Synthesis and hypnotic activities of 4-thio analogues of N3-substituted uridines

Article abstract of DOI:10.1248/cpb.49.1185

Reaction of tri-O-acetyluridine (1) with benzyl bromide or 2-chloroacetophenone in the presence of K₂CO₃ gave the N³-substituted analogues 2a,c. Condensation of 1 with (±)-1-phenylethanol or 3,5-dimethylbenzyl alcohol usin

Full text of DOI:10.1248/cpb.49.1185

September 2001
Notes
Chem. Pharm. Bull. 49(9) 1185—1188 (2001)
1185
Synthesis and Hypnotic Activities of 4-Thio Analogues of N3-Substituted
Uridines
a
b
Shigetada KOZAI, Tokumi MARUYAMA, ,a Toshiyuki KIMURA,b and Ikuo YAMAMOTO
*
Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University,a Yamashiro-cho, Tokushima
770–8514, Japan and Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University,b
Kanazawa 920–1181, Japan. Received February 23, 2001; accepted June 4, 2001
Reaction of tri-O-acetyluridine (1) with benzyl bromide or 2-chloroacetophenone in the presence of K2CO3
gave the N3-substituted analogues 2a,c. Condensation of 1 with (؎)-1-phenylethanol or 3,5-dimethylbenzyl alco-
hol using the Mitsunobu reaction also gave 2b, d in good yields. These compounds were allowed to react with
Lawesson’s reagent and were subsequently treated with ammonia to afford the 4-thiouracil derivatives 5a—d.
Compounds 5a—c showed moderate hypnotic activity in mice. However, N3-(3,5-dimethyl)benzyl derivatives 3d,
5d were found to be almost inactive in this assay.
Key words 4-thiouridine; hypnotic activity; central nervous system depressant; Mitsunobu reaction
It has been reported that uridine shows depressant effects thiouridines was explored as follows. Methods concerning
toward the central nervous system (CNS). For instance, uri- the thiation of uracil or uridine have been universally re-
dine decreased spontaneous activity in mice and showed pro- ported. However, the introduction of an alkyl group on N3 of
tection against seizures caused by penicillin or metrazol.1,2) 4-thiouridine has been difficult because 4-alkylthio deriva-
In addition, uridine was extracted from the brainstems of tives were inevitably formed.11) Recently, 3-alkyluracils were
24 h sleep-deprived rats3) and caused natural sleep following successfully converted to the 4-thio congener by Lawesson’s
nocturnal infusion into the rat brain.4,5) However, uridine it- reagent.12) We adopted this method for the synthesis of com-
self does not possess any hypnotic activity, as determined by pounds 5a—d. Thus, compound 2a was refluxed with Lawes-
loss of the righting reflex in experimental animals. In 1985, it son’s reagent in benzene to give 4a in 52% yield, and subse-
was demonstrated that N3-benzyluridine exerts hypnotic ac- quent treatment of the product with ammonia in MeOH gave
tivity on mice by intracerebroventicular (i.c.v.) administra- N3-benzyl-4-thiouridine 5a, which showed an absorption
tion,6) and the structure–activity relationship has been further maximum at 330 nm on UV.13) In a similar manner, com-
explored.7—9) It became clear that the introduction of methyl- pounds 5b—d were prepared from the corresponding N3-
benzyl, as well as a benzyl group, at N3 of uridine is effective substituted tri-O-acetyluridine (2b—d). To confirm the site
in producing CNS depressant effects.7b,c) Trials to modify the of alkylation, the most biologically active compound, 5c, was
sugar showed a diminished effect,7b,e—g) except for N3-substi- subjected to heteronuclear multiple bond connectivity
tuted thymidine7d) and arabinofuranosyluracil.7h) It has been (HMBC) study. As shown in Fig. 1, this compound was
proven that N3-phenacyluridine strongly intensifies the sleep demonstrated to be the 3-phenacyl analogue, since correla-
induced by pentobarbital (PB) or diazepam.8a,b) Although tion between the methylene protons of the phenacyl group
N1-allyl-5,6-substituted 2-thiouracil derivatives have been and C(4) as well as C(2) was observed.
synthesized and evaluated in terms of sedative-hypnotic ac-
tivity,9) no report concerning N3-substituted 4-thiouridines Pharmacological Results
has appeared. Barbiturates have been in use as a sedative
The hypnotic activities of the N3-substituted 4-thiouridine
hypnotic since 1903, and 2-thiobarbituric acids (2-thioxo- were assayed according to previously established proce-
hexahydropyrimidine-4,6-dione) continue to be used as dures,7) and the results are presented in Table 1 and Fig. 2.
short-acting barbiturates. This background prompted us to By comparison with the earlier result of N3-benzyluridine
explore the 4-thio analogues of N3-substituted uridine. In this (3a, 36Ϯ2 min),7b) 4-thio congener (5a) exhibited better hyp-
paper, we wish to report the synthesis and CNS-depressant notic activity (84Ϯ10 min) when administered to mice by
effect of N3-substituted 4-thiouridines (5a—d).
i.c.v. injection at 2.0 mmol/mouse. This is the first demonstra-
Synthesis Tri-O-acetyl derivatives of N3-benzyluridine tion that N3-substituted 4-thiouridine has CNS-depressant
(2a) and N3-phenacyluridine (2c) were prepared by the nu- activity. In contrast, 5a reduced a prolongation of PB-in-
cleophilic displacement of 2Ј,3Ј,5Ј-tri-O-acetyluridine (1) duced sleep by 24% compared with 3a. In the series of N3-
with benzyl bromide or 2-chloroacetophenone in the pres- (1-phenylethyl) derivatives, it was reported that a uracil con-
ence of K2CO3 in N,N-dimethylformamide (DMF), according gener (3b) caused only 7 min sleep at the same dosage.7b)
to the published method.7a,8a) In the case of 2d, condensation However, the 4-thiouridine derivative (5b) showed moderate
of 1 with 3,5-dimethylbenzyl alcohol using diisopropyl hypnotic activity (58Ϯ15 min). The PB-induced sleep-pro-
azodicarboxylate and tributylphosphine was employed,10) moting activity of 5b was similar to that 3b.7b) These results
since aralkyl halide was not commercially obtainable. Also, indicate that N3-benzyl (5a) or the N3-(1-phenylethyl) deriv-
(Ϯ)-1-phenylethanol was similarly reacted with 1 to give a 1- ative (5b) of 4-thiouracil show enhanced hypnotic activity
phenylethyl derivative (2b) as a mixture of diastereomers. and decreased PB-induced sleep-promoting activity com-
Compound 2d was deprotected by treatment with ammonia pared to the corresponding uracil congener (3a, b). Although
in MeOH to give 3d. Next, the synthesis of N3-substituted 4- 5c showed the most potent hypnotic activity (96Ϯ19 min)
To whom correspondence should be addressed. e-mail: maruyama@ph.bunri-u.ac.jp
© 2001 Pharmaceutical Society of Japan

1186
Vol. 49, No. 9
Chart 1
Fig. 1. Selected HMBC Correlations of 5c in DMSO-d6
Fig. 2. Effects of N3-Substituted 4-Thiouridine and Related Compounds
on Pentobarbital-Induced Sleep by i.c.v. Injection to Mice
Table 1. Hypnotic Activities of N3-Substituted 4-Thiouridines and Related
Compounds by i.c.v. Injection to Mice
** pϽ0.01 vs. control. The reported data for compounds 3a, 3b and 3c is 292, 231
and 230%, respectively.7b,8a)
Hypnotic activityb)
Compounda)
n/nc)
(min)
and its activity was more than 30% stronger compared with
the reported data of 3c.8a) Since N3-benzyluridines bearing a
methyl group onto the benzene ring, i.e. o-, m- and p-methyl-
benzyl derivatives, have been proved to be better CNS-de-
pressants than N3-benzyluridine (3a),7b,c) the activity of N3-
(3,5-dimethylbenzyl)uridine (3d) and its 4-thio congener
(5d) was also examined. However, the hypnotic activity of 3d
and 5d was poor, and 3d showed the weakest PB-induced
sleep-prolonging activity in this series.
Control
3a7b)
5a
None
36Ϯ2
84Ϯ10
7
58Ϯ15
184Ϯ13
96Ϯ19
None
0/8
6/8
3b7b)
5b
5/6
7/7
6/7
0/8
0/8
3c
5c
3d
5d
None
In conclusion, N3-benzyl- (5a) or N3-(1-phenylethyl)-4-
a) Compounds were administered by i.c.v. injection at the dose of 2.0 mmol/mouse.
b) Results are expressed as the mean sleeping time (min)ϮS.E.M. “None” indicates no thiouridine (5b) enhanced hypnotic activity compared with
hypnotic activity. c) Ratio of animals which slept to animals tested.
the original compounds 3a and 5a, respectively. However, the
strong hypnotic activity of N3-phenacyluridine (3c) was re-
among the 4-thio series, its activity was almost half that of 3c
(184Ϯ13 min). It is indicated that the oxygen of the 4 posi-
tion of the uracil ring is important in the hypnotic activity of
3c. However, 5c caused a prolongation of PB-induced sleep
duced to half by 4-thio modification, as shown in Table 1.
This tendency was reversed in the PB-induced sleep-prolong-
ing activity. The PB-induced sleeping time of 5a was shorter
than that of 3a, and 5c showed more prolongation than 3c.

September 2001
1187
Experimental
(CDCl3) d: 7.46—8.04 (5H, m, C6H5), 7.28 (1H, d, Jϭ7.7 Hz, H6), 6.68
(1H, d, Jϭ7.7 Hz, H5), 5.84—6.07 (3H, m, H1Ј, CH2), 5.30—5.45 (2H, m,
H2Ј, H3Ј), 4.38—4.40 (3H, m, H4Ј, H5Ј), 2.15 (3H, s, Ac), 2.12 (3H, s, Ac),
2.10 (3H, s, Ac). UV lmax (MeOH) nm: 325. HR-MS m/z: 504.1205 (Mϩ,
C23H24N2O9S requires 504.1203).
Melting points (mp) were determined using a Yanagimoto micro-melting
point apparatus (hot stage type) and are uncorrected. UV spectra were
recorded with a Shimadzu UV-190 digital spectrometer. Low-resolution
mass spectra were obtained on a Shimadzu-LKB 9000B mass spectrometer
in the direct-inlet mode. 1H-NMR spectra were recorded on a Varian UNITY
200 (200 MHz) or UNITY 600 (600 MHz) in CDCl3 [or dimethyl sulfoxide
(DMSO)-d6] with tetramethylsilane as an internal standard. Merck Art 5554
plates precoated with Silica gel 60 containing fluorescent indicator F254 were
used for thin-layer chromatography, and Silica gel 60 (Merck 7734, 60—200
mesh) was employed for column chromatography.
N3-(3,5-Dimethylbenzyl)-2؅,3؅,5؅-tri-O-acetyl-4-thiouridine (4d): Com-
pound 4d was obtained as a caramel (2.17 g, 84%) from 2d (2.50 g,
5.1 mmol). 1H-NMR (CDCl3) d: 7.17 (1H, d, Jϭ7.7 Hz, H6), 7.01 (2H, br s,
two of C6H3), 6.88 (1H, br s, one of C6H3), 6.66 (1H, d, Jϭ7.7 Hz, H5), 6.02
(1H, d, Jϭ4.4 Hz, H1Ј), 5.63 (2H, dd, Jϭ13.9, 31.1 Hz, CH2), 5.31—5.38
(2H, m, H 2Ј, H3Ј), 4.36 (3H, m, H4Ј, H5Ј), 2.28 (6H, s, CH3ϫ2), 2.13 (3H,
s, Ac), 2.11 (3H, s, Ac), 2.05 (3H, s, Ac). UV lmax (MeOH) nm: 329.5. HR-
MS m/z: 504.1584 (Mϩ, C24H28N2O8S requires 504.1567).
N3-Benzyl-2؅,3؅,5؅-tri-O-acetyluridine (2a). General Procedure for 2c
To a solution of 2Ј,3Ј,5Ј-O-triacetyluridine (1, 3.7 g, 10 mmol) in DMF
(50 ml) was added potassium carbonate (1.04 g, 7.5 mmol) and benzyl bro-
mide (1.62 ml, 15 mmol), and they were stirred at 50 °C for 1 h; then acetic
acid (0.9 ml) was added and the mixture was concentrated to a small volume.
The residue was partitioned between CHCl3 (50 ml) and water (50 ml). The
organic layer was dried over MgSO4, and the residual solution was chro-
matographed over a column of Silica gel G (3.1ϫ40 cm) using 33—66%
N3-Benzyl-4-thiouridine (5a). General Procedures for 3b, 5b—d
A
solution of 4a (220 mg, 0.46 mmol) in MeOH (5 ml) saturated with ammonia
at 0 °C was stirred at room temperature overnight. The solution was concen-
trated to a small volume, and crystallization from EtOH gave yellowish crys-
1
tals. (157 mg, 97%). mp 160—162.5 °C. H-NMR (DMSO-d6) d: 7.93 (1H,
d, Jϭ7.7 Hz, H6), 7.29 (5H, m, Ph), 6.61 (1H, d, Jϭ7.7 Hz, H5), 5.20—5.74
(4H, m, H1Ј, 2ЈOH, CH2), 5.09—5.20 (2H, m, 3ЈOH, 5ЈOH), 3.90—4.10
(3H, m, H2Ј, H3Ј, H4Ј), 3.55—3.73 (2H, m, H5Ј). UV lmax (MeOH) nm:
330. MS m/z: 350 (Mϩ). Anal. Calcd for C16H18N2O5S: C, 54.85; H, 5.18; N,
7.99. Found: C, 55.02; H, 5.30; N, 8.29.
1
AcOEt in hexane (1 l) to give a caramel (3.8 g, 83%). H-NMR (CDCl3) d:
7.27—7.46 (6H, m, H6, C6H5), 6.04 (1H, d, Jϭ4.4 Hz, H1Ј), 5.84 (1H, d,
Jϭ8.1 Hz, H5), 5.29—5.34 (2H, m, H 2Ј, H3Ј), 5.09 (2H, d, Jϭ2.7 Hz,
CH2), 4.34 (3H, br s, H4Ј, H5Ј), 2.12 (3H, s, Ac), 2.11 (3H, s, Ac), 2.05 (3H,
s, Ac). UV lmax (MeOH) nm: 258.5. MS m/z: 460 (Mϩ).
N3-(1-Phenylethyl)uridine (3b): Compound 3b was obtained as white
crystals (506 mg, 97%) from 2b (712 mg, 1.5 mmol). mp 152.5—154.5 °C.
1H-NMR (CDCl3) d: 7.61 (1H, dd, Jϭ6.8, 8.0 Hz, H6), 7.21—7.38 (5H, m,
Ph), 6.26 (1H, ddd, Jϭ7.1, 14.3, 17.0 Hz, CH), 5.74 (1H, dd, Jϭ2.7, 8.0 Hz,
H5), 5.61 (1H, dd, Jϭ3.8, 18.7 Hz, H1Ј), 4.16—4.25 (2H, m, H2Ј, H3Ј),
4.09—4.13 (1H, m, H4Ј), 3.91 (1H, ddd, Jϭ2.7, 8.8, 11.7 Hz, H5Јa), 3.76
(1H, ddd, Jϭ2.7, 9.1, 11.8 Hz, H5Јb), 1.83 (3H, dd, Jϭ4.9, 7.1 Hz, CH3).
UV lmax (MeOH) nm: 264. MS m/z: 348 (Mϩ). Anal. Calcd for C17H20N2O6:
C, 58.61; H, 5.79; N, 8.04. Found: C, 58.94; H, 5.91; N, 8.22.
N3-Phenacyl-2؅,3؅,5؅-tri-O-acetyluridine (2c): Compound 2c was ob-
tained as a caramel (2.34 g, 96%) from 1 (1.85 g, 5 mmol). 1H-NMR
(CDCl3) d: 7.98—8.01 (2H, m, two of C6H5), 7.46—7.62 (4H, m, H6, three
of C6H5), 6.03 (1H, d, Jϭ4.6 Hz, H1Ј), 5.90 (1H, d, Jϭ8.1 Hz, H5), 5.33—
5.42 (4H, m, H 2Ј, H3Ј, CH2), 4.36—4.36 (3H, m, H4Ј, H5Ј), 2.15 (3H, s,
Ac), 2.11 (3H, s, Ac), 2.10 (3H, s, Ac). UV lmax (MeOH) nm: 246. High-res-
olution mass spectrometry (HR-MS) m/z: 488.1423 (Mϩ, C23H24N2O10 re-
quires 488.1431).
N3-(1-Phenylethyl)-2؅,3؅,5؅-tri-O-acetyluridine (2b). General Proce-
dure for 2d To a mixture of 1 (3.7 g, 10 mmol) and (Ϯ)-1-phenylethanol
(2.4 ml, 20 mmol) in dry tetrahydrofuran (THF) (100 ml) was added triph-
enylphosphine (5.25 g, 20 mmol) and diisopropyl azodicarboxylate (4 ml,
20 mmol). The solution was stirred at 50 °C for 6 h, then concentrated over a
small volume. The residual solution was chromatographed over a column of
Silica gel G (4.2ϫ30 cm) using 20—75% AcOEt in hexane (2 l) to give a
N3-(1-Phenylethyl)-4-thiouridine (5b): Compound 5b was obtained as
yellowish crystals (317 mg, 87%) from 4b (490 mg, 1 mmol). mp 169—
1
170.5 °C. H-NMR (DMSO-d6) d: 7.89 (1H, d, Jϭ7.5 Hz, H6), 7.19—7.32
(6H, m, Ph, CH), 6.68 (1H, d, Jϭ7.7 Hz, H5), 5.58 (1H, d, Jϭ3.7 Hz, H1Ј),
5.01—5.49 (3H, m, 2ЈOH, 3ЈOH, 5ЈOH), 3.83—3.97 (3H, m, H2Ј, H3Ј,
H4Ј), 3.52—3.73 (2H, m, H5Ј), 1.79 (3H, d, Jϭ6.8 Hz, CH3). UV lmax
(MeOH) nm: 334. MS m/z: 364 (Mϩ). Anal. Calcd for C17H20N2O5S: C,
56.03; H, 5.53; N, 7.69. Found: C, 55.83; H, 5.60; N, 7.81.
1
caramel (2.86 g, 60%). H-NMR (CDCl3) d: 7.21—7.41 (6H, m, H6, Ph),
N3-Phenacyl-4-thiouridine (5c): Compound 5c was obtained as yellowish
6.24—6.28 (1H, m, CH), 6.07 (1H, dd, Jϭ3.7, 5.4 Hz, H1Ј), 5.82 (1H, d,
Jϭ8.1 Hz, H5), 5.21—5.28 (2H, m, H 2Ј, H3Ј), 4.31—4.33 (3H, m, H4Ј,
H5Ј), 2.13 (3H, d, Jϭ2.2 Hz, Ac), 2.10 (3H, s, Ac), 2.09 (3H, s, Ac), 1.82—
1.88 (3H, m, CH3). UV lmax (MeOH) nm: 260. HR-MS m/z: 474.1628 (Mϩ,
C23H26N2O9 requires 474.1638).
1
crystals (514 mg, 68%) from 4c (1.00 g, 2 mmol). mp 157.5—159 °C. H-
NMR (600 MHz, DMSO-d6) d: 8.01—8.09 (2H, m, two of C6H5), 8.01 (1H,
d, Jϭ7.7 Hz, H6), 7.72—7.74 (1H, m, one of C6H5), 7.58—7.61 (2H, m, two
of C6H5), 6.65 (1H, d, Jϭ7.7 Hz, H5), 5.94 (2H, dd, Jϭ17.3, 44.8 Hz, CH2),
5.76 (1H, d, Jϭ4.4 Hz, H1Ј), 5.54 (1H, d, Jϭ5.5 Hz, 2ЈOH), 5.21 (1H, dd,
Jϭ4.9, 5.2 Hz, 5ЈOH), 5.16 (1H, d, Jϭ5.8 Hz, 3ЈOH), 4.09 (1H, dd, Jϭ4.9,
10.2 Hz, H2Ј), 4.01 (1H, q, Jϭ5.2 Hz, H3Ј), 3.91—3.93 (1H, m, H4Ј), 3.71
(1H, ddd, Jϭ3.3, 5.2, 12.4 Hz, H5Јa), 3.61 (1H, ddd, Jϭ3.3, 4.9, 12.4 Hz,
H5Јb). 13C-NMR (150 MHz, DMSO-d6) d: 191.2 (CϭO), 189.6 (C4), 148.6
(C2), 133.8 (C6), 134.4, 134.1, 129.0 and 127.9 (C6H5), 112.9 (C5), 89.9
(C2Ј), 84.9 (C4Ј), 74.1 (C1Ј), 69.3 (C3Ј), 60.3 (C5Ј), 53.4 (CH2). UV lmax
(MeOH) nm: 330.3. MS m/z: 378 (Mϩ). Anal. Calcd for C17H18N2O6S: C,
53.96; H, 4.79; N, 7.40. Found: C, 54.14; H, 4.85; N, 7.55.
N3-(3,5-Dimethylbenzyl)-2؅,3؅,5؅-tri-O-acetyluridine (2d): Compound 2d
was obtained as a caramel (10.5 g, 72%) from 1 (11.1 g, 30 mmol). 1H-NMR
(CDCl3) d: 7.36 (1H, d, Jϭ8.1 Hz, H6), 7.04 (2H, br s, two of C6H3), 6.89
(1H, br s, one of C6H3), 6.07 (1H, dd, Jϭ2.2, 2.6 Hz, H1Ј), 5.84 (1H, d,
Jϭ8.1 Hz, H5), 5.31—5.36 (2H, m, H 2Ј, H3Ј), 5.02 (2H, dd, Jϭ13.6,
21.2 Hz, CH2), 4.35 (3H, br s, H4Ј, H5Ј), 2.28 (6H, s, CH3 (2) 2.13 (3H, s,
Ac), 2.11 (3H, s, Ac), 2.06 (3H, s, Ac). UV lmax (MeOH) nm: 259. HR-MS
m/z: 488.1783 (Mϩ, C24H28N2O9 requires 488.1795).
N3-Benzyl-2؅,3؅,5؅-tri-O-acetyl-4-thiouridine (4a). General Procedures
for 4b—d A mixture of 2a (460 mg, 1 mmol) and Lawesson’s Reagent
(0.80 g, 2 mmol) in dry benzene (20 ml) was refluxed overnight, then fil-
trated to remove the precipitation. The filtrate was concentrated over a small
volume and chromatographed over a column of Silica gel G (2.3ϫ37 cm)
using 16—33% AcOEt in hexane (1 l) to give a caramel (247 mg, 52%). 1H-
NMR (CDCl3) d: 7.24—7.47 (5H, m, C6H5), 7.17 (1H, d, Jϭ7.7 Hz, H6),
6.66 (1H, d, Jϭ7.7 Hz, H5), 6.00 (1H, d, Jϭ4.4 Hz, H1Ј), 5.65 (2H, d,
Jϭ13.9 Hz, CH2), 5.31—5.38 (2H, m, H2Ј, H3Ј), 4.36—4.38 (3H, m, H4Ј,
H5Ј), 2.12 (3H, s, Ac), 2.11 (3H, s, Ac), 2.05 (3H, s, Ac). UV lmax (MeOH)
nm: 333. MS m/z: 476 (Mϩ).
N3-(3,5-Dimethylbenzyl)-4-thiouridine (5d): Compound 5d was obtained
as yellowish crystals (580 mg, 61%) from 4d (1.26 g, 2.5 mmol). mp
1
155.5—157 °C. H-NMR (DMSO-d6) d: 7.92 (1H, d, Jϭ7.3 Hz, H6), 6.88
(3H, br s, C6H3), 6.61 (1H, d, Jϭ7.3 Hz, H5), 5.73 (1H, d, Jϭ3.3 Hz, H1Ј),
5.43—5.63 (3H, m, 2ЈOH, CH2), 5.09—5.20 (2H, m, 3ЈOH, 5ЈOH), 3.91—
4.07 (3H, m, H2Ј, H3Ј, H4Ј), 3.52—3.77 (2H, m, H5Ј), 2.22 (6H, s,
CH3ϫ2). UV lmax (MeOH) nm: 332. MS m/z: 378 (Mϩ). Anal. Calcd for
C18H22N2O5S: C, 57.13; H, 5.86; N, 7.40. Found: C, 57.22; H, 5.75; N, 7.65.
References and Notes
1) Krooth R. S., Hsiao W. L., Lam G. F. M., J. Pharmacol. Exp. Ther.,
207, 504—514 (1978).
N3-(1-Phenylethyl)-2؅,3؅,5؅-tri-O-acetyl-4-thiouridine (4b): Compound 4b
was obtained as a caramel (1.03 g, 90%) from 2b (1.10 g, 2.3 mmol). H-
1
NMR (CDCl3) d: 7.16—7.42 (6H, m, CH, Ph), 7.12 (1H, d, Jϭ7.7 Hz, H6),
6.73 (1H, d, Jϭ7.7 Hz, H5), 5.92—5.99 (1H, m, H1Ј), 5.14—5.28 (2H, m, H
2Ј, H3Ј), 4.28—4.40 (3H, m, H4Ј, H5Ј), 2.13 (3H, d, Jϭ2.2 Hz, Ac), 2.08
(3H, s, Ac), 2.07 (3H, s, Ac), 1.86 (3H, d, Jϭ7.0 Hz, CH3). UV lmax
(MeOH) nm: 329.5. HR-MS m/z: 490.1404 (Mϩ, C23H26N2O8S requires
490.1410).
2) Roberts C. A., Brain Res., 55, 291—307 (1973).
3) Komoda Y., Ishikawa M., Nagasaki H., Iriki M., Honda K., Inoue S.,
Higashi A., Uchizono K., Biomed. Res., 4, 223—228 (1983).
4) Honda K., Komoda Y., Nishida S., Nagasaki H., Higashi A., Uchizono
K., Inoue S., Neurosci. Res., 1, 243—252 (1984).
5) Inoue S., Honda K., Komoda Y., Uchizono K., Ueno R., Hayashi O.,
Proc. Natl. Acad. Sci. U.S.A., 81, 6240—6244 (1984).
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