).
1H NMR (300 MHz, DMSO-d6):
d 1.92 (s, 3H, thymine-CH3), 1.88–
2.05 (m, 2H, 6-H), 3.63–3.87 (m, 2H, 7-H), 3.88–3.92 (m, 1H, 2-H),
4.01 (dd,1H, J5a,4¼2.7 Hz, J5a,5b¼10.5 Hz, 5a-H), 4.04–4.09 (m,1H, 3-
H), 4.19 (dd, 1H, J5b,4¼6.9 Hz, 5b-H), 4.51 (t, J¼5.0 Hz, 1H, 7-OH),
4.95–4.99 (m, 1H, J3,4¼6.6 Hz, 4-H), 5.73 (d, J¼5.5 Hz, 1H, 3-OH),
7.27 (s, 1H, 6-H in thymine), 9.39 (br s, 1H, –NH); 13C NMR (75 MHz,
1H NMR (300 MHz, CDCl3):
d 1.87 (s, 3H, thymine-CH3), 4.02 (dd,
1H, J5a,4¼2.7 Hz, J5a,5b¼10.5 Hz, 5a-H), 4.23 (dd, 1H, J5b,4¼6.9 Hz,
5b-H), 4.36–4.40 (m, 1H, 2-H), 5.13 (dd, 1H, J2,3¼6.0 Hz, 3-H), 5.26–
5.31 (m, 2H, 4-H, 7a-H), 5.42–5.45 (m, 1H, 7b-H), 6.04 (dd, 1H,
J6,7¼17.8, 5.28 Hz, 6-H), 7.19 (s, 1H, 6-H in thymine), 7.38 (t, 2H, Bz-
H), 7.53 (t,1H, Bz-H), 7.96 (d, 2H, Bz-H), 8.90 (br s,1H, NH); 13C NMR
DMSO-d6): d 12.1, 35.8, 57.7, 62.4, 68.2, 78.7, 80.4, 109.5, 137.7, 151.1,
163.8; HRMS (TOF) calcd for C12H17N2O5 (MþH)þ: 257.1137, found:
257.1140.
3.1.9. {2S-[2-Hydroxyethyl]-3R-hydroxyl-4S-(adenin-1-yl)}-
(75 MHz, CDCl3):
d
12.6, 61.0, 70.9, 81.5, 82.4, 112.2, 118.4, 128.6,
tetrahydrofuran (2b)
20
128.8, 129.9, 133.7, 136.7, 136.4, 150.4, 163.0, 165.7; HRMS (TOF)
[a
]
þ41.07 (c 0.056, MeOH); UV (MeOH): lmax¼260.5 nm
D
calcd for C18H19N2O5 (MþH)þ: 343.1288, found: 343.1287.
(3 d 1.68–1.75 (m, 1H, 6-H),
12,250). 1H NMR (500 MHz, DMSO-d6):

9634
Y.-C. Liu et al. / Tetrahedron 64 (2008) 9630–9635
1.79–1.86 (m, 1H, 6-H), 3.35–3.60 (m, 2H, 7-H), 3.73–3.77 (m, 1H, 2-
H), 4.12 (dd, J5a,5b¼9.5 Hz, J5a,4¼1.0 Hz, 1H, 5a-H), 4.16 (dd,
J5b,4¼2.0 Hz, 1H, 5b-H), 4.27–4.31 (m, 1H, 3-H), 4.51 (t, J¼5.0 Hz, 1H,
7-OH), 4.84–4.88 (m, 1H, 4-H), 5.73 (d, J¼5.5 Hz, 1H, 3-OH), 7.25 (s,
2H, –NH2), 8.16 (s, 1H, 2-H in adenine), 8.17 (s, 1H, 8-H in adenine);
d 36.2, 57.7, 61.8, 68.7, 79.0, 81.0,
119.0, 139.3, 149.5, 152.4, 156.0. Anal. Calcd for C11H15N5O3: C,
49.81; H, 5.70; N, 26.40. Found: C, 50.01; H, 6.00; N, 26.33.
1H NMR (500 MHz, CDCl3):
d 0.88–0.93 (m, 15H, butyl–CH2–
CH3), 1.28–1.36 (m, 6H, butyl–CH2–),1.48–1.54 (m, 6H, butyl–CH2–),
2.39 (s, 3H, Ts-CH3), 3.83 (dd, J5a,5b¼10.5 Hz, J5a,4¼2.5 Hz, 1H, 5a-H),
4.40 (dd, J5b,4¼5.5 Hz, 1H, 5b-H), 4.55–4.57 (m, 1H, 2-H), 5.08 (dd,
J3,4¼2.0 Hz, J2,3¼4.0 Hz, 1H, 3-H), 5.39–5.40 (m, 1H, 4-H), 6.00 (dd,
J2,6¼6.0 Hz, J6,7¼19 Hz, 1H, 6-H), 6.44 (dd, J2,7¼1.0 Hz, 1H, 7-H),
7.29–7.32 (m, 2H, Bz), 7.44–7.48 (m, 2H, Bz), 7.58–7.64 (m, 1H, Bz),
7.81–7.84 (m, 2H, Ts), 7.96–8.00 (m, 2H, Ts); 13C NMR (125 MHz,
13C NMR (125 MHz, DMSO-d6):
CDCl3):
d 9.4, 10.7, 13.6, 21.6, 27.2, 29.0, 71.1, 77.7, 83.1, 127.9, 128.1,
3.1.10. [2R-Dimethoxymethyl-3S-p-toluenesulfonyl-4R-benzoxy]-
tetrahydrofuran (11)
128.4, 129.0, 129.7, 129.8, 133.5, 136.0, 139.7, 145.1, 165.0. Anal. Calcd
for C32H46O6SSn: C, 56.73; H, 6.84. Found: C, 56.87; H, 6.80.
To the solution of 1018 (1.99 g, 5.99 mmol) in dry pyridine
(40 mL), BzCl (1.05 mL, 9.11 mmol) and DMAP (77 mg, 0.63 mmol)
were added. The reaction mixture was stirred at room temperature
overnight and then evaporated. The residue was dissolved in EtOAc,
washed with satd NaHCO3 solution and brine, dried over anhydrous
Na2SO4, and evaporated. The residue was purified by silica gel
column chromatography (petroleum ether/EtOAc) to give 11
(2.56 g, 98.1%).
3.1.13. [2S-2-Vinyl-3R-p-toluenesulfonyl-4R-benzoxy]-
tetrahydrofuran (15)
To the solution of 14 (129 mg, 0.19 mmol) in dry EtOH (6 mL),
NH4F (331 mg, 10.03 mmol) was added and the resulting solution
was refluxed for 28 h and then evaporated. The residue was puri-
fied by silica gel column chromatography (petroleum ether/EtOAc)
to yield 15 (50 mg, 67.6%) as a white solid.
20
1H NMR (500 MHz, CDCl3):
d
2.42 (s, 3H, Ts-CH3), 3.32 (s, 3H,
[
a
]
ꢁ1.25 (c 0.400, MeOH). 1H NMR (500 MHz, CDCl3):
d 2.40
D
–OCH3), 3.46 (s, 3H, –OCH3), 3.90 (dd, J5a,5b¼11.0 Hz, J5a,4¼2.5 Hz,
1H, 5a-H), 4.15 (dd, J2,3¼3.5 Hz, J2,6¼7.0 Hz, 1H, 2-H), 4.37 (dd,
J5b,4¼5.0 Hz, 1H, 5b-H), 4.53 (d, 1H, 6-H), 5.15 (dd, J3,4¼1.0 Hz,
J2,3¼3.5 Hz, 1H, 3-H), 5.35–5.36 (m, 1H, 4-H), 7.35 (d, 2H, Bz), 7.43–
7.47 (m, 2H, Bz-H), 7.58–7.60 (m, 1H, Bz-H), 7.88 (d, 2H, Ts), 7.96–
(s, 3H, Ts-CH3), 3.84 (dd, J5a,5b¼10.5 Hz, J5a,4¼3.0 Hz, 1H, 5a-H), 4.39
(dd, J5b,4¼4.5 Hz, 1H, 5b-H), 4.56–4.59 (m, 1H, 2-H), 5.07 (dd,
J3,4¼4.0 Hz, J2,3¼1.5 Hz, 1H, 3-H), 5.28–5.30 (m, J7a,7b¼1.5 Hz,
J7a,6¼10.5 Hz, 1H, 7a-H), 5.36–5.42 (m, 2H, 4-H, 7b-H), 5.80–5.80
(m, J7b,6¼17.0 Hz, 1H, 6-H), 7.30–7.32 (d, 2H, Bz), 7.44–7.48 (m, 2H,
Bz), 7.59–7.62 (m, 1H, Bz), 7.82–7.84 (d, 2H, Ts), 7.96–7.99 (m, 2H,
7.98 (m, 2H, Ts); 13C NMR (125 MHz, CDCl3):
d 21.6, 53.9, 55.5, 71.9,
76.9, 79.2, 82.3, 101.9, 128.0, 128.4, 128.8, 129.7, 129.9, 133.3, 133.6,
145.3, 164.8. Anal. Calcd for C21H24O8S: C, 57.79; H, 5.54. Found: C,
57.54; H, 5.46.
Ts); 13C NMR (125 MHz, CDCl3):
d 21.6, 71.2, 77.7, 80.9, 83.3, 119.9,
128.0, 128.5, 128.9, 129.7, 129.9, 130.9, 133.2, 133.6, 145.3, 165.0.
Anal. Calcd for C20H20O6S: C, 61.84; H, 5.19. Found: C, 61.70; H, 5.32.
3.1.11. {2S-[2(E)-p-Toluenesulfonylethylene]-3R-p-toluenesulfonyl-
4R-benzoxy}-tetrahydrofuran (13)
3.1.14. {2S-[2-O-tert-Butyldimethylsilyl-ethyl]-3R-p-
toluenesulfonyl-4R-benzoxy}-tetrahydrofuran (17)
Compound 11 (440 mg, 1.01 mmol) was dissolved in trifluoro-
acetic acid (3.5 mL) and water (0.5 mL). The solution was stirred for
5 h at room temperature. After evaporation of most solvents, the
residue was dissolved in CH2Cl2, washed with satd NaHCO3 and
brine, and dried over Na2SO4. Solvents were removed to afford
white foam (crude 12). To a solution of crude 12 in anhydrous
THF (10 mL), [(p-tolylsulfonyl)methylene]triphenylphosphorane
(475 mg, 1.10 mmol) was added and the mixture was stirred for
20 h at room temperature. Saturated NH4Cl solution was added to
quench the reaction and the aqueous system was thoroughly
extracted with EtOAc. After drying over Na2SO4, the organic ex-
tracts were evaporated and the residue was purified by silica gel
column chromatography (petroleum ether/EtOAc) to yield 13
To a solution of 15 (169 mg, 0.435 mmol) in anhydrous THF
(3.5 mL), 9-BBN (0.5 M in THF, 4.5 mL, 2.25 mmol) was added under
an inert atmosphere. The mixture was stirred for 3 h at room
temperature and then H2O (1 mL), 0.5 M NaOH solution (15.8 mL,
7.9 mmol), and 30% H2O2 (3.05 mL, 30.32 mmol) were added. After
the mixture was kept stirring for another 3 h at 0 ꢀC, satd NH4Cl
solution was added to quench the reaction. The aqueous system
was extracted with EtOAc, washed with brine, dried over anhy-
drous Na2SO4, and then evaporated. The residue was purified
quickly by silica gel column chromatography (petroleum ether/
EtOAc) to give crude 16. To the solution of crude 16 in dry DMF
(3.5 mL), TBDMSCl (69 mg, 0.46 mmol) and imidazole (76 mg,
1.11 mmol) were added and the mixture was stirred for 2 h at room
temperature. Water was added to quench the reaction and the
solvent was evaporated. The residue was purified by silica gel col-
umn chromatography (petroleum ether/EtOAc) to yield 17 (137 mg,
(390 mg, 71.3%) as a white foam.
20
[a
]
ꢁ97.50 (c 0.040, MeOH). 1H NMR (500 MHz, CDCl3):
d 2.44
D
(s, 6H, Ts-CH3), 3.92 (dd, J5a,5b¼11.0 Hz, J5a,4¼2.0 Hz, 1H, 5a-H), 4.34
(dd, J5b,4¼4.5 Hz, 1H, 5b-H), 4.82–4.84 (m, 1H, 2-H), 5.13 (dd,
J3,4¼1.5 Hz, J2,3¼4.0 Hz, 1H, 3-H), 5.40–5.41 (m, 1H, 4-H), 6.79 (dd,
J6,7¼15 Hz, J2,7¼1.5 Hz, 1H, 7-H), 6.81 (dd, J2,6¼4.0 Hz, 1H, 6-H),
7.34–7.38 (m, 4H, Ts, Bz), 7.44–7.47 (m, 2H, Bz), 7.59–7.62 (m, 1H,
Bz), 7.78–7.84 (m, 4H, Ts), 7.95–7.96 (m, 2H, Ts); 13C NMR (125 MHz,
60.6%) as a colorless syrup.
[
a
]
D
ꢁ73.08 (c 0.026, MeOH). 1H NMR (500 MHz, CDCl3):
d 0.04
20
(s, 6H, TBDMS-CH3), 0.88 (s, 9H, TBDMS-tBu), 1.74–1.80 (m, 1H,
–CH2–), 1.86–1.93 (m, 1H, –CH2–), 2.38 (s, 3H, Ts-CH3), 3.66–3.75
(m, 3H, 5a-H, –CH2–O–), 4.27–4.30 (m, 1H, 2-H), 4.34 (dd,
J5a,5b¼10.5 Hz, J5b,4¼5.5 Hz, 1H, 5b-H), 5.03 (dd, J3,4¼1.0 Hz,
J2,3¼4.0 Hz, 1H, 3-H), 5.30–5.32 (m, 1H, 4-H), 7.31 (d, 2H, Bz-H),
7.43–7.46 (m, 2H, Bz-H), 7.58–7.61 (m, 1H, Bz-H), 7.84–7.85 (m, 2H,
CDCl3):
d 21.6, 21.7, 71.6, 77.3, 78.2, 81.5, 128.0, 128.1, 128.6, 128.7,
129.8, 130.0, 130.3, 132.4, 133.7, 133.8, 136.8, 137.5, 144.6, 145.8,
164.8. Anal. Calcd for C27H26O8S2: C, 59.76; H, 4.83. Found: C, 59.90;
H, 5.02.
Ts), 7.95–7.97 (m, 2H, Ts); 13C NMR (125 MHz, CDCl3):
18.2, 21.6, 25.8, 31.6, 59.4, 71.0, 76.6, 77.8, 83.4, 127.9, 128.4, 129.0,
129.7, 130.0, 133.3, 133.5, 145.3, 164.9. Anal. Calcd for C26H36O7SSi:
C, 59.97; H, 6.97. Found: C, 60.14; H, 6.83.
d
ꢁ5.5, ꢁ5.4,
3.1.12. {2S-[2(E)-Tributylstannylvinyl]-3R-p-toluenesulfonyl-4R-
benzoxy}-tetrahydrofuran (14)
To a solution of 13 (1.68 g, 3.10 mmol) and AIBN (118 mg,
0.71 mmol) in toluene (40 mL), Bu3SnH (2.7 mL, 9.7 mmol) was
added under an inert atmosphere. The reaction mixture was
refluxed for 5 h and then evaporated. The residue was purified by
silica gel column chromatography (petroleum ether/EtOAc) to give
14 (1.85 g, 88.1%) as a colorless syrup.
3.1.15. {2S-[2-O-tert-Butyldimethylsilyl-ethyl]-3S,4R-epoxy}-
tetrahydrofuran (18)
Compound 17 (176 mg, 0.34 mmol) and anhydrous K2CO3
(224 mg, 1.62 mmol) were dissolved in dry methanol (4 mL), the
resulting suspension was stirred for 1.5 h at room temperature. The

Y.-C. Liu et al. / Tetrahedron 64 (2008) 9630–9635
9635
mixture was neutralized with acetic acid and evaporated. The
residue was purified by silica gel column chromatography (petro-
leum ether/EtOAc) to yield 18 (74 mg, 89.6%) as a colorless syrup.
TOF MS m/z: 371 (MþH)þ. Anal. Calcd for C17H30N2O5Si: C, 55.11; H,
8.16; N, 7.56. Found: C, 55.16; H, 8.18; N, 7.46.
Compound 20a. 1H NMR (300 MHz, DMSO-d6):
d 0.00 (s, 3H,
20
[
a]
ꢁ17.10 (c 0.025, MeOH). 1H NMR (500 MHz, CDCl3):
d
0.06
TBDMS-CH3), 0.01 (s, 3H, TBDMS-CH3), 0.85 (s, 9H, TBDMS-tBu),
1.17–1.23 (m, 2H, 6-H), 1.92 (s, 3H, thymine-CH3), 3.56–3.60 (m, 3H,
2-H, 7-H), 4.28–4.30 (m, 1H, 5a-H), 4.56–4.58 (m, 2H, 5b-H, 4-H),
4.89 (d, 1H, 3-H), 5.90 (d, 1H, 4-OH), 7.27 (s, 1H, 6-H in thymine),
9.39 (br s, 1H, –NH); ESI-TOF MS m/z: 371 (MþH)þ.
D
(s, 6H, TBDMS-CH3), 0.90 (s, 9H, TBDMS-tBu), 1.56–1.61 (m, 1H, 6a-
H), 1.64–1.71 (m, 1H, 6b-H), 3.69–3.76 (m, 5H, 7-H, 3-H, 4-H, 5b-H),
3.98 (d, J5a,5b¼11.0 Hz, 1H, 5a-H), 4.23 (dd, J2,6a¼5.5 Hz, J2,6b¼7.5 Hz,
1H, 2-H); 13C NMR (125 MHz, CDCl3):
d
ꢁ5.4, 18.2, 25.9, 34.0, 55.9,
59.1, 59.3, 66.0, 75.2. Anal. Calcd for C12H24O3Si: C, 58.97; H, 9.90.
Found: C, 58.69; H, 9.76.
3.1.18. Deprotection procedure of 19a or 19b to synthesize 2a or 2b
A solution of compound 19b (56 mg, 0.148 mmol) and TBAF (1 M
in THF, 0.3 mL, 0.3 mmol) in THF (2 mL) was stirred for 3 h at room
temperature. The resulting mixture was evaporated and the residue
was purified by silica gel column chromatography (CH2Cl2/MeOH)
to give 2b (26 mg, 66.5%) as a white solid.
3.1.16. {2S-[2-O-tert-Butyldimethylsilyl-ethyl]-3R-hydroxy-4S-
(adenin-9-yl)}-tetrahydrofuran (19b) and {2S-[2-O-tert-
butyldimethylsilyl-ethyl]-3R-(adenin-9-yl)-4S-hydroxy}-
tetrahydrofuran (20b)
To a solution of 18 (121 mg, 0.50 mmol) and dry adenine
(130 mg, 0.96 mmol) in dry DMF (12 mL), DBU (0.25 mL,
1.64 mmol) was added, the mixture was heated to 110 ꢀC for 5 days.
After the mixture was cooled to room temperature, the solvent was
evaporated and the residue was purified by silica gel column
chromatography (CH2Cl2/MeOH) to give 19b (white solid, 88 mg,
46.8%) and 20b (white solid, 9.4 mg, 5.0%).
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20332010 and 20472006) and a Foundation
for the Author of National Excellent Doctoral Dissertation of PR
China (FANEDD200265).
Compound 19b. 1H NMR (500 MHz, DMSO-d6):
d 0.03 (s, 3H,
TBDMS-CH3), 0.04 (s, 3H, TBDMS-CH3), 0.87 (s, 9H, TBDMS-tBu),
1.69–1.76 (m, 1H, 6-H), 1.82–1.88 (m, 1H, 6-H), 3.67–3.77 (m, 3H, 2-
H, 7-H), 4.10–4.17 (m, 2H, 5-H), 4.28–4.30 (m, 1H, 3-H), 4.83–4.87
(m, 1H, 4-H), 5.72 (d, J¼6.0 Hz, 1H, 3-OH), 7.23 (br s, 2H, 6-NH2 in
adenine), 8.14 (s, 1H, 2-H in adenine), 8.15 (s, 1H, 8-H in adenine);
References and notes
1. Zamecnik, P. C.; Stephensen, M. L. Proc. Natl. Acad. Sci. U.S.A. 1978, 75, 280–284.
2. Wagner, R. W.; Flanagan, W. M. Mol. Med. Today 1997, 3, 31–38.
3. Holmlund, J. T.; Monia, B. P.; Kwoh, T. J.; Dorr, F. A. Curr. Opin. Mol. Ther. 1999, 1,
372–385.
4. Opalinska, J. B.; Gewirtz, A. M. Nat. Rev. Drug. Discov. 2002, 1, 1503–1514.
5. Lebedeva, I. V.; Stein, C. A. Biodrugs 2000, 13, 195–216.
6. Baker, B. F.; Lot, S. S.; Condon, T. P.; Cheng-Flournoy, S.; Lesnik, E. A.; Sasmor, H.
M.; Bennett, C. F. J. Biol. Chem. 1997, 272, 11994–12000.
7. Wahlestedt, C.; Salmi, P.; Good, L.; Kela, J.; Johnsson, T.; Hokfelt, T.; Broberger,
C.; Porreca, F.; Lai, J.; Ren, K.; Ossipov, M.; Koshkin, A.; Jakobsen, N.; Skouv, J.;
Oerum, H.; Jacobsen, M. H.; Wengel, J. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5633–
5638.
8. Yang, Z.-J.; Zhang, H.-Y.; Min, J.-M.; Ma, L.-T.; Zhang, L.-H. Pure Appl. Chem. 1999,
71, 1143–1146.
9. Yang, Z.-J.; Zhang, H.-Y.; Min, J.-M.; Ma, L.-T.; Zhang, L.-H. Helv. Chim. Acta 1999,
82, 2037–2043.
10. Lei, Z.; Zhang, L.; Zhang, L.-R.; Chen, J.; Min, J.-M.; Zhang, L.-H. Nucleic Acids Res.
2001, 29, 1470–1475.
11. Chen, J.; Zhang, L.-R.; Min, J.-M.; Zhang, L.-H. Nucleic Acids Res. 2002, 30, 3005–
3014.
13C NMR (125 MHz, DMSO-d6):
d
ꢁ5.4, ꢁ5.3, 17.9, 25.8, 36.0, 59.5,
61.9, 68.7, 78.8, 80.5, 119.0, 139.2, 149.4, 152.3, 156.0; ESI-TOF MS
m/z: 380.28 (MþH)þ, 402.27 (MþNa)þ. Anal. Calcd for
C
17H29N5O3Si: C, 53.80; H, 7.70; N, 18.45. Found: C, 53.93; H, 7.77;
N, 18.35.
Compound 20b. 1H NMR (300 MHz, DMSO-d6):
d
0.01 (s, 3H,
TBDMS-CH3), 0.00 (s, 3H, TBDMS-CH3), 0.86 (s, 9H, TBDMS-tBu),
1.16–1.22 (m, 2H, 6-H), 3.55–3.59 (m, 3H, 2-H, 7-H), 4.28–4.29 (m,
1H, 5a-H), 4.56–4.58 (m, 2H, 5b-H, 4-H), 4.89 (d, 1H, J¼4.0 Hz, 3-H),
5.90 (d, 1H, J¼3.5 Hz, 4-OH), 7.37 (s, 2H, –NH2 in adenine), 7.96 (s,
1H, 2-H in adenine), 8.23 (s, 1H, 8-H in adenine); ESI-TOF MS m/z:
380.28 (MþH)þ, 402.27 (MþNa)þ.
12. Wang, Z. L.; Shi, J. F.; Jin, H. W.; Zhang, L. R.; Lu, J. F.; Zhang, L. H. Bioconjugate
Chem. 2005, 16, 1081–1087.
3.1.17. {2S-[2-O-tert-Butyldimethylsilyl-ethyl]-3R-hydroxy-4S-
(thymin-9-yl)}-tetrahydrofuran (19a) and {2S-[2-O-tert-
butyldimethylsilyl-ethyl]-3R-(thymin-1-yl)-4S-hydroxy}-
tetrahydrofuran (20a)
13. Li, Z. S.; Qiao, R. P.; Du, Q.; Yang, Z. J.; Zhang, L. R.; Zhang, P. Z.; Liang, Z. C.;
Zhang, L. H. Bioconjugate Chem. 2007, 18, 1017–1024.
14. Tian, X. B.; Min, J. M.; Zhang, L. H. Tetrahedron: Asymmetry 2000, 11, 1877–1889.
15. Guan, Z.; Tian, X.-B.; Zhang, L.-R.; Min, J.-M.; Zhang, L.-H. Helv. Chim. Acta 2002,
82, 1479–1484.
16. Yu, H. W.; Zhang, L. R.; Zhou, J. C.; Ma, L. T.; Zhang, L. H. Bioorg. Med. Chem. 1996,
4, 609–614.
17. Wang, J. F.; Yang, X. D.; Zhang, L. R.; Yang, Z. J.; Zhang, L. H. Tetrahedron 2004, 60,
8535–8546.
18. Tam, S.; Holman, M.; Huryn, D.; Cislo, A. Nucleosides Nucleotides 1991, 10, 245–
248.
19. (a) See Ref. 16. (b) Yang, Z. J.; Yu, H. W.; Min, J. M.; Ma, L. T.; Zhang, L. H. Tet-
rahedron: Asymmetry 1997, 8, 2739–2747.
20. Zhang, J.; Qiao, R. P.; Wang, Z.; Yang, Z. J.; Zhang, L. R.; Zhang, L. H., unreported
results, 2008.
Compounds 19a (white solid, 35.5%) and 20a (white solid, 4.0%)
were obtained by the same method as that for compounds 19b and
20b.
Compound 19a. 1H NMR (500 MHz, DMSO-d6):
d 0.03 (s, 3H,
TBDMS-CH3), 0.04 (s, 3H, TBDMS-CH3), 0.87 (s, 9H, TBDMS-tBu),
1.69–1.76 (m, 1H, 6-H), 1.82–1.88 (m, 1H, 6-H), 1.92 (s, 3H, thymine-
CH3), 3.67–3.77 (m, 3H, 2-H, 7-H), 4.10–4.17 (m, 2H, 5-H), 4.29–4.31
(m, 1H, 3-H), 4.83–4.86 (m, 1H, 4-H), 5.72 (d, J¼6.0 Hz, 1H, 3-OH),
7.27 (s, 1H, 6-H in thymine), 9.39 (br s, 1H, 3-NH in thymine); ESI-