Stereocontrolled synthesis of the enantiomers of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one

Article abstract of DOI:10.1016/S0957-4166(01)00390-1

The asymmetric synthesis of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one 1 is described. Enantiomers of compound 1 were obtained using the Sharpless asymmetric dihydroxylation (AD) or hydrolytic kinetic resolution (HKR) methods. The enantiomers of compound 1, which were obtained by HKR had higher enantiomeric excesses than those which were synthesized by AD and epoxidation. The enantiomeric purity of the synthesized compounds was determinated by capillary electrophoresis.

Full text of DOI:10.1016/S0957-4166(01)00390-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2533–2536
Stereocontrolled synthesis of the enantiomers of
-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one
1
a
b
a,
Katarzyna Kulig, Ulrike Holzgrabe and Barbara Malawska *
a
Department of Pharmaceutical Chemistry, Collegium Medicum Jagiellonian University, ul. Medyczna 9, 30-688 Krak o´ w, Poland
b
Institut f u¨ r Pharmazie und Lebensmittelchemie, Universit a¨ t W u¨ rzburg, Am Hubland, 97074 W u¨ rzburg, Germany
Received 6 August 2001; accepted 4 September 2001
Abstract—The asymmetric synthesis of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one 1 is described. Enan-
tiomers of compound 1 were obtained using the Sharpless asymmetric dihydroxylation (AD) or hydrolytic kinetic resolution
(
HKR) methods. The enantiomers of compound 1, which were obtained by HKR had higher enantiomeric excesses than those
which were synthesized by AD and epoxidation. The enantiomeric purity of the synthesized compounds was determinated by
capillary electrophoresis. © 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
Preliminary biological studies showed that compound 1
prevented or ameliorated the adrenaline-, barium chlo-
ride induced arrhythmia and statistically diminished
arrhythmias associated with coronary artery occlusion
and reperfusion in the isolated rat heart. Compound 1
demonstrates potent local anesthetic properties and
depressed the depolarization phase of the action poten-
tial of cardiac cells. According to Williams classification
Chiral drugs have long been used as therapeutic agents,
but in most cases only in racemic form. Over the last 20
years, however, great advances in production technol-
ogy and quality control techniques have made chirality
an important issue. In the development process of a
new drug, differentiation due to chirality is now an
integral part of preclinical and clinical investigations.
The choice of racemate must be justified and the crite-
ria for this will become more demanding in the
5
compound 1 is in class Ia of antiarrhythmic drugs.
Compound 1 also showed hypotensive effects and dis-
4,6,7
played a and a adrenergic blocking activities.
1
,2
1
2
future.
Knowing that the interactions between compound and
receptor site are stereoselective, efforts to synthesize
enantiomers of compound 1 were undertaken. In our
earlier studies racemic 1-[2-hydroxy-3-(4-phenyl-1-
piperazinyl)-propyl]-pyrrolidin-2-one 1 was obtained
from the reaction between phenylpiperazine and 1-(2,3-
epoxypropyl)-pyrrolidin-2-one 4. Based on this as a
starting material for the stereoselective synthesis of
compound 1, enantiomers of 1-(2,3-epoxypropyl)-
pyrrolidin-2-one 4 were selected. Herein we report a
comparison between the two methods of synthesis of
the enantiomers of 1.
For example, it has been demonstrated in the case of
b-blocker of type ArOCH CH(OH)CH NHR that only
2
2
the (S)-enantiomer is sufficiently active. Thus b-block-
ers, such as timolol, penbutolol and levobunolol are
3
used in therapy only as (S)-enantiomers.
In the context of our studies on new therapeutic agents
for arrhythmia and hypertension a series of pyrrolidin-
2
-one was synthesized. One of the most active com-
pounds was 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-
propyl]-pyrrolidin-2-one 1.
4
2
. Results and discussion
As shown in Scheme 1, we considered that the stereo-
genic center in compound 4 could be installed by
catalytic asymmetric dihydroxylation (AD) of olefin 2
8,9
*
0
Corresponding author. E-mail: mfmalaws@cyf-kr.edu.pl
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00390-1

2
534
K. Kulig et al. / Tetrahedron: Asymmetry 12 (2001) 2533–2536
and stereospecific conversion of diols 3 into epoxides
According to this procedure, the required non-racemic
epoxides were obtained via the Sharpless AD and epox-
idation. As the starting material for our synthesis,
1-allylpyrrolidin-2-one 2 was used. Compound 2 was
obtained by reaction between tetrahydrofuran-2-one
and allylamine. Oxidation of 2 by standard procedures
with commercially available AD-mix a or b provided
the diols (S)-(+)-3 or (R)-(−)-3 in 70–80% yield. AD
mix a or b is a mixture of potassium osmate,
K [Fe(CN) ], K CO and (DHQ) -PHAL (AD mix a)
1
0
4,
or by hydrolytic kinetic resolution (HKR) of the
terminal 1,e12poxide
4
catalyzed by
a
(Salen)Co
1
complex.
3
6
2
3
2
and (DHQD) -PHAL (AD mix b), respectively. The
2
diols (S)-(+)-3 and (R)-(−)-3 were easily converted to
the epoxides (S)-(+)-4 and (R)-(−)-4 using the process
based on the acetoxonium ion-mediated formation of
acetate esters of halohydrins. Subsequently, base-medi-
ated ester saponification and cyclization give the enan-
tiomeric epoxides (S)-(+)-4 and (R)-(−)-4 (Scheme 2).
Design of low-molecular-weight catalysts for reaching
enantioselectivities similar to those obtained in enzy-
matic reactions has become an important goal of asym-
metric synthesis. HKR processes introduced by
Jacobsen are recent examples of achievements in this
area. In the presence of (R,R)- or (S,S)-SalenCo(III)Ac
and water racemic, 1-(2,3-epoxypropyl)-pyrrolidin-2-
one 4 was transformed into enantiomers of (S)-(+)-4 or
Scheme 1.
(
R)-(−)-4 and enantiomers of 1-(2,3-dihydroxypropyl)-
pyrrolidin-2-one (not isolated) (Scheme 3).
The aminolysis of compounds (+)-4 and (−)-4 with
1
-phenylpiperazine gave the enantiomers of compound
(
S)-(+)-1 and (R)-(−)-1 in about 65% yield. The enan-
tiomeric excess of the enantiomer of compound 1 was
established by capillary electrophoresis using sulfated
b-cyclodextrin as a chiral pseudostationary phase. The
ees for compounds (+)-1 and (−)-1, which were synthe-
sized by asymmetric dihydroxylation using AD-mix a
or AD-mix b, were in range 20–24%. The highest ees
were determined for (S)-(+)-1 enantiomer (64%) and
(
R)-(−)-1 enantiomer (96%), which were synthesized via
hydrolytic kinetic resolution of 4 using (R,R)- and
S,S)-SalenCo(III)OAc as the catalyst. The yields in the
(
HKR reactions are essentially identical (44 and 42%)
for the two enantiomers. It is possible that the conver-
sions were not the same or a racemization of (S)-(+)-4
took place during aminolysis.
In summary, the enantiomers of compounds 1 were
synthesized via two synthetic pathways. The enan-
tiomers of 1, which were obtained by HKR character-
ized higher enantiomeric excess than those which were
synthesized by AD and epoxidation. The above
described method of HKR could be used in the synthe-
sis of pharmacologically active analogues of com-
pounds 1.
iv
3
. Experimental
Scheme 2. Conditions: (i) 1-allylamine; (ii) t-BuOH/H O, 0°C;
3.1. General
2
(
iii) MeC(OMe) , MeSiCl/CH Cl , K CO , MeOH, rt; (iv)
3 2 2 2 3
phenylpiperazine, MeOH, rt. The relative configurations are
tentatively assigned by comparison of closely related diols.
Uncorrected melting points were determined in open
capillary on a B u¨ chi melting point apparatus. Elemen-
9

K. Kulig et al. / Tetrahedron: Asymmetry 12 (2001) 2533–2536
2535
Scheme 3. Conditions: (i) H O, rt; (ii) phenylpiperazine, MeOH, rt, 48 h; (iii) phenylpiperazine, MeOH, 40°C, 12 h. The relative
2
12
configurations are tentatively assigned according to the literature.
tal analyses (C, H, N) were determined within 0.4% of
theoretical values. Optical rotations were determined at
the sodium D line with a Kr u¨ ss P-3002 polarimeter.
TLC was performed on Merck aluminium precoated
plates of silica gel 60 F-254 (detection by UV and by
reduced pressure. Yield: 77.9% (19.5 g), bp 110°C/20
mbar, anal: C H NO, M =125.17, R (S )=0.78, R
f
7
11
r
f
2
(S )=0.63, R (S )=0.60.
3
f
4
3.4. 1-(2,3-Dihydroxypropyl)-pyrrolidin-2-one (S)-(+)-3
or (R)-(−)-3
spraying with 0.05 mol J solution in 10% HCl. Column
2
chromatography was carried out on a Merck Kieselgel
6
0 (0.063–0.200 mm). Solvent for chromatography: S –
To a mixture of 50 ml of tert-butyl alcohol and 50 ml
of water, 14 g of AD-mix a or b was added. Stirring at
room temperature produced two clear phases. The mix-
ture was cooled to 0°C then 0.001 mol (1.25 g) of 2 was
added at once and the heterogeneous slurry was stirred
at 0°C for 21 h (progress monitored by TLC). While
the mixture was stirred solid sodium sulfite (15 g) was
added and the mixture was allowed to warm to room
temperature and stirred for 30 min. Methylene chloride
was added to the reaction mixture, and after separation
of the layers, the aqueous phase was further extracted
with methylene chloride. The combined organic layers
were dried over anhydrous sodium sulfate and concen-
trated. The crude product was purified by column
1
chloroform:acetone (1:1), S – methanol:25% ammo-
2
nium (98:2), S – chloroform:methanol:25% ammonium
3
(
(
90:10:3), S4 – n-butanol:i-propanol:25% ammonium
11:6:2).
3.2. Capillary electrophoresis
All experiments were performed on a Beckman P/ACE
MDQ system (Beckman Instruments, Fullerton, CA,
USA) using a fused-silica capillary with a total length
of 60 cm, a detection length of 50 cm, and an internal
diameter of 50 mm. Samples were loaded by 5 s of
pressure injection and separated at 25°C using a con-
stant voltage of 20 KV. Phosphate buffer (100 mM) pH
chromatography using S as an eluent.
2
6
.0 was prepared by mixing appropriate concentrations
AD-mix a gave 1.28 g of (S)-(+)-3 (yield 81%). Anal.
2
0
of H PO and KH PO solution. The sulfated cyclodex-
159.00, C H O N R (S )=0.66, [h] =+14.3 (c=1,
3
4
2
4
7
13
3
f
2
D
trin (Aldrich, Steinheim, FRG) was dissolved in buffer,
the samples subjected to the CE were dissolved in
deionized water (conc. :1 mg/ml). All solutions were
filtered through a 0.45 mm syringe (Schleicher and
Sch u¨ ll, Dassel, FRG). The drug solution had a concen-
tration of 25 mg/ml and was detected using a diode
array detector at 194 nm. The capillary was conditioned
for 20 min with 0.1 M NaOH, and 10 min with water.
Additionally, the capillary was washed for 2 min with
MeOH).
AD-mix b gave 1.15 g of (R)-(−)-3 (yield 72%). Anal.
2
0
159.00, C H O N R (S )=0.66, [h] =−16.3 (c=1,
7
13
3
f
2
D
MeOH).
3.5. 1-(2,3-Epoxypropyl)-pyrrolidin-2-one (S)-(+)-4 or
(R)-(−)-4
0
.1 M NaOH, 1 min with water, and 2 min with the
3.5.1. Epoxidation of 1-(2,3-dihydroxypropyl)-pyrrolidin-
running buffer before each run.
2-one (S)-(+)-3 or (R)-(−)-3. Trimethylsilyl chloride
3
(
0.01 mol, 1.4 cm ) was added to a solution of (S)-(+)-3
3.3. 1-Allylpyrrolidin-2-one (2)
or (R)-(−)-3 and trimethyl orthoacetate (0.01 mol, 1.3
cm ) in methylene chloride at 0°C. The solution was
3
3
Tetrahydrofuran-2-one [0.2 mol (9.1 cm )] and allyl-
amine [0.4 mol (16.0 cm )] were heated in an autoclave
stirred for 1 h, then evaporated. The crude product was
dissolved in dry methanol and K CO (0.02 mol, 2.91 g)
3
2
3
for 21 h at 200°C. The obtained oil was distilled under
was added. The suspension was stirred for 2 h, then

2
536
K. Kulig et al. / Tetrahedron: Asymmetry 12 (2001) 2533–2536
filtered and the residue was washed with methylene
chloride. The filtrate was evaporated under vacuum and
the residue was purified by column chromatography
The asymmetric dihydroxylation method using AD-mix
b gave 0.83 g of (R)-(−)-1 (yield 53%). The condition of
2
0
reaction: rt, 48 h. Anal. 302.42, C H O N , [h] =
16
26
3
3
D
using S as a solvent.
−18.6 (c=1, MeOH), mp 91.3–92.7°C, ee=24%.
1
From (S)-(+)-3 was obtained 0.77 g of (S)-(+)-4 (yield
Hydrolytic kinetic resolution method using (R,R)-
SalenCo(III)OAc gave 1.84 g of (S)-(+)-1 (yield 62%).
The condition of reaction: 40°C, 12 h. Anal. 302.42,
20
6
8%). Anal. 141.17, C H O N R (S )=0.59, [h] =
7 11 2 f 1 D
10.3 (c=1, MeOH).
20
C H O N , [h] =24.5 (c=1, MeOH), mp 91.3–
16
26
3
3
D
From (R)-(−)-3 was obtained 0.69 g of (R)-(−) 4 (yield
92.7°C, ee=64%.
2
0
6
8.3%). Anal. 141.17, C H O N R (S )=0.59, [h] =
7 11 2 f 1 D
Hydrolytic kinetic resolution method using (S,S)-Salen-
Co(III)OAc gave 2.06 g of (R)-(−)-1 (yield 68%). The
condition of reaction: rt, 48 h. Anal. 302.42,
−11.65 (c=1, MeOH).
2
0
D
C H O N , [h] =−30.0 (c=1, MeOH), mp 91.3–
3
.5.2. Hydrolytic kinetic resolution of racemic 1-(2,3-
epoxypropyl)-pyrrolidin-2-one 4. A mixture of (R,R)- or
S,S)-N,N%-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo-
16 26
3
3
9
2.7°C, ee=96%.
(
hexanediaminocobalt(II) (SalenCo(II)) (0.2 mmol, 0.12
g) and acetic acid (0.4 mmol, 0.02 cm ) was stirred for
3
Acknowledgements
1
h at room temperature. The solvent was removed by
The study was supported by the project KBN 4 P 05 F
3919.
rotary evaporation and the brown residue was dried
0
under vacuum. 1-(2,3-Epoxypropyl)-pyrrolidin-2-one 4
(
0.1 mol, 14.1 g) was added in one portion, and the
stirred mixture was cooled in an ice-water bath. Water
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26
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