Enantioselective synthesis of (R)-(-)-praziquantel (PZQ)

Article abstract of DOI:10.1016/j.tetasy.2006.04.023

Praziquantel 8 (2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline-4-one), a powerful anti-worm drug, has been synthesized in its enantiopure form via asymmetric transfer hydrogenation according to the Noyori protocol. Initially, the reduction of prochiral imine 4 afforded product 5 in 62% ee, but a single crystallization amplified the enantiomeric purity to 98% ee. The final (R)-(-)-praziquantel 8 was prepared in three subsequent steps in 56% chemical yield.

Full text of DOI:10.1016/j.tetasy.2006.04.023

Tetrahedron: Asymmetry 17 (2006) 1415–1419
Enantioselective synthesis of (R)-(ꢀ)-praziquantel (PZQ)
Piotr Roszkowski,a Jan K. Maurinb,c and Zbigniew Czarnockia,*
aFaculty of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
bNational Institute of Public Health, Chełmska 30/34, 00-725 Warsaw, Poland
c
´
Institute of Atomic Energy, 05-400 Otwock-Swierk, Poland
Received 7 April 2006; accepted 24 April 2006
Available online 24 May 2006
Abstract—Praziquantel 8 (2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline-4-one), a powerful anti-worm
drug, has been synthesized in its enantiopure form via asymmetric transfer hydrogenation according to the Noyori protocol. Initially,
the reduction of prochiral imine 4 afforded product 5 in 62% ee, but a single crystallization amplified the enantiomeric purity to 98%
ee. The final (R)-(ꢀ)-praziquantel 8 was prepared in three subsequent steps in 56% chemical yield.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Praziquantel (PZQ, l,2-cyclohexylcarbonyl-1,2,3,6,7,11b-
hexahydro-4H-pyrazino[2,1-a]isoqunoline-4-one) 8, is a
drug of tremendous importance in treating schistosomiasis
and soil-transmitted helminthiasis.1,2 The recently esti-
mated global number of cases of infection with Schisto-
soma spp. approaches 200 million, with 650 million
being at risk of infection. Praziquantel 8 is still the sole
existing drug for these diseases.3 Although its precise
mode of action still remains unknown, the mechanism
that involves tegumental damage and paralytic muscular
contraction of parasites is known to relay solely on the
(R)-(ꢀ)-enantiomer of PZQ, the other one being its harm-
less distomer. However, due to both economic reasons
and uncertain long-term side effects associated with the
administration of large doses of racemic PZQ, it seems
advisable to develop an enantioselective route to this
important isoquinoline derivative. Numerous synthetic
approaches to racemic praziquantel, including a recent
report utilizing a solid support,4 have been published to
date.5–11 The problem of stereoselective construction of
this rather simple molecule has attracted much less atten-
tion and only one contribution to this field by Zhang
et al.12 can be found in the literature. The Pictet–Spengler
reaction of the intermediate containing the Andersen
reagent was claimed to effectively control the transfer of
stereochemistry.12
Having been encouraged by the rather positive results in the
enantioselective formation of isoquinoline13 and b-carbo-
line14 derivatives with the use of an asymmetric transfer
hydrogenation protocol,15,16 we decided to apply this cata-
lytic methodology to a praziquantel synthesis with the hope
to make it attractive from an industrial point of view.
Imine 4, a suitable prochiral substrate, was prepared in
75% overall yield from N-phthaloylglycine chloride 1 and
phenylethylamine 2 via the Bischler–Napieralski cycliza-
tion17 on intermediate amide 3 (Scheme 1).
Subsequent asymmetric transfer hydrogenation on imine 4
was performed under classical Noyori conditions.18 Ini-
tially, a combination of N-tosyl-(1R,2R)-diphenylethylene-
diamine19 and [RuCl2(g6-benzene)]2 formed a catalyst
(R,R)-9, which was then used in S/C = 160 ratio in the
presence of a formic acid:triethylamine mixture (Fig. 1).
Tos
N
Tos
N
Ru
Ru
Cl
Cl
N
N
H2
H2
(S,S)-9
(R,R)-9
*
Corresponding author. Tel.: +48 22 822 02 11; fax: +48 22 822 59 96;
e-mail: czarnoz@chem.uw.edu.pl
Figure 1. Chiral ruthenium catalysts.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.023

1416
P. Roszkowski et al. / Tetrahedron: Asymmetry 17 (2006) 1415–1419
O
CHCl3, Et3N
rt, 78%
ClOC
O
+
NH2
HN
N
N
O
O
O
3
2
1
reflux, 96%
CH3CN,
POCl3
.
H2N-NH2 H2O,
C2H5OH
(R,R)-9
HCOOH / Et3N
NH
NH
N
reflux,
N
O
CH3CN, rt, 52%
O
93%
H
H
NH2
N
O
6
5
4
O
C6H11COCl, CH3CN
pyridine, 2N HCl,
rt, 78%
1. ClCH2COCl, CH2Cl2,
NaOH 50%, TEBAC, rt
N
N
O
NH
NH
H
77%
H
O
8
7
O
PZQ
Scheme 1.
Product 5, which was formed in 52% isolated yield, showed
23
F3C
O
the specific rotation ½aꢁD ¼ þ52:0, which upon comparison
OCH3
23
with the literature12 value ½aꢁD ¼ ꢀ60:7 for apparent enan-
N
tiopure 5, appeared to be of 86.0% enantiomeric excess. On
the basis of a sign of the specific rotation, the absolute
stereochemistry assignment reported by Zhang et al.12
appears to be incorrect. Moreover, when amine 5 was trans-
formed into its amide derivative 10 with (S)-Mosher acid,
both the spectroscopic (1H NMR) and chromatographic
methods revealed the presence of diastereomers in an
81:19 ratio. The formation of diastereomeric amides derived
from amine 5 indicated that the previously reported data12
did not correspond to an enantiopure substance. Indeed, we
found that amine 5 obtained in our experiment could be
H
N
O
O
(1S,2'R)-10
Figure 2. Structural analysis of compound (1S,20R)-10.
ee. Therefore, it seems that the classical Noyori’s catalyst
remains the most effective in the reduction of imine 4.
Although amine 5 was initially formed with only a moder-
ate enrichment (62% ee), it can be effectively transformed
into the enantiopure form upon one recrystallization from
chloroform/diethyl ether mixture.
quite effectively recrystallized to afford a substance of
23
½aꢁD ¼ þ84:0, a value, which remained unchanged upon
repeated crystallization. The complete enantiomeric purity
of this sample was further confirmed by 1H NMR and chro-
matographic data of its (S)-Mosher acid derivative.
In a parallel experiment, when N-tosyl-(1S,2S)-diphenyl-
ethylenediamine was used to prepare the catalyst (S,S)-9,
and the resultant amine (S)-5 was subjected to the forma-
tion of the amide derivative with (R)-Mosher acid, the
absolute stereochemical outcome was additionally con-
firmed by X-ray analysis of compound 10 (Fig. 2).
Subsequent treatment of amine 5 with hydrazine in reflux-
ing ethanol afforded diamine 6 in 93% yield,21 which was
then subjected to a reaction with cyclohexanecarbonyl
chloride in dichloromethane in the presence of potassium
carbonate. Under these conditions,12 cyclohexanoyl deriva-
tive 7 was obtained in 24% yield only but the undesired
N,N-dicyclohexanoyl amide was formed in 49% yield.
Much better results were obtained using a selective
procedure described by Cizin et al.,22 upon which only
monoamide 7 was isolated in 78% yield. Finally, monocy-
clohexanoyl derivative 7 was converted to enantiopure
praziquantel 8 with chloroacetyl chloride in 77% yield, un-
der Schotten–Bauman conditions in a mixture of dichloro-
In the search for improved chiral induction during the
hydrogenation step, we examined several other ligands
known to be highly effective,20 including those already uti-
lized by us.13 The attempted application of those ligands
was unsuccessful and only N-tosyl-(1R,2R)-cyclohexane-
diamine gave product 5 in a non-racemic form with 4%

P. Roszkowski et al. / Tetrahedron: Asymmetry 17 (2006) 1415–1419
1417
methane and 50% (aq) NaOH in the presence of TEBA
chloride.23
8.9 mL (97.3 mmol) of POCl3 was added in one portion.
The mixture was refluxed for 1 h (light yellow colour devel-
oped), cooled to room temperature and concentrated under
reduced pressure. Toluene (100 mL) and 36% HCl (50 mL)
were added to the residue and the mixture was heated at
reflux for 0.5 h and then cooled to room temperature. The
water phase was then alkalized with (aq) NH3, extracted
with CHCl3 and dried over MgSO4. Column chromatogra-
phy on silica gel using chloroform as eluent allowed the
separation of imine 4 (1.50 g, 16% yield, 96% yield based
on the consumed amide). Crystallization from CHCl3/hex-
ane/Et2O (5:30:0.5) gave the analytical sample of 4 as col-
ourless crystals mp = 201–203 ꢁC. 1H NMR (500 MHz,
CDCl3): d 2.68 (t, J = 3.5) 2H-4; 3.61 (tt, J1 = 1 Hz,
J2 = 3.5 Hz) 2H-3; 4.93 (t, J = 1 Hz) 2H-10; 7.27 (dd,
J1 = 0.5 Hz, J2 = 7.5 Hz) 1H-5; 7.33 (td, J1 = 1.5 Hz,
J2 = 7.5 Hz) 1H-6; 7.38 (td, J1 = 1.5 Hz, J2 = 7.5 Hz) 1H-
7; 7.52 (dd, J1 = 1.0 Hz, J2 = 7.5 Hz) 1H-8. 13C NMR
(125 MHz, CDCl3): d 25.9; 41.2; 46.8; 123.4; 123.8; 126.9;
127.5; 127.7; 130.9; 132.4; 133.8; 137.8; 158.7; 168.3.
LRMS (ESI) m/z = 313.0 [M+Na]+.
3. Conclusions
In conclusion, an effective method for the enantioselective
preparation of praziquantel is described, starting with eas-
ily available phenylethyl amine, phthalyl anhydride and
glycine. The asymmetric transfer hydrogenation proved
to be a key step for chirality induction.
4. Experimental
The NMR spectra were recorded on a Varian Unity Plus
1
spectrometer operating at 500 MHz for H NMR and at
125 MHz for 13C NMR. The spectra were measured in
CDCl3 and are given as d values (in ppm) relative to
TMS. Mass spectra were collected on Quatro LC Micro-
mass and LCT Micromass TOF HiRes apparatus. Optical
rotations were measured on a Perkin–Elmer 247 MC polari-
meter. TLC analyses were performed on silica gel plates
(Merck Kiesegel GF254) and visualized using UV light or
iodine vapour. Column chromatography was carried out
at atmospheric pressure using Silica Gel 60 (230–400 mesh,
Merck) using mixtures of chloroform/methanol as eluents.
Melting points were determined on a Boetius hot-plate
microscope and were uncorrected. All solvents used in
the reactions were anhydrous. The single crystal X-ray
measurement was carried out on a KUMA KM4 CCD
j-axis diffractometer. After initial corrections and data
reduction, intensities of reflections were used to solve and
consecutively refine the structure.
4.3. (1R)-(+)-1-Phthalimidomethyl-1,2,3,4-tetrahydroiso-
quinoline 5
Catalyst (R,R)-9 was pre-formed from [RuCl2(C6H6)]2
(6 mg, 24 lmol) and (1R,2R)-1,2-diphenyl-N-(p-tolu-
oylsulfonyl)ethylenediamine (7.3 mg, 20 lmol) in 4 mL of
CH3CN. To a solution of imine 4 (870 mg, 3.00 mmol) in
CH3CN (5 mL), a 5:2 formic acid/triethylamine mixture
(2.5 mL) was introduced, followed by the addition of the
pre-formed catalyst. The mixture was then stirred at room
temperature for 5 h and after evaporation of the solvents,
the residue was made basic with aqueous K2CO3 solution
and extracted with chloroform. The organic phase was
dried over MgSO4 and concentrated under reduced pres-
sure. The residue was purified with column chromatogra-
phy on silica gel using chloroform/methanol 0–0.8%
MeOH as a solvent system to afford 454 mg (52% yield)
4.1. N-Phthalimidoacetyl-b-phenylethylamnine 3
To a stirred solution of b-phenylethylamine 1 (11.2 g,
90.3 mmol) and triethylamine (26.0 mL, 0.18 mol) in
CHCl3 (300 mL), a solution of phthalylglycyl chloride
(20.7 g, 92.6 mmol) dissolved in CHCl3 (100 mL) was
added over 20 min. The mixture was stirred at room tem-
perature for 2 h and then was treated with aqueous
Na2CO3 solution and extracted with chloroform
(2 · 50 mL). The organic phase was washed with brine
(2 · 50 mL), dried over MgSO4 and the solvent was evapo-
rated in vacuo. The residue was purified by crystallization
from MeOH to give 22.0 g of product 3 (77%) as colourless
of
compound
(+)-(R)-5
as
colourless
needles
23
½aꢁD ¼ þ52:0 (c 1, CHCl3); recrystallization from chloro-
form/diethyl ether (1:4) mixture gave 210 mg of pure enan-
23
tiomer mp = 174–176 ꢁC, ½aꢁD ¼ þ84:0 (c 1, CHCl3),
23
23
½aꢁD ¼ þ81:6 (c 1, acetone), lit.12 ½aꢁD ¼ ꢀ60:7 (c 0.5, ace-
1
tone), H NMR (500 MHz, CDCl3): d 1.73 (s) N–H; 2.78
(m) 2H-4; 2.97 (m) 1H-3; 3.27 (m) 1H-3; 3.89 (dd,
J1 = 14 Hz, J2 = 3.5 Hz) 1H-10; 4.08 (dd, J1 = 14 Hz,
J2 = 3.5 Hz) 1H-10; 4.36 (dd, J1 = 11 Hz, J2 = 3.5 Hz)
1H-1; 7.12–7.33 (m) 4H-5,6,7,8; 7.72 (m) 2H-50,60; 7.87
(m) 2H-40,70. 13C NMR (125 MHz, CDCl3): d 29.5; 38.8;
42.5; 54.2; 123.4; 126.0; 126.7; 126.9; 129.6; 132.15; 133.9;
135.6; 135.9, 168.9. HRMS (ESI) calcd for C18H17N2O2
([M+H]+): 293.1290. Found: 293.1297. Enantiomer
1
solid, mp = 186–188 ꢁC. H NMR (500 MHz, CDCl3): d
2.81 (t, J = 6.5 Hz) 2H-b to NH; 3.52 (apparent q,
J = 6.5 Hz) 2H-a to NH; 4.28 (s) 2H; 5.87 (broad s) N–
H; 7.15–7.18 (m) 3H–Ar; 7.22–7.26 (m) 2H–Ar; 7.72–7.76
(m) 2H–Pht.; 7.85–7.89 (m) 2H–Pht. 13C NMR
(125 MHz, CDCl3): d 35.4; 40.84; 40.9; 123.6; 126.5;
128.64; 128.79; 131.9; 134.3; 138.5; 166.0; 167.7. LRMS
(ESI) m/z = 331.0 [M+Na]+.
(ꢀ)-(S)-5 was obtained as colourless needles using (S,S)-9
23
form of the catalyst; ½aꢁD ¼ ꢀ52:8; recrystallization from
chloroform/diethyl ether (1:4) mixture gave pure enantio-
23
mer; mp = 175–176 ꢁC, ½aꢁD ¼ ꢀ83:4 (c 1, CHCl3).
4.2. 3,4-Dihydro-1-phthalimidomethylisoquinoline 4
4.4. (1R)-(ꢀ)-1-Aminomethyl-1,2,3,4-tetrahydroisoquinoline 6
This procedure was adapted from the work of Humber.21
This procedure was adapted from the lit.17 To a stirred sus-
pension of N-phthalimidoacetyl-b-phenylethylamnine 3
(10.0 g, 32.4 mmol) in CH3CN (100 mL), a volume of
To a solution of (1R)-(+)-5 (290 mg, 0.98 mmol) in 8 mL

1418
P. Roszkowski et al. / Tetrahedron: Asymmetry 17 (2006) 1415–1419
of ethanol was added 0.1 mL (2.73 mmol) of anhydrous
hydrazine in ethanol (0.5 mL). The mixture was refluxed
for 40 min, cooled to room temperature, concentrated un-
der reduced pressure and then heated again for 40 min with
5 mL of 36% hydrochloric acid. The precipitate was filtered
off and the filtrate made alkaline with solid sodium hydr-
and the mixture was heated and stirred for 2 h at reflux.
After that time, a portion of 3 mL of water was added
and the mixture extracted with CH2Cl2 (2 · 3 mL). The or-
ganic phase was washed with water (2 · 2 mL), 5% HCl
(2 mL), again with water (2 mL) and dried over Na2SO4.
After evaporation of the solvent, the residue was purified
with column chromatography on silica gel using
chloroform/methanol 0–0.3% MeOH as a solvent system
oxide and extracted with CHCl3 (4 · 10 mL) to afford a
23
colourless oil (150 mg, 93.5%); ½aꢁD ¼ ꢀ78:7 (c 1, CHCl3),
23
lit.12 ½aꢁD ¼ ꢀ55:6 (c 0.5, acetone). The 1H NMR spectrum
to afford 93 mg (77%) of (1R)-(ꢀ)-8, mp = 113–115 ꢁC,
23
was similar to that described by Beaumont et al.24 and
Jones et al.25 1H NMR (500 MHz, CDCl3): d 2.22 (s)
3H–N–H2, N–H; 2.72–2.85 (m) 2H-4; 3.00–3.04 (m) 3H-
3, 10; 3.17–3.21 (m) 1H-10; 3.98 (t, J = 5.5) 1H-1; 7.09–
lit.26 Mp = 107–108 ꢁC; ½aꢁD ¼ ꢀ135:0 (c 1, CHCl3),
23
23
½aꢁD ¼ ꢀ126:9 (c 1, EtOH 99.8%), lit.26 ½aꢁD ¼ ꢀ146:9,
23
lit.27 ½aꢁD ¼ ꢀ132:4 (c 1, EtOH); the NMR spectra were
in full accordance with the published data for the
racemate.9,28
1
7.18 (m) 4H–Ar. H NMR (500 MHz, CDCl3 + D2O): d
2.72–2.81 (m) 2H-4; 2.98–3.03 (m) 3H-3, 10; 3.16–3.19
(m) 1H-10; 3.95 (t, J = 5.5) 1H-1; 7.10–7.15 (m) 4H–Ar.
13C NMR (125 MHz, CDCl3): d 29.8; 40.3; 46.3; 57.5;
126.0; 126.09; 126.2; 129.4; 135.9; 136.7. HRMS (ESI)
calcd for C10H15N2 ([M+H]+): 163.1235. Found: 163.1219.
4.7. (1S)-1-Phthalimidomethyl-2-[(20R)-30,30,30-trifluoro-20-
methoxy-20-phenylpropanoyl]-1,2,3,4-tetrahydroisoquinoline 10
The Mosher acid chloride was prepared without isolation:
(R)-(+)-a-methoxy-a-trifluoromethylphenylacetic acid (42
mg, 0.18 mmol) and SOCl2 (0.02 mL, 0.27 mmol) in tolu-
ene (2.5 mL) was heated at reflux for 3 h. To a stirred solu-
tion of amine (1S)-5 (40 mg, 0.14 mmol) and triethylamine
(0.04 mL, 0.27 mmol) in CHCl3 (7 mL), a pre-formed
Mosher acid chloride (0.043 g, 0.17 mmol) in CHCl3
(3 mL) was added dropwise and after 0.5 h, the reaction
mixture was treated with saturated NaHCO3 solution and
extracted with CHCl3. The organic phase was washed with
brine and dried over MgSO4. The solvent was removed un-
der reduced pressure and the crude product purified via
column chromatography on silica gel using with CHCl3/
4.5. (1R)-(ꢀ)-1-(N-Cyclohexylcarbonylamido methyl)-
1,2,3,4-tetrahydroisoquinoline 7
This compound was obtained by the procedure described
by Cizin et al.22 To a stirred solution of diamine (1R)-6
(150 mg, 0.91 mmol) in 1.5 mL of CH3CN, pyridine
(0.1 mL, 0.1 mmol) and 2 N hydrochloric acid (0.45 mL,
0.91 mmol), a solution of cyclohexanecarbonyl chloride
(0.13 mL, 0.1 mmol) dissolved in 0.5 mL CHCl3 was slowly
introduced during 1 h. The mixture was stirred at room
temperature for 2 h and then concentrated under reduced
pressure. Diethyl ether (5 mL) ether was added to the resi-
due and the mixture was extracted with 1 N HCl
(2 · 2 mL). The water phase was made alkaline with 30%
NaOH solution, extracted with CHCl3 (4 · 10 mL) and
the organic phase was dried over MgSO4. The crude prod-
uct was purified with column chromatography on silica gel
using chloroform/methanol 0.1–0.4% MeOH as a solvent
system to afford 190 mg (78%) of compound (ꢀ)-(R)-7 as
a pale yellow crystals (crystallization from Et2O/hexane),
CH3OH (98:2) as eluent to give (1S,200R)-10 (60 mg, 86%)
23
as a colourless crystals, mp = 187–189 ꢁC, ½aꢁD ¼ þ35:0
1
(c 1.0, CHCl3). H NMR (500 MHz, CDCl3): d 2.69 (m)
1H; 3.02 (m) 1H; 3.18 (m) 1H; 3.56 (d, J = 2.0 Hz) 3H–
OCH3; 3.78 (m) 2H; 4.17 (m) 1H; 6.13 (dd, J1 = 4.5 Hz,
J2 = 10.0 Hz) 1H-1; 7.12 (m) 1H–Ar; 7.20–7.24 (m) 2H–
Ar; 7.29 (m) 2H–Ar; 7.34–7.38 (m) 2H–Ar; 7.39–7.44 (m)
2H–Ar; 7.78 (m) 2H-50,60; 7.96 (m) 2H-40,70. 13C NMR
(125 MHz, CDCl3): d 27.7; 39.0; 41.1; 52.1; 56.1; 84.8 (q,
23
1
1
mp = 111–112.5 ꢁC, ½aꢁ ¼ ꢀ17:6 (c 1, CHCl3). H NMR
(500 MHz, CDCl3): dD1.16–1.29 (m) 4H–Cy; 1.35–1.47
(m) 2H–Cy; 1.64–1.84 (m) 4H–Cy; 2.73–2.83 (m) 2H-4;
3.01–3.06 (m) 1H-3; 3.13–3.18 (m) 1H-3; 3.32–3.37 (m)
1H-10; 3.76–3.81 (m) 1H-10; 4.09 (dd, J1 = 3.5 Hz,
J2 = 9.0 Hz) 1H-1; 6.29 (s) 1H–N–H; 7.08–7.20 (m) 4H–
Ar. 13C NMR (125 MHz, CDCl3): d 25.72; 25.73; 25.75;
29.5; 29.61; 29.64; 39.82; 43.27; 45.48; 55.03; 126.2; 126.5;
126.6; 129.3; 135.3; 135.7; 176.5. HRMS (ESI) calcd for
C17H25N2O ([M+H]+): 273.1967. Found: 273.1980.
2JCF = 25.5 Hz); 123.4; 124.9 (q, JCF = 131 Hz); 126.0;
126.4; 126.5; 127.5; 127.9; 128.3; 128.9; 129.4; 132.2;
133.3; 133.55; 133.59; 134.1; 134.3; 165.9; 167.9.
The parallelepiped colourless crystal of 10 of dimension
0.3 · 0.35 · 0.4 mm was placed on Kuma KM4 j-axis dif-
˚
fractometer. Mo Ka radiation (k = 0.71073 A) and the
x ꢀ 2h scan mode were used to collect the data. After
locating and centring 32 strong reflections with
13 < 2h < 21.5ꢁ the orthorhombic unit cell of dimensions
˚
a = 9.5670(19), b = 10.920(2), c = 23.452(5) A and a =
3
˚
4.6. (1R)-(ꢀ)-2-Cyclohexylcarbonyl-1,2,3,6,7,11b-hexa-
hydro-4H-pyrazino[2,1-a]isoqunoline-4-one, praziquantel
(PZQ) 8
b = c = 90ꢁ and V = 2450.1(8) A was established. The ob-
served systematic absences led us to ascertain the P212121
space group. The unit cell contains Z = 4 molecules of 10
of general formula C28H23F3N2O4. Crystal density is of
Dx = 1.379 Mg/m3 (g/cm3), whereas F(000) = 1056,
l(Mo Ka) = 0.108 mmꢀ1. Two thousand six hundred and
fourteen reflections were collected up to 2h = 44.41ꢁ. Of
these, 2453 of them were independent (Rint = 0.0375 for
symmetry related reflections). Direct methods from
SHELXS93 were used to solve the structure whereas
SHELXL93 software was employed for structure refinement.
This compound was obtained according to the procedure
described by Sergovskaya and Chernyak.23 To a stirred
solution of amine (1R)-7 (110 mg, 0.39 mmol) in 1.0 mL
CH2Cl2, a solution of 50% NaOH (0.12 mL, 2.33 mmol)
was added, followed by the addition of a solution of chlo-
roacetyl chloride (0.034 mL, 0.43 mmol) in 0.15 mL of
CH2Cl2. After 0.5 h, TEBAC (9 mg, 0.04 mmol) was added

P. Roszkowski et al. / Tetrahedron: Asymmetry 17 (2006) 1415–1419
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All carbon, nitrogen, oxygen and fluorine atoms were lo-
cated from the E maps and subsequent difference density
maps, whereas hydrogen atoms were located geometrically
using standard geometrical criteria. In the final cycles of
structure refinement all non-hydrogen atoms were refined
anisotropically whereas remaining atoms were treated as
fixed contributors, placed geometrically with their isotropic
displacement parameters being related to the displacement
parameters of the corresponding carbon atoms. Final R
and wR were of 0.0285 and 0.0757, respectively, for 1757
observed reflections with I > 2r(I). The data were depos-
ited with Cambridge Crystallographic Data Centre under
the number CCDC 604432.
16. Yim, A. S. Y.; Wills, M. Tetrahedron: Asymmetry 2005, 16,
7994–8004.
17. Croisy-Delcey, M.; Huel, C. J. Heterocycl. Chem. 1987, 25,
655–660.
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We thank the Ministry of Education and Science for grant
K136/H03/2005.
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