Efficient and β-stereoselective synthesis of 4(5)-(β-D-ribofuranosyl)- and 4(5)-(2-deoxyribofuranosyl)imidazoles

Article abstract of DOI:10.1021/jo952136z

A synthetic route to 4(5)-(β-D-ribofuranosyl)imidazole (1), starting from 2,3,5-tri-O-benzyl-D-ribose (5), was developed via a Mitsunobu cyclization. Reaction of 5 with the lithium salt of bis-protected imidazole afforded the corresponding 5-ribosylimidazole 7RS. Hydrolysis of 7RS gave a 1:1 mixture of diol isomers 8R and 8S having an unsubstituted imidazole. Mitsunobu cyclization of the mixture 8RS using N,N,N',N'-tetramethylazodicarboxamide and Bu₃P exclusively afforded benzylated β-ribofuranosyl imidazole 9β in 92% yield, accompanied by α-anomer 9α, in a ratio of 26.3:1. The configuration of 9β was established by X-ray crystallography of ethoxycarbonyl derivative 10β. Reductive debenzylation of 9β over Pd/C was carried out, and the synthesis of 1 was attained from starting 5 in four steps and 87% overall yield. This synthetic methodology was extended to the synthesis of 4(5)-(2-deoxy-β-D-ribofuranosyl)imidazole (2). Mitsunobu cyclization of a 1:1 mixture of the corresponding diol isomers 14RS produced 15β and 15α in a ratio of 5.4:1. The synthesis of 2 was attained in a 59% overall yield from the starting 3,5-di-O-benzyl-2-deoxy-D-ribose (12). β-Stereoselective glycosylation in the key step is discussed and explained by intramolecular hydrogen bonding between an NH in the imidazole and the oxygen functional group in the sugar moiety.

Full text of DOI:10.1021/jo952136z

J . Org. Chem. 1996, 61, 4405-4411
4405
Efficien t a n d â-Ster eoselective Syn th esis of
4(5)-(â-D-Ribofu r a n osyl)- a n d
4(5)-(2-Deoxyr ibofu r a n osyl)im id a zoles1
Shinya Harusawa, Yoshihiko Murai, Hideki Moriyama, Tomonari Imazu, Hirofumi Ohishi,
Ryuji Yoneda, and Takushi Kurihara*
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-11, J apan
Received December 1, 1995X
A synthetic route to 4(5)-(â-D-ribofuranosyl)imidazole (1), starting from 2,3,5-tri-O-benzyl-D-ribose
(5), was developed via a Mitsunobu cyclization. Reaction of 5 with the lithium salt of bis-protected
imidazole afforded the corresponding 5-ribosylimidazole 7RS. Hydrolysis of 7RS gave a 1:1 mixture
of diol isomers 8R and 8S having an unsubstituted imidazole. Mitsunobu cyclization of the mixture
8RS using N,N,N′,N′-tetramethylazodicarboxamide and Bu3P exclusively afforded benzylated
â-ribofuranosyl imidazole 9â in 92% yield, accompanied by R-anomer 9R, in a ratio of 26.3:1. The
configuration of 9â was established by X-ray crystallography of ethoxycarbonyl derivative 10â.
Reductive debenzylation of 9â over Pd/C was carried out, and the synthesis of 1 was attained from
starting 5 in four steps and 87% overall yield. This synthetic methodology was extended to the
synthesis of 4(5)-(2-deoxy-â-D-ribofuranosyl)imidazole (2). Mitsunobu cyclization of a 1:1 mixture
of the corresponding diol isomers 14RS produced 15â and 15R in a ratio of 5.4:1. The synthesis of
2 was attained in a 59% overall yield from the starting 3,5-di-O-benzyl-2-deoxy-D-ribose (12).
â-Stereoselective glycosylation in the key step is discussed and explained by intramolecular hydrogen
bonding between an NH in the imidazole and the oxygen functional group in the sugar moiety.
In tr od u ction
C-4(5) linked 2′-deoxy-â-D-ribofuranosylimidazoles were
recently reported by Bergstrom et al.6 The synthetic
methods of C-nucleosides, in general, require many steps,
and the kinds of C-nucleosides that can be prepared are
limited in number.2 Since most biologically active nu-
cleosides possess â-stereochemistry at C-1 of the sugar
moiety, â-stereoselective glycosylation is the most im-
portant task in nucleoside synthesis. However, a major
practical drawback in current synthetic methods is poor
â-selectivity.
C-Nucleosides having 5-membered nitrogen hetero-
cycles, such as showdomycin and pyrazofurin, display
remarkable antiviral and antitumor activities.2 Imida-
zoles are biologically important heterocyclic compounds,
and a variety of useful therapeutic agents containing the
imidazole moiety have been developed.3 Imidazole nucle-
otides play central roles in purine biosynthesis,4 and thus,
there should be significant potential utility for antime-
tabolites based on C-4 linkage rather than N-1 linkage
to the sugar moiety. We thus directed our attention to
synthesizing C-nucleosides having the imidazole as the
base moiety. Although several imidazole C-nucleosides
linked through C-2 have been synthesized,5 the first
We report herein an efficient and stereoselective
synthesis of novel 4(5)-(â-D-ribofuranosyl)imidazole (1)
and its 2′-deoxy derivative 26 using a Mitsunobu cycliza-
tion as the key step. Their N-(ethoxycarbonyl) com-
pounds 3 and 4, useful intermediates to supply related
nucleosides, were also synthesized by this method. We
used the hydrogen-bonding potential of imidazole in this
approach to control â-stereoselective glycosylation.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) Preliminary communication: Harusawa, S.; Murai, Y.; Moriya-
ma, H.; Ohishi, H.; Yoneda, R.; Kurihara, T. Tetrahedron Lett. 1995,
36, 3165.
(2) For recent reviews on the chemisty, biochemistry, and synthesis
of C-nucleoside analogues, see: (a) Suhadolnik, R. J . Nucleosides as
Biological Probes; Wiley-Interscience: New York, 1979. (b) Hacksell,
U.; Daves, G. D. Prog. Med. Chem. 1985, 22, 1. (c) Sato, T.; Noyori, R.
Yuki Gosei Kagaku Kyokai Shi 1980, 38, 862. (d) Sato, T.; Noyori, R.
Ibid. 1980, 38, 947. (e) Watanabe, K. A. Ibid. 1987, 45, 212. (f) Katagiri,
N. Ibid. 1989, 47, 707. (g) Postema, M. H. D. Tetrahedron 1992, 48,
8545. (h) J aramillo, C.; Knapp, S. Synthesis 1994, 1. (i) Watanabe, K.
A. The Chemistry of C-Nucleosides. In Chemistry of Nucleosides and
Nucleotides; Townsend, L. B., Ed.; Plenum Press: New York, 1994;
Vol. 3, pp 421-535.
Resu lts
(3) Imidazole-based enzyme models: (a) Eberson, L.; Radner, F. Acc.
Chem. Res. 1987, 20, 53. Imidazole-based Angiotensin II receptor
antagonists: (b) Greenlee, W. J .; Siegl, P. K. S. Annu. Rep. Med. Chem.
1992, 27, 59. (c) Hodges, J . C.; Hamby, J . M.; Blankley, C. J . Drugs
Future 1992, 17, 575. Imidazole-based nonprostanoid prostacyclin
mimetics: (d) Meanwell, N. A.; Romine, J . L.; Seiler, S. M. Drugs
Future 1994, 19, 361. Imidazole-based acyl-CoA inhibitors: (e) Kimura,
T.; Watanabe, N.; Matsui, M.; Hayashi, K.; Tanaka, H.; Ohtsuka, I.;
Saeki, T.; Kogushi, M.; Kabayashi, H.; Akasaka, K.; Yamagishi, Y.;
Saitou, I.; Yamatsu, I. J . Med. Chem. 1993, 36, 1641. Imidazole-based
H2 antagonists: (f) Ganellin, R. J . Med. Chem. 1981, 24, 913.
Imidazole-based H3 ligands: (g) Timmerman, H. J . Med. Chem. 1990,
33, 4. Imidazole-based 5-HT3 antagonists: (h) Rosen, T.; Nagel, A. A.;
Rizzi, J . P. Synlett 1991, 213 and references cited therein.
(4) Stryer, L. Biochemistry, 3rd ed.; Freeman: New York, 1988; pp
603-4.
Syn th esis of 4(5)-(â-D-Ribofu r a n osyl)im id a zoles.
We initially attempted the direct reaction of a protected
D-ribosyl chloride with 5-lithioimidazole, but it did not
afford the desired glycoside due to the formation of 1-(5-
(5) (a) Poonian, M. S.; Nowoswiat, E. F. J . Org. Chem. 1980, 45,
203. (b) Igolen, J .; Dinh, T. H. J . Chem. Soc., Chem. Commun. 1971,
1267. (c) Kolb, A.; Gouyette, C.; Tam, H. D.; Igolen, J . Tetrahedron
Lett. 1973, 2971. (d) Ferris, J . P.; Hung, H. C. J . Chem. Soc., Chem.
Commun. 1978, 1094. (e) Ferris, J . P.; Badesha, S. S.; Ren, W. Y.;
Huang, H. C.; Sorcek, R. J . Ibid. 1981, 110.
(6) Bergstrom, D. E.; Zhang, P.; Zhou, J . J . Chem. Soc., Perkin
Trans. 1 1994, 3029.
S0022-3263(95)02136-0 CCC: $12.00 © 1996 American Chemical Society

4406 J . Org. Chem., Vol. 61, No. 13, 1996
Harusawa et al.
Ta ble 1. Mitsu n obu Cycliza tion of Diols 8
Sch em e 1
run
1
8
reaction condns (equiv)
productsa (%)
8RSb
DEAD (2.2), Ph3P (2.6),
THF, rt, 3 h
ADDP (2.0), Bu3P (2.0),
benzene, rt, 22 h
c
10â (R ) CO2Et, 15)
2
8RSb
9âd (53)
3
4
5
8R
9âd (47)
8S
c
9âd (78)
8RSb
TMAD (1.5), Bu3P (1.5),
benzene, rt, 16 h
9âd (92), 9Rd (3.5)
a
b
Isolated yields. Referred to a 1:1 mixture of 8R and 8S. c The
reaction was carried out under the same conditions as in run 2.
d
R ) H.
and position of the ethoxycarbonyl group in the product
could not be determined from spectral data, the structure
was established as the desired â-anomer, ethyl 4-(2,3,5-
tri-O-benzyl-â-D-ribofuranosyl)imidazole-1-carboxylate, by
single-crystal X-ray diffraction analysis.11
Tsunoda et al.12 recently reported 1,1′-(azodicarbonyl)-
dipiperidine (ADDP)-Bu3P12a and N,N,N′,N′-tetramethy-
lazodicarboxamide (TMAD)-Bu3P12b as new reagent
systems for the Mitsunobu reaction, and we applied these
to the cyclization of 8RS. Treatment of the mixture with
ADDP-Bu3P afforded the â-anomer (9â) having an
unsubstituted imidazole in modest yield (Table 1, run 2).
The structure was confirmed by conversion to 10â with
ethyl chloroformate. This experiment interestingly sug-
gests the â-anomer (9â) to be produced from both isomers
(8R and 8S), whose configurations at C-1′ were assigned
by the 1H-NMR data and NOE experiments of their
derivatives, as described in the next section. The cy-
clization of 8R isolated by SiO2 chromatography afforded
9â in 47% yield, and the S-isomer (8S) also brought about
9â in 78% yield (Table 1, runs 3 and 4). These reactions
were clear, but the isolated yields were variable and less
satisfactory owing to the difficulty in product isolation
from the hydrazine byproduct. The problem was solved
by a water-soluble TMAD. Treatment of the mixture
8RS with TMAD and Bu3P at room temperature in
benzene exclusively produced the desired â-anomer (9â)
in 92% yield, together with a small amount of R-anomer
(9R, 3.5%). The ratio of â- and R-isomers was 26.3:1.
Importantly, it has been possible to synthesize the
â-anomer without separation of the isomers (8R, 8S) or
stereoselective synthesis of the R-isomer. This is in
contrast to the results of Yokoyama et al. mentioned
above.10a
imidazolyl)ribofuranoid glycal.7 This failure led to an-
other synthetic approach using the Mitsunobu cycliza-
tion.
The reaction of 2,3,5-tri-O-benzyl-D-ribose (5),8 easily
available from D-ribose, with lithium salt 6 of bis-
protected imidazole9 gave an inseparable epimeric mix-
ture 7RS of the corresponding 5-ribosylimidazole in
quantitative yield, as illustrated in Scheme 1. Hydrolysis
of 7RS in refluxing 1.5 N HCl afforded a 1:1 mixture of
diols 8R and 8S having an unsubstituted imidazole in
95% yield. Yokoyama et al.10a recently reported synthesis
of C-ribonucleosides having typical aromatic heterocycles,
in which the cyclization of the corresponding diols
proceeds through intramolecular SN2 reaction under
Mitsunobu conditions and orientation of the glycosidic
linkage is controlled by the C-1′ configuration of the sub-
strate: one isomer affords an R-anomer and the other a
â-anomer. When we first carried out the cyclization of
the mixture 7RS under standard Mitsunobu conditions
[diethyl azodicarboxylate (DEAD)/Ph3P], only a complex
mixture was obtained. However, the same treatment of
the mixture of 8R and 8S having the unsubstituted
imidazole afforded a single crystalline compound 10â
with an ethoxycarbonyl group at N in the imidazole
moiety in only 15% yield, after partial chromatographic
separation followed by recrystallization from hexane
(Table 1, run 1). Although the stereochemistry at C-1′
Patil et al.13 recently reported the X-ray crystal-
lographic analysis of a pyrrole analogue of 9â, 5-(2,3,5-
tri-O-benzyl-â-D-ribofuranosyl)pyrrole-2-carbaldehyde, with
strong hydrogen-bonding between N1-H and O-5′. Chemi-
(7) Harusawa, S.; Kawabata, M.; Murai, Y.; Yoneda, R.; Kurihara,
T. Chem. Pharm. Bull. 1995, 43, 152.
(8) Barker, R.; Fletcher, H. G., J r. J . Org. Chem. 1961, 26, 4605.
We obtained 5 in an improved yield (68%) from D-ribose by the Barker
procedure.
(11) Monoclinic, P21. More details on the crystal structure analysis
(refcode: ZAPSUE) were submitted to the Cambridge Crystallographic
Data Centre. The details can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK.
(9) (a) Ngochindo, R. I. J . Chem. Soc., Perkin Trans. 1 1990, 1645.
(b) Kudzma, L. V.; Turbull, S. P., J r. Synthesis 1991, 1021.
(10) (a) Yokoyama, M.; Toyoshima, A.; Akiba, T.; Togo, H. Chem.
Lett. 1994, 265. (b) Yokoyama, M.; Akiba, T.; Togo, H. Synthesis 1995,
638. (c) Yokoyama, M.; Tanabe, T.; Toyoshima, A.; Togo, H. Synthesis
1993, 517.
(12) (a) Tsunoda, T.; Yamamiya, Y.; Itoˆ, S. Tetrahedron Lett. 1993,
34, 1639. (b) Tsunoda, T.; Otsuka, J .; Yamamiya, Y.; Itoˆ, S. Chem. Lett.
1994, 539. (c) Tsunoda, T.; Ozaki, F.; Itoˆ, S. Tetrahedron Lett. 1994,
35, 5081.
(13) Patil, S. A.; Otter, B. A.; Klelin, R. S. Tetrahedron Lett. 1994,
35, 5339.

Synthesis of 4-Substituted Imidazoles
J . Org. Chem., Vol. 61, No. 13, 1996 4407
Sch em e 2
relatively few examples have been reported, and the
number of direct synthetic procedures remains limited.17
Bergstrom et al.6 recently reported the synthesis of 4(5)-
(2-deoxy-â-D-ribofuranosyl)imidazole-2-carboxamide de-
signed as a universal nucleoside. The synthetic inter-
mediate, 4(5)-(2-deoxy-â-ribofuranosyl)-1H-imidazole (2),
was synthesized from 2-deoxy-3,5-di-O-(p-toluoyl)-â-D-
ribofuranosyl cyanide in six steps, in only 9.2% overall
yield. The synthetic approach is construction of the
C-linked imidazole from the cyano group on C-1 of sugar,
but it would be difficult to make 2 on a large scale owing
to the use of an unstable intermediate. Yokoyama et
al.10b very recently reported the conversion yields of
Mitsunobu cyclization to be low (30-40%) for the syn-
thesis of C-2′-deoxy-D-ribonucleosides bearing typical
aromatic heterocycles as the base moiety. The authors
thus intend to synthesize the 2′-deoxy compound 2 and
its ethoxycarbonyl derivative 4 as an extension of our
synthetic methodology.
Reaction of 3,5-di-O-benzyl-2-deoxy-D-ribose (12),18
readily available in three steps from D-2-deoxyribose,
with 5-lithioimidazole 6 afforded an adduct 13RS in 99%
yield, as shown in Scheme 3. Double deprotection of the
adduct by treatment with 1.5 N HCl afforded a 1:1
epimeric mixture of diols 14RS in 92% yield. Mitsunobu
cyclization (TMAD-Bu3P) of the mixture produced an
inseparable mixture of â- and R-anomers in a ratio of ca.
5:1. The ratio was assigned from methylene protons at
C-2′ in 1H NMR (δ 2.20, 2.35 for 15â vs 2.19, 2.60 for
15R).6,19 The signals for the two C-2′ protons of 15â
spanned a total region of 0.27 ppm, which is typical of
the â-anomer. The large total region (0.55 ppm) of 15R
provides evidence for the R-anomer.
cal shifts and coupling constants of 1H-NMR on the sugar
moiety of 9â are consistent with those of the pyrrole
analogue. This supports the existence of hydrogen-
bonding in 9â. Debenzylation of 9â over Pd-C was
carried out to achieve the synthesis of 4(5)-(â-D-ribofura-
nosyl)imidazole (1) in four steps and an 87% overall yield
from 5. Similarly, Mitsunobu cyclization of the RS
mixture of 8 followed by treatment with ethyl chlorofor-
mate without purification of crude 9 afforded a â-anomer
(10â) in 86% yield (Scheme 1). Deprotection of 10â with
Pd(OH)2-cyclohexene produced an ethoxycarbonyl de-
rivative 3 in 97% yield. The ethoxycabonyl derivative 3
was obtained from 5 in five steps and 79% overall yield.
C-1′ Con figu r a tion s in 8R a n d 8S. The configura-
tions at C-1′ of 8R and 8S were assigned by comparison
of J 1′,2′ coupling constants and NOE difference spectra of
per-O,N-acetyl derivatives 11R and 11S at -25 °C.14 The
respective epimers of 8 were separated by column chro-
matography and then transformed into 11R and 11S by
hydrogenolytic debenzylation followed by acetylation
(Scheme 2). The J 1′,2′ coupling constant (3.9 Hz) of 11R
was relatively small in comparison to 11S which exhib-
ited large J 1′,2′ (6.5 Hz). By analogy with data15 for acetyl
derivatives of acyclic carbohydrates (coupling constants,
<4 Hz for protons having a gauche orientation and the
values >7 Hz for those having antiparallel orientation),
it appears that there is a gauche relationship for 11R
and an antiparallel orientation for 11S. In the NOE
experiments, mutual enhancement between H1 and H2
was found to be substantially greater in the case of 11R
(7-8%) compared to that of 11S (3-4%). Respective
configurations at C-1′ are thus indicated as shown in
Scheme 2. C-1′ configurations in the original compounds
8R and 8S were tentatively assigned based on 11R and
11S.
Their mesyl derivatives 16 could be separated by flash
column chromatography, giving â- and R-anomers (16â,
16R) in 59% and 11% yields from 14RS, respectively.
Deprotection of 16â with 1.5 N HCl followed by treatment
10c
with BCl3 completed the synthesis of 2 in 94% yield,
and the spectroscopic data were consistent with those
reported by Bergstrom et al. Ethoxycarbonyl derivative
4 was similarly synthesized (Scheme 3), and deprotection
with hydrazine hydrate also afforded 2 via an alternative
route. We thus achieved an efficient and stereocontrolled
synthesis of C-2′-deoxy-D-ribonucleoside 2 bearing the
imidazole in 59% overall yield from 12.
The advantageous feature of this approach is the
supply of 2 or 4 on a multigram scale; for example, we
obtained 6.65 g (72%) of the â-anomer (17â) from 8.08 g
of 14RS.
Mech a n istic Con sid er a tion s on â-Ster eoselective
Glycosyla tion on th e Mitsu n obu Cycliza tion . Mit-
sunobu cyclization of the diols (8RS, 14RS) bearing an
unsubstituted imidazole exhibited excellent â-selective
glycosylation. Importantly, the reaction supplied exclu-
sively the desired â-anomers from both R- and S-isomers.
Mitsunobu cyclization of diols 13 and 18 bearing mono-
substituted or disubstituted imidazole proceeded via a
Syn th esis of 4(5)-(2-Deoxy-â-D-r ibofu r a n osyl)im i-
d a zoles. C-2′-Deoxy-D-ribonucleosides are of interest as
potential antiviral and antitumor agents.16 However,
S
N2 process of the standard Mitsunobu reaction, as
shown in Table 2. The intact-imidazole moiety is thus
shown to be indispensable for the exclusive formation of
â-anomers. Intramolecular hydrogen bonding between
the nitrogen in the imidazole and OH groups in the sugar
(14) The J 1′,2′ and NOE values of 11R and 11S did not show
significant differences at 24 °C.
(15) (a) Rashed, N.; Ibrahim, E. I.; El Ashry, E. S. H. Carbohydr.
Res. 1994, 254, 295. (b) Khadem, H. E.; Horton, D.; Wander, J . D. J .
Org. Chem. 1972, 37, 1630.
(16) (a) Chu, C. K.; Reichmann, U.; Watanabe, K. A.; Fox, J . J . J .
Heterocycl. Chem. 1977, 14, 1119. (b) Matsuda, A.; Chu, C. K.;
Reichman, U.; Pankiewicz, K.; Watanabe, K. A.; Fox, J . J . J . Org.
Chem. 1981, 46, 3603. (c) Matsuda, A.; Pankiewicz, K.; Marcus, B. K.;
Watanabe, K. A.; Fox, J . J . Carbohydr. Res. 1982, 100, 297.
(17) Reference 10b and references cited therein.
(18) (a) Huang, B.; Hui, Y. Nucleosides Nucleotides 1993, 12, 139.
(b) Wierenga, W.; Skulnick, H. I. Carbohydr. Res. 1981, 90, 41.
(19) Srivastava, P. C.; Robins, R. K.; Takusagawa, F.; Berman, H.
M. J . Heterocycl. Chem. 1981, 18, 1659.

4408 J . Org. Chem., Vol. 61, No. 13, 1996
Harusawa et al.
Sch em e 3
Ta ble 2. Mitsu n obu Cycliza tion of Su bstitu ted
Im id a zoles 13 a n d 18
In conclusion, we describe an efficient and highly
stereocontrolled synthesis of novel 4(5)-(â-D-ribofurano-
syl)imidazoles (1, 3) and their 2′-deoxy derivatives (2, 4).
The synthetic approach should supply a variety of
derivatives by which their biological activity of C-4-linked
imidazole nucleosides can be assessed.
Exp er im en ta l Section
Gen er a l P r oced u r e. Melting points were determined with
a hot-stage apparatus and are uncorrected. Optical rotation
measurements were recorded at 20 °C. 1H and 13C NMR
spectra were taken with tetramethylsilane as the internal
standard in CDCl3 unless otherwise noted. All reactions with
air- and moisture-sensitive compounds were carried out under
an argon atmosphere. Unless otherwise noted, all extracts
were dried over Na2SO4, and the solvent was removed by
rotary evaporation under reduced pressure. THF was distilled
from sodium-benzophenone.
run
13 or 18
products (%)
1
2
3
4
13S
13R
18S
18R
19â (12)a
19R (7)b
20â (94)
20R (88)
a
b
Recovery of 13S (65%). Recovery of 18R (67%).
moiety should be essential to the determination of the
ratio of â- vs R-glycosylation. Epimerization between R-
and â-anomers did not take place under the present
reaction conditions. From these results, â-selectivity in
our reaction may be explained as in Scheme 4.
2-(ter t-Bu tyld im eth ylsilyl)-5-(2,3,5-tr i-O-ben zyl-D-r ibo-
syl)-N,N-d im eth ylim id a zole-1-su lfon a m id e (7RS). A solu-
tion of 2-(tert-butyldimethylsilyl)-N,N-dimethylimidazole-1-
sulfonamide9a (918 mg, 3.18 mmol) in THF (7.0 mL) was cooled
to -60 °C and treated dropwise with 1.6 M BuLi-hexane (2.0
mL, 3.18 mmol), and the resulting mixture was stirred for 15
min at -55 °C. The mixture was cooled to -70 °C, and a
solution of 58 (445 mg, 1.06 mmol) in THF (5.0 mL) was added
slowly. The dry ice bath was removed, and the reaction
mixture was stirred at rt. After 2 h, the reaction was quenched
with H2O, and the THF was removed under reduced pressure.
The residue was dissolved in EtOAc, and the solution was
washed with H2O, dried, and evaporated to give a crude oil.
Flash chromatography on silica gel using 20% and 60%
EtOAc-hexane as eluent gave 7RS (751 mg, quantitative) as
a pale yellow oil. 1H NMR indicated a ca. 1:1 mixture of R-
Reaction of the TMAD-Bu3P adduct with 8R forms the
zwitterion 21R. Preferential elimination of Bu3P)O from
21R leads to isoimidazole 22. Spontaneous cyclization
assisted by a hydrogen bond gives the â-anomer (9â),
which is stabilized by intramolecular hydrogen bonding.
Although the S-isomer (8S) similarly leads to the active
species 22′, it exclusively gave the â-anomer via rotomer
22 which is thermodynamically more stable. The re-
markable stereoselectivity (â/R ) 26/1) of the ribofurano-
sylimidazoles 9 is facilitated by electronic repulsion in
22′. The somewhat low selectivity (â/R ) 5.4/1) of the
2′-deoxy compounds 16 may be due to lack of the OBn
group at C-2′.
1
and S-isomers: IR (neat, cm-1) 3400, 1375, 1150; H NMR δ
0.40 (br s, 6H), 1.00 (s, 9H), 2.66 (s, 2.4 H), 2.73 (s, 3.6H), 3.51-
3.82 (m, 2H), 3.82-4.28 (m, 3H), 4.35-4.77 (m, 6H), 5.35 (br
s, 0.6H), 5.39 (br s, 0.4H), 7.11-7.43 (m, 16H); HRMS (SIMS)
(M+) 710.3292 calcd for C37H52N3O7SSi, found 710.3300.
4(5)-(2,3,5-Tr i-O-b en zyl-D-r ib osyl)im id a zole (8R a n d
8S). A solution of 7RS (9.86 g, 13.9 mmol) in THF (45 mL)
was refluxed with 1.5 N HCl (75 mL) for 2.5 h and then cooled.
After neutralization by addition of 30% NH4OH, the solvent
was evaporated to give a residue, which was extracted with
EtOAc. The extract was washed with H2O and brine, dried,
Compounds 1 and 26 were tested for antiviral20 and
anticancer21 activity, but no activity or toxicity was found.
(20) HIV in MT-4 cells and type A Influenza virus in MDBK cells.
(21) CCD-19 Lu, CCRF-CEM, p388, p388/ADM, B16, Lewis, Lu-65,
Lu-99, A549, RERF-LC-AI, and HT-29 cell lines.

Synthesis of 4-Substituted Imidazoles
J . Org. Chem., Vol. 61, No. 13, 1996 4409
Sch em e 4
and evaporated to give an oil, which was subjected to chro-
matography. Elution with MeOH-EtOAc (1:9) afforded a ca.
1:1 mixture of 8R and 8S (6.44 g, 95%). Although the
separation of 8R and 8S was not required for the following
experiment, they could be isolated by a use of MeOH-CHCl3
(1:24) as eluent. 8R (less polar): IR (neat, cm-1) 3300, 1080;
1H NMR δ 3.51-3.69 (m, 2H), 3.79 (br s, 2H), 4.23 (br d, J )
4.1 Hz, 1H), 4.40-4.76 (m, 6H), 5.08 (d, J ) 5.1 Hz, 1H), 6.80
(s, 1H), 7.15-7.40 (m, 16H); HRMS (M+) 488.2309 calcd for
benzene (50 mL) was added Bu3P (0.92 mL, 3.47 mmol) at rt.
Then, TMAD (597 mg, 3.47 mmol) was added rapidly to the
mixture at ice bath temperature. After a few min, the reaction
mixture was warmed to rt and the stirring was continued for
16 h. The insoluble material was removed by filtration, and
the filtrate was condensed to give a residue, which was diluted
with EtOAc. The solution was washed with H2O (× 2) and
brine, dried, and evaporated. The residue was purified by
flash chromatography using EtOAc-hexane (8:2) for elution
to give 9â (1004 mg, 92%) and 9R (38 mg, 3.5%). 9â (less
polar): colorless oil; [R]D +52.3° (c ) 3.08, CHCl3); IR (neat,
C29H32N2O5, found 488.2306. 8S (more polar): IR (neat, cm-1
)
3250, 1090; 1H NMR δ 3.56 (dd, J ) 6.0, 9.8 Hz, 1H), 3.65 (dd,
J ) 3.0, 9.8 Hz, 1H), 3.77 (dd, J ) 2.3, 7.9 Hz, 1H), 4.11 (m,
1H), 4.16 (dd, J ) 2.3, 6.2 Hz, 1H), 4.35-4.66 (m, 6H), 5.06
(d, J ) 5.8 Hz, 1H), 6.77 (s, 1H), 7.13-7.40 (m, 16H); HRMS
(M+) 488.2309 calcd for C29H32N2O5, found 488.2300.
1
cm-1) 3280, 1210; H NMR δ 3.68 (dd, J ) 1.9, 10.4 Hz, 1H),
3.95 (overlapped, 2H), 4.14 (dd, J ) 4.8, 7.2 Hz, 1H), 4.31 (dt,
J ) 7.2, 2.1 Hz, 1H), 4.34-4.74 (m, 6H), 5.21 (d, J ) 2.4 Hz,
1H), 6.78 (s, 1H), 6.83 (s, 1H), 7.15-7.50 (m, 15H); 13C NMR
δ 69.1, 72.1, 73.6, 76.9, 77.2, 80.2, 80.3, 120.1, 127.9-128.7,
135.0, 137.4-137.8; HRMS (M+) 470.2204 calcd for C29H30N2O4,
Eth yl 4-(2,3,5-Tr i-O-ben zyl-â-D-r ibofu r an osyl)im idazole-
1-ca r boxyla te (10â). (A) Mitsu n obu Cycliza tion u sin g
DEAD a n d P h 3P . To a stirred solution of the epimeric
mixture of 8RS (1.92 g, 3.93 mmol) and Ph3P (2.68 g, 10.2
mmol) in THF (40 mL) at rt was added dropwise over 10 min
a solution of DEAD (1.33 mL, 8.66 mmol) in THF (3 mL). The
reaction mixture was stirred at rt for 2 h. The solvent was
evaporated to give a residual oil, which was chromatographed
[EtOAc-benzene (1:9)] to give a crude oil that solidified on
standing. This was recrystallized from hexane for single-
crystal X-ray analysis11 to give 10â (320 mg, 15%) as colorless
needles: mp 71-73 °C; [R]D -1.27° (c ) 1.09, CHCl3); IR
found 470.2209. 9R (more polar): colorless oil; IR (neat, cm-1
)
1
3300, 1220; H NMR δ 3.54 (dd, J ) 3.7, 10.6 Hz, 1H), 3.59
(dd, J ) 3.8, 10.6 Hz, 1H), 4.21 (t, J ) 4.8 Hz, 1H), 4.31 (m,
2H), 4.36-4.71 (m, 6H), 5.27 (d, J ) 5.4 Hz, 1H), 7.09 (s, 1H),
7.10-7.39 (m, 15H), 7.54 (s, 1H); 13C NMR δ 70.4, 73.0, 73.6,
74.0, 78.5, 79.4, 80.9, 125.8, 127.7-129.2, 135.4, 137.3-138.0;
HRMS (M+) 470.2204 calcd for C29H30N2O4, found 470.2202.
4(5)-(â-D-Ribofu r a n osyl)im id a zole (1). A solution of 9â
(295 mg, 0.63 mmol) in EtOH (60 mL) was hydrogenated over
10% Pd on carbon (255 mg) at 4.0 kg/cm2 for 14 h. After
filtration through Celite, the filtrate was evaporated to give a
residue, which was purified by column chromatography
[MeOH-EtOAc (3:7)] to give a white amorphous product 1 (125
mg, quantitative): [R]D -30.2° (c ) 1.67, MeOH); IR (Nujol,
cm-1) 3400; 1H NMR (CD3OD) δ 3.72 (dd, J ) 3.5, 12.3 Hz,
1H), 3.80 (dd, J ) 3.5, 12.3 Hz, 1H), 3.98-4.19 (m, 3H), 4.83
(d, J ) 6.9 Hz, 1H), 7.58 (s, 1H), 8.87 (s, 1H); 13C NMR (CD3-
OD) δ 63.2, 72.7, 77.2, 77.5, 87.5, 118.1, 135.3, 136.2; HRMS
(M+) 200.0796 calcd for C8H12N2O4, found 200.0800.
1
(Nujol, cm-1) 1750; H NMR δ 1.41 (t, J ) 7.5 Hz, 3H), 3.61
(dd, J ) 4.6, 10.6 Hz, 1H), 3.71 (dd, J ) 4.6, 10.6 Hz, 1H),
4.04 (t, J ) 6.1 Hz, 1H), 4.21 (t, J ) 5.0 Hz, 1H), 4.33 (m, 1H),
4.38-4.64 (m, 8H), 5.08 (d, J ) 4.6 Hz, 1H), 7.26-7.32 (m,
15H), 7.41 (s, 1H), 8.10 (s, 1H); 13C NMR δ 14.2, 64.4, 70.1,
72.0, 73.3, 77.5, 78.2, 80.4, 80.9, 115.2, 127.5-128.3, 137.2-
138.3, 142.7, 148.5; HRMS (M+) 542.2415 calcd for C32H34N2O6,
found 542.2428. Anal. Calcd for C32H34N2O6‚1/2H2O: C,
69.47; H, 6.40; N, 5.08. Found: C, 69.26; H, 6.31; N, 5.29.
(B) The mixture of 8RS (2.45 g, 5.02 mmol), TMAD (1.04 g,
6.02 mmol), and Bu3P (1.60 mL, 6.02 mmol) was treated
overnight in benzene (90 mL) to give a crude oil 9 (3.76 g).
The solution of 9 obtained in benzene (40 mL) was refluxed
with ethyl chloroformate (0.48 mL, 5.02 mmol) and pyridine
(0.32 mL, 4.02 mmol) for 15 min. The standard workup and
purification gave 10â (2.34 g, 86%).
Eth yl 4-(â-D-Ribofu r an osyl)im idazole-1-car boxylate (3).
A mixture of 10â (1.73 g, 3.19 mmol), 20% Pd(OH)2-C (1.13 g),
and cyclohexene (29 mL, 288 mmol) in EtOH (100 mL) was
refluxed for 9 h. After filtration through Celite, the filtrate
was evaporated to give a residue which was purified by column
chromatography [MeOH-EtOAc (3:17)] to give 3 (845 mg,
97%) as a pale yellow oil; IR (neat, cm-1) 3340, 1760; 1H NMR
(CD3OD) δ 1.43 (t, J ) 7.5 Hz, 3H), 3.65 (dd, J ) 4.3, 12.3 Hz,
1H), 3.81 (dd, J ) 3.1, 12.3 Hz, 1H), 3.95 (m, 1H), 4.12 (m,
2H), 4.49 (q, J ) 7.5 Hz, 2H), 4.72 (m, 1H), 7.61 (s, 1H), 8.28
(s, 1H); HRMS (M+) 272.1007 calcd for C11H16N2O6, found
272.1021.
1-Acetyl-4(5)-(1,2,3,4,5-p en ta -O-a cetyl-D-r ibosyl)im id a -
zoles (11R a n d 11S). (A) A solution of 8R (490 mg, 1.00
mmol) in EtOH (50 mL) was hydrogenated over 10% Pd on
carbon (355 mg) at 4.1 kg/cm2 for 19 h. After filtration through
Celite, the filtrate was concentrated to give an amorphous
(C) A solution of 9â (577 mg, 1.23 mmol), pyridine (129 µL,
1.60 mmol), ethyl chloroformate (117 µL, 1.23 mmol), and a
catalytic amount of 4-DMAP in benzene (50 mL) was stirred
at rt for 30 min. After addition of H2O (1 mL), the solvent
was evaporated, and the residue was extracted with EtOAc.
The extract was washed with brine, dried, and evaporated.
The residual oil was purified by flash chromatography using
EtOAc-hexane (3:7) for elution to give 10â (637 mg, 96%).
4(5)-(2,3,5-Tr i-O-ben zyl-D-r ibofu r a n osyl)im id a zole (9â
a n d 9r). To a solution of 8RS (1.13 g, 2.32 mmol) in dry

4410 J . Org. Chem., Vol. 61, No. 13, 1996
Harusawa et al.
material (245 mg). This was stirred with acetic anhydride (1.0
mL, 10.6 mmol) in pyridine (2.0 mL) at rt for 15 h. Ice was
added to the mixture, and the stirring was continued for 1 min.
The resulting mixture was dissolved in EtOAc-hexane-H2O
(5:3:1) (20 mL), and the organic layer was washed with H2O
and brine, dried, and evaporated. The residue was purified
by column chromatography [EtOAc-hexane (3:2)] to give 11R
Hz, 1H), 4.18 (m, 1H), 4.27 (m, 1H), 5.16 (dd, J ) 6.0, 10.3
Hz, 1H), 7.20-7.40 (m, 10H), 7.92 (s, 1H); MS m/ z (M+) 442.
Anal. Calcd for C23H26N2O5S: C, 62.43; H, 5.92; N, 6.33.
Found: C, 62.40; H, 5.88; N, 6.26. 16R (more polar): oil; [R]D
1
+52.4° (c ) 1.1, CHCl3); IR (neat, cm-1) 1372, 1175; H NMR
δ 2.33 (ddd, J ) 4.0, 6.5, 14.0 Hz, 1H), 2.68 (dt, J ) 14.0, 7.0
Hz, 1H), 3.12 (s, 3H), 3.60 (d, J ) 5.0 Hz, 2H), 4.22 (m, 1H),
4.34 (m, 1H), 4.48 (d, J ) 2.5 Hz, 2H), 4.59 (s, 2H), 5.18 (t, J
) 6.5 Hz, 1H), 7.20-7.42 (m, 10H), 7.90 (s, 1H); HRMS (M+)
442.1561 calcd for C23H26N2O5S, found 442.1558.
1
(171 mg, 36%) as a pale yellow oil: IR (neat, cm-1) 1740; H
NMR δ 2.03-2.09 (m, 15H), 2.60 (s, 3H), 4.11 (dd, J ) 7.1,
12.2 Hz, 1H), 4.32 (dd, J ) 3.5, 12.2 Hz, 1H), 5.17 (quint, J )
3.7 Hz, 1H), 5.35 (dd, J ) 4.4, 6.7 Hz, 1H), 5.61 (dd, J ) 4.3,
6.7 Hz, 1H), 6.04 (d, J ) 5.0 Hz, 1H), 7.46 (s, 1H), 8.07 (s,
1H); HRMS (M+) 471.1613 calcd for C20H27N2O11, found
471.1615.
Eth yl 4(5)-(3,5-Di-O-ben zyl-2-d eoxy-â-D-r ibofu r a n osyl)-
im id a zole-1-ca r boxyla te (17â). To a solution of 14RS (8.08
g, 21.2 mmol) in dry benzene (250 mL) was added Bu3P (6.85
mL, 27.46 mmol) at ice bath temperature. TMAD (4.73 g,
27.46 mmol) was added in two portions to the mixture at the
same temperature. The resulting mixture was stirred at rt
for 14 h. The insoluble material was filtered through Celite,
and the filtrate was condensed. The resulting crude oil was
diluted with EtOAc, and the organic layer was washed with
H2
(B) By the same procedure as above, 8S (240 mg, 0.49 mmol)
was converted to 11S (54 mg, 23%): IR (neat, cm-1) 1740; 1H
NMR δ 2.04-2.10 (m, 15H), 2.60 (s, 3H), 4.09 (dd, J ) 6.6,
12.0 Hz, 1H), 4.42 (dd, J ) 2.8, 12.0 Hz, 1H), 5.27-5.41 (m,
2H), 5.70 (t, J ) 6.0 Hz, 1H), 5.97 (d, J ) 6.0 Hz, 1H), 7.49 (s,
1H), 8.06 (s, 2H); HRMS (M+) 471.1613 calcd for C20H27N2O11
found 471.1614.
,
O (× 3) and brine, dried, and evaporated. The obtained oil
was dissolved in benzene (150 mL) containing pyridine (2.05
mL, 25.35 mmol), ethyl chloroformate (2.42 mL, 25.35 mmol)
was added slowly at 0 °C to the solution, and the whole was
subsequently stirred at rt for 20 min. After addition of H2O
followed by evaporation of the benzene, the resulting residue
was extracted with EtOAc. The extract was washed with H2O
and brine, dried, and evaporated to give a crude oil, which was
purified by flash chromatography using EtOAc-hexane for
elution [EtOAc-hexane (3:7 to 4:6)] to give 17â (6.65 g, 72.1%)
as a pale yellow oil: [R]D -1.28° (c ) 10.45, CHCl3); IR (neat,
cm-1) 1760; 1H NMR δ 1.42 (t, J ) 7.2 Hz, 3H), 2.22 (ddd, J )
6.2, 10.3, 13.8 Hz, 1H), 2.36 (ddd, J ) 2.1, 5.8, 13.8 Hz, 1H),
3.52 (dd, J ) 6.2, 10.3 Hz, 1H), 3.64 (dd, J ) 4.7, 10.3 Hz,
1H), 4.17 (dt, J ) 6.0, 2.3 Hz, 1H), 4.25 (m, 1H), 4.46 (q, J )
7.2 Hz, 2H), 4.56 (d, J ) 3.5 Hz, 4H), 5.14 (dd, J ) 5.8, 10.3
Hz, 1H), 7.22-7.42 (m, 10H), 8.10 (d, J ) 1.0 Hz, 1H); HRMS
(M+) 436.1997 calcd for C25H28N2O5, found 436.1996.
2-(ter t-Bu tyld im eth ylsilyl)-5-(2-d eoxy-3,5-d i-O-ben zyl-
D-r ibosyl)-N,N-d im eth ylim id a zole-1-su lfon a m id es (13R
a n d 13S). To a solution of 2-(tert-butyldimethylsilyl)-N,N-
dimethylimidazole-1-sulfonamide9a (3.855 g, 13.34 mmol) in
THF (100 mL) was added dropwise at -50 °C 1.6 M BuLi in
hexane (8.34 mL, 13.34 mmol), and the mixture was stirred
for 20 min at the same temperature. A solution of 12 (1.676
g, 5.34 mmol) in THF (20 mL) was added slowly. The dry ice
bath was removed, and the reaction mixture was stirred at rt
for 1 h. The mixture was then treated as described for the
preparation of 7RS to give a ca. 1:1 mixture of a 13R and 13S
(3.191 g, 99%), which were partially isolated by column
chromatography [EtOAc-hexane (1:2)]. 13S22 (less polar):
pale yellow oil; IR (neat, cm-1) 3320, 1390; 1H NMR δ 0.40 (s,
6H), 1.00 (s, 9H), 2.11 (m, 2H), 2.70 (s, 6H), 3.34 (br s, 1H),
3.62 (m, 2H), 3.90 (m, 1H), 4.03 (m, 1H), 4.57 (s, 2H), 4.65
(dd, J ) 11.1, 22.7 Hz, 2H), 5.18 (br t, J ) 6.1 Hz, 1H), 7.20
(s, 1H), 7.25-7.45 (m, 10H). 13R (more polar): pale yellow
Eth yl 4(5)-(2-Deoxy-â-D-r ibofu r a n osyl)im id a zole-1-ca r -
boxyla te (4). A mixture of 17â (7.52 g, 17.23 mmol), 20%
Pd(OH)2-C (3.50 g), and cyclohexene (175 mL, 1.72 mol) in
EtOH (200 mL) was refluxed for 6 h to give 422 (4.40 g,
quantitative) by the same procedure for the preparation of 3:
1
oil; IR (neat, cm-1) 3400, 1370; H NMR δ 0.40 (s, 6H), 1.00
(s, 9H), 2.24 (m, 2H), 2.73 (s, 6H), 3.60 (dd, J ) 5.5, 10.1 Hz,
1H), 3.68 (dd, J ) 3.5, 10.1 Hz, 1H), 3.78 (m, 1H), 4.04 (m,
1H), 4.55 (d, J ) 6.0 Hz, 4H), 5.20 (t, J ) 5.5 Hz, 1H), 7.23-
7.44 (m, 11H); HRMS (SIMS/M+ + 1) 604.2874 calcd for
C30H46N3O6SSi, found 604.2888.
1
[R]D +14.4° (c ) 1.7, MeOH); IR (neat, cm-1) 3350, 1762; H
NMR (CD3OD) δ 1.43 (t, J ) 7.1 Hz, 3H), 2.03-2.24 (m, 2H),
3.60 (dd, J ) 4.9, 11.9 Hz, 1H), 3.68 (dd, J ) 3.9, 11.9 Hz,
1H), 3.92 (td, J ) 4.9, 2.6 Hz, 1H), 4.36 (dt, J ) 5.1, 2.6 Hz,
1H), 4.49 (q, J ) 7.1 Hz, 2H), 5.11 (dd, J ) 2.2, 3.4 Hz, 1H),
7.57 (s, 1H), 8.26 (s, 1H); 13C NMR (CD3OD) δ 150.1, 145.0,
139.2, 116.0, 89.6, 75.6, 74.5, 66.3, 64.4, 42.7, 14.8.
4(5)-(2-D e o x y -3,5-d i-O -b e n zy l-D-r ib o s y l)im id a zo le
(14RS). A mixture of 13RS (136 mg, 0.23 mmol) in THF (1.5
mL) and 1.5 N HCl (6.0 mL) was refluxed for 1 h as described
for the preparation of 8RS to give 14RS (81 mg, 92%) as an
oil: 1H NMR δ 2.10 (m, 2H), 3.60 (br s, 2H), 3.82 (m, 1H), 3.96
(m, 1H), 4.41-4.62 (m, 4H), 4.93 (m, 1H), 6.64 (s, 1H), 7.17-
7.40 (m, 11H); HRMS (SIMS/M+ + 1) 383.1969 calcd for
C22H27N2O4, found 383.1964.
4(5)-(3,5-Di-O-ben zyl-2′-d eoxy-D-r ibofu r a n osyl)-1H-im i-
d a zoles (15â a n d 15r). (A) A solution of 16â (758 mg, 1.7
mmol) in THF (5 mL) was refluxed with 1.5 N HCl (20 mL)
for 1 h as described in previous experimental procedures to
give 15â (619 mg, quantitative) as an oil: 1H-NMR δ 2.20 (ddd,
J ) 5.6, 9.0, 13.1 Hz, 1H), 2.35 (ddd, J ) 2.6, 6.6, 13.1 Hz,
1H), 3.64 (dd, J ) 3.6, 10.9 Hz, 1H), 3.73 (dd, J ) 4.1, 10.9
Hz, 1H), 4.23 (m, 2H), 4.47-4.63 (m, 4H), 5.24 (dd, J ) 6.6,
[4(5)-(3,5-Di-O-ben zyl-2-d eoxy-D-r ibofu r a n osyl)im id a -
zolyl]m eth yl Su lfon es (16â a n d 16r). A mixture of 14RS
(184 mg, 0.48 mmol), Bu3P (194 mg, 0.96 mmol), and TMAD
(165 mg, 0.96 mmol) in benzene (17 mL) was stirred at rt for
18 h. The mixture was diluted with hexane and allowed to
stand for 0.5 h. The insoluble material was removed by
filtration, and the filtrate was concentrated to give a crude
oil, which was purified by column chromatography (EtOAc)
to give a ca. 5:1 mixture of 15â and 15R. The obtained oil
was treated with MeSO2Cl (82 mg, 0.72 mmol) in pyridine (3
mL) for 2 h at rt. After addition of cold H2O, the mixture was
extracted with a mixture of EtOAc-hexane (1:1), and the
extract was washed with brine, dried, and evaporated. The
residue was purified by column chromatography to give 16â
[EtOAc-hexane (3:7)] (124 mg, 59%) and 16R [EtOAc-hexane
(6:4)] (24 mg, 11%). 16â (less polar): colorless needles
(EtOAc-hexane); mp 97 °C; [R]D +0.79° (c ) 0.38, CHCl3); IR
9.0 Hz, 1H), 6.88 (s, 1H), 7.23 (s, 1H), 7.28-7.45 (m, 10H); 13
C
NMR δ 138.5, 138.1, 136.7, 135.7, 129.2, 129.0, 128.6, 128.2,
120.2, 83.6, 81.2, 74.1, 74.0, 71.6, 39.1; HRMS (SIMS/M+ + 1)
365.1864 calcd for C22H25N2O3, found 365.1866.
(B) By the same procedure as above, 16R (19 mg, 0.04 mmol)
was converted to 15R (14 mg, quantitative): oil; 1H NMR δ
2.19 (ddd, J ) 2.7, 3.6, 14.5 Hz, 1H), 2.60 (ddd, J ) 6.4, 9.1,
14.5 Hz, 1H), 3.47 (dd, J ) 5.5, 10.5 Hz, 1H), 3.59 (dd, J )
5.1, 10.5 Hz, 1H), 4.27 (dt, J ) 6.4, 2.0 Hz, 1H), 4.41 (td, J )
5.1, 2.0 Hz, 1H), 4.56 (s, 2H), 4.60 (d, J ) 2.4 Hz, 2H), 5.29
(dd, J ) 3.6, 9.1 Hz, 1H), 6.98 (s, 1H), 7.28-7.42 (m, 4H), 7.44
(s, 1H); 13C NMR 138.5, 137.8, 136.0, 134.6, 129.2, 129.0, 128.7,
128.5, 128.3, 128.2, 124.0, 83.4, 81.8, 73.9, 73.2, 72.0, 71.2, 37.6;
HRMS (SIMS/M+ + 1) 365.1864 calcd for C22H25N2O3, found
365.1865.
1
(KBr, cm-1) 1382, 1175; H NMR δ 2.19 (ddd, J ) 6.0, 10.3,
12.8 Hz, 1H), 2.39 (ddd, J ) 2.6, 6.0, 12.8 Hz, 1H), 3.22 (s,
3H), 3.54 (dd, J ) 5.1, 10.0 Hz, 1H), 3.62 (dd, J ) 5.1, 10.0
4(5)-(2-Deoxy-â-r ibofu r a n osyl)-1H-im id a zole (2). (A) To
a solution of 15â (57 mg, 0.16 mmol) in CH2Cl2 (18 mL) was
added dropwise a solution of 1 M BCl3 in CH2Cl2 (0.7 mL. 0.7
mmol) at -70 °C. After being stirred for 75 min at -70 °C,
(22) The expected MS peaks were not obtained because of thermal
instability.

Synthesis of 4-Substituted Imidazoles
J . Org. Chem., Vol. 61, No. 13, 1996 4411
the mixture was diluted with dry MeOH/CH2Cl2 (1:1, 7 mL)
and then neutralized with powder NaHCO3 at rt. The result-
ing mixture was filtered through Celite, and the filtrate was
evaporated to give a syrup, which was purified by flash
chromatography using 15% MeOH in EtOAc as the eluent to
give a white solid of 2 (27 mg, 94%): colorless prisms from
MeOH-CHCl3; mp 164-166 °C; [R]D +24.0° (c ) 1.0, MeOH);
(5 mg, 12%) as an oil, together with the recovery of 13S (26
mg, 65%): 1H NMR δ 0.40 (s, 6H), 1.00 (s, 9H), 2.02-2.18 (m,
1H), 2.45 (dd, J ) 4.1, 14.2 Hz, 1H), 2.88 (s, 6H), 3.48 (dd, J
) 5.1, 10.1 Hz, 1H), 3.57 (dd, J ) 5.1, 10.1 Hz, 1H), 4.15 (m,
1H), 4.55 (s, 4H), 5.32 (dd, J ) 4.6, 10.1 Hz, 1H), 7.20-7.40
(m, 11H).
(B) By the same procedure as above, 13R (43 mg, 0.07 mmol)
was converted into 19R (3 mg, 7%) as an oil, together with
the recovery of 13R (29 mg, 67%): 1H NMR δ 0.38 (s, 6H),
1.00 (s, 9H), 2.12-2.30 (m, 1H), 2.65 (dt, J )14.2, 7.1 Hz, 1H),
2.80 (s, 6H), 3.48-3.60 (m, 2H), 4.10-4.28 (m, 2H), 4.44-4.62
(m, 4H), 5.37 (t, J ) 7.1 Hz, 1H), 7.23-7.40 (m, 11H).
5-(2-Deoxy-3,5-d i-O-b en zyl-D-r ib ofu r a n osyl)-N,N-d i-
m eth ylim id a zole-1-su lfon a m id e (20â a n d 20r). (A) A
mixture of 18S (99 mg, 0.20 mmol), TMAD (69 mg, 0.40 mmol),
and Bu3P (87 mg, 0.40 mmol) in benzene (5 mL) was stirred
for 18 h at rt to give 20â (88 mg, 94%) as an oil: 1H NMR δ
2.12 (ddd, J ) 5.6, 10.3, 13.3 Hz, 1H), 2.47 (ddd, J ) 1.9, 5.3,
13.3 Hz, 1H), 2.92 (s, 6H), 3.49 (dd, J ) 4.7, 10.8 Hz, 1H),
3.58 (dd, J ) 5.2, 10.8 Hz, 1H), 4.11-4.25 (m, 2H), 4.47-4.63
(m, 4H), 5.38 (dd, J ) 5.6, 10.3 Hz, 1H), 7.10 (s, 1H), 7.20-
7.41 (m, 10H), 7.93 (s, 1H).
1
IR (neat, cm-1) 3700-2200, 1082, 1028; the H and 13C NMR
spectra were in agreement with those of the previous report;6
1H NMR (CD3OD) δ 2.09 (ddd, J ) 1.9, 5.7, 13.0 Hz, 1H), 2.24
(ddd, J ) 5.6, 10.6, 13.0 Hz, 1H), 3.60 (dd, J ) 4.6, 11.1 Hz,
1H), 3.68 (dd, J ) 4.6, 11.1 Hz, 1H), 3.90 (td, J ) 4.6, 2.4 Hz,
1H), 4.36 (dt, J ) 5.6, 1.9 Hz, 1H), 5.16 (dd, J ) 5.7, 10.6 Hz,
1H), 7.07 (s, 1H), 7.67 (s, 1H); 13C NMR (CD3OD) d 139.7,
137.1, 118.1, 89.4, 75.4, 74.5, 64.3, 42.9. Anal. Calcd for
C8H12N2O3: C, 52.17; H, 6.57; N, 15.21. Found: C, 51.72; H,
6.36; N, 15.07.
(B) The mixture of 4 (191 mg, 0.75 mmol) and NH2NH2‚H2O
(0.04 mL, 0.75 mmol) in EtOH (5 mL) was refluxed for 1 h.
The solvent was evaporated to give a residue, which was
purified by the same procedure as above to give 2 (124 mg,
90%).
5-(2-Deoxy-3,5-d i-O-ben zyl-D-r ibosyl)-N,N-d im eth ylim -
id a zole-1-su lfon a m id e (18S a n d 18R). (A) To a solution of
13S (132 mg, 0.22 mmol) in THF (5 mL) was added a 1 M
solution of a Bu4NF (0.22 mL, 0.22 mmol) at 0 °C. The mixture
was stirred at 0 °C for 15 min and then at rt for 45 min. Ice
was added to the mixture, and the THF was evaporated to
give a crude oil, which was extracted with EtOAc. The extract
was washed with brine, dried, and evaporated. The residue
was purified by column chromatography [EtOAc-hexane (8:
(B) By the same procedure as above, 18R (137 mg, 0.28
mmol) was converted into 20R (116 mg, 88%) as an oil: 1H NMR
δ 2.24 (ddd, J ) 5.2, 6.5, 13.0 Hz, 1H), 2.65 (dt, J ) 13.0, 7.4
Hz, 1H), 2.88 (s, 6H), 3.57 (m, 2H), 4.12-4.28 (m, 2H), 4.46-
4.52 (m, 4H), 5.44 (t, J ) 7.4 Hz, 1H), 7.25 (s, 1H), 7.25-7.40
(m, 10H), 7.91 (s, 1H).
Ack n ow led gm en t. We are grateful to Shionogi
Research Laboratories, Shionogi & Co., Ltd., for anti-
viral and anticancer assays.
1
2)] to give 18S22 (107 mg, quantitative) as an oil: H NMR δ
2.15 (dd, J ) 5.0, 7.6 Hz, 2H), 2.80 (s, 6H), 3.63 (m, 2H), 3.89
(q, J ) 5.0 Hz, 1H), 4.04 (m, 1H), 4.59 (s, 2H), 4.63 (dd, J )
11.1, 20.2 Hz, 2H), 5.17 (dd, J ) 5.0, 7.6 Hz, 1H), 7.07 (s, 1H),
7.28-7.43 (m, 10H), 7.88 (s, 1H).
(B) By the same procedure as above, 13R (188 mg, 0.31
mmol) was converted into 18R22 (145 mg, 95%): 1H NMR δ 2.21
(t, J ) 6.0 Hz, 2H), 2.84 (s, 6H), 3.62 (m, 2H), 3.80 (q, J ) 6.0
Hz, 1H), 4.06 (m, 1H), 4.56 (s, 4H), 5.20 (dd, J ) 6.0, 7.6 Hz,
1H), 7.25-7.45 (m, 10H), 7.89 (s, 1H).
2-(ter t-Bu tyld im eth ylsilyl)-5-(2-d eoxy-3,5-d i-O-ben zyl-
D-r ib o fu r a n o s y l)-N ,N -d im e t h y lim id a z o le -1-s u lfo n -
a m id e (19â a n d 19r). (A) A mixture of 13S (40 mg, 0.07
mmol), TMAD (24 mg, 0.14 mmol), and Bu3P (30 mg, 0.14
mmol) in benzene (3 mL) was stirred for 18 h at rt to give 19â
Su p p or tin g In for m a tion Ava ila ble: Copies of spectra for
the following compounds: 1NMR 1-4, 7RS, 8R/S, 9R/â, 10â,
11R/S, 13R/S, 14RS, 15R/â, 16R/â, 17â, 18R/S, 19R/â, and
20R/â; 13C NMR 1, 2 , 4, 9â, 10â, and 15R/â; 1H-13C shift-
correlated 2-D NMR 9R/â and 10â; DEPT-NMR 9R/â, 10â.
ORTEP plots for 10 â (40 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 O952136Z