Synthesis of 4(5)-[5-(Aminomethyl)tetrahydrofuran-2-yl- Or 5-(Aminomethyl)-2,5-dihydrofuran-2-yl]imidazoles by Efficient Use of a PhSe Group: Application to Novel Histamine H3-Ligands1

Article abstract of DOI:10.1021/jo9910637

(+)-4(5)-[(2R,5S)-(5-Aminomethyl)tetrahydrofuran-2-yl]imidazole 1 and its C2′ epimer (-)-2, which are the 5′-amino derivatives of a novel imidazole C-nucleoside, were synthesized via Β- and α-2′-phenylselenenyl nucleosides 15 and 16. The anomers 15 and 16 were provided by a new synthetic method for C-nucleosides via the elimination of PhSeCl and selenocyclization from diol intermediates 12 and 14, starting from L-glutamic acid. Their ent-1 and ent-2 (imifuramine), the latter of which was indicated as a novel type of histamine H₃-agonist confirmed by an in vivo brain microdialysis method, were synthesized by the same methodology from D-glutamic acid. The four isomers (3, 4, ent-3, and ent-4) of a 4(5)-[(5-aminomethyl)-2,5-dihydrofuran-2-yl]imidazole were also synthesized via the oxidative elimination of the PhSe group of the key intermediates (15, 16, ent-15, and ent-16). In connection with this study, 4(5)-(5-aminomethylfuran-2-yl)-1H-imidazole (5) was also synthesized starting from D-ribose.

Full text of DOI:10.1021/jo9910637

8608
J . Org. Chem. 1999, 64, 8608-8615
Syn th esis of 4(5)-[5-(Am in om eth yl)tetr a h yd r ofu r a n -2-yl- or
5-(Am in om eth yl)-2,5-d ih yd r ofu r a n -2-yl]im id a zoles by Efficien t Use
of a P h Se Gr ou p : Ap p lica tion to Novel Hista m in e H3-Liga n d s1
Shinya Harusawa,† Tomonari Imazu,† Seiichiroh Takashima,† Lisa Araki,† Hirofumi Ohishi,†
Takushi Kurihara,*,† Yasuhiko Sakamoto,‡ Yumiko Yamamoto,§ and Atsushi Yamatodani§
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, J apan,
R&D Division, AZWELL, Inc., 2-24-3, Sho, Ibaraki, Osaka 567-0806, J apan, and School of Allied Health
Sciences, Faculty of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, J apan
Received J uly 2, 1999
(+)-4(5)-[(2R,5S)-(5-Aminomethyl)tetrahydrofuran-2-yl]imidazole 1 and its C2′ epimer (-)-2, which
are the 5′-amino derivatives of a novel imidazole C-nucleoside, were synthesized via â- and R-2′-
phenylselenenyl nucleosides 15 and 16. The anomers 15 and 16 were provided by a new synthetic
method for C-nucleosides via the elimination of PhSeCl and selenocyclization from diol intermediates
12 and 14, starting from L-glutamic acid. Their ent-1 and ent-2 (imifuramine), the latter of which
was indicated as a novel type of histamine H3-agonist confirmed by an in vivo brain microdialysis
method, were synthesized by the same methodology from D-glutamic acid. The four isomers (3, 4,
ent-3, and ent-4) of a 4(5)-[(5-aminomethyl)-2,5-dihydrofuran-2-yl]imidazole were also synthesized
via the oxidative elimination of the PhSe group of the key intermediates (15, 16, ent-15, and ent-
16). In connection with this study, 4(5)-(5-aminomethylfuran-2-yl)-1H-imidazole (5) was also
synthesized starting from D-ribose.
The histamine H3(H3) receptors2 exist at the varicosi-
tissues. Since the first H3-agonist (R)-R-methylhistamine2
was shown to possess inhibitory action against airway
smooth muscle contraction,9,10 the H3-agonists are re-
garded as a target for new therapeutics of bronchial
asthma.11 Besides (R)-R-methylhistamine, imetit and
immepip, which are potent and selective agonists for the
H3-receptors, have been extensively used as a pharma-
cological tool.4
ties and endings of the histaminergic fibers in the brain
and modulate the synthesis and release of histamine as
an autoreceptor.3 Moreover, H3-receptors have been
shown to be heteroreceptors4d that modulate the release
of a number of different neurotransmitters.4 Therefore,
histamine neurons play an important role in the arousal,
learning, and memory mechanisms, working together
with other neuromodulatory systems.5-8 H3-antagonists
are now expected to be potential drugs for memory
degenerative disorders such as Alzheimer’s disease.4 This
type of receptor can be also found in many peripheral
* Tel: +81-726-90-1087. Fax: +81-726-90-1086. E-mail: kurihara@
oysun01.oups.ac.jp.
† Osaka University of Pharmaceutical Sciences.
‡ AZWELL, Inc.
Theoretical calculations of histamine or some H3-
agonists have emphasized the importance of an intramo-
lecular hydrogen bonding between the cationic primary
§ Osaka University.
(1) Preliminary communication: Harusawa, S.; Imazu, T.; Takash-
ima, S.; Araki, L.; Ohishi, H.; Kurihara, T.; Yamamoto, Y.; Yamatodani,
A. Tetrahedron Lett. 1999, 40, 2561.
1
amine and the N atom of the imidazole.12,13 The H NMR
study on putative intramolecular hydrogen bonding for
two H3-agonists was recently reported.14 However, the
function of the intramolecular hydrogen bonding for
activation of the H3-receptor has not been experimentally
demonstrated. On the other hand, 2-(1H-imidazol-4-yl)-
cyclopropylamine (cyclopropylhistamine) has been re-
ported as a H3-agonist in a patent application by Arrang
et al.15 Unfortunately, the stereochemical identity of the
(2) Arrang, J .-M.; Garbarg, M.; Schwartz, J .-C. Nature (London)
1983, 302, 837.
(3) Arrang, J .-M.; Garbag, M.; Lancelot, J .-C.; Lecomte, J .-M.;
Pollard, H.; Robba, M.; Schunack, W.; Schwartz, J .-C. Nature (London)
1987, 327, 117.
(4) For recent reviews on the medicinal chemistry and therapeutic
potentials of ligands of the histamine H3 receptor, see: (a) Schunak,
W. Actual. Chim. Ther. 1993, 20, 9. (b) Schunack, W.; Stark, H. Eur.
J . Drug Metab. Pharmacokinet. 1994, 19, 173. (c) Leurs, R.; Vollinga,
R. C.; Timmerman, H. Prog. Drug Res. 1995, 45, 107. (d) Schlicker,
E.; Malinowska, B.; Kathmann, M.; Go¨thert, M. Fundam Clin Phar-
macol. 1994, 8, 128. (e) Stark, H.; Schlicker, E.; Schunack, W. Drugs
Future 1996, 21, 507. (f) Leurs, R.; Blandina, P.; Tedford, C.; Timmer-
man, H. TiPS 1998, 19, 177.
(9) Ichinose, M.; Stretton, C. D.; Schwartz, J .-C.; Barnes P. J . Br.
J . Pharmacol. 1989, 97, 13.
(5) Wada, H.; Inagaki, N.; Yamatodani, A.; Watanabe, T. Trends
Neurosci. 1991, 14, 415.
(6) Schwartz, J . C.; Arrang, J . M.; Garbarg, M.; Pollard, H.; Ruat,
M. Physiol Rev. 1991, 71, 1.
(7) Yamatodani, A.; Inagaki, N.; Panula, P.; Itowi, N.; Watanabe,
T.; Wada, H. In Handbook of Experimental Pharmacology. Histamine
and Histamine antagonists; Uvna¨s, B., Ed.; Springer-Verlag: Berlin
and Heidelberg, 1991; Vol. 97, pp 243-283.
(8) Onodera, K.; Yamatodani, A.; Watanabe, T.; Wada, H. Prog
Neurobiol. 1994, 42, 685.
(10) Hey, J . A.; del Prado, M.; Egan, R. W.; Kreutner, W.; Chapman,
R. Eur. J . Phamacol. 1992, 211, 421.
(11) Shin, N.-Y.; Lupo, A. T., J r.; Aslanian, R.; Orlando, S.; Piwinski,
J . J .; Green, M. J .; Ganguly, A. K.; Clark, M. A.; Tozzi, S.; Kreutner,
W.; Hey, J . A. J . Med. Chem. 1995, 38, 1593.
(12) Nagy, P. I.; Durant, G. J .; Hoss, W. P.; Smith, D. A. J . Am.
Chem. Soc. 1994, 116, 4898.
(13) Mazurek, A. P.; Karpinska, G. Z. Naturforsch. 1994, 49c, 471.
(14) Kovalainen, J . T.; Christiaans, J . A. M.; Poso, A.; Vepsa¨la¨inen,
J .; Laatikainen, R.; Gynther, J . Tetrahedron Lett. 1999, 40, 2425.
10.1021/jo9910637 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/16/1999

Synthesis of Imidazole C-Nucleoside Derivatives by PhSe Groups
J . Org. Chem., Vol. 64, No. 23, 1999 8609
material tested was not reported. Recently, two groups16,17
independently reported the synthesis18 and evaluation
of the H3-agonistic activity of trans-cyclopropylhistamine.
Khan et al.16 determined that the trans-(1R,2R)-isomer
was 1 order of magnitude more active than the (1S,2S)-
isomer. Contrary to the results reported, Timmerman et
al.17 concluded that the (1S,2S)-isomer was about 10
times more active than its enantiomer.
As an outcome of the many structure-activity rela-
tionship studies in this drug discovery area,4 it has been
suggested that H3-receptor agonists exhibit three com-
mon and essential structural features: an imidazole
headgroup, a spacer, and an amino group. We recently
reported19,20 an efficient and stereoselective synthesis of
â-imidazole C-nucleosides bearing 4(5)-substituted imid-
azole as a common structural unit, using the Mitsunobu
cyclization. Hence, we became interested in the synthesis
of novel trans- and cis-2,5-disubstituted tetrahydrofurans
bearing imidazole and amino groups as an H3-receptor
activation model. We envisioned that, while the cis
isomer 1 or its enantiomer ent-1 could adopt a folded
conformation through intramolecular hydrogen bonding,
the trans isomer 2 or ent-2 would take an extended
conformation. The enhanced lipophilicity of these com-
pounds lacking the hydroxy groups in the sugar moiety
may also accentuate membrane permeability. Since only
a limited number of imidazole C-nucleosides and their
derivatives has been known so far,19,20 we first endeav-
ored to find a simple and efficient synthetic method of
2′,3′-dideoxyimidazole C-nucleosides to supply these com-
pounds for biological evaluation. We recently communi-
cated1 the synthesis of novel cis- and trans-4(5)-[5-
(aminomethyl)tetrahydrofuran-2-yl]imidazoles (1, 2) and
their enantiomers (ent-1, ent-2) using a synthetic method
characterized by use of a PhSe group for the formation
of the tetrahydrofuran ring. It is of particular interest
that the preliminary results of an in vivo brain microdi-
alysis23 indicated that, among them, only ent-(+)-2 (imi-
furamine) exhibited H3-agonistic activity. The activity of
imifuramine measured by the microdialysis was ap-
proximately equal to that of immepip.24 We now disclose
the details of the synthesis of the four isomers and
further report the synthesis of the four stereoisomers (3,
4, ent-3, and ent-4) of a novel 4(5)-[5-(aminomethyl)-2,5-
dihydrofuran-2-yl]imidazole and 4(5)-(5-aminomethylfu-
ran-2-yl)-1H-imidazole (5), which were conformationally
restricted due to a planar dihydrofuran and furan rings,
as part of our synthetic studies directed toward the
preparation of new H3 receptor ligands.
Resu lts
(S)-Benzyloxymethyl-γ-butyrolactone 6 was easily syn-
thesized from L-glutamic acid as described by Taniguchi
et al.25 Introduction of a phenylselenyl group into lactone
6 by the Chu procedure26 gave C2R-and C2â-selenolac-
tones 7 (52%) and 8 (30%) (Scheme 1). The poor R/â ratio
was not of consequence in this synthetic method, since
the two isomers could be favorably used as substrates
for key intermediates 15 and 16. Reduction of major
lactone 7 with diisobutylaluminum hydride (DIBAL) gave
lactol 9. The reaction of 9 with lithium salt 1119 of the
bis-protected imidazole resulted in a diol 12 (73%) with
a C1′S configuration, together with C1′ epimer 13 (10%).
The C1′ stereochemical assignments to 12 and 13,
respectively, were based on the analogy of our precedent.19b
(15) Arrang, J . M.; Garbarg, M.; Schunack, W.; Schwartz, J . C. Eur.
Patent Appl. 0214058, 1987.
(16) Khan, M. A.; Yates, S. L.; Tedford, C. E.; Kirschbaum, K.;
Philips, J . Bioorg. Med. Chem. Lett. 1997, 7, 3017.
(17) De Esch, I. J . P.; Vollinga, R. C.; Goubitz, K.; Schenk, H.;
Appelberg, U.; Hacksell, U.; Lemstra, S.; Zuiderveld, O. P.; Hoffmann,
M.; Leurs, R.; Menge, W. M. P. B.; Timmerman, H. J . Med. Chem.
1
In H NMR, their C1′ configurations were assigned by a
small J 1′,2′ coupling constant (2.7 Hz) of minor isomer 13
compared to that of 12 (5.9 Hz) having a 1′,2′-antiparallel
orientation. The anti selectivity for 12 may be accounted
for by a chelation-cyclic model as illustrated in Figure
1999, 42, 1115.
1.
(18) Khan et al. synthesized only trans-cyclopropylhistamine via
diastereoselective cyclopropanation, and the synthetic attempts for cis-
cyclopropylhistamine by Timmerman et al. were unsuccessful.
(19) (a) Harusawa, S.; Murai, Y.; Moriyama, H.; Ohishi, H.; Yoneda,
R.; Kurihara, T. Tetrahedron Lett. 1995, 36, 3165. (b) Harusawa, S.;
Murai, Y.; Moriyama, H.; Imazu, T.; Ohishi, H.; Yoneda, R.; Kurihara,
T. J . Org. Chem. 1996, 61, 4405.
(20) Harusawa, S.; Moriyama, H.; Murai, Y.; Imazu, T.; Ohishi, H.;
Yoneda, R.; Kurihara, T.; Hata, H.; Sakamoto, Y. Chem. Pharm. Bull.
1997, 45, 53.
When we next tried deprotection of the imidazole
moiety in the diol 12 in aqueous HCl-THF,19 â- and
(23) Mochizuki, T.; Yamatodani, A.; Okakura, K.; Takemura, M.;
Inagaki, N.; Wada, H. Naunyn Schmiedebergs Arch. Pharmacol. 1991,
343, 190.
(24) Yamamoto, Y.; Mochizuki, T.; Okakura-Mochizuki, K.; Uno, A.;
Yamatodani, A. Methods Find. Exp. Clin. Pharmacol. 1997, 19, 289.
(25) Taniguchi, M.; Koga, K.; Yamada, S. Tetrahedron 1974, 30,
3547.
(21) Lipp, R.; Arrang, J . M.; Garbarg, M.; Luger, P.; Schwartz, J .
C.; Schunack, W. J . Med. Chem. 1992, 35, 4434.
(22) Arrang, J . M.; Schwartz, J . C.; Schunack, W. Eur. J . Pharmacol.
1985, 117, 109.
(26) Beach, J . W.; Kim, H. O.; J eong, L. S.; Nampalli, S.; Islam, Q.;
Ahn, S. K.; Babu, J . R.; Chu, C. K. J . Org. Chem. 1992, 57, 3887.

8610 J . Org. Chem., Vol. 64, No. 23, 1999
Harusawa et al.
Sch em e 1a
a
Reagents: (a) (i) LHMDS, TMSCl; (ii) PhSeBr; (b) DIBAL (c) (i) 11; (d) (i) aqueous 1.5 N HCl-THF; (ii) benzene, reflux, Dean-Stark
water separator; yields 15 (42%), 16 (56%) from 12; 15 (35%), 16 (53%) from 14.
R-anomers 15 and 16 through selenium-induced cycliza-
tion at both faces of the double bond of 17. This is well
supported by the fact that the reaction of the 17 with
PhSeCl smoothly proceeded to give 15 (31%) and 16 (55%)
in refluxing THF. Although such cyclization appears to
be inconsistent with Baldwin’s protocol,27 being formally
a 5-endo-trig process, it may be explained by the fact that
F igu r e 1. Anti selectivity for 12 by a chelation-cyclic model.
this is an electrophile-driven rather than a nucleophile-
driven cyclization.28 In the case of the epimeric diol 13
Sch em e 2
having a 1′,2′-syn configuration, the cyclization did not
proceed under refluxing HCl-THF, and only a linear diol
having unsubstituted imidazole resulted.
The minor lactone 8 effectively supplied â anomer 15
and R anomer 16 by a parallel sequence of reactions.
Addition of 5-lithioimidazole 11 to C2â-lactol 10 afforded
only diol 14 with C1′R configuration. The cyclization of
14 cleanly provided the anomers 15 and 16 in 35% and
53% yields, respectively. To date, this synthetic approach
for the preparation of C-nucleosides using a combination
of the elimination of PhSeCl and selenocyclization has
not been reported.29
After the N-ethoxycarbonylation20 of the â-anomer 15,
the phenylselenenyl group at the C2′ position of the
R-C2′-phenylseleneyl nucleosides 15 (22%) and 16 (38%)
resulting 18 was removed to give 2′,3′-dideoxynucleoside
were generated, together with trans-homoallylic alcohol
19 by treatment with n-Bu3SnH and Et3B (Scheme 3).26
17 (26%). On the other hand, if the water in the reaction
Debenzylation of 19 with Pd(OH)2-C in cyclohexene gave
mixture was removed as an azeotrope with benzene, the
a dideoxynucleoside 20, which was subsequently sub-
yields of 15 and 16 were improved to 42% and 56%,
jected to phthaloylimination20 using the Mitsunobu reac-
respectively. In this case, the isolation of the R- and
tion. Although the reaction of 20 with diethyl azodicar-
â-anomers could be easily done by SiO2 column chroma-
boxylate (DEAD), Ph3P, and phthalimide was inert, we
tography, presumably due to the presence of the large
found that the use of diisopropyl azodicarboxylate (DIAD)
PhSe group directly bound to the THF ring. This result
and 4-(dimethylamino)phenyldiphenylphosphine success-
facilitated our subsequent reactions, since we have often
fully proceeded to give phthalimide 21 in 92% yield.
encountered considerable difficulty in the isolation of the
Double deprotection of 21 with hydrazine hydrate yielded
the desired 4(5)-[(2R,5S)-5-(5-aminomethyl)tetrahydro-
1
two anomers.19 In H NMR, the two C5′ protons (δ 3.58,
3.80) of â-anomer 15 were individually observed and
shifted downfield compared to those (δ 3.46) of R-anomer
(27) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
16. These results presumably reflect the rotational
hindrance of the C4′-C5′ bond and deshielding effects due
to imidazole. The correctness of the assignment was
indicated by the positive nuclear Overhauser effect (NOE)
between the C2′- and C4′-protons in 16. The formation
of 15 and 16 can be reasonably rationalized by the
postulated mechanism shown in Scheme 2. The reaction
of 12 with HCl generates the homoallylic alcohol 17 by a
trans-stereospecific elimination of PhSeCl. Recombina-
tion of 17 and PhSeCl proceeds to give the â- and
(28) Andrey, O.; Ducry, L.; Landais, Y. Planchenault, D.; Weber, V.
Tetrahedron 1997, 53, 4339 and references therein.
(29) For recent reviews on the chemistry, biochemistry, and syn-
thesis of C-nucleoside analogues, see: (a) Watanabe, K. A. The
Chemistry of C-Nucleosides. In Chemistry of Nucleosides and Nucle-
otides; Townsend, L. B., Ed.; Plenum Press: New York, 1994; Vol. 3,
pp 421-535. (b) Shaban, M. A. E.; Nasr, A. Z. The Chemistry of
C-Nucleosides and Their Analogues I: C-Nucleosides of Hetero
Monocyclic Bases. In Advances In Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic Press: New York, 1997; Vol. 68, pp 223-432. (c)
Levy, D. E.; Tang, C. The Chemistry of C-Glycosides. In Tetrahedron
Organic Chimistry Series; Baldwin, J . E., Magnus, P. D., Eds.;
Pergamon: New York, 1995.

Synthesis of Imidazole C-Nucleoside Derivatives by PhSe Groups
J . Org. Chem., Vol. 64, No. 23, 1999 8611
Sch em e 3a
Sch em e 4a
a
Reagents: (a) ClCO2Et; (b) Et3B, Bu3SnH; (c) Pd(OH)2-C,
cyclohexene;(d)DIAD,4-Me2NC6H4PPh2,phthalimide;(e)hydrazine‚
H2O.
a
Reagents: (a) H2O2, pyridine (cat.); (b) sodium naphthalenide;
(c) ClCO2Et; (d) phthalimide, DEAD, Ph3P; (e) CH3NH2 in EtOH;
(f) TMSl or BCl3; (g) Pd(OH)2-C, cyclohexene.
furan-2-yl]imidazole (1) in 66% overall yield from 15.
Thus, synthesis of trans isomer 2 was attained in 87.5%
overall yield from R-anomer 16 via a route similar to that
employed for 15. The structures of â- and R-anomers 1
and 2 were determined on the basis of comparison of their
1H NMR. The C4′-H (δ 4.17) in 2 was observed in a lower
field in comparison with that (δ 4.04) in 1, because of
the deshielding effect of the proton that was syn to the
imidazole ring.30 It is important to note that simply
switching the starting material to D-glutamic acid allows
the synthesis of enantiomers of 1 and 2. Accordingly,
ent-1 and ent-2 (imifuramine) were synthesized through
the respective intermediates ent-15 and ent-16 by the
same reaction sequence described herein.
alcohol 27 in low yield.33 However, treatment of 26 with
15 equiv of sodium naphthalenide34 in DME at room
temperature for 15 min produced the unsaturated imid-
azole 27 in 93% yield. The N-ethoxycarbonylation of 27
afforded the intermediate 28, which was subsequently
transformed into the crude phthalimide compound under
Mitsunobu conditions. The phthalimide was treated with
methylamine35 in ethanol to afford (+)-4(5)-[(2R,5S)-5-
(aminomethyl)-2,5-dihydrofuran-2-yl]imidazole (3) in 84%
overall yield from 27. In a similar manner, the unsatur-
ated derivative (-)-4 was synthesized from the R-anomer
16, as shown in Scheme 4. The ent-3 and ent-4 were led
from the selenonucleosides ent-15 and ent-16, respec-
tively.
Synthesis of 4(5)-(5-aminomethylfuran-2-yl)-1H-imid-
azole (5) was carried out by using the synthetic method
of 1-(5-imidazoyl)ribofuranoid glycals, which we had
previously reported36 (Scheme 5). The reaction of crude
R-D-ribofuranosyl chloride 34,37 prepared from protected
D-ribose 33,38 with 2 equiv of the lithium salt 11 affords
a labile furanoid glycal 35 bearing an imidazole moiety.
Subsequent treatment of 35 with silica gel in CH2Cl2
resulted in a furan formation to give 36 in 36% overall
yield from 33. The formed 36 was successively trans-
formed into an aminomethyl compound 38 by desilylation
with Bu4NF, phthalimination under Mitsunobu condi-
tions, and deprotection with hydrazine hydrate. Hydroly-
sis of 38 with 1.5 N aqueous HCl afforded the furylimid-
azole 5 in 77% overall yield from 36.
The finding of imifuramine, which is a novel type of
histamine H3-agonist, encouraged us to synthesize the
unsaturated compounds 3, 4, and their enantiomers from
the selenonucleosides 15 or 16. As 2′-phenylselenenyl
nucleoside is prone to produce a C2′-C3′ double bond by
facile oxidative elimination,26 the N-(ethoxycarbonyl)-
compound 18 was converted to the 2′,3′-unsaturated
nucleoside 32 by treatment with H2O2/pyridine (Scheme
4). However, the selective debenzylation of 32 with
conventional reagents TMSI31 or BCl3 in CH2Cl2 gave
32
the desired alcohol 28 in poor yields. Treatment of 32
with Pd(OH)2-C in cyclohexene indicated the suscepti-
bility of the double bond toward hydrogenation, giving a
saturated compound 19.
After various trials, we found an alternative route
using single electron-transfer reduction to the alcohol 27.
Treatment of 15 with H2O2/pyridine afforded â-anomer
26 (84%) having a C2′,3′ double bond. The debenzylation
of 26 with lithium in liquid ammonia at -78 °C followed
by workup with NH4Cl brought about the expected
(33) The isolated yield was variable and less satisfactory owing to
the difficulty in product isolation from contamination with some
inorganic material.
(34) Scott, N. D.; Walker, J . F.; Hansley, V. L. J . Am. Chem. Soc.
1936, 58, 2442.
(35) Deprotection by hydrazine hydrate caused a partial hydrogena-
tion of the double bond in 3.
(30) Okabe, M.; Sun, R. C.; Tam, S. Y. K.; Todaro, L. J .; Coffen, D.
L. J . Org. Chem. 1988, 53, 4780.
(31) J ung, M. E., Lyster, M. A. J . Org. Chem. 1977, 42, 3761.
(32) Williams, D. R.; Brown, D. L.; Benbow, J . W. J . Am. Chem.
Soc. 1989, 111, 1923.
(36) Harusawa, S.; Kawabata, M.; Murai, Y.; Yoneda, R.; Kurihara,
T. Chem. Pharm. Bull. 1995, 43, 152.
(37) Rosemryer, H.; Seela, F. Helv. Chim. Acta 1988, 71, 1573.
(38) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R.
Synthesis 1990, 1031.

8612 J . Org. Chem., Vol. 64, No. 23, 1999
Harusawa et al.
Sch em e 5a
3.1, 11.0 Hz), 4.01 (dd, 1H, J ) 5.1, 8.9 Hz), 4.41 (m, 1H), 4.48
(s, 2H), 7.10-7.75 (m, 10H); EIMS m/z 362 (M+); HRMS m/z
362.0417 (calcd for C18H18O3Se 362.0420); EIMS m/z 362 (M+).
1
8: oil; IR (neat, cm-1) 1765 (COO); H NMR (CDCl3) δ 2.12
(ddd, 1H, J ) 7.3, 8.7, 13.8 Hz), 2.67 (ddd, 1H, J ) 7.3, 9.7,
13.8 Hz), 3.36 (dd, 1H, J ) 5.1, 10.9 Hz), 3.44 (dd, 1H, J )
4.2, 10.9 Hz), 3.93 (dd, 1H, J ) 8.7, 9.9 Hz), 4.46 (s, 2H), 4.53
(m, 1H), 7.18-7.37, 7.58-7.65 (m, 10H); EIMS m/z 362 (M+);
HRMS m/z 362.0416 (calcd for C18H18O3Se 362.0420).
5-O-Ben zyl-3-d eoxy-2-Se-p h en yl-2-selen o-r- a n d -â-D-
er yth r o-p en tofu r a n ose (9). To a solution of 7 (1.76 g, 4.87
mmol) in dry toluene (50 mL) at -70 °C was added a 1 M
solution of DIBAL in toluene (6.33 mL, 6.33 mmol) over 20
min. After being stirred for 10 min at -70 °C, the reaction
mixture was quenched with MeOH (10 mL) and further stirred
at room temperature. Saturated NaHCO3 solution (2 mL) was
then added to the reaction mixture with stirring. After
anhydrous MgSO4 was added to the resulting suspension, the
reaction mixture was stirred for a while, filtered through a
Celite pad, and washed with EtOAc. The solvent was evapo-
rated, and the residue was purified by column chromatography
[EtOAc-hexane (1:4)] to give 9 (1.74 g, 99%) as a colorless
1
oil: IR (KBr, cm-1) 3340 (OH); H NMR (CDCl3) δ 1.99 (dd,
1/2H, J ) 7.6, 14.1 Hz), 2.26 (dd, 1/2H, J ) 6.7, 9.1 Hz), 2.53
(quint, 1/2H, J ) 7.6, 14.1 Hz), 3.15 (d, 1/2H, J ) 4.1 Hz),
3.36-3.50, 3.59-3.72 (m, 3H), 3.96 (d, 1/2H, J ) 8.6 Hz), 4.38-
4.63 (m, 3H), 5.33 (d, 1/2H, J ) 8.6 Hz), 5.46 (t, 1/2H, J ) 4.1
Hz), 7.22-7.34, 7.45-7.55 (m, 10H).
a
Reagents: (a) (i) CCl4, (Me2N)3P, -70 °C; (ii) -70 °C to rt; (b)
11 (2.0 equiv), -70 °C to reflux, (c) SiO2, CH2Cl2, 3 days; (d)
Bu4NF; (e) phthalimide, Ph3P, DEAD; (f) hydrazine‚H2O; (g) 1.5
N HCl.
5-O-Ben zyl-3-d eoxy-2-Se-p h en yl-2-selen o-r- a n d -â-D-
th r eo-p en tofu r a n ose (10). Using a procedure used for 9,
lactone 8 (1.49 g, 4.13 mmol) was converted to 10 (1.21 g, 81%)
as a colorless oil: IR (KBr, cm-1) 3370 (OH); 1H NMR (CDCl3)
δ 2.08-2.63 (m, 2H), 3.30-3.67 (m, 3H), 3.77 (br, 1/2H), 4.16
(d, 1/2H, J ) 7.6 Hz), 4.20-4.32, 4.39-4.62 (m, 3H), 5.37 (dd,
1/2H, J ) 3.7, 6.6 Hz), 5.55 (s, 1/2H), 7.20-7.57 (m, 10H).
5-[(1S,2R,4S)-5-Ben zyloxy-1,4-d ih yd r oxy-2-Se-p h en yl-
2-selen open tyl]-2-(ter t-bu tyldim eth ylsilyl)-N,N-dim eth yl-
1H-im id a zolesu lfon a m id e (12) a n d Its C-1′ Ep im er (13).
A solution of 2-(tert-butyldimethylsilyl)-N,N-dimethyl-1H-imid-
azolesulfonamide (1.35 g, 4.68 mmol) in THF (14 mL) was
cooled to -70 °C and treated dropwise with 1.6 M BuLi-
hexane (2.92 mL, 4.68 mmol), and the reaction mixture was
warmed to -50 °C over 50 min to precipitate the white lithium
salts 11. The resulting suspension was again cooled to -70
°C, and a solution of 9 (0.51 g, 1.42 mmol) in THF (8 mL) was
added. The reaction mixture was stirred at the same temper-
ature for 5 min. The dry ice bath was removed, and the
reaction mixture was stirred at room temperature to dissolve
the salts. After 1 h, the resulting yellow solution was quenched
with H2O, and the solvent 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 30% EtOAc in
hexane as eluent gave 12 (0.67 g, 73%) and 13 (0.09 g, 10%).
12 (less polar): recrystallized from hexane to give colorless
needles; mp 95-96 °C; IR (KBr, cm-1) 3180 (OH), 1380, 1175
(SO2); 1H NMR (CDCl3) δ 0.33 (s, 6H), 0.90 (s, 9H), 1.66 (ddd,
1H, J ) 3.0, 5.5, 15.1 Hz), 1.88 (ddd, 1H, J ) 4.5, 9.4, 15.4
Hz), 2.65 (s, 6H), 3.00 (s, 1H), 3.21 (t, 1H, J ) 8.8 Hz), 3.32
(dd, 1H, J ) 3.7, 9.2 Hz), 3.86 (q, 1H, J ) 4.9 Hz), 4.17 (br,
1H), 4.46 (s, 2H), 4.65 (d, 1H, J ) 6.2 Hz), 5.20 (t, 1H, J ) 5.9
Hz), 7.13-7.36, 7.49-7.53 (m, 11H). Anal. Calcd for C29H43N3O5-
SSeSi: C, 53.36; H, 6.64; N, 6.44. Found: C, 53.13; H, 6.61;
In summary, the respective four possible stereoisomers
of two novel imidazole C-nucleoside derivatives were
synthesized by the efficient use of a PhSe group. This
synthetic approach should enable the supply of a variety
of derivatives by which their biological activity can be
assessed. The evaluation for H1- and H2- as well as H3-
receptors of the nine compounds synthesized is in progress
in our laboratories and will be reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r es. The melting points were determined
on a hot-stage apparatus and are uncorrected. The ORD
spectra were recorded at 25 °C. 1H and 13C NMR spectra were
taken with tetramethyllsilane. Reactions with air- and moisture-
sensitive compounds were carried out under an argon atmo-
sphere. Unless otherwise noted, all extracts were dried over
Na2SO4, and the solvent was removed in a rotary evaporator
under reduced pressure. Chromatography was performed on
a silica gel. THF was distilled from sodium-benzophenone.
5-O-Ben zyl-3-deoxy-2-Se-ph en yl-2-selen o-D-er yth r o-pen -
ton ic Acid γ-La cton e (7) a n d 5-O-Ben zyl-3-d eoxy-2-Se-
p h en yl-2-selen o-D-th r eo-p en ton ic Acid γ-La cton e (8). Ac-
cording to Chu’s procedure,26 lithium hexamethyldisilazide (1
M in THF) (13.4 mL, 13.4 mmol) was added dropwise over 5
min to a solution of (+)-625 (2.512 g, 12.2 mmol) in THF (25
mL) at -70 °C with stirring. After the reaction mixture was
stirred for 1 h at the same temperature, TMSCl (1.93 mL, 15.3
mmol) was added, and the reaction mixture was allowed to
reach rt and stirred for 30 min at this temperature. The
reaction mixture was again cooled to -70 °C, and a solution
of phenylselenenyl bromide (4.319 g, 18.3 mmol) in THF (10
mL) was added. The dark brown color of the phenylselenenyl
bromide disappeared as it was added and finally persisted at
the end. The reaction mixture was diluted with diethyl ether
(100 mL), washed with H2O (50 mL × 5) until the ether layer
was light yellow in color, dried, filtered, and concentrated. The
resulting oily residue was purified by column chromatography
using a gradient solvent system from 5% to 40% EtOAc in
hexane to give 7 (2.296 g, 52%) followed by 8 (1.307 g, 30%).
1
N, 6.37. 13: IR (neat, cm-1) 3360 (OH), 1370, 1180 (SO2). H
NMR (CDCl3) δ 0.35 (s, 6H, J ) 6.0 Hz), 0.92 (s, 9H), 1.77-
1.95 (m, 2H), 2.70 (s, 6H), 3.01 (br, 1H), 3.33 (dd, 1H, J ) 7.7,
9.4 Hz), 3.44 (dd, 1H, J ) 4.1, 9.4 Hz), 3.62 (m, 1H), 4.35
(m, 1H), 4.50 (s, 3H), 5.10 (t, 1H, J ) 2.7 Hz), 7.06-7.37 (m,
10H), 7.47 (s, 1H); SIMS m/z 654 (M+ + 1).
5-[(1R,2S,4S)-5-Ben zyloxy-1,4-d ih yd r oxy-2-Se-p h en yl-
2-selen open tyl]-2-(ter t-bu tyldim eth ylsilyl)-N,N-dim eth yl-
1H-im id a zolesu lfon a m id e (14). The same procedure as
described for the synthesis of 12 provided 14 (0.30 g, 75%) as
a colorless oil from 10 (0.22 g, 0.60 mmol) and the lithium salt
7: oil; IR (neat, cm-1) 1765 (COO); H NMR (CDCl3) δ 2.24
(ddd, 1H, J ) 5.1, 7.3, 13.8 Hz), 2.55 (ddd, 1H, J ) 6.6, 8.9,
13.8 Hz), 3.46 (dd, 1H, J ) 4.1, 11.0 Hz), 3.60 (dd, 1H, J )
1
1
11 (1.63 mmol). 14: colorless oil; H NMR (CDCl3) δ 0.33 (s,

Synthesis of Imidazole C-Nucleoside Derivatives by PhSe Groups
J . Org. Chem., Vol. 64, No. 23, 1999 8613
6H), 0.91 (s, 9H), 1.57 (m, 1H), 1.86 (m, 1H), 2.49 (s, 1H), 2.55
(s, 6H), 3.25 (dd, 1H, J ) 7.7, 8.8 Hz), 3.41 (dd, 1H, J ) 3.0,
8.8 Hz), 3.94 (m, 1H), 4.16 (br, 1H), 4.48 (s, 2H), 5.09 (s, 1H),
7.14-7.34, 7.53-7.59 (m, 11H).
Hz), 7.22-7.31 (m, 6H), 8.01(s, 1H); EIMS m/z 330 (M+);
HRMS m/z 330.1578 (calcd for C18H22N2O4 330.1578).
Eth yl 4-(2,3-Did eoxy-â-D-glycer o-p en tofu r a n osyl)im id -
a zole-1-ca r boxyla te (20). A mixture of 19 (113 mg, 0.34
mmol), 20% Pd(OH)2-C (79 mg), and cyclohexene (1.0 mL,
10.26 mmol) in EtOH (15 mL) was refluxed for 1 h. After
filtration through a Celite pad, the filtrate was evaporated to
give a residue that was purified by column chromatography
using EtOAc to give 20 (77 mg, 94%) as a colorless oil: 1H
NMR (CD3OD) δ 1.46 (t, 3H, J ) 7.1 Hz), 1.83-2.39 (m, 4H),
3.59 (dd, 1H, J ) 5.3, 11.8 Hz), 3.72 (dd, 1H, J ) 4.0, 11.8 Hz),
4.14 (m, 1H), 4.52 (q, 2H, J ) 7.1 Hz), 4.93 (overlapped with
H2O in CD3OD, 1′-H), 7.54 (s, 1H), 8.25 (s, 1H); EIMS m/z 241
(M+ + 1); HRMS m/z 241.1184 (calcd for C11H17N2O4 240.1187).
Eth yl 4-(5-P h th a loyla m in o-2,3,5-tr id eoxy-â-D-glycer o-
p en tofu r a n osyl)im id a zole-1-ca r boxyla te (21). Phthalim-
ide (71 mg, 0.48 mmol) and 4-dimethylaminophenyldiphen-
ylphosphine (207 mg, 0.64 mmol) were dissolved in a solution
of 20 (77 mg, 0.32 mmol) in THF (5 mL). To this mixture was
added DIAD (0.13 mL, 0.64 mmol) with a stirring. The reaction
mixture was stirred at room temperature for 12 h, and then
the whole was evaporated to give a residue, which was
subsequently dissolved in EtOAc. The solution was washed
with H2O and brine, dried, and evaporated to give a crude oil.
It was purified by flash chromatography with EtOAc-hexane
(2:3) to give a colorless oil 21 (110 mg, 92%) that solidified on
standing. This was recrystallized from EtOAc-hexane to give
white leaflets: mp 96-97 °C; ORD (c 2.06, EtOH) [R] (nm)
+104.4° (589), +121.4° (550), +151.8° (500), +201.9° (450),
+276.7° (400), +405.3° (350), +535.8° (330); 1H NMR (CDCl3)
δ 1.35 (t, 3H, J ) 7.1 Hz), 1.64-1.83 (m, 1H), 1.92-2.29 (m,
3H), 3.72 (dd, 1H, J ) 5.2, 13.9 Hz), 3.84 (dd, 1H, J ) 7.1,
13.7 Hz), 4.30 (m, 1H), 4.38 (q, 2H, J ) 7.1 Hz), 4.88 (t, 1H, J
) 6.3 Hz), 7.44 (s, 1H), 7.57-7.65 (m, 2H), 7.71-7.77 (m, 2H),
7.94 (s, 1H). Anal. Calcd for C19H19N3O5: C, 61.78; H, 5.18;
N, 11.38. Found: C, 61.59; H, 5.23; N, 11.24.
(+)-4(5)-[(2R,5S)-(5-Am in om et h yl)t et r a h yd r ofu r a n -2-
yl]im id a zole (1). A solution of 21 (57 mg, 0.16 mmol) and
NH2NH2‚H2O (38 µL, 0.78 mmol) in EtOH (4 mL) was refluxed
for 90 min and then cooled. A small amount of 10% Pd-C was
then added to the solution, and the reaction mixture was
further refluxed for 60 min. After removal of the catalyst by
filtration through a Celite pad, a small amount of silica gel
was added to the filtrate. The solvent was evaporated to give
a coated silica gel, which was subsequently placed in a column
(Chromatorex NH-DM 1020). Chromatography using MeOH -
EtOAc (3:17) as the eluent gave (+)-1 (23 mg, 85%) as a
colorless oil: ORD (c 0.60, EtOH) [R] (nm) +23.3° (589), +25.0°
(550), +30.0° (500), +37.7° (450), +47.7° (400), +70.0° (350),
+106.4° (300), +206.7° (250); IR (Nujol, cm-1) 3350, 1585 (NH);
1H NMR (CD3OD) δ 1.68-2.35 (m, 4H), 2.75 (m, 2H), 4.04 (m,
1H), 4.93 (overlapped with H2O in CD3OD, 1′-H), 7.03 (s, 1H),
7.65 (s, 1H); 13C NMR (CD3OD) 29.9, 33.1, 47.3, 76.6, 82.1,
118.0, 137.0, 140.3; EIMS m/z 167(M+); HRMS m/z 167.1060
(calcd for C8H13N3O 167.1058).
Eth yl 4-(5-O-Ben zyl-2,3-d id eoxy-2-Se-p h en yl-2-selen o-
r-D-th r eo-p en tofu r a n osyl)im id a zole-1-ca r boxyla te (22).
By the same procedure as used for the preparation of 18,
R-anomer 16 (116 mg, 0.28 mmol) was converted to 22 (149
mg, 100%) as a colorless oil: IR (Nujol, cm-1) 1765 (COO); 1H
NMR (CDCl3) δ 1.37 (t, 3H, J ) 7.2 Hz, CH3), 1.96 (ddd, 1H,
J ) 8.4, 10.1, 12.8 Hz), 2.52 (dt, 1H, J ) 7.2, 12.9 Hz), 3.47 (d,
2H, J ) 5.1 Hz), 3.95 (dt, 1H, J ) 8.2, 10.2 Hz), 4.30-4.45 (m,
1H), 4.40 (q, 2H, J ) 7.2 Hz), 4.50 (s, 2H), 4.80 (d, 1H, J ) 8.2
Hz), 7.08-7.44, (m, 11H), 7.98 (s, 1H); HRMS m/z 486.1057
(calcd for C24H26N2O4Se 486.1056); EIMS m/z 486 (M+).
4(5)-(5-O-Ben zyl-3-deoxy-2-Se-ph en yl-2-selen o-â-D-er yth -
r o-p en tofu r a n osyl)im id a zole (15) a n d 4(5)-(5-O-Ben zyl-
3-d eoxy-2-Se-p h en yl-2-selen o-r-th r eo-p en t ofu r a n osyl)-
im id a zole (16). Meth od A. A solution of 12 (151 mg, 0.23
mmol) in THF (1.5 mL) was refluxed with 1.5 N HCl (1.5 mL)
for 15 h and then cooled. After neutralization by addition of
NH4OH, the solvent was evaporated to give a residue, which
was extracted with EtOAc. The extract was washed with H2O
and brine, dried, and evaporated. The residual oil was chro-
matographed using EtOAc for elution to give 15 (21 mg, 22%),
16 (36.4 mg, 38%), and then (E)-4(5)-[(4S)-5-O-benzyoxy-4-
hydroxy-1-pentenyl)]imidazole (17) (17 mg, 28%), in turn. 15
(less polar): colorless oil; ORD (c 1.93, EtOH) [R] (nm) -33.7°
(589), -38.9° (550), -49.2° (500), -64.8° (450), -85.5° (400),
-129.5° (350), -268.4° (300); 1H NMR (CDCl3) δ 2.05 (ddd,
1H, J ) 4.8, 6.9, and 13.6 Hz), 2.47 (dt, 1H, J ) 7.7, 13.6 Hz),
3.58 (dd, 1H, J ) 3.5, 10.4 Hz), 3.80 (m, 2H), 4.40 (m, 1H),
4.52 (s, 2H), 4.98 (d, 1H, J ) 4.8 Hz), 6.70 (s, 1H), 7.00 (s,
1H), 7.13-7.45 (m, 10H); EIMS m/z 414 (M+); HRMS m/z
414.0849 (calcd for C21H22N2O2Se 414.0845). 16: oil that
solidified on standing. This was recrystallized from EtOAc-
hexane to give 16 as colorless needles: mp 120-121 °C; ORD
(c 1.58, EtOH) [R] (nm) +30.4° (589), +30.4° (550), +41.1°
(500), +44.3 ° (450), +60.1° (400), +82.3° (350), +158.2° (308);
1H NMR (CDCl3) δ 1.90 (ddd, 1H, J ) 8.5, 9.8, 12.7 Hz), 2.49
(dt, 1H, J ) 6.8, 12.7 Hz), 3.46 (d, 2H, J ) 4.9 Hz), 3.91 (dt,
1H, J ) 8.1, 9.8 Hz), 4.33 (m, 1H), 4.49 (s, 2H), 4.84 (d, 1H, J
) 8.1 Hz), 6.70 (s, 1H), 7.06-7.40 (m, 11H). Anal. Calcd for
C
21H22N2O2Se: C, 61.02; H, 5.36; N, 6.78. Found: C, 61.08;
1
H, 5.30; N, 6.57. 17: colorless oil; H NMR (CDCl3) δ 2.33 (t,
2H, J ) 6.8 Hz), 3.37 (dd, 1H, J ) 7.5, 9.6 Hz), 3.50 (dd, 1H,
J ) 3.4, 9.6 Hz), 3.88 (m, 1H), 4.50 (s, 2H), 6.10 (dt, 1H, J )
7.4, 16.1 Hz), 6.32 (d, 1H, J ) 16.2 Hz), 6.86 (s, 1H), 7.28 (s,
5H), 7.49 (s, 1H).
Meth od B. A solution of 12 (1.32 g, 2.03 mmol) in THF (24
mL) was refluxed with 1.5 N HCl (9 mL) for 1 h and then
diluted with benzene (50 mL). The resulting mixture was
further refluxed to remove water for 1 h as an azeotrope using
a Dean-Stark water separator. Workup and purification
described above gave 15 (0.35 g, 42%) and 16 (0.46 g, 56%).
The diol 14 (180 mg, 0.28 mmol) could be converted into 15
(40 mg, 35%) and 16 (60 mg, 53%) by method B.
Eth yl 4-(5-Ã-Ben zyl-2,3-d id eoxy-2-Se-p h en yl-2-selen o-
â-D-er yth r o-p en tofu r a n osyl)im id a zole-1-ca r boxyla te (18).
A solution of â-anomer 15 (40 mg, 0.1 mmol), ethyl chlorofor-
mate (18 µL, 0.19 mmol), pyridine (15 µL, 0.19 mmol), and a
catalytic amount of 4-(dimethylamino)pyridine (DMAP) in
benzene (2 mL) was refluxed for 15 min. After addition of H2O,
the solvent was evaporated and the residue was extracted with
EtOAc. The extract was washed with H2O and brine, dried,
and evaporated. The residual oil was purified by flash column
chromatography using EtOAc-hexane (7:13) for elution to give
18 (48 mg, quant) as a colorless oil: IR (Nujol, cm-1) 1765
1
(COO); H NMR (CDCl3) δ 1.47 (t, 3H, J ) 7.1 Hz), 2.08 (dt,
1H, J ) 6.8, 13.2 Hz), 2.34 (dt, 1H, J ) 7.6, 13.2 Hz), 3.55 (d,
2H, J ) 5.1 Hz), 3.92 (dt, 1H, J ) 6.7, 7.8 Hz), 4.29 (m, 1H),
4.38 (q, 2H, J ) 7.1 Hz), 4.52 (s, 2H), 4.78 (d, 1H, J ) 6.8 Hz),
7.11-7.29, 7.42-7.48 (m, 11H), 7.98 (s, 1H); EIMS m/z 486
(M+); HRMS m/z 486.1056 (calcd for C24H26N2O4Se 486.1056).
Eth yl 4-(5-O-Ben zyl-2,3-d id eoxy-â-D-glycer o-p en tofu -
r a n osyl)im id a zole-1-ca r boxyla te (19). A mixture of 18 (100
mg, 0.21 mmol), Et3B (0.23 mL, 0.23 mmol), and Bu3SnH (0.09
mL, 0.31 mmol) in benzene (7 mL) was stirred at room
temperature for 90 min. The benzene was removed under
reduced pressure. The residue was dissolved in CH3CN, and
the solution was washed with hexane and evaporated to give
a crude oil. Flash chromatography using EtOAc-hexane (7:
13) for elution gave 19 (61 mg, 90%) as a colorless oil: 1H NMR
(CDCl3) δ 1.35 (t, 3H, J ) 7.1 Hz), 1.71-2.30 (m, 4H), 3.52
(ddd, 2H, J ) 5.5, 9.9, and 11.9 Hz), 4.18 (quint, 1H, J ) 5.9
Hz), 4.39 (q, 2H, J ) 5.5 Hz), 4.54 (s, 2H), 4.91 (t, 1H, J ) 6.5
Eth yl 4-(5-O-Ben zyl-2,3-d id eoxy-r-D-glycer o-p en tofu -
r a n osyl)im id a zole-1-ca r boxyla te (23). A mixture of 22 (149
mg, 0.31 mmol), Et3B (0.34 mL, 0.34 mmol), and Bu3SnH (0.12
mL, 0.46 mmol) in benzene (8 mL) was treated at room
temperature as described for the preparation of 19 to give 23
(97 mg, 96%) as a colorless oil: 1H NMR (CDCl3) δ 1.36 (t,
3H, J ) 7.1 Hz), 1.67-1.78 (m, 1H), 1.86-2.32 (m, 3H), 3.48
(d, 2H, J ) 5.0 Hz), 4.28-4.45 (m, 1H), 4.39 (q, 2H, J ) 7.1

8614 J . Org. Chem., Vol. 64, No. 23, 1999
Harusawa et al.
Hz), 4.54 (s, 2H), 4.99 (t, 1H, J ) 6.4 Hz), 7.21-7.30 (m, 6H),
8.02 (s, 1H); EIMS m/z 330 (M+).
mL). The aqueous solution was extracted five times with
EtOAc (50 mL × 5). The extract was dried and evaporated to
give a crude oil, which was purified by column chromatography
using EtOAc to give 28 (39 mg, 70%) as a colorless oil: 1H
NMR (CDCl3) δ 1.41 (t, 3H, J ) 7.5 Hz), 3.72 (dd, 1H, J ) 1.5,
12.3 Hz), 3.97 (dd, 1H, J ) 1.2, 12.3 Hz), 4.46 (q, 2H, J ) 7.5
Hz), 5.07 (s, 1H), 5.75 (s, 1H), 5.81 (d, 1H, J ) 6.0 Hz), 5.98
(d, 1H, J ) 6.0 Hz), 7.35 (s, 1H), 8.09 (s, 1H); EIMS m/z 239
(M+ + H); HRMS m/z 239.1026 (calcd for C11H15N2O4 239.1031).
4(5)-(5-Am in o-2,3,5-tr id eoxy-â-D-glycer o-p en t-2-en ofu -
r a n osyl)im id a zole (3). Phthalimde (49 mg, 0.33 mmol) and
Ph3P (116 mg, 0.44 mmol) were dissolved in a solution of 28
(53 mg, 0.22 mmol) in THF (10 mL). To this mixture was added
DEAD (0.08 mL, 0.44 mmol) slowly with stirring at 0 °C. The
reaction mixture was stirred for 19 h at room temperature and
then quenched with two drops of MeOH. The whole was
evaporated to give a residue, which was chromatographed
[EtOAc-hexane (50% to 70%)] to give a mixture of the
desirable phthalimide compound [EIMS m/z 367 (M+); HRMS
m/z 367.1174 (calcd for C19H17N3O5 367.1167)] and Ph3PdO.
The mixture was dissolved in MeOH (10 mL), and 40% MeNH2
in MeOH (1.7 mL, 22.1 mmol) was added to the solution. The
reaction mixture was refluxed for 0.5 h, and then a small
amount of silica gel was added to the cooled solution. The
solvent was evaporated to give a coated silica gel, which was
subsequently placed in a column (Chromatorex NH-DM 1020).
Chromatography using a gradient solvent system (5% to 20%
in MeOH-EtOAc) gave (+)-3 (31 mg, 84%) as an oil: ORD (c
1.69, EtOH) [R] (nm) +38.6 (589), +50.4 (550), +62.3 (500),
Eth yl 4-(2,3-Did eoxy-r-D-glycer o-p en tofu r a n osyl)im id -
a zole-1-ca r boxyla t e (24). The mixture of 23 (48 mg, 0.14
mmol), cyclohexene (0.44 mL, 4.32 mmol), and 20% Pd(OH)2-C
(29 mg) in EtOH (6 mL) was refluxed to give 24 (33 mg, 97%)
as a colorless oil by the same procedure for the preparation
for 20: 1H NMR (CD3OD) δ 1.46 (t, 3H, J ) 7.0 Hz), 1.76-
2.40 (m, 4H), 3.57 (dd, 1H, J ) 5.6, 11.9 Hz), 3.65 (dd, 1H, J
) 4.2, 11.9 Hz), 4.27 (m, 1H), 4.52 (q, 2H, J ) 7.0 Hz), 5.02 (t,
1H, J ) 7.0 Hz), 7.50 (s, 1H), 8.25 (s, 1H); EIMS m/z 240 (M+).
Eth yl 4-(5-P h th a loyla m in o-2,3,5-tr id eoxy-r-D-glycer o-
p en tofu r a n osyl)im id a zole-1-ca r boxyla te (25). A mixture
of 24 (67 mg, 0.28 mmol), phthalimide (61 mg, 0.42 mmol),
4-dimethylaminophenyldiphenylphosphine (179 mg, 0.56 mmol),
and DIAD (0.11 mL, 0.56 mmol) was stirred overnight at room
temperature to give 25 (103 mg, quant) as a colorless oil: ORD
(c 2.47, EtOH) [R] (nm) +36.5° (589), +43.8° (550), +53.6°
(500), +71.8° (450), +99.8° (400), +145.3° (357); 1H NMR
(CDCl3) δ 1.34 (t, 3H, J ) 7.1 Hz), 1.66-1.84 (m, 1H), 1.98-
2.41 (m, 3H), 3.62 (dd, 1H, J ) 5.2, 13.5 Hz), 3.83 (dd, 1H, J
) 7.9, 13.5 Hz), 4.47 (q, 2H, J ) 7.0 Hz), 4.51 (m, 1H), 5.04 (t,
1H, J ) 6.1 Hz), 7.23 (s, 1H), 7.60-7.69 (m, 2H), 7.75-7.81
(m, 2H), 8.00 (s, 1H); EIMS m/z 369 (M+).
(-)-4(5)-[(2S,5S)-(5-Am in om et h yl)t et r a h yd r ofu r a n -2-
yl]im id a zole (2). By the same procedure for the preparation
of 1, phthalimide 25 (105 mg, 0.28 mmol) was converted into
2 (44 mg, 94%) as a colorless oil: ORD (c 1.25, EtOH) [R] (nm)
-5.4° (589), -9.0° (550), -12.2° (500), -15.0° (450), -23.0°
(400), -42.9° (350), -102.7° (300), -272.3° (266); IR (Nujol,
cm-1) 3350, 1585 (NH); 1H NMR (CD3OD) δ 1.61-1.82 (m, 1H),
2.02-2.38 (m, 3H), 2.73 (d, 2H), 4.17 (m, 1H), 5.02 (t, 1H, J )
6.5 Hz), 7.02 (s, 1H), 7.64 (s, 1H); 13C NMR (CD3OD) δ 30.6,
33.5, 47.1, 76.0, 81.5, 117.9, 137.0, 140.4; HRMS m/z 167.1075
(calcd for C8H13N3O 167.1058); EIMS m/z 167 (M+).
4(5)-(5-O-Ben zyl-2,3-d id eoxy-â-D-glycer o-p en to-2-en o-
fu r a n osyl) im id a zole (26). A solution of 15 (296 mg, 0.72
mmol) in CH2Cl2 (25 mL) containing a catalytic amount of
pyridine (1 drop) was cooled in an ice-water bath. A 35%
solution of hydrogen peroxide (0.37 mL) diluted with water
(0.74 mL) was added dropwise to the above solution over a
period of 20 min with stirring. The temperature of the reaction
mixture was allowed to come to 20 °C slowly, and the mixture
was stirred at this temperature for an additional 2 h. The
reaction mixture was diluted with CH2Cl2, washed with water,
saturated NaHCO3 solution, and finally water. After the
reaction mixture was dried, the solvent was removed and the
residue was chromatographed over a column of silicagel using
5% MeOH in EtOAc for elution to give 26 (155 mg, 84%) as
an oil: 1H NMR (CDCl3) δ 3.79 (dd, 1H, J ) 2.7, 10.8 Hz),
3.97 (dd, 1H, J ) 3.0, 10.8 Hz), 4.59 (dd, 2H, J ) 10.2 Hz,
29.1 Hz), 5.11 (br s, 1H), 5.81-6.01 (m, 3H), 6.85 (s, 1H), 6.90
(s, 1H), 7.40 (s, 5H); EIMS m/z 256 (M+); HRMS m/z 256.1208
(calcd for C15H16N2O2 256.1211).
4(5)-(2,3-Did e oxy-â-D-glycer o-p e n t -2-e n ofu r a n osyl)-
im id a zole (27). Sodium naphthalenide (1 M in DME) (8 mL,
8.0 mmol) was added dropwise over 10 min to a solution of 26
(136 mg, 0.53 mmol) in DME (6 mL) at room temperature. The
reaction mixture was stirred at room temperature for 10 min.
The reaction was quenched with MeOH (3 mL), and a small
amount of silica gel was added to the solution. The solvent
was evaporated to give a coated silica gel, which was subse-
quently placed in a column. Chromatography first with EtOAc
and then 5% MeOH in EtOAc as the eluent gave 27 (82 mg,
93%) as an oil: 1H NMR (CDCl3) δ 3.77 (d, 1H, J ) 12.0 Hz),
3.98 (d, 1H, J ) 12.0 Hz), 5.06 (s, 1H), 5.78-5.96 (m, 3H),
6.91 (s, 1H), 7.47 (s, 1H); EIMS m/z 166 (M+); HRMS m/z
166.0749 (calcd for C8H10N2O2 166.0742).
1
+90.2 (450), +121.7 (400); H NMR (CD3OD) δ 2.81 (m, 2H),
4.90 (overlapped with H2O in CD3OD, 4′-H), 5.81 (d, 1H, J )
2.1 Hz), 6.01 (m, 2H), 7.02 (s, 1H), 7.64 (s, 1H); EIMS m/z 165
(M+); HRMS m/z 165.0897 (calcd for C8H11N3O 165.0901).
4(5)-(5-O-Ben zyl-2,3-d id eoxy-r-D-glycer o-p en t -2-en o-
fu r a n osyl)im id a zole (29). A mixture of 16 (341 mg, 0.83
mmol), 35% H2O2 (0.43 mL), and pyridine (1 drop) in CH2Cl2
(30 mL) was stirred for 3 h at room temperature to give 29
(198 mg, 94%) by the same procedure for the preparation of
26: 1H NMR (CDCl3) δ 3.59 (d, 2H, J ) 5.0 Hz), 4.61 (s, 2H),
5.13 (m, 1H), 5.95 (m, 3H), 6.90 (s, 1H), 7.36 (s, 5H), 7.53 (s,
1H); EIMS m/z 256 (M+); HRMS m/z 256.1218 (calcd for
C
15H16N2O2 256.1211).
4(5)-(2,3-Did e oxy-r-D-glycer o-p e n t -2-e n ofu r a n osyl)-
im id a zole (30). Sodium naphthalenide (1 M, 5.0 mL, 5.0
mmol) in DME was added slowly over 10 min to a solution of
29 (213 mg, 0.83 mmol) in DME (12 mL) at room temperature.
The mixture was stirred at the same temperature for 0.5 h.
The same workup and purification as used for the preparation
of 27 gave 30 (127 mg, 92%) as an oil: 1H NMR (CD3OD) δ
3.77 (dd, 1H, J ) 4.8, 11.4 Hz), 3.83 (dd, 1H, J ) 3.9 Hz, 11.4
Hz), 5.20 (overlapped with H2O in CD3OD, 4′-H), 6.07 (d, 1H,
J ) 5.7 Hz), 6.21 (m, 2H), 7.25 (s, 1H), 8.01 (s, 1H); EIMS m/z
166 (M+); HRMS m/z 166.0747 (calcd for C8H10N2O2 166.0742).
Eth yl 4-(2,3-Did eoxy-r-D-glycer o-p en t-2-en ofu r a n osyl)-
im id a zole-1-ca r boxyla te (31). A solution of ethyl chlorofor-
mate (43 mg, 0.40 mmol) in dioxane (0.5 mL) was added
dropwise over 5 min to a stirred solution of 30 (60 mg, 0.36
mmol) and 4-DMAP (44 mg, 0.36 mmol) in dioxane (20 mL) at
room temperature. The mixture was stirred for 0.5 h to give
31 (73 mg, 84%) by the same procedure as used for the
preparation of 28: oil; 1H NMR (CDCl3) δ 1.42 (t, 3H, J ) 7.4
Hz), 2.40 (brs, 1H), 3.64 (dd, 1H, J ) 5.0, 11.6 Hz), 3.80 (dd,
1H, J ) 3.2, 11.6 Hz), 4.46 (q, 2H, J ) 7.4 Hz), 5.12 (brs, 1H),
5.88 (d, 1H, J ) 5.4 Hz), 5.96 (d, 1H, J ) 6.0 Hz), 6.09 (d, 1H,
J ) 6.0 Hz), 7.35 (s, 1H), 8.09 (s, 1H); EIMS m/z 238 (M+);
HRMS m/z 238.0956 (calcd for C11H14N2O4 238.0953).
4(5)-(5-Am in o-2,3,5-t r id eoxy-r-D-glycer o-p en t -2-en o-
fu r a n osyl)im id a zole (4). Phthalimide (117 mg, 0.80 mmol)
and Ph3P (279 mg, 1.1 mmol) were dissolved in a solution of
31 (127 mg, 0.53 mmol) in THF (15 mL). To this mixture was
added slowly DEAD (0.18 mL, 1.06 mmol) with stirring at 0
°C. The reaction mixture was stirred for 14 h at room
temperature to give a mixture of the phthalimide compound
[EIMS m/z 367 (M+); HRMS m/z 367.1174 (calcd for C19H17N3O5
367.1167)] and Ph3PdO. The mixture was then dissolved in
Eth yl 4-(2,3-Did eoxy-â-D-glycer o-p en t-2-en ofu r a n osyl)-
im id a zole-1-ca r boxyla te (28). A solution of ethyl chlorofor-
mate (26 mg, 0.24 mmol) in THF (5 mL) was added dropwise
over 20 min to a stirred solution of 27 (39 mg, 0.24 mmol) and
4-DMAP (32 mg, 0.26 mM) in THF (13 mL) at room temper-
ature. After 10 min, the solvent was evaporated to give a
residual oil, which was subsequently dissolved in brine (15

Synthesis of Imidazole C-Nucleoside Derivatives by PhSe Groups
J . Org. Chem., Vol. 64, No. 23, 1999 8615
MeOH (15 mL), and 40% MeNH2 in MeOH (4.1 mL) was added
to the solution. The reaction mixture was treated by the same
procedure as used for the preparation of 3 to 4 (88 mg,
quant): oil; ORD (c 2.62, EtOH) [R] (nm) -195.0 (589), -229.5
(550), -298.3 (500), -401.5 (450), -573.6 (400), -883.4 (350);
1H NMR (CD3OD) δ 2.80 (m, 2H), 5.02 (overlapped with H2O
in CD3OD, 4′-H), 5.92 (d, 1H, J ) 5.2 Hz), 6.09 (m, 2H), 7.02
(s, 1H), 7.67 (s, 1H); 13C NMR (CD3OD) δ 40.8, 76.7, 82.2, 112.1,
123.7, 125.2, 130.9; CIMS m/z 166 (M+ + H); HRMS m/z
166.0989 (calcd for C8H12N3O 166.0980).
1-N,N-Dim et h ylsu lfa m oyl-5-(5-a m in om et h ylfu r a n -2-
yl)-1H-im id a zole (38). Phthalimide (74 mg, 0.50 mmol) and
Ph3P (354 mg, 1.35 mmol) were dissolved in a solution of 37
(122 mg, 0.45 mmol) in THF (15 mL). To this mixture was
added DEAD (0.23 mL, 1.35 mmol) at 0 °C and the resulting
mixture stirred for 0.5 h at room temperature. The reaction
was quenched with two drops of H2O, and the whole was
evaporated to give crude phthalimide (yellow powder). A
solution of the phthalimide and NH2NH2‚H2O (0.11 mL, 2.25
mmol) in EtOH (15 mL) was then refluxed for 1 h to give 38
(53 mg, 44% from 37) as an oil by the same procedure as used
for the preparation of 1: IR (neat, cm-1) 1390, 1170 (SO2); 1H
NMR (CDCl3) δ 2.70 (s, 6H), 3.85 (s, 2H), 6.22 and 6.65 (each
d, each 1H, J ) 3.3 Hz), 7.22 and 7.99 (each s, each 1H); EIMS
m/z 270 (M+); HRMS m/z 270.0786 (calcd for C10H14N4O3S
270.0793).
4(5)-(5-Am in om eth ylfu r a n -2-yl)-1H-im id a zole (5). A so-
lution of 38 (7 mg, 0.03 mmol) in THF (5 mL) was refluxed
with 1.5 N HCl (1 mL) for 1 h and then cooled. The solution
was neutralized by addition of 30% NH4OH, and a small
amount of Chromatorex NH-DM 1020 was added to the
solution. The solvent was evaporated to give a coated silica
gel, which was subsequently placed in a column (Chromatorex
NH-DM 1020). Chromatography using MeOH-EtOAc (1:9) as
the eluent gave 5 (4 mg, 91%) as an oil: 1H NMR (CD3OD) δ
3.83 (s, 2H), 6.30 and 6.51 (each d, each 1H, J ) 3.3 Hz), 7.30
and 7.71 (each s, each 1H); EIMS m/z 163 (M+); HRMS m/z
163.0736 (calcd for C8H9N3O 163.0745).
The configuration counterparts were synthesized by the
present method. The ORD values of main compounds are
described below.
ent-15: ORD (c 1.03, EtOH) [R] (nm) +33.2° (589), +39.0°
(550), +46.8° (500), +62.4° (450), +85.9° (400), +130.7° (350),
+240.0 (308).
ent-16: mp 117.5-118.5 °C; ORD (c 1.52, EtOH) [R] (nm)
-21.1° (589), -28.0° (550), -34.3° (500), -42.2° (450), -58.1°
(400), -80.5° (350), -170.3° (308).
ent-21: mp 98-98.5 °C; ORD (c 0.95, EtOH) [R] (nm)
-102.1° (589), -120.6° (550), -146.0° (500), -190.5° (450),
-266.7° (400), -390.5° (350), -535.2° (374).
1-N,N-Dim eth ylsu lfa m oyl-2-ter t-bu tyld im eth ylsilyl-5-
(5-t er t -b u t y ld im e t h y ls ily lo x y m e t h y lfu r a n -2-y l)-1H -
im id a zole (36). Carbon tetrachloride (1.31 mL, 13.6 mmol)
was added to a stirred solution of 33 (2.58 g, 8.50 mmol) in
THF (30 mL). After the solution was cooled to -70 °C,
hexamethylphosphorus triamide (2.03 mL, 11.2 mmol) was
added dropwise over 5 min, and the mixture was stirred at
the same temperature for 5 min. Then the resulting gelatinoid
was allowed to warm to room temperature and further stirred
for 2 h. The solvent was evaporated to give a residue, which
was dissolved in diethyl ether-petroleum ether (1:1). The
resulting insoluble material was removed by decantation, and
the organic layer was evaporated to give crude 34 as an orange
oil. On the other hand, a solution of 1.6 M BuLi in hexane
(10.6 mL, 17 mmol) was added slowly over 10 min to a solution
of 1-N,N-dimethylsulfamoyl-2-tert-butyldimethylsilylimidazole
(4.90 g, 17 mmol) in THF (20 mL) to give white precipitates of
11 at -70 °C. After the suspension was stirred at the same
temperature for 0.5 h, a solution of 34 in THF (15 mL) was
added over 10 min to the mixture, and the dry ice bath was
removed. The resulting mixture was stirred for 0.5 h at room
temperature and then refluxed for 1 h. Then a small amount
of water was added to the reaction mixture and the solvent
was removed by evaporation under reduced pressure. The
residue was dissolved in EtOAc, and the solution was washed
with H2O and brine and dried. Evaporation of the solvent gave
crude glycal 35 as a brown oil. Silica gel (BW127ZH) (5.2 g)
was added to a solution of 35 in CH2Cl2 (50 mL), and the
resulting suspension was stirred at room temperature for 3
days. The silica gel was removed by filtration, washed with
EtOAc, and the filtrate was diluted with EtOAc. The solution
was washed with H2O and brine, dried, and evaporated. The
residue was purified by column chromatography using EtOAc-
hexane (1:19) to give 36 (1.51 g, 36% overall yield from 33) as
white powder, which was recrystallized from hexane to give
colorless needles: mp 92.5-93.0 °C; IR (Nujol, cm-1) 1630,
1580 (CdC), 1160 (SO2); 1H NMR (CDCl3) δ 0.11 (s, 6H), 0.42
(s, 6H), 0.90 (s, 9H), 1.06 (s, 9H), 2.57 (s, 6H), 4.65 (s, 2H),
6.32 and 6.62 (each d, each 1H, J ) 3.4 Hz), 7.29 (s, 1H); EIMS
m/z 499 (M+). Anal. Calcd for C22H41N3O4SSi2: C, 52.87; H,
8.27; N, 8.41. Found: C, 52.74; H, 8.28; N, 8.31.
ent-25: ORD (c 2.21, EtOH) [R] (nm) -40.7° (589), -48.9°
(550), -62.4° (500), -81.4° (450), -122.2° (400), -198.2° (350).
ent-1: ORD (c 0.53, EtOH) [R] (nm) -22.9° (589), -22.9°
(550), -28.6° (500), -45.7° (450), -57.2° (400), -91.4° (350),
-131.4° (300), -262.9° (250).
ent-2 (imifuramine): ORD (c 1.41, EtOH) [R] (nm) +5.7°
(589), +5.7° (550), +18.5° (500), +15.5° (450), +25.5° (400),
+48.2° (350), +102.1° (300).
ent-3: ORD (c 1.60, EtOH) [R] (nm) -37.6° (589), -43.9°
(550), -60.2° (500), -84.0° (450), -115.4° (400).
ent-4: ORD (c 2.24, EtOH) [R] (nm) +193.3° (589), +225.5°
(550), +289.9° (500), +386.6° (450), +547.7° (400).
1-N,N-Dim eth ylsu lfa m oyl-5-(5-h yd r oxym eth ylfu r a n -2-
yl)-1H-im id a zole (37). A 1 M THF solution of TBAF (3.0 mL,
3.0 mmol) was added to a solution of 36 (504 mg, 1.01 mmol)
in THF (10 mL) at 0 °C. After the reaction mixture was stirred
for 1 h at this temperature, the solvent was removed by
evaporation under reduced pressure to give a residue. It was
then dissolved in EtOAc-hexane (3:1), and the solution was
washed with H2O and brine and dried. Evaporation of the
solvent gave a crude oil, which was purified by column
chromatography using EtOAc to give 37 (264 mg, 96%) as an
oil: IR (neat, cm-1) 3300 (OH), 1630, 1580 (CdC), 1390, 1170
Ack n ow led gm en t. We thank President M. Oka,
Osaka University of Pharmaceutical Sciences, for en-
couraging us in this study. Financial support of this
work by the Ministry of Education, Science, and Culture
of J apan [Grant No. 09877421 (S.H.) and 90067281
(T.K.)] is gratefully acknowledged.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for the following compounds: 1-5, 7-10, 12-16, 18-
31, and 36-38. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
(SO2); H NMR (CDCl3) δ 2.72 (s, 6H), 4.63 (s, 2H), 6.38 and
6.70 (each d, each 1H, J ) 3.3 Hz), 7.26 and 8.01 (each s, each
1H); EIMS m/z 271 (M+); HRMS m/z 271.0619 (calcd for
C
10H13N3O4S 271.0626).
J O9910637