Nucleosides and Nucleotides. 156. Chelation-Controlled and Nonchelation-Controlled Diastereofacial Selective Thiophenol Addition Reactions at the 2′-Position of 2′-[(Alkoxycarbonyl)methylene]-2′-deoxyuridines: Conversion of (Z)-2′-[(Alkoxycarbonyl)methylene]-2′-deoxyuridines into Their (E)-Isomers

Article abstract of DOI:10.1021/jo9613601

The Wittig reaction of 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-β-D-erythro- pentofuranos-2-ulosyl]uracil (4) with Ph₃P=CHCO₂R (R = ethyl or tert-butyl) exclusively gave (Z)-2′-[(alkoxycarbonyl)methylene] derivatives 5 and 13, respectively, in high yields. An unusual β-facial selectivity of thiophenol addition to the 2′-[(alkoxycarbonyl)methylene] moiety of 5 and 13 was observed, and this facial selectivity was found to be influenced by both the thiolate counter cation and the bulkiness of the alkoxy moiety. Treatment of 2′-[(ethoxycarbonyl)methylene] derivative 5 with LiSPh (1.5 equiv) in the presence of PhSH in THF selectively gave 2′β-(phenylthio) derivative 11 in high yield along with a trace of 2'α-(phenylthio) derivative 10. On the other hand, when 2′-[(tert-butoxycarbonyl)methylene] derivative 13 was treated with KSPh in the presence of PhSH in dioxane/DMF, the facial selectivity was reversed to selectively give the 2′α-(phenylthio) adduct 14 (α:β, 77:23) in 90% yield. Oxidation of 14 with m-chloroperbenzoic acid in CH₂Cl₂ and subsequent pyrolysis of the resulting sulfoxides exclusively gave the (Z)-isomer 13 in 92% yield. The oxidative syn-elimination of the (2′R)-2′-[(tert-butoxycarbonyl)methyl]-2′-deoxy-2′- thiophenoxy-5′-O-(triisopropylsilyl)uridine (17), which was obtained from 14 in two steps, exclusively gave the desired (E)-[(tert-butoxycarbonyl)methylene] derivatives 18 in 90% yield. Deprotection of 18 gave the (E)-(carboxymethylene)-2′-deoxyuridine (3). The (Z)-(carboxymethylene)-2′-deoxyuridine (2) was synthesized from 13 in a similar manner.

Full text of DOI:10.1021/jo9613601

J . Org. Chem. 1997, 62, 11-17
11
Nu cleosid es a n d Nu cleotid es. 156. Ch ela tion -Con tr olled a n d
Non ch ela tion -Con tr olled Dia ster eofa cia l Selective Th iop h en ol
Ad d ition Rea ction s a t th e 2′-P osition of
2′-[(Alk oxyca r bon yl)m eth ylen e]-2′-d eoxyu r id in es: Con ver sion of
(Z)-2′-[(Alk oxyca r bon yl)m eth ylen e]-2′-d eoxyu r id in es in to Th eir
(E)-Isom er s1
Abdalla E. A. Hassan, Satoshi Shuto, and Akira Matsuda*
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060, J apan
Received J uly 18, 1996X
The Wittig reaction of 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-â-D-erythro-pentofuranos-
2-ulosyl]uracil (4) with Ph3PdCHCO2R (R ) ethyl or tert-butyl) exclusively gave (Z)-2′-[(alkoxy-
carbonyl)methylene] derivatives 5 and 13, respectively, in high yields. An unusual â-facial
selectivity of thiophenol addition to the 2′-[(alkoxycarbonyl)methylene] moiety of 5 and 13 was
observed, and this facial selectivity was found to be influenced by both the thiolate counter cation
and the bulkiness of the alkoxy moiety. Treatment of 2′-[(ethoxycarbonyl)methylene] derivative 5
with LiSPh (1.5 equiv) in the presence of PhSH in THF selectively gave 2′â-(phenylthio) derivative
11 in high yield along with a trace of 2’R-(phenylthio) derivative 10. On the other hand, when
2′-[(tert-butoxycarbonyl)methylene] derivative 13 was treated with KSPh in the presence of PhSH
in dioxane/DMF, the facial selectivity was reversed to selectively give the 2′R-(phenylthio) adduct
14 (R:â, 77:23) in 90% yield. Oxidation of 14 with m-chloroperbenzoic acid in CH2Cl2 and subsequent
pyrolysis of the resulting sulfoxides exclusively gave the (Z)-isomer 13 in 92% yield. The oxidative
syn-elimination of the (2′R)-2′-[(tert-butoxycarbonyl)methyl]-2′-deoxy-2′-thiophenoxy-5′-O-(triiso-
propylsilyl)uridine (17), which was obtained from 14 in two steps, exclusively gave the desired
(E)-[(tert-butoxycarbonyl)methylene] derivatives 18 in 90% yield. Deprotection of 18 gave the (E)-
(carboxymethylene)-2′-deoxyuridine (3). The (Z)-(carboxymethylene)-2′-deoxyuridine (2) was syn-
thesized from 13 in a similar manner.
In tr od u ction
activity against various solid tumors as well as leukemias
and lymphomas.3b-e The time-dependent irreversible
inhibition of RDPR by its 5′-diphosphate (DMDCDP)3f
may be related to its antitumor activity, together with
inhibition of DNA polymerases by its 5′-triphosphate.3g
Based on the proposed mechanism of inactivation of
RDPR by DMDCDP,3f the introduction of an electron-
withdrawing substituent, such as a carboxy group,4 at
the terminus of the 2′-exo-methylene group may result
in a stabilized allylic radical, which would increase its
inhibitory effect on RDPR. We report here the synthesis
of (Z)- and (E)-2′-(carboxymethylene)-2′-deoxyuridines (2
and 3) as potential mechanism-based inhibitors of RDPR.
We previously described a facile method for conversion
of the easily accessible (Z)-2′-(cyanomethylene)-2′-deoxy-
5′-O-(triisopropylsilyl)uridine into its E-isomer via the
sequential stereoselective addition of PhSH to the cya-
nomethylene moiety at the 2′-position from the R-face
followed by a stereoselective oxidative syn-elimination
reaction.5 While using this method to convert (Z)-2′-
deoxy-2′-[(ethoxycarbonyl)methylene] derivative 7 into its
E-isomer, we encountered an unusual â-facial selectivity
Ribonucleoside diphosphate reductase (RDPR), an es-
sential enzyme in DNA synthesis, catalyzes the conver-
sion of ribonucleoside diphosphates into their correspond-
ing 2′-deoxyribonucleoside diphosphates.2 The high ac-
tivity of RDPR in tumor cells, in addition to the positive
correlation between antitumor activity and inhibitory
activity against RDPR,2b,c has led to intensive studies to
find potent inhibitors of this enzyme.2d 2′-Deoxy-2′-
methylenecytidine (DMDC, 1)3a has potent antitumor
* Author to whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) Part 155 in the series, see: Shuto, S.; Awano, H.; Fujii, A.;
Yamagami, K.; Matsuda, A. BioMed. Chem. Lett. 1996, 6, 2177.
(2) (a) Cory, G. P.; Carter, G. L. Adv. Enzyme Regul. 1985, 24, 385.
(b) Mao, S. S.; J ohnson, M. I.; Bollinger, J . M.; Baker, C. H.; Stubbe,
J . In Molecular Mechanisms in Bioorganic Processes; Bleasdale, C.,
Goldman, B. T., Eds.; Royal Society of Chemistry: London, 1990, p
305. (c) Elford, H. L.; Freese, M.; Passamani, E.; Morris, H. P. J . Biol.
Chem. 1970, 245, 5258. (d) Moore, E. C.; Hurlbert, R. B. In Inhibitors
of Ribonucleoside Diphosphate Reductase Activity; Cory, E. J ., Cory,
A. H., Eds.; Pergamon Press: New York, 1989; Chap. 9.
(3) (a) Takenuki, K.; Matsuda, A.; Ueda, T.; Sasaki, T.; Fuji, 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.; Fuji, A.; Arita, M.; Okumoto, T.; Sakata,
S.; Matsuda, A.; Ueda, T. Cancer Res. 1991, 51, 2319. (d) Ono, T.; Fujii,
A.; Yamagami, K.; Hosoya, M.; Okumoto, T.; Sakata, S.; Matsuda, A.;
Sasaki, T. Biochem. Pharmacol. 1996, 52, 1279. (e) Lin. T.-S.; Luo,
M.-Z.; Liu, M.-C.; Clarke-Katzenburg, R. C.; Cheng, Y.-C.; Prusoff, W.
H.; Mancini, W. R.; Birnbaum, G. I.; Gabe, E. J .; Giziewicz, J . J . Med.
Chem. 1991, 34, 2607. (f) Baker, H.; Bazon, A.; Bollinger, J r, J . M.;
Stubbe, J .; Samano, V.; Robins, M. J .; Lippert, B.; J arvi, E.; Resvick,
R. J . Med. Chem. 1991, 34, 1879. (g) Matsuda, A.; Azuma, A.;
Nakajima, Y.; Takenuki, K.; Dan, A.; Yoshimura, Y.; Minakawa, N.;
Tanaka, M.; Sasaki, T. In Nucleosides and Nucleotides as Antitumor
and Antiviral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press:
New York, 1993; pp 1-22.
(4) Radical-stabilizing effect of carbonyl groups has been known: (a)
Beckwith, A. L. J .; Gream, G. E.; Struble, D. L. Aust. J . Chem. 1972,
25, 1081. (b) J ulia, M. Pure Appl. Chem. 1967, 15, 167.
(5) Hassan, A. E. A.; Nishizono, N.; Minakawa, N.; Shuto, S.;
Matsuda, A. J . Org. Chem. 1996, 61, 6261.
(6) For references of the conjugate addition of thiolates to R,â-
unsaturated esters see: (a) Kuwajima, I.; Murobushi, T.; Nakamura,
E. Synthesis 1978, 602. (b) Kobayashi, N.; Iwai, K. J . Org. Chem. 1981,
46, 1823. (c) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 363.
(d) Kamimura, A.; Ono, N. J . Chem. Soc., Chem. Commun. 1988, 1278.
(e) Miyata, O.; Shinada, T.; Kawakami, N.; Taji, K.; Ninomiya, I.; Naito,
T.; Date, T.; Okamura, K. Chem. Pharm. Bull. 1992, 40, 2579 and
references cited therein.
S0022-3263(96)01360-6 CCC: $14.00 © 1997 American Chemical Society

12 J . Org. Chem., Vol. 62, No. 1, 1997
Hassan et al.
Ch a r t 1
PhSH in THF unexpectedly gave the lactone 8a exclu-
sively in 92% yield (Scheme 1). The structure of 8a was
confirmed by the absence of both the 3′-hydroxyl proton
and ethyl protons of the ester moiety and the presence
of a pair of methylene protons (H-2′′) at 3.53 and 3.03
1
ppm in the H NMR spectrum. Furthermore, the oxida-
tive syn-elimination of 8a with mCPBA gave the unsat-
urated lactone derivative 9 in high yield, thus confirming
the structure of 8a . However, attempts to cleave the
lactone moiety of 9 under various conditions to obtain
the target 3 were unsuccessful. We first considered that
formation of the lactone 8a might be mediated by an
equilibration between the R-(phenylthio) and the â-(phe-
nylthio) adducts, where the â-(phenylthio) adduct is
irreversibly converted into the stable 8a with the as-
sistance of the 3′-hydroxyl group under basic reaction
conditions. If this indeed occurs, treatment of the more
hindered ester 5 with LiSPh would result in at least a
mixture of the two diastereomers or the R-(phenylthio)
adduct selectively. However, the reaction again selec-
tively gave the â-(phenylthio) derivative 11, along with
a trace of the R-(phenylthio) derivative 10 (Scheme 2;
Table 1, entry 1).8 The adducts 10 and 11 could be
separated on silica gel column chromatography, and their
structures were confirmed by 1H NMR spectra and NOE
experiments. Moreover, the (S)-configuration at the 2′-
position of 11 was confirmed by the facile formation of
lactone 8b upon deprotection of the silyl groups with
tetrabutylammonium fluoride (TBAF) in THF followed
by neutralization with AcOH and chromatography on
silica gel. The observed â-facial selectivity of the thiophe-
nol addition to the (Z)-2′-[(ethoxycarbonyl)methylene]
moiety of 59 and 7 contrasts with the well-known R-facial
selectivity of nucleophilic additions at the trigonal center
of 2′-ketonucleosides,10,11 2′-deoxy-2′-methyleneuridines,12
and 2′,3′-didehydro-2′,3′-dideoxy-3′-(nitro, cyano, or sul-
fonyl)uridines13 as well as our recent results with (Z)-2′-
(cyanomethylene)-2′-deoxyuridine derivatives.5 The fact
that â-facial selectivity occurs in the 1,4-addition of
benzenethiolate to 514 and 7 suggests involvement of a
chelated intermediate. To verify this proposition, the 13C-
NMR spectrum of 5 was measured in THF/C6D6 (10:1)
Sch em e 1a
in the presence of different molar ratios of LiClO4.15
A
in the addition of benzenethiolate to its (Z)-[(2′-ethoxy-
carbonyl)methylene] moiety.6 In this paper, we describe
this unusual â-facial selectivity, its origin, and its
reversal to the desired R-facial selective addition, as a
key step in the preparation of the (E)-isomer.
noteworthy feature of the spectra was the downfield
(8) However, upon treatment of 10 and 11 with LiSPh/PhSH in THF,
neither interconversion between the two isomers nor the generation
of the starting material 5 was observed in the 1H NMR spectrum, even
at elevated temperatures. This implies that this facial selectivity is
not related to the thermodynamic stability of the two adducts.
(9) A preferential R-selective hydride attack at the (ethoxycarbonyl)-
methylene moiety of 5 was observed upon treatment with NaBH4 in
MeOH. See: Ueda, T.; Shuto, S.; Sato, M.; Inoue, H. Nucleosides
Nucleotides 1985, 4, 401.
(10) For examples of the hydride reduction of 4 see: (a) ref 7. (b)
Hansske, F.; Robins, M. J . J . Am. Chem. Soc. 1983, 105, 6736.
(11) For examples on the R-facial selective addition of carbon
nucleophiles to 2′-keto-pyrimidine nucleosides see: (a) Matsuda, A.;
Itoh, H.; Takenuki, K.; Sasaki, T.; Ueda, T. Chem. Pharm. Bull. 1988,
36, 945. (b) Awano, H.; Shuto, S.; Baba, M.; Kira, T.; Shigeta, S.;
Matsuda, A. BioMed. Chem. Lett. 1994, 4, 367. (c) Iino, T.; Yoshimura,
Y.; Matsuda, A. Tetrahedron 1994, 50, 10397. (d) Ueda, T.; Shuto, S.;
Inoue, H. Nucleosides Nucleotides 1984, 3, 173. (e) Yoshimura, Y.;
Saitoh, K.; Ashida, N.; Sakata, S.; Matsuda, A. BioMed. Chem. Lett.
1994, 4, 721. (f) Takenuki, K.; Itoh, H.; Matsuda, A.; Ueda, T. Chem.
Pharm. Bull. 1990, 38, 2947.
Resu lts a n d Discu ssion
Treatment of 1-[3,5-O-[1,1,3,3-tetraisopropyldisiloxane-
1,3-diyl (TIPDS)]-â-D-erythro-pentofuranos-2-ulosyl]uracil
(4)7 with Ph3PdCHCO2Et in THF gave (Z)-2′-deoxy-2′-
ethoxycarbonylmethyleneuridine derivative 5 as a single
stereoisomer in a quantitative yield. Desilylation of 5
followed by the selective protection of the 5′-hydroxyl
group of 6 by a triisopropylsilyl (TIPS) group gave
substrate 7 of the addition reaction in high yield (Scheme
1). We previously reported that the steric effects of both
the nucleobase and the 5′-O-TIPS group together with
the alleviated steric hindrance at the R-face of (Z)-2′-
(cyanomethylene)-2′-deoxy-5′-O-(TIPS)uridine lead to the
conjugate addition of PhSH to the 2′-(cyanomethylene)
selectively from the R-face.4 However, the treatment of
7 with LiSPh (1.5 equiv) in the presence of an excess of
(12) Cicero, D. O.; Neuner, P. J . S.; Franzese, O.; D’Onofrio, C.;
Iribarren, A. M. BioMed. Chem. Lett. 1994, 4, 861.
(13) Hossain, N.; Garg, N.; Chattopadhyaya, J . Tetrahedron 1993,
49, 10061.
(14) 1H NMR and MM2 calculations suggest that both 5 and the
2′-ketouridine derivative 4 have similar 3′-endo-puckering. This implies
that the (ethoxycarbonyl)methylene moiety of 5 does not alter the sugar
puckering to elevate the steric hindrance at the â-face of the 2′-position.
(7) Hansske, F.; Madej, D.; Robins, M. J . Tetrahedron 1984, 40, 125.

(E)-2′-(Carboxymethylene)-2′-deoxyuridine
J . Org. Chem., Vol. 62, No. 1, 1997 13
Sch em e 2a
Ta ble 1. Ad d ition of Th iop h en ol to 5 a n d 13
entry
substrate
reagent (equiv)a
additives (equiv)
solvent
conditions
yield (%)
ratio (R: â)b
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
13
13
13
LiSPh (1.5)
LiSPh (1.5)
LiSPh (1.5)
NaSPh (1.5)
NaSPh (1.5)
KSPh (2.0)
CsSPh (10)
LiSPh (1.5)
KSPh (1.5)
KSPh (1.5)
none
THF
THF
THF
THF
THF
THF
0 °C, 24 h
-10 °C, 0.5 h
rt, 5 days
rt, 9 h
rt, 1 h
rt, 31 h
reflux, 48 h
-10 °C, 4 h
rt, 48 h
98
98
6:94
13:87
6:94
26:74
31:69
44:56
-
32:68
82:18
77:23
12-C-4 (1.5)
DABCO (2.0)
none
18-C-6 (1.5)
18-C-6 (2.0)
none
12-C-4 (1.5)
none
none
91
45c
65c
88
THF/DMF
THF
THF/DMF (6:1)
dioxane/DMF (5:1)
smd
89
58
90
10
50 °C, 24 h
a
b
All the reactions were performed in the presence of 10 equiv of PhSH, except for entry 10 (50 equiv). The ratios were determined
by the integration of the corresponding H-1′ in the 1H NMR spectra. c The rest of the products was uracil. The starting material was
d
recovered.
F igu r e 2. A possible explanation for the â-facial selectivity
of the benzenethiolate addition at the 2′-ethoxycarbonylmeth-
ylene moiety of 5.
chelation may be accompanied by the intramolecular
delivery of the thiolate group from the sterically hindered
â-face in the formation of 11 (Figure 2).
Attempts to selectively increase the R-facial addition
via impeding the postulated chelation effect by perform-
F igu r e 1. 13C NMR chemical shift difference (∆δ) of 5 as a
ing the addition reaction in the presence of 12-crown-4
function of the molar equivalence of LiClO4. 13C NMR was
ether or DABCO18 (Table 1, entries 2,3), or by conducting
measured at a concentration of 0.07 M in THF-C6D6 (10:1).
the addition reaction under high pressure in the absence
Values were referenced to C6D6 at 128 ppm.
of a base (data not shown), were unsuccessful. On the
other hand, upon changing the countercation of the
shifts of C-2, C-6, C-2′′, and C-4′′ and the upfield shift of
benzenethiolate to Na+ or K+, â-facial selectivity was lost
the carbonyl carbon of the ester moiety (C-3′′) and C-1′16
(Table 1, entries 4-6). The 13C NMR spectrum of 5 in
the presence of NaClO4 in THF/C6D6 showed a similar
chemical shift difference pattern, but to a lesser degree
than with LiClO4 (data not shown). The similarity of the
degree of 13C chemical shifts of 5 in the presence of LiClO4
and NaClO4 with the observed facial selectivity, together
with the unusual 13C shift pattern of the ester moiety
(an upfield shift of C-3′′ and a downfield shift of C-4′′)
implied that the introduction of a bulky alkyl group at
with the addition of LiClO4 (Figure 1).17 The observed
downfield shifts of both the C-2 and C-4′′ in the ethyl
ester moiety, which is consistent with electron depletion,
suggests chelation of the LiSPh between the C-2 carbonyl
oxygen in the uracil moiety and the ester moiety. This
(15) (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.
(16) Although an upfield shift was observed at C-1′ upon the addition
of LiClO4, it is not certain whether this shift is due to an increased
electron density on C-1′ or to the dimensional anisotropic effect of the
2-carbonyl group.
(18) Addition of thiophenol to 5 in the presence of counter cations
incapable of chelation such as Et3N, i-Pr2NEt, or 1,1,3,3-tetrameth-
ylguanidine was attempted. However, decomposition or recovery of the
starting material was observed.
(17) Assignment of 13C signals was based on DEPT and HSQC
(heteronuclear single quantum coherence) experiments.

14 J . Org. Chem., Vol. 62, No. 1, 1997
Hassan et al.
Sch em e 3a
the ester moiety would prevent chelate formation. There-
fore, (Z)-2′-[(tert-butoxycarbonyl)methylene] derivative 13
was synthesized by the Wittig reaction of 4, as a
substrate for the thiophenol addition reaction. Treat-
ment of 13 with an excess of PhSH in the presence of
LiSPh in THF gave a mixture of the R-(phenylthio)
derivative 14 and the â-(phenylthio) derivative 15 in a
ratio of 32:68 (Table 1, entry 8). The 13C NMR spectrum
of 13 in the presence of LiClO4 showed chemical shift
differences at the nucleobase and the ester moiety similar
to those in the [(ethoxycarbonyl)methylene] derivative 5
(data not shown), suggesting that the (Z)-2′-[(alkoxycar-
bonyl)methylene] moiety was likely to accommodate the
aforementioned chelate even in the presence of the bulky
tert-butyl group. On the other hand, treatment of 13 with
an excess of PhSH in the presence of KSPh in dioxane/
DMF selectively gave the desired 2′R-(phenylthio) deriva-
tive 14 (Table 1, entries 9, 10). In the reaction of 13, the
relatively softer K+ would not form chelates probably due
to the presence of the bulky tert-butyl group, to selectively
give the R-addition product.19 The (E)-2′-[(tert-butoxy-
carbonyl)methylene] derivatives 18 and 20 were synthe-
sized as described below. When 20 was treated with
LiSPh/PhSH in THF, none of the addition products was
obtained even after a prolonged reaction time at elevated
temperature. On the other hand, treatment of 18 with
LiSPh under the same reaction conditions selectively
gave the 2′R-(phenylthio) derivative 17 along with the
lactone 8a (87:13) in 83% yield. These results also imply
the necessity of a chelated intermediate for the â-facial
attack of the benzenethiolate, and the increased steric
hindrance at the R-face would impede the R-facial attack
of the benzenethiolate.
Treatment of 14 with mCPBA in CH2Cl2 at -78 °C,
followed by warming the reaction mixture to room
temperature with stirring for a further 72 h, gave the
anticipated (Z)-[(tert-butoxycarbonyl)methylene] deriva-
tive 13 in 92% yield. This Z-selectivity is consistent with
the previously observed reliance of the geometrical
selectivity of the oxidative syn-elimination reaction on
the conformation of the 2′â-(cyanomethyl) moiety.5 We
previously reported that a highly stereoselective oxidative
syn-elimination of the (2′R)-2′-(cyanomethyl)-2′-(phe-
nylthio) derivative into the corresponding (E)-(cyano-
methylene) was achieved upon maximizing the steric
effects at the 5′-position and allowing the cooperative
coordination effect20 of the 3′-hydroxyl. Therefore, 14 was
converted into its 5′-O-TIPS derivative 17 after de-O-
silylation of 14 and subsequent selective protection of the
5′-hydroxyl group in 16. Treatment of 17 with mCPBA
in CH2Cl2 at -78 °C followed by warming the mixture to
room temperature exclusively gave the desired (E)-[(tert-
butoxycarbonyl)methylene] derivative 18 in high yield
(Scheme 3). Deprotection of 18 by TBAF in the presence
of AcOH21 in THF gave 19 in high yield. The Dowex 50
(H+)-catalyzed hydrolysis22 of the tert-butoxy ester group
of 19 in CH3CN/H2O gave the (E)-2′-(carboxymethylene)-
2′-deoxyuridine (3) in 95% yield. The (Z)-2′-(carboxy-
methylene)-2′-deoxyuridine (2) was synthesized from 13
in a similar manner.
In conclusion, phenylsulfenylation of (Z)-2′-[(alkoxycar-
bonyl)methylene]uridine derivatives proceeded smoothly
by 1,4-addition. The diastereofacial selectivity of the
reaction could be controlled by chelation- and nonchela-
tion manner to selectively produce either the 2′R-(phe-
nylthio) or 2′â-(phenylthio) derivatives. â-Facial selectiv-
ity was achieved by using a small 2′-[(alkoxycarbonyl)-
methylene] moiety, such as 5 and 7, and a hard cation,
in this case Li+, that can chelate strongly with the
2-carbonyl oxygen at the uracil moiety and the alkoxy
oxygen of the 2′-[(alkoxycarbonyl)methylene] moiety. The
R-facial selectivity was attained by using a bulky tert-
butoxy group, as in 14, and KSPh as a thiolate source.
Dehydrophenylsulfenylation of the 2′R-(phenylthio) de-
rivative 17 proceeded stereoselectively to give (E)-2′-[(tert-
butoxycarbonyl)methylene]-2′-deoxyuridine (18), which is
difficult to synthesize by Wittig-related reactions.
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. Thin-layer
chromatography was done on Merck coated plate 60F254. Silica
gel chromatography was done with YMC gel 60 A (70-230
mesh).
(Z)-2′-Deoxy-2′-eth oxycar bon ylm eth ylen e-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 (5). A solution
of Ph3PdCHCO2Et (2.6 g, 6.8 mmol) in CH2Cl2 (10 mL) was
added to 4 (3.0 g, 6.2 mmol) in THF (15 mL) dropwise at 0 °C.
The mixture was stirred at room temperature for 4.5 h and
then quenched with aqueous saturated NH4Cl. Aqueous
workup and silica gel column chromatography with 20%
EtOAc/hexane gave 5 (3.6 g, 96% as a colorless foam): 13C
NMR [THF-C6D6 (10:1), 13C signals were assigned on the basis
of DEPT and HSQC experiments] δ 165.0 (C4), 163.0 (C2),
160.4 (C3′′), 150.2 (C2′), 145.3 (C6), 115.4 (C2′′), 101.2 (C5),
88.0 (C1′), 82.4 (C4′), 75.2 (C3′), 63.9 (C5′), 60.7 (C4′′), 17.3
(i-Pr), 17.5 (i-Pr), 17.4 (i-Pr), 17.3 (i-Pr), 17.2 (i-Pr), 17.0 (i-
Pr), 14.0 (i-Pr), 13.8 (i-Pr), 13.6 (i-Pr), 13.2 (i-Pr), 13.1 (i-Pr);
1H NMR (CDCl3) δ 8.28 (s, 1H, H-N3), 7.32 (d, 1H, H-6, J )
8.0 Hz), 6.45 (d, 1H, H-1′, J ) 1.7 Hz), 6.10 (t, 1H, H-2′′, J )
2.2 Hz), 5.66 (dd, 1H, H-5, J ) 1.7, J ) 8.0 Hz), 5.32 (dt, 1H,
H-3′, J ) 2.2, J ) 8.2 Hz), 4.21-4.09 (m, 3H, CH2 and H-5′a),
4.06 (dd, 1H, H-5′b, J ) 2.9, J ) 12.6 Hz), 3.65 (ddd, 1H, H-4′,
J ) 8.2, J ) 2.9, J ) 4.6 Hz), 1.26 (t, 3H, CH3, J ) 7.1 Hz),
1.13-0.90 (m, 28H, H-isopropyl); NOE: irradiate H-2′′, observe
H-1′ (0.6%), H-3′ (2.0%), and isopropyl-H (8.2%); irradiate H-3′,
observe H-2′′ (3.0%), H-1′ (0.4%), H-4′ (3.0%), H-5′ (4.3%), and
(19) Due to solubility problems, the 13C NMR spectrum of 5 in the
presence of KClO4 in THF/C6D6 could not be measured.
(20) For examples of the cooperative coordination to mCPBA see:
(a) J ohnson, 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.; Luthman,
K.; Cso¨regh, I.; Hacksell, U. J . Org. Chem. 1995, 60, 1026.
(21) Azuma, A.; Nakajima, Y.; Nishizono, N.; Minakawa, N.; Suzuki,
M.; Hanaoka, K.; Kobayashi, T.; Tanaka, M.; Sasaki, T.; Matsuda, A.
J . Med. Chem. 1993, 36, 4183.
(22) Basu, M. K.; Sarkar, D. C.; Ranu, B. C. Synth. Commun. 1989,
19, 627.

(E)-2′-(Carboxymethylene)-2′-deoxyuridine
J . Org. Chem., Vol. 62, No. 1, 1997 15
H-6 (3.5%); irradiate CH3, observe CH2 (4.9%) and no other
NOE enhancement was observed; FABMS m/ z 555 (M+ + 1).
Anal. Calcd for C25H42N2O8Si2: C, 54.12; H, 7.63; N, 5.05.
Found: C, 54.39; H, 7.56; N, 4.86.
the same conditions as described for the synthesis of 8a .
Aqueous workup and silica gel column chromatography with
10% EtOAc/hexane gave 10 (130 mg, 6%, as a white solid
which was crystallized from EtOAc/hexane) and then with 12%
EtOAc/hexane gave 11 (1.98 g, 92% as a white solid, which
was crystallized from EtOAc/hexane). The physical data of
(Z)-2′-Deoxy-2′-eth oxyca r bon ylm eth ylen eu r id in e (6).
A THF solution of TBAF (1 M, 13.5 mL) was added to 5 (3.0 g,
5.4 mmol) in THF (25 mL) at 0 °C. The mixture was stirred
for 30 min and then neutralized with AcOH, and the solvent
was evaporated. The residue was purified on a silica gel
column with 6% EtOH/CHCl3 to give 6 (1.64 g, 97% as a pale
gray solid): 1H NMR (DMSO-d6) δ 11.30 (s, 1H), 7.50 (s, 1H,
J ) 8.3 Hz), 6.60 (s, 1H), 6.02 (s, 1H, J ) 2.2 Hz), 6.01 (d, 1H,
J ) 6.6 Hz), 5.55 (d, 1H, J ) 8.3 Hz), 4.87 (t, 1H, J ) 5.5 Hz),
4.69 (br m, 1H, became d after addition of D2O, J ) 8.2 Hz),
4.06 (q, 2H, J ) 7.1 Hz), 3.72 (m, 1H), 3.51 (m, 2H), 1.14 (t,
3H); FABMS m/ z 313 [M+ + 1]. Anal. Calcd for C13H16N2O7:
C, 50.00; H, 5.16; N, 8.97. Found: C, 49.80; H, 5.21; N, 9.16.
(Z)-2′-Deoxy-2′-eth oxyca r bon ylm eth ylen e-5′-O-(tr iiso-
p r op ylsilyl)u r id in e (7). Triisopropylsilyl chloride (0.44 mL,
2.04 mmol) was added to a mixture of 6 (400 mg, 1.27 mmol)
and imidazole (139 mg, 2.04 mmol) in DMF (8 mL) at 0 °C.
The mixture was stirred for 24 h at room temperature.
Aqueous workup and silica gel column chromatography with
30% EtOAc/hexane gave 7 (526 mg, 90% as a white solid): 1H
NMR (CDCl3) δ 8.33 (br s, 1H), 7.25 (d, 1H, J ) 8.0 Hz), 6.55
(t, 1H, J ) 1.8 Hz), 6.21 (t, 1H, J ) 2.2 Hz), 5.65 (dd, 1H, J )
8.0, J ) 2.3 Hz), 5.11 (m, 1H, became dt after addition of D2O,
J ) 8.2, J ) 2.0 Hz), 4.15 (m, 2H), 4.09 (dd, 1H, J ) 4.8, J )
10.1 Hz), 3.95 (dd, 1H, J ) 6.2, J ) 10.1 Hz), 3.74 (ddd, 1H, J
) 4.8, J ) 6.2, J ) 8.2 Hz), 2.56 (br s, 1H), 1.25 (t, 3H, J ) 7.2
Hz), 1.18-0.97 (m, 21H); FABMS m/ z 469 [M+ + 1]. Anal.
Calcd for C22H36N2O7Si: C, 56.39; H, 7.74; N, 5.98. Found:
C, 56.42; H, 7.80; N, 5.82.
(2′S)-2′-Deoxy-2′-(ca r boxym eth yl)-2′-(p h en ylth io)-5′-O-
(tr iisop r op ylsilyl)u r id in e-3′,2′-γ-la cton e (8a ). Compound
7 (550 mg, 1.17 mmol) was treated with a THF solution of
LiSPh (0.58 M, 3.0 mL, 1.74 mmol) and PhSH (1.2 mL, 12
mmol) in THF (15 mL) at 0 °C. The mixture was stirred for
2 h and then neutralized with aqueous AcOH. Aqueous
workup and silica gel column chromatography with 25%
EtOAc/hexane gave 8a (571 mg, 92% as a colorless foam): 1H
NMR (CDCl3) δ 8.45 (s, 1H), 7.72 (d, 1H, J ) 8.2 Hz), 7.47-
7.34 (m, 5H), 6.16 (s, 1H), 5.73 (dd, 1H, J ) 8.2, J ) 2.1 Hz),
5.03 (d, 1H, J ) 3.9 Hz), 4.19 (m, 1H), 4.13 (dd, 1H, J ) 11.0,
J ) 4.9 Hz), 4.10 (dd, 1H, J ) 11.0, J ) 4.2 Hz), 3.53 (d, 1H,
J ) 18.9 Hz), 3.03 (d, 1H, J ) 18.9 Hz), 1.26-0.99 (m, 21H);
FABMS m/ z 533 [M+ + 1]. Anal. Calcd for C26H36N2O6SSi:
C, 58.62 H, 6.81; N, 5.26. Found: C, 58.42; H, 6.92; N, 5.20.
2′-Deoxy-2′-(ca r b oxym et h ylen e)-5′-O-(t r iisop r op ylsi-
lyl)u r id in e-3′,2′-γ-la cton e (9). Compound 8a (590 mg, 1.11
mmol) in CH2Cl2 (10 mL) was treated with mCPBA (213 mg,
1.23 mmol) in CH2Cl2 (3 mL) at -78 °C. The mixture was
stirred for 15 min and then warmed gradually to room
temperature. The mixture was neutralized with saturated
aqueous NaHCO3, and the solvent was removed under reduced
pressure. The residue was taken in EtOAc and the solution
washed with H2O and brine. The organic phase was dried
(Na2SO4) and evaporated. The residue was dissolved in
toluene and heated under reflux for 1 h. The solvent was
removed under reduced pressure, and the residue was purified
on a silica gel column with 50% EtOAc/hexane to give 9 (418
mg, 89% as a white solid): 1H NMR (CDCl3) δ 8.88 (br s, 1H),
7.97 (d, 1H, J ) 8.2 Hz), 6.56 (s, 1H), 6.42 (d, 1H, J ) 2.0 Hz),
5.74 (d, 1H, J ) 8.2 Hz), 5.62 (dd, 1H,J ) 8.4 Hz), 4.24 (dd,
1H, J ) 1.4, J ) 12.0 Hz), 4.05 (dd, 1H, J ) 1.4, J ) 12.0 Hz),
3.75 (dt, 1H, J ) 8.4, J ) 1.4 Hz), 1.21-0.96 (m, 21H); FABMS
m/ z 423 [M+ + 1]. Anal. Calcd for C20H30N2O6Si: C, 56.85;
H, 7.16; N, 6.63. Found: C, 56.82; H, 7.08; N, 6.69.
1
10: mp 185-187 °C; H NMR (CDCl3) δ 7.90 (s, 1H, H-N3),
7.81 (d, 1H, H-6, J ) 8.3 Hz), 7.68 (m, 2H, 2′-SPh), 7.47-7.38
(m, 3H, 2′-SPh), 6.12 (s, 1H, H-1′), 5.56 (dd, 1H, H-5, J ) 2.4,
J ) 8.3 Hz), 5.47 (d, 1H, H-3′, J ) 9.3 Hz), 4.57 (dd, 1H, H-4′,
J ) 2.4, J ) 9.3 Hz), 4.25 (d, 1H, H-5′a, J ) 13.7 Hz), 4.11
(dd, 1H, H-5′b, J ) 13.7, J ) 2.9 Hz), 4.00 (dq, 1H, CH2CH3,
J ) 14.2, J ) 7.3 Hz), 3.74 (dq, 1H, CH2CH3, J ) 14.2, J ) 7.3
Hz), 3.01 (d, 1H, 2′-CH2aCO2Et, J ) 16.1 Hz), 2.89 (d, 1H, 2′-
CH2bCO2Et, J ) 16.1 Hz), 1.13-0.94 (m, 31H, CH2CH3, and
H-isopropyl); NOE: irradiate H-1′, observe H-6 (1.3%), SPh
(7.9%), H-3′ (0.5%), H-4′ (1.8%), CH2a (1.2%), and no NOE
enhancement was observed at CH2b signal; irradiate CH2a,
observe SPh (8.3%), H-1′ (4.9%), CH2b (24.8%), and no NOE
enhancement was observed at H-3′; irradiate CH2b, observe
SPh (2.0%), H-3′ (3.3%), CH2b (26.0%), and no NOE enhance-
ment was observed at H-1′; FABMS m/ z 665 [M+ + 1]. Anal.
Calcd for C31H48N2O8SSi2: C, 55.99; H, 7.28; N, 4.21. Found:
C, 55.74; H, 7.24; N, 4.14. The physical data of 11: mp 146-
1
146.5 °C; H NMR (CDCl3) δ 8.03 (s, 1H, H-N3), 7.74 (d, 1H,
H-6, J ) 8.3 Hz), 7.38-7.30 (m, 5H, 2′-SPh), 6.88 (s, 1H, H-1′),
5.81 (dd, 1H, H-5, J ) 2.4, J ) 8.3 Hz), 4.35 (d, 1H, H-3′, J )
6.8 Hz), 4.16-4.03 (m, 5H, H-4′, H-5′a,b, and 2′-CH2CH3, J )
6.8, J ) 3.4, J ) 10.7 Hz), 2.99 (d, 1H, 2′-CH2aCO2Et, J )
16.6 Hz), 2.91 (d, 1H, 2′-CH2bCO2Et, J ) 16.6 Hz), 1.21 (t,
3H, CH2CH3, J ) 7.3 Hz), 1.14-1.00 (m, 28H, H-isopropyl);
NOE: irradiate H-1′, observe H-6 (2%), H-3′ (1%), H-4′ (5.6%),
CH2a (2.7%), CH2b (0.4%), isopropyl-H (1.5%), and no NOE
enhancement was observed at SPh signal; irradiate CH2a,
observe SPh (4.3%), H-1′ (9.3%), CH2b (11.7%), H-4′ (0.7%),
isopropyl-H (2.7%); irradiate CH2b, observe SPh (7.4%), H-3′
(0.9%), H-4′ (2.6%), CH2b (15.0), isopropyl-H (4.6%); FABMS
m/ z 665 [M+ + 1]. Anal. Calcd for C31H48N2O8SSi2: C, 55.99;
H, 7.28; N, 4.21. Found: C, 55.73; H, 7.22; N, 4.17.
(2′S )-2′-De oxy-2′-e t h oxyca r b on ylm e t h yl-2′-(p h e n yl-
th io)u r id in e (12) a n d (2′S)-2′-(Ca r boxym eth yl)-2′-d eoxy-
2′-(p h en ylth io)u r id in e-3′,2′-γ-la cton e (8b). A THF solution
of TBAF (1 M, 5.2 mL) was added to a solution of 11 (1.38 g,
2.10 mmol) in THF (15 mL) at 0 °C. The mixture was stirred
at room temperature for 1.5 h and then neutralized with
AcOH. The solvent was evaporated, and the residue was
purified on a silica gel column with 1% EtOH/CHCl3 to give
12 (0.11 g, 12%, as a white solid) and then with 2% EtOH/
CHCl3 to give 8b (0.51 g, 65% as a colorless foam). The
physical data of 12: 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 8.18
(br d, 1H), 7.64-7.40 (m, 5H), 6.27 (s, 1H), 5.72 (d, 1H, J )
3.8 Hz), 5.50 (d, 1H, J ) 8.1 Hz), 5.40 (br s, 1H), 4.97 (br dd,
1H, J ) 9.1 Hz), 4.18 (dd, 1H, J ) 9.1 Hz), 3.98 (m, 1H), 3.88-
3.80 (m, 2H), 3.69 (br dd, became dd after addition of D2O,
1H, J ) 2.0, J ) 12.0 Hz), 2.80 (d, 1H, J ) 15.5 Hz), 2.62 (d,
1H, J ) 15.5 Hz), 1.13 (t, 3H, J ) 7.2 Hz); FABMS m/ z 423
[M+ + 1]. Anal. Calcd for C19H22N2O7S: C, 54.02; H, 5.25; N,
6.63. Found: C, 53.83; H, 5.24; N, 6.44. The physical data of
8b: 1H NMR (DMSO-d6) δ 11.47 (s, 1H), 7.87 (d, 1H, J 5,6 )
8.1 Hz), 7.48-7.35 (m, 5H), 6.27 (s, 1H), 5.70 (d, 1H, J 5,6 ) 8.1
Hz), 5.33 (br t, 1H), 4.91 (d, 1H, J 3′,4′ ) 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 C17H16N2O6S: C, 54.25; H, 4.28; N, 7.44. Found: C, 54.22;
H, 4.47; N,7.23.
(Z)-2′-[(ter t-Bu toxyca r bon yl)m 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 (13).
Compound 13 (4.6 g, 95% as a colorless foam) was obtained
by the reaction of 4 (4.0 g, 8.3 mmol) with Ph3PdCHCO2But
(6.2 g, 17 mmol) in THF (50 mL) by the method described for
the synthesis of 5: 13C NMR [THF-C6D6 (10:1), 13C signals
were assigned on the basis of DEPT and HSQC experiments]
δ 164.7 (C4), 163.1 (C2), 159.5 (C3′′), 150.2 (C2′), 145.3 (C6),
117.1 (C2′′), 101.0 (C5), 87.9 (C1′), 82.5 (C4′), 81.1 (C4′′), 75.1
(C3′), 63.9 (C5′), 27.7 (CH3) 17.5 (i-Pr), 17.4 (i-Pr), 17.3 (i-Pr),
17.2 (i-Pr), 17.0 (i-Pr), 14.0 (i-Pr), 13.9 (i-Pr), 13.6 (i-Pr), 13.2
(2′R)-2′-Deoxy-2′-eth oxycar bon ylm eth yl-2′-(ph en ylth io)-
3′,5′-O-(1,1,3,3-t e t r a isop r op yld isiloxa n e -1,3-d iyl)u r i-
d in e (10) a n d (2′S)-2′-d eoxy-2′-eth oxyca r bon ylm eth yl-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 (11). Compound 5 (1.80 g, 3.25 mmol) was
treated with a THF solution of LiSPh (0.58 M, 8.4 mL, 4.9
mmol) and PhSH (3.35 mL, 32.5 mmol) in THF at 0 °C under

16 J . Org. Chem., Vol. 62, No. 1, 1997
Hassan et al.
(i-Pr), 13.1 (i-Pr); 1H NMR (CDCl3) δ 8.18 (s, 1H), 7.23 (d, 1H,
J ) 8.1 Hz), 6.47 (t, 1H,J ) 1.8 Hz), 6.01 (t, 1H, J ) 2.2 Hz),
5.64 (dd, 1H, J ) 2.4, J ) 8.1 Hz), 5.27 (dt, 1H, J ) 2.0, J )
8.3 Hz), 4.11 (dd, 1H, J ) 5.0, J ) 12.6 Hz), 4.05 (dd, 1H, J )
3.0, J ) 12.6 Hz), 3.65 (ddd, 1H, J ) 8.3, J ) 3.0, J ) 5.0 Hz),
1.42 (s, 9H), 1.13-0.99 (m, 28H); FABMS m/ z 583 [M+ + 1].
Anal. Calcd for C27H46N2O8Si2: C, 55.64; H, 7.96; N, 4.81.
Found: C, 55.61; H, 7.89; N, 4.67.
the mixture was stirred for further 72 h. The mixture was
neutralized with 5% aqueous NaHCO3 and diluted with
EtOAc, and the organic phase was dried (Na2SO4) and
evaporated. The residue was purified by silica gel column
chromatography with 20% EtOAc/hexane to give 13 (156 mg,
92% as a colorless foam).
(Z)-2′-[(ter t-Bu t oxyca r b on yl)m et h ylen e]-2′-d eoxyu r i-
d in e (21). A THF solution of TBAF (1 M, 15.9 mL) was added
to a mixture of 13 (3.7 g, 6.35 mmol) and AcOH (0.9 mL, 16
mmol) in THF (20 mL) at 0 °C. The mixture was stirred for
1 h. The solvent was evaporated, and the residue was purified
on a silica gel column with 2% EtOH in CHCl3 to give 21 (2.0
g, 91% as a white solid): 1H NMR (DMSO-d6) δ 11.29 (s,
1H),7.46 (d, 1H, J ) 8.0 Hz), 6.60 (t, 1H, J ) 1.8 Hz), 5.95 (t,
1H, J ) 2.3 Hz), 5.93 (d, 1H, J ) 6.8 Hz), 5.56 (d, 1H, J ) 8.0
Hz), 4.85 (t, 1H, J ) 5.1 Hz), 4.63 (m, became dt after addition
of D2O, 1H, J ) 8.2 Hz), 3.70 (m, 1H, J ) 10.2, J ) 5.1 Hz),
3.53-3.39 (m, 2H), 1.35 (s, 9H); FABMS m/ z 341 [M+ + 1].
Anal. Calcd for C15H20N2O7: C, 52.94; H,5.92; N, 8.23. Found:
C, 52.86; H, 5.97; N, 8.23.
(E)-2′-[(ter t-Bu t oxyca r b on yl)m et h ylen e]-5′-O-(t r iiso-
p r op ylsilyl)u r id in e (18). Compound 17 (1.8 g, 3.0 mmol)
in CH2Cl2 (10 mL) was treated with mCPBA (614 mg, 3.56
mmol) in CH2Cl2 (5 mL) at -78 °C. The mixture was stirred
for 15 min and then warmed gradually to room temperature,
and the stirring was continued for further 10 h. Aqueous
workup and silica gel column chromatography gave 18 (1.33
g, 90% as a colorless foam): 13C NMR (CDCl3) δ 166.2, 162.8,
160.3, 150.4, 140.5, 120.4, 103.3, 84.6, 84.5, 83.0, 68.6, 61.8,
28.0, 17.9, 11.9; 1H NMR (CDCl3) δ 8.66 (br s, 1H), 7.51 (d,
1H, J ) 8.1 Hz), 6.75 (t, 1H, J ) 1.7 Hz), 5.94 (t, 1H, J ) 2.0
Hz), 5.70 (dd, 1H, J ) 8.1, J ) 2.0 Hz), 5.18 (dt, 1H, J ) 6.6,
J ) 2.0 Hz), 4.96 (br s, 1H), 4.13 (m, 1H), 4.05 (dt, 1H, J )
6.6, J ) 2.1 Hz), 4.00 (dd, 1H, J ) 2.1, J ) 11.0 Hz), 1.49 (s,
9H), 1.27-0.94 (m, 21H); HR FABMS calcd for C24H41N2O7Si
497.2682, found 497.2680.
(E)-2′-[(ter t-Bu t oxyca r b on yl)m et h ylen e]-2′-d eoxyu r i-
d in e (19). A THF solution of TBAF (1 M, 1.4 mL) was added
to a mixture of 18 (560 mg, 1.13 mmol) and AcOH (1 M, 1.4
mL) in THF (7 mL) at 0 °C. The mixture was stirred for 1 h
and then the solvent was evaporated in vacuo. The residue
was purified on a silica gel column with 2% EtOH/CHCl3 to
give 19 (350 mg, 91% as a colorless foam): 13C NMR (DMSO-
d6) δ 164.1, 163.1, 156.9, 150.8, 141.5, 118.5, 102.9, 86.0, 84.1,
80.9, 68.7, 61.2, 40.1, 39.9, 39.7, 39.5, 39.3, 39.1, 38.9, 27.7;
1H NMR (DMSO-d6) δ 11.36 (s, 1H), 7.52 (d, 1H, J ) 8.1 Hz),
6.59 (s, 1H), 5.74 (s, 1H), 5.66 (dd, 1H, J ) 8.1, J ) 1.3 Hz),
5.42 (d, 1H, J ) 5.5 Hz), 5.02 (br m, 1H), 4.96 (t, 1H, J ) 5.2
Hz), 3.88 (ddd, 1H, J ) 7.7, J ) 3.1, J ) 4.4 Hz), 3.63 (m, 1H,
became dd after addition of D2O, J ) 12.0, J ) 3.1 Hz), 3.58
(m, became dd after addition of D2O, 1H, J ) 12.0, J ) 4.4
Hz), 1.45 (s, 9H); HR FABMS calcd for C15H21N2O7 341.1348,
found 341.1320.
(E)-2′-[(ter t-Bu toxyca r bon yl)m 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 (20).
1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane (120 µL, 0.37 mmol)
was added to 19 (100 mg, 0.29 mmol) in pyridine (3 mL) at 0
°C. The mixture was stirred at room temperature for 12 h.
The solvent was evaporated and coevaporated with toluene.
The residue was purified on a silica gel column with 20%
EtOAc/hexane to give 20 (93 mg, 55% as a colorless foam): 1H
NMR (CDCl3) δ 8.31 (s, 1H), 7.04 (d, 1H, J ) 8.2 Hz), 6.69 (s,
1H), 5.77 (d, 1H, J ) 8.2 Hz), 5.70 (br s, 1H), 5.53 (m, 1H),
4.13-4.07 (m, 2H), 3.75 (dd, 1H, J ) 11.2 Hz), 1.47 (s, 9H),
1.25-0.93 (m, 28H); HR FABMS calcd for C27H47N2O8Si2
583.2870, found 583.2879.
(Z)-2′-(Ca r boxym eth ylen e)-2′-d eoxyu r id in e (2). A sus-
pension of 21 (1.07 g, 3.14 mmol) and Dowex 50 (ca. 1 g, H+)
in CH3CN-H2O (1:2, 20 mL) was heated at 100 °C for 9 h.
The mixture was cooled to room temperature and the resin
was removed by filtration. The filtrate was evaporated and
coevaporated with MeOH. The residual syrup was purified
on a silica gel column with 45% MeOH/CHCl3 to give 2 (0.85
g, 95% as a white powder): 13C NMR (DMSO-d6) δ 169.0,
163.6, 151.5, 150.2, 143.9, 123.7, 100.7, 84.6, 82.9, 70.7, 61.0;
1H NMR (DMSO-d6 + D2O) δ 7.43 (d, 1H, J ) 8 Hz), 6.66 (s,
(2′R)-2′-[(ter t-Bu toxycar bon yl)m eth yl]-2′-deoxy-2′-(ph e-
n ylt h io)-3′,5′-O-(1,1,3,3-t et r a isop r op yld isiloxa n e-1,3-d i-
yl)u r idin e (14) an d (2′S)-2′-[(ter t-Bu toxycar bon yl)m eth yl]-
2′-d e o x y -2′-(p h e n y lt h io )-3′,5′-O -(1,1,3,3-t e t r a is o p r o -
p yld isiloxa n e-1,3-d iyl)u r id in e (15). A mixture of 13 (8.0
g, 14 mmol), KSPh (3.1 g, 21 mmol), and PhSH (71 mL, 6.9
mol) was dissolved in dioxane/DMF (5:1, 100 mL) and was
heated for 24 h at 50 °C. The mixture was cooled to room
temperature and neutralized with aqueous AcOH. Aqueous
workup and silica gel column chromatography with 25%
EtOAc/hexane gave a mixture of 14 and 15 (8.6 g, 90% as a
white solid, in a 14/15 ratio of 77:23, determined by HPLC).
Crystallization of the mixture from EtOAc/hexane provided
14 (4.4 g, as a white crystals). The physical data of 14: mp
189-190 °C; 1H NMR (CDCl3) δ 7.92 (d, 1H, J ) 8.1 Hz), 7.80
(s, 1H), 7.69 (m, 2H), 7.48-7.39 (m, 3H), 6.07 (s, 1H), 5.75 (d,
1H, J ) 8.1 Hz), 5.58 (d, 1H, J ) 9.0 Hz), 4.58 (br d, 1H), 4.27
(d, 1H, J ) 13.5 Hz), 4.11 (dd, 1H, J ) 13.5, J ) 1.6 Hz), 3.04
(d, 1H, J ) 18.3 Hz), 2.92 (d, 1H, J ) 18.3 Hz), 1.26 (s, 9H),
1.14-0.95 (m, 28H); FABMS m/ z 694 [M+ + 1]. Anal. Calcd
for C33H52N2O8SSi2: C, 57.19; H, 7.56; N, 4.04. Found: C,
57.07; H, 7.54; N, 4.12. The physical data of 15: 1H NMR
(CDCl3) δ 8.10 (s, 1H), 7.73 (d, 1H, J ) 8.2 Hz), 7.38-7.28 (m,
5H), 6.84 (s, 1H), 5.79 (d, 1H,J ) 8.2 Hz), 4.33 (d, 1H, J ) 7.4
Hz), 4.17 (ddd, 1H, J ) 7.4, J ) 3.6, J ) 3.7 Hz), 4.09 (m, 2H),
2.86 (d, 1H, J ) 16.5 Hz), 2.82 (d, 1H, J ) 16.5 Hz), 1.42 (s,
9H), 1.14-0.95 (m, 28H).
(2′R)-2′-[(ter t-Bu toxycar bon yl)m eth yl]-2′-deoxy-2′-(ph e-
n ylth io)u r id in e (16). A THF solution of TBAF (1 M, 12.6
mL) was added to a mixture of 14 (3.5 g, 5.1 mmol) and AcOH
(0.72 mL) in THF (25 mL) at 0 °C. The mixture was stirred
for 2 h and then the solvent was evaporated. The residue was
purified on a silica gel column with 2% MeOH/CHCl3 to give
16 (2.16 g, 95% as a white solid): 1H NMR (DMSO-d6) δ 11.10
(s, 1H), 8.20 (br d, 1H), 7.64 (m, 2H), 7.44 (m, 3H), 6.10 (br s,
1H), 5.52-5.49 (m, 2H, J ) 8.2 Hz), 5.40 (br s, 1H), 4.84 (dd,
1H, J ) 8.9 Hz), 4.17 (d, 1H, J ) 8.9 Hz), 3.87 (br d, 1H, J )
12.4 Hz), 3.68 (br d, 1H, J ) 12.4 Hz), 2.67 (d, 1H, J ) 16.0
Hz), 2.54 (d, 1H, J ) 16.0 Hz), 1.39 (s, 9H); FABMS m/ z 451
[M+ + 1]. Anal. Calcd for C21H26N2O7S: C, 55.99; H, 5.82; N,
6.22. Found: C, 55.86; H, 5.90; N, 6.05.
(2′R)-2′-[(ter t-Bu toxycar bon yl)m eth yl]-2′-deoxy-2′-(ph e-
n ylth io)-5′-O-(tr iisop r op ylsilyl)u r id in e (17). Triisopro-
pylsilyl chloride (0.88 mL, 4.1 mmol) was added to a mixture
of 16 (1.6 g, 3.4 mmol) and imidazole (290 mg, 4.2 mmol) in
DMF (10 mL) at 0 °C. The mixture was stirred at room
temperature for 24 h. Aqueous workup and silica gel column
chromatography with 30% EtOAc/hexane gave 17 (1.9 g, 91%
as a colorless foam): 1H NMR (CDCl3) δ 8.31 (d, 1H, J ) 8.1
Hz), 7.85 (br s, 1H), 7.71-7.42 (m, 5H), 6.17 (s, 1H), 5.61 (dd,
1H, J ) 8.1, J ) 1.7 Hz), 4.89 (br s, 1H), 4.65 (d, 1H, J ) 9.0
Hz), 4.47 (d, 1H, J ) 9.0 Hz), 4.23 (d, 1H, J ) 11.6 Hz), 4.05
(d, 1H, J ) 11.6 Hz), 2.94 (d, 1H, J ) 15.4 Hz), 2.18 (d, 1H, J
) 15.4 Hz), 1.57 (s, 9H), 1.20-0.71 (m, 21H); FABMS m/ z 607
[M+ + 1]. Anal. Calcd for C30H46N2O7SSi: C, 59.38; H, 7.64;
N, 4.62. Found: C, 59.15; H, 7.64; N, 4.39.
Ad d ition of Th iop h en ol to 18. A THF solution of LiSPh
(0.58 M, 0.52 mL, 0.3 mmol) was added to a mixture of 18
(100 mg, 0.2 mmol) and PhSH (0.21 mL, 2 mmol) in THF (3
mL) at 0 °C. The mixture was stirred at room temperature
for 20 h and then neutralized with AcOH. Aqueous workup
and silica gel column chromatography gave 17 and 8a (100
mg, 84% in a 17/8a ratio of 83:17, determined by the integra-
tion of the H-1′ in the 1H NMR spectrum).
Oxid a tive Syn -Elim in a tion of 14. mCPBA (60 mg, 0.35
mmol) in CH2Cl2 (1 mL) was added to a solution of 14 (200
mg, 0.29 mmol) in CH2Cl2 (4 mL) at -78 °C. The mixture was
stirred for 15 min and then warmed to room temperature, and

(E)-2′-(Carboxymethylene)-2′-deoxyuridine
J . Org. Chem., Vol. 62, No. 1, 1997 17
1H), 5.98 (s, 1H), 5.54 (d, 1H, J ) 8 Hz), 4.59 (dt, 1H, J ) 7.5
Hz), 3.57-3.50 (m, 3H); HR FABMS calcd for C11H11N2O7
283.0566, found 283.0552.
2H), 3.56 (m, 1H); HR FABMS calcd for C11H11N2O7 283.0566,
found 283.0577.
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.
(E)-2′-(Ca r boxym eth ylen e)-2′-d eoxyu r id in e (3). A sus-
pension of 20 (120 mg, 0.35 mmol) and Dowex 50 (ca. 120 mg,
H+) in CH3CN-H2O (1:2, 5 mL) was heated at 50 °C for 24 h.
The mixture was cooled to room temperature, and the resin
was filtered off. The filtrate was evaporated and coevaporated
with MeOH. The residual syrup was purified on a silica gel
column with 45% MeOH/CHCl3 to give 3 (91 mg, 91% as a
white powder): 13C NMR (DMSO-d6) δ 170.3, 163.0, 151.5,
150.6, 141.7, 127.1, 102.5, 84.4, 84.1, 69.4, 60.7; 1H NMR
(DMSO-d6 + D2O): δ 7.46 (d, 1H, J ) 8 Hz), 6.44 (s, 1H), 5.76
(s, 1H), 5.66 (d, 1H, J ) 8 Hz), 4.73 (br dd, 1H), 3.74-3.68 (m,
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of 2, 3, 18, 19, and 20 (5 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.
J O9613601