Nucleosides and nucleotides. 151. Conversion of (Z)-2'-(cyanomethylene)-2'-deoxyuridines into their (E)-isomers via addition of thiophenol to the cyanomethylene moiety followed by oxidative syn-elimination reactions

Article abstract of DOI:10.1021/jo960577s

The Wittig reaction of 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-β-D-erythro-pent ofuranos-2-ulosyl]uracil (6) with Ph₃P=CHCN afforded (Z)-2'-cyanomethylene derivative 7 exclusively. The (E)-isomer was accessed from its (Z)-isomer through a sequence of addition of thiophenol to the 2'-cyanomethylene moiety of the (Z)-isomer from the α-face, selectively, and stereoselective oxidative syn-elimination of the resulting adduct. The diastereofacial selectivity of the benzenethiolate addition to the cyanomethylene moiety was found to be influenced by participation of the 2-carbonyl group at the base moiety and steric hindrance of the sugar protecting groups. Although nucleophilic addition reactions at the 2'-position of 6 have been well-known to occur from the α-face selectively, treatment of 7 with LiSPh in THF unexpectedly afforded a mixture of α- and β-phenylthio derivatives 8 and 9 in almost equal ratio. Furthermore, an unusual β-facial selective addition was observed on treatments of 7 with PhSAlMe₂ in CH₂Cl₂ or with LiSPh in the presence of Mg(ClO₄)₂ in THF. On the other hand, when (Z)-2'-(cyanomethylene)-5'-O-triisopropylsilyl derivative 10 was treated with LiSPh, the α-phenylthio derivative 13 was obtained predominantly (89:11). Oxidation of 8 with m-chloroperbenzoic acid (m-CPBA) in CH₂Cl₂ and pyrolysis of the resulting sulfoxides afforded the (Z)-isomer 7 exclusively. Treatment of 13 with m-CPBA under the same conditions afforded the desired (E)-cyanomethylene derivatives 18 as a major product (E:Z = 14:1) in good yield. Deprotection of 18 by the standard procedures furnished (E)-2'-(cyanomethylene)-2'deoxyuridine (5).

Full text of DOI:10.1021/jo960577s

J . Org. Chem. 1996, 61, 6261-6267
6261
Nu cleosid es a n d Nu cleotid es. 151. Con ver sion of
(Z)-2′-(Cya n om eth ylen e)-2′-d eoxyu r id in es in to Th eir (E)-Isom er s
via Ad d ition of Th iop h en ol to th e Cya n om eth ylen e Moiety
F ollow ed by Oxid a tive Syn -elim in a tion Rea ction s1
Abdalla E. A. Hassan, Naozumi Nishizono, Noriaki Minakawa, Satoshi Shuto, and
Akira Matsuda*,†
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060, J apan
Received March 27, 1996X
The Wittig reaction of 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-â-D-erythro-pentofuranos-
2-ulosyl]uracil (6) with Ph3PdCHCN afforded (Z)-2′-cyanomethylene derivative 7 exclusively. The
(E)-isomer was accessed from its (Z)-isomer through a sequence of addition of thiophenol to the
2′-cyanomethylene moiety of the (Z)-isomer from the R-face, selectively, and stereoselective oxidative
syn-elimination of the resulting adduct. The diastereofacial selectivity of the benzenethiolate
addition to the cyanomethylene moiety was found to be influenced by participation of the 2-carbonyl
group at the base moiety and steric hindrance of the sugar protecting groups. Although nucleophilic
addition reactions at the 2′-position of 6 have been well-known to occur from the R-face selectively,
treatment of 7 with LiSPh in THF unexpectedly afforded a mixture of R- and â-phenylthio
derivatives 8 and 9 in almost equal ratio. Furthermore, an unusual â-facial selective addition was
observed on treatments of 7 with PhSAlMe2 in CH2Cl2 or with LiSPh in the presence of Mg(ClO4)2
in THF. On the other hand, when (Z)-2′-(cyanomethylene)-5′-O-triisopropylsilyl derivative 10 was
treated with LiSPh, the R-phenylthio derivative 13 was obtained predominantly (89:11). Oxidation
of 8 with m-chloroperbenzoic acid (m-CPBA) in CH2Cl2 and pyrolysis of the resulting sulfoxides
afforded the (Z)-isomer 7 exclusively. Treatment of 13 with m-CPBA under the same conditions
afforded the desired (E)-cyanomethylene derivatives 18 as a major product (E:Z ) 14:1) in good
yield. Deprotection of 18 by the standard procedures furnished (E)-2′-(cyanomethylene)-2′-
deoxyuridine (5).
Ch a r t 1
In tr od u ction
2′-Deoxy-2′-methylenecytidine (DMDC, 1; Chart 1)2 has
potent antiproliferative activity against a variety of
human tumor cells both in vitro and in vivo and is now
under clinical investigation in J apan. We and others
have previously reported that the structural modifica-
tions of the 3′-allylic alcohol moiety of DMDC, e.g.,
inversion,3a deoxygenation,3b and substitution with an
amino3c,d or a fluoride group3e or by construction of an
endocyclic allylic alcohol moiety at the 2′,3′-positions,3f
resulted in nucleosides completely devoid of antitumor
activity. These consequences emphasize the crucial role
†
Tel:
(011) 706-3228.
Fax:
(011) 706-4980.
E-mail:
matuda@pharm.hokudai.ac.jp.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) For part 150 in the series, see: Shuto, S.; Awano, H.; Shimazaki,
N.; Hanaoka, K.; Sasaki, T.; Matsuda, A. BioMed. Chem. Lett. 1996,
6, 1021-1024.
of both the 2′-exo-methylene group and the 3′-R-hydroxyl
group of DMDC in its antitumor activity. The antitumor
activity of DMDC is believed to be related to inhibition
of DNA synthesis, since the 5′-triphosphate of DMDC
strongly inhibited DNA polymerases from calf thymus2d
and its 5′-diphosphate (DMDCDP) showed a time-de-
pendent irreversible inactivation of ribonucleotide diphos-
phate reductase (RDPR) from Escherichia coli.2f
(2) (a) Takenuki, K.; Matsuda, A.; Ueda, T.; Sasaki, T.; Fujii, A.;
Yamagami, K. J . Med. Chem. 1988, 31, 1063. (b) Matsuda, A.;
Takenuki, K.; Tanaka, M.; Sasaki, T.; Ueda, T. J . Med. Chem. 1991,
34, 812. (c) Yamagami, K.; Fujii, A.; Arita, M.; Okumoto, T.; Sakata,
S.; Matsuda, A.; Ueda, T. Cancer Res. 1991, 51, 2319. (d) Matsuda,
A.; Azuma, A.; Nakajima, Y.; Takenuki, K.; Dan, A.; Iino, T.; Yoshimu-
ra, Y.; Minakawa, N.; Tanaka, M.; Sasaki, T. In Nucleosides and
Nucleotides as Antitumor and Antiviral Agents; Chu, C. K., Baker, D.
C., Eds.; Plenum Publishing Co.: New York, 1993; pp 1-22. (e) Cory,
A. H.; Samano, V.; Robins, M. J .; Cory, J . P. Biochem. Pharmacol. 1994,
47, 365. (f) Baker, H.; Bazon, A.; Bollinger, J . M., J r.; Stubbe, J .;
Samano, V.; Robins, M. J .; Lippert, B.; J arvi, E.; Resvick, R. J . Med.
Chem. 1991, 34, 1879.
The synthesis of (E)- and (Z)-2′-deoxy-2′-(fluorometh-
ylene)cytidines (dFMCyd; 2 and 3) has been reported.4a,b
The (E)-dFMCyd was more cytotoxic than the parent
(3) (a) Hassan, A. E. A.; Matsuda, A. Unpublished results. (b)
Matsuda, A.; Okajima, H.; Masuda, A.; Kakefuda, A.; Yoshimura, Y.;
Ueda, T. Nucleosides Nucleotides 1992, 11, 197. (c) Hassan, A. E. A.;
Matsuda, A. Heterocycles 1992, 34, 657. (d) Hassan, A. E. A.; Shuto,
S.; Matsuda, A. Tetrahedron 1994, 50, 689. (e) Hassan, A. E. A.; Shuto,
S.; Matsuda, A. Nucleosides Nucleotides 1994, 13, 197. (f) Ioannidis,
P.; Classon, B.; Samuelsson, B.; Kavarnstro¨m, I. Nucleosides Nucle-
otides 1993, 12, 449.
(4) (a) McCarthy, J . R.; Matthewes, D. P.; Steerick, D. M.; Huber,
E. W.; Bey, P.; Lipert, J . P.; Snyder, R. D.; Sunkara, P. S. J . Am. Chem.
Soc. 1991, 113, 7439. (b) Matthewes, D. P.; Persichetti, R. A.; Sabol,
J . S.; Stewart, K. T.; McCarthy, J . R. Nucleosides Nucleotides 1993,
12, 115. (c) Bitonti, A. J .; Dumont, J . A.; Bush, T. L.; Cashman, E. A.;
Cross-Doersen, D. E.; Wright, P. S.; Matthewes, D. P.; McCarthy, J .
R.; Kaplan, D. A. Cancer Res. 1994, 54, 1485.
S0022-3263(96)00577-4 CCC: $12.00 © 1996 American Chemical Society

6262 J . Org. Chem., Vol. 61, No. 18, 1996
Hassan et al.
Sch em e 1a
a
(a) Ph3PdCHCN, CH2Cl2/THF, rt; (b) PhS- (see Table 1); (c) LiSPH, HMPA, THF, 0 °C to rt, or NaSePh; (d) m-CPBA or H2O2 (see
Table 2); (e) TBAF, AcOH, THF, 0 °C.
nucleoside DMDC and (Z)-dFMCyd, and its 5′-diphos-
phate was also found to be a time-dependent irreversible
inhibitor of RDPR.4c This together with the proposed
mechanism of inactivation of RDPR by DMDCDP2e
indicates that introduction of an electron-withdrawing
group at the terminal of the exo-methylene moiety with
(E)-geometry would elevate the activity of DMDC. There-
fore, we selected a cyano group, which has good electron-
withdrawing property and is not bulky, to be introduced
at the terminus of the 2′-exo-methylene moiety. Herein,
we describe an easy method for stereoselective conversion
of the readily accessible (Z)-2′-deoxy-2′-(cyanomethylene)-
uridine derivatives to their corresponding (E)-cyano-
methylene derivatives through a sequence of a stereose-
lective addition of PhSH to the cyanomethylene moiety
and stereoselective oxidative syn-elimination reactions
of the resulting sulfoxides.
F igu r e 1. Newman projections of the rotamers around the
C2′-C2′′ bond.
cessive oxidation and stereoselective syn-elimination of
the sulfoxide.7 We envisioned that, if the 2′â-cyano-
methyl group of the resulting adduct could adopt the
conformation A, in which the cyano group is between the
C-3′ and the 2′-SOPh, rather than B or C (Figure 1), the
Resu lts a n d Discu ssion
(6) For references of thiolate conjugate addition to alkenoic acids
and their derivatives, see: (a) Abrammovich, R. A.; Rogic, M. M.;
Singer, S. S.; Venkateswaran, N. J . Org. Chem. 1972, 37, 3577. (b)
Wynberg, H.; Greijdanus, B. J . Chem. Soc., Chem. Commun. 1978,
427. (c) Kuwajima, I.; Murobushi, T.; Nakamura, E. Synthesis 1978,
602. (d) Kobayashi, N.; Iwai, K. J . Org. Chem. 1981, 46, 1823. (e)
Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 363. (f) Kamimura,
A.; Ono, N. J . Chem. Soc., Chem. Commun. 1988, 1278. (g) Nelson,
C. F. Y.; Bryan, H.; Huffman, W. F.; Moore, M. L. J . Org. Chem. 1988,
53, 4605. (h) Miyata, O.; Shinada, T.; Kawakami, N.; Taji, K.;
Ninomiya, I.; Naito, T.; Date, T.; Okamura, K. Chem. Pharm. Bull.
1992, 40, 2579.
(7) For examples of the utility and mechanistic aspects of the
dehydrosulfenylation of sulfides, see: (a) Trost, B. M.; Sazmann, T.
N.; Hiroi, K. J . Am. Chem. Soc. 1976, 98, 4887. (b) Yoshimura, T.;
Tsukurimichi, E.; Iizuka, Y.; Mizuno, H.; Isaji, H.; Shimasaki, C. Bull.
Chem. Soc. J pn. 1989, 62, 1891. (c) Yoshimura, T.; Yoshizawa, M.;
Tsukurimichi, E. Bull. Chem. Soc. J pn. 1987, 60, 2491. (d) Naito, T.;
Shinada, T.; Miyata, O.; Ninomiya, I. Tetrahedron Lett. 1989, 30, 2941.
Treatment of 1-[3,5-O-[1,1,3,3-tetraisopropyldisiloxane-
1,3-diyl (TIPDS)]-â-D-erythro-pentofuranos-2-ulosyl]uracil
(6)5 with the stable ylide Ph3PdCHCN in THF/CH2Cl2
afforded (Z)-2′-cyanomethylene derivative 7 as a single
stereoisomer in quantitative yield (Scheme 1). The
geometry of the terminal cyanomethylene group in 7 was
confirmed by NOE experiments. Our strategy to build
up a cyanomethylene group with (E)-geometry at the 2′-
position is based on an addition of a benzeneselenolate
or benzenethiolate group to the cyanomethylene moiety6
of 7 stereoselectively from the R-face, followed by suc-
(5) Hansske, F.; Madej, D.; Robins, M. J . Tetrahedron 1984, 40, 125.

(Z)-2′-(Cyanomethylene)-2′-deoxyuridine
J . Org. Chem., Vol. 61, No. 18, 1996 6263
Ta ble 1. Ad d ition of Th iop h en ol to 7
entry
reagent (equiv)a
solvent
additives (equiv)
conditions
yield (%)b
ratio (8:9)c
1
2
3
4
5
6
7
LiSPh (0.1)
LiSPh (1.5)
Me2AlSPh (1.5)
LiSPh (1.5)
LiSPh (0.1)
LiSPh (1.5)
NaSPh (2.5)
THF
THF
CH2Cl2
THF
THF
THF
THF
none
none
none
Mg(ClO4)2 (5)
12-c-4 (10)
HMPA (5)
none
rt, 25 h
rt, 3 h
rt, 3 days
60 °C, 5 days
rt, 26 h
rt, 3 h
85
95d
80
87
81
e
55:45
62:38
17:83
15:85
59:41
rt, 2 h
68
60:40
a
b
All reactions were done in the presence of 10 equiv of PhSH. Yields after purification by silica gel chromatography. c Ratio of 8:9
was measured by 1H NMR spectra. The cycloadduct 21 was isolated in 4% yield. e Compound 17 was isolated in 91%.
d
syn-elimination of the corresponding sulfoxide would give
rise to the corresponding (E)-cyanomethylene derivative.
Addition of benzeneselenolate to the cyanomethylene
moiety of 7 was first attempted under various conditions;
however, none of the addition products was obtained and
only 1′,2′-didehydro-2′-cyanomethyl derivative 17 was
isolated in good yield. On the other hand, treatment of
7 with LiSPh in the presence of an excess of PhSH in
THF afforded unexpectedly a mixture of the R-phenylthio
derivative 8, the â-phenylthio derivative 9, and the
cycloadduct 21 (Table 1, entries 1 and 2). The structures
of 8 and 9 were identified on the basis of 1H NMR spectra
and NOE experiments. Irradiation at H-1′ of 8 showed
an NOE enhancement at the 2′-PhS protons (8.2%). On
F igu r e 2. 13C NMR chemical shift difference (∆δ) of 7 as a
the other hand, irradiation at the 2′-cyanomethyl protons
of 9 showed NOE enhancements at H-1′ (4.8% and 5.1%,
respectively).
function of the molar equivalence of the LiClO4. 13C NMR was
measured at a concentration of 0.07 M in THF-C6D6 (10:1).
Values were referenced relative to C6D6 at 128 ppm.
When the addition product 8 or 9 was further treated
molar ratios of LiClO4, as a monitor of changes in the
electron density.10,11 A noteworthy feature of the 13C
chemical shifts is the significant downfield shift of C-2
as well as C-6 and C-5 and the upfield shift of C-1′,12
while the cyano carbon showed a slight upfield shift
(Figure 2). The observed electron deficiency at the C-2
suggests a complexation of LiSPh with the 2-carbonyl
oxygen. Further, when the addition reaction was done
with a countercation of higher affinity for the carbonyl
oxygen as in the aluminum thiophenoxy “ate” complex,
with LiSPh under the conditions described above, no
interchange between the two diastereomers was ob-
served, which suggested that the addition reaction was
irreversible.
This nonselective π-facial addition of PhSH contrasts
to the well-known R-facial selectivity of nucleophilic
additions at the trigonal center of 2′-ketonucleosides.8 For
5
8a
instance, NaBH4 and LiBHEt3 as well as the carbon
nucleophiles, such as MeMgBr,8n-d LiCtCR,8e NaCH2-
NO2,8f and (CH3)2S(O)dCH2,8g add to 6 from the R-face
selectively. Moreover, R-facial selective benzenethiolate
addition at the 2′-position of 2′,3′-didehydro-2′,3′-dideoxy-
3′-nitrothymidine was reported.9 However, we have
previously encountered an exceptional example of the
nonselective addition reaction at the 2′-position of 4-ethoxy-
1-[3,5-O-(TIPDS)-â-D-erythro-2-pentofuranos-2-ulosyl]-2-
(1H)-pyrimidinone upon treatment with MeMgBr in
Et2O.8h The unusual methyl addition reaction was
interpreted to be a result of a chelation of the Grignard
reagent between the relatively basic 2-carbonyl oxygen
and the 2′-carbonyl oxygen, by which the methyl carban-
ion would be delivered from the sterically hindered
â-face.8h To investigate whether the unusual â-facial
nucleophilic attack is related to the aforementioned
nucleobase participation or not, 13C NMR of 7 was
measured in THF/C6D6 (10:1) in the presence of different
13
PhSAlMe2 (Table 1, entry 3) or LiSPh in the presence
of Mg(ClO4)2 (Table 1, entry 4), the â-facial selective
addition proceeded selectively. These results suggested
that the nucleobase participation directs the â-facial
attack of the thiolate anion at the 2′-cyanomethylene
moiety of 7. Attempts to elevate the R-facial selectivity
through impeding the postulated 2-carbonyl participation
by carrying out the reaction in the presence of 12-crown-4
ether14 or HMPA, however, were unsuccessful (Table 1,
entries 5 and 6).15 Also, the use of NaSPh did not show
any advantage over the use of LiSPh in respect to the
facial selectivity (Table 1, entry 7).16
(10) Kanai, M.; Koga, K.; Tomioka, K. Tetrahedron Lett. 1992, 33,
7193.
(11) (a) Childs, R. F.; Mulholland, D. L.; Nixon, A. Can. J . Chem.
1982, 60, 801. (b) Childs, R. F.; Mulholland, D. L.; Nixon, A. Ibid.
1982, 60, 809.
(12) Although an upfield shift was observed at the C-1′ upon addition
of LiClO4, it is not certain whether this shift is due to an increased
electron density on C-1′ or to the dimensioned anisotropic effect of the
2-carbonyl group. However, 1H NMR of 7 in the presence of 1 equiv
of LiClO4 (data not shown) showed a considerable downfield shift of
the protons of the uracil moiety; H-6, H-5, H-N3, and, unexpectedly, a
slight downfield shift of H-1′ was also observed.
(13) Armistead, D. M.; Danishefsky, S. J . Tetrahedron Lett. 1987,
28, 4959.
(14) Loupy, A.; Seyden-Penne, J . Tetrahedron 1980, 36, 1937.
(15) Upon attempted addition of thiophenol to 7 in the presence of
countercations incapable of chelation such as Et3N, i-Pr2NEt, or 1,1,3,3-
tetramethylguanidine, however, decomposition or recovering of the
starting material was observed.
(8) (a) Hansske, H.; Robins, M. J . J . Am. Chem. Soc. 1983, 6736.
(b) Matsuda, A.; Itoh, H.; Takenuki, K.; Sasaki, T.; Ueda, T. Chem.
Pharm. Bull. 1988, 36, 945. (c) Awano, H.; Shuto, S.; Baba, M.; Kira,
T.; Shigeta, S.; Matsuda, A. BioMed. Chem. Lett. 1994, 4, 367. (d)
Hayakawa, H.; Tanaka, H.; Itoh, N.; Nakajima, M.; Miyasaka, T.;
Yamaguchi, K.; Iitaka, Y. Chem. Pharm. Bull. 1987, 36, 2605. (e) Iino,
T.; Yoshimura, Y.; Matsuda, A. Tetrahedron 1994, 50, 10397. (f) Ueda,
T.; Shuto, S.; Inoue, H. Nucleosides Nucleotides 1984, 3, 173. (g)
Yoshimura, Y.; Saitoh, K.; Ashida, N.; Sakata, S.; Matsuda, A. BioMed.
Chem. Lett. 1994, 4, 721. (h) Takenuki, K.; Itoh, H.; Matsuda, A.;
Ueda, T. Chem. Pharm. Bull. 1990, 38, 2947.
(9) Hossain, N.; Garg, N.; Chattopadhyaya, J . Tetrahedron 1993,
49, 10061.

6264 J . Org. Chem., Vol. 61, No. 18, 1996
Ta ble 2. Oxid a tive Syn -elim in a tion a
Hassan et al.
entry
substrate
R1
R2
reagent
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/THF
CH2Cl2
AcOH
conditionsb
yield (%)c
ratio (E:Z)d
1
2
3
4
5
6
7
8
13
14
15
16
13
9
TIPDS
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
H2O2
rt, 11 h
rt, 1.5 h
rt, 7 h
rt, 19 h
rt, 20 h
79
82
85
96
80
85
37
1:99
93:7
TIPS
TBDMS
H
TIPS
TIPS
H
H
H
Ac
H
84:16
75:25
52:48
59:41
1:99
60 °C, 2 h
90 °C, 72 h
TIPDS
m-CPBA
CH2Cl2
a
b
All reactions were done using 1.2 equiv of the oxidant. Oxidation with m-CPBA was completed within 30 min at -78 °C. c Yields
after purification by silica gel chromatography. The E:Z ratios were identified by 1H NMR spectra.
d
these conditions gave the desired (E)-cyanomethylene
derivative 18 (E:Z ) 93:7) in 82% yield (Table 2, entry
2). Similarly, the m-CPBA oxidation of 5′-O-TBDMS
derivative 14 also afforded the corresponding (E)-deriva-
tive 19 selectively (Table 2, entry 3). The contradiction
in the geometrical selectivity of the oxidative syn-
elimination between 8 and 13 may imply a substantial
difference in the conformations of the 2′â-cyanomethyl
moiety upon changing the sugar protecting groups.
To verify the importance of the remote effects of the
F igu r e 3. Molecular structures of 7 (A) and 10 (B). Hydrogen
atoms and lone pairs are omitted for clarity. Global minimal
optimizations were done by using MM2 implemented in
MacroModel program version 4.5.
bulky 5′-O-TIPS group on the conformational preference
of the 2′â-cyanomethyl group, and consequently on the
geometrical selectivity of the oxidative syn-elimination,
the 3′,5′-unprotected derivative 15 was prepared and
subjected to the oxidative elimination reaction. As a
result, the (E)-cyanomethylene derivative 5 was obtained
predominantly (Table 2, entry 4) while the selectivity was
reduced compared with those of the reaction with 13 or
14. These results suggested that the geometrical selec-
tivity does not depend only on bulkiness of the protecting
group at the 5′-position. Therefore, we next investigated
the role of the 3′-hydroxyl group in the stereoselective
syn-elimination of the sulfoxide. The 3′-hydroxyl of 13
was acetylated to give 16, which was then subjected to
the oxidative elimination reaction. However, the (E)-
selectivity was lost (20:12 ) 52:48) (Table 2, entry 5).
When the oxidative syn-elimination of 13 was carried out
using an oxidizing reagent incapable of coordinative
interaction18 with the 3′-hydroxyl such as H2O2, the E:Z
ratio was 59:41 (Table 2, entry 6). Therefore, it appears
that both the cooperative coordination effect of the 3′-
hydroxyl group and the steric effects of both the 5′-
protecting group and the nucleobase would be synchro-
nized to direct the oxidative syn-elimination via the
conformation A (Figure 1) to produce 18 selectively.
Although the configuration of the sulfoxides would also
be an important determinant of the stereoselectivity of
the syn-elimination reactions, it was difficult to isolate
these sulfoxides due to their fragmentations to the
corresponding cyanomethylene derivatives on silica gel
column chromatography. Attempts to identify the sul-
foxide configuration by doing the reaction in an NMR
tube in CD2Cl2 at -60 °C, however, were unsuccessful
The addition reaction was next done with 5′-O-(triiso-
propylsilyl (TIPS))-2′-(cyanomethylene)uridine (10) as the
substrate, in which the R-face of the sugar moiety would
be sterically hindered due to the bulky 5′-TIPS group so
that â-selective nucleophilic attack at the 2′-potition
might proceed. Deprotection of the 3′,5′-protecting groups
of 7, followed by selective protection of the 5′-hydroxyl
by the bulky TIPS group, furnished 10 (Scheme 1). When
10 was treated with LiSPh, the desired R-phenylthio
derivative 13 was obtained predominantly along with the
â-phenylthio derivative in a ratio of 89:11 in 91% yield,
from which 13 was isolated in a pure form by crystal-
lization. 1H NMR spectra of 7 and 10 gave information
about the sugar-puckering difference between the two
nucleosides, where J 3′,4′ of 10 (7.7 Hz) implies a less 3′-
endo puckered conformation than that of 7 (8.4 Hz). We
also carried out molecular mechanics calculations17 on
the two nucleosides. A 2′-exo,3′-endo conformational
preference was observed for 7, while a 2′-endo,3′-exo
conformational preference was observed for 10 (Figure
3). The latter conformation might result in alleviation
of the steric hindrance at the R-face of the 2′-position due
to both the 5′-O-TIPS group and the uracil base. The
participation of the 2-carbonyl in the reaction of 7 may
also be indicated by the result of treatment of 10 with
PhSAlMe2 in CH2Cl2 which did not give any addition
product, but recovery of 10.
The oxidative syn-elimination of the R-phenylthio
derivatives 8 and 13 was next investigated. First, 8 was
treated with m-CPBA in CH2Cl2 at -78 °C, followed by
stirring the reaction mixture at room temperature for
further 11 h. However, none of the desired (E)-cyano-
methylene derivative was obtained, but the (Z)-isomer 7
was isolated in 79% yield (Table 2, entry 1). On the
contrary, treatment of 13 with m-CPBA in CH2Cl2 under
1
due to low resolution of the H NMR spectra. It is also
worth noting that the oxidative syn-elimination of the
â-phenylthio derivative 9 afforded only the (Z)-cyano-
methylene derivative 7 (Table 2, entry 7). Since at-
tempted desilylation of 9, however, gave the lactone 22,
we could not study further the effects of the protecting
groups on the geometrical selectivity as described above.
(16) A 13C NMR spectrum of 7 in THF/C6D6 in the presence of
NaClO4 (data not shown) showed a shift pattern similar to that
measured in the presence of LiClO4, but in a smaller degree than that
of LiClO4.
(17) Global minimal optimizations were carried out by using MM2
force field implemented in MacroModel version 4.5; default parameters
were used.
(18) For examples of directive coordination to m-CPBA, see: (a)
J onson, M. R.; Kishi, Y. Tetrahedron Lett. 1979, 4347. (b) Clayden,
J .; Collington, E. W.; Egert, E.; McElroy, A. B.; Warran, S. J . Chem.
Soc., Perkin Trans. 1 1994, 2801. (c) Kogen, H.; Nishi, T. J . Chem.
Soc., Chem. Commun. 1987, 311. (d) J enmalm, A.; Berts, W.; Luth-
man, K.; Cso¨regh, I.; Hacksell, U. J . Org. Chem. 1995, 60, 1026.

(Z)-2′-(Cyanomethylene)-2′-deoxyuridine
J . Org. Chem., Vol. 61, No. 18, 1996 6265
Finally, desilylation of 18 and 7 by NH4F in MeOH19
furnished (E)- and (Z)-2′-deoxy-2′-(cyanomethylene)-
uridines 5 and 4, respectively.
mmol), and HMPA (0.18 mL, 1 mmol) in THF (4 mL) was
treated with a THF solution of LiSPh (0.58 M, 0.5 mL, 0.3
mmol) at -15 °C. The mixture was stirred for 3 h and then
neutralized with AcOH and evaporated. The residue was
washed with brine and H2O, dried (Na2SO4), and evaporated.
The residue was purified on a silica gel column with 30%
EtOAc/hexane to give 17 (93 mg, 91% as a white solid, which
was crystallized from EtOAc/hexane): mp 153-155 °C, IR νmax
(film)/cm-1 2250 (CN); UV λmax (MeOH) 258, 214 nm, 1H NMR
(CDCl3) δ 8.48 (br s, 1H), 7.30 (d, 1H, J ) 8.3 Hz), 5.84 (dd,
1H, J ) 2.4, J ) 8.3 Hz), 5.33 (d, 1H, J ) 4.9 Hz, appeared as
a singlet on irradiation at 4.53 ppm), 4.53 (ddd, 1H, J ) 4.9,
J ) 9.8, J ) 10.7 Hz), 4.17 (dd, 1H, J ) 4.8, J ) 11.2 Hz), 3.80
(dd, 1H, J ) 11.2, J ) 10.7 Hz), 3.23 (d, 1H, J ) 18.6 Hz),
In conclusion, phenylsulfenylation of the cyanometh-
ylene moiety proceeded smoothly in a conjugate manner.
The diastereofacial selectivity of this benzenethiolate
addition can be controlled by the thiolate countercation
and/or manipulation of the sugar protecting groups to
produce stereoselectively either the 2′R-phenylthio or 2′â-
phenylthio derivatives. Dehydrophenylsulfenylation of
the R-phenylthio derivatives 13 and 14 proceeded ste-
reoselectively providing an access to the synthesis of the
(E)-2′-(cyanomethylene)-2′-deoxyuridine (5), which is dif-
ficult to attain by Wittig and related reactions. Applica-
tion of this method to the synthesis of cytidine derivatives
is now in progress.
3.17 (d, 1H, J ) 18.6 Hz), 1.25 (m, 28H); FABMS 508 [M+
+
1], 464 [M+ - i-Pr]. Anal. Calcd for C23H37N3O6Si2: C, 54.41;
H, 7.35; N, 8.28. Found: C, 54.29; H, 7.35; N, 8.07. Meth od
B. Sodium borohydride (40 mg, 0.8 mmol) was added to a
solution of (PhSe)2 (410 mg, 1.3 mmol) in EtOH (5 mL) at room
temperature. The mixture was stirred for 15 min until the
solution turned clear. Compound 7 (416 mg, 0.82 mmol) in
EtOH (2 mL) was added to the mixture and was heated at 60
°C for 8 h. The mixture was neutralized with AcOH, and the
solvent was evaporated. The residue was partitioned between
EtOAc and H2O. The water phase was evaporated, and the
residue was purified on a silica gel column to give 34 mg (37%)
of uracil as a white solid. The organic phase was washed with
brine and H2O, dried (Na2SO4), and evaporated. The residue
was purified on a silica gel column with 25% EtOAc/hexane
to give 17 (254 mg, 61% as a white solid).
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. NMR spectra
were recorded at 270, 400, or 500 MHz (1H) and at 100 or 125
MHz (13C) and are reported in ppm downfield from TMS. Mass
spectra were obtained by fast atom bombardment (FAB) mode.
Silica gel chromatography was done with YMC gel 60 A (70-
230 mesh).
(Z)-2′-(Cya n om eth ylen e)-2′-d eoxy-3′,5′-O-(1,1,3,3-tetr a -
isop r op yld isiloxa n e-1,3-d iyl)u r id in e (7). A solution of
Ph3PdCHCN (1.7 g, 5.6 mmol) in CH2Cl2 (10 mL) was added
to a solution of 6 (1.0 g, 2.1 mmol) in THF (15 mL) dropwise
at 0 °C. The mixture was stirred at room temperature for 3
h, and the reaction was then quenched with aqueous 1 M NH4-
Cl. The volatile was evaporated, and the residue was parti-
tioned between EtOAc and H2O. The organic phase was
washed with brine and H2O, dried (Na2SO4), and evaporated.
The residue was purified on a silica gel column with EtOAc/
hexane (1:3) to give 7 (1.0 g, 93% as a colorless foam): IR νmax
(neat)/cm-1 2220 (CN); 1H NMR (CDCl3) δ 8.17 (br s, 1H, NH),
7.20 (d, 1H, H-6, J ) 8.1 Hz), 6.14 (d, 1H, H-1′, J ) 2.2 Hz),
5.75 (dd, 1H, H-5, J ) 2.2, J ) 8.1 Hz), 5.64 (t, 1H, H-2′′, J )
2.2 Hz), 5.30 (dt, 1H, H-3′, J ) 2.2, J ) 8.3 Hz), 4.12 (dd, 1H,
H-5′a, J ) 4.5, J ) 12.7 Hz), 4.06 (dd, 1H, H-5′b, J ) 3.1, J )
12.7 Hz), 3.73 (ddd, 1H, H-4′, J ) 8.3, J ) 3.1, J ) 4.5 Hz),
1.11-0.90 (m, 28 H, i-Pr); NOE, irradiate H-1′, observe H-2′′
(0.7%), H-3′ (0.3%), H-4′ (3.8%), and H-6 (14.6%); irradiate
H-2′′, observe H-1′ (0.2%), H-3′ (2.1%), and isopropyl-H (7.6%);
irradiate H-3′, observe H-2′′ (2.3%), H-1′ (0.2%), and H-6
(2.2%); 13C NMR [THF/C6D6 (10:1)] δ 166.6, 162.7, 150.1, 143.5,
114.6, 102.8, 94.6, 87.7, 83.2, 74.9, 63.4, 17.4, 17.3, 17.2, 17.1,
16.9, 13.8, 13.5, 13.2, 13.1; FABMS m/z 508 [M+ + 1]; HR
FABMS calcd for C23H38N3O6Si2 508.2299, found 508.2272.
(Z)-2′-(Cya n om eth ylen e)-2′-d eoxyu r id in e (4). A mix-
ture of 7 (500 mg, 0.99 mmol), and NH4F (500 mg, 12.5 mmol)
in MeOH (15 mL) was heated at 65 °C for 2.5 h. After the
mixture was cooled to room temperature and the insoluble
material was removed by filtration, the filtrate was evaporated
and purified on a silica gel column with 5% MeOH/CHCl3 to
give 4 (250 mg, 96% as a white solid, which was crystallized
from EtOH/hexane); mp 197-199 °C; IR νmax (film)/cm-1 2240
(CN); 1H NMR (DMSO-d6) δ 11.51 (br s, 1H, NH), 7.61 (d, 1H,
H-6, J ) 8.0 Hz), 6.59 (t, 1H, H-1′, J ) 2.2 Hz), 6.15 (d, 1H,
3′-OH, J ) 6.9 Hz), 5.97 (t, 1H, H-2′′, J ) 2.5 Hz), 5.72 (d, 1H,
H-5, J ) 8.0 Hz), 4.96 (t, 1H, 5′-OH, J ) 5.6 Hz), 4.70 (m, 1H,
H-3′, J ) 2.3, J ) 8.0 Hz), 3.74 (m, 1H, H-5′a), 3.67 (m, 1H,
H-5′b), 3.55 (m, 1H, H-4′); NOE, irradiate H-1′, observe H-2′′
(1.1%), H-4′ (3.3%), and H-6 (9.1%); irradiate H-2′′, observe
H-1′ (0.9%) and 3′-OH (2.2%); irradiate H-3′, observe H-1′
(0.5%), H-2′′ (4.7%), H-6 (3.8%), and 3′-OH (12.0%). Anal.
Calcd for C11H11N3O5‚0.6H2O: C, 47.86; H, 4.60; N, 15.22.
Found: C, 47.99; H, 4.36; N, 15.16.
(2′S)-2′-(Cya n om eth yl)-2′-d eoxy-2′-(p h en ylth io)-3′,5′-O-
(1,1,3,3-tetr aisopr opyldisiloxan e-1,3-diyl)u r idin e (8), (2′R)-
2′-(Cya n om eth yl)-2′-d eoxy-2′-(p h en ylth io)-3′,5′-O-(1,1,3,3-
tetr a isop r op yld isiloxa n e-1,3-d iyl)u r id in e (9), a n d (2′R)-
2 ′-D e o x y -2 ′-( p h e n y l t h i o ) -3 ′, 5 ′-O -( 1 , 1 , 3 , 3 -t e t r a -
isop r op yld isiloxa n e-1,3-d iyl)-6,2′-(cya n om eth a n o)-5,6-d i-
h yd r ou r id in e (21). A THF solution of LiSPh (0.58 M, 17.6
mL, 10.2 mmol) in THF was added to a mixture of 7 (3.45 g,
6.8 mmol) and PhSH (7 mL, 68 mmol) in THF (40 mL) at 0
°C. The mixture was stirred at room temperature for 3 h. The
mixture was neutralized with AcOH, and the whole was taken
in EtOAc, which was washed with brine and H2O, dried (Na2-
SO4), and evaporated. The residue was purified on a silica
gel column with 15% EtOAc/hexane to give 21 (168 mg, 4% as
a white solid, which was crystallized from hexane), with 20%
EtOAc/hexane to give 8 (2.48 g, 59% as a white solid, which
was crystallized from EtOAc/hexane), and then with 25%
EtOAc/hexane to give 9 (1.51 g, 36% as a white solid, which
was crystallized from EtOAc/hexane). The physical data of 8:
mp 131-132 °C; IR νmax (neat)/cm-1 2240 (CN); 1H NMR
(CDCl3) δ 8.22 (br s, 1H, NH), 7.96 (d, 1H, H-6, J ) 8.2 Hz),
7.64 (dd, 2H, SPh, J ) 1.7, J ) 6.6 Hz), 7.45 (m, 3H, SPh),
6.05 (s, 1H, H-1′), 5.71 (dd, 1H, H-5, J ) 1.7, J ) 8.2 Hz), 4.66
(d, 1H, H-3′, J ) 8.8 Hz), 4.57 (dd, 1H, H-4′, J ) 2.2, J ) 8.8
Hz), 4.32 (d, 1H, H-5′a, J ) 14.3 Hz), 4.12 (dd, 1H, H-5′b, J )
14.3, J ) 2.2 Hz), 3.15 (d, 1H, CH2aCN, J ) 17.0 Hz), 3.00 (d,
1H, CH2bCN, J ) 17.0 Hz), 1.12-1.02 (m, 28H, i-Pr); NOE,
irradiate H-1′, observe CH2bCN (1.5%) and SPh (8.2%); irradi-
ate CH2aCN, observe H-3′ (2.4%), CH2bCN (23.9%), and SPh
(2.7%); irradiate CH2bCN, observe H-1′ (4.3%), H-3′ (1.3%),
CH2aCN (22.3%), and SPh (6.8%); FABMS m/z 618 [M+ + 1].
Anal. Calcd for C29H43N3O6SSi2: C, 56.37; H, 7.01; N, 6.80.
Found: C, 56.14; H, 7.05; N, 6.90. The physical data of 9: mp
1
147-148 °C; IR νmax (film)/cm-1 2240 (CN); H NMR (CDCl3)
δ 8.19 (br s, 1H, NH), 7.66 (d, 1H, H-6, J ) 8.2 Hz), 7.47-7.31
(m, 5H, SPh), 6.19 (s, 1H, H-1′), 5.84 (dd, 1H, H-5, J ) 2.8, J
) 8.2 Hz), 4.43 (d, 1H, H-3′, J ) 6.1 Hz), 4.17 (m, 2H, H-5′a,b),
4.11 (ddd, 1H, H-4′, J ) 6.1, J ) 4.4 Hz), 2.96 (d, 1H, CH2a
-
CN, J ) 17.0 Hz), 2.84 (d, 1H, CH2bCN, J ) 17.0 Hz), 1.14-
0.94 (m, 28H, i-Pr); NOE, irradiate H-1′, observe H-6 (1.7%),
CH2aCN (1.7%), and CH2bCN (1.9%); irradiate CH2aCN, ob-
serve H-1′ (5.1%), CH2bCN (11.5%), and SPh (3.7%); irradiate
CH2bCN, observe H-1′ (4.8%), CH2aCN (14.4%), and SPh (5.2%);
FABMS m/z 618 [M+ + 1]. Anal. Calcd for C29H43N3O6SSi2:
C, 56.37; H, 7.01; N, 6.80. Found: C, 56.09; H, 7.09; N, 6.83.
The physical data of 21: mp 108-109 °C; IR νmax (neat)/cm-1
2′-(Cyan om eth yl)-2′-deoxy-1′,2′-dideh ydr o-3′,5′-O-(1,1,3,3-
tetr a isop r op yld isiloxa n e-1,3-d iyl)u r id in e (17). Meth od
A. A solution of 7 (102 mg, 0.2 mmol), PhSH (0.2 mL, 1.9
(19) Zhang, W.; Robins, M. J . Tetrahedron Lett. 1992, 33, 1177.

6266 J . Org. Chem., Vol. 61, No. 18, 1996
Hassan et al.
1
2240 (CN); H NMR (CDCl3) δ 7.79 (m, 2H, SPh), 7.69 (br s,
Hz), 4.16 (ddd, 1H, J ) 5.0, J ) 2.8, J ) 3.3 Hz), 4.02 (dd, 1H,
J ) 11.5, J ) 2.8 Hz), 3.97 (dd, 1H, J ) 11.5, J ) 3.3 Hz), 2.15
(s, 3H), 1.16-1.03 (m, 21H); FABMS m/z 464 [M+ + 1]; HR
FABMS calcd for C22H34N3O6Si 464.2217, found, 464.2245.
1H, NH), 7.42-7.30 (m, 3H, SPh), 5.75 (s, 1H, H-1′), 4.33 (ddd,
1H, H-6, J ) 6.6, J ) 6.1 Hz), 4.29 (d, 1H, H-3′, J ) 7.8 Hz),
3.96 (dd, 2H, H-5′a,b, J ) 3.2 Hz), 3.85 (ddd, 1H, H-4′, J )
7.8, J ) 3.2 Hz), 3.58 (d, 1H, H-2′′, J ) 6.6 Hz), 2.82 (dd, 2H,
H-5a,b, J ) 6.2, J ) 11.5 Hz), 1.13-1.05 (m, 28H, i-Pr); NOE,
irradiate H-1′, observe H-4′ (3.6%), H-6 (0.7%), isopropyl
(3.7%), and SPh (9.7%); irradiate H-2′′, observe H-1′ (0.5%),
H-5′a (0.9%), H-5′b (1.7%), H-6 (18.9%), isopropyl (5.3%), and
SPh (1.8%); FABMS m/z 618 [M+ + 1]. Anal. Calcd for
C29H43N3O6SSi2: C, 56.37; H, 7.01; N, 6.80. Found: C, 56.02;
H, 7.03; N, 6.59.
Oth er Exp er im en ts in Ta ble 1. En tr y 3. The reaction
of 7 (102 mg, 0.2 mmol) with Me3AlSPh [prepared from 31 µL
(0.30 mmol) of PhSH and Me3Al (0.99 M in hexane, 0.30 mL)]
in CH2Cl4 (4 mL) gave a mixture of 8 and 9 [17:83 (determined
by the H-1′ integration ratio in the 1H NMR spectrum), 98 mg,
80%]. En tr y 4. The reaction of 7 (102 mg, 0.2 mmol) with a
mixture of LiSPh (0.58 M, 0.52 mL, 0.3 mmol) and PhSH (0.2
mL, 2 mmol) in the presence of Mg(ClO4)2 (223 mg, 1 mmol)
in THF (6 mL) gave a mixture of 8 and 9 (15:85, 108 mg, 87%).
En tr y 5. The reaction of 7 (102 mg, 0.2 mmol) with LiSPh
(0.58 M, 52 µL, 0.03 mmol) and PhSH (0.2 mL, 2 mmol) in the
presence of 12-crown-4 (0.5 mL, 3 mmol) in THF (4 mL) gave
a mixture of 8 and 9 (59:41, 100 mg, 81%). En tr y 7. The
reaction of 7 (102 mg, 0.2 mmol) with NaSPh (66 mg, 0.5 mmol)
and PhSH (0.2 mL, 2 mmol) in THF (3 mL) gave a mixture of
8 and 9 in a ratio of 60:40 (84 mg, 68%).
(Z)-2′-(Cya n om eth ylen e)-2′-d eoxy-5′-O-(tr iisop r op ylsi-
lyl)u r id in e (10). A mixture of 4 (150 mg, 0.57 mmol),
imidazole (62 mg, 0.91 mmol), and triisopropylsilyl chloride
(0.20 mL, 0.93 mmol) was dissolved in DMF (5 mL) at 0 °C.
The mixture was stirred for 17 h at room temperature. After
water workup, the residue was purified on a silica gel column
with 2% EtOH/CHCl3 to give 10 (267 mg, 94% as a white solid,
which was crystallized from EtOH/EtOAc): mp >245 °C (dec);
1H NMR (CDCl3) δ 7.91 (br s, 1H), 7.20 (d, 1H, J ) 8.1 Hz),
6.34 (dd, 1H, J ) 2.2, J ) 1.8 Hz), 5.77 (t, 1H, J ) 2.2 Hz),
5.77 (dd, 1H, J ) 8.1, J ) 2.2 Hz), 5.11 (dd, 1H, J ) 7.7, J )
2.2 Hz), 4.08 (dd, 1H, J ) 4.2, J ) 10.3 Hz), 3.96 (dd, 1H, J )
5.8, J ) 10.3 Hz), 3.83 (ddd, 1H, J ) 4.2, J ) 5.8, J ) 7.7 Hz),
2.50 (br d, 1H), 1.11-1.01 (m, 21H); 13C NMR [THF/C6D6 (10:
1)] δ 167.4, 162.7, 150.2, 142.1, 114.5, 103.1, 95.4, 85.9, 84.2,
71.7, 63.0, 17.9, 17.4, 12.4; FABMS m/z 422 [M+]. Anal. Calcd
for C20H32N3O5Si: C, 56.85; H, 7.63; N, 9.94. Found: C, 56.92;
H, 7.44; N, 9.97.
(Z)-2′-(Cya n om et h ylen e)-2′-d eoxy-5′-O-(ter t-b u t yld i-
m eth ylsilyl)u r id in e (11). A mixture of 4 (42 mg, 0.16 mmol),
imidazole (17 mg, 0.25 mmol), and tert-butyldimethylsilyl
chloride (39 mg, 0.26 mmol) was dissolved in DMF (2 mL) at
0 °C. The mixture was stirred for 14 h at room temperature
and then quenched with H2O. The whole was taken in EtOAc,
which was washed with brine and H2O. The organic phase
was dried (Na2SO4) and evaporated. The residue was purified
on a silica gel column with 25% EtOAc/hexane to give 11 (32
mg, 53% as a white solid, which was crystallized from
EtOAc/hexane): mp 205-206 °C; IR νmax (neat)/cm-1 2240
(CN); 1H NMR (CDCl3 + D2O) δ 8.61 (br s, 1H), 7.23 (d, 1H, J
) 8.2 Hz), 6.36 (br dd, 1H, J ) 2.1 Hz), 5.79 (dd, 1H, J ) 2.2,
J ) 2.8 Hz), 5.76 (d, 1H, J ) 8.2 Hz)], 5.04 (dt, 1H, J ) 7.7
Hz), 3.95 (m, 2H, J ) 11.0, J ) 4.4, J ) 5.0 Hz), 4.83 (ddd,
1H, J ) 7.7, J ) 4.4, J ) 5.0 Hz), 0.90 (m, 9H), 0.10 (s, 3H),
0.09 (s, 3H); FABMS m/z 380 [M+ + 1]. Anal. Calcd for
C17H25N3O5Si: C, 53.81; H, 6.64; N, 11.07. Found: C, 53.56;
H, 6.57; N, 10.97.
(2′S)-2′-(Cya n om et h yl)-2′-d eoxy-2′-(p h en ylt h io)-5′-O-
(tr iisop r op ylsilyl)u r id in e (13). Meth od A. Compound 10
(285 mg, 0.68 mmol) was treated with a THF solution of LiSPh
(0.58 M, 1.8 mL, 1.0 mmol) and PhSH (1.4 mL, 14 mmol) in
THF (5 mL) under the same conditions as described for the
synthesis of 8 to give a mixture of 17 and its 2′-diastereomer
in a ratio of 89:11 (327 mg, 91%), from which 13 was separated
as a white powder from hot EtOAc/hexane. Meth od B.
Compound 15 (150 mg, 0.40 mmol) was treated with triiso-
propylsilyl chloride under the same conditions as described
for the synthesis of 10 to give 13 (150 mg, 71%): IR νmax (neat)/
1
cm-1 2240 (CN); H NMR (CDCl3) δ 8.25 (br s, 1H, NH), 8.23
(d, 1H, H-6, J ) 8.2 Hz), 7.71 (m, 2H, SPh), 7.52-7.44 (m,
3H, SPh), 6.27 (s, 1H, H-1′), 5.66 (dd, 1H, H-5, J ) 1.9, J )
8.2 Hz), 4.66 (dd, 1H, H-3′, J ) 9.1, J ) 7.1 Hz), 4.32 (dt, 1H,
H-4′, J ) 9.1, J < 1 Hz), 4.24 (d, 1H, H-5′a, J ) 12.1 Hz), 4.04
(d, 1H, H-5′b, J ) 12.1 Hz), 2.88 (d, 1H, H-2′′a, J ) 17.2 Hz),
2.67 (br d, 1H, 3′-OH), 2.60 (d, 1H, H-2′′b, J ) 17.2 Hz), 1.26-
0.80 (m, 21H, i-Pr); NOE, irradiate H-1′, observe CH2bCN
(0.7%) and SPh (7.2%); irradiate H-3′, observe CH2aCN (2.4%)
and 3′-OH (3.0%); irradiate CH2aCN, observe H-1′ (1.1%) and
SPh (5.3%); irradiate CH2bCN, observe H-1′ (1.6%) and H-3′
(4.0%); FABMS m/z 532 [M+ + 1]. Anal. Calcd for C26H37N3O5-
SSi: C, 58.73; H, 7.01; N, 7.90. Found: C, 58.73; H, 7.04; N,
7.94.
(2′S )-2′-(Cya n om e t h yl)-2′-d e oxy-2′-(p h e n ylt h io)u r i-
d in e (15). A mixture of 8 (513 mg, 0.83 mmol) and NH4F (310
mg, 8.4 mmol) was dissolved in MeOH (10 mL) and heated at
65 °C for 2 h. The mixture was cooled to room temperature,
and the solvent was evaporated. The residue was suspended
in EtOH, and the insoluble material was removed by filtration.
The filtrate was evaporated and purified on a silica gel column
with 5% MeOH/CHCl3 to give 15 (221 mg, 71% as a white solid,
which was crystallized from EtOH/EtOAc): mp >205 °C (dec);
IR νmax (neat)/cm-1 2240 (CN); 1H NMR (DMSO-d6) δ 11.15
(br s, 1H), 8.29 (d, 1H, J ) 8.2 Hz), 7.65 (m, 2H), 7.38 (m, 3H),
6.25 (d, 1H, J ) 5.5 Hz), 6.00 (s, 1H), 5.55 (d, 1H, J ) 8.2 Hz),
5.48 (br s, 1H), 4.42 (dd, 1H, J ) 8.8, J ) 5.5 Hz), 4.19 (br d,
1H, J ) 8.8 Hz), 3.90 (ddd, 1H, J ) 12.6, J ) 2.2 Hz), 3.71
(ddd, 1H, J ) 12.6 Hz), 3.08 (d, 1H, J ) 17.0 Hz), 2.94 (d, 1H,
J ) 17.0 Hz); FABMS m/z 376 [M+ + 1]; HR FABMS calcd for
C17H18N3O5S 376.0967, found 376.0953.
(2′S)-2′-(Cya n om et h yl)-2′-d eoxy-2′-(p h en ylt h io)-5′-O-
(ter t-bu tyld im eth ylsilyl)u r id in e (14). Compound 14 (130
mg, 86% as a white solid) was synthesized from 15 (116 mg,
0.31 mmol) by the method described for the synthesis of 11:
1
IR νmax (neat)/cm-1 2240 (CN); H NMR (CDCl3) δ 8.42 (br s,
1H), 8.24 (d, 1H, J ) 8.2 Hz), 7.72 (m, 2H), 7.55 (m, 3H), 6.27
(d, 1H, J ) 2.2 Hz), 5.67 (d, 1H, J ) 8.2 Hz), 4.55 (dd, 1H, J
) 8.8, J ) 5.5 Hz), 4.31 (dd, 1H, J ) 8.8, J ) 2.0 Hz), 4.18
(dd, 1H, J ) 12.1, J ) 1.7 Hz), 3.95 (d, 1H, J ) 12.1 Hz), 2.88
(d, 1H, J ) 17.0 Hz), 2.60 (d, 1H, J ) 17.0 Hz), 0.95 (s, 9H),
0.16 (s, 3H), 0.15 (s, 3H); FABMS m/z 490 [M+ + 1]. Anal.
Calcd for C23H31N3O5SSi: C, 56.42; H, 6.38; N, 8.58. Found:
C, 56.56; H, 6.49; N, 8.24.
(2′S)-3′-O-Acetyl-2′-(cya n om eth yl)-2′-d eoxy-2′-(p h en yl-
th io)-5′-O-(tr iisop r op ylsilyl)u r id in e (16). Triethylamine
(0.1 mL, 0.7 mmol) was added to a mixture of 13 (186 mg,
0.35 mmol) and Ac2O (66 µL, 0.7 mmol) in MeCN (5 mL) at 0
°C and stirred for 1 h. After water workup, the residue was
purified on a silica gel column with 25% EtOAc/hexane to give
16 (182 mg, 91% as a white solid): IR νmax (neat)/cm-1 2240
(Z)-3′-O-Acetyl-2′-(cya n om eth ylen e)-2′-d eoxy-5′-O-(tr i-
isop r op ylsilyl)u r id in e (12). Triethylamine (26 µL, 0.19
mmol) was added to a mixture of 10 (72 mg, 0.17 mmol) and
Ac2O (20 µL, 0.19 mmol) in MeCN (3 mL) at 0 °C. The mixture
was stirred for 15 min. After water workup, the residue was
purified on a silica gel column with 15% EtOAc/hexane to give
12 (61 mg, 77% as a white solid, which was crystallized from
1
(CN); H NMR (CDCl3) δ 8.32 (d, 1H, J ) 8.0 Hz), 7.70 (br s,
1H), 7.54-7.45 (m, 5H), 6.26 (s, 1H), 5.86 (d, 1H, J ) 9.4 Hz),
5.69 (d, 1H, J ) 8.0 Hz), 4.63 (br dt, 1H, J ) 9.4 Hz), 4.23 (dd,
1H, J ) 11.5, J ) 1.2 Hz), 3.87 (dd, 1H, J ) 11.5, J ) 1.5 Hz),
2.94 (d, 1H, J ) 11.5 Hz), 2.66 (d, 1H, J ) 11.5 Hz), 2.19 (s,
3H), 1.18-1.07 (m, 21H); FABMS m/z 574 [M+ + 1]. Anal.
Calcd for C28H39N3O6SSi: C, 58.61; H, 6.85; N, 7.32. Found:
C, 58.41; H, 6.98; N, 7.05.
EtOAc): mp 182-183 °C; IR νmax (neat)/cm-1 2240 (CN); H
NMR (CDCl3) δ 8.20 (br s, 1H), 7.40 (d, 1H, J ) 8.2 Hz), 6.75
(dd, 1H, J ) 1.7, J ) 2.2 Hz), 5.98 (dt, 1H, J ) 2.2, J ) 5.0
Hz), 5.82 (t, 1H, J ) 2.2 Hz), 5.75 (dd, 1H, J ) 8.2, J ) 2.2
1

(Z)-2′-(Cyanomethylene)-2′-deoxyuridine
J . Org. Chem., Vol. 61, No. 18, 1996 6267
Oxid a tive Syn -Elim in a tion : Gen er a l P r oced u r e. The
sulfide derivatives 8, 9, and 13-16 in CH2Cl2 were treated
with m-CPBA (1.2 equiv) at -78 °C under argon. The
oxidation to the corresponding sulfoxide(s) was completed
within 10-30 min as monitored by TLC. The mixtures were
then allowed to warm gradually to room temperature. Stirring
was further continued for appropriate times at temperatures
depicted in Table 2 until the syn-elimination was completely
finished (monitored by TLC). Neutralization by 5% NaHCO3
and water workup followed by silica gel column chromatog-
raphy provided the corresponding cyanomethylene derivatives.
En tr y 1. The reaction of 8 (510 mg, 0.825 mmol) with
m-CPBA (171 mg, 0.99 mmol) in CH2Cl2 (18 mL) gave 7 (331
mg, 79% as a colorless foam). En tr y 4. The reaction of 15
(205 mg, 0.55 mmol) with m-CPBA (114 mg, 0.66 mmol) in
CH2Cl2/THF (5:1, 12 mL) gave a mixture of 4 and 5 [25:75
(measured by the H-1′ integration ratio in the 1H NMR
spectrum), 140 mg, 96% as a white solid]. En tr y 6. To a
solution of 13 (106 mg, 0.2 mmol) in AcOH (4 mL) was added
30% H2O2 (30 µL), and the mixture was heated at 60 °C for 2
h. The solvent was evaporated, and the residue was purified
on a silica gel column to give a mixture of 4 and 5 in a ratio of
41:59 (45 mg, 85%). En tr y 7. The reaction of 9 (210 mg, 0.34
mmol) with m-CPBA (70 mg, 0.41 mmol) in CH2Cl2 (6 mL)
gave 7 (64 mg, 37% as a colorless foam).
(E)-3′-O-Acetyl-2′-(cya n om eth ylen e)-2′-d eoxy-5′-O-(tr i-
isop r op ylsilyl)u r id in e (20). The reaction of 15 (100 mg, 0.17
mmol) with m-CPBA (36 mg, 0.20 mmol) in CH2Cl2 (4 mL)
gave a mixture of 20 and 12 (52:48, 65 mg, 80%), from which
an analytically pure sample of 20 was obtained by preparative
TLC (hexane/EtOAc, 2:1). The physical data of 20: IR νmax
(film)/cm-1 2240 (CN); 1H NMR (CDCl3) δ 9.18 (br s, 1H), 7.71
(d, 1H, J ) 8.1 Hz), 6.83 (br t, 1H), 6.17 (dt, 1H, J ) 5.3, J )
2.2 Hz), 5.75 (t, 1H), 5.73 (d, 1H, J ) 8.1 Hz), 4.08 (dd, 1H, J
) 5.3 Hz), 4.02 (dd, 1H, )11.7, J ) 1.5 Hz), 3.97 (dd, 1H, J )
11.7, J ) 1.7 Hz), 2.20 (s, 3H), 1.17-1.01 (m, 21H); FABMS
m/z 464 [M+ + 1]; HR FABMS calcd for C22H34N3O6Si 464.2217,
found 464.2214.
(E)-2′-(Cya n om et h ylen e)-2′-d eoxyu r id in e (5). Com-
pound 5 was synthesized from 18 (100 mg, 0.24 mmol) by the
same method as described for the synthesis of 4 to give 5 (50
mg, 79% as a white solid, which was crystallized from
EtOH/hexane): mp 209-211 °C; IR νmax (neat)/cm-1 2240 (CN);
1H NMR (DMSO-d6) δ 11.42 (br s, 1H, NH), 7.54 (d, 1H, H-6,
J ) 8.1 Hz), 6.52 (t, 1H, H-1′, J ) 1.9 Hz), 6.16 (d, 1H, 3′-OH,
J ) 7.8 Hz), 6.06 (t, 1H, H-2′′, J ) 2.4 Hz), 5.66 (d, 1H, H-5,
J ) 8.1 Hz), 4.98 (t, 1H, 5′-OH, J ) 5.5 Hz), 4.73 (m, 1H, H-3′,
J ) 2.4, J ) 7.3 Hz), 3.76 (ddd, 1H, H-4′, J ) 7.3, J ) 2.6, J
) 1.1 Hz), 3.69 (ddd, 1H, H-5′a, J ) 2.6, J ) 5.3, J ) 12.1 Hz),
3.56 (ddd, 1H, H-5′b, J ) 1.1, J ) 5.3, J ) 12.1 Hz); NOE,
irradiate H-1′, observe H-2′′ (7.0%), H-4′ (2.6%), and H-6
(5.5%); irradiate H-2′′, observe H-1′ (3.5%) and H-6 (1.2%);
irradiate H-3′, observe H-1′ (0.6%), H-2′′ (0.7%), and H-6
(2.6%). Anal. Calcd for C11H11N3O5‚0.4H2O: C, 48.49; H, 4.37;
N, 15.42. Found: C, 48.60; H, 4.27; N, 15.18.
(E)-2′-(Cya n om eth ylen e)-2′-d eoxy-5′-O-(tr iisop r op ylsi-
lyl)u r id in e (18). Compound 13 (220 mg, 0.41 mmol) in CH2-
Cl2 (10 mL) was treated with m-CPBA (86 mg, 0.50 mmol) in
CH2Cl2 (1 mL) under the above-described conditions to give a
mixture of 18 and 10 in a ratio of 93:7 (143 mg, 82% as a white
solid, from which 18 was separated by crystallization from
(2′R)-2′-C-(Ca r b oxym et h yl)-2′-d eoxy-2′-(p h en ylt h io)-
u r id in e 2′,3′-La cton e (22). A THF solution of TBAF (1 M,
2.7 mL, 2.7 mmol) was added to a mixture of 9 (680 mg, 1.10
mmol) and AcOH (0.16 mL, 2.8 mmol) in THF at 0 °C. The
mixture was stirred at room temperature for 30 min. The
solvent was evaporated, and the residue was purified on a
silica gel column with 2% EtOH/CHCl3 to give 22 (282 mg,
68% as a white solid): 1H NMR (DMSO-d6) δ 11.47 (s, 1H),
7.87 (d, 1H, J ) 8.1 Hz), 7.48-7.35 (m, 5H), 6.27 (s, 1H), 5.70
(d, 1H), 5.33 (br t, 1H), 4.91 (d, 1H, J ) 5.5 Hz), 4.12 (br dd,
1H), 3.80-3.71 (m, 2H), 3.62 (d, 1H, J ) 19.2 Hz), 3.02 (d,
1H, J ) 19.2 Hz); FABMS m/z 377 [M+ + 1]. Anal. Calcd for
1
hexane): mp 156-157 °C; IR νmax (film)/cm-1 2240 (CN); H
NMR (CDCl3) δ 8.82 (br s, 1H), 7.62 (d, 1H, J ) 8.1 Hz), 6.68
(br t, 1H), 5.84 (dd, 1H, J ) 2.1, J ) 1.9 Hz), 5.70 (d, 1H, J )
8.1 Hz), 5.18 (m, 1H, J ) 6.9 Hz), 4.12 (dd, 1H, J ) 11.6, J )
2.2 Hz), 4.05-3.97 (m, 2H), 3.35 (d, 1H, J ) 5.6 Hz), 1.25-
0.95 (m, 21H); NOE, irradiate H-1′, observe H-2′′ (3.6%) and
H-6 (1.4%); irradiate H-2′′, observe H-1′ (3.8%), and H-6 (0.8%);
FABMS m/z 422 [M+ + 1]. Anal. Calcd for C20H31N3O5Si: C,
56.98; H, 7.41; N, 9.97. Found: C, 56.98; H, 7.21; N, 9.80.
(E)-2′-(Cya n om et h ylen e)-2′-d eoxy-5′-O-(ter t-b u t yld i-
m eth ylsilyl)u r id in e (19). The reaction of 14 (100 mg, 0.20
mmol) with m-CPBA (42 mg, 0.24 mmol) in CH2Cl2 (4 mL)
gave a mixture of 19 and 11 in a ratio of 84:26 (64 mg, 83% as
a colorless foam), from which an analytical sample of 19 (as a
foam) was obtained by preparative TLC. The physical data
C
17H16N2O6S: C, 54.25; H, 4.28; N, 7.44. Found: C, 54.22; H,
4.47; N, 7.23.
1
of 19: IR νmax (film)/cm-1 2240 (CN); H NMR (CDCl3) δ 9.21
Ack n ow led gm en t . This investigation was sup-
ported in part by a Grant-in-Aid for Cancer Research
from the Ministry of Education, Science, Sports, and
Culture of J apan.
(br s, 1H), 7.67 (d, 1H, J ) 7.8 Hz), 6.70 (t, 1H, J ) 2.0 Hz),
5.82 (dd, 1H, J ) 2.0, J ) 2.4 Hz), 5.72 (d, 1H, J ) 7.8 Hz),
5.09 (m, 1H), 4.03-3.92 (m, 3H), 3.68 (d, 1H, J ) 5.9 Hz),
0.93-0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); FABMS m/z 380
[M+ + 1]; HR FABMS C17H26N3O5Si 380.1642, found 380.1657.
J O960577S