Synthesis of (+/-)-trans- or cis-(5-aminomethyltetrahydrofuranyl)imidazole by Mitsunobu cyclization: synthetic studies toward novel histamine H3 or H4-ligands.

Article abstract of DOI:10.1248/cpb.51.325

The (+/-)-trans- or cis-4(5)-(5-aminomethyltetrahydrofuranyl)imidazole [1 and 2] were synthesized by the Mitsunobu cyclization, starting from L-glutamic acid.

Full text of DOI:10.1248/cpb.51.325

March 2003
Notes
Chem. Pharm. Bull. 51(3) 325—329 (2003)
325
Synthesis of (؎)-trans- or cis-(5-Aminomethyltetrahydrofuranyl)imidazole
by Mitsunobu Cyclization: Synthetic Studies toward Novel Histamine H3
or H4-Ligands
Shinya HARUSAWA,a Lisa ARAKI,a Tomonari IMAZU,a Hirofumi OHISHI,a Yasuhiko SAKAMOTO,b and
,a
*
Takushi KURIHARA
a Osaka University of Pharmaceutical Sciences; 4–20–1 Nasahara, Takatsuki, Osaka 569–1094, Japan: and b R&D
Division, AZWELL, Inc., 2–24–3, Sho, Ibaraki, Osaka 567–0806, Japan.
Received September 30, 2002; Accepted January 9, 2003
The (؎)-trans- or cis-4(5)-(5-aminomethyltetrahydrofuranyl)imidazole [1 and 2] were synthesized by the
Mitsunobu cyclization, starting from L-glutamic acid.
Key words Mitsunobu reaction; cyclization; 1,4-diol; H3; H4
A new histamine receptor designed as histamine H4(H4)-
receptor has been characterized through homology searching
of genomic databases by several groups in 2000.1) The H4-re-
ceptor has a very similar amino acid sequence and pharma-
cological characteristics to the histamine H3(H3)-receptor.2,3)
Thus, all the well-known H3-receptor ligands bind to the H4-
receptor. To investigate the possible physiological function of
the H4-receptor, a specific ligand is required.
The H3-agonistic activity of (Ϯ)-trans-4(5)-(5-amino-
methyltetrahydrofuranyl)imidazole [(Ϯ)-1] was found from
the preliminary results of an in vivo rat microdialysis.4—6)
The H3-agonistic activity of (Ϯ)-1 was approximately equal
to that of the current H3-agonist, immepip. Further, (ϩ)-
(2R,5R)-1 (imifuramine) was identified as the eutomer ex-
hibiting H3-agonistic activity (Fig. 1). We very recently re-
vealed that the enantiomer (Ϫ)-1 of imifuramine showed ap-
Fig. 1
proximately 300-fold higher selectivity at the human H3-re-
ceptor than the human H4-receptor.7) More interestingly, a
cyanoguanidine derivative [(Ϫ)-3, OUP-16] of imifuramine
and its cis-stereoisomer [(ϩ)-4, OUP-13] having the 2R,5S-
configuration exhibited the full agonistic activities for the
human histamine H4-receptor with a 40- to 45-fold selectiv-
ity over the human H3-receptor.7)
We herein describe the synthesis of trans- or cis-4(5)-(5-
aminomethyltetrahydrofuranyl)imidazole [(Ϯ)-1 and 2],
which was the clue to the development of H3- or H4-ligands,
starting from L-glutamic acid. It was also found that Mit-
sunobu cyclization in this synthesis gave products with low
optical purities owing to indistinguishable activation between
two hydroxy groups of a chiral 1,4-diol intermediate.
trolled by the C1Ј configuration of the substrate: one isomer
affords an a-anomer and the other, b-anomer (Chart 2).
Thus, Mitsunobu cyclizations of 7a (1ЈR) or 1ЈS-diastere-
omer 7b are required selective formations of C1Ј-oxyphos-
phonium intermediates to obtain products with high optical
purities.
The cyclization of 7ab using N,N,NЈ,NЈ-tetramethylazodi-
carboxamide (TMAD)13) and Bu3P at room temperature for
18 h afforded an inseparable 1 : 1 mixture of trans- and cis-
cyclization product 8ab in 97% yield. Desilylation of 8ab
using tetrabutylammonium fluoride, followed by flash chro-
matography provided 9a and the less polar 9b, in 47% and
1
53% yields, respectively. In H-NMR, two C5Ј-protons (d
Results and Discussion
3.51, 3.55) of cis-isomer 9b were individually observed and
shifted downfield compared to those (d 3.49) of the trans-
isomer. These results presumably reflect the rotational hin-
drance of the C4Ј–C5Ј bond and deshielding effects due to
imidazole. However, since nuclear Overhauser effect (NOE)
experiments of 9a and 9b did not show significant differ-
ences, their relative configurations were not established at
this stage. On the other hand, in the measurements of the op-
tical rotatory dispersion (ORD) of 9a and 9b, their ORD
curves did not, unexpectedly, show variations of optical ac-
tivities with respect to wavelengths. Furthermore, HPLC on a
chiral stationary column demonstrated that compounds 9a
Reduction of (S)-benzyloxymethyl-g-butyrolactone (5)8)
with DIBAL-H followed by an addition of lithium salt 69) of
2-(tert-butyldimethylsilyl)-N,N-dimethyl-1H-imidazolesul-
fonamide10) afforded adduct 7ab in quantitative yield as an
inseparable 1 : 1 diastereomeric mixture (Chart 1). Yokoyama
et al. previously reported11) the synthesis of C-ribonucleo-
sides having typical aromatic heterocycles using standard
Mitsunobu conditions (DEAD, Ph3P),12) in which the cycliza-
tion of the corresponding diols proceeds through an in-
tramolecular SN2 reaction of the C1Ј-oxyphosphonium inter-
mediate, and the orientation of the glycosidic linkage is con-
* To whom correspondence should be addressed. e-mail: kurihara@gly.oups.ac.jp
© 2003 Pharmaceutical Society of Japan

326
Vol. 51, No. 3
Chart 1
Chart 2
Fig. 2. X-Ray Determined Structure of (Ϯ)-11a
and 9b were 1 : 1.2 (9% ee) and 1 : 1.5 (20% ee) enantiomeric
mixtures, respectively. These results suggested that the cy-
clization of 7ab proceeded through simultaneous cyclization configuration, phthalimide 11a was recrystallized from EtOH
via C1Ј and C4Ј-oxyphosphonium salts. to afford a racemic crystal, which was analyzed using X-ray
Debenzylation of 9a and 9b using Pd(OH)2–C in cyclo- crystallography indicating trans-configuration between C2Ј
hexene afforded primary alcohols 10a and 10b in 94% and and C5Ј of 11a, as shown in Fig. 2. The space group of the
88% yields, respectively, which were subjected to phthalimi- single crystal 11a from the X-ray analysis belonged to P-1,
dation using DEAD, Ph3P, and phthalimide to yield 11a which indicated a racemic compound. It has been reported
(76%) and 11b (92%), respectively. To determine the relative that in some cases, racemates crystallize more readily than

March 2003
327
Chart 3
their optically pure compounds.14) Deprotection of phthalim-
ides (Ϯ)-11a using hydrazine hydrate, followed by hydrolysis
using aqueous 1.5 N HCl produced (Ϯ)-trans-amine 1 in 72%
yields. In a similar manner, the (Ϯ)-cis-amine 2 was synthe-
sized from phthalimide 11b, as shown in Chart 1.
To clarify the mechanism of the cyclization reaction, we
obtained the corresponding diol intermediates 7a and 7b via
an alternative route using phenylselenenyldiols 13a and 13b,
which was reported in our previous paper6) (Chart 3). The
PhSe groups at the C2Ј position of diols 13a and 13b were
removed by treatment with n-Bu3SnH and Et3B to give 7a
and 7b in 96% and 85% yields, respectively. Mitsunobu cy-
clization of 7a afforded exclusively trans-product 8a in 91%
yield, while that of 7b afforded exclusively cis-product 8b in
90% yield.
The HPLC analysis on a chiral stationary column demon-
strated that diols 7a and 7b showed a single peak, respec-
tively, while it indicated that cyclization products 8a and 8b
were 1 : 1.2 and 1 : 1.5 enantiomeric mixtures, respectively.
The decrease of regioselectivity of the cyclodehydration dur-
ing the Mitsunobu cyclization of 7ab may be due to the lack
of C2Ј and/or C3Ј-oxygen functional groups, which is pre-
sent in linear heterocyclic sugar derivatives.
3.30 (1/2H, br), 3.40—3.68 (2H, m), 3.80 (1/2H, d, Jϭ6.5 Hz), 4.30 (1/2H,
m), 4.44 (1/2H, m), 4.56 (2/4H, s), 4.60 (2/4H, s), 5.45 (1/2H, br d,
Jϭ6.5 Hz), 5.60 (1/2H, br d, Jϭ6.5 Hz), 7.32 (5H, m). Electron impact (EI)-
MS m/z: 208 (Mϩ).
A solution of 2-(tert-butyldimethylsilyl)-N,N-dimethyl-1H-imidazolesul-
fonamide10) (1.04 g, 3.61 mmol) in THF (10 ml) was cooled to Ϫ70 °C and
was treated dropwise with 1.6 M BuLi–hexane (2.31 ml, 3.61 mmol), and the
resulting mixture was stirred for 30 min at Ϫ50 °C to precipitate the white
lithium salt (6). The resulting suspension was again cooled to Ϫ70 °C, and a
THF solution (5 ml) of the lactol (280 mg, 1.34 mmol) in THF (5 ml) was
added slowly. The dry ice bath was removed, and the reaction mixture was
stirred at rt. After 30 min, 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 40% EtOAc–hexane as eluent
1
gave 7ab (670 mg, quant) as an oil. H-NMR (CDCl3) d: 0.39 (6H, s), 0.99
(9H, s), 1.40—2.11 (4H, m), 2.82 (6H, s), 3.35 (1H, t, Jϭ7.7 Hz), 3.50 (1H,
dd, Jϭ7.7, 3.6 Hz), 3.90 (1H, m), 4.58 (2H, s), 4.93 (1H, m), 7.22 (1H, s),
7.35 (5H, m). High resolution (HR)-MS m/z: 498.2447 (Calcd for
C23H40N3O5SSi: 498.2456). EI-MS m/z: 498 (Mϩϩ1).
5-[(trans and cis-2,5)-5-Benzyloxymethyltetrahydrofuran-2-yl]-2-(tert-
butyldimethylsilyl)-N,N-dimethy-1H-imidazolesulfonamide (8ab) To a
solution of 7ab (665 mg, 1.34 mmol) in dry benzene (45 ml) was added Bu3P
(1.10 ml, 4.02 mmol) at rt. TMAD (691 mg, 4.02 mmol) was then added
rapidly to the mixture at ice bath temperature. After a few minutes, the reac-
tion mixture was warmed to rt and the stirring was continued for 18 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 (ϫ2) and brine, dried, and evaporated. The residual oil was pu-
Experimental
rifed by flash chromatography using EtOAc–hexane (3 : 17) for elution to
1
The melting points were determined on a hot-stage apparatus and are un- give 8ab (621 mg, 97%) as a brown oil of inseparable mixture. H-NMR
corrected. Optical rotation measurements were recorded with a JASCO DIP- (CDCl3) d: 0.38 (6H, s), 1.00 (9H, s), 1.72—2.50 (4H, m), 2.84 (6H, s), 3.50
1000 digital polarimeter. IR spectra were recorded on a Shimadzu IR-435 (2/2H, d, Jϭ2.7 Hz), 3.55 (2/2H, d, Jϭ5.6 Hz), 4.17 (1/2H, quint,
spectrometer. 1H- and 13C-NMR spectra were taken with tetramethylsilane as Jϭ5.6 Hz), 4.32 (1/2H, quint, Jϭ5.6 Hz), 4.54 (2/2H, s), 4.57 (2/2H, s), 5.17
an internal standard on a Varian Gemini-200, Varian Mercury-300, and Var- (1/2H, t, Jϭ6.5 Hz), 5.28 (1/2H, t, Jϭ6.5 Hz), 7.18 (1/2H, s), 7.23 (1/2H, s),
ian UNITY INOVA-500 spectrometers. Reactions with air- and moisture- 7.32 (5H, m). HR-MS m/z: 480.2352 (Calcd for C23H38N3O4SSi: 480.2350).
sensitive compounds were carried out under an argon atmosphere. Unless EI-MS m/z: 480 (Mϩϩ1).
otherwise noted, all extracts were dried over Na2SO4, and the solvent was re-
5-[(trans-2,5)-5-Benzyloxymethyltetrahydrofuan-2-yl]-N,N-dimethyl-
moved in a rotary evaporator under reduced pressure. Tetrahydrofuran 1H-imidazolesulfonamide (9a) and Its cis-2؅,5؅-Isomer (9b) To a solu-
(THF) was distilled from sodium-benzophenone. HPLC analysis was carried tion of 8ab (172 mg, 0.36 mmol) in THF (25 ml) was added a 1 M solution of
out with a Waters Associates instrument [column; Daicel CHIRALPAK® a Bu4NF (0.40 ml, 0.40 mmol) at 0 °C. The mixture was stirred at rt for
AD, 0.46 cmϫ25 cm; eluent, 10% 2-propanol in hexane; detection 254 nm].
20 min. The THF was evaporated to give a crude oil, which was then puri-
5-[(1RS,4S)-5-Benzyloxy-1,4-dihydroxypentyl]-2-(tert-butyldimethyl- fied by column chromatography [EtOAc–hexane (2 : 3)] to give 9b (70 mg,
silyl)-N,N-dimethyl-1H-imidazolesulfonamide (7ab) To a solution of 58) 53%) and 9a (62 mg, 47%), in that order. 9b: oil, 20% e.e. by chiral HPLC
1
(618 mg, 3.00 mmol) in dry toluene (6 ml) at Ϫ70 °C was added a 1.0 M so-
(flow rate 2 ml/min; tR 10.0 and 11.4 min). H-NMR (CDCl3) d: 1.72—2.12
lution of DIBAL in toluene (4.50 ml, 4.50 mmol) over 15 min. After being (3H, m), 2.21—2.42 (1H, m), 2.89 (6H, s), 3.51 (1H, d, Jϭ2.5 Hz), 3.55
stirred for 5 min at Ϫ70 °C, the reaction mixture was quenched with MeOH (1H, s), 4.20 (1H, m), 4.55 (2H, s), 5.20 (1H, t, Jϭ6.6 Hz), 7.09 (1H, s) 7.31
(2.5 ml) and further stirred for 1 h at room temperature (rt). Saturated (5H, m), 7.89 (1H, s). HR-MS m/z: 366.1486 (Calcd for C17H24N3O4S:
NaHCO3 solution (1.5 ml) and EtOAc (4.0 ml) were added to the resulting 366.1486). EI-MS m/z: 366 (Mϩϩ1). 9a: oil, 9% e.e. by chiral HPLC (flow
1
mixture, which was further stirred for 25 min. After anhydrous MgSO4 was rate 2 ml/min; tR 9.5 and 13.4 min). H-NMR (CDCl3) d: 1.68—1.89 (1H,
added to the resulting suspension, the reaction mixture was stirred for a m), 1.94—2.20 (2H, m), 2.27—2.45 (1H, m), 2.85 (6H, s), 3.49 (2H, d,
while, filtered through a Celite pad, and washed with EtOAc. The filtrate was Jϭ4.5 Hz), 4.29 (1H, m), 4.52 (2H, s), 5.30 (1H, t, Jϭ6.5 Hz), 7.05 (1H, s),
evaporated to give a crude oil, which was subjected to chromatography. Elu- 7.30 (5H, m), 7.88 (1H, s). HR-MS m/z: 366.1495 (Calcd for C17H24N3O4S:
tion with EtOAc–hexane (3 : 17) afforded 5S-benzyloxymethyltetrahydrofu- 366.1486). EI-MS m/z: 366 (Mϩϩ1).
ran-2-ol (590 mg, 95 %) as a colorless oil.
5-[(cis-2,5)-5-Hydroxymethyltetrahydrofuran-2-yl]-N,N-dimethyl-1H-
imidazolesulfonamide (10b) A mixture of 9b (460 mg, 1.27 mmol), 20%
1
IR (neat) cmϪ1: 3400 (OH). H-NMR (CDCl3) d: 1.56—2.22 (4H, m),

328
Vol. 51, No. 3
Pd(OH)2–C (230 mg), and cyclohexene (3.2 ml, 31.7 mmol) in EtOH (50 ml)
was refluxed for 30 min. After filtration through Celite, the filtrate was evap-
orated to give a residue which was purified by column chromatography
2.33—2.52 (1H, m), 2.75 (2H, d, Jϭ6.0 Hz), 2.95 (6H, s), 4.16 (1H, m),
5.36 (1H, t, Jϭ6.4 Hz), 7.15 (1H, s), 8.12 (1H, s). EI-MS m/z: 275 (Mϩϩ1).
By the same procedure as (Ϯ)-2, the sulfonamide (109 mg, 0.40 mmol) was
1
1
converted to (Ϯ)-1 (48 mg, 72%).6) IR (nujol) cmϪ1: 3350, 1585 (NH). H-
[MeOH–EtOAc (1 : 20)] to give 10b (300 mg, 87%) as a colorless oil. H-
NMR (CD3OD) d: 1.76—2.16 (3H, m), 2.27—2.46 (1H, m), 2.95 (6H, s),
3.59 (2H, m), 4.10 (1H, m), 5.23 (1H, t, Jϭ6.5 Hz), 7.19 (1H, s), 8.08 (1H,
s). HR-MS m/z: 276.1015 (Calced for C10H18N3O4S: 276.1017). EI-MS m/z:
276 (Mϩϩ1).
NMR (CD3OD) d: 1.61—1.82 (1H, m), 2.02—2.38 (3H, m), 2.73 (2H, d,
Jϭ6.0 Hz), 4.17 (1H, m), 5.02 (1H, t, Jϭ6.5 Hz), 7.02 (1H, s), 7.64 (1H, s).
HR-MS m/z: 167.1060 (Calcd for C8H13N3O: 167.1058). EI-MS m/z: 167
(Mϩ).
5-[(cis-2,5)-5-Phthaloylaminotetrahydrofuran-2-yl]-N,N-dimethyl-1H-
imidazolesulfonamide [(؎)-11b] Phthalimide (160 mg, 1.12 mmol) and
Ph3P (530 mg, 2.03 mmol) were dissolved in a solution of 10b (280 mg,
1.02 mmol) in THF (15 ml). To this mixture was added DEAD (0.35 ml,
2.03 mmol) with stirring. The reaction mixture was stirred at rt for 30 min,
and then the whole was evaporated to give a residue, which was subse-
quently dissolved in EtOAc. The solution was washed with H2O and brine,
dried, and evaporated to give a crude oil. It was purified by flash chromatog-
raphy with EtOAc–hexane (3 : 2) to 11b (380 mg, 92%) as a white solid,
which was recrystallized from EtOH to give white leaflets [(Ϯ)-11b]. mp
98—100 °C. IR (KBr) cmϪ1: 1770 (N–CO), 1710 (N–CO), 1390, 1175
5-[(1R,4S)-5-Benzyloxy-1,4-dihydroxypentyl]-2-(tert-butyldimethylsi-
lyl)-N,N-dimethyl-1H-imidazolesulfonamide (7a) A mixture of 13a6)
(204 mg, 0.31 mmol), 1 M hexane solution of Et3B (0.34 ml, 0.34 mmol), and
Bu3SnH (0.095 ml, 0.34 mmol) in benzene (6 ml) was stirred at room tem-
perature for 15 min. The benzene was removed under reduced pressure. The
residue was dissolved in CH3CN, and the solution was washed with hexane
and evaporated. The resulting residue was purified by column chromatogra-
phy using a gradient solvent from 30 to 70% EtOAc in hexane to give 7a
(148 mg, 96%) as an oil. [a]D ϩ3.30° (cϭ2.4, CHCl3). HPLC (flow rate
3 ml/min; tR 7.2 min) exhibited a single peak. 1H-NMR (CDCl3) d: 0.38 (6H,
s), 1.00 (9H, s), 1.45—1.80 (2H, m), 2.00 (2H, quint, Jϭ6.0 Hz), 2.80 (6H,
s), 3.34 (1H, t, Jϭ7.5 Hz), 3.48 (1H, dd, Jϭ7.5, 3.0 Hz), 3.87 (1H, m), 4.55
(1H, s), 4.94 (1H, dd, Jϭ6.0, 5.0 Hz), 7.25—7.45 (5H, br s). HR-MS m/z:
498.2452 (Calcd for C23H40N3O5SSi: 498.2456). EI-MS m/z: 498 (Mϩϩ1).
5-[(trans-2,5)-5-Benzyloxymethyltetrahydrofuran-2-yl]-2-(tert-butyl-
dimethylsilyl)-N,N-dimethyl-1H-imidazolesulfonamide (8a) By the
same procedure as the preparation of 8ab, a mixture of 7a (43 mg,
0.09 mmol), Bu3P (0.07 ml, 0.26 mmol), and TMAD (45 mg, 0.26 mmol) in
benzene (3 ml) was stirred for 18 h at rt to give 8a (38 mg, 91%) as an oil.
9% e.e. by chiral HPLC (flow rate 2 ml/min; tR 2.9 and 4.7 min). ORD
1
(SO2). H-NMR (CDCl3) d: 1.79—2.22 (3H, m), 2.29—2.50 (1H, m), 2.85
(6H, s), 3.80 (1H, dd, Jϭ14.1, 5.0 Hz), 3.90 (1H, dd, Jϭ14.1, 6.0 Hz), 4.37
(1H, m), 5.17 (1H, t, Jϭ6.0 Hz), 7.16 (1H, s), 7.68—7.77 (2H, m), 7.80—
7.86 (2H, m), 7.86 (1H, s). Anal. Calcd for C18H20N4O5S: C, 53.45; H, 4.98;
N, 13.85. Found: C, 53.65; H, 4.94; N, 13.84.
4(5)-[(cis-2,5)-5-Aminomethyltetrahydrofuran-2-yl]imidazole [(؎)-2]
A solution of (Ϯ)-11b (340 mg, 0.85 mmol) and NH2NH2·H2O (0.21 ml,
4.24 mmoli) in EtOH (30 ml) was refluxed for 2 h and then cooled. A small
amount of 10% Pd–C was then added to the solution, and the reaction mix-
ture was further refluxed for 10 min. After removal of the catalyst by filtra-
tion through a Celite pad, a small amount of silica gel was added to the fil-
trate. The solvent was evaporated to give a coated silica gel, which was sub-
sequently placed in a column (Chromatorex NH-DM 1020). Chromatogra-
phy using EtOAc as the eluent gave 5-[(cis-2,5)-5-aminomethyltetrahydrofu-
ran-2-yl]-N,N-dimethyl-1H-imidazolesulfonamide (210 mg, 92%) as an oil.
IR (nujol) cmϪ1: 3370, 1580 (NH), 1375, 1170 (SO2). 1H-NMR (CD3OD) d:
1.63—1.90 (1H, m), 1.97—2.20 (2H, m), 2.29—2.46 (1H, m), 2.76 (2H, d,
Jϭ6.1 Hz), 2.99 (6H, s), 4.04 (1H, m), 5.23 (1H, t, Jϭ6.6 Hz), 7.17 (1H, s),
8.10 (1H, s). EI-MS m/z: 275 (Mϩϩ1). To a EtOH solution (5 ml) of the sul-
fonamide (48 mg, 0.17 mmol) thus obtained was added 1.5 N HCl (2 ml). The
resulting mixture was refluxed for 90 min and neutralized by addition of
30% NH4OH. The whole was diluted with EtOH and evaporated to remove
water as an azeotrope under reduced pressure. The residue was further di-
luted with EtOH and the resulting white salts were filtered off. A small
amount of silica gel (Chromatorex NH-DM 1020) was added to the filtrate.
The solvent was evaporated to give a coated silica gel, which was placed in a
column (Chromatorex NH-DM 1020). Chromatography using MeOH–
1
(cϭ1.18, EtOH) [a] (nm) 0 (589), ϩ5.1 (450). H-NMR (CDCl3) d: 0.39
(6H, s), 1.00 (9H, s), 1.78—1.91 (1H, br m), 1.97—2.21 (2H, m), 2.31—
2.48 (1H, m), 2.84 (6H, s), 3.52 (2H, br s), 4.32 (1H, quint, Jϭ5.0 Hz), 4.55
(2H, s), 5.28 (1H, t, Jϭ6.6 Hz), 7.25—7.45 (5H, m). HR-MS m/z: 480.2351
(Calcd for C23H38N3O4SSi: 480.2350). EI-MS m/z: 480 (Mϩϩ1).
5-[(1S,4S)-5-Benzyloxy-1,4-dihydroxypentyl]-2-(tert-butyldimethylsi-
lyl)-N,N-dimethyl-1H-imidazolesulfonamide (7b) The same procedure
as used for the preparation of 7a provided 7b (30 mg, 85%) as an oil from
13b6) (46 mg, 0.07 mmol). [a]D ϩ3.00° (cϭ1.4, CHCl3). HPLC (flow rate
3 ml/min; tR 6.4 min) exhibited a single peak. 1H-NMR (CDCl3) d: 0.38 (6H,
s), 0.99 (9H, s), 1.55—1.72 (2H, m), 2.03 (2H, q, Jϭ7.5 Hz), 2.83 (6H, s),
3.36 (1H, t, Jϭ7.5 Hz), 3.50 (1H, dd, Jϭ7.5, 3.0 Hz), 3.80—3.97 (1H, m),
4.55 (1H, s), 4.90 (1H, t, Jϭ6.0 Hz), 7.25—7.45 (5H, br s). HR-MS m/z:
498.2450 (Calcd for C23H40N3O5SSi: 498.2456). EI-MS m/z: 498 (Mϩϩ1).
5-[(cis-2,5)-5-Benzyloxymethyltetrahydrofuran-2-yl]-2-(tert-butyl-
dimethylsilyl)-N,N-dimethyl-1H-imidazolesulfonamide (8b) By the
same procedure as the preparation of 8ab, a mixture of 7b (62 mg,
0.13 mmol), Bu3P (0.10 ml, 3.7 mmol), and TMAD (64 mg, 3.7 mmol) in
benzene (10 ml) was stirred for 18 h at room temperature to give 8b (54 mg,
90%) as an oil. 20% e.e. by chiral HPLC (flow rate 2 ml/min; tR 2.3 and
4.3 min). ORD (cϭ2.69, EtOH) [a] (nm) Ϫ9.2 (589), Ϫ11.6 (550), Ϫ14.2
AcOEt (2 : 23) gave (Ϯ)-2 (26 mg, 90%) as a colorless oil.6) IR (nujol) cmϪ1
:
3350, 1585 (NH). 1H-NMR (CD3OD) d: 1.68—2.35 (4H, m), 2.75 (2H, m),
4.04 (1H, m), 4.93 (overlapped with H2O in CD3OD), 7.03 (1H, s), 7.65
(1H, s). HR-MS m/z: 167.1060 (Calcd for C8H13N3O: 167.1058). EI-MS
m/z: 167 (mϩ).
1
(500), Ϫ18.1 (450). H-NMR (CDCl3) d: 0.39 (6H, s), 1.00 (9H, s), 1.75—
2.12 (3H, br m), 2.12—2.42 (1H, m), 2.85 (6H, s), 3.55 (2H, br s), 4.17 (1H,
quint, Jϭ7.5 Hz), 4.55 (2H, quint, Jϭ5.0 Hz), 4.55 (2H, s), 5.15 (1H, t,
Jϭ7.5 Hz), 7.2—7.45 (5H, m). HR-MS m/z: 480.2353 (Calcd for
C23H38N3O4SSi: 480.2350). EI-MS m/z: 480 (Mϩϩ1).
5-[(trans-2,5)-5-Hydroxymethyltetrahydrofuran-2-yl]-N,N-dimethyl-
imidazole-1-sulfonamide (10a) By the same procedure as 10b, ben-
zylether 9a (48 mg, 0.13 mmol) was converted to 10a (34 mg, 94%) as a col-
1
orless oil. H-NMR (CD3OD) d: 1.72—1.94 (1H, m), 1.98—2.22 (2H, m),
X-Ray Structure Determination The 6300 reflections were collected
up to 0.89 Å resolution with cell dimensions aϭ11.868(6) Å,
bϭ20.476(6) Å, cϭ7.931(6) Å, aϭ95.62(1)°, bϭ97.22(1)°, gϭ93.82(1)°,
crystal system triclinic, space group P-1, Zϭ2 and calculated density
1.416 g/cm3. The structure of 10b was determined by direct method using
program SHELXS-9715) and refined by full matrix least-squares method
using program SHELXSL-97.15) The final R-value was 0.0589 with 5973 re-
flections (FOϾ4sFO).
2.33—2.50 (1H, m), 2.95 (6H, s), 3.54 (1H, dd, Jϭ12.0, 5.5 Hz), 3.62 (1H,
dd, Jϭ12.0, 4.1 Hz), 4.19 (1H, m), 5.36 (1H, t, Jϭ6.4 Hz), 7.12 (1H. s). 8.10
(1H, s). HR-MS m/z: 276.1018 (Calced for C10H18N3O4S: 276.1017). EI-MS
m/z: 276 (Mϩϩ1).
5-[(trans-2,5)-5-Phthaloylaminotetrahydrofuran-2-yl]-N,N-dimethyl-
imidazole-1-sulfonamide [(؎)-11a] By the same procedure as 11b, 10a
(33 mg, 0.12 mmol) was converted to 11a (37 mg, 76%), which was recrys-
tallized from EtOH to give colorless prisms. mp 133—135 °C. IR (KBr)
cmϪ1: 1790 (N–CO), 1710 (N–CO), 1395, 1175 (SO2). 1H-NMR (CDCl3) d:
1.74—1.90 (1H, m), 2.00—2.28 (2H, m), 2.39—2.52 (1H, m), 2.88 (6H, s),
3.70 (1H, dd, Jϭ14.1, 5.0 Hz), 3.85 (1H, dd, Jϭ14.1, 7.1 Hz) 4.43 (1H, m),
5.38 (1H, t, Jϭ6.8 Hz), 7.00 (1H, s), 7.69—7.75 (2H, m), 7.80—7.85 (2H,
m), 7.85 (1H, s). Anal. Calcd for C18H20N4O5S: C, 53.45; H, 4.98; N, 13.85.
Found: C, 53.69; H, 4.91; N, 13.84.
5-[(trans-2,5)-5-Aminomethyltetrahydrofuran-2-yl]imidazole [(؎)-1]
By the same procedure as (Ϯ)-2, 11a (160 mg, 0.41 mmol) was converted to
5-[(trans-2,5)-5-aminomethyltetrahydrofuran-2-yl]-N,N-dimethylimidazole-
1-sulfonamide (120 mg, quant). IR (nujol) cmϪ1: 3350, 1585 (NH), 1375,
1170 (SO2). 1H-NMR (CD3OD) d: 1.71—1.95 (1H, m), 2.00—2.26 (2H, m),
References
1) For a review, see: Hough L. B., Mol. Pharmacol., 59, 415—419
(2001).
2) For a review, see: Stark H, Schlicker E., Schunack W., Drugs Future,
21, 507—520 (1996).
3) For a review, see: Leurs R., Blandina P., Tedford C., Timmerman H.,
TiPS, 19, 177—183 (1998).
4) Harusawa S., Imazu T., Takashima S., Araki L., Ohishi H., Kurihara
T., Yamamoto Y., Yamatodani A., Tetrahedron Lett., 40, 2561—2564
(1999).
5) Watanabe T., Timmerman H., Yanai K., “Histamine Research in the

March 2003
329
New Millennium,” Elsevier, Amsterdam, 2001.
(1990).
6) Harusawa S., Imazu T., Takashima S., Araki L., Ohishi H., Kurihara 11) Yokoyama M., Toyoshima A., Akiba T., Togo H., Chem. Lett., 1994,
T., Sakamoto Y., Yamamoto Y., Yamatodani A., J. Org. Chem., 64,
8608—8615 (1999).
7) Hashimoto T., Harusawa S., Araki L., Zuiderveld O. P., Smit M. J.,
Imazu T., Takashima, S., Yamamoto Y., Sakamoto Y., Kurihara T.,
265—268 (1994).
12) For a review, see: “The Mitsunobu Reaction,” Vol. 42, ed. by Hughes
D. L., in the series of “Org. Reaction,” ed. by Paquette L. A., John
Wiley & Sons Inc., New York, 1992, pp. 335—656.
Leurs R., Bakker R. A., Yamatodani A., J. Med. Chem., submitted 13) Tsunoda T., Otsuka J., Yamamiya Y., Ito S., Chem. Lett., 539—542
(JM0300025). (1994).
8) Taniguchi M., Koga K., Yamada S., Tetrahedron, 30, 3547—3552 14) Brock C. P., Schweizer W. B., Dunitz J. D., J. Am. Chem. Soc., 113,
(1974). 9811—9820 (1991).
9) Harusawa S., Murai Y., Moriyama H., Imazu T., Ohishi H., Yoneda R., 15) Sheldrick G. M., SHELXS97, Program for Direct Method of Crystal
Kurihara T., J. Org. Chem., 61, 4405—4411 (1996).
Structure, University of Goettingen, Goettingen, 1997.
10) Ngochindo R. I., J. Chem. Soc., Perkin Trans. 1, 1990, 1645—1648