Direct synthesis of novel 2-imino-1,3-selenazolidine derivatives from O-methanesulfonyl β-amino alcohol hydrochlorides

Article abstract of DOI:10.1016/j.tetlet.2004.11.064

A synthetic approach to novel 4,5-dialkylsubstituted 2-imino-1,3- selenazolidine derivatives from O-methanesulfonyl β-amino alcohol hydrochlorides using potassium selenocyanate was described. Recently, we have reported that 4,5-dialkylsubstituted 2-imino-1,3-azolidine derivatives (1) strongly inhibit inducible nitric oxide synthase (iNOS). To our knowledge, only few methods have been reported for the synthesis of 4,5-dialkylsubstituted 2-imino-1,3-selenazolidine derivatives (2), which are the selenium analogue of 1. Herein, we report the direct synthesis of 2 from the corresponding O-methanesulfonyl β-amino alcohol hydrochlorides using potassium selenocyanate and evaluation for the inhibitory activity against iNOS of the newly synthesized selenazolidine derivatives.

Full text of DOI:10.1016/j.tetlet.2004.11.064

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 233–236
Direct synthesis of novel 2-imino-1,3-selenazolidine derivatives from
O-methanesulfonyl b-amino alcohol hydrochlorides
Shigeo Ueda,a,* Hideo Terauchi,a,b Kenji Suzukia and Nobuhide Watanabea
aChemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd, Enoki-cho 33-94, Suita, Osaka 564-0053, Japan
bPharmaceutical Research and Technology Center, Dainippon Pharmaceutical Co., Ltd, Ebie 1-5-51,
Fukushima, Osaka 553-0001, Japan
Received 17 October 2004; revised 11 November 2004; accepted 12 November 2004
Available online 26 November 2004
Abstract—Recently, we have reported that 4,5-dialkylsubstituted 2-imino-1,3-azolidine derivatives (1) strongly inhibit inducible
nitric oxide synthase (iNOS). To our knowledge, only few methods have been reported for the synthesis of 4,5-dialkylsubstituted
2-imino-1,3-selenazolidine derivatives (2), which are the selenium analogue of 1. Herein, we report the direct synthesis of 2 from
the corresponding O-methanesulfonyl b-amino alcohol hydrochlorides using potassium selenocyanate and evaluation for the inhib-
itory activity against iNOS of the newly synthesized selenazolidine derivatives.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Selenium-containing compounds have enthusiastically
been studied in the fields of chemistry and pharmacol-
ogy, because they biologically act as antioxidants and
can inhibit human fibro sarcoma DNA fragmentation,
eukaryotic elongation factor-2 kinase and inducible ni-
tric oxide production.1,2 In addition, selenium itself
has pharmacologically been explored for the prevention
of prostate and ovarian cancer.3 Therefore, the biologi-
cal role of compounds containing selenium is subject to
intense current interest.
(iNOS). Combining this finding with the results of previ-
ous studies,1–3 we anticipated that the selenium ana-
logues of 1 that are 4,5-dialkylsubstituted 2-imino-1,3-
selenazolidine derivatives (2) would pharmacologically
be active and might display a similar profile to that of
1 (Chart 1). However, to our knowledge, no synthetic
method of 2 has been reported.
According to a recent report by Xu,5 when O-metha-
nesulfonyl b-amino alcohol hydrochlorides are reacted
with sodium sulfite under appropriate reaction condi-
tions, aziridines are produced as intermediates. Subse-
quent attack of sodium sulfite as a nucleophile on the
aziridine ring affords taurine derivatives. On the basis
of this reported mechanism, we hypothesized that reac-
tion of O-methanesulfonyl b-amino alcohol hydrochlo-
rides with potassium selenocyanate (KSeCN) instead
of sodium sulfite would lead to 2. Herein, we first report
the direct synthesis of novel 4,5-dialkylsubstituted 2-imi-
no-1,3-selenazolidine derivatives from the correspond-
ing O-methanesulfonyl b-amino alcohol hydrochlorides
using potassium selenocyanate, and evaluate the inhibi-
tory activity against iNOS of the newly synthesized
compounds.
We have recently reported that 4,5-dialkyl-2-imino-1,3-
azolidine derivatives (1, Chart 1)4 show strong inhibi-
tory activity against inducible nitric oxide synthase
H
N
R1
R2
H
N
R1
R2
NH
NH
Se
X
X = O, S
1
2
R1, R2 = alkyl
-cis-1a: (X = S, R1 = R2 = Et)
( )
( ) -trans-1b: (X = S, R1 = R2 = Et)
Chart 1.
Initially, we targeted the synthesis of the 4,5-diethylsub-
stituted derivative ( )-cis-9a as representative of 2 be-
cause its thiazolidine analogue [( )-cis-1a, Chart 1]
shows strong inhibitory activity against iNOS.4b
Keywords: 1,3-Selenazolidine; Aziridine; iNOS.
*
Corresponding author. Tel.: +81 6 6337 5901; fax: +81 6 6338
7656; e-mail: shigeo-ueda@dainippon-pharm.co.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.064

234
S. Ueda et al. / Tetrahedron Letters 46 (2005) 233–236
Table 1. Optimization of reaction for the conversion of ( )-6a using
KSeCN to 2-imino-1,3-selenazolidine ( )-cis-9aa
NH2
R2
R1
c, d
e, d
H
N
OH
NH3Cl
NBn2
O
NH2
KSeCN
solvent
H3C
H3C
a, b
H3C
( )-5a-c
NH
CH3
R1
R1
Se
OMs
( )-6a
NH2
OH
R2
( )-cis-9a
R1
( )-4a-c
( )-3a-c
OH
( )-7a
Entry
KSeCN
(equiv)
Solvent
Time
(h)
Temp
(ꢁC)
Yield
(%)
b
1
2
3
4
5
6
7
2
2
1
2
2
2
2
H2O
H2O
48
1
0
80
—
( )-3, 4
a (R1 = Et)
89
<5
60
75
71
71
b (R1 = Me)
H2O
24
1
80
NH3Cl
c (R1 = Octyl)
MeOH
EtOH
DMF
THF
Reflux
Reflux
100
f-h
R2
R1
( )-5a-c
1
OMs
1
( )-6a-c
1
Reflux
a (R1 = Et, R2 = Et)
b (R1 = Me, R2 = Me)
c (R1 = Octyl, R2 = Octyl)
a Isolated as a fumarate.
b Not yielded.
NH3Cl
R2
f-h
R1
( )-7a,d7
OMs
( )-7, 8
a (R1 = Et, R2 = Et)
( )-8a,d
d (R1 = -(CH2)4- = R2)
Interestingly, all solvents led to moderate to good yield
of ( )-cis-9a (Table 1, entries 4–7).
Scheme 1. Synthesis of O-methanesulfonyl b-amino alcohol hydro-
chlorides ( )-6a–c and ( )-8a,d. Reagents and conditions: (a) BnBr,
K2CO3, CH3CN, 60ꢁC; (b) Swern oxidn; (c) R2MgBr, THF, 0ꢁC; (d)
H2, 20% Pd(OH)2–C, MeOH; (e) (R2)2Zn, toluene, 0ꢁC; (f) Boc2O,
CH2Cl2; (g) MsCl, Et3N, CH2Cl2; (h) 30% HCl/EtOH.
The possible mechanism for the conversion of ( )-6a to
( )-cis-9a is shown in Scheme 2 and may be explained as
follows. Initially, KSeCN neutralizes ( )-6a to afford the
free methanesulfonate A. The intermediate A undergoes
cyclization to form the aziridine A0, which is subse-
quently attacked by the selenocyanic ion (ꢀSeCN) to
open the aziridine ring. Finally intramolecular cycliza-
tion furnishes ( )-cis-9a. When ꢀSeCN attacks the car-
bon atom connected to the mesylate (–OMs) of
intermediate A before aziridination (Scheme 2, dotted
arrow down), the configuration of the mesylate carbon
is inverted, followed by intramolecular cyclization, to af-
ford ( )-trans-10a.
As shown in Scheme 1, the requisite O-methanesulfonyl
b-amino alcohol hydrochloride ( )-6a was prepared
from the corresponding amino alcohol ( )-3a in seven
steps according to a previously reported procedure.4b,5,6
Reaction conditions for the conversion of ( )-6a to ( )-
cis-9a were optimized as shown in Table 1. Reaction of
( )-6a with 2equiv of KSeCN in H2O at 80ꢁC gave the
best yield of ( )-cis-9a8 (89%, entry 2), however, this
reaction hardly proceeded when using the same equiva-
lent of KSeCN at low temperature or 1equiv of KSeCN
even at high temperature (Table 1, entries 1 and 3). The
production of ( )-cis-9a from ( )-6a was also attempted
in other solvents, that is MeOH, EtOH, DMF and THF.
On the other hand, when ( )-8a is reacted with KSeCN
under reaction conditions similar to that under which
( )-cis-9a was produced from ( )-6a, ( )-trans-10a is
produced via intermediate B and B0. When ꢀSeCN
attacks the carbon atom connected to the mesylate
NH2
A
A'
Et
NH3Cl
Et
NH2
Et
a
b
H
NH
Et
KSeCN
Et
Et
Et
SeCN
NH2
Et
N
Et
Et
Et
b
( )-cis-9a
NH
OMs
( )-6a
OMs
Se
a
-SeCN
-
Et
S
e
C
N
(
S
SeCN
N
2
)
NH2
)
2
Et
SN
(
Et
Et
NH3Cl
Et
N
c
C
NH2
e
- S
H
N
NH
Et
SeCN
NH2
Et
KSeCN
Et
Et
Et
Et
Et
d
-SeCN
Et
( )-trans-10a
NH
OMs
( )-8a
OMs
Se
c
d
B
SeCN
B'
Scheme 2. Possible mechanism for the synthesis of 2-imino-1,3-selenazolidine derivatives ( )-cis-9a and ( )-trans-10a.

S. Ueda et al. / Tetrahedron Letters 46 (2005) 233–236
235
Table 2. Synthesis of 4,5-dialkyl-2-imino-1,3-selenazolidines ( )-cis-
9b,c, ( )-trans-10a,d and 2-iminothiazolidine ( )-cis-1aa
(–OMs) before aziridination (Scheme 2, dotted arrow
up), the configuration of the mesylate carbon is inverted,
followed by intramolecular cyclization, to afford ( )-cis-
9a.
( )
( )
-6b,c
-8a,d
( )
-cis-9b,c
KSeCN
H2O, 80 o
1h
C
( )
-trans-10a,d
In order to confirm the mechanism explained above, we
synthesized the optically active isomer of cis-9a from the
corresponding optically active amino alcohol (S)-3a
according to a method similar to that for the synthesis
of ( )-cis-9a from ( )-6a, and examined its stereochem-
istry using X-ray analysis. Based on the mechanism, the
synthesized compound should have a (4S,5R) configura-
tion. The ORTEP view revealed that the synthesized
compound had a cisoid configuration (Fig. 1). In addi-
tion, the analysis of Flack parameter9 together with
experimental data on this compound confirmed the
absolute configuration of the synthesized compound as
(4S,5R).
KSCN
( )
-6a
( )-cis-1a
H2O, 80 o
1h
C
Entry Compound
Structure
Yield (%)
70
H
H3C
N
1
2
( )-cis-9b
( )-cis-9c
NH
Se
H3C
H
N
H3C
H3C
65
84
NH
Se
H
N
H3C
H3C
Having confirmed the mechanism for the conversion of
( )-6a to ( )-cis-9a and optimized the reaction condi-
tions, we next examined the conversion of various
O-methanesulfonyl b-amino alcohol hydrochlorides [( )-
6b,c and ( )-8a,d] into 2-imino-1,3-selenazolidines. The
requisite hydrochlorides were synthesized by a method
similar to that for the synthesis of ( )-6a (Scheme 1).
As shown in Table 2, the hydrochlorides were trans-
formed into the corresponding 1,3-selenazolidines ( )-
cis-9b,c and ( )-trans-10a,d in moderate to satisfactory
yield. In addition, potassium thiocyanate (KSCN) in-
stead of KSeCN was reacted with ( )-6a under the same
condition to afford ( )-cis-1a in good yield.
3
( )-trans-10a
NH
Se
H
N
4
5
( )-trans-10d
( )-cis-1a
77
87
NH
Se
H
N
H3C
H3C
NH
S
a Isolated as a fumarate except for ( )-trans-10d.
Table 3. Inhibitory activity of 4,5-diethylsubstituted 2-imino-1,3-
selena and thiazolidine against iNOSa
Finally, we evaluated the inhibitory activity against
iNOS of two selected compounds, that is, ( )-cis-9a,
( )-trans-10a and their sulfur analogues according to a
previously reported procedure.4b As shown in Table 3,
the inhibitory activity of the selenazolidine derivatives
against iNOS was very strong and in the same range
as that of thiazolidine analogues. Therefore, selenazo-
lidine derivatives may be expected to have pharmaco-
logical activity similar to that of thiazolidine derivatives.
Compound
Inhibitory activity IC50 (nM)b
( )-cis-9a
( )-cis-1a
96
34
18
14
( )-trans-10a
( )-trans-1b
a All compounds were evaluated as a fumarate.
b IC50 value for iNOS was determined by testing each compound at
eight concentration according to previous report.4b
As many aziridine or aziridinium ion derivatives have
been reported as important intermediates for the synthe-
sis of biologically active compounds,10 our study add on
to that concept by providing a direct synthetic method
for the pharmacologically active 4,5-dialkylsubstituted
2-imino-1,3-selenazolidine derivatives via aziridine
intermediates.
In conclusion, by reacting O-methanesulfonyl b-amino
alcohol hydrochlorides with KSeCN, we provide here
a direct synthetic method of the pharmacologically ac-
tive 4,5-dialkylsubstituted 2-imino-1,3-selenazolidine
derivatives via aziridine intermediates. This synthetic
method will be helpful in the preparation of selenium-
containing organic compounds. Further study is now
in progress.
Acknowledgements
We thank Dr. Katsumi Chiba for his thorough and
helpful comments on this letter. We also thank Mr.
Akihiro Yano for conducting all biological assays. We
Figure 1. ORTEP view of X-ray structure of (4S,5R)-9a.

236
S. Ueda et al. / Tetrahedron Letters 46 (2005) 233–236
8. Representative synthetic methods and characteristic data
are given for ( )-cis-4,5-diethyl-2-iminoselenazolidine
(9a): to a stirred solution of ( )-6a4b (1.88g, 8.11mmol)
in water (17mL) was added KSeCN (2.34g, 16.2mmol) at
0ꢁC and the reaction mixture was allowed to warm up to
80ꢁC with stirring for additional 2h. The reaction mixture
was then cooled in an ice bath, basified with 10% sodium
hydroxy solution (17mL), extracted with chloroform
(20mL · 2), dried with sodium sulfate and finally concen-
trated under reduced pressure, to give a crude brown oil.
Purification of this crude oil by column chromatography
using Chromatorexꢂ (NH) gave ( )-cis-9a (1.49g, 89%) as
a yellow oil: 1H NMR (CDCl3): d 0.96 (3H, t, J = 7.2Hz),
1.05 (3H, t, J = 7.4Hz), 1.48–1.67 (2H, m), 1.78–1.93 (2H,
m), 3.84 (1H, dt, J = 8.4, 6.0Hz), 3.97 (1H, ddd, J = 11.5,
5.5, 3.7Hz), 4.74 (2H, br). APCI-MS m/z 206 [M+H]+.
This compound was treated with fumaric acid in EtOH/n-
hexane solution to give its fumarate as a white solid, mp
138–142ꢁC. Anal. Calcd for C7H14N2SeÆC4H4O4: C, 41.13;
H, 5.65; N, 8.72. Found: C, 41.15; H, 5.71; N, 8.71.
Caution! KSeCN or HSeCN produced in situ is very
stenchful.
9. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881; X-ray
crystallographic analysis: a colourless prismatic crystal of
this compound having approximate dimension of
0.7 · 0.5 · 0.3mm were obtained from EtOH solution by
slow evaporation at room temperature. All measurements
were made on a Bruker APEX CCD detector with
graphite monochromated MoKa radiation. The structure
was solved by direct methods and refined by full-matrix
least-squares methods with anisotropic temperature fac-
tors for non-H atoms. All hydrogen atoms calculated at
idealized positions were included in the calculation of the
structure factors. The crystal data are as follows:
also would like to thank Professor T. Ishida at Osaka
University of Pharmaceutical Sciences for allowing us
to use the Brucker CCD system and computational
resources.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.11.064.
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