Efficient synthesis of trans- or cis-4(5)-(5-aminomethyltetrahydrofuran-2- yl)imidazoles via diazafulvene intermediates: Synthetic approach toward human histamine H4-ligands

Article abstract of DOI:10.1248/cpb.51.832

(+)-4(5)-[(2R,5R)-5-Aminomethyltetrahydrofuran-2-yl]imidazole [(+)-1, imifuramine] and its 2R,5S-stereoisomer (+)-2 were expected as base compounds to develop selective human histamine H₄-receptor ligands. The improved synthesis of (+)-1 was done via cyclization of a diazafulvene intermediate generated by Bu₃P/N,N,N′,N′-tetramethylazodicarboxamide (TMAD) treatment of a diol 17ab bearing an unsubstituted imidazole moiety in good yields. This methodology also afforded an alternative synthetic route to trans- and cis-ethyl 4(5)-(5-hydroxymethyltetrahydrofuran-2-yl)imidazole carboxylates (5 and 6), reported previously. Also, 4(5)-[(2R,5S)-5- aminomethyltetrahydrofuran-2-yl]imidazole (+)-2 was synthesized from ethyl 4(5)-(2-deoxy-β-D-ribofuranosyl) imidazole-1-carboxylate (35) via the four steps involving deoxygenation.

Full text of DOI:10.1248/cpb.51.832

832
Chem. Pharm. Bull. 51(7) 832—837 (2003)
Vol. 51, No. 7
Efficient Synthesis of trans- or cis-4(5)-(5-Aminomethyltetrahydrofuran-2-
yl)imidazoles via Diazafulvene Intermediates: Synthetic Approach toward
Human Histamine H4-Ligands
Shinya HARUSAWA,a Lisa ARAKI,a Hirotaka TERASHIMA,a Makoto KAWAMURA,a Seiichiro TAKASHIMA,a
Yasuhiko SAKAMOTO,b Takeshi HASHIMOTO,c Yumiko YAMAMOTO,c Atsushi YAMATODANI,c and
,a
*
Takushi KURIHARA
a Department of Synthetic Organic Chemistry, Osaka University of Pharmaceutical Sciences; 4–20–1 Nasahara, Takatsuki,
Osaka 569–1094, Japan: b R&D Division, AZWELL, Inc.; 2–24–3, Sho, Ibaraki, Osaka 567–0806, Japan: and
c Department of Bioinformatics, Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University; 1–7
Yamadaoka, Suita, Osaka 565–0871, Japan. Received March 17, 2003; accepted April 21, 2003
(؉)-4(5)-[(2R,5R)-5-Aminomethyltetrahydrofuran-2-yl]imidazole [(؉)-1, imifuramine] and its 2R,5S-
stereoisomer (؉)-2 were expected as base compounds to develop selective human histamine H4-receptor ligands.
The improved synthesis of (؉)-1 was done via cyclization of a diazafulvene intermediate generated by
Bu3P/N,N,N؅,N؅-tetramethylazodicarboxamide (TMAD) treatment of a diol 17ab bearing an unsubstituted imi-
dazole moiety in good yields. This methodology also afforded an alternative synthetic route to trans- and cis-ethyl
4(5)-(5-hydroxymethyltetrahydrofuran-2-yl)imidazole carboxylates (5 and 6), reported previously. Also, 4(5)-
[(2R,5S)-5-aminomethyltetrahydrofuran-2-yl]imidazole (؉)-2 was synthesized from ethyl 4(5)-(2-deoxy-b-D-ribo-
furanosyl)imidazole-1-carboxylate (35) via the four steps involving deoxygenation.
Key words imifuramine; diazafulvene; H4-receptor
Histamine H4 (H4)-receptor is the most recently discovered strategy was effective as an initial step for accessing these
histamine receptor which has approximately 35% overall ho- compounds, it lacks the stereoselective formation of 7 or 8
mology to the human histamine H3 (H3)-receptor.1—7) How- and, further, requires phenylselenenylation and deselenenyla-
ever, the tissue distribution of the two receptors is quite dif- tion steps in the synthetic sequence. On the other hand, we
ferent. The H3-receptor is mainly found in the central ner- reported an efficient and stereoselective synthesis of b-imida-
vous system, whereas the mRNA of the H4-receptor is ex- zole C-nucleosides bearing 4(5)-substituted imidazole as a
pressed exclusively in peripheral tissues, such as bone mar-
row,1,4) small intestine,1,6,7) spleen,4,6,7) and leukocytes.7) The
physiological and pathophysiological functions of the recep-
tor are unknown. However, the abundant expression of
human H4-receptor mRNA in the hematopoietic and lym-
phatic tissues indicates that the receptor might be related to
regulation of hematopoiesis and/or an immune function. To
investigate the pharmacology of the receptor, specific ligands
are indispensable, but most H3-ligands are active at the H4-
receptor as well and no specific ligands for the H4-receptor
are available.8)
We very recently examined the binding affinity and func-
tional activity of 2,5-disubstituted tetrahydrofuranylimida-
zoles for human H3- and H4-receptors expressed in SK-N-
MC cells.9) Among them, (ϩ)-4(5)-[(2R,5R)-5-aminomethyl-
tetrahydrofuran-2-yl] imidazole [(ϩ)-1, imifuramine]10,11) ex-
hibited potent agonistic activities for the H3-receptor, while
its enantiomer (Ϫ)-1 was found to be a selective H3-agonist,
which was approximately 300-fold more active at the H3-re-
ceptor than the H4-receptor (Fig. 1). It is of particular interest
to find that methylcyanoguanidine derivatives (Ϫ)-3 (OUP-
16) and (ϩ)-4 (OUP-13) exhibited full agonistic activities for
the H4-receptor with 40- to 45-fold selectivity over the H3-re-
ceptor. Hence, the two OUP compounds would be lead com-
pounds to develop selective human H4-receptor ligands.8)
We previously reported a stereodivergent synthesis of
trans- or cis-4(5)-(5-aminomethyltetrahydrofuran-2-yl- or 5-
aminomethyl-2,5-dihydrofuranyl)imidazoles, which is char-
acterized by use of a- or b-phenylselenenyl nucleosides 7 or
8 as key intermediates (Fig. 1).10—12) Although the synthetic
Fig. 1
To whom correspondence should be addressed. e-mail: kurihara@gly.oups.ac.jp
© 2003 Pharmaceutical Society of Japan

July 2003
833
Chart 1
common structural unit, using the cyclization of 1,3-diazaful-
vene generated in situ (Chart 1).13,14) In that report, we also
indicated that an unsubstituted imidazole moiety is indis-
pensable for the generation of the diazafulvene 10, and the
benzyloxy group at the C2Ј-position of the substrate 9RS (di-
astereomeric mixtue at C1Ј) acts as the directing group to
control the stereochemistry of b-imidazole C-nucleoside
11b.13,14) The methodology was recently extended to stereo-
controlled synthesis of heterocyclic C-nucleosides (indole,
C-2 linked imidazole, benzimidazole, and 6-iodobenzimida-
zole) by Benhida et al.15,16) In such circumstances, the find-
ings of OUP-16 and 13 encouraged us to synthesize trans- or
cis-tetrahydrofuranylimidazoles using the diazafulvene-cy-
clization.
We herein describe a simple and effective synthesis of imi-
furamine [(ϩ)-1] via a diazafulvene intermediate. Also, this
synthetic method was independently used for the synthesis of
trans- and cis-ethyl 4-(5-hydroxymethyltetrahydrofuranyl)-
imidazole-1-carboxylates 5 and 6, useful intermediates in our
quest for specific H4-ligands. Further, 4(5)-[(2R,5S)-5-
aminomethyltetrahydrofuran-2-yl]imidazole [(ϩ)-2], which
is a substrate of OUP-13, was efficiently synthesized from
ethyl 4(5)-(2-deoxy-b-D-ribofuranosyl)imidazole-1-carboxy-
late (35).
Chart 2
Table 1. Solvent Effects of Cyclization to 23ab
Synthesis of Imifuramine We recently reported that in-
tramolecular Mitsunobu reaction of a diol 14ab17) (1 : 1 di-
astereomeric mixture), which was prepared starting from (R)-
benzyloxymethyl-g-butyrolactone (12),18) with N,N,NЉ,NЉ-
tetramethylazodicarboxamide (TMAD)19) and Bu3P followed
by desilylation affords trans- and cis-cyclization products 15
(47%, 9% ee) and 16 (53%, 20% ee) with low optical purities
(Chart 2). The low optical purities were attributed to indistin-
guishable activities between two hydroxy groups of 14ab.17)
Thus, we directed our attention to imifuramine synthesis
using diazafulvene cyclization. Hydrolysis of 14ab in reflux-
ing 1.5 N HCl afforded a diol 17ab having unsubstituted imi-
dazole in 95% yield. The cyclization of 17ab was examined
under various conditions to optimize the yield of the trans-
product.14,20) The results are summarized in Table 1. When
the reaction of 17ab was first carried out using TMAD and
Run
Solvent
Temp. (°C)
Yield (%)
23a/23b
1
2
3
4
5
6
7
8
THF
THF
THF
Benzene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
rt
0
12
12
15
56
50
68
80
15
2.3/1
3/1
2/1
2/1
2/1
1/1
3/1
5/1
Reflux
rt
0
rt
0
Ϫ35
Bu3P at rt in tetrahydrofuran (THF) for 2 h, a crude tetrahy- zene or toluene, respectively (run 4 and 5). Further, the use
drofuranylimidazole 18ab was obtained. The crude mixture of CH2Cl2 at 0 °C increased the yield to 80% with a 3 : 1 ratio
was then treated with ethyl chloroformate to separate it from of trans- and cis-products (run 7). The predominant forma-
the Bu3PϭO by-product, followed by column chromatogra- tion of the trans-isomer was also observed in CH2Cl2 at
phy to afford a 2.3 : 1 mixture of trans- and cis-N-ethoxycar- Ϫ35 °C, but in only 15% yield (run 8). From these results, it
bonylated products 23a and 23b in only 12% overall yield became clear that the reaction was significantly influenced by
from 17ab (Table 1, run 1). In the case of THF (Table 1, run the selection of solvents.
1—3), the reaction was suppressed to give low yields, but the
The structures of 23a and 23b were assigned on the basis
yields of 23ab were improved to 56% or 50% yields in ben- of 1H-NMR. The C5Ј-H (d 4.32—4.55, m, 5ЈH and CO2CH2)

834
Vol. 51, No. 7
in trans-23a was observed in lower field in comparison with
that (d 4.16—4.31, m) in cis-23b, because of the deshielding
effect of the imidazole ring located syn in 23a.17)
At a practical level, a serious drawback of the N-ethoxy-
carbonyl product 23ab is the difficulty in separating the re-
spective trans- and cis-isomers 23a and 23b by SiO2 column
chromatography. It required a large column to avoid contami-
nation of the trans-product by the cis-isomer. After many tri-
als, we found that N-Boc-phthalimides 21 and 22 could be
separated more easily by column chromatography. Thus, the
Boc derivatives were prepared from 17ab (Chart 2). The cy-
clodehydration of 17ab with TMAD and Bu3P in CH2Cl2 at
0 °C for 15 h followed by N-Boc-protection was carried out
to produce a 3 : 1 mixture of 19a and 19b in 90% yield from
17ab. Debenzylation of 19ab using H2/Pd-C and subsequent
Mitsunobu phthaloylimination afforded crude phthalimides.
After chromatographic separation of the trans-isomer 21
contaminated by diethyl 1,2-hydrazine-dicarboxylate formed
in the Mitsunobu reaction, deprotection of the crude 21 with
hydrazine hydrate and purification yielded (ϩ)-1, imifu-
ramine,12) in 37% overall yield21) from the diol intermediate
17ab. Similarly, cis-(Ϫ)-212) was obtained from crude 22 in
6% overall yield from 17ab. This synthetic process allows
the synthesis of the enantiomer (Ϫ)-1 by simply switching
the starting material to (ϩ)-12.
Synthesis of trans- and cis-Ethyl 4-(5-Hydroxymethylte-
trahydrofuranyl)imidazole-1-carboxylates Schunack et
al. used 3-(1H-imidazole-4-yl)propanol,22) which is easily
synthesized from urocanic acid, as the central building block
to develop many potent H3-agonists or antagonists.23) Thus,
trans- or cis-alcohols 5 and 6 may be useful intermediates to
supply a variety of derivatives (Fig. 1). Since hydrogenolysis
of benzyl ethers 19ab or 23ab synthesized above afforded an
inseparable mixture of the corresponding alcohols, we in-
tended an easy isolation of 5 and 6 by the cyclization of a
diol 29ab having a bulky trityloxy group at the C5Ј-position
(Chart 3).
Novel N-[2-(trimethylsilyl)ethoxy]methyl (SEM) protected
4- and 5-iodoimidazoles 24 and 25 were first prepared from
4(5)-iodoimidazole24,25) in 55% and 37% yields, respectively
(Chart 3, Eq. 1). The N-SEM compounds 24 and 25 were as-
signed by the respective NOE experiments, as illustrated in
Chart 3. According to the Lindell procedure,26) 24 or 25 was
treated with ethylmagnesium bromide to generate C4 or C5-
imidazole anions, which were then reacted with lactol 28,27)
which was prepared by reduction of 2,3-dideoxy-5-O-trityl-L-
glyceropentanoic acid g-lactone27) with DIBAL-H, to give
the corresponding diols 26ab or 27ab in 81% and 56%
yields, respectively (Chart 3, Eq. 2). Thus, without their iso-
lation, the mixture of 24 and 25 was treated as above to give
an isomeric mixture (26ab, 27ab) in 78% yield (Chart 3).
The following cleavage of the SEM group with tetra-n-butyl
ammonium fluoride sluggishly proceeded in refluxing THF
to give unsubstituted imidazole 29ab (41%), but this reaction
was improved to give a much higher yield (84%) under coex-
isting ethylenediamine28) in refluxing THF for 20 h. Cycliza-
tion (TMAD-Bu3P) of 29ab in CH2Cl2, followed by ethoxy-
carbonylation of the resulting 30ab produced trans- and cis-
isomers 31 and 32 after flash column chromatography. The
better result [31 (43 %) and 32 (25%)] for the cyclization
was attained in refluxing CH2Cl2 for 2 h in this case. Detrity-
Chart 3
lation of 31 with Pd(OH)2-C in cyclohexene gave the desir-
able (Ϫ)-5 (57%) and 4-(5-hydroxymethyltetrahydrofuranyl)-
imidazole 33 (37%), the latter of which could revert to 5 by
N-ethoxycarbonylation.12) In a similar manner, cis-isomer
(Ϫ)-6 (63%) and 34 (25%) were obtained from 32.
Their configuration counterparts (ϩ)-5 and (ϩ)-6 were
also synthesized from 2,3-dideoxy-5-O-trityl-D-glyceropen-
tanoic acid g-lactone27) by the same methodology. The con-
version of 5 or 6 into trans-1 or its cis-isomer 2 has already
been described in our previous report.12) Accordingly, the
present method may become a more efficient stereodivergent
synthetic route to the trans- and cis-amino compounds than
the previous method using the PhSe group.
Synthesis of 4(5)-[(2R,5S)-5-Aminomethyltetrahydrofu-
ran-2-yl]imidazole [(؉)-2] We reported an efficient and
stereoselective synthesis of ethyl 4(5)-(2-deoxy-b-ribofura-
nosyl)imidazole-1-carboxylate (35) by using the cyclization
via a diazafulvene intermediate.14) An advantageous feature
of this approach is that it enables the supply of a multigram
scale of 35 from D-2-deoxyribose. Thus, we selected 35 for
the synthesis of (ϩ)-2 (Chart 4).
After phthaloylimination of 35, the deoxygenation of the
resulting secondary alcohol 36 was achieved as follows.28)
Reaction of 36 with 1,1Ј-thiocarbonyldiimidazole in DMF
gave crude thiocarbonylimidazolide 37, which was subse-
quently treated with Bu3SnH and AIBN to give an ethoxycar-

July 2003
835
stirred with Boc2O (1.671 g, 7.67 mmol) and Et3N (1.06 ml, 7.67 mmol) at
room temperature (rt) for 22 h. The solvent was evaporated, and the residue
was extracted twice with EtOAc. The extract was washed with H2O, brine,
dried, and concentrated. The residual oil was subjected to flash chromatogra-
phy using EtOAc–hexane (1 : 4) for elution to give 19ab [1.232 g (90%),
19a/19bϭ3 : 1]. Although the separation of 19a (55%) and 19b (13%) was
not required for the following experiment, 19a and 19b were carefully iso-
lated by column chromatography by use of EtOAc–hexane (3 : 7) and char-
acterized spectroscopically. 19a: Colorless oil, Rf (ethyl acetate) 0.6. IR
(nujol) cmϪ1: 1750. 1H-NMR (CDCl3, 300 MHz) d: 1.60 (9H, s), 1.77—1.97
(1H, m), 2.03—2.20 (2H, m), 2.24—2.40 (1H, m), 3.54 (2H, d, Jϭ5.1 Hz),
4.39 (1H, quint, Jϭ5.7 Hz), 4.60 (2H, s), 5.04 (1H, t, Jϭ6.2 Hz), 7.23—7.40
(6H, m), 8.00 (1H, s). HR-MS m/z: 358.1878 (Calcd for C20H26N2O4:
358.1891). EI-MS m/z: 358 (Mϩ). 19b: Colorless oil; Rf (ethyl acetate) 0.55;
1
IR (nujol) cmϪ1: 1750. H-NMR (CDCl3, 300 MHz) d: 1.60 (9H, s), 1.77—
1.96 (1H, m), 1.98—2.16 (2H, m), 2.21—2.46 (1H, m), 3.48—3.64 (2H, m),
4.23 (1H, quint, Jϭ5.9 Hz), 4.58 (2H, s), 4.95 (1H, t, Jϭ6.2 Hz), 7.23—7.40
(6H, m), 8.00 (1H, s). HR-MS m/z: 358.1878 (Calcd for C20H26N2O4:
358.1891). EI-MS m/z: 358 (Mϩ).
Chart 4
Ethyl 4-(5-Benzyloxymethyltetrahydrofuran-2-yl)imidazole-1-car-
boxylate (23ab) By the same procedure as for the preparation of 18ab, a
mixture of 17ab (130 mg, 0.47 mmol), Bu3P (0.14 ml, 0.52 mmol), and
bonyl compound 38 and unsubstituted imidazole 39 in 42%
and 30% yields from 36, respectively. We first encountered a TMAD (89 mg, 0.52 mmol) in benzene (15 ml) was stirred for 2 h at rt to
give crude 18ab, which was refluxed with ethyl chloroformate (0.05 ml,
0.52 mmol), pyridine (0.04 ml, 0.52 mmol), and a catalytic amount of 4-(di-
low yield of 37, but the problem was solved by high concen-
tration (1 M concentration of 36) of DMF. This result indi-
cates the close contact of 1,1Ј-thiocarbonyldiimidazole and
methylamino)pyridine (DMAP) in benzene (20 ml) for 15 min to give a 2 : 1
1
mixture (87 mg, 56%) of 23a and 23b as an oil: H-NMR (CDCl3) d: 1.41
36 in high concentration is essential to promote the reac-
tion.30) Deprotection of 38 and 39 with hydrazine hydrate af-
forded (ϩ)-2 in 85% and 75% yields, respectively.
In conclusion, we have described a simple and efficient
synthesis of imifuramine (ϩ)-1 and N-ethoxycarbonyl inter-
mediates 5 and 6 via diazafulvene intermediates. Further,
(ϩ)-cis-amino compound 2 was obtained from 35. The syn-
thetic processes would supply a variety of derivatives by
which the H4-receptor activities of tetrahydrofuranylimida-
zoles can be assessed.
(3H, t, Jϭ7.3 Hz), 1.75—2.41 (4H, m), 3.54 (4/3H, d, Jϭ5.0 Hz), 3.59
(2/3H, dd, Jϭ5.0, 1.6 Hz), 4.16—4.31 (1/3H, m), 4.32—4.55 (8/3H, m),
4.60 (2H, s), 4.98 (1/3H, t, Jϭ6.4 Hz), 5.06 (2/3H, t, Jϭ6.4 Hz), 7.24—7.40
(6H, m), 8.10 (1H, s).
tert-Butyl 4-[(2RS,5R)-5-Hydroxymethyltetrahydrofuran-2-yl]imida-
zole-1-carboxylate (20ab) A solution of 19ab (680 mg, 1.90 mmol) in
MeOH (20 ml) was hydrogenated over 10% Pd–C (408 mg) at 3.0 kg/cm2 for
12 h. After filtration through Celite, the filtrate was concentrated to give a
crude oil, which was purified by column chromatography [MeOH–EtOAc
(3 : 97)] to give 20ab (421 mg, 83%) as a colorless oil. IR (nujol) cmϪ1
:
1
1750. H-NMR (CD3OD) d: 1.62 (9H, s), 1.76—1.92 (1H, m), 2.02—2.37
(3H, m), 3.48—3.73 (2H, m), 4.05—4.16 (1/4H, m), 4.22 (3/4H, m), 4.84—
5.02 (1H, overlapped with H2O in CD3OD), 7.62 (3/4H, s), 7.67 (1/4H, s),
8.17 (1H, s). HR-MS m/z: 269.1513 (Calcd for C13H21N2O4: 269.1500). SI-
Experimental
The melting points were determined on a hot-stage apparatus and were MS m/z: 269 (Mϩϩ1).
uncorrected. Optical rotation measurements were recorded with a JASCO
4(5)-[(2R,5R)-5-Aminomethyltetrahydrofuran-2-yl]imidazole [(؉)-1]
DIP-1000 digital polarimeter. IR spectra were recorded on a Shimadzu IR- Phthalimide (440 mg, 2.99 mmol) and PPh3 (1.809 g, 6.90 mmol) were dis-
1
435 spectrometer. H- and 13C-NMR spectra were taken with tetramethylsi- solved in a solution of 20ab (618 mg, 2.30 mmol) in THF (13 ml). To this
lane as an internal standard on a Varian Gemini-200, Varian Mercury-300, mixture was added DEAD (1.07 ml, 6.90 mmol) with stirring at 0°C. The re-
and Varian UNITY INOVA-500 spectrometers. Reactions with air- and action mixture was stirred at rt for 1 h, and then the whole was concentrated
moisture-sensitive compounds were carried out under an argon atmosphere. to give a residue, which was subsequently dissolved in EtOAc. The solution
Unless otherwise noted, all extracts were dried over Na2SO4, and the solvent was washed with H2O and brine, dried, and concentrated to give a crude oil,
was removed in a rotary evaporator under reduced pressure. Bu3P (Ͼ90%) which was subjected to chromatography {Rf (80% EtOAc in hexane); 0.68
was purchased from Tokyo Kasei Kogyou Co., Ltd. For column chromatog- (21), 0.62 (22)}. Elution with EtOAc–hexane (19 : 31) afforded a mixture
1
raphy, BW-127ZH, FL-60D, and Chromatorex NH-DM 1020 (Fuji Silysia (1.1 g) of 21 and diethyl 1,2-hydrazinedicarboxylate. 21: H-NMR (CDCl3)
Chemical Ltd.) were used. THF was distilled from sodium-benzophenone. d: 1.60 (9H, s), 1.75—1.90 (1H, m), 2.11—2.40 (3H, m), 3.68 (1H, dd,
HPLC analyses were carried out with a Waters Associates instrument [col- Jϭ13.8, 5.0 Hz), 3.89 (1H, dd, Jϭ13.8, 8.2 Hz), 4.56 (1H, quint, Jϭ6.5 Hz),
umn; Daicel CHIRALPAK® AD, 0.46 cmϫ25 cm; eluent, 10% 2-propanol in 5.10 (1H, t, Jϭ6.3 Hz), 7.24 (1H, s), 7.66—7.88 (4H, m), 7.99 (1H, s). 22:
hexane; detection 254 nm]. TLC were performed on pre-coated TLC plates 1H-NMR (CDCl3) d: 1.60 (9H, s), 1.74—1.94 (1H, m), 2.00—2.20 (3H, m),
with 60F254 (silica gel, Merck).
4(5)-[(1RS,4R)-5-Benzyloxy-1,4-dihydroxypentyl]imidazole (17ab)
3.80 (1H, dd, Jϭ13.3, 4.9 Hz), 3.95 (1H, dd, Jϭ13.3, 7.4 Hz), 4.33—4.49
(1H, m), 4.98 (1H, t, Jϭ6.2 Hz), 7.56 (1H, s), 7.66—7.92 (4H, m), 7.99 (1H,
A
solution of 14ab (439 mg, 0.88 mmol) in THF (10 ml) was refluxed with s). A solution of the crude 21 thus obtained and NH2NH2·H2O (813 mg,
1.5 N HCl (7 ml) for 4 h and then cooled. After neutralization by addition of 16.25 mmol) in EtOH (30 ml) was refluxed for 2 h and then cooled. A small
28% NH4OH, the solvent was evaporated to give a residue, which was ex- amount of 10% Pd–C was then added to the solution, and the reaction mix-
tracted with EtOAc (ϫ3) by salting-out techniques. The extract was washed ture was further refluxed for 10 min. After removal of the catalyst by filtra-
with brine, dried, and concentrated to give an oil, which was subjected to tion through a Celite pad, the solvent was evaporated to give a residual oil. It
chromatography. Elution with MeOH–EtOAc (3 : 7) afforded 17ab (231 mg, was purified by chromatography (Chromatorex NH-DM 1020) with
1
95%) as a pale yellow oil. H-NMR (CDCl3) d: 1.30—2.12 (4H, m), 3.43 MeOH–EtOAc (1 : 9) to give (ϩ)-112,21) (170 mg, 64% converted from a 3 : 1
(2H, d, Jϭ7.6 Hz), 3.70—3.85 (1H, m), 4.54 (2H, s), 4.68 (1H, t, Jϭ6.0 Hz), mixture of 20a and 20b) as an oil: ORD (cϭ3.35, EtOH) [a] (nm) ϩ7.8°
6.96 (1H, s), 7.21—7.42 (5H, m), 7.62 (1H, s).
(589), ϩ11.1° (550), ϩ16.1° (500), ϩ22.2° (450), ϩ38.2° (400), ϩ73.0°
tert-Butyl 4-[(2RS,5R)-5-Benzyloxymethyltetrahydrofuran-2-yl]imida- (350). 1H-NMR (CD3OD) d: 1.61—1.82 (1H, m), 2.02—2.38 (3H, m), 2.73
zole-1-carboxylate (19ab) To a solution of 17ab (1.058 g, 3.83 mmol) and (2H, d, Jϭ6.0 Hz), 4.17 (1H, m), 5.02 (1H, t, Jϭ6.5 Hz), 7.02 (1H, s), 7.64
Bu3P (1.52 ml, 5.75 mmol) in CH2Cl2 (195 ml) at 0 °C was added TMAD (1H, s).
(989 mg, 5.75 mmol). The resulting mixture was stirred at 0 °C for 15 h. The
4- and 5-Iodo-1-[2-(trimethylsilyl)ethoxymethyl]-1H-imidazole (24,
solvent was evaporated to give a residual oil, which was dissolved with 25) A suspension of NaH (60% in mineral oil, 134 mg, 3.30 mmol) in
CHCl3 and H2O. The CHCl3 layer was washed with brine, dried, and concen- hexane was stirred for 5 min. After removal of the supernatant solution, THF
trated to give a crude oil of 18ab. The solution of 18ab in THF (8 ml) was (4 ml) was added therein. A solution of 4(5)-iodoimidazole24,25) (582 mg,

836
Vol. 51, No. 7
m), 5.04 (1H, t, Jϭ6.3 Hz), 7.16—7.53 (16H, m), 8.09 (1H, s). 13C-NMR
(CDCl3) d: 14.6, 29.0, 32.1, 64.4, 66.4, 75.3, 78.4, 113.1, 126.5, 127.3,
128.3, 136.6, 143.6, 145.0, 148.1. HR-MS m/z: 482.2199 (Calcd for
C30H30N2O4: 482.2204). EI-MS m/z: 482 (Mϩ). (ϩ)-32: Colorless oil, Rf
(50% EtOAc in hexane) 0.40. [a]Dϭϩ18.3° (cϭ3.60, MeOH). IR (nujol)
3.00 mmol) in THF (3 ml) was added to the resulting suspension of NaH at
0 °C. The whole was stirred for 0.5 h at rt, and then 2-(trimethylsilyl)-
ethoxymethyl chloride (0.60 ml, 3.15 mmol) was added to the mixture at
0 °C. After 15 min at the same temperature, the reaction was quenched with
saturated NH4Cl solution and the THF was concentrated. The residue was
extracted twice with CH2Cl2, and the solution was subsequently washed with
H2O, brine, dried, and concentrated to give a crude oil. Chromatography
using EtOAc and hexane (1 : 3) as eluent gave 24 (535 mg, 55%) and 25
(362 mg, 37%). 24: Colorless oil, 1H-NMR (CDCl3) d: 0—0.10 (9H, m),
0.92 (2H, t, Jϭ8.0 Hz), 3.49 (2H, t, Jϭ8.0 Hz), 5.26 (2H, s), 7.15 (1H, s),
7.50 (1H, s). 13C-NMR (CDCl3) d: Ϫ0.9, 18.1, 66.8, 76.0, 124.1, 138.2. HR-
MS m/z: 324.0158 (Calcd for C9H17IN2OSi: 324.0156). EI-MS m/z: 324
1
cmϪ1: 1755. H-NMR (CDCl3) d: 1.35 (3H, t, Jϭ7.1 Hz), 1.77—1.92 (1H,
m), 1.95—2.14 (2H, m), 2.21—2.35 (1H, m), 3.14 (1H, dd, Jϭ9.6, 4.5 Hz),
3.27 (1H, dd, Jϭ9.6, 5.4 Hz), 4.23 (1H, m), 4.33—4.49 (2H, m), 5.00 (1H, t,
Jϭ6.1 Hz), 7.17—7.51 (16H, m), 8.06 (1H, s). 13C-NMR (CDCl3) d: 14.5,
28.5, 31.9, 64.3, 66.5, 76.0, 79.1, 113.0, 126.5, 127.3, 128.3, 136.4, 143.6,
145.5, 148.0. HR-MS m/z: 482.2208 (Calcd for C30H30N2O4: 482.2204). EI-
MS m/z: 482 (Mϩ). The configuration counterparts (Ϫ)-31 and (Ϫ)-32 were
synthesized by the present method from L-glutamic acid. (Ϫ)-31:
[a]DϭϪ20.1° (cϭ1.80, MeOH), (Ϫ)-32: [a]DϭϪ17.3° (cϭ1.92, MeOH).
(؊)-Ethyl 4-[(2R,5R)-5-Hydroxymethyltetrahydrofuran-2-yl]imida-
zole-1-carboxylate [(؊)-5] A mixture of 31 (126 mg, 0.26 mmol), 20%
Pd(OH)2–C (76 mg), and cyclohexene (0.79 ml, 7.83 mmol) was refluxed for
2.5 h. After filtration through a Celite pad, the filtrate was concentrated to
1
(Mϩ). 25: Colorless oil, H-NMR (CDCl3) d: 0—0.16 (9H, m), 0.93 (2H, t,
Jϭ8.0 Hz), 3.54 (2H, t, Jϭ8.0 Hz), 5.28 (2H, s), 7.15 (1H, s), 7.75 (1H, s).
13C-NMR (CDCl3) d: Ϫ0.9, 18.1, 66.5, 76.0, 137.0, 139.8. HR-MS m/z:
324.0156 (Calcd for C9H17IN2OSi: 324.0156). EI-MS m/z: 324 (Mϩ).
1-(2-Trimethylsilyl)ethoxymethyl-4-[(1RS,4R)-1,4-dihydroxy-5-trity-
loxypentyl]imidazole (26ab) A solution of 24 (925 mg, 2.86 mmol) in dry
CH2Cl2 (11 ml) was added to a 3 M Et2O solution of EtMgBr (0.95 ml,
2.86 mmol) at 0 °C. After 40 min at rt, 2827) (411 mg, 1.14 mmol) in dry
CH2Cl2 (2.5 ml) was added dropwise at 0 °C, and the mixture was stirred at
rt for 14 h. Saturated NH4Cl solution was then added, and the aqueous phase
was extracted twice with CH2Cl2. The combined organic extracts were
washed with H2O, dried (MgSO4) and concentrated. Flash chromatography
of the residue yielded 26ab (517 mg, 81%) as a colorless oil. 1H-NMR
(CD3OD) d: Ϫ0.03 (9/2H, s), 0.01 (9/2H, s), 0.85 (2H, t, Jϭ9.4 Hz), 1.25—
2.08 (4H, m), 2.90—3.14 (2H, m), 3.50 (2H, t, Jϭ9.4 Hz), 3.74 (1H, m),
4.60 (1H, t, Jϭ6.3 Hz), 5.38 (2H, s), 7.09 (1H, s), 7.13—7.50 (15H, m), 7.71
(1H, s). HR-MS m/z: 559.2992 (Calcd for C33H43N2O4Si: 559.2990). SI-MS
m/z: 559 (Mϩϩ1).
give
a residue. It was purified by column chromatography using
MeOH–EtOAc (1 : 19) to give (Ϫ)-512) (36 mg, 57%) as a colorless oil. Fur-
ther elution with MeOH provided 33 (16 mg, 37%) as an oil, which was sub-
sequently reverted to (Ϫ)-5 (53%) by treatment with ethyl chloroformate
and DMAP.12) (Ϫ)-5: Rf (10% MeOH in EtOAc); 0.42. H-NMR (CD3OD)
1
d: 1.41 (3H, t, Jϭ6.9 Hz), 1.77—1.89 (1H, m), 1.97—2.16 (2H, m), 2.22—
2.36 (1H, m), 3.53 (1H, dd, Jϭ11.0, 5.1 Hz), 3.60 (1H, dd, Jϭ11.0, 4.2 Hz),
4.22 (1H, quint, Jϭ5.5 Hz), 4.47 (2H, q, Jϭ6.9 Hz), 4.98 (1H, t, Jϭ6.5 Hz),
1
7.46 (1H, s), 8.22 (1H, s). 33: H-NMR (CD3OD) d: 1.76—1.92 (1H, m),
1.96—2.19 (2H, m), 2.24—2.42 (1H, m), 3.54 (1H, dd, Jϭ11.8, 5.4 Hz),
3.62 (1H, dd, Jϭ11.8, 3.7 Hz), 4.17—4.27 (1H, m), 5.09 (1H, t, Jϭ6.9 Hz),
7.30 (1H, s), 8.38 (1H, s). The configuration counterpart (ϩ)-5 was synthe-
sized by the present method from L-glutamic acid. (ϩ)-5: [a]Dϭϩ3.20°
(cϭ1.97, CHCl3).31) HPLC (flow rate 2 ml/min; tR 15.6 min) exhibited a sin-
gle peak.
1-(2-Trimethylsilyl)ethoxymethyl-5-[(1RS,4R)-1,4-dihydroxy-5-trityl-
oxypentyl]imidazole (27ab) In the same manner as 26ab, a solution of
2827) (443 mg, 1.23 mmol) in CH2Cl2 (2 ml) was added to a mixture of 25
(997 mg, 3.01 mmol) and 3 M Et2O solution of EtMgBr (1.00 ml, 3.00 mmol)
(؊)-Ethyl 4-[(2S,5R)-5-Hydroxymethyltetrahydrofuran-2-yl]imida-
zole-1-carboxylate [(؊)-6] The mixture of 32 (70 mg, 0.15 mmol), cyclo-
hexene (0.44 ml, 4.35 mmol), and 20% Pd(OH)2–C (42 mg) in EtOH (4 ml)
was refluxed to give (Ϫ)-612) (22 mg, 63%) and 34 (6 mg, 25%) as colorless
oils by the same procedure for the preparation for 5. (Ϫ)-6: Rf (10% MeOH
1
to give 27ab (387 mg, 56%) as a colorless oil. H-NMR (CD3OD) d: 0.00
(9H, s), 0.86 (2H, t, Jϭ8.0 Hz), 1.37—2.12 (4H, m), 2.95—3.18 (2H, m),
3.44—3.59 (2H, m), 3.70—3.84 (1H, m), 4.77 (1H, t, Jϭ7.2 Hz), 5.28—
5.59 (2H, m), 6.92 (1H, s), 7.16—7.53 (15H, m), 7.76 (1H, s). HR-MS m/z:
559.2991 (Calcd for C33H43N2O4Si: 559.2990). SI-MS m/z: 559 (Mϩϩ1).
1-(2-Trimethylsilyl)ethoxymethyl-4(5)-[(1RS,4R)-1,4-dihydroxy-5-
trityloxypentyl]imidazole (26ab/27ab) By the same procedure as for the
preparation of 26ab, a 1 : 1 mixture (2.309 g, 7.13 mmol) of 24 and 25 in dry
CH2Cl2 (29 ml) was added to a 3 M Et2O solution of EtMgBr (2.38 ml,
7.13 mmol) at 0 °C. After 0.5 h at rt, 2827) (1.026 g, 2.85 mmol) in dry
CH2Cl2 (6 ml) was added at 0 °C, and the mixture was stirred at rt for 14 h
followed by column chromatography to yield a 3.6 : 1 mixture of 26ab and
27ab (1.243 g, 78%) as an oil.
1
in EtOAc); 0.33. H-NMR (CD3OD) d: 1.41 (3H, t, Jϭ7.1 Hz), 1.77—2.11
(3H, m), 2.14—2.35 (1H, m), 3.55 (1H, dd, Jϭ11.9, 5.3 Hz), 3.67 (1H, dd,
Jϭ11.9, 3.9 Hz), 4.10 (1H, quint, Jϭ5.7 Hz), 4.48 (2H, q, Jϭ7.1 Hz), 4.84—
4.94 (1H, m, overlapped with H2O in CD3OD), 7.52 (1H, s), 8.23 (1H, s).
34: 1H-NMR (CD3OD) d: 1.80—2.14 (3H, m), 2.20—2.36 (1H, m), 3.57
(1H, dd, Jϭ11.7, 5.0 Hz), 3.70 (1H, dd, Jϭ11.7, 3.6 Hz), 4.06—4.18 (1H,
m), 5.00 (1H, t, Jϭ6.6 Hz), 7.23 (1H, s), 8.20 (1H, s).
The configuration counterparts were synthesized by the present method
from L-glutamic acid. (ϩ)-6: [a]Dϭϩ9.78° (cϭ1.64, CHCl3).31) HPLC (flow
rate 2 ml/min; tR 10.4 min) exhibited a single peak.
4(5)-[(1RS,4R)-1,4-Dihydroxy-5-trityloxypentyl]imidazole (29ab) To
a solution of 26ab/27ab (200 mg, 0.36 mmol) in THF (1.5 ml) 1 M THF solu-
tion of tetra-n-butylammonium fluoride (1.08 ml, 1.07 mmol) and ethylene-
diamine (0.14 ml, 2.15 mmol) were added, and the resulting mixture was re-
fluxed for 20 h. A small amount of silica gel was added to the cooled solu-
tion. The solvent was evaporated to give a coated silica gel, which was sub-
sequently placed in a column. Chromatography using MeOH–EtOAc (1 : 9)
Ethyl 4-(2,5-Dideoxy-5-phthaloylamino-b-ribofuranosyl)imidazole-1-
carboxylate (36) Phthalimide (828 mg, 5.63 mmol) and PPh3 (1.48 g,
5.63 mmol) were dissolved in a solution of 35 (1.31 g, 5.12 mmol) in THF
(70 ml). To this mixture was added DEAD (0.96 ml, 5.63 mmol) with stir-
ring. The reaction mixture was stirred at rt for 2 h, and then the THF was
evaporated to give a residue. It was purified by flash chromatography with
EtOAc–hexane (11 : 9) to give 36 (1.795 g, 95%) as a white amorphous
product. IR (KBr) cmϪ1: 3400, 1762, 1712. 1H-NMR (CDCl3) d: 1.43 (3H, t,
Jϭ7.0 Hz), 2.30 (2H, dd, Jϭ7.0, 4.5 Hz), 3.00 (1H, br s), 3.88 (2H, m), 4.18
(1H, m), 4.45 (3H, m), 5.16 (1H, t, Jϭ7.0 Hz), 7.38 (1H, s), 7.64—7.75 (2H,
m), 7.78—7.89 (2H, m), 8.00 (1H, s). 13C-NMR (CDCl3) d: 14.7, 40.6, 40.8,
64.9, 74.6, 74.9, 84.2, 114.4, 123.8, 132.5, 134.5, 137.5, 144.8, 149.0, 169.0.
HR-MS m/z: 386.1352 (Calcd for C19H20N3O6: 386.1351). SI-MS m/z: 386
(Mϩϩ1).
Deoxygenation of 36 A mixture of 36 (237 mg, 0.615 mmol) and thio-
carbonyldiimidazole (135 mg, 0.737 mmol) in DMF (0.6 ml) was stirred at rt
for 13 h. The resulting mixture was dissolved with EtOAc, and the solution
was washed with H2O and brine, dried, and concentrated to give a crude 37.
To a toluene solution (15 ml) of the crude 37 were added a mixture of
Bu3SnH (0.20 ml, 0.74 mmol) and AIBN (10 mg, 0.06 mmol) in toluene
(0.5 ml), and then the whole was refluxed for 0.5 h. Evaporation of the sol-
vent afforded a residual oil, which was subsequently dissolved with CH3CN.
The solution was washed with hexane and evaporated to give a residue.
Flash chromatography using EtOAc–hexane (1 : 1) as eluent gave ethyl 4-
[(2R,5S)-5-phthaloylaminotetrahydrofuran-2-yl]imidazole-1-carboxylate
3812) (96 mg, 42%) as a white solid. Further elution with EtOAc–MeOH
1
gave 29ab (129 mg, 84%) as white amorphous product. H-NMR (CD3OD)
d: 1.28—2.04 (4H, m), 2.91—3.15 (2H, m), 3.64—3.80 (1H, m), 4.66 (1H,
t, Jϭ6.4 Hz), 6.97 (1H, s), 7.12—7.51 (15H, m), 7.70 (1H, s). HR-MS m/z:
429.2199 (Calcd for C27H28N2O3: 429.2176). SI-MS m/z: 429 (Mϩϩ1).
Ethyl 4-[(2R,5R)-(5-Trityloxymethyl)tetrahydrofuran-2-yl]imidazole-
1-carboxylate (31) and Its 2S,5R-Isomer (32) To a solution of 29ab
(320 mg, 0.75 mmol) in CH2Cl2 (25 ml) were added Bu3P (0.31 ml, 1.12 ml)
and TMAD (193 mg, 1.12 ml). The mixture was refluxed for 2 h and then
washed with H2O, dried (MgSO4), and evaporated to give a crude oil of
30ab.
A solution of the crude 30ab, ethyl chloroformate (0.14 ml,
1.50 mmol), pyridine (0.12 ml, 1.50 mmol), and DMAP (10 mg) in benzene
(2.5 ml) was stirred at rt for 1 h. After addition of H2O, the solvent was evap-
orated and the residue was extracted twice with EtOAc–hexane (2 : 1). The
extract was washed with H2O, dried, and concentrated. The residual oil was
purified by flash column chromatography using EtOAc–hexane (3 : 7) for
elution to give 31 (153 mg, 43%), and then 32 (91 mg, 25%). (ϩ)-31: Color-
less oil, Rf (50% EtOAc in hexane); 0.47. IR (nujol) cmϪ1: 1755.
[a]Dϭϩ21.9° (cϭ3.57, MeOH). 1H-NMR (CDCl3) d: 1.42 (3H, t,
Jϭ7.1 Hz), 1.82—1.93 (1H, m), 2.04—2.21 (2H, m), 2.23—2.38 (1H, m),
3.11 (1H, dd, Jϭ9.6, 5.1 Hz), 3.19 (1H, dd, Jϭ9.6, 5.1 Hz), 4.38—4.49 (3H,

July 2003
837
(97 : 3) provided 4(5)-[(2R,5S)-5-phthaloylaminotetrahydrofuran-2-yl]imida-
zole 3912) (56 mg, 30%) as an amorphous product. 38: IR (KBr) cmϪ1: 1760,
1722. 1H-NMR (CDCl3) d: 1.45 (3H, t, Jϭ7.3 Hz), 1.73—1.94 (1H, m),
2.00—2.22 (2H, m), 2.22—2.40 (1H, m), 3.81 (1H, dd, Jϭ14.1, 5.6 Hz),
3.94 (1H, dd, Jϭ14.1, 5.6 Hz), 4.38 (1H, td, Jϭ7.0, 5.6 Hz), 4.47 (2H, q,
Jϭ7.3 Hz), 4.97 (1H, dd, Jϭ4.7, 3.7 Hz), 7.54 (1H, s), 7.70—7.73 (2H, m),
7.84—7.88 (2H, m), 8.03 (1H, s). HR-MS m/z: 369.1320 (Calcd for
C19H19N3O5: 369.1323). EI-MS m/z: 369 (Mϩ). 39: 1H-NMR (CDCl3) d:
1.74—1.84 (1H, m), 2.01—2.18 (3H, m), 3.75—3.83 (2H, m), 4.37—4.44
(1H, m), 5.11 (1H, dd, Jϭ5.1, 3.6 Hz), 6.94 (1H, s), 7.11 (1H, s), 7.69—7.79
(2H, m), 7.81—7.93 (2H, m). Although the separation of 37 was not re-
quired for the following experiment, it could be isolated as a white solid by
7) Coge F., Guenin S. P., Rique H., Boutin J. A., Galizzi J. P., Biochem.
Biophys. Res. Commun., 284, 301—309 (2001).
8) For a review, see: Hough L. B., Mol. Pharmacol., 59, 415—419
(2001).
9) Hashimoto T., Harusawa S., Araki L., Zuiderveld O. P., Smit M. J.,
Imazu T., Takashima S., Yamamoto Y., Sakamoto Y., Kurihara T.,
Leurs R., Bakker R. A., Yamatodani A., J. Med. Chem., in press
(JM0300025).
10) We recently reported imifuramine as a new type of H3-agonist, whose
activity measured by in vivo rat brain microdialysis was approximately
equal to that of the current H3-agonist, immepip: Harusawa S., Imazu
T., Takashima S., Araki L., Ohishi H., Kurihara T., Yamamoto Y.,
Yamatodani A., Tetrahedron Lett., 40, 2561—2564 (1999).
11) Harusawa S., Imazu T., Takashima S., Araki L., Ohishi H., Kurihara
T., Sakamoto Y., Yamamoto Y., Hashimoto T., Yamatodani A., “Hista-
mine Reseach in the New Millennium,” ed. by Watanabe T., Timmer-
man H., Yanai K., Elsevier, Amsterdam, 2001, pp. 83—88.
use of MeOH–CHCl3 (1 : 100) as eluent: mp 176—178 °C. IR (KBr) cmϪ1
:
1760, 1710. 1H-NMR (CDCl3) d: 1.46 (3H, t, Jϭ7.5 Hz), 2.65 (2H, m), 3.99
(2H, d, Jϭ7.5 Hz), 4.49 (2H, q, Jϭ7.5 Hz), 4.60 (1H, t, Jϭ7.5 Hz), 5.26
(1H, dd, Jϭ9.8, 6.9 Hz), 6.00 (1H, d, Jϭ3.9 Hz), 7.02 (1H, s), 7.46 (1H, s),
7.55 (1H, s), 7.75 (2H, m), 7.87 (2H, m), 8.09 (1H, s), 8.28 (1H, s). HR-MS
m/z: 496.1287 (Calcd for C23H22N5O6S: 496.1289). SI-MS m/z: 496 12) Harusawa S., Imazu T., Takashima S., Araki L., Ohishi H., Kurihara
(Mϩϩ1).
(؉)-4(5)-[(2R,5S)-5-Aminomethyltetrahydrofuranyl]imidazole [(؉)-2]
T., Sakamoto Y., Yamamoto Y., Yamatodani A., J. Org. Chem., 64,
8608—8615 (1999).
By the same procedure for the preparation of (ϩ)-1, a solution of 38 13) Harusawa S., Murai Y., Moriyama H., Ohishi H., Yoneda R., Kurihara
(382 mg, 1.04 mmol) and hydrazine hydrate (0.25 ml, 5.18 mmol) in EtOH T., Tetrahedron Lett., 36, 3165—3168 (1995).
(20 ml) was refluxed for 1 h to yield (ϩ)-2 (147 mg, 85%) as an oil. Simi- 14) Harusawa S., Murai Y., Moriyama H., Imazu T., Ohishi H., Yoneda R.,
larly, 41 (149 mg, 0.50 mmol) was converted into (ϩ)-2 (63 mg, 75%) as an Kurihara T., J. Org. Chem., 61, 4405—4411 (1996).
oil. [a]Dϭϩ27.0° (cϭ3.40, MeOH). IR (film) cmϪ1: 3700—2200, 1038. 1H- 15) Guianvarc’h D., Benhida, R., Fourrey J.-L., Tetrahedron Lett., 42,
NMR (CDCl3) d: 1.70—1.92 (1H, m), 1.96—2.33 (3H, m), 2.72 (1H, dd,
Jϭ12.2, 7.0 Hz), 2.80 (1H, dd, Jϭ12.2, 5.2 Hz), 4.03 (1H, ddd, Jϭ12.2, 7.0,
5.2 Hz), 4.94 (overlapped with H2O in CD3OD), 7.03 (1H, s), 7.65 (1H, s).
647—650 (2001).
16) Guianvarc’h D., Fourrey J.-L., Dau M.-E. T. H., Guerineau V., Benhida
R., J. Org. Chem., 67, 3724—3732 (2002).
HR-MS m/z: 168.1134 (Calcd for C8H14N3O: 168.1136). SI-MS m/z: 168 17) Harusawa S., Araki L., Imazu T., Ohishi H., Sakamoto Y., Kurihara T.,
(Mϩϩ1).
Chem. Pharm. Bull., 51, 325—329 (2003).
18) Taniguchi M., Koga K., Yamada S., Tetrahedron, 30, 3547—3552
(1974).
Acknowledgement This work was partially supported by a grant (No.
11672127) from the Ministry of Education, Culture, Sports, Science and 19) Tsunoda T., Otsuka J., Yamamiya Y., Ito S., Chem. Lett., 1994, 539—
Technology of Japan.
542 (1994).
20) Araki L., Harusawa S., Suzuki H., Kurihara T., Heterocycles, 53,
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31) The optical rotation measurements were recorded in CHCl3, since 5
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