Synthesis of novel iso-4-thionucleosides using the Mitsunobu reaction

Article abstract of DOI:10.1021/jo980667s

A novel class of isomeric 4'-thionucleosides with the base moiety at the 2'-position was synthesized from D-glucose. The coupling of 1,4-anhydro-4- thioarabitol (13) with various nucleobases using the Mitsunobu reaction was investigated. With both purines and N³-benzoyluracils, the reaction predominantly gave β-isomers, suggesting that these were produced via an episulfonium intermediate. The β-anomers produced by the reaction of N³- benzoyluracils included both N- and O-alkylated derivatives. Interestingly, only the reaction of N³-benzoyluracil gave a mixture of N-alkylated adduct (20d) and O-alkylated bipyrimidinyl adduct (22), the structure of which was unambiguously determined by NMR spectroscopic data including HMBC and NOE. Deprotection of the Mitsunobu reaction products gave the desired iso-4'- thionucleosides.

Full text of DOI:10.1021/jo980667s

J . Org. Chem. 1998, 63, 6891-6899
6891
Syn th esis of Novel Iso-4′-th ion u cleosid es Usin g th e Mitsu n obu
Rea ction
Kohei Yamada, Shinji Sakata, and Yuichi Yoshimura*,†
Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, J apan
Received April 10, 1998
A novel class of isomeric 4′-thionucleosides with the base moiety at the 2′-position was synthesized
from D-glucose. The coupling of 1,4-anhydro-4-thioarabitol (13) with various nucleobases using
the Mitsunobu reaction was investigated. With both purines and N 3-benzoyluracils, the reaction
predominantly gave â-isomers, suggesting that these were produced via an episulfonium intermedi-
ate. The â-anomers produced by the reaction of N 3-benzoyluracils included both N- and O-alkylated
derivatives. Interestingly, only the reaction of N 3-benzoyluracil gave a mixture of N-alkylated
adduct (20d ) and O-alkylated bipyrimidinyl adduct (22), the structure of which was unambiguously
determined by NMR spectroscopic data including HMBC and NOE. Deprotection of the Mitsunobu
reaction products gave the desired iso-4′-thionucleosides.
Ch a r t 1
In tr od u ction
New compounds that are effective against human
immunodeficiency virus (HIV), a causative agent of
acquired immunodeficiency syndrome (AIDS), are ur-
gently required. Nucleoside analogues, most of which act
as inhibitors of reverse transcriptase (RT) coded by HIV,
play an important role in the treatment of AIDS. To
date, five nucleoside RT inhibitors, including some
dideoxynucleosides (ddC, ddI, d4T), have been approved
for clinical use. However, such dideoxynucleosides have
shown limited stability: the glycosidic linkage of dideoxy-
nucleosides is susceptible to both acidic and enzymatic
hydrolysis. To circumvent this problem, a new class of
dideoxynucleosides, isonucleosides (1: R ) H; Chart 1),
in which the base moiety is transposed from the natural
1′- to the 2′-position, were synthesized and shown to have
potent anti-HIV activity and to be stable against hy-
drolysis of the glycosidic bond.1 In addition to being anti-
HIV agents, Tino2 and Matsuda3 independently reported
that isonucleosides (2, R ) OH; 3, R ) CH2OH) had
antiherpes virus and -hepatitis B virus (HBV) activity.
skeleton. From another perspective, 3TC is similar to
2′-isomeric-3′-oxo-4′-thio-â-D-cytidine or belongs to a novel
class of iso-4′-thionucleosides. Thus, iso-4′-thionucleo-
sides may be promising candidates as anti-HIV agents.
However, despite such attractive structural features,
there are few reports concerning iso-4′-thionucleosides.5
This prompted us to design iso-4′-thionucleosides (6) as
a hybrid constructive analogue of 2′-deoxynucleosides and
3TC.
A new anti-HIV dideoxynucleoside, 2′-deoxy-3′-thiacy-
tidine4 (3TC, 4), which has been used for the treatment
of AIDS in clinical fields, has unique structural fea-
tures: it is a synthetic L-nucleoside with an oxathiolane
Recently, we developed a new route to the synthesis
of 4′-thionucleosides (5) with 2′-substituents,6 and this
may be applicable to the preparation of iso-4′-thionucleo-
sides (6), using the same chiral synthon, 1,4-anhydro-4-
thio-D-arabitol derivatives (7), as a starting material. We
expected that it would be possible to introduce nucleo-
bases at the 2-position of 7 with an “up” configuration,
when the direct substitution reaction of the hydroxyl
group proceeds with a retention of configuration. It has
† Tel: 479-22-0095 ext. 384. Fax: 479-22-9821. E-mail:
chem2yms@choshinet.or.jp.
(1) (a) Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Weigele, M.; Sim,
I.; Anderson, B. D.; Mitsuya, H.; Broder, S. J . Med. Chem. 1992, 35,
2347. (b) Nair, V.; Nuesca, Z. M. J . Am. Chem. Soc. 1992, 114, 7951.
(2) Tino, J . A.; Clark, J . M.; Kirk Field, A.; J acobs, G. A.; Lis, K. A.;
Michalik, T. L.; McGeever-Rubin, B.; Slusarchyk, W. A.; Spergel, S.
H.; Sundeen, J . E.; Tuomari, A. V.; Weaver, E. R.; Young, M. G.; Zahler,
R. J . Med. Chem. 1993, 36, 1221.
(3) Kakefuda, A.; Shuto, S.; Nagahata, T.; Seki, J .; Sasaki, T.;
Matsuda, A. Tetrahedron 1994, 50, 10167.
(4) (a) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis,
R.; Cannon, D.; J eong, L.-S.; Beach, J . W.; Choi, W.-B.; Yeola, S.; Liotta,
D. C. Antimicrob. Agents Chemother. 1992, 36, 672. (b) Coates, J . A.
V.; Cammack, N.; J enkinson, H. J .; J owett, A. J .; J owett, M. I.; Pearson,
B. A.; Penn, C. R.; Rouse, P. L.; Viner, K. C.; Cameron, J . M.
Antimicrob. Agents Chemother. 1992, 36, 733. (c) Poong, S.-L.; Tsai,
C.-H.; Schinazi, R. F.; Liotta, D. C.; Chen, Y.-C. Proc. Natl. Acad. Sci.
U.S.A. 1991, 88, 8495. (d) Beach, J . W.; J eong, L.-S.; Alves, A. J .; Pohl,
D.; Kim, H. O.; Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.; Cheng,
Y.-C.; Chu, C. K. J . Org. Chem. 1992, 57, 2217.
(5) J ones, M. F.; Noble, S. A.; Robertson, C. A.; Storer, R. Tetrahe-
dron Lett. 1991, 32, 247.
(6) (a) Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura,
S.; Sakata, S.; Sasaki, T.; Matsuda, A. J . Org. Chem. 1996, 61, 822.
(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. (c) Yoshimura, Y.; Watanabe, M.; Satoh, H.; Ashida, N.; Ijichi,
K.; Sakata, S.; Machida, H.; Matsuda, A. J . Med. Chem. 1997, 40, 2177.
S0022-3263(98)00667-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/12/1998

6892 J . Org. Chem., Vol. 63, No. 20, 1998
Yamada et al.
Sch em e 1
been reported that some SN2-type reactions at the â-posi-
tion to the sulfur atom of tetrahydrothiopyran and
tetrahydrothiophene derivatives proceeded with retention
of configuration because of the formation of episulfonium
intermediates.7 This finding encouraged us to use the
Mitsunobu reaction8 to introduce nucleobases with an
“up” configuration. In this report, we describe the
coupling reaction of 1,4-anhydro-4-thio-D-arabitol deriva-
tive (7) with various nucleobases using the Mitsunobu
reaction and the synthesis of iso-4′-thionucleosides.
Sch em e 2
Resu lts a n d Discu ssion
Ta ble 1. Mitsu n obu Rea ction of
1,4-An h yd r o-4-th io-D-a r a bitol Der iva tives (13) w ith
P u r in e Ba ses
We intended to use the Mitsunobu reaction to intro-
duce nucleobases into the 2-position of 1,4-anhydro-4-
thio-D-arabitol (7), which was readily obtained from
D-glucose, as we reported previously.6 If the Mitsunobu
reaction proceeded via an episulfonium cation (9), as
depicted in Scheme 1, the nucleobase moiety could be
introduced at the 2-position with high â-stereoselectivity.
Initially, a coupling reaction of 3-O-benzyl derivative
13 with 6-chloropurine in THF was examined.9,10 This
reaction gave a mixture of two diastereoisomers11 in 29%
yield (â/R ) 1.1; see Table 1, entry 1). This result showed
that the episulfonium intermediate (9), which gave rise
to the formation of â-isomer, might compete with a direct
SN2 reaction (Scheme 1). In addition, thietane deriva-
tives (12), which would be formed by nucleophilic attack
at the 1-position of 9, were not found in the reaction
mixture. This also showed that nucleophilic ring-opening
of the episulfonium cation (9) would take place regiose-
lectively, controlled by the thermodynamic stability of the
products.7b
yield
â/R
entry
purine base
solvent
product (%)d ratio
1
2
3
4
5
6
7
8
9
X1 ) Cl, X2 ) H
X1 ) Cl, X2 ) H
X1 ) Cl, X2 ) H
X1 ) Cl, X2 ) H
X1 ) Cl, X2 ) H
X1 ) Cl, X2 ) H
X1 ) Cl, X2 ) NH2
X1 ) X2 ) NH2
THFa
14a
14a
14a
14a
14a
14a
29
24
34
21
1.1e
1.4e
0.8e
6.0e
1.2e
THFb
benzenea
CH3CNa
a
CH2Cl2
22
DMFc
THFc
THFc
trace
NR
NR
38
NR
33
X1 ) Cl, X2 ) NHAc THFa
14b
14c
1.8f
3.1e
10
11
X1 ) X2 ) NHAc
X1 ) X2 ) Cl
THFa
THFa
a
b
Reaction was carried out at room temperature. Reaction was
d
carried out at 50 °C. c Reaction was carried out at 70 °C. Isolated
yields. e Isolated yields of two isomers. f â/R ratio was determined
by 1H NMR analysis.
On the other hand, we also attempted to react 6-chlo-
ropurine with a 2-O-mesylate of 13 in the presence of
K2CO3 and 18-crown-6 in DMF. However, the formation
of negligible amount of iso-4′-thionucleoside could only
be observed even at the reflux temperature (data not
shown). Thus, we tried to investigate the Mitsunobu
coupling reaction of 3-O-benzyl derivative (13) with
various purine bases in an appropriate solvent. The
results are summarized in Table 1. The â-isomer was
predominant (â/R ) 6.0) when acetonitrile was used;
however, there was no improvement in the yield of 14a
(entry 4). In a previous report, the Mitsunobu reaction
of 13 with diphenylphosphoryl azide gave a ribo-azide
derivative, suggesting that a direct SN2 reaction of azide
anion, without the participation of episulfonium ion, had
occurred from the R-side.6b In contrast, the same Mit-
sunobu reaction with 6-chloropurine gave predominantly
the â-isomer or a mixture of R- and â-isomers. These
results can be explained in terms of the potency of their
(7) (a) J eong, L.-S.; Nicklaus, M. C.; George, C.; Marquez, V. E.
Tetrahedron Lett. 1994, 35, 7573. (b) Recently, it has been reported
that the Mitsunobu reaction of tetrahydrothiopyran derivatives with
benzoic acid proceeded with retention of configuration and was
associated with the formation of the benzoated tetrahydrothiophen as
a minor product: Fuzier, M.; Merrer, Y. L.; Depezay J .-C. Tetrahedron
Lett. 1995, 36, 6443.
(8) Mitsunobu, O. Synthesis 1981, 1.
(9) The Mitsunobu reaction of the 3-O-benzoyl derivative, instead
of 13, with 6-chloropurine gave an undesired R-isonucleoside, stereo-
selectively, the stereochemistry of which was determined by NOE
experiments. This result suggests that the more electron-withdrawing
benzoyl group at the 3-position makes the carbon at the 2-position
electron deficient, thus potentiating the external nucleophilic attack.
(10) Contrary to our expectation, when tributylphosphine was used
instead of triphenylphosphine, the reaction was not complete in THF
at 50 °C even after 44 h. Only R-14a was obtained in 11% yield with
a recovery of 13 in 32% yield.
(11) The undesired N7-adduct of 6-chloropurine was not obtained.
Similarly, none of the N7-adducts were found in the reaction of the
other purine bases. The structure of N9-adducts were confirmed by
UV spectra after being converted to the deblocked compounds.

Iso-4′-thionucleosides
J . Org. Chem., Vol. 63, No. 20, 1998 6893
Next, we tried to prepare pyrimidine analogues using
the above-mentioned reaction. In contrast to purine
bases, the reaction with N 3-benzoyluracil derivatives14
hardly proceeded at room temperature. However, the
reaction at 70 °C gave pyrimidine isonucleosides in
moderate yields. In the case of pyrimidine bases, a
mixture of four isomers (R- and â-isomers of N-/O-
alkylated derivatives) was produced, and these were
difficult to separate. Fortunately, the R-isomers of the
N-and O-alkyl compounds were not detected when aceto-
nitrile was used as a solvent (e.g., R/â ratio of N-alkyl-
5-fluorouracil derivative 20a : R, 7%, and â, 11%, in THF
vs R, ∼0%, and â, 18%, in acetonitrile). However, the
reaction did not proceed regioselectively, and the product
contained a mixture of N- and O-alkylated uracil (N/O
ratio ) 1.2-2.3), as shown in Table 2. These regioiso-
mers could not be separated at this step on a silica gel
column, with the exception of 5-fluorouracil derivative
20a . Interestingly, only the reaction of N 3-benzoyluracil
(R3 ) H) gave an N-alkylated product 20d along with
O-alkylated compound 22, whose structure was unknown
and determined later (vide infra).
As shown in Scheme 5, the desired N-alkylated 5-fluo-
rouracil derivative 23a was obtained in 91% yield by the
debenzoylation of the N-alkyl-5-fluorouracil 20a . Simi-
larly, deprotection of the mixture of N,O-alkyl-5-methyl-
uracil 20b/21b and (E)-5-(bromovinyl)uracil 20c/21c gave
desired N-alkyluracils in yields of 46% and 59%, respec-
tively. These were easily separated from their O-alkyl-
uracils on a silica gel column at this step. Removal of
the benzyl group and subsequent desilylation gave
5-fluorouracil 25a , 5-methyluracil 25b, and (E)-5-(bro-
movinyl)uracil derivative 25c in yields of 85%, 74%, and
71%, respectively.
F igu r e 1.
nucleophilicities. The nucleophilic reaction of azide anion
is faster than the formation of the strained episulfonium
cation and, thus, proceeds via direct SN2 reaction with
inversion.6b On the other hand, the weak nucleophilicity
of 6-chloropurine makes the formation of episulfonium
cation energetically favorable. As a result, the reaction
proceeds via competition between a direct SN2 reaction
and an episulfonium intermediate. In more polar aceto-
nitrile, the latter path would be favored.
In the case of 2,6-dichloropurine, a similar result was
obtained (33% yield, â/R ) 3.1, entry 11). The R,â-
isomers (14a ,c) could be easily separated on a silica gel
column. On the other hand, the reactions with 2,6-
diaminopurine or 2-amino-6-chloropurine did not proceed
at all because they were scarcely soluble in THF (entries
7 and 8).12 Accordingly, the reaction of 2-(acetylamino)-
6-chloropurine gave 14b in 38% yield, as an inseparable
mixture of R,â-isomers (â/R ) 1.8, entry 9), which could
be successfully separated in the next step.
The assignment of R- and â-stereochemistry was
confirmed by NOE experiments. As shown in Figure 1,
irradiation of H-2′ and H-3′ of â-14a enhanced the H-4′
and H-8 protons by 6.5% and 2.7%, respectively. The
1
stereochemistry of â-17 was also confirmed by H NMR
Assignment of N,O-regio- and R,â-stereochemistry was
in comparison with the chemical shift of the H-2′ proton13
of the corresponding R-17 (data not shown).
1
strictly determined on the basis of H NMR and NOE
spectra. For example, as shown in Figure 2, irradiation
of H-3′ and H-2′ of N-alkyl compound 23b enhanced the
H-6 and H-4′ protons by 8.1% and 5.2%, respectively. In
contrast, irradiation of H-4′ of O-alkyl compound 24b
enhanced the H-2′ proton by 2.5%, while irradiation of
H-3′ did not enhance the H-6 proton. It has been
reported that the resonance of the H-2′ proton in O-alkyl
compounds shifted downfield compared with that in
N-alkyl compounds.3 This held true for all of the iso-4′-
thionucleosides that we synthesized.
Furthermore, as shown in Scheme 6, the mixture of
N,O-alkyl uracil 20d /22 was debenzoylated and aminated
at the 4-position by treatment with 2,4,6-triisopropyl-
benzenesulfonyl chloride (TPSCl) in acetonitrile in the
presence of triethylamine and 4-(dimethylamino)pyridine
(DMAP), followed by aqueous ammonia, to give cytosine
derivative 27 in 55% yield as a mixture with O-alkyl
compound 28. Treatment of 27/28 with BCl3 at -78 °C
gave 29 in 53% yield, which was successfully separated
from O-alkyl compound 30. Finally, iso-4′-thiocytidine
31 was synthesized in 69% yield by desilylation using
NH4F‚HF in DMF. Likewise, O-alkyl compound 30 was
converted into 32 in 79% yield.
The Mitsunobu adducts 14a ,b were converted to their
corresponding adenine and guanine iso-4′-thionucleo-
sides, as shown in Scheme 3. The benzyl group of the
desirable â-isomer of 14a was effectively removed by
treatment with boron trichloride (BCl3) in dichloromethane
at -78 °C. Subsequently, compound â-15 was desilylated
by ammonium hydrogen fluoride in methanol and con-
verted into iso-4′-thioadenosine â-16 by amination of the
6-position with ethanolic ammonia. Likewise, the 2,6-
diaminopurine derivative â-18 and guanine derivative
â-19 were prepared. Debenzylation of a mixture of R-
and â-isomers of 14b under the conditions described
above gave only the deprotected â-isomer (â-17) in 32%
yield with unreacted R-isomer (R-14b) recovered in 8%
yield. Although the R- and â-isomers of 14b were
effectively separated, the yields were relatively low. This
is presumably due to complexation of the products with
borane. However, attempts to recover further â-14b from
the complex were not successful. The desirable â-isomer
of 17 was desilylated and then converted into 2,6-
diaminopurine derivative â-18 by treatment with aque-
ous ammonia in methanol. In addition, guanine deriva-
tive â-19 was synthesized by acidic hydrolysis of the
6-chloro moiety of â-17 and subsequent deacetylation.
The spectral analysis of 32 revealed an unexpected
1
structure. In the H NMR spectrum of 32, the chemical
(12) Although the reaction mixture became clear when DMF was
used as a solvent, there was also no reaction (cf. Table 1, entry 6).
(13) In the 1H NMR spectra of R- and â-15, the resonance of the
H-2′ proton in the â-isomer was shifted upfield compared with that in
the R-isomer.
(14) (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wakisaka, K.;
Haga, S.; Nagamatsu, Y.; Sugi, H.; Fukawa, K.; Irino, O.; Yamamoto,
T.; Nishimura, N.; Taguchi, A.; Okada, T.; Nakayama, M. J . Med.
Chem. 1980, 23, 1324. (b) Cruickshank, K. A.; J iricny, J .; Reese, C. B.
Tetrahedron Lett. 1984, 25, 681.

6894 J . Org. Chem., Vol. 63, No. 20, 1998
Yamada et al.
Sch em e 3a
a
Reagents and conditions: (a) BCl3, CH2Cl2, -78 °C, 87%; (b) NH4‚HF, MeOH; (c) NH3, EtOH, 80 °C, 77% from â-15; (d) BCl3, CH2Cl2,
-78 °C, 32% (8% recovery of R-14b); (e) NH4‚HF, DMF; (f) NH4OH, MeOH, 80 °C, yield a â-18 in 66% from â-17; (g) TFA, H2O and then
NH4OH, MeOH, 80 °C, yield of â-19 in 80% from â-17.
Sch em e 4
Sch em e 5a
a
Reagents and conditions: (a) NH4OH, MeOH, THF, 23a (91%),
24a (49%), 23b (46%), 24b (39%), 23c (59%), 24c (39%); (b) (i) BCl3,
CH2Cl2, -78 °C, (ii) NH4F‚HF, DMF, 25a (85%), 25b (74%), 25c
(71%), 26a (71%), 26b (77%), 26c (65%).
Ta ble 2. Mitsu n obu Rea ction of
1,4-An h yd r o-4-th io-D-a r a bitol Der iva tives (13) w ith
P yr im id in e Ba sesa
entry
pyrimidine base
R ) F
R ) Me
product
yield (%)b N/O ratio
F igu r e 2.
1
2
3
4
20a /21a
20b/21b
R ) (E)-bromovinyl 20c/21c
R ) H 20d /22
26
36
40
39
2.3c
1.3d
1.4d
1.2d
doublet peaks at 8.29 and 5.99 ppm (J ) 7.8 Hz). The
other showed another set of doublets, which were shifted
downfield, at 8.60 and 7.80 ppm (J ) 5.4 Hz). The 13C
NMR spectrum of 32 also showed eight carbon peaks of
two pyrimidines (see Experimental Section). These
results clearly indicated that this compound had two
pyrimidine moieties per molecule. This was also sup-
ported by the results of mass spectrum and elemental
analysis. Moreover, the UV spectrum of 32 suggested
that one pyrimidine ring combined with the other, i.e., a
Reaction was carried out at 70 °C. Isolated yields. c Isolated
a
b
yields of two regioisomers. Ratio was determined by 1H NMR
analysis.
d
shift of the H-2′ proton (5.35 ppm) suggested a 2′-O2-
alkylated structure. Surprisingly, two sets of protons
corresponding to the 5- and 6-positions of the pyrimidine
ring were observed. One of the pyrimidines showed two

Iso-4′-thionucleosides
J . Org. Chem., Vol. 63, No. 20, 1998 6895
Sch em e 6a
Sch em e 7
the reaction of N 3-benzoyluracil gave the bipyrimidinyl
compound.
In summary, the coupling of 1,4-anhydro-4-thio-D-
arabitol (13) with various nucleobases using the Mit-
sunobu reaction was investigated. â-Adducts were pre-
dominantly formed when acetonitrile was used as a
solvent. This result suggests that the reaction proceeded
with retention of configuration via an episulfonium
intermediate. This method could be effectively applied
to the synthesis of iso-4′-thionucleosides. However, none
of the compounds which we tested showed any antiviral
activity (herpes simplex virus type 1 and type 2, varicella
zoster virus, human cytomegalovirus, HIV) or cytotoxic-
ity.15
a
Reagents and conditions: (a) NH4OH, MeOH, THF; (b) TPSCl,
Et3N, DMAP, CH3CN, and then NH4OH, 55% (27/28 ) 2.2) from
20d /22; (c) BCl3, CH2Cl2, -78 °C, 29 (53%), 30 (22%); (d) NH4F‚HF,
DMF, 31 (69%), 32 (79%).
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H
NMR spectra were recorded at 400 MHz (1H) and at 100 MHz
(13C) using CDCl3 or DMSO-d6 with TMS as internal standard.
Mass spectra were obtained by the fast atom bombardment
(FAB) mode. Silica gel for chromatography was Merck Kie-
selgel 60.
(2R)-1,4-An h yd r o-3-O-ben zyl-5-O-(ter t-bu tyld ip h en yl-
silyl)-2-(6-ch lor op u r in -9-yl)-2-d eoxy-4-th io-D-r ibitol (r-
14a ) a n d (2S)-1,4-An h yd r o-3-O-b en zyl-5-O-(ter t-b u t yl-
d ip h en ylsilyl)-2-(6-ch lor op u r in -9-yl)-2-d eoxy-4-t h io-D-
a r a bitol (â-14a ). To a solution of 136a,b (1.20 g, 2.5 mmol)
and triphenylphosphine (2.0 g, 7.5 mmol) in anhydrous THF
(42 mL) were added 6-chloropurine (1.16 g, 7.5 mmol) and
DEAD (1.2 mL, 7.5 mmol), and the mixture was stirred for 21
F igu r e 3.
4-O2′′- or 4-N 1′′-alkylated structure. Finally, its regio- (at
the 2′- and 4-positions, respectively) and stereochemistry
(at the 2′-position) were determined by HMBC and NOE
experiments. In the HMBC spectrum of 32, a cross-peak
of H-2′ to C-2 was observed, indicating a 2′-O2-alkylated
compound. Furthermore, the NOE experiment of 32, in
which irradiation of H-4′ enhanced the H-2′ proton by
2.3%, supported its â-stereochemistry at the 2′-position.
On the other hand, a cross-peak of H-6′′ to C-4 was also
observed in the HMBC spectrum. This ruled out the
4-O2′′-alkylated structure, as did the NOE experiment:
irradiation of H-5 of 32 enhanced the H-6′′ proton by
2.3%. Thus, the structure of 32 was unambiguously
determined, as depicted in Figure 3.
h
at room temperature under argon. The reaction was
quenched by addition of EtOH. After the solvent was evapo-
rated under reduced pressure, the concentrated residue was
purified by column chromatography over silica gel (3.6 × 19
cm, CHCl3, and then 2.5 × 30 cm, 5-30% AcOEt in hexane)
to give less polar R-14a (222 mg, 14%) and more polar â-14a
(228 mg, 15%) as an amorphous foam, respectively.
1
Da ta for r-14a : H NMR (CDCl3) δ 8.66 (1H, s, H-2), 8.41
The bipyrimidinyl compound seemed to be produced
by an extra Mitsunobu-type reaction as shown in Scheme
7. Initially, the O-alkylated derivative 33 was produced
like those of other 5-substituted uracils. The second
reaction then took place at the 4-position, when aroma-
tization of the pyrimidine ring occurred along with
cleavage of the N 3-benzoyl group. Presumably, this
aromatization might cause differences in the reactivities
of O- and N-alkylated derivatives in the extra Mitsunobu
reaction at the 4-position. Although the O2- and/or N 1-
anion of the extra benzoyluracil might attack the 4-posi-
tion of 34, 4-N 1′′-bipyrimidinyl compound 35, in which
substitution occurred at the softer N 1-site, was obtained.
The 4-N 1′′-bipyrimidinyl product 35 was not attacked by
further N 3-benzoyluracil. It was not obvious that only
(1H, s, H-8), 7.72-7.67 (4H, m, Ar H), 7.45-7.37 (6H, m, Ar
H), 7.19-7.12 (3H, m, Ar H), 7.00-6.98 (2H, m, Ar H), 5.27
(1H, ddd, H-2′, J ) 3.9, 6.8, 10.7 Hz), 4.60 (1H, d, PhCH, J )
11.7 Hz), 4.40 (1H, d, H-3′, J ) 3.9 Hz), 4.31 (1H, d, PhCH, J
) 11.7 Hz), 3.78-3.71 (3H, m, H-4′, H-5′a,b), 3.52 (1H, t, H-1′a,
J ) 10.7 Hz), 3.21 (1H, dd, H-1′b, J ) 6.8, 10.7 Hz), 1.10 (9H,
s, t-Bu); FAB-MS m/z 615, 617 (M+ + H). Anal. Calcd for
C
33H35N4O2SSiCl‚0.25H2O: C, 63.95; H, 5.77; N, 9.04.
Found: C, 63.92; H, 5.80; N, 8.83.
1
Da ta for â-14a : H NMR (CDCl3) δ 8.59 (1H, s, H-2), 8.08
(1H, s, H-8), 7.69 (4H, dd, Ar H, J ) 1.5, 7.8 Hz), 7.47-7.37
(6H, m, Ar H), 7.09-6.99 (3H, m, Ar H), 6.80 (2H, d, Ar H, J
(15) Antiviral activities, except against HIV, and cytotoxicity were
assayed at the Biological Laboratory of Yamasa Corp. Anti-HIV activity
was tested at the Rational Drug Design Laboratories, Fukushima,
J apan. We greatly appreciate their assistance.

6896 J . Org. Chem., Vol. 63, No. 20, 1998
Yamada et al.
) 7.8 Hz), 5.01-4.95 (1H, m, H-2′), 4.74 (1H, dd, H-3′, J )
5.9, 8.3 Hz), 4.48 (1H, d, PhCH, J ) 11.7 Hz), 4.19 (1H, d,
PhCH, J ) 11.7 Hz), 3.89 (1H, dd, H-5′a, J ) 5.9, 10.8 Hz),
3.85 (1H, dd, H-5′b, J ) 5.9, 10.8 Hz), 3.75 (1H, t, H-1′a, J )
11.2 Hz), 3.59 (1H, q, H-4′, J ) 5.9 Hz), 3.08 (1H, dd, H-1′b, J
) 6.8, 11.2 Hz), 1.11 (9H, s, t-Bu); FAB-MS m/z 615, 617 (M+
+ H). Anal. Calcd for C33H35N4O2SSiCl: C, 64.42; H, 5.73;
N, 9.11. Found: C, 64.25; H, 5.90; N, 8.86.
FAB-MS m/z 525, 527 (M+ + H). Anal. Calcd for C26H29N4O2-
SSiCl: C, 59.47; H, 5.57; N, 10.67. Found: C, 59.40; H, 5.72;
N, 10.37.
(2S)-2-(Ad en in -9-yl)-1,4-a n h yd r o-2-d eoxy-4-th io-D-a r a -
bitol (â-16). A mixture of â-15 (169 mg, 0.32 mmol) and
NH4F‚HF (253 mg, 4.44 mmol) in MeOH (5.5 mL) was stirred
for 40 h at room temperature. After concentration, the residue
was passed through a short silica gel column. The eluate with
10% MeOH in CHCl3 was collected and concentrated. The
residue was dissolved in saturated methanolic ammonia (10
mL) and heated at 80 °C in a sealed tube for 20 h. After
cooling, the solvent was removed under reduced pressure and
the residue was purified by column chromatography over silica
gel (1.5 × 5.5 cm, 1-10% MeOH in CHCl3) to give â-16 (66
mg, 77%) as crystals: mp 96 °C (dec, crystallized from MeOH);
(2R)-2-(2-(Acetyla m in o)-6-ch lor op u r in -9-yl)-1,4-a n h y-
d r o-3-O-b en zyl-5-O-(ter t-b u t yld ip h en ylsilyl)-2-d eoxy-4-
th io-D-r ibitol a n d (2S)-2-(2-(Acetyla m in o)-6-ch lor op u r in -
9-yl)-1,4-an h ydr o-3-O-ben zyl-5-O-(ter t-bu tyldiph en ylsilyl)-
2-d eoxy-4-th io-D-a r a bitol (r,â-14b). Compound 13 (3.60 g,
2.84 mmol) was converted as described for the synthesis of
R,â-14a to give R,â-14b (1.91 g, 38%, â/R ) 1.8, as an
amorphous foam): 1H NMR (CDCl3) δ 8.28 (0.36H, s, H-2),
7.95 (0.64H, s, H-8), 7.91 (0.64H, br s, NH), 7.88 (0.36H, br s,
NH), 7.69-6.80 (15H, m, Ar H), 5.12-5.05 (0.36H, m, H-2′),
4.91-4.85 (0.64H, m, H-2′), 4.60 (0.36H, d, PhCH, J ) 11.7
Hz), 4.54-4.48 (1.28H, m, PhCH, H-3′), 4.36-4.33 (0.72H, m,
PhCH, H-3′), 4.22 (0.64H, d, PhCH, J ) 12.2 Hz), 4.13-3.56
(3.64, m, H-4′ × 2, H-5′a,b × 2, 1′-Ha), 3.49 (0.36H, t, H-1′a, J
) 10.3 Hz), 3.21 (0.36H, dd, H-1′b, J ) 6.3, 10.3 Hz), 3.09
(0.64H, dd, H-1′b, J ) 7.3, 11.2 Hz), 2.45 (1.92H, s, Ac), 2.44
1
UV (MeOH) λmax 261 nm; H NMR (DMSO-d6) δ 8.18 (1H, s,
H-2 or H-8), 8.12 (1H, s, H-2 or H-8), 7.19 (2H, br s, NH2),
5.56 (1H, d, 3′-OH, J ) 6.8 Hz), 4.92 (1H, dd, 5′-OH, J ) 4.4,
5.9 Hz), 4.81-4.74 (1H, m, H-2′), 4.43 (1H, dt, H-3′, J ) 6.8,
8.3 Hz), 3.86 (1H, dt, H-5′a, J ) 4.4, 10.8 Hz), 3.45-3.37 (1H,
m, H-5′b), 3.39 (1H, t, H-1′a, J ) 10.7 Hz), 3.24 (1H, dt, H-4′,
J ) 4.4, 8.3 Hz), 3.03 (1H, dd, H-1′b, J ) 7.3, 10.7 Hz); FAB-
MS m/z 268 (M+ + H). Anal. Calcd for C10H13N5O2S‚
0.33MeOH: C, 44.65; H, 5.20; N, 25.19. Found: C, 44.42; H,
4.96; N, 24.91.
(1.08H, s, Ac), 1.10 (9H, s, t-Bu); FAB-MS m/z 672, 674 (M+
H). Anal. Calcd for C35H38N5O3SSiCl‚0.5H2O: C, 61.70; H,
5.77; N, 10.28. Found: C, 61.78; H, 5.74; N, 10.31.
+
(2S)-2-(2-(Acet yla m in o)-6-ch lor op u r in -9-yl)-1,4-a n h y-
d r o-5-O-(ter t-bu tyld ip h en ylsilyl)-2-d eoxy-4-th io-D-a r a bi-
t ol (â-17). To a solution of R,â-14b (1.91 g, 2.84 mmol) in
CH2Cl2 (61 mL) was added slowly a solution of BCl3 (25 mL of
a 1 M CH2Cl2 solution, 25.0 mmol) at -78 °C under argon.
After being stirred for 1.5 h at the same temperature, the
reaction was quenched by addition of pyridine-MeOH (33 mL,
2:1). The mixture was allowed to warm to room temperature
and was stirred for 1 h. After the solvents were removed under
reduced pressure, the concentrated residue was purified by
column chromatography over silica gel (3.4 × 16 cm, 20%
MeOH in CHCl3 and then 3.4 × 10 cm, 50% AcOEt in hexane)
to give â-17 (529 mg, 32%) as a white solid. Unreacted R-14b
was recovered as a single isomer (145 mg, 8%): mp 180-184
(2R)-1,4-An h yd r o-3-O-ben zyl-5-O-(ter t-bu tyld ip h en yl-
silyl)-2-d eoxy-2-(2,6-d ich lor op u r in -9-yl)-4-t h io-D-r ib it ol
(r-14c) a n d (2S)-1,4-An h yd r o-3-O-ben zyl-5-O-(ter t-bu tyl-
d ip h en ylsilyl)-2-d eoxy-2-(2,6-d ich lor op u r in -9-yl)-4-th io-
D-a r a bitol (â-14c). Compound 13 (120 mg, 0.25 mmol) was
converted as described for the synthesis of R,â-14a to give less
polar R-14c (12.7 mg, 8%) and more polar â-14c (40 mg, 25%)
as a colorless oil, respectively.
Da ta for r-14c: 1H NMR (CDCl3) δ 8.31 (1H, s, H-8), 7.66-
7.61 (4H, m, Ar H), 7.39-7.32 (6H, m, Ar H), 7.19-7.08 (3H,
m, Ar H), 6.95-6.93 (2H, m, Ar H), 5.12-5.07 (1H, m, H-2′),
4.54 (1H, d, PhCH, J ) 11.7 Hz), 4.35 (1H, d, H-3′, J ) 3.9
Hz), 4.25 (1H, d, PhCH, J ) 11.7 Hz), 3.71-3.59 (3H, m, 4′-
H, H-5′a,b), 3.41 (1H, t, H-1′a, J ) 10.3 Hz), 3.13 (1H, dd,
H-1′b, J ) 6.4, 10.3 Hz), 1.04 (9H, s, t-Bu); FAB-MS m/z 649,
651 (M+ + H).
Da ta for â-14c: 1H NMR (CDCl3) δ 8.03 (1H, s, H-8), 7.70-
7.68 (4H, m, Ar H), 7.47-7.39 (6H, m, Ar H), 7.07-7.01 (3H,
m, Ar H), 6.87-6.85 (2H, m, Ar H), 4.93-4.87 (1H, m, H-2′),
4.63 (1H, dd, H-3′, J ) 6.3, 8.3 Hz), 4.53 (1H, d, PhCH, J )
12.2 Hz), 4.24 (1H, d, PhCH, J ) 12.2 Hz), 3.90 (1H, dd, H-5′a,
J ) 5.4, 10.7 Hz), 3.82 (1H, dd, H-5′b, J ) 5.4 Hz, 10.7 Hz),
3.63 (1H, t, H-1′a, J ) 10.7 Hz), 3.58-3.54 (1H, m, H-4′), 3.06
(1H, dd, H-1′b, J ) 6.8, 10.7 Hz), 1.12 (9H, s, t-Bu); FAB-MS
m/z 649, 651 (M+ + H).
(2S)-1,4-An h ydr o-5-O-(ter t-bu tyldiph en ylsilyl)-2-(6-ch lo-
r op u r in -9-yl)-2-d eoxy-4-th io-D-a r a bitol (â-15). To a solu-
tion of â-14a (227 mg, 0.37 mmol) in CH2Cl2 (7.5 mL), was
added slowly a solution of BCl3 (3.0 mL of a 1 M CH2Cl2
solution, 3.0 mmol) at -78 °C under argon. After being stirred
for 0.5 h at room temperature, the reaction was quenched by
addition of pyridine-MeOH (4.5 mL, 2:1). The mixture was
allowed to warm to room temperature and was stirred for 1
h. After the most of organic solvents were removed under
reduced pressure, the remaining material was extracted with
AcOEt (×2). The organic phase was washed with H2O and
brine and then dried (Na2SO4). After the solvent was evapo-
rated under reduced pressure, the concentrated residue was
purified by column chromatography over silica gel (1.5 × 11
cm, 10-30% AcOEt in hexane) to give â-15 (169 mg, 87%) as
an amorphous foam: 1H NMR (CDCl3) δ 8.65 (1H, s, H-2), 8.11
(1H, s, H-8), 7.61-7.57 (4H, m, Ar H), 7.41-7.31 (6H, m, Ar
H), 4.91 (1H, dt, H-2′, J ) 7.3, 10.3 Hz), 4.70 (1H, dd, H-3′, J
) 8.3, 10.3 Hz), 3.89 (1H, dd, H-5′a, J ) 5.4, 10.3 Hz), 3.83
(1H, dd, H-5′b, J ) 7.8, 10.3 Hz), 3.53 (1H, t, H-1′a, J ) 10.3
Hz), 3.48 (1H, dt, H-4′, J ) 5.4, 8.3 Hz), 3.18 (1H, dd, H-1′b, J
) 7.3, 10.3 Hz), 2.45-2.02 (1H, br, 3′-OH), 1.00 (9H, s, t-Bu);
1
°C; H NMR (CDCl3) δ 8.17 (1H, br s, NH), 8.14 (1H, s, H-8),
7.69-7.65 (4H, m, Ar H), 7.46-7.36 (6H, m, Ar H), 4.93-4.89
(1H, m, H-2′), 4.69 (1H, t, H-3′, J ) 8.3 Hz), 3.93 (2H, d,
H-5′a,b, J ) 8.9 Hz), 3.61-3.56 (1H, m, H-4′), 3.45 (1H, t,
H-1′a, J ) 10.3 Hz), 3.29 (1H, dd, H-1′b, J ) 7.3, 10.3 Hz),
2.99-2.45 (1H, br, 3′-OH), 1.05 (9H, s, t-Bu); FAB-MS m/z 582,
584 (M+ + H). Anal. Calcd for C28H32N5O3SSiCl‚0.2hexane:
C, 58.51; H, 5.85; N, 11.68. Found: C, 58.35; H, 5.80; N, 11.62.
(2S)-1,4-An h yd r o-2-d eoxy-2-(2,6-d ia m in op u r in -9-yl)-4-
th io-D-a r a bitol (â-18). A mixture of â-17 (46 mg, 0.08 mmol)
and NH4F‚HF (54 mg, 0.95 mmol) in DMF (1 mL) was stirred
at room temperature overnight. After concentration, the
residue was passed through a short silica gel column. The
eluate with 20% MeOH in CHCl3 was collected and concen-
trated. The residue was dissolved in MeOH (2 mL) and
concentrated NH4OH (4 mL). The mixture was heated at 60
°C in a sealed tube for 11 h. After cooling, the solvent was
removed under reduced pressure and the residue was purified
by column chromatography over silica gel (1 × 8 cm, 20%
MeOH in CHCl3) to give â-18 (15 mg, 66%) as crystals: mp
207-209 °C (crystallized from MeOH); UV (MeOH) λmax 258,
283 nm; 1H NMR (DMSO-d6) δ 7.77 (1H, s, H-8), 6.63 (2H, br
s, NH2), 5.76 (2H, br s, NH2), 5.56 (1H, d, 3′-OH, J ) 6.4 Hz),
4.91 (1H, t, 5′-OH, J ) 4.4 Hz), 4.60 (1H, dt, H-2′, J ) 7.3,
10.3 Hz), 4.37-4.31 (1H, m, H-3′), 3.88 (1H, dt, H-5′a, J )
4.4, 10.7 Hz), 3.46-3.38 (1H, m, H-5′b), 3.30-3.19 (2H, m,
H-1′a, H-4′), 2.98 (1H, dd, H-1′b, J ) 7.3, 10.3 Hz); FAB-MS
m/z 283 (M+ + H). Anal. Calcd for C10H14N6O2S‚0.75MeOH:
C, 42.15; H, 5.59; N, 27.43. Found: C, 42.35; H, 5.49; N, 27.31
(2S)-1,4-An h yd r o-2-d eoxy-2-(gu a n in -9-yl)-4-th io-D-a r a -
bitol (â-19). A mixture of â-17 (233 mg, 0.40 mmol) and
NH4F‚HF (276 mg, 4,8 mmol) in DMF (5 mL) was stirred at
room temperature overnight. After concentration, the residue
was passed through a short silica gel column. The eluate with
20% MeOH in CHCl3 was collected and concentrated. The
residue was dissolved in TFA-H2O (5 mL, 3:1) and stirred for

Iso-4′-thionucleosides
J . Org. Chem., Vol. 63, No. 20, 1998 6897
40 h at room temperature. After the solvent was removed
under reduced pressure, the residue was dissolved in MeOH
(10 mL) and concentrated NH4OH (20 mL). The mixture was
heated at 80 °C in a sealed tube for 5 h. After cooling, the
solvent was removed under reduced pressure and the residue
was applied to a column of adsorption resin (8 mL, Sepabeads
SP206, Mitsubishi Chemical Corp., Tokyo, J apan). The eluate
of 10% aqueous EtOH was collected and concentrated to give
â-19 (91 mg, 80%) as crystals: mp >250 °C (dec, crystallized
(2S)-1,4-An h yd r o-2-(N3-ben zoyl-5-(E)-(br om ovin yl)u r a -
cil-1-yl)-3-O-ben zyl-5-O-(ter t-bu tyldiph en ylsilyl)-2-d eoxy-
4-t h io-D-a r a b it ol (20c) a n d (2S)-1,4-An h yd r o-2-O-(N3-
b e n zoyl-5-(E )-(b r om ovin yl)p yr im id in -4-on -2-yl)-3-O-
b en zyl-5-O-(ter t-b u t yld ip h en ylsilyl)-2-d eoxy-4-t h io-D-
a r a bitol (21c). Compound 13 (960 mg, 2.0 mmol) was
converted as described for the synthesis of 20a to give a
mixture of 20c and 21c (630 mg, 40%, 20c/21c ) 1.5) as an
amorphous foam: 1H NMR (CDCl3) δ 7.88-7.16 (22H, m, Ar
H, H-6, 5-vinyl H), 6.79 (0.4H, d, 5-vinyl H, J ) 13.2 Hz), 6.45
(0.6H, d, 5-vinyl H, J ) 13.7 Hz), 5.60-5.55 (0.4H, m, H-2′),
5.00-4.93 (0.6H, m, H-2′), 4.69 (0.4H, d, PhCH, J ) 11.7 Hz),
4.61 (1H, d, PhCH, J ) 11.7 Hz), 4.42 (0.6H, d, PhCH, J )
11.7 Hz), 4.36-4.31 (1H, m, H-3′), 3.87 (0.6H, dd, H-5′a, J )
5.9, 10.7 Hz), 3.81 (0.6H, dd, H-5′b, J ) 5.9, 10.7 Hz), 3.71-
3.51 (1.8H, m, H-5′a,b, H-4′×2), 3.36 (0.4H, dd, H-1′a, J ) 4.9,
12.2 Hz), 3.08 (1.2H, d, H-1′a,b, J ) 8.3 Hz), 2.95 (0.4H, dd,
H-1′b, J ) 3.4, 12.2 Hz), 1.08 (5.4H, s, t-Bu), 1.04 (3.6H, s,
t-Bu); FAB-MS m/z 781, 783 (M+ + H).
(2S)-1,4-An h yd r o-2-(N3-ben zoylu r a cil-1-yl)-3-O-ben zyl-
5-O-(ter t-b u t yld ip h en ylsilyl)-2-d eoxy-4-t h io-D-a r a b it ol
(20d ) a n d (2S)-1,4-An h yd r o-2-O-(4-(N3-ben zoylu r a cil-1-
yl)p yr im id in -2-yl)-3-O-ben zyl-5-O-(ter t-bu tyld ip h en ylsi-
lyl)-2-d eoxy-4-th io-D-a r a bitol (22). Compound 13 (1.91 g,
4.0 mmol) was converted as described for the synthesis of 20a
to give a mixture of 20d and 22 (1.10 g, 39%, 20d /22 ) 1.2) as
an amorphous foam: 1H NMR (CDCl3) δ 8.54 (0.45H, d, H-6,
J ) 5.4 Hz), 8.44 (0.45H, d, H-6′′, J ) 8.3 Hz), 7.97-7.17 (21H,
m, Ar H, H-6, H-5), 6.02 (0.45H, d, H-5′′, J ) 8.3 Hz), 5.71-
5.68 (0.45H, m, H-2′), 5.65 (0.55H, d, H-5, J ) 7.8 Hz), 4.95-
4.89 (0.55H, m, H-2′), 4.72 (0.45H, d, PhCH, J ) 11.7 Hz), 4.67
(0.45H, d, PhCH, J ) 11.7 Hz), 4.59 (0.55H, d, PhCH, J )
11.7 Hz), 4.48-4.45 (1H, m, PhCH, H-3′), 4.37 (0.55H, dd, H-3′,
J ) 5.4, 6.9 Hz), 3.95-3.49 (3H, m, H-5′a,b × 2, H-4′ × 2),
3.40 (0.45H, dd, H-1′a, J ) 5.4, 11.7 Hz), 3.12-3.09 (1.1H, m,
H-1′a,b), 3.05 (0.45H, dd, H-1′b, J ) 4.4, 11.7 Hz), 1.06 (4.95H,
s, t-Bu), 1.02 (4.05H, s, t-Bu); FAB-MS m/z 677 (M+ + H) and
771 (M+ + H).
1
from H2O); UV (MeOH) λmax 256 nm; H NMR (DMSO-d6) δ
10.60 (1H, br s, NH), 7.78 (1H, s, H-8), 6.45 (2H, br s, NH2),
5.58 (1H, d, 3′-OH, J ) 5.8 Hz), 4.92 (1H, br s, 5′-OH), 4.59
(1H, dt, H-2′, J ) 7.3, 10.3 Hz), 4.32-4.26 (1H, m, H-3′), 3.88
(1H, br d, H-5′a, J ) 10.7 Hz), 3.46-3.40 (1H, m, H-5′b), 3.23-
3.17 (2H, m, H-1′a, H-4′), 2.97 (1H, dd, H-1′b, J ) 7.3, 10.3
Hz); FAB-MS m/z 284 (M+ + H). Anal. Calcd for C10H13N5O3S‚
0.9H2O: C, 40.10; H, 5.01; N, 23.38. Found: C, 40.33; H, 5.31;
N, 23.12.
(2S)-1,4-An h yd r o-2-(N3-ben zoyl-5-flu or ou r a cil-1-yl)-3-
O-ben zyl-5-O-(ter t-bu tyld ip h en ylsilyl)-2-d eoxy-4-th io-D-
a r a bitol (20a ) a n d (2S)-1,4-An h yd r o-2-O-(N3-ben zoyl-5-
fl u o r o p y r i m i d i n -4 -o n -2 -y l )-3 -O -b e n z y l -5 -O -(t e r t -
bu tyld ip h en ylsilyl)-2-d eoxy-4-th io-D-a r a bitol (21a ).
A
solution of DEAD (2.9 mL, 40% toluene solution, 6.3 mmol)
was added to a mixture of 13 (1.91 g, 4.0 mmol), N 3-benzoyl-
5-fluorouracil (1.40 g, 6.0 mmol), and triphenylphosphine (3.14
g, 4.0 mmol) in CH3CN (64 mL) at 0 °C and stirred for 1 h at
70 °C. After cooling, the reaction was quenched by addition
of EtOH. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography over
silica gel (3.6 × 20 cm, 1% MeOH in CHCl3, and then 3.6 × 20
cm, 10-20% AcOEt in hexane) to give less polar 21a (213 mg,
8%) and more polar 20a (497 mg, 18%) as an amorphous foam,
respectively.
1
Da ta for 20a : H NMR (CDCl3) δ 7.87 (2H, dd, Ar H, J )
1.5, 8.8 Hz), 7.70-7.64 (5H, m, Ar H), 7.49-7.18 (14H, m, Ar
H, H-6), 4.98-4.92 (1H, m, H-2′), 4.63 (1H, d, PhCH, J ) 11.7
Hz), 4.42 (1H, d, PhCH, J ) 11.7 Hz), 4.28 (1H, dd, H-3′, J )
5.9, 6.9 Hz), 3.87 (1H, dd, H-5′a, J ) 5.9, 10.7 Hz), 3.81 (1H,
dd, H-5′b, J ) 5.9, 10.7 Hz), 3.53 (1H, q, H-4′, J ) 5.9 Hz),
3.08 (1H, dd, H-1′a, J ) 7.3, 11.7 Hz), 3.00 (1H, dd, H-1′b, J )
8.3, 11.7 Hz), 1.08 (9H, s, t-Bu); FAB-MS m/z 695 (M+ + H).
Anal. Calcd for C39H39N2O5SSiF‚0.75H2O: C, 66.12; H, 5.76;
N, 3.95. Found: C, 66.18; H, 5.66; N, 3.96.
(2S)-1,4-An h yd r o-3-O-ben zyl-5-O-(ter t-bu tyld ip h en yl-
silyl)-2-deoxy-2-(5-flu or ou r acil-1-yl)-4-th io-D-ar abitol (23a).
To a solution of 20a (490 mg, 0.71 mmol) in MeOH-THF (18
mL, 4:5) was added concentrated NH4OH (9 mL) and stirred
for 2 h at room temperature. After the solvent was evaporated
under reduced pressure, the concentrated residue was purified
by column chromatography over silica gel (2.2 × 18 cm, 20-
30% AcOEt in hexane) to give 23a (379 mg, 91%) as an
amorphous foam: 1H NMR (CDCl3) δ 8.49-8.40 (1H, br, NH),
7.68 (4H, dd, Ar H, J ) 1.5, 7.8 Hz), 7.48-7.38 (7H, m, Ar H),
7.28-7.24 (2H, m, Ar H), 7.17-7.14 (3H, m, Ar H, H-6), 4.91-
4.85 (1H, m, H-2′), 4.62 (1H, d, PhCH, J ) 12.2 Hz), 4.40 (1H,
d, PhCH, J ) 12.2 Hz), 4.26 (1H, dd, H-3′, J ) 5.4, 7.3 Hz),
3.84 (2H, d, H-5′a,b, J ) 5.4 Hz), 3.53 (1H, q, H-4′, J ) 5.4
Hz), 3.05 (1H, dd, H-1′a, J ) 7.8, 11.2 Hz), 2.96 (1H, dd, H-1′b,
Da ta for 21a : 1H NMR (CDCl3) δ 8.30-8.12 (3H, m, Ar H,
H-6), 7.71-7.21 (18H, m, Ar H), 5.73-5.70 (1H, m, H-2′), 4.68
(1H, d, PhCH, J ) 12.2 Hz), 4.64 (1H, d, PhCH, J ) 12.2 Hz),
4.47 (1H, t, H-3′, J ) 2.9 Hz), 3.87 (1H, dd, H-5′a, J ) 8.3,
10.3 Hz), 3.71 (1H, dd, H-5′b, J ) 3.4, 10.3 Hz), 3.62-3.58 (1H,
m, H-4′), 3.42 (1H, dd, H-1′a, J ) 4.9, 12.2 Hz), 3.04 (1H, dd,
H-1′b, J ) 3.9, 12.2 Hz), 1.03 (9H, s, t-Bu); FAB-MS m/z 695
(M+ + H). Anal. Calcd for C39H39N2O5SSiF‚0.5hexane: C,
68.36; H, 6.28; N, 3.80. Found: C, 68.34; H, 6.42; N, 3.68.
(2S)-1,4-An h yd r o-2-(N3-ben zoyl-5-m eth ylu r a cil-1-yl)-3-
O-ben zyl-5-O-(ter t-bu tyld ip h en ylsilyl)-2-d eoxy-4-th io-D-
a r a bitol (20b) a n d (2S)-1,4-An h yd r o-2-O-(N3-ben zoyl-5-
m e t h y lp y r i m i d i n -4-o n -2-y l)-3-O -b e n z y l-5-O -(t er t -
bu tyld ip h en ylsilyl)-2-d eoxy-4-th io-D-a r a bitol (21b). Com-
pound 13 (720 mg, 1.5 mmol) was converted as described for
the synthesis of 20a to give a mixture of 20b and 21b (367
mg, 36%, 20b/21b ) 1.3) as an amorphous foam: 1H NMR
(CDCl3) δ 7.88-7.06 (21H, m, Ar H, H-6), 5.56-5.53 (0.43H,
m, H-2′), 4.96-4.90 (0.57H, m, H-2′), 4.68 (0.43H, d, PhCH, J
) 12.2 Hz), 4.62 (0.43H, d, PhCH, J ) 12.2 Hz), 4.60 (0.57H,
d, PhCH, J ) 12.2 Hz), 4.43 (0.57H, d, PhCH, J ) 12.2 Hz),
4.37 (0.57H, dd, H-3′, J ) 5.9, 7.3 Hz), 4.32 (0.43H, t, H-3′, J
) 3.4 Hz), 3.88 (0.57H, dd, H-5′a, J ) 5.9, 10.7 Hz), 3.79
(0.57H, dd, H-5′b, J ) 5.9, 10.7 Hz), 3.74-3.66 (0.86H, m,
H-5′a,b), 3.63-3.59 (0.43H, m, H-4′), 3.52 (0.57H, q, H-4′, J )
5.9 Hz), 3.55 (0.43H, dd, H-1′a, J ) 4.9, 12.2 Hz), 3.12 (0.57H,
dd, H-1′a, J ) 9.3, 11.2 Hz), 3.04 (0.57H, dd, H-1′b, J ) 7.3,
11.2 Hz), 2.95 (0.43H, dd, H-1′b, J ) 3.4, 12.2 Hz), 1.96 (1.29H,
d, 5-Me, J ) 1.0 Hz), 1.83 (1.71H, s, 5-Me), 1.07 (5.13H, s,
t-Bu), 1.03 (3.87H, s, t-Bu); FAB-MS m/z 691 (M+ + H).
J ) 8.8, 11.2 Hz), 1.10 (9H, s, t-Bu); FAB-MS m/z 591 (M+
+
H). Anal. Calcd for C32H35N2O4SSiF‚1.25AcOEt: C, 63.40; H,
6.47; N, 4.00. Found: C, 63.18; H, 6.58; N, 3.99.
(2S)-1,4-An h yd r o-3-O-ben zyl-5-O-(ter t-bu tyld ip h en yl-
silyl)-2-d eoxy-2-(5-m et h ylu r a cil-1-yl)-4-t h io-D-a r a b it ol
(23b) a n d (2S)-1,4-An h yd r o-3-O-ben zyl-5-O-(ter t-bu tyl-
d ip h en ylsilyl)-2-d eoxy-2-O-(5-m eth ylp yr im id in -4(3H)-on -
2-yl)-4-th io-D-a r a bitol (24b). A mixture of compound 20b
and 21b (360 mg, 0.52 mmol) was converted as described for
the synthesis of 23a to give less polar 24b (119 mg, 39%) and
more polar 23b (141 mg, 46%) as an amorphous foam,
respectively.
Da ta for 23b: 1H NMR (CDCl3) δ 8.30 (1H, br s, NH), 7.68
(4H, dd, Ar H, J ) 1.5, 8.3 Hz), 7.47-7.37 (6H, m, Ar H), 7.25-
7.23 (3H, m, Ar H), 7.13-7.11 (2H, m, Ar H), 6.91 (1H, d, H-6,
J ) 1.0 Hz), 4.92-4.85 (1H, m, H-2′), 4.58 (1H, d, PhCH, J )
12.2 Hz), 4.39 (1H, d, PhCH, J ) 12.2 Hz), 4.34 (1H, dd, H-3′,
J ) 5.9, 7.8 Hz), 3.87 (1H, dd, H-5′a, J ) 5.9, 10.3 Hz), 3.82
(1H, dd, H-5′b, J ) 5.9, 10.3 Hz), 3.52 (1H, q, H-4′, J ) 5.9
Hz), 3.08 (1H, dd, H-1′a, J ) 9.3, 11.2 Hz), 3.00 (1H, dd, H-1′b,
J ) 7.3, 11.2 Hz), 1.78 (3H, d, 5-Me, J ) 1.0 Hz), 1.09 (9H, s,

6898 J . Org. Chem., Vol. 63, No. 20, 1998
Yamada et al.
t-Bu); FAB-MS m/z 587 (M+ + H). Anal. Calcd for C33H38N2O4-
SSi: C, 67.54; H, 6.53; N, 4.77. Found: C, 67.27; H, 6.65; N,
4.50.
J ) 3.4 Hz), 5.77-5.35 (1H, br, 3′-OH), 5.26 (1H, q, H-2′, J )
4.9 Hz), 4.90 (1H, br s, 5′-OH), 4.12 (1H, t, H-3′, J ) 4.9 Hz),
3.71-3.68 (1H, m, H-5′a), 3.44-3.40 (1H, m, H-5′b), 3.21-3.02
(2H, m, H-1′a, H-4′), 2.81 (1H, dd, H-1′b, J ) 4.9, 11.2 Hz);
FAB-MS m/z 263 (M+ + H). Anal. Calcd for C9H11N2O4SF‚
0.25H2O: C, 40.52; H, 4.35; N, 10.50. Found: C, 40.60; H,
4.39; N, 10.39.
Da ta for 24b: 1H NMR (CDCl3) δ 9.57 (1H, br s, NH), 7.65-
7.61 (4H, m, Ar H), 7.50 (1H, s, H-6), 7.46-7.27 (11H, m, Ar
H), 5.55-5.52 (1H, m, H-2′), 4.68 (1H, d, PhCH, J ) 12.2 Hz),
4.64 (1H, d, PhCH, J ) 12.2 Hz), 4.31 (1H, t, H-3′, J ) 3.4
Hz), 3.75 (1H, dd, H-5′a, J ) 8.3, 10.7 Hz), 3.69 (1H, dd, H-5′b,
J ) 5.9, 10.7 Hz), 3.59 (1H, ddd, H-4′, J ) 3.4, 5.9, 8.3 Hz),
3.36 (1H, dd, H-1′a, J ) 4.9, 12.2 Hz), 2.95 (1H, dd, H-1′b, J )
3.9, 12.2 Hz), 1.92 (3H, s, 5-Me), 1.03 (9H, s, t-Bu); FAB-MS
m/z 587 (M+ + H). Anal. Calcd for C33H38N2O4SSi: C, 67.54;
H, 6.53; N, 4.77. Found: C, 67.51; H, 6.56; N, 4.53.
(2S)-1,4-An h yd r o-3-O-ben zyl-2-(5-(E)-(br om ovin yl)u r a -
cil-1-yl)-5-O-(ter t-b u t yld ip h en ylsilyl)-2-d eoxy-4-t h io-D-
a r a bitol (23c) a n d (2S)-1,4-An h yd r o-3-O-ben zyl-2-O-(5-
(E )-(b r o m o v in y l)p y r im id in -4(3H )-o n -2-y l)-5-O -(t er t -
(2S)-1,4-An h ydr o-2-deoxy-2-(5-m eth ylu r acil-1-yl)-4-th io-
D-a r a bitol (25b). Compound 23b (257 mg, 0.46 mmol) was
converted as described for the synthesis of 25a to give 25b
(99 mg, 74%) as a white solid: mp 268-270 °C (dec); UV
(MeOH) λmax 271 nm; 1H NMR (DMSO-d6) δ 11.05-11.48 (1H,
br, NH), 7.63 (1H, s, H-6), 5.51 (1H, d, 3′-OH, J ) 6.4 Hz),
4.88 (1H, dd, 5′-OH, J ) 4.4, 6.3 Hz), 4.70-4.63 (1H, m, H-2′),
4.04 (1H, dt, H-3′, J ) 6.4, 10.3 Hz), 3.87 (1H, dt, H-5′a, J )
4.4, 10.7 Hz), 3.44-3.37 (1H, m, H-5′b), 3.17-3.12 (1H, m,
H-4′), 2.90 (1H, dd, H-1′a, J ) 10.3, 11.2 Hz), 2.80 (1H, dd,
H-1′b, J ) 7.3, 10.3 Hz), 1.77 (3H, s, 5-Me); FAB-MS m/z 259
(M+ + H). Anal. Calcd for C10H14N2O4S‚0.5MeOH: C, 45.97;
H, 5.88; N, 10.21. Found: C, 45.92; H, 5.69; N, 10.16.
(2S )-1,4-An h yd r o-2-d e oxy-2-O-(5-m e t h ylp yr im id in -
4(3H)-on -2-yl)-4-th io-D-a r a bitol (26b). Compound 24b (130
mg, 0.22 mmol) was converted as described for the synthesis
of 25a to give 26b (43 mg, 77%) as a white solid: mp 109-
111 °C; UV (MeOH) λmax 271 nm; 1H NMR (DMSO-d6) δ 12.50-
12.10 (1H, br, NH), 7.58 (1H, s, H-6), 5.68-5.34 (1H, br, 3′-
OH), 5.29 (1H, q, H-2′, J ) 4.9 Hz), 4.90 (1H, br s, 5′-OH),
4.12 (1H, t, H-3′, J ) 4.9 Hz), 3.74-3.69 (1H, m, H-5′a), 3.40-
3.34 (1H, m, H-5′b), 3.21-3.16 (2H, m, H-1′a, H-4′), 2.80 (1H,
dd, H-1′b, J ) 4.9, 11.7 Hz), 1.83 (3H, s, 5-Me); FAB-MS m/z
259 (M+ + H). Anal. Calcd for C10H14N2O4S‚0.75MeOH: C,
45.73; H, 6.07; N, 9.92. Found: C, 45.48; H, 5.77; N, 10.20.
(2S)-1,4-An h yd r o-2-(5-(E)-(b r om ovin yl)u r a cil-1-yl)-2-
d eoxy-4-th io-D-a r a bitol (25c). Compound 23c (132 mg, 0.23
mmol) was converted as described for the synthesis of 25a to
give 25c (42 mg, 71%) as a white solid: mp 173-174 °C; UV
bu t yld ip h en ylsilyl)-2-d eoxy-4-t h io-D-a r a b it ol (24c).
A
mixture of compounds 20c and 21c (630 mg, 0.81 mmol) was
converted as described for the synthesis of 23a to give less
polar 24c (212 mg, 39%) and more polar 23c (324 mg, 59%) as
an amorphous foam, respectively.
Da ta for 23c: 1H NMR (CDCl3) δ 8.39 (1H, br s, NH), 7.69-
7.67 (4H, m, Ar H), 7.48-7.38 (6H, m, Ar H), 7.33 (1H, d,
5-vinyl H, J ) 13.7 Hz), 7.26-7.22 (3H, m, Ar H), 7.13-7.10
(2H, m, Ar H), 7.03 (1H, s, H-6), 6.43 (1H, d, 5-vinyl H, J )
13.7 Hz), 4.91-4.85 (1H, m, H-2′), 4.60 (1H, d, PhCH, J ) 12.2
Hz), 4.38 (1H, d, PhCH, J ) 12.2 Hz), 4.33 (1H, dd, H-3′, J )
5.9, 7.3 Hz), 3.89-3.81 (2H, m, H-5′a,b), 3.52 (1H, q, H-4′, J )
5.9 Hz), 3.07-3.02 (2H, m, H-1′a,b), 1.10 (9H, s, t-Bu); FAB-
MS m/z 677, 679 (M+ + H). Anal. Calcd for C34H37N2O4SSiBr‚
0.5AcOEt: C, 59.91; H, 5.73; N, 3.88. Found: C, 60.04; H,
5.99; N, 3.73.
Da ta for 24c: 1H NMR (CDCl3) δ 9.95 (1H, br s, NH), 7.66-
7.59 (5H, m, Ar H, H-6), 7.52 (1H, d, 5-vinyl H, J ) 13.7 Hz),
7.45-7.22 (11H, m, Ar H), 6.77 (1H, d, 5-vinyl H, J ) 13.7
Hz), 5.60-5.57 (1H, m, H-2′), 4.69 (1H, d, PhCH, J ) 11.7 Hz),
4.63 (1H, d, PhCH, J ) 11.7 Hz), 4.31 (1H, t, H-3′, J ) 2.9
Hz), 3.72 (2H, d, H-5′a,b, J ) 7.3 Hz), 3.61 (1H, dt, H-4′, J )
2,9, 7.3 Hz), 3.36 (1H, dd, H-1′a, J ) 4.9, 11.7 Hz), 2.95 (1H,
dd, H-1′b, J ) 3.9, 11.7 Hz), 1.03 (9H, s, t-Bu); FAB-MS m/z
677, 679 (M+ + H).
1
(MeOH) λmax 252, 297 nm; H NMR (DMSO-d6) δ 11.54 (1H,
br s, NH), 8.01 (1H, s, H-6), 7.26 (1H, d, 5-vinyl H, J ) 13.2
Hz), 6.84 (1H, d, 5-vinyl H, J ) 13.2 Hz), 5.58 (1H, d, 3′-OH,
J ) 5.9 Hz), 4.91 (1H, t, 5′-OH, J ) 4.9 Hz), 4.69 (1H, dt, H-2′,
J ) 7.3, 10.7 Hz), 4.07-4.01 (1H, m, H-3′), 3.89-3.84 (1H, m,
H-5′a), 3.43-3.38 (1H, m, H-5′b), 3.15 (1H, dt, H-4′, J ) 3.4,
8.3 Hz), 2.90 (1H, t, H-1′a, J ) 10.7 Hz), 2.83 (1H, dd, H-1′b,
J ) 7.3, 10.3 Hz); FAB-MS m/z 349, 351 (M+ + H). Anal. Calcd
for C11H13N2O4SBr: C, 37.83; H, 3.75; N, 8.02. Found: C,
37.69; H, 3.94; N, 7.98.
(2S)-1,4-An h yd r o-2-d eoxy-2-(5-flu or ou r a cil-1-yl)-4-th io-
D-a r a bitol (25a ). A solution of BCl3 (3.5 mL of a 1 M CH2Cl2
solution, 3.5 mmol) was added slowly to a solution of 23a (372
mg, 0.63 mmol) in CH2Cl2 (13 mL) at -78 °C. After being
stirred for 1 h at the same temperature, the reaction was
quenched by addition of pyridine-MeOH (5 mL, 2:1). The
mixture was allowed to warm to room temperature and was
stirred for 1 h. After the solvents were removed under reduced
pressure, the whole was extracted with CHCl3 (×2). The
organic phase was washed with H2O and brine and then dried
(Na2SO4). After the solvent was removed under reduced
pressure, the residue was dissolved in DMF (9 mL) and NH4F‚
HF (410 mg, 7.2 mmol) was added to the solution. After the
mixture was stirred at room temperature overnight, the
solvent was removed under reduced pressure. The residue was
purified by column chromatography over silica gel (1.5 × 12
cm, 20% MeOH in CHCl3) to give 25a (141 mg, 85%) as
crystals: mp 266-268 °C (crystallized from MeOH); UV
(MeOH) λmax 273 nm; 1H NMR (DMSO-d6) δ 12.10-11.55 (1H,
br, NH), 8.17 (1H, d, H-6, J ) 7.3 Hz), 5.73-5.41 (1H, br, 3′-
OH), 5.10-4.74 (1H, br, 5′-OH), 4.69-4.62 (1H, m, H-2′), 4.03
(1H, t, H-3′, J ) 9.3 Hz), 3.87 (1H, dd, H-5′a, J ) 3.4, 10.7
Hz), 3.42-3.37 (1H, m, H-5′b), 3.14 (1H, dt, H-4′, J ) 3.4, 9.3
Hz), 2.91 (1H, t, H-1′a, J ) 10.7 Hz), 2.80 (1H, dd, H-1′b, J )
7.3, 10.7 Hz); FAB-MS m/z 263 (M+ + H). Anal. Calcd for
C9H11N2O4SF: C, 41.22; H, 4.23; N, 10.68. Found: C, 41.37;
H, 4.28; N, 10.50.
(2S)-1,4-An h yd r o-2-O-(5-(E)-(b r om ovin yl)p yr im id in -
4(3H)-on -2-yl)-2-d eoxy-4-th io-D-a r a bitol (26c). Compound
24c (53 mg, 0.08 mmol) was converted as described for the
synthesis of 25a to give 26c (18 mg, 65%) as a white solid:
1
mp 82-86 °C (dec); UV (MeOH) λmax 255, 302 nm; H NMR
(DMSO-d6) δ 13.20-12.40 (1H, br, NH), 7.89 (1H, s, H-6), 7.44
(1H, d, 5-vinyl H, J ) 13.2 Hz), 6.96 (1H, d, 5-vinyl H, J )
13.2 Hz), 5.74-5.40 (1H, br, 3′-OH), 5.35 (1H, q, H-2′, J ) 4.9
Hz), 4.91 (1H, t, 5′-OH, J ) 4.9 Hz), 4.14 (1H, t, H-3′, J ) 4.9
Hz), 3.73-3.68 (1H, m, H-5′a), 3.51-3.38 (1H, m, H-5′b), 3.21-
3.16 (2H, m, H-1′a, H-4′), 2.83 (1H, dd, H-1′b, J ) 4.9, 11.7
Hz); FAB-MS m/z 349, 351 (M+ + H). Anal. Calcd for
C
11H13N2O4SBr‚0.45H2O: C, 36.98; H, 3.92; N, 7.84. Found:
C, 36.69; H, 3.62; N, 7.60.
(2S)-1,4-An h yd r o-3-O-ben zyl-5-O-(ter t-bu tyld ip h en yl-
silyl)-2-(cytosin -1-yl)-2-d eoxy-4-th io-D-a r a bitol (27) a n d
(2S)-1,4-An h ydr o-3-O-ben zyl-5-O-(ter t-bu tyldiph en ylsilyl)-
2-O-(4-(cytosin -1-yl)p yr im id in -2-yl)-2-d eoxy-4-th io-D-a r a -
bitol (28). To a solution of 20d and 22 (1.10 g, 1.54 mmol) in
MeOH-THF (45 mL, 3:4) was added concentrated NH4OH (23
mL), and the mixture was stirred for 2 h at room temperature.
After concentration, the residue was passed through a short
silica gel column. The eluate with 10-50% AcOEt in hexane
was collected and concentrated. The residue was dissolved in
CH3CN (34 mL), and DMAP (295 mg, 2.42 mmol), TPSCl (733
mg, 2.42 mmol), and triethylamine (0.34 mL, 2.42 mmol) were
added to the solution at 0 °C. After the mixture was stirred
at room temperature for 2 h, concentrated NH4OH was added
at 0 °C, and then the new mixture stirred for 1.5 h at room
(2S)-1,4-An h ydr o-2-deoxy-2-O-(5-flu or opyr im idin -4(3H)-
on -2-yl)-4-th io-D-a r a bitol (26a ). Compound 24a (70 mg,
0.12 mmol), which was obtained by the debenzoylation of 21a ,
was converted as described for the synthesis of 25a to give
26a (22 mg, 71%) as a white solid: mp 169-170 °C; UV
(MeOH) λmax 270 nm; 1H NMR (DMSO-d6) δ 7.82 (1H, d, H-6,

Iso-4′-thionucleosides
J . Org. Chem., Vol. 63, No. 20, 1998 6899
temperature. After the solvents were removed under reduced
pressure, the residue was purified by column chromatography
over silica gel (3.6 × 18 cm, 1-10% MeOH in CHCl3) to give
a mixture of 27 and 28 (507 mg, 55%, 27/28 ) 2.2) as an
amorphous foam: 1H NMR (CDCl3) δ 9.82-9.47 (0.62H, br,
NH2), 9.27-8.88 (1.38H, br, NH2), 8.56 (0.31H, d, H-6′′, J )
5.9 Hz), 8.36 (0.69H, d, H-6, J ) 7.8 Hz), 7.94 (0.31H, d, H-6,
J ) 5.4 Hz), 7.67-7.10 (15.31H, m, Ar H, H-5′′), 6.30 (0.69H,
d, H-5, J ) 7.8 Hz), 6.28 (0.31H, d, H-5, J ) 5.4 Hz), 5.69-
5.65 (0.31H, m, H-2′), 4.83-4.78 (0.69H, m, H-2′), 4.70 (0.31H,
d, PhCH, J ) 12.2 Hz), 4.67 (0.31H, d, PhCH, J ) 12.2 Hz),
4.57 (0.69H, d, PhCH, J ) 12.2 Hz), 4.45 (0.31H, t, H-3′, J )
3.9 Hz), 4.39 (0.69H, d, PhCH, J ) 12.2 Hz), 4.36 (0.69H, t,
H-3′, J ) 6.8 Hz), 3.91 (0.31H, dd, H-5′a, J ) 7.8, 10.3 Hz),
3.85-3.74 (1.69H, m, H-5′a,b, H-5′b), 3.59 (0.31H, dt, H-4′, J
) 3.9, 10.3 Hz), 3.54-3.49 (0.69H, m, H-4′), 3.52 (0.31H, dd,
H-1′a, J ) 5.9, 11.7 Hz), 3.38 (0.69H, dd, H-1′a, J ) 5.4, 11.7
Hz), 3.14-3.00 (1H, m, H-1′b×2), 1.07 (9H, s, t-Bu); FAB-MS
m/z 572 (M+ + H) and 666 (M+ + H).
7.8, 10.7 Hz), 1.04 (9H, s, t-Bu); FAB-MS m/z 576 (M+ + H).
Anal. Calcd for C29H33N5O4SSi‚0.5AcOEt: C, 60.07; H, 6.02;
N, 11.30. Found: C, 59.78; H, 6.05; N, 11.25.
(2S)-1,4-An h yd r o-2-(cytosin -1-yl)-2-d eoxy-4-th io-D-a r a -
bitol (31). A mixture of 29 (234 mg, 0.50 mmol) and NH4F‚
HF (342 mg, 6.00 mmol) in DMF (7.6 mL) was stirred at room
temperature overnight. After concentration, the residue was
purified by column chromatography over silica gel (1.5 × 12
cm, 10-20% MeOH in CHCl3) to give 31 (84 mg, 69%) as
crystals: mp 239-241 °C (crystallized from MeOH); UV
(MeOH) λmax 276 nm; 1H NMR (DMSO-d6) δ 7.60 (1H, d, H-6,
J ) 7.3 Hz), 7.05 (1H, br s, NH), 7.00 (1H, br s, NH), 5.67
(1H, d, H-5, J ) 7.3 Hz), 5.38 (1H, d, 3′-OH, J ) 6.8 Hz), 4.85
(1H, dd, 5′-OH, J ) 4.4, 6.4 Hz), 4.63 (1H, dt, H-2′, J ) 7.8,
10.7 Hz), 4.12-4.06 (1H, m, H-3′), 3.86 (1H, dt, H-5′a, J )
4.4, 10.3 Hz), 3.39 (1H, ddd, H-5′b, J ) 6.4, 8.3, 10.3 Hz), 3.18-
3.12 (1H, m, H-4′), 2.85 (1H, t, H-1′a, J ) 10.7 Hz), 2.80 (1H,
dd, H-1′b, J ) 7.8, 10.7 Hz); FAB-MS m/z 244 (M+ + H). Anal.
Calcd for C9H13N3O3S: C, 44.43; H, 5.39; N, 17.27. Found:
C, 44.23; H, 5.36; N, 17.03.
(2S)-1,4-An h yd r o-2-O-(4-(cytosin -1-yl)p yr im id in -2-yl)-
2-d eoxy-4-th io-D-a r a bitol (32). Compound 30 (85.4 mg, 0.15
mmol) was converted as described for the synthesis of 31 to
give 33 (39.8 mg, 79%) as a white solid: mp 145 °C (dec); UV
(MeOH) λmax 253, 300 nm; 1H NMR (DMSO-d6) δ 8.60 (1H, d,
H-6, J ) 5.4 Hz), 8.29 (1H, d, H-6′′, J ) 7.8 Hz), 7.80 (1H, d,
H-5, J ) 5.4 Hz), 7.70 (1H, br s, NH), 7.66 (1H, br s, NH),
5.99 (1H, d, H-5′′, J ) 7.8 Hz), 5.54 (1H, d, 3′-OH, J ) 4.9
Hz), 5.35 (1H, q, H-2′, J ) 4.9 Hz), 4.91 (1H, t, 5′-OH, J ) 5.4
Hz), 4.17 (1H, q, H-3′, J ) 4.9 Hz), 3.77-3.72 (1H, m, H-5′a),
3.43-3.38 (1H, m, H-5′b), 3.28-3.18 (2H, m, H-4′, H-1′a), 2.83
(1H, dd, H-1′b, J ) 4.9, 11.2 Hz); 13C NMR (DMSO-d6-D2O) δ
166.24 (C-4′′), 164.30 (C-2), 161.40 (C-6), 160.25 (C-4), 155.00
(C-2′′), 142.35 (C-6′′), 110.81 (C-5), 97.64 (C-5′′), 83.41 (C-2′),
76.89 (C-3′), 64.13 (C-5′), 53.68 (C-4′), 31.69 (C-1′); FAB-MS
m/z 338 (M+ + H). Anal. Calcd for C13H15N5O4S‚1.0H2O: C,
43.94; H, 4.82; N, 19.71. Found: C, 43.76; H, 4.32; N, 19.44.
(2S)-1,4-An h yd r o-5-O-(ter t-b u t yld ip h en ylsilyl)-2-(cy-
tosin -1-yl)-2-d eoxy-4-th io-D-a r a bitol (29) a n d (2S)-1,4-
An h yd r o-5-O-(ter t-bu tyld ip h en ylsilyl)-2-O-[4-(cytosin -1-
yl)p yr im id in -2-yl]-2-d eoxy-4-th io-D-a r a bitol (30). To a
solution of 27 and 28 (500 mg, 0.83 mmol) in CH2Cl2 (16 mL)
was added slowly a solution of BCl3 (5.3 mL of a 1 M CH2Cl2
solution, 5.3 mmol) at -78 °C. After being stirred for 1.5 h at
the same temperature, the reaction was quenched by addition
of pyridine-MeOH (5.5 mL, 2:1). The mixture was allowed
to warm to room temperature and was stirred for 1 h. After
the most of organic solvents were removed under reduced
pressure, the whole was extracted with CHCl3 (×2). The
organic phase was washed with H2O and brine and then dried
(Na2SO4). After the solvent was evaporated under reduced
pressure, the concentrated residue was purified by column
chromatography over silica gel (2.8 × 20 cm, 1-10% MeOH
in CHCl3, and then 2.8 × 5 cm, AcOEt) to give less polar 30
(104 mg, 22%) and more polar 29 (256 mg, 53%) as an
amorphous foam, respectively.
1
Da ta for 29: H NMR (CDCl3 + D2O) δ 7.69-7.62 (4H, m,
Ack n ow led gm en t. The authors are grateful to
Professor A. Matsuda, Hokkaido University, for his
valuable discussions and Dr. K. Kodama, Yamasa Corp.,
for his continuing interest and encouragement. The
authors also acknowledge Mr. M. Morozumi and Dr. K.
Kondo, Yamasa Corp., for their helpful discussions.
Ar H), 7.41-7.31 (7H, m, Ar H), 5.99 (1H, d, H-5, J ) 7.8 Hz),
4.95-4.88 (1H, m, H-2′), 4.21 (1H, t, H-3′, J ) 8.8 Hz), 4.02
(1H, dd, H-5′a, J ) 4.9, 10.3 Hz), 3.82 (1H, dd, H-5′b, J ) 7.3,
10.3 Hz), 3.55-3.50 (1H, m, H-4′), 2.97 (1H, dd, H-1′a, J )
7.8, 10.3 Hz), 2.76 (1H, t, H-1′b, J ) 10.3 Hz), 1.04 (9H, s,
t-Bu); FAB-MS m/z 482 (M+ + H). Anal. Calcd for C25H31N3O3-
SSi‚0.7H2O: C, 60.75; H, 6.61; N, 8.50. Found: C, 60.72; H,
6.41; N, 8.35.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR, HMBC, and NOE spectral charts of 32 (4 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
Da ta for 30: H NMR (CDCl3) δ 9.46-8.84 (2H, br, NH2),
8.52-8.42 (2H, m, H-6, H-6′′), 7.71 (1H, d, H-5, J ) 5.4 Hz),
7.68-7.65 (4H, m, Ar H), 7.43-7.26 (6H, m, Ar H), 5.58 (1H,
d, H-5′′, J ) 7.3 Hz), 5.57-5.52 (1H, m, H-2′), 4.44 (1H, t, H-3′,
J ) 6.8 Hz), 3.96 (1H, dd, H-5′a, J ) 6.8, 10.3 Hz), 3.84 (1H,
dd, H-5′b, J ) 6.8, 10.3 Hz), 3.51 (1H, q, H-4′, J ) 3.5 Hz),
3.32 (1H, dd, H-1′a, J ) 6.8, 10.7 Hz), 2.92 (1H, dd, H-1′b, J )
J O980667S