A short and efficient synthesis of L-thioarbinose derivative: A versatile synthon for the synthesis of l-2'-deoxy-2',2'-disubstituted-4'- thionucleosides

Full text of DOI:10.1021/jo980196+

J . Org. Chem. 1998, 63, 4821-4825
4821
exhibited weak antineoplastic activity, while 2′-C-meth-
ylene derivative (2) showed very potent antileukemic
activity.10
A Sh or t a n d Efficien t Syn th esis of
L-Th ioa r a bin ose Der iva tive: A Ver sa tile
Syn th on for th e Syn th esis of L-2′-Deoxy-
2′,2′-d isu bstitu ted -4′-th ion u cleosid es
Lak Shin J eong,*,† Hyung Ryong Moon,† Yeon J u Choi,‡
Moon Woo Chun,‡ and Hea Ok Kim§
Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans University, Seoul 120-750, Korea, College of
Pharmacy, Seoul National University, Seoul 151-742, Korea,
and Department of Industrial Safety and Hygiene, Kyungin
Women’s College, Incheon 407-050, Korea
Received February 4, 1998
Another type of nucleoside belonging to the L-series,
such as (-)-L-â-1,3-dioxolanylcytosine [3, L(-)OddC],11
has been shown to be highly active against solid tumors
and is currently under development. Its mechanism of
action appears to be chain termination of the DNA
polymer after incorporation.12 This finding prompted us
to investigate the corresponding L-2′-deoxy-2′,2′-disub-
stituted-4′-thiocytidine analogues (4 and 5), which were
expected to combine the properties of 4′-thio and L-
nucleoside series. In keeping with Yoshimura’s meth-
odology, L-glucose appeared to be the logical starting
material of choice. However, L-glucose is too expensive,
and D-xylose was chosen instead. In this paper, we wish
to report a short and efficient synthesis of L-4-thioarabitol
derivative 12 starting from 1,2-isopropyidene-D-xylose.
Compound 12 represents a versatile synthon for the
synthesis of L-2′-deoxy-2′,2′-disubstituted-4′-thionucleo-
sides 4 and 5.
In tr od u ction
4′-Thionucleosides, which are bioisosteric to clinically
useful 4′-oxonucleosides, show interesting activities such
as antibiotic,1 antiviral,2 and antineoplastic.3 Despite
these encouraging results and other inherent advantages,
such as having a more stable glycosyl bond and increased
metabolic stability,4 difficulties in accessing the requisite
4-thiosugars,5 which normally involves numerous and
low-yielding steps, have prevented their development as
clinical agents. Although several groups published im-
proved syntheses of D-2′-deoxy-4′-thio-,6 D-4′-thioribo-,7
and D-2′,3′-dideoxy-4′-thionucleosides8 in the early 1990s,
the synthesis of 4-thiosugars continues to be a challenge
for the synthesis of 4′-thionucleosides.
Current interest in the L-nucleosides as biologically
active compounds has also spilled over to the 4′-thio
series. Indeed, both D- and L-2′-deoxy-4′-thiopyrimidine
nucleosides have been shown to have antitumor activi-
ties.9 More recently, Yoshimura and co-workers have
reported the elegant synthesis of D-2′-deoxy-2′,2′-disub-
stituted-4′-thiocytidines 1 and 2 via an anhydrothiosugar
prepared from D-glucose. The 2′,2′-difluoro analogue (1)
Resu lts a n d Discu ssion
The synthesis of our key L-4-thioarabitol intermediate
12 is illustrated in Scheme 1. Commercially available
1,2-isopropylidene-D-xylose (6) was benzylated as the
dibenzyl ether 7, which was obtained in quantitative
yield. Removal of the isopropylidene group under acidic
conditions (p-TsOH, MeOH) followed by esterification of
the 2-hydroxyl function provided compound 8 in excellent
yield (86%). Next, we attempted to perform an acid-
catalyzed ring opening reaction with benzyl mercaptan
(BnSH). Although several groups have tried this reaction
on similar substrates, they involved the use of perben-
zylated sugars, which required a rather lengthy process
to later functionalize selectively 2-position. The advan-
tage of compound 8 is that 2-position is protected as a
benzoyl ester that can be easily and selectively removed
for proper functionalization.
* To whom correspondence should be addressed. Tel.: 82-2-360-
3466. Fax: 82-2-360-2851. E-mail: lakjeong@mm.ewha.ac.kr.
† Ewha Womans University.
‡ Seoul National University.
§ Kyungin Women’s College.
(1) Bobek, M.; Whistler, R. L. J . Med. Chem. 1972, 15, 168-171.
(2) Dyson, M. R.; Coe, P. L.; Walker, R. T. J . Chem. Soc., Chem.
Commun. 1991, 741-742.
(3) (a) Ototani, N.; Whistler, R. L. J . Med. Chem. 1974, 17, 535-
537. (b) Secrest, J . A., III; Tiwari, K. N.; Riordan, J . M.; Montgomery,
J . A. J . Med. Chem. 1991, 34, 2361-2366.
(4) Parks, R. E., J r.; Stoeckler, J . D.; Cambor, C.; Savarese, T. M.;
Crabtree, G. W.; Chu, S.-H. Purine Nucleoside Phosphorylase and 5′-
Methylthioadenosine Phosphorylase: Targets of Chemotherapy. In
Molecular Actions and Targets for Cancer Chemotherapeutic Agents;
Sartorelli, A. C., Lazo, J . S., Bertino, J . R., Eds.; Academic Press: New
York, 1981; pp 229-252.
(5) Fu, Y.-L.; Bobek, M. J . Org. Chem. 1976, 41, 3831-3834.
(6) (a) Dyson, M. R.; Coe, P. L.; Walker, R. T. J . Med. Chem. 1991,
34, 2782-2786. (b) Uenishi, J .; Mototama, M.; Nishiyama, Y.; Waka-
bayashi, S. J . J . Chem. Soc., Chem. Commun. 1991, 1421-1422. (c)
Dyson, M. R.; Coe, P. L.; Walker, R. T. Carbohydr. Res. 1991, 216,
237-248. (d) Uenishi, J .; Takahashi, K.; Motoyama, M.; Akashi, H.;
Sasaki, T. Nucleosides Nucleotides 1994, 13, 1347-1361.
(7) (a) Bellon, L.; Barascut, J .-L.; Imbach, J .-L. Nucleosides Nucle-
otides 1992, 13, 1467-1479. (b) Leydier, C.; Bellon, L.; Barascut, J .-
L.; Deydier, J .; Maury, G.; Pelicano, H.; El Alaoui, M. A.; Imbach, J .-
L. Nucleosides Nucleotides 1994, 13, 2035-2050.
We first tried a conventional approach involving the
reaction of 8 with BnSH in conc HCl,13 but the reaction
produced many byproducts and the yield of 9 was very
(10) (a) Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura,
S.; Sakata, S.; Sasaki, T.; Matsuda, A. J . Org. Chem. 1996, 61, 822-
823. (b) Yoshimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.; Watanabe,
M.; Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. J . Org. Chem. 1997,
62, 3140-3152.
(11) (a) Kim, H. O.; Shanmuganathan, K.; Alves, A. J .; J eong, L. S.;
Beach, J . W.; Schinazi, R. F.; Chang, C.-N.; Cheng, Y.-C.; Chu, C. K.
Tetrahedron Lett. 1992, 57, 2217-2219. (b) Kim, H. O.; Schinazi, R.
F.; Shanmuganathan, K.; J eong, L. S.; Beach, J . W.; Nampalli, S.;
Cannon, D. L.; Chu, C. K. J . Med. Chem. 1993, 36, 519-528.
(8) Secrest, J . A., III; Riggs, R. M.; Tiwari, K. N.; Montgomery, J .
A. J . Med. Chem. 1992, 35, 533-538.
(9) Uenishi, J .; Takahashi, K.; Motoyama, M.; Akashi, H.; Sasaki,
T. Nucleosides Nucleotides 1994, 13, 1347-1361.
S0022-3263(98)00196-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/12/1998

4822 J . Org. Chem., Vol. 63, No. 14, 1998
Notes
Sch em e 1a
a
Reagents: (a) NaH, n-Bu4NI, BnBr, THF; (b) p-TsOH, MeOH, rt; (c) BzCl, pyridine, rt; (d) BnSH, BF3‚Et2O, 40 °C; (e) MsCl, pyridine,
rt, then n-Bu4NI, BaCO3, reflux; (f) NaOMe, MeOH, CH2Cl2, rt; (g) DMSO, Ac2O, rt; (h) DAST, CH2Cl2, rt; (i) Hg(OAc)2, AcOH, rt; (j)
Et3SiH, TMSOTf, rt; (k) Ph3PCH3Br, NaH, tert-amyl alcohol, rt.
low. Among the several combinations of Lewis acid
catalysts14 (i.e., TiCl4, TMSOTf, SnCl4, and BF3‚Et2O) and
solvents (i.e., THF, CH2Cl2, and ClCH2CH2Cl) only
BF3‚Et2O in CH2Cl2 at 40 °C gave a clean reaction with
an excellent yield of 9 (84%).15 A longer reaction time
(>2 h) resulted in increased decomposition of the product
9. Compound 9 was recyclized to the corresponding
thiosugar 10 in 94% yield via the corresponding meth-
anesulfonate ester in the presence of n-Bu4NI and
BaCO3.7 Initially, we wanted to synthesize the difluoro
anlogue 11 in three steps involving hydrolysis of 10,
oxidation of the resulting alcohol to the ketone, and DAST
fluorination. However, during the oxidation, extensive
decomposition was observed without formation of the
desired ketone. Since it was felt that the benzylthio
aglycon was associated with the failure of the oxidation
reaction, it was decided to remove this functionality prior
to modifying the 2-position. Thus, compound 10 was
converted to the acetate after treatment with Hg(OAc)2/
AcOH, and the removal of the acetate was subsequently
performed with Et3SiH and TMSOTf to give the L-
arabitol derivative.16 To the best of our knowledge, this
is the first example describing the removal of an anomeric
acetate group from a thiofuranose with Et3SiH/TMSOTf.
Hydrolysis of the benzoate ester produced the desired key
intermediate 12, which was obtained in 50% overall yield
from 1,2-isopropylidene-D-xylose (6). Oxidation of 12
with DMSO/Ac2O afforded the corresponding ketone,
which was smoothly converted either to the difluoro
derivative 13 after DAST treatment or into the meth-
ylidene 14 by Wittig reaction.10
Synthesis of the target nucleosides 4 and 5 is shown
in Scheme 2. The difluoro derivative 13 was oxidized to
the sulfoxide with m-CPBA, and this was condensed with
persilylated N-benzoylcytosine and TMSOTf as Lewis
acid catalyst to give 16R (22%) and 16â (18%) after silica
gel column chromatography.10,17 When benzyl ether
groups in 13 were changed to benzoates, to simplify the
final deblocking step, condensation with persilylated
N-benzoylcytosine under the same conditions resulted in
an inseparable anomeric mixture of products with an
increased R/â ratio of products (6.5/1). In the case of the
methylidene derivative, however, benzoate protection
improved the R/â ratio of products (2/1) and resulted in
a better separation, by TLC, than that achieved with
benzyl ether protection. Treatment of 14 with BBr3 in
CH2Cl2 gave the corresponding diol, which was benzoy-
lated to give dibenzoate 15. Under the same conditions
used in the preparation of 16R,â, the condensation
reaction with 15 produced 17R (27%) and 17â (14%).
Treatment of 16R and 16â with BBr3/CH2Cl2 followed by
hydrolysis with NaOMe afforded target compounds 4R
(65%) and 4â (85%), respectively. All benzoyl groups
were removed from 17R and 17â using NaOMe/MeOH
to give 5R (99%) and 5â (99%), respectively. The spec-
troscopic data of the final products (4 and 5) were
identical to those of their enantiomers (1 and 2).10
(12) Cheng, Y.-C.; Chu, C. K.; Grove, K. L.; Guo, X. XII International
Roundtable, Sep 15-19, 1996, La J olla, CA, pp 40 (OP26).
(13) (a) Beauchamp, L.; Sterling, B. L.; Kelsey, J . E.; Biron, K. K.;
Collins, P.; Selway, J .; Lin, J . J .; Schaeffer, H. J . J . Med. Chem. 1988,
31, 144-149. (b) Hatch, R. P.; Shringarpure, J .; Weinreb, S. M. J . Org.
Chem. 1978, 43, 4172-4177.
(14) Branalt, J .; Kvarnstrom, I.; Niklasson, G.; Svensson, S. C. T.
J . Org. Chem. 1994, 59, 1783-1788.
(15) The ring-opening reaction of 8 with BF3‚Et2O proceeded via an
intermediate 2-benzoyl-3,5-dibenzyl-1-(benzylthio)-D-xylofuranose, which
was detectable by TLC. This intermediate, which could be isolated by
column chromatography, was easily converted to the desired product
9 after further reaction with benzyl mercaptan and BF3‚Et2O. This
two-step process is recommended over a direct conversion approach
that leads to the formation of a major side product on longer reaction
time. This side product was almost overlapped with the intermediate
when detected on TLC.
(16) (a) Nair, V.; J effery, A. Tetrahedron Lett. 1995, 36, 3627-3630.
(b) The anomeric thiobenzyl group in 10 could not be removed directly
unless it was converted to the acetate. The successful removal of the
acetate depended upon the amounts of Et3SiH and TMSOTf used.
Optimal conditions were achieved with 3 equiv of Et3SiH and 2 equiv
of TMSOTf.
The nucleosides 4R, 4â, 5R, and 5â were evaluated for
antitumor activity against a panel of cancer cell lines
including SKMEL-2 (melanoma), A 549 (lung cancer),
SKOV3 (ovarian cancer), SNU-1 (stomach cancer), and
K562 (leukemia). In contrast to D-4′-thio compounds 1
and 2, none of our compounds were effective against these
tumor cell lines at concentrations >100 µg/mL.
(17) (a) Kita, Y.; Tamura, O.; Yasuda, H.; Itoh, F.; Tamura, Y. Chem.
Pharm. Bull. 1985, 33, 4235-4241. (b) O’Neil, I. A.; Hamilton, K. M.
Synlett 1992, 791-792.

Notes
J . Org. Chem., Vol. 63, No. 14, 1998 4823
Sch em e 2a
ethyl acetate (500 mL). The organic layer was washed with
brine (200 mL), dried (MgSO4), filtered, and evaporated to give
crude 7 (58 g) as an oil. The crude sample was purified by silica
gel column chromatography (hexanes/ethyl acetate ) 5:1) to give
analytical sample 7: 1H NMR (CDCl3) δ 1.31 (s, 3 H), 1.48 (s, 3
H), 3.74 (dd, 1H, J ) 6.0, 9.6 Hz), 3.78 (dd, 1 H, J ) 6.0, 9.6
Hz), 3.97 (d, 1 H, J ) 3.3 Hz), 4.40 (dt, 1 H, J ) 3.3, 9.6 Hz),
4.51 (d, 1 H, J ) 12.0 Hz), 4.52 (d, 1 H, J ) 12.0 Hz), 4.60 (d, 1
H, J ) 3.9 Hz), 4.61 (d, 1 H, J ) 12.0 Hz), 4.66 (d, 1 H, J ) 12.0
Hz), 5.93 (d, 1 H, J ) 3.9 Hz), 7.24-7.36 (m, 10 H).
Anal. Calcd for C22H26O5: C, 71.33; H, 7.07. Found: C, 71.55;
H, 6.97.
Meth yl 2-Ben zoyl-3,5-d iben zyl-r,â-D-xylofu r a n osid e (8).
To a solution of crude 7 (58 g) in methanol (210 mL) was added
p-TsOH (5.98 g, 31 mmol), and the mixture was stirred at room
temperature overnight. The mixture was neutralized with
triethylamine and evaporated to give the residue. The residue
was dissolved in ethyl acetate (300 mL), washed with brine (150
mL), dried (MgSO4), filtered, and evaporated. The residue was
purified by silica gel column chromatography (hexanes/ethyl
acetate ) 2:1) to give methyl glycoside (50.1 g, 92% from 6) as
an oil.
r-Isom er : 1H NMR (CDCl3) δ 1.86 (d, 1 H, J ) 1.8 Hz), 3.41
(s, 3 H), 3.70 (dd, 1 H, J ) 7.3, 10.3 Hz), 3.77 (dd, 1H, J ) 4.9,
10.3 Hz), 3.96 (dd, 1 H, J ) 2.9, 6.1 Hz), 4.22 (m, 1 H), 4.48 (m,
1 H), 4.55 (d, 1 H, J ) 12.2 Hz), 4.56 (d, 1 H, J ) 12.2 Hz), 4.62
(d, 1 H, J ) 12.2 Hz), 4.65 (d, 1 H, J ) 12.2 Hz), 4.81 (d, 1 H, J
) 1.7 Hz), 7.28-7.35 (m, 10 H).
â-Isom er : 1H NMR (CDCl3) δ 2.72 (d, 1 H, J ) 7.3 Hz), 3.53
(s, 3 H), 3.65 (dd, 1 H, J ) 6.5, 10.5 Hz), 3.72 (dd, 1H, J ) 4.1,
10.5 Hz), 3.99 (dd, 1 H, J ) 4.1, 5.9 Hz), 4.26 (dt, 1 H, J ) 4.1,
7.3 Hz), 4.39 (dt, 1 H, J ) 4.1, 6.5 Hz), 4.52 (d, 1 H, J ) 12.0
Hz), 4.54 (d, 1 H, J ) 12.0 Hz), 4.63 (d, 1 H, J ) 12.0 Hz), 4.73
(d, 1 H, J ) 12.0 Hz), 4.99 (d, 1 H, J ) 4.7 Hz), 7.24-7.35 (m,
10 H).
To a solution of methyl glycoside (50.1 g, 0.146 mol), (N,N-
dimethylamino)pyridine (1.78 g, 0.0146 mol), and pyridine (35
mL, 0.433 mol) in anhydrous methylene chloride (500 mL) was
added benzoyl chloride (18 mL, 0.155 mol) at 0 °C, and the
mixture was stirred at room temperature overnight. The
mixture was diluted with ethyl acetate (400 mL), washed with
diluted HCl and saturated sodium bicarbonate solution, dried
(MgSO4), filtered, and evaporated. The residue was purified by
silica gel column chromatography (hexanes/ethyl acetate ) 7:1)
to give 8 (60.9 g, 93%) as a syrup: 1H NMR (CDCl3) δ 3.36 (s, 3
H), 3.46 (s, 3 H), 3.71 (dd, 1H, J ) 5.9, 10.5 Hz), 3.77-3.82 (m,
3 H), 4.07 (d, 1 H, J ) 5.3 Hz), 4.43-4.70 (m, 10 H), 4.85 (d, 1
H, J ) 12.0 Hz), 5.08 (s, 1 H), 5.22 (t, 1 H, J ) 4.5 Hz), 5.29 (d,
1 H, J ) 4.5 Hz), 5.41 (s, 1 H), 7.25-7.35 (m, 10 H), 7.42-8.05
(m, 5 H).
a
Reagents: (a) m-CPBA, CH2Cl2, -40 °C; (b) silylated N-
benzoylcytosine, TMSOTf, ClCH2CH2Cl, 0 °C to rt; (c) BBr3,
CH2Cl2, -40 °C; (d) BzCl, pyridine, 50 °C; (e) BBr3, CH2Cl2, -40
°C, then NaOMe, MeOH for 16, NaOMe, MeOH for 17.
In summary, we have completed a short and efficient
synthesis of L-4-thioarabinose derivative, the versatile
synthon 12 from an inexpensive source, such as D-xylose.
This compound serves as a convenient synthon for the
synthesis of 2′-deoxy-2′,2′-disubstituted-4′-thionucleo-
sides. None of the target compounds showed antitumor
activity against a panel of five different tumor cell lines.
Anal. Calcd for C27H28O6: C, 73.30; H, 6.29. Found: C, 72.99;
H, 6.57.
2-Ben zoyl-3,5-d iben zyl-D-xylose Diben zyl Dith ioa ceta l
(9). To a solution of 8 (47.7 g, 0.106 mol) and benzyl mercaptan
(50 mL, 0.426 mol) in methylene chloride (210 mL) was added
boron trifluoride etherate (6.5 mL, 0.053 mol), and the mixture
was stirred at 40 °C for 2 h. The mixture was diluted with
saturated NaHCO3 solution and extracted with methylene
chloride (500 mL). The organic layer was dissolved in ethyl
acetate (300 mL), washed with brine (150 mL), dried (MgSO4),
filtered, and evaporated. The residue was purified by silica gel
column chromatography (hexanes/ethyl acetate ) 4:1) to give 9
as a syrup and the intermediate, 2-benzoyl-3,5-dibenzyl-1-
benzylthio-D-xylofuranose, which was repeated under the same
conditions except reaction time (1 h) to give total 59.3 g (84%)
of 9 as a colorless syrup.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. NMR
data were recorded on a 250 and 300 MHz NMR spectrometer
using tetramethylsilane (TMS) as an internal standard, and the
chemical shifts are reported in ppm (δ). Coupling constants are
reported in hertz. The abbreviations used are as follows:
s
(singlet), d (doublet), m (multiplet), dd (doublet of doublet), br s
(broad singlet). Elemental analyses were performed by Ewha
Womans University, general instrument laboratory, Seoul,
Korea. All anhydrous solvents were distilled over CaH2 or P2O5
or Na/benzophenone prior to use.
3,5-Diben zyl-1,2-isopr opyliden e-r-D-xylofu r an ose (7). To
a suspension of NaH (60% in oil, 21.5 g, 0.537 mol) and n-Bu4-
NI (5.83 g, 0.0158 mol) in anhydrous THF (700 mL) was added
6 (30 g, 0.158 mol) in THF (50 mL) slowly at 0 °C, and the
mixture was stirred for 20 min at the same temperature and
then for 30 min at room temperature. The mixture was cooled
to 0 °C, treated with BnBr (41 mL, 0.345 mol) in anhydrous THF
(30 mL), and then stirred at room temperature for 19 h. The
reaction mixture was quenched with water and extracted with
2-Be n zoyl-3,5-d ib e n zyl-1-b e n zylt h io-D-xylofu r a n ose .
â-Isom er : 1H NMR (CDCl3) δ 3.82 (d, 1 H, J ) 5.3 Hz), 3.96 (d,
1 H, J ) 5.3 Hz), 3.90 (d, 1 H, J ) 13.5 Hz), 3.99 (d, 1H, J )
13.5 Hz), 4.05 (d, 1 H, J ) 4.5 Hz), 4.38 (pseudo q, 1 H, J ) 4.5,
5.3 Hz), 4.53 (d, 1 H, J ) 12.0 Hz), 4.60 (d, 1 H, J ) 12.3 Hz),
4.61 (d, 1 H, J ) 12.0 Hz), 4.88 (d, 1 H, J ) 12.3 Hz), 5.17 (d, 1
H, J ) 1.8 Hz), 5.55 (d, 1 H, J ) 1.8 Hz), 7.24-7.98 (m, 20 H).
Anal. Calcd for C33H32O5S: C, 73.31; H, 5.97; S, 5.93.
Found: C, 73.43; H, 6.01; S, 5.99.
r-Isom er : 1H NMR (CDCl3) δ 3.76 (dd, 1 H, J ) 6.3, 10.0
Hz), 3.82 (dd, 1 H, J ) 5.8, 10.0 Hz), 3.90 (s, 2 H), 4.15 (dd, 1H,

4824 J . Org. Chem., Vol. 63, No. 14, 1998
Notes
J ) 1.5, 4.3 Hz), 4.52 (pseudo q, 1 H, J ) 4.3, 5.3 Hz), 4.54 (d,
1 H, J ) 12.0 Hz), 4.60 (d, 1 H, J ) 13.0 Hz), 4.61 (d, 1 H, J )
12.0 Hz), 4.78 (d, 1 H, J ) 13.0 Hz), 5.56 (dd, 1 H, J ) 1.5, 5.3
Hz), 5.64 (d, 1 H, J ) 5.3 Hz), 7.15-8.06 (m, 20 H).
(m, 1 H), 4.30 (t, 1 H, J ) 1.8 Hz), 4.46 (d, 1 H, J ) 12.0 Hz),
4.52 (d, 1 H. J ) 12.0 Hz), 4.69 (s, 2 H), 5.64 (dt, 1 H, J ) 3.3,
5.1 Hz), 7.21-7.95 (m, 15 H).
Anal. Calcd for
C26H26O4S: C, 71.86; H, 6.03; S, 7.38.
Anal. Calcd for C33H32O5S: C, 73.31; H, 5.97; S, 5.93.
Found: C, 73.67; H, 6.32; S, 5.55.
Found: C, 71.67; H, 6.40; S, 7.05.
To a solution of 1,4-anhydro-2-benzoyl-3,5-dibenzoyl-4-thio-
L-arabitol (24.6 g, 56.7 mmol) in methyl alcohol (350 mL) and
methylene chloride (70 mL) was added sodium methoxide (5.7
mL, 5.7 mmol, 1 M methyl alcohol solution), and the mixture
was stirred at room temperature for 2 h. The mixture was
neutralized with acetic acid and evaporated to give the residue.
The residue was dissolved in ethyl acetate (500 mL), washed
with brine (100 mL), dried (MgSO4), filtered, and evaporated.
The residue was purified by silica gel column chromatography
(hexanes/ethyl acetate ) 3.5:1) to give L-thioarabitol 12 (18.4 g,
98%) as an oil: 1H NMR (CDCl3) δ 2.90 (dd, 1 H, J ) 2.4, 11.4
Hz), 3.23 (dd, 1 H, J ) 4.2, 11.4 Hz), 3.51-3.57 (m, 2H), 3.61-
3.66 (m, 2 H), 3.94 (br. t, 1 H), 4.36-4.40 (m, 1 H), 4.53-4.64
(m, 4 H), 7.26-7.35 (m, 10 H).
Com p ou n d 9: 1H NMR (CDCl3) δ 2.13 (d, 1 H, J ) 7.8 Hz),
3.13 (m, 1 H), 3.21 (dd, 1 H, J ) 5.9, 9.3 Hz), 3.56 (dd, 1 H, J )
6.3, 9.3 Hz), 3.66 (d, 1 H, J ) 13.4 Hz), 3.70 (d, 1H, J ) 13.7
Hz), 3.71 (d, 1 H, J ) 13.4 Hz), 3.76 (d, 1 H, J ) 3.7 Hz), 3.84
(d, 1 H, J ) 13.7 Hz), 3.97 (dd, 1 H, J ) 2.4, 7.3 Hz), 4.34 (d, 1
H, J ) 11.9 Hz), 4.40 (d, 1 H, J ) 11.0 Hz), 4.42 (d, 1 H, J )
11.9 Hz), 4.49 (d, 1 H, J ) 11.0 Hz), 5.87 (dd, 1 H, J ) 3.7, 7.3
Hz), 6.89-7.35 (m, 20 H), 7.41-8.09 (m, 5H); 13C NMR (CDCl3)
δ 35.34, 35.91, 49.19, 69.01, 70.75, 73.15, 73.78, 75.15, 78.27,
127.05, 127.06, 127.65, 127.68, 127.70, 128.13, 128.16, 128.35,
128.39, 128.51, 128.61, 129.00, 129.28, 129.94, 129.97, 133.03,
137.58, 137.94, 138.09, 165.84.
Anal. Calcd for C40H40O5S2: C, 72.26; H, 6.06; S, 9.65.
Found: C, 72.56; H, 6.46; S, 9.35.
Anal. Calcd for C19H22O3S: C, 69.06; H, 6.71; S, 9.70.
Found: C, 69.33; H, 6.70; S, 9.43.
Ben zyl 2-Ben zoyl-3,5-d iben zyl-1,4-d ith io-r,â-L-a r a bin o-
fu r a n osid e (10). To a solution of dithioacetal 9 (56 g, 84.3
mmol) in anhydrous pyridine (720 mL) was added methane-
sulfonyl chloride (8.5 mL, 110.0 mmol) at 0 °C, and the mixture
was stirred at room temperature for 5 h. To the mixture were
added barium carbonate (16.7 g, 84.6 mmol) and n-tetrabuty-
lammonium iodide (31 g, 84.0 mmol), and the reaction mixture
was heated under reflux for 3 h. The mixture was evaporated
to give the residue. The residue was dissolved in methylene
chloride (500 mL), washed with brine (150 mL), dried (MgSO4),
filtered, and evaporated. The residue was purified by silica gel
column chromatography (hexanes/ethyl acetate ) 7:1) to give
10 (44 g, 94%) as an oil. 1H NMR indicated that the R-isomer
was the major isomer.
1,4-An h yd r o-2-d eoxy-3,5-d iben zyl-2,2-d iflu or o-4-th io-L-
er yth r o-p en titol (13). A mixture of 12 (0.978 g, 2.96 mmol),
DMSO (15.8 mL, 0.223 mol), and acetic anhydride (7.9 mL, 83.3
mmol) was stirred at room temperature for 5 h. Diethyl ether
and water were added to the mixture. The organic layer was
washed with brine (50 mL) twice, saturated NaHCO3 solution,
and brine, dried (MgSO4), filtered, and evaporated to give the
residue. The residue was purified by silica gel column chroma-
tography (hexanes/ethyl acetate ) 8:1) to give ketone (0.858 g,
88%) as a syrup: 1H NMR (CDCl3) δ 3.35 (s, 2 H), 3.49-3.63
(m, 2 H), 3.72 (dd, 1 H, J ) 4.2, 9.6 Hz), 4.02 (d, 1 H, J ) 8.4
Hz), 4.48 (d, 1 H, J ) 12.0 Hz), 4.54 (d, 1 H. J ) 12.0 Hz), 4.60
(d, 1 H, J ) 11.7 Hz), 4.92 (d, 1 H, J ) 11.7 Hz), 7.26-7.37 (m,
10 H).
r-Isom er : 1H NMR (CDCl3) δ 3.51-3.62 (m, 2 H), 3.75-3.76
(m, 1 H), 3.80 (s, 2H), 4.38 (dd, 1 H, J ) 3.5, 5.3 Hz), 4.46 (d, 1
H, J ) 12.0 Hz), 4.52 (d, 1 H, J ) 12.0 Hz), 4.66 (s, 2 H), 4.69 (d,
1 H. J ) 5.3 Hz), 5.89 (t, 1 H, J ) 5.3 Hz), 7.21-8.04 (m, 20 H);
13C NMR (CDCl3) δ 31.12, 38.27, 49.90, 53.09, 73.86, 74.09,
74.56, 81.71, 85.81, 128.68, 129.08, 129.13, 129.21, 129.78,
129.82, 129.97, 130.01, 130.41, 130.85, 131.31, 134.81, 138.45,
139.07, 139.22, 166.90.
To a solution of ketone (0.308 g, 0.94 mmol) in anhydrous CH2-
Cl2 (5 mL) was added DAST (0.56 mL, 4.2 mmol) solution in
anhydrous CH2Cl2 (2 mL) dropwise over 10 min, and the mixture
was stirred at room temperature for 20 h. Saturated NaHCO3
solution (50 mL) was poured into the mixture and extracted with
CH2Cl2. The organic layer was washed with brine (50 mL), dried
(MgSO4), filtered, and evaporated to give the residue. The
residue was purified by silica gel column chromatography
(hexanes/ethyl acetate ) 15:1) to give 13 (0.241 g, 73%) as a
Anal. Calcd for C33H32O4S2: C, 71.19; H, 5.79; S, 11.52.
Found: C, 71.19; H, 5.98; S, 11.23.
1,4-An h yd r o-3,5-d iben zyl-4-th io-L-a r a bitol (12). To a so-
lution of 10 (42.6 g, 76.6 mmol) in acetic acid (680 mL) was added
mercuric acetate (48.8 g, 153.1 mmol) at 0 °C, and the mixture
was stirred at room temperature for 44 h. The mixture was
evaporated to give the residue. The residue was dissolved in
methylene chloride (700 mL), washed with saturated NaHCO3
solution (150 mL) and brine (150 mL), dried (MgSO4), filtered,
and evaporated. The residue was purified by silica gel column
chromatography (hexanes/ethyl acetate ) 5.5:1) to give acetyl
2-benzoyl-3,5-dibenzyl-L-thioarabinofuranoside (34.2 g, 91%) as
an oil: 1H NMR (CDCl3) δ 1.97 (s, 3 H, R), 2.11 (s, 3 H, â), 3.51-
3.73 (m, 3 H, R; 2 H, â; 1 Η), 3.93 (td, 1 H, J ) 6.0, 6.6 Hz, â),
4.27 (t, 1 H, J ) 4.2 Hz, â), 4.43 (dd, 1 H, J ) 6.0, 9.0 Hz, R),
4.46 (d, 1H, J ) 12.3 Hz, â), 4.51 (d, 1 H, J ) 12.3 Hz, â), 4.56
(s, 2 H, R), 4.62 (d, 1 H, J ) 12.0 Hz, â), 4.69 (d, 1 H, J ) 12.0
Hz, R), 4.70 (d, 1 H, J ) 12.0 Hz, â), 4.74 (d, 1 H, J ) 12.0 Hz,
R), 5.54 (dd, 1 H, J ) 4.5, 9.0 Hz, R), 5.82 (dd, 1 H, J ) 1.8, 4.2
Hz, â), 6.07 (d, 1 H, J ) 1.8 Hz, â), 6.23 (d, 1 H, J ) 4.5 Hz, R),
7.23-8.02 (m, 30 H, R; 15 H, â; 15 Η).
To a solution of acetyl 2-benzoyl-3,5-dibenzyl-L-thioarabino-
furanoside (34.2 g, 69.5 mmol) and triethylsilane (31 mL, 208
mmol) in anhydrous methylene chloride (400 mL) was slowly
added trimethylsilyl trifluoromethanesulfonate (25 mL, 138
mmol) at 0 °C, and the mixture was stirred at room temperature
for 3 h. The reaction mixture was poured into cold saturated
NaHCO3 solution and extracted with methylene chloride (500
mL). The organic layer was washed with brine (200 mL), dried
(MgSO4), filtered, and evaporated to give the residue. The
residue was purified by silica gel column chromatography
(hexanes/ethyl acetate ) 6:1) to give 1,4-anhydro-2-benzoyl-3,5-
dibenzoyl-4-thio-L-arabitol (24.6 g, 82%) as an oil: 1H NMR
(CDCl3) δ 3.01 (dd, 1 H, J ) 3.3, 12.0 Hz), 3.42 (dd, 1 H, J )
5.1, 12.0 Hz), 3.53-3.59 (m, 1H), 3.65 (d, 1 H, J ) 8.1 Hz), 3.70
syrup: [R]25 -63.0° (c 1, MeOH); 1H NMR (CDCl3) δ 3.13 (q, 1
D
H, J ) 12.0 Hz), 3.27 (dt, 1 H, J ) 12.0, 15.2 Hz), 3.46-3.52 (m,
1 H), 3.54-3.63 (m, 2 H), 4.00 (dt, 1 H, J ) 5.2, 8.0 Hz), 4.49 (s,
2 H), 4.62 (d, 1 H, J ) 12.0 Hz), 4.80 (d, 1 H, J ) 12.0 Hz),
7.26-7.37 (m, 10 H).
Anal. Calcd for C19H20F2O2S: C, 65.12; H, 5.75; S, 9.15.
Found: C, 65.52; H, 5.45; S, 9.06.
1,4-An h yd r o-2-d eoxy-3,5-d iben zyl-2-C-m eth ylen e-4-th io-
L-er yth r o-p en titol (14). To a mixture of methyl triphenylphos-
phonium bromide (1.73 g, 4.84 mmol) and tert-amyl alcohol (0.58
mL, 5.3 mmol) in anhydrous THF (5 mL) was added NaH (60%
in mineral oil, 0.213 g, 5.3 mmol) at 0 °C, and the mixture was
stirred at room temperature for 2 h. The reaction mixture was
cooled to -10 °C, treated with a solution of the ketone inter-
mediate (0.48 g, 1.46 mmol) in THF (2.5 mL) over 20 min, and
stirred at room temperature overnight. The mixture was
quenched with 1 M NH4Cl (10 mL) and extracted with EtOAc.
The organic layer was washed with brine (50 mL), dried
(MgSO4), filtered, and evaporated to give the residue. The
residue was purified by silica gel column chromatography
(hexanes/ethyl acetate ) 20:1) to give 14 (0.404 g, 74%) as a
1
syrup: [R]25 +2.67° (c 0.15, MeOH); H NMR (CDCl3) δ 3.21-
D
3.41 (m, 3 H), 3.52-3.58 (m, 1 H), 4.29 (d, 1 H, J ) 1.2 Hz), 4.43
(d, 1 H, J ) 12.0 Hz), 4.45 (d, 1 H, J ) 12.0 Hz), 4.53 (d, 1 H, J
) 12.0 Hz), 4.61 (d, 1 H, J ) 12.0 Hz), 5.08 (d, 1 H, J ) 1.2 Hz),
5.19 (s, 1 H), 7.26-7.34 (m, 10 H).
Anal. Calcd for C20H22O2S: C, 73.58; H, 6.79; S, 9.82.
Found: C, 73.24; H, 6.56; S, 9.74.
1,4-An h ydr o-2-deoxy-3,5-diben zoyl-2-C-m eth ylen e-4-th io-
L-er yth r o-p en titol (15). To a solution of 14 (0.223 g, 0.68
mmol) in anhydrous CH2Cl2 (5 mL) was added BBr3 (1 M in CH2-
Cl2, 2.7 mL, 2.7 mmol) at -40 °C, and the mixture was stirred
at the same temperature for 20 min. The mixture was quenched

Notes
J . Org. Chem., Vol. 63, No. 14, 1998 4825
with pyridine (2.7 mL) and methanol (2.7 mL) and evaporated.
The residue was purified by silica gel column chromatography
(methylene chloride/methanol ) 13:1) to give the debenzylated
compound (73 mg, 74%): 1H NMR (CDCl3) δ 2.12 (br s, 1 H),
2.34 (br s, 1 H), 3.29 (q, 1 H, J ) 5.7 Hz), 3.47-3.59 (m, 2 H),
3.70 (dd, 1 H, J ) 6.0, 11.4 Hz), 3.75 (dd, 1 H, J ) 5.4, 11.4 Hz),
4.50 (d, 1 H, J ) 5.7 Hz), 5.10 (q, 1 H, J ) 1.5 Hz), 5.24 (q, 1 H,
J ) 1.5 Hz).
the residue, which was purified by silica gel column chroma-
tography (methylene chloride/methanol ) 3.5:1) to give 4R (14
mg, 92%): mp 151 °C; UV (MeOH) λmax 272 nm (pH 7). Anal.
Calcd for C9H11F2N3O3S: C, 38.71; H, 3.97; F, 13.61; N, 15.05;
S, 11.48. Found: C, 38.77; H, 3.67; N, 15.23; S, 11.45.
1-(2-Deoxy-2,2-d iflu or o-4-th io-â-L-er yth r o-p en tofu r a n o-
syl)cytosin e (4â). 16â (37 mg, 0.07 mmol) was converted to
4â (16 mg, 85%) according to the similar procedure used for the
preparation of 4R.
The debenzylated compound (93 mg, 0.64 mmol) in anhydrous
pyridine (2 mL) was treated with benzoyl chloride (0.19 mL, 1.64
mmol), and the mixture was stirred at 50 °C for 15 h. The
mixture was poured into EtOAc, and the organic layer was
washed with 1 M HCl (10 mL), saturated NaHCO3 solution, and
brine (10 mL), dried (MgSO4), filtered, and evaporated to give
the residue. The residue was purified by silica gel column
chromatography (hexanes/ethyl acetate ) 8:1) to give 15 (0.194
g, 86%) as a syrup: 1H NMR (CDCl3) δ 3.56 (dt, 1 H, J ) 1.2,
13.2 Hz), 3.76 (dt, 1 H, J ) 1.2, 13.2 Hz), 3.78-3.84 (m, 1 H),
4.27 (dd, 1 H, J ) 9.0, 11.4 Hz), 4.40 (dd, 1 H, J ) 5.7, 11.4 Hz),
5.29 (t, 1 H, J ) 1.2 Hz), 5.41 (t, 1 H, J ) 0.6 Hz), 5.92 (dd, 1 H,
J ) 0.6, 2.7 Hz), 7.38-8.07 (m, 10 H).
Deben zyla ted com p ou n d : 1H NMR (DMSO-d6) δ 3.27-3.32
(m, 1 H), 3.72-3.85 (m, 2 H), 4.10-4.19 (m, 1 H), 5.45 (t, 1 H,
J ) 5.1 Hz), 6.35-6.39 (m, 2 H), 7.41 (d, 1 H, J ) 7.5 Hz), 7.49-
8.01 (m, 5 H), 8.66 (d, 1 H, J ) 7.5 Hz), 11.38 (br s, 1 H).
4â: mp 153 °C; [R]25 -8.16° (c 0.1, MeOH); UV (MeOH) λmax
D
270 nm (pH 7). Anal. Calcd for C9H11F2N3O3S: C, 38.71; H,
3.97; N, 15.05; S, 11.48. Found: C, 38.47; H, 4.08; N, 14.93; S,
11.08.
N4-Ben zoyl-1-(2-d eoxy-3,5-d ib en zoyl-2-C-m et h ylen e-4-
th io-r-L-er yth r o-p en tofu r a n osyl)cytosin e (17r) a n d N4-
Ben zoyl-1-(2-d eoxy-3,5-d iben zoyl-2-C-m eth ylen e-4-th io-â-
L-er yth r o-pen tofu r an osyl)cytosin e (17â). Compound 15 (0.18
g, 0.51 mmol) was converted to 17R (0.078 g, 27%) and 17â (0.04
g, 14%) according to the similar procedure used for the prepara-
tion of 16R and 16â.
Anal. Calcd for C20H18O4S: C, 67.78; H, 5.12; S, 9.05.
Found: C, 67.77; H, 5.02; S, 9.00.
N4-Ben zoyl-1-(2-d eoxy-3,5-d ib en zyl-2,2-d iflu or o-4-t h io-
r-L-er yth r o-p en tofu r a n osyl)cytosin e (16r) a n d N4-Ben zoyl-
1-(2-deoxy-3,5-diben zyl-2,2-diflu or o-4-th io-â-L-er yth r o-pen to-
fu r a n osyl)cytosin e (16â). To a solution of 13 (0.170 g, 0.49
mmol) in anhydrous CH2Cl2 (5 mL) was added 70% m-CPBA
(0.12 g, 0.49 mmol) at -78 °C, and the mixture was stirred at
-40 °C for 30 min. The mixture was quenched with saturated
Na2S2O3 solution and NaHCO3 solution. The mixture was
poured into CH2Cl2, and the organic layer was washed with brine
(10 mL), dried (MgSO4), filtered, and evaporated to give the
sulfoxide. To a solution of silylated N-benzoylcytosine, prepared
from refluxing N-benzoylcytosine (0.157 g, 0.73 mmol) and
ammonium sulfate (catalytic amount) in HMDS (5 mL, 40.5
mmol), in anhydrous ClCH2CH2Cl (3 mL) was added a solution
of the sulfoxide in anhydrous ClCH2CH2Cl (2 mL) followed by
addition of TMSOTf (0.13 mL, 0.72 mmol) at 0 °C, and the
mixture was stirred at the same temperature for 1.5 h and then
at room temperature for 30 min. The mixture was quenched
with saturated NaHCO3 solution, filtered through a Celite pad,
and poured into CH2Cl2. The organic layer was washed with
brine (10 mL), dried (MgSO4), filtered, and evaporated. The
residue was purified by silica gel column chromatography
(hexanes/ethyl acetate ) 1.8:1) to give 16R (60 mg, 22%) and
16â (49 mg, 18%).
17R: UV (MeOH) λmax 300 nm (pH 7); 1H NMR (CDCl3) δ
4.08-4.13 (m, 1 H), 4.41 (dd, 1 H, J ) 10.8, 11.7 Hz), 4.55 (dd,
1 H, J ) 6.0, 11.7 Hz), 5.70 (s, 1 H), 5.77 (s, 1 H), 6.08 (d, 1 H,
J ) 3.6 Hz), 7.01 (s, 1 H), 7.40-8.06 (m, 16 H), 8.31 (d, 1 H, J
) 7.2 Hz).
Anal. Calcd for C31H25N3O6S: C, 65.60; H, 4.44; N, 7.40; S,
5.65. Found: C, 65.85; H, 4.30; N, 7.66; S, 5.80.
17â: UV (MeOH) λmax 301 nm (pH 7); 1H NMR (CDCl3) δ 3.91-
3.97 (m, 1 H), 4.49 (dd, 1 H, J ) 7.8, 11.7 Hz), 4.62 (dd, 1 H, J
) 5.7, 11.7 Hz), 5.23 (s, 1 H), 5.68 (s, 1 H), 6.10 (d, 1 H, J ) 1.8
Hz), 7.16 (s, 1 H), 7.45-8.09 (m, 17 H).
Anal. Calcd for C31H25N3O6S: C, 65.60; H, 4.44; N, 7.40; S,
5.65. Found: C, 66.01; H, 4.58; N, 7.80; S, 5.35.
1-(2-Deoxy-2-C-m eth ylen e-4-th io-r-L-er yth r o-p en tofu r a -
n osyl)cytosin e (5r). Compound 17R (73 mg, 0.13 mmol) was
treated with NaOMe (1 M in methanol, 0.13 mL, 0.13 mmol) in
a solution of MeOH (4 mL) and CH2Cl2 (3 mL) and stirred at
room temperature for 1 h. The mixture was neutralized with
acetic acid and evaporated to give the residue, which was
purified by silica gel column chromatography (methylene chloride/
methanol ) 3.5:1) to give 5R (34 mg, 100%): mp 92 °C; UV
(MeOH) λmax 270 nm (pH 7).
Anal.
Calcd for
C10H13N3O3S: C, 47.05; H, 5.13; N, 16.46; S, 12.56. Found: C,
47.45; H, 5.04; N, 16.75; S, 12.17.
16r: UV (MeOH) λmax 301 nm (pH 7); 1H NMR (CDCl3) δ
3.51-3.55 (m, 1 H), 3.61-3.66 (m, 1 H), 3.72 (dd, 1 H, J ) 3.3,
10.2 Hz), 4.18-4.23 (m, 1 H), 4.41 (d, 1 H, J ) 10.8 Hz), 4.48 (d,
1 H, J ) 10.8 Hz), 4.54 (d, 1 H, J ) 11.7 Hz), 4.85 (d, 1 H, J )
11.7 Hz), 6.63 (dd, 1 H, J ) 3.9, 9.9 Hz), 7.27-7.92 (m, 16 H),
8.53 (d, 1 H, J ) 7.5 Hz).
1-(2-Deoxy-2-C-m eth ylen e-4-th io-â-L-er yth r o-p en tofu r a -
n osyl)cytosin e (5â). Compound 17â (0.03 g, 0.05 mmol) was
converted to 5â (14 mg, 100%), according to the similar procedure
used for the preparation of 5R: mp 95 °C; [R]25 +72.2° (c 0.12,
D
MeOH); UV (MeOH) λmax 270 nm (pH 7). Anal. Calcd for
C10H13N3O3S: C, 47.05; H, 5.13; N, 16.46; S, 12.56. Found: C,
47.24; H, 5.12; N, 16.46; S, 12.67.
Anal. Calcd for C30H27F2N3O4S: C, 63.93; H, 4.83; N, 7.46;
S, 5.69. Found: C, 63.86; H, 4.65; N, 7.67; S, 5.43.
16â: UV (MeOH) λmax 302 nm (pH 7); 1H NMR (CDCl3) δ 3.46-
3.52 (m, 1 H), 3.63-3.68 (m, 1 H), 3.81-3.85 (m, 1 H), 4.19 (dt,
1 H, J ) 6.6, 9.0 Hz), 4.51 (s, 2 H), 4.61 (d, 1 H, J ) 11.4 Hz),
4.78 (d, 1 H, J ) 11.4 Hz), 6.77 (dd, 1 H, J ) 7.8, 10.2 Hz), 7.27-
7.92 (m, 16 H), 8.28 (d, 1 H, J ) 7.8 Hz).
In Vitr o An titu m or Assa y. Cells (5000, 10 000, and 20 000
cells/well) were exposed to drugs in a 96-well plate for 24-96 h,
and cytotoxicities were determined by SRB assay18 (SKMEL-2,
A 549, and SKOV3) or MTT assay19 (SNU-1) or dye exclusion
method20 (K562).
Anal. Calcd for C30H27F2N3O4S: C, 63.93; H, 4.83; N, 7.46;
S, 5.69. Found: C, 63.88; H, 4.31; N, 7.26; S, 5.60.
Ack n ow led gm en t. This research was supported by
grants from the Korea Science and Engineering Foun-
dation (KOSEF 96-0403-01-01-3) and Good Health R &
D Project, Ministry of Health & Welfare (1996-1997).
Dr. H. R. Moon thanks KOSEF for the postdoctoral
fellowship award. The authors also wish to thank Dr.
Eun-Ran Woo (Korea Advanced Institute of Science and
Technology) for the antitumor activity testing.
1-(2-Deoxy-2,2-d iflu or o-4-th io-r-L-er yth r o-p en tofu r a n o-
syl)cytosin e (4r). To a solution of 16R (0.042 g, 0.08 mmol) in
anhydrous CH2Cl2 (5 mL) was added BBr3 (1 M in CH2Cl2, 0.3
mL, 0.3 mmol) at -40 °C, and the mixture was stirred at the
same temperature for 20 min. The mixture was quenched with
pyridine (0.3 mL) and methanol (0.3 mL) and evaporated. The
residue was purified by silica gel column chromatography
(methylene chloride/methanol ) 11:1) to give the debenzylated
compound (21 mg, 73%): UV (MeOH) λmax 270 nm (pH 7); 1H
NMR (DMSO-d6) δ 3.47-3.58 (m, 1 H), 3.61-3.64 (m, 1 H),
3.77-3.84 (m, 1 H), 4.18-4.32 (m, 1 H), 5.23 (t, 1 H, J ) 3.3
Hz), 6.45 (br s, 1 H), 6.61 (dd, 1 H, J ) 9.9, 11.1 Hz), 7.38 (d, 1
H, J ) 8.1 Hz), 7.48-8.01 (m, 5 H), 8.40 (d, 1 H, J ) 8.1 Hz).
The debenzylated compound (21 mg, 0.055 mmol) was treated
with NaOMe (1 M in methanol, 0.055 mL, 0.055 mmol) and
MeOH (3 mL) and stirred at room temperature for 1.5 h. The
mixture was neutralized with acetic acid and evaporated to give
J O980196+
(18) Monks, A.; Scudieero, D.; Skehan, P.; Boyd, M. R. Proc. Am.
Assoc. Cancer Res. 1989, 30, 607.
(19) Park, J .-G.; Kramer, B. S.; Lai, S.-L.; Goldstein, L. J .; Gazdar,
A. F. J . Natl. Cancer Inst. 1990, 82, 193.
(20) Mossman, T. J . Immunol. Methods 1983, 65, 55-63.