A straightforward and efficient synthesis of praziquantel enantiomers and their 4′-hydroxy derivatives

Article abstract of DOI:10.1016/j.tetasy.2013.11.004

A new method for the synthesis of praziquantel enantiomers via resolution of praziquanamine with (S)-(+)-naproxen was developed. The four 4′-hydroxy derivatives were obtained through each single praziquanamine enantiomer, coupling with cis- and trans-4-(benzyloxy)cyclohexanecarboxylic acids and subsequent hydrogenolysis for the deprotection of the 4′-OH cyclohexane residue. Additionally, the in vitro cysticidal activity of the compounds was tested, finding that (R)-(-)-praziquantel is the eutomer.

Full text of DOI:10.1016/j.tetasy.2013.11.004

Tetrahedron: Asymmetry 25 (2014) 133–140
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A straightforward and efficient synthesis of praziquantel
enantiomers and their 40-hydroxy derivatives
a
a
b
Alberto Cedillo-Cruz a, , María Isabel Aguilar , Marcos Flores-Alamo , Francisca Palomares-Alonso ,
⇑
Helgi Jung-Cook a,b
a Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Cd. Universitaria, Coyoacán, México 04510, Mexico
b Laboratorio de Neuropsicofarmacología, Instituto Nacional de Neurología y Neurocirugía, México, DF 14269, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the synthesis of praziquantel enantiomers via resolution of praziquanamine with
(S)-(+)-naproxen was developed. The four 40-hydroxy derivatives were obtained through each single
praziquanamine enantiomer, coupling with cis- and trans-4-(benzyloxy)cyclohexanecarboxylic acids
and subsequent hydrogenolysis for the deprotection of the 40-OH cyclohexane residue. Additionally,
the in vitro cysticidal activity of the compounds was tested, finding that (R)-(ꢀ)-praziquantel is the
eutomer.
Received 7 October 2013
Accepted 7 November 2013
Available online 16 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
salt formation10 and (b) diastereoisomeric covalent bond forma-
tion.11 Hence, based on this last point, (b) is a suitable method for
Praziquantel (PZQ) is a racemic compound containing equal
parts of its isomers, (R)-(ꢀ)-4a and (S)-(+)-praziquantel 4b. PZQ
is a pyrazinoisoquinolone derivative, which has been shown to
be highly effective against a broad range of cestodes and trema-
todes in humans and animals;1 the mechanism of the action of
PZQ is not known exactly. PZQ undergoes rapid first-pass drug
metabolism and its principal metabolites are the mono- and
di-hydroxy derivatives, highlighting the trans-40-hydroxypraziquantel
by high plasma concentrations.2
Experimental and clinical studies with the trematodes Schisto-
soma japonicum and Schistosoma mansoni have demonstrated that
4a is the active component against these species.3 Moreover, the
use of the pure eutomer resulted in fewer side effects with respect
to the racemate.4 (R)-(ꢀ)-trans-40-Hydroxypraziquantel 9b has also
been shown to be an effective schistosomicidal agent, but not at
the same level of potency as 4a.5
the production of large quantities of enantiomerically pure 4a and
4b, allowing the determination of the diastereoisomer ratio by
TLC, 1H NMR, or HPLC and thus providing direct information of
the enantiomeric purity of the final product.
Herein we report a new method for the resolution of praziquan-
amine as a key intermediate for the formation of praziquantel
enantiomers, the synthesis of its 40-hydroxy derivatives, single-
crystal X-ray diffraction analysis as well as the in vitro cysticidal
activity of PZQ and compounds 4a, 4b, (R)-(ꢀ)-cis-40-hydrox-
ypraziquantel 9a, 9b, and (S)-(+)-trans-40-hydroxypraziquantel
monohydrate 9d.
2. Results and discussion
2.1. Chemistry
Praziquantel is also effective in the treatment of taeniasis; the
cysticercosis is more complex to treat, nevertheless a combination
of drugs such as praziquantel or albendazole with corticosteroids
may be used.6 To date, studies have not been carried out in order
to determine if 4a and its 40-hydroxy derivatives are the only active
stereoisomers against Taenia cysts.
For the production of 4a, the following methods have been used:
(1) enantioselective chromatography;7 (2) enantioselective synthe-
sis;8 (3) enrichment of partially resolved mixtures;9 and (4) resolu-
tion by the formation of diastereomers via: (a) diastereoisomeric
The synthesis of the praziquantel enantiomers 4a and 4b in
enantiomerically pure form is outlined in Scheme 1. The racemic
praziquanamine 1 was synthesized following the procedures re-
ported by Kim et al.12 Next, 1 was acylated with (S)-(+)-naproxen
acid chloride followed by separation of the resulting diastereoiso-
meric amides 2a and 2b using flash column chromatography (SiO2,
hexane–ethyl acetate). In order to define the absolute configura-
tion of the C11b stereogenic center of compounds 2a and 2b, di-
verse crystallization conditions were explored. Only compound
2a formed crystals suitable for further X-ray investigation. The
absolute C11b configuration of compound 2a was determined as
(R), assigned by reference to the unchanged stereogenic center of
the naproxen acid moiety with an (S)-configuration (Fig. 1). On
⇑
Corresponding author. Tel.: +52 55 5622 5281; fax: +52 55 5622 5329.
E-mail address: albertocedillo_cruz@comunidad.unam.mx (A. Cedillo-Cruz).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.004

134
A. Cedillo-Cruz et al. / Tetrahedron: Asymmetry 25 (2014) 133–140
O
O
H
N
N
N
N
N
O
d)
c)
O
O
N
O
H
N
a), b)
2a
3a
4a
N
O
O
O
H
N
1a
N
N
N
N
O
c)
d)
O
N
O
O
2b
3b
4b
Scheme 1. Synthesis of enantiomerically pure 4a and 4b. Reagents and conditions: (a) (S)-(+)-naproxen acid chloride, NMM, CH2Cl2, room temp, 4 h; (b) separation by flash
chromatography; (c) 85% H3PO4, MW, 150 °C, 20 min then 5 M NaOH; (d) Na2CO3, cyclohexanecarbonyl chloride, CH2Cl2, 0 °C to room temp, 2 h.
was synthesized from the single praziquanamine enantiomer via
acylation with cyclohexanecarbonyl chloride. The structure of 4a
was confirmed by X-ray diffraction (Fig. 2).
Figure 1. Molecular structure of 2a with thermal ellipsoids at the 50% probability
level.
the basis of this analysis we assigned the (11bS,20S)-configuration
to diastereoisomer 2b.
Figure 2. Molecular structure of 4a with thermal ellipsoids at the 50% probability
From the NMR spectra of 2a and 2b at room temperature, a pair
of rotamers derived from slow rotation of the amide bond was
identified. Dynamic 1H NMR measurements were performed for
these two compounds. Coalescence for 2a was observed at 60 °C.
The presence of rotamers in these types of structures derived from
PZQ was inferred by Blaschke13 through molecular mechanics cal-
culations; it was pointed out that their concentration in solutions
should depend on the solvent polarity and the value of the dipole
moment for the respective form of the molecule.
The hydrolysis of 2a by refluxing with 1 M HCl for 7 days gave
3a in 52% yield, whereas the hydrolysis in concentrated H3PO4 at
100 °C for 3 days gave 3a in 72% yield. As can be seen, both condi-
tions provided the desired product in low to moderate yields. In or-
der to reduce the reaction time, we carried out the hydrolysis
under microwave irradiation. The optimum conditions were found
with irradiation at 150 °C and 85 W maximum power for 20 min in
85% w/w H3PO4 with 88% yield being obtained after chromato-
graphic purification. Using this methodology it was possible to
quickly prepare. In contrast to conventional heating, the use of
microwave irradiation drastically reduced the reaction time of at
least 3 days to only 20 min with excellent yield. Finally, 4a or 4b
level.
In order to prepare the 40-hydroxy derivatives of (R)-(ꢀ)-
praziquantel 9a and 9b,
a mixture of cis- and trans-ethyl
4-hydroxycyclohexanecarboxylates (5a and 5b) with benzyl
bromide, sodium hydride in THF or DMF gave 6a and 6b in poor
yields as complex mixtures of several compounds (visualized by
GC/MS). When the mixture of 5a and 5b was subjected to reductive
etherification,14 the diastereoisomers 6a and 6b were obtained and
separated in good yields using flash column chromatography (SiO2,
hexane–ethyl acetate). A detailed analysis of the 1H NMR spectrum
of 6a showed the 10-H atom to be in the axial position (J1-Ha/2-
Ha = 9.6 Hz, J1-Ha/2-He = 4.0 Hz) and the 40-H atom to be in the equa-
torial position (J4–He/3–Ha = 5.1 Hz, J4–He/3–He = 2.8 Hz), while the 1H
NMR spectrum of isomer 6b indicated that the 10-H atom exists in
the axial position (J1-Ha/2-Ha = 11.6 Hz, J1-Ha/2-He = 3.6 Hz) as well as
the 40-H atom (J4–Ha/3–Ha = 10.3 Hz, J4–Ha/3–He = 4.1 Hz), thus con-
firming the cis- and trans-conformations for 6a and 6b,
respectively. Basic hydrolysis of each diastereoisomer gave the
corresponding carboxylic acids, 7a or 7b and both acids were

A. Cedillo-Cruz et al. / Tetrahedron: Asymmetry 25 (2014) 133–140
135
H
H
O
O
O
OH
O
O
H
H
c)
d)
e)
N
N
N
N
O
OH
O
O
OBn
7a
OBn
6a
O
OEt
9a
8a
a), b)
H
H
O
OH
O
O
O
O
OH
O
OH
5a (cis) and 5b (trans)
c)
d)
e)
N
N
N
N
60:31
H
H
O
O
H2O
OBn
OBn
7b
8b
9b
6b
Scheme 2. Synthesis of enantiomerically pure 9a and 9b. Reagents and conditions: (a) PhCHO, Et3SiH, 5% mol FeCl3, MeNO2, room temp, 1 h; (b) separation by flash
chromatography; (c) 12.5 M NaOH, MeOH/THF, room temp, 6 h; (d) 3a, PyBOP, NMM, DMSO, room temp, 30 min; (e) ethanol, Pd/C (10%), H2, room temp to 45 °C, 3 h.
coupled with amine 3a. The hydrogenolysis of (R)-(ꢀ)-cis-40-benzyl-
oxypraziquantel 8a with palladium on carbon at room temperature
for 6 h gave (R)-(ꢀ)-cis-40-hydroxypraziquantel 9a in very low
yield, however the reaction time for the complete conversion
could be reduced to 3 h at 45 °C. Thus, the synthesis of
(R)-(ꢀ)-trans-40-hydroxypraziquantel 9b was also carried out un-
der those conditions (Scheme 2). With respect to the spectroscopic
characterization of 9a and 9b by 1H NMR, we found a discrepancy
in some chemical shift values for this compound with those re-
ported in the literature.15 The molecular structures of compounds
8a, 8b, and 9b were confirmed by single-crystal X-ray analysis
(Figs. 3–5).
Figure 4. Molecular structure of 8b with thermal ellipsoids at the 50% probability
level.
Figure 3. Molecular structure of 8a with thermal ellipsoids at the 50% probability
level.
It is noteworthy that trans-isomers 9b and 9d crystallized with
Figure 5. Molecular structure of 9b with thermal ellipsoids at the 50% probability
one water molecule, in contrast with the cis-isomers 9a and 9c,
which crystallized as anhydrous forms. This was observed by the
elemental analysis and was confirmed by single-crystal X-ray dif-
fraction of 9b (Fig. 5). In this compound, the crystal structure is sta-
bilized by a two-dimensional network of O–Hꢁ ꢁ ꢁO hydrogen bonds.
Intermolecular hydrogen bonds were observed between the O1W
atom of the water molecule and the O2 atom of the amide carbonyl
group and also with the O3 atom of the hydroxyl group, which
level.
seemed to be very effective in the stabilization of the crystal
structure.
For derivatives 2a, 4a, 8b, and 9b with a praziquanamino moi-
ety, the most stable conformation was observed in which the
O@Camide group was anti to the N–C(C@Olactam) moiety; the

136
A. Cedillo-Cruz et al. / Tetrahedron: Asymmetry 25 (2014) 133–140
syn-conformation occurs at 0°, while the anti conformation at 180°.
Compound 8a showed a syn conformation with a dihedral angle of
ꢀ1.4 and ꢀ4.0° for the two independent molecules per asymmetric
unit. Nevertheless, it is possible to find another conformation due
to the rotation of the amide bond, such as that observed in the
complex between glutathione S-transferase (Schistosoma japonica)
and PZQ16 with a gauche conformation and a dihedral angle of
ꢀ71.05°.
and Heteronuclear Multiple Bond Correlation (HMBC). All 2D
NMR spectra were recorded using the standard pulse sequences
and parameters recommended by the manufacturer. Dulbecco’s
Modified Eagle’s Minimal Essential Medium (Sigma-Aldrich Co.,
U.S.A.) culture medium was used for the cysticidal activity, supple-
mented with 10% fetal calf serum, 2 mM L-glutamine, 8 mg/dL of
gentamicin sulfate and 200,000 IU/dL of penicillin G sodium
(Gibco, U.S.A.). The Taenia crassiceps cysts were observed with an
inverted light microscope (Reichert, 569).
2.2. Cysticidal activity
4.1.1. Racemic praziquanamine 1
This is the first study in which the in vitro cysticidal activity of
PZQ and compounds 4a, 4b, 9a, 9b, and (S)-(+)-trans-40-hydrox-
ypraziquantel monohydrate 9d was evaluated on Taenia crassiceps
cysts (ORF strain). The results showed that the EC50 values for PZQ
and 4a were 61.798 (56.567–66.942) and 29.654 (27.237–
32.461) nM, respectively, showing that the potency of 4a was 2
times greater than that for PZQ. We found that, as in Schistosoma
japonicum and S. mansoni,3 for cysticidal activity, 4a is the eutomer
of PZQ. Moreover, 4b, 9a, and 9d did not display cysticidal activity;
only 9b showed 20% of activity at a concentration of 2886.66 nM.
Racemic praziquanamine 1 was prepared according to pub-
lished methods.12
4.1.2. (R)-(ꢀ)-2-((S)-2-(6-Methoxynaphthalen-2-yl)propanoyl)-
1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one
2a and (S)-(+)-2-((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)- 1,2,
3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one 2b
A
solution of (S)-(+)-naproxen acid chloride (2.705 g,
10.88 mmol) in dichloromethane (20 mL) was slowly added to a
stirred mixture of 1 (2 g, 9.89 mmol) and 4-methylmorpholine
(3.25 mL, 29.56 mmol) in dichloromethane (20 mL). The mixture
was stirred at room temperature for 4 h, then washed consecu-
tively with 1 M HCl (3 ꢂ 50 mL), a saturated solution of NaHCO3
(3 ꢂ 50 mL), water (3 ꢂ 50 mL), and dried over Na2SO4, filtered,
and concentrated. The residue was purified by column chromatog-
raphy (SiO2, hexane–ethyl acetate from 100:0, v/v to 30:70, v/v)
and gave 2a (faster eluting diastereoisomer, 1.927 g, 47%), and 2b
(slower eluting diastereoisomer, 1.763 g, 43%). Overall yield: 90%.
3. Conclusion
A new method for the resolution of praziquanamine as a key
intermediate for the formation of the praziquantel enantiomers
(R)-(ꢀ)-4a and (S)-(+)-praziquantel 4b and the synthesis of its
40-hydroxy derivatives ((R)-(ꢀ)-cis-40-hydroxypraziquantel 9a,
(R)-(ꢀ)-trans-40-hydroxypraziquantel 9b and the optical antipo-
des) was developed. The method involved the formation of a pair
of diastereoisomers derived from (S)-(+)-naproxen 2a and 2b,
which were easily separated by flash column chromatography,
with a subsequent acid hydrolysis and acylation of each resultant
single praziquanamine enantiomer with cyclohexanecarbonyl
chloride to provide 4a and 4b, respectively with overall yields of
70%. The 40-hydroxy cis- and trans-derivatives of 4a and 4b, 9a,
9b, 9c, and 9d were obtained by a 4-step sequence. In each case,
they were obtained with overall yields of 72% and their structures
were confirmed by spectroscopic techniques and single-crystal
X-ray diffraction. The in vitro cysticidal activity of praziquantel
toward Taenia crassiceps (ORF strain) was attributed to enantiomer
4a, while the contribution of 4b to the cysticidal activity of the
racemic mixture was negligible.
Compound 2a: mp 154–156 °C. ½aꢃD ¼ ꢀ2:32 (c 1, CHCl3). IR mmax
1641, 1603, 1481, 1441, 1202, 1031 cmꢀ1. MS (EI) m/z (relative
intensity, %) 414 (M+, 9), 312 (17), 256 (10), 228 (8), 201 (72),
185 (100), 173 (18), 145 (28), 132 (82). HRMS (EI) Calcd for
C
C
26H26N2O3 (M+): m/z 414.1938, Found: 414.1948. Anal. Calcd for
26H26N2O3: C, 75.34; H, 6.32; N, 6.76. Found: C, 75.26; H, 6.11;
N, 6.78. For clarity, the NMR spectra of the two rotamers are sepa-
rately described.
Major rotamer (73.40%): 1H NMR (400 MHz, CDCl3) d 7.77–7.66
00
00 00
00
(m, 3H, HC4
,
), 7.43 (d, J = 8.5 Hz, 1H, HC3 ), 7.34–7.21 (m, 3H,
8 ,1
00
00
HC11,10,9), 7.19–7.11 (m, 3H, HC7 ,8,5 ), 5.15 (dd, J = 13.4, 3.5 Hz,
1H, HC1), 4.67 (dd, J = 10.3, 3.4 Hz, 1H, HC11b), 4.64–4.55 (m, 1H,
HC6), 4.35 (AB, J = 17.2 Hz, 1H, HC3), 4.16 (AB, J = 17.2 Hz, 1H,
0
0
HC3), 3.97 (q, J = 6.8 Hz, 1H, HC2 ), 3.93 (s, 3H, HC4 ), 2.96–2.81
(m, 2H, HC1,7), 2.78–2.67 (m, 2H, HC6,7), 1.56 (d, J = 6.8 Hz, 3H,
13
1
0
0
HC3 ) ppm. C{ H} NMR (101 MHz, CDCl3) d 172.9 (C1 ), 164.1
4. Experimental
4.1. General
00
00
00
(C4), 157.9 (C6 ), 136.0 (C2 ), 135.0 (C7a), 133.8 (C4a ), 132.6 (C11a),
00
00
00
129.4 (C8), 129.3 (C8 ), 129.2 (C8a ), 128.0 (C4 ), 127.6 (C9), 127.1
(C10), 126.0 (C3 ), 125.7 (2C, C1 ,11), 119.3 (C7 ), 105.8 (C5 ), 55.4
00
00
00
00
0
0
(C4 ), 54.8 (C11b), 48.8 (C3), 45.8 (C1), 43.6 (C2 ), 39.0 (C6), 28.8
All commercial reagents used for the synthesis were purchased
from Sigma–Aldrich (Toluca, Mexico) unless otherwise specified.
Flash column chromatography was carried out on Merck Silicagel
60 (0.015–0.040 mm). Melting points were determined on a
Fisher–Johns apparatus and are uncorrected. Optical rotations
were measured with a Perkin–Elmer model 343 polarimeter. The
IR spectra were registered with a Perkin–Elmer Spectrum 400 FT-
IR/FT-FIR spectrometer. Elemental analyses were determined with
a Perkin–Elmer 2400 Series II CHNS/O Analyzer. Mass spectra were
registered in a Thermo-Electron spectrometer model DFS (Double
Focus Sector). NMR spectra were recorded in CDCl3 solution in a
Varian INOVA 400 spectrometer using the solvent signal
7.26 ppm for 1H and 77.16 ppm for 13C as references. NMR signals
assignments were made with a combination of 2D homonuclear
(1H–1H) and heteronuclear (1H–13C) correlation techniques, which
included 1H–1H COSY, 1H–1H Nuclear Overhauser Effect Spectros-
copy (NOESY), Heteronuclear Single Quantum Correlation (HSQC)
0
(C7), 20.8 (C3 ).
Minor rotamer (26.60%): 1H NMR (400 MHz, CDCl3) d 7.78–7.67
00 00
00
00
(m, 2H, HC4 ,8 ), 7.64 (s, 1H, HC1 ), 7.39 (d, J = 8.6 Hz, 1H, HC3 ),
00 00
7.36–7.20 (m, 2H, HC8,10), 7.19–7.09 (m, 3H, HC9,7 ,5 ), 7.00 (m,
1H, HC11), 4.93 (AB, J = 18.6 Hz, 1H, HC3), 4.89–4.79 (m, 1H,
HC11b,6), 4.43 (d, J = 12.3 Hz, 1H, HC1), 4.18–4.13 (m, 1H, HC2 ),
3.93 (s, 3H, HC4 ), 3.85 (AB, J = 18.7 Hz, 1H, HC3), 2.97–2.78 (m,
3H, HC7,6,1), 2.78–2.67 (m, 1H, HC7), 1.62 (d, J = 6.6 Hz, 3H, HC3 ).
C{ H} NMR (101 MHz, CDCl3) d 172.1 (C1 ), 165.3 (C4), 157.9
(C6 ), 136.2 (C2 ), 135.5 (C7a), 133.7 (C4a ), 132.1 (C11a), 129.7 (C8),
129.6 (C8a ), 129.3 (C8 ), 128.0 (C4 ), 127.7 (C9), 127.1 (C10), 125.9
0
0
0
13
1
0
00
00
00
00
00
00
00
00
00
00
(C3 ), 125.4 (C1 ), 125.1 (C11), 119.4 (C7 ), 105.8 (C5 ), 55.6 (C11b),
55.4 (C4 ), 49.5 (C1), 46.9 (C3), 44.1 (C2 ), 38.7 (C6), 28.8 (C7), 20.5
0
0
0
(C3 ).
Compound 2b: mp 92–94 °C. ½aꢃD ¼ þ128:4 (c 0.5, CHCl3). IR
mmax 1644, 1604, 1443, 1417, 1207, 1031 cmꢀ1. MS (EI) m/z (rela-
tive intensity, %) 312 (32), 201 (100), 185 (24), 173 (18), 145

A. Cedillo-Cruz et al. / Tetrahedron: Asymmetry 25 (2014) 133–140
137
(32), 132 (98). HRMS (EI) Calcd for C26H26N2O3 (M+): m/z 414.1938,
Found: 414.1943. Anal. Calcd for C26H26N2O3: C, 75.34; H, 6.32; N,
6.76. Found: C, 75.32; H, 6.74; N, 6.84.
J = 13.0, 4.7, 1.5 Hz, 1H, HC1), 3.66 (AB, J = 17.4 Hz, 1H, HC3), 3.52
(AB, J = 17.3 Hz, 1H, HC3), 3.04–2.93 (m, 1H, HC7), 2.92–2.85 (m,
1H, HC1), 2.87–2.79 (m, 1H, HC6), 2.78–2.70 (m, 1H, HC7), 1.85 (s,
1H, HN2) ppm. 13C{1H} NMR (101 MHz, CDCl3) d 167.4 (C4), 135.1
(C7a), 134.4 (C11a), 129.5 (C8), 127.1 (C9), 126.7 (C10), 124.8 (C11),
57.0 (C11b), 50.2 (C3), 50.0 (C1), 38.9 (C6), 29.0 (C7) ppm. IR mmax
3318, 2878, 1618, 1432 cmꢀ1. MS (EI) m/z (relative intensity, %)
202 (M+, 30), 173 (92), 145 (100), 131 (70), 117 (23), 103 (10),
77 (8). HRMS (EI) Calcd for C12H14N2O (M+): m/z 202.1101, Found:
202.1100. Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85.
Found: C, 70.79; H, 7.14; N, 13.73.
Major rotamer (52.21%): 1H NMR (400 MHz, CDCl3) d 7.83–7.72
00 00 00
00
(m, 3H, HC4 ,8 ,1 ), 7.43 (dd, J = 8.4, 1.3 Hz, 1H, HC3 ), 7.19–7.07 (m,
00
00
3H, HC7 ,9,5 ), 7.07–6.97 (m, 2H, HC8,10), 6.32 (d, J = 7.9 Hz, 1H,
HC11), 4.98 (AB, J = 18.8 Hz, 1H, HC3), 4.82–4.78 (m, 1H, HC6), 4.39
0
(dd, J = 13.3, 2.7 Hz, 1H, HC1), 4.03 (qd, J = 6.8, 3.2 Hz, 1H, HC2 ),
0
3.91–3.86 (m, 3H, HC4 ), 3.84 (AB, J = 18.9 Hz, 1H, HC3), 3.77 (dd,
J = 10.6, 4.0 Hz, 1H, HC11b), 3.05 (dd, J = 13.4, 10.6 Hz, 1H, HC1),
2.84–2.73 (m, 1H, HC7), 2.57 (dt, J = 16.2, 2.8 Hz, 1H, HC7), 2.48 (td,
J = 12.7, 3.4 Hz, 1H, HC6), 1.55 (d, J = 6.8 Hz, 3H, HC3 ) ppm. 13C{1H}
0
0
00
NMR (101 MHz, CDCl3) d 171.6 (C1 ), 165.2 (C4), 157.8 (C6 ), 136.8
4.1.5. (R)-(ꢀ)-2-(Cyclohexanecarbonyl)-1,2,3,6,7,11b-hexahydro-
4H-pyrazino[2,1-a]isoquinolin-4-one 4a
00
00
00
(C2 ), 135.0 (C7a), 133.6 (C4a ), 131.7 (C11a), 129.3 (C8), 129.1 (C8a ),
00
00
00
128.8 (C8 ), 128.2 (C4 ), 127.1 (C9), 126.5 (C10), 125.6 (C3 ), 125.6
To a solution of 3a (200 mg, 988.9
1.74 mmol) in dichloromethane (5 mL) was added dropwise a solu-
tion of cyclohexanecarbonyl chloride (135 L, 1.01 mmol) in
dichloromethane (5 mL) at 0 °C. After stirring at room temperature
for 2 h, dichloromethane (20 mL) was added, and the mixture was
then washed successively with 1 M HCl (3 ꢂ 30 mL), saturated
solution of NaHCO3 (3 ꢂ 30 mL), water (3 ꢂ 30 mL), and dried over
Na2SO4, filtered, and concentrated. The residue was purified by col-
umn chromatography (SiO2, hexane–ethyl acetate 70:30, v/v). A
white powder was obtained (271.7 mg, 88% yield). Mp 108–
lmol) and Na2CO3 (184.7 mg,
00
00
00
0
(C1 ), 125.2 (C11), 119.6 (C7 ), 105.7 (C5 ), 55.2 (C4 ), 55.1 (C11b),
0
0
49.5 (C1), 46.4 (C3), 44.2 (C2 ), 38.2 (C6), 28.7 (C7), 20.8 (C3 ) ppm.
l
Minor rotamer (47.79%): 1H NMR (400 MHz, CDCl3) d 7.72–7.63
00 00
00
(m, 2H, HC4 ,8 ), 7.58 (d, J = 1.7 Hz, 1H, HC1 ), 7.36–7.06 (m, 6H,
HC3 ,11,10,9,8,7 ,5 ), 5.22 (dd, J = 13.3, 2.8 Hz, 1H, HC1), 4.83 (dd,
J = 10.3, 4.3 Hz, 1H, HC11b), 4.78–4.73 (m, 1H, HC6), 4.49 (AB,
00
00 00
0
J = 17.7 Hz, 1H, HC3), 4.03 (qd, J = 6.8, 3.2 Hz, 1H, HC2 ), 3.91–3.85
0
(m, 3H, HC4 ), 3.63 (AB, J = 17.7 Hz, 1H, HC3), 2.94–2.66 (m, 4H,
HC7,6,1,7), 1.55 (d, J = 6.8 Hz, 3H, HC3 ) ppm. 13C{1H} NMR
0
0
00
00
(101 MHz, CDCl3) d 172.4 (C1 ), 164.1 (C4), 157.6 (C6 ), 135.5 (C2 ),
110 °C. ½aꢃD ¼ ꢀ147:5 (c 1, CHCl3). IR mmax 2933, 2923, 1637,
134.7 (C7a), 133.5 (C4a ), 132.6 (C11a), 129.2 (C8), 129.1 (C8 ),
129.0 (C8a ), 127.7 (C4 ), 127.4 (C9), 126.9 (C10), 125.8 (C3 ), 125.7
(C1 ), 125.4 (C11), 119.1 (C7 ), 105.5 (C5 ), 55.2 (C4 ), 54.9 (C11b),
1495, 1439, 1418, 1296, 1214, 757 cmꢀ1. MS (EI) m/z (relative
00
00
intensity, %) 312 (M+, 44), 201 (100), 185 (17), 173 (15), 145
00
00
00
(25), 132 (70). HRMS (EI) Calcd for C
19H24N2O2 (M+): m/z
00
00
00
0
0
0
49.1 (C3), 45.2 (C1), 43.3 (C2 ), 39.0 (C6), 28.6 (C7), 20.4 (C3 ) ppm.
312.1832, Found: 312.1840. Anal. Calcd for C19H24N2O2: C, 73.05;
H, 7.74; N, 8.97. Found: C, 72.76; H, 7.67; N, 8.92. For clarity, the
NMR spectra of the two rotamers are described separately.
Major rotamer (77.52%): 1H NMR (400 MHz, CDCl3): d 7.34–7.19
(m, 4H, HC11,10,9,8), 5.18 (dd, J = 13.3, 2.6 Hz, 1H, HC1), 4.87–4.79 (m,
2H, HC6,11b), 4.49 (AB, J = 17.5 Hz, 1H, HC3), 4.10 (AB, J = 17.4 Hz, 1H,
4.1.3. (R)-(ꢀ)-1,2,3,6,7,11b-Hexahydro-4H-pyrazino[2,1-a]isoqui-
nolin-4-one 3a
Compound 2a (100 mg, 0.241 mmol) was suspended in 85 w/w
H3PO4 (2 mL) in a proper vial which was heated to an external tem-
perature of 150 °C over a 3 min period ramping up to a microwave
power of 300 W (Synthos 3000). Thevial was held at this temperature
for 20 min to a microwave power of 85 W. The mixture was cooled to
4 °C, poured into crushed ice (15 mL) and an aqueous solution of 5 M
NaOH was added to pH 12. The aqueous layer was extracted with
dichloromethane (3 ꢂ 15 mL). The organic layers were combined,
dried over Na2SO4, filtered, and concentrated. The residue was puri-
fied by column chromatography (SiO2, dichloromethane–methanol
gradient from 100:0, v/v to 90:10, v/v). A white crystalline product
0
HC3), 3.06–2.78 (m, 4H, HC7,6,1,7), 2.49 (t, J = 11.4 Hz, 1H, HC1 ), 1.94–
0
0
0
0
1.69 (m, 5H, HC3 ,2 ,4 ), 1.69–1.49 (m, 2H, HC2 ), 1.41–1.21 (m, 3H,
HC4 ,3 ) ppm. 13C{1H} NMR (101 MHz, CDCl3) d 174.9 (C12), 164.5
0
0
(C4), 134.9 (C7a), 132.92 (C11a), 129.4 (C8), 127.6 (C9), 127.1 (C10),
0
125.6 (C11), 55.1 (C11b), 49.2 (C3), 45.3 (C1), 40.9 (C1 ), 39.2 (C6),
0
0
0
0
29.4 (C2 ), 29.2 (C2 ), 28.9 (C7), 25.9 (C3 ,4 ) ppm.
Minor rotamer (22.48%): 1H NMR (400 MHz, CDCl3): d 7.34–
7.19 (m, 4H, HC9,10,8,11), 4.94–4.79 (m, 3H, HC6,11b,3), 4.39 (d,
J = 12.0 Hz, 1H, HC1), 3.89 (AB, J = 18.4 Hz, 1H, HC3), 3.28 (t,
J = 11.6 Hz, 1H, HC1), 3.06–2.78 (m, 3H, HC7,6,7), 2.64–2.54 (m,
was obtained (43.1 mg, 88% yield). mp 124–126 °C. ½aꢃD ¼ ꢀ306:1 (c
1, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.25–7.10 (m, 4H, HC10,9,8,11),
4.86 (ddd, J = 12.5, 5.1, 2.6 Hz, 1H, HC6), 4.79 (dd, J = 10.0, 4.6 Hz,
1H, HC11b), 3.73 (ddd, J = 13.0, 4.7, 1.4 Hz, 1H, HC1), 3.72 (AB,
J = 17.6 Hz, 1H, HC3), 3.52 (AB, J = 17.3 Hz, 1H, HC3), 3.03–2.93 (m,
1H, HC7), 2.92–2.85 (m, 1H, HC1), 2.87–2.79 (m, 1H, HC6), 2.78–2.70
(m, 1H, HC7), 1.98 (s, 1H, HN2) ppm. 13C{1H} NMR (101 MHz, CDCl3)
d 167.4 (C4), 135.1 (C7a), 134.3 (C11a), 129.5 (C8), 127.1 (C9), 126.7
(C10), 124.8 (C11), 57.0 (C11b), 50.1 (C3), 49.9 (C1), 38.9 (C6), 28.9
1H, HC1 ), 1.94–1.69 (m, 5H, HC3 ,2 ,4 ), 1.69–1.49 (m, 2H, HC2 ),
0
0
0
0
0
1.41–1.21 (m, 3H, HC4 ,3 ) ppm. 13C{1H} NMR (101 MHz, CDCl3) d
174.5 (C12), 165.7 (C4), 135.7 (C7a), 132.2 (C11a), 129.8 (C8), 127.8
(C9), 127.1 (C10), 125.3 (C11), 55.9 (C11b), 49.7 (C1), 46.5 (C3), 40.9
0
0
0
0
0
0
0
(C1 ), 38.8 (C6), 29.3 (C2 ), 29.2 (C2 ), 28.9 (C7), 25.9 (C3 ,4 ) ppm.
4.1.6. (S)-(+)-2-(Cyclohexanecarbonyl)-1,2,3,6,7,11b-hexahydro-
4H-pyrazino[2,1-a]isoquinolin-4-one 4b
Following the procedure reported above for the preparation of
4a and starting with amine 3b (138 mg, 0.36 mmol), compound
4b was obtained as a white powder (268.6 mg, 87% yield). Mp
(C7) ppm. IR
m
max 3319, 2878, 1618, 1432 cmꢀ1. MS (EI) m/z (relative
intensity, %) 202 (M+, 20), 173 (76), 145 (100), 131 (71), 117 (33), 103
(16), 77 (17). HRMS (EI) Calcd for C12H14N2O (M+): m/z 202.1101,
Found: 202.1102. Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N,
13.85. Found: C, 71.30; H, 6.92; N, 14.02.
107–109 °C. ½aꢃD ¼ þ147:2 (c 1, CHCl3). IR mmax 2933, 2923, 1637,
1495, 1439, 1418, 1296, 1214, 757 cmꢀ1. MS (EI) m/z (relative
intensity, %) 312 (M+, 29), 201 (92), 185 (28), 173 (18), 145 (32),
132 (100). HRMS (EI) Calcd for C19H24N2O2 (M+): m/z 312.1832,
Found: 312.1826. Anal. Calcd for C19H24N2O2: C, 73.05; H, 7.74;
N, 8.97. Found: C, 72.67; H, 7.58; N, 8.89.
4.1.4. (S)-(+)-1,2,3,6,7,11b-Hexahydro-4H-pyrazino[2,1-a]isoqui-
nolin-4-one 3b
Following the procedure reported above for the preparation of
3a and starting with amide 2b (100 mg, 0.241 mmol) compound
3b was obtained as a white crystalline solid (42.8 mg, 88% yield).
4.1.7. Ethyl cis-4-(benzyloxy)cyclohexanecarboxylate 6a and
ethyl trans-4-(benzyloxy)cyclohexanecarboxylate 6b
mp 124–126 °C. ½a D
ꢃ
¼ þ305:6 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3) d 7.35–7.04 (m, 4H, HC10,9,8,11), 4.86 (ddd, J = 12.5, 5.1,
2.6 Hz, 1H, HC6), 4.79 (dd, J = 10.0, 4.5 Hz, 1H, HC11b), 3.73 (ddd,
This compound was obtained by the procedure described by
Oriyama et al.14 To a suspension of anhydrous iron(III) chloride

138
A. Cedillo-Cruz et al. / Tetrahedron: Asymmetry 25 (2014) 133–140
(21.0 mg, 0.13 mmol) and benzaldehyde (264
nitromethane (13 mL) were added successively ethyl 4-hydroxy-
cyclohexanecarboxylate, a mixture of cis and trans (dr value
l
L, 2.60 mmol) in
(m, 2H, HC2), 1.44–1.31 (m, 2H, HC3) ppm. 13C{1H} NMR
(101 MHz, CDCl3) d 180.3 (C10), 139.0 (C6), 128.5 (C8), 127.7 (C7),
127.6 (C9), 76.5 (C4), 70.2 (C5), 42.1 (C1), 31.3 (C3), 27.0 (C2) ppm.
69:31, determined by NMR) (500
lL, 3.10 mmol) and triethylsilane
IR m
max 2940, 2863, 1687, 1219, 1112 cmꢀ1. MS (FAB) m/z (relative
(495 L, 3.10 mmol) at room temperature under a nitrogen atmo-
l
intensity, %) 235 (M++H+, 7), 217 (5), 143 (3), 107 (9), 91 (100).
HRMS (FAB) Calcd for C14H19O3 [M+H]+: m/z 235.1329, Found:
235.1312. Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C,
71.91; H, 7.50.
sphere. After stirring for 1 h, water (100 mL) was added, and the
aqueous layer was extracted with dichloromethane (3 ꢂ 30 mL).
The organic layers were combined, dried over Na2SO4, filtered,
and concentrated. The residue was purified by column chromatog-
raphy (SiO2, hexane–ethyl acetate from 100:0, v/v to 95:5, v/v) to
give 6a (faster eluting diastereoisomer, 438.5 mg, 64%), and 6b
(slower eluting diastereoisomer, 180.1 mg, 26%). Overall yield:
90%. Compound 6a: 1H NMR (400 MHz, CDCl3) d 7.39–7.30 (m,
4H, HC7,8), 7.30–7.23 (m, 1H, HC9), 4.51 (s, 2H, HC5), 4.13 (q,
J = 7.1 Hz, 2H, HC11), 3.58 (tt, J = 5.1, 2.8 Hz, 1H, HC4), 2.36 (tt,
J = 9.6, 4.0 Hz, 1H, HC1), 1.97 (ddd, J = 10.7, 8.7, 3.4 Hz, 2H, HC2),
1.93–1.84 (m, 2H, HC3), 1.68 (ddd, J = 12.9, 8.8, 4.2 Hz, 2H, HC2),
1.61–1.50 (m, 2H, HC3), 1.25 (t, J = 7.1 Hz, 3H, HC12) ppm. 13C
{1H} NMR (101 MHz, CDCl3) d 175.6 (C10), 139.2 (C6), 128.4 (C8),
127.5 (C7), 127.4 (C9), 73.2 (C4), 69.8 (C5), 60.3 (C11), 42.0 (C1),
29.2 (C3), 24.0 (C2), 14.4 (C12) ppm. IR mmax 2937, 2866, 1727,
1453 cmꢀ1. MS (FAB) m/z (relative intensity, %) 263 (M++H+, 100),
217 (8), 181 (9), 155 (43), 91 (75). HRMS (FAB) Calcd for
4.1.10. (R)-(ꢀ)-2-(cis-4-(Benzyloxy)cyclohexanecarbonyl)-1,2,3,
6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one 8a
Compound 3a (101.1 mg, 0.50 mmol), 7a (117.2 mg, 0.50 mmol),
PyBOP (284.3 mg, 0.55 mmol), and 4-methylmorpholine (272 lL,
2.47 mmol) were dissolved under a nitrogen atmosphere in DMSO
(2 mL), and the mixture was stirred at room temperature for
30 min. It was then poured into a funnel and dichloromethane
(20 mL) was added. The organic layer was successively washed with
1 M HCl (3 ꢂ 10 mL), a saturated solution of NaHCO3 (3 ꢂ 30 mL),
water (3 ꢂ 30 mL) and dried over Na2SO4, filtered, and concentrated.
The residue was purified by column chromatography (SiO2, ethyl
acetate 100%). A white powder was obtained (185.7 mg, 89% yield).
Mp 132–135 °C. ½a D
ꢃ
¼ ꢀ99:2 (c 1, CHCl3). IR
mmax 2927, 2862, 1645,
1625, 1439, 1420, 1206, 1066, 735 cmꢀ1. MS (EI) m/z (relative inten-
sity, %) 418 (M+, 14), 327 (36), 201 (100), 185 (4), 173 (10), 145 (16),
132 (50). HRMS (EI) Calcd for C26H30N2O3 (M+): m/z 418.2251,
Found: 418.2236. Anal. Calcd for C26H30N2O3: C, 74.61; H, 7.22; N,
6.69. Found: C, 74.37; H, 6.62; N, 6.74. For clarity, the NMR spectra
of the two rotamers are separately described.
C
C
16H23O3 [M+H]+: m/z 263.1642, Found: 263.1629. Anal. Calcd for
16H22O3: C, 73.25; H, 8.45. Found: C, 72.71; H, 8.33. Compound
6b: 1H NMR (400 MHz, CDCl3) d 7.37–7.34 (m, 4H, HC7,8), 7.33–
7.26 (m, 1H, HC9), 4.58 (s, 2H, HC5), 4.14 (q, J = 7.1 Hz, 2H, HC11),
3.37 (tt, J = 10.3, 4.1 Hz, 1H, HC4), 2.30 (tt, J = 11.6, 3.6 Hz, 1H,
HC1), 2.16 (dd, J = 12.4, 2.5 Hz, 2H, HC3), 2.05 (d, J = 12.0 Hz, 2H,
HC2), 1.57–1.44 (m, 2H, HC2), 1.43–1.30 (m, 2H, HC3), 1.27 (t,
J = 7.1 Hz, 3H, HC12) ppm. 13C {1H} NMR (101 MHz, CDCl3) d 175.7
(C10), 139.0 (C6), 128.5 (C8), 127.7 (C7), 127.6 (C9), 76.6 (C4), 70.1
(C5), 60.4 (C11), 42.6 (C1), 31.4 (C3), 27.3 (C2), 14.3 (C12) ppm. IR
mmax 2937, 2863, 1728, 1454 cmꢀ1. MS (FAB) m/z (relative inten-
sity, %) 263 (M++H+, 17), 217 (3), 181 (4), 155 (29), 91 (100). HRMS
(FAB) Calcd for C16H23O3 [M+H]+: m/z 263.1642, Found: 263.1632.
Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.30; H, 8.42.
Major rotamer (81.28%): 1H NMR (400 MHz, CDCl3) d 7.39–7.14
0
0
0
(m, 9H, HC7 ,8 ,11,10,9,9 ,8), 5.16 (d, J = 12.6 Hz, 1H, HC1), 4.88–4.77
0
(m, 2H, HC6,11b), 4.50 (s, 2H, HC5 ), 4.46 (AB, J = 17.6 Hz, 1H, HC3),
0
4.08 (AB, J = 17.4 Hz, 1H, HC3), 3.68 (s, 1H, HC4 ), 3.03–2.74 (m, 4H,
0
0
0
HC7,6,1,7), 2.51 (t, J = 10.6 Hz, 1H, HC1 ), 2.13–1.91 (m, 4H, HC3 ,2 ),
1.60–1.41 (m, 4H, HC2 ,3 ) ppm. 13C{1H} NMR (101 MHz, CDCl3) d
0
0
0
174.4 (C12), 164.5 (C4), 139.2 (C6 ), 134.8 (C7a), 132.9 (C11a), 129.4
0
0
0
(C8), 128.4 (C8 ), 127.5 (C9), 127.4 (C7 ), 127.4 (C9 ), 127.1 (C10),
0
0
125.6 (C11), 72.0 (C4 ), 69.8 (C5 ), 55.1 (C11b), 49.2 (C3), 45.3 (C1),
0
0
0
0
40.3 (C1 ), 39.2 (C6), 29.2 (C3 ), 28.8 (C7), 23.7 (C2 ), 23.5 (C2 ) ppm.
4.1.8. cis-4-(Benzyloxy)cyclohexanecarboxylic acid 7a
Minor rotamer (18.72%): 1H NMR (400 MHz, CDCl3): d 7.39–
0
0
0
0
To a solution of 6a (262.3 mg, 1.00 mmol) in 1:1 methanol/tetra-
hydrofuran (4 mL) was added dropwise 12.5 M sodium hydroxide
7.14 (7 ,8 ,9,10,9 ,8,11), 4.90–4.73 (m, 3H, HC6,11b,3), 4.50 (s, 2H, HC5 ),
4.34 (d, J = 12.1 Hz, 1H, HC1), 3.86 (AB, J = 17.5 Hz, 1H, HC3), 3.68
0
(400
l
L, 5.00 mmol) at room temperature. After stirring for 6 h, it
(s, 1H, HC4 ), 3.25 (t, J = 12.7 Hz, 1H, HC1), 3.03–2.72 (m, 3H,
0
0
0
was concentrated and water (20 mL) was added. The aqueous phase
was washed with diethyl ether (3 ꢂ 20 mL) and an aqueous solution
of 4 M HCl was added to pH 1. The aqueous layer was extracted with
dichloromethane (3 ꢂ 30 mL). The organic layers were combined,
dried over Na2SO4, filtered, and concentrated. A white powder was
obtained (230.5 mg, 98% yield). Mp 87–88 °C. 1H NMR (400 MHz,
CDCl3) d 7.40–7.25 (m, 5H, HC7,8,9), 4.54 (s, 2H, HC5), 3.61 (tt,
J = 5.2, 2.9 Hz, 1H, HC4), 2.45 (tt, J = 9.6, 4.0 Hz, 1H, HC1), 2.06–1.98
(m, 2H, HC2), 1.96–1.90 (m, 2H, HC3), 1.77–1.71 (m, 2H, HC2),
1.63–1.56 (m, 2H, HC3) ppm. 13C{1H} NMR (101 MHz, CDCl3) d
181.8 (C10), 139.2 (C6), 128.5 (C8), 127.5 (C7), 127.5 (C9), 73.1 (C4),
69.8 (C5), 41.7 (C1), 29.2 (C3), 23.8 (C2) ppm. IR mmax 2940, 2864,
1691, 1242 cmꢀ1. MS (EI) m/z (relative intensity, %) 234 (M+, 2),
216 (3), 188 (2), 172 (2), 107 (50), 91 (100). HRMS (FAB) Calcd for
HC7,6,7), 2.51 (t, J = 11.3 Hz, 1H, HC1 ), 2.13–1.91 (m, 4H, HC3 ,2 ),
1.60–1.41 (m, 4H, HC2 ,3 ) ppm. 13C{1H} NMR (101 MHz, CDCl3) d
0
0
0
173.7 (C12), 165.6 (C4), 139.2 (C6 ), 135.7 (C7a), 132.2 (C11a), 129.8
(C8), 127.8 (C9), 127.4 (C7 ), 127.4 (C9 ), 127.1 (C10), 125.2 (C11),
72.1 (C4 ), 69.6 (C5 ), 55.9 (C11b), 49.7 (C1), 46.4 (C3), 40.3 (C1 ),
38.7 (C6), 29.4 (C3 ), 29.2 (C7), 24.0 (C2 ), 23.7 (C2 ) ppm.
0
0
0
0
0
0
0
0
4.1.11. (R)-(ꢀ)-2-(trans-4-(Benzyloxy)cyclohexanecarbonyl)-1,2,
3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one 8b
Following the procedure reported above for the preparation of
8a and starting with amine 3a (101.1 mg, 0.50 mmol) and acid
7b (117.2 mg, 0.50 mmol), compound 8b was obtained as a white
powder (183.9 mg, 88% yield). Mp 135–137 °C. ½aꢃD ¼ ꢀ97:0 (c 1,
CHCl3). IR mmax 2935, 2863, 1644, 1451, 1418, 1202, 1076,
734 cmꢀ1. MS (EI) m/z (relative intensity, %) 418 (M+, 16), 327
(10), 201 (75), 185 (9), 173 (17), 145 (25), 132 (70), 91 (100). HRMS
(EI) Calcd for C26H30N2O3 (M+): m/z 418.2251, Found: 418.2259.
Anal. Calcd for C26H30N2O3: C, 74.61; H, 7.22; N, 6.69. Found: C,
74.09; H, 7.08; N, 6.80. For clarity, the NMR spectra of the two rota-
mers are described separately.
C
C
14H19O3 [M+H]+: m/z 235.1329, Found: 235.1315. Anal. Calcd for
14H18O3: C, 71.77; H, 7.74. Found: C, 72.05; H, 7.74.
4.1.9. trans-4-(Benzyloxy)cyclohexanecarboxylic acid 7b
Following the procedure reported above for the preparation of
7a and starting with ester 6b (180.1 mg, 0.69 mmol), compound
7b was obtained as a white powder (158.1 mg, 98% yield). Mp
Major rotamer (76.54%): 1H NMR (400 MHz, CDCl3) d 7.41–7.08
105–107 °C. 1H NMR (400 MHz, CDCl3)
d
7.38–7.25 (m, 5H,
(m, 9H, HC7 ,8 ,11,10,9,9 ,8), 5.13 (dd, J = 13.5, 2.7 Hz, 1H, HC1), 4.88–
0
0
0
0
HC7,8,9), 4.58 (s, 2H, HC5), 3.37 (tt, J = 10.1, 4.0 Hz, 1H, HC4), 2.35
4.73 (m, 2H, HC6,11b), 4.57 (s, 2H, HC5 ), 4.46 (AB, J = 17.5 Hz, 1H,
0
(tt, J = 11.4, 3.6 Hz, 1H, HC1), 2.20–2.05 (m, 4H, HC3,2), 1.59–1.44
HC3), 4.09 (AB, J = 17.5 Hz, 1H, HC3), 3.44–3.33 (m, 1H, HC4 ),

A. Cedillo-Cruz et al. / Tetrahedron: Asymmetry 25 (2014) 133–140
139
0
3.03–2.75 (m, 4H, HC7,6,1,7), 2.46 (t, J = 11.6 Hz, 1H, HC1 ), 2.20 (d,
145 (33), 132 (85). HRMS (EI) Calcd for C19H24N2O3 (M+): m/z
328.1781, Found: 328.1795. Anal. Calcd for C19H24N2O3ꢁH2O: C,
65.87; H, 7.56; N, 8.09. Found: C, 65.73; H, 7.62; N, 8.24. For clarity,
the NMR spectra of the two rotamers are described separately.
Major rotamer (67.11%): 1H NMR (400 MHz, CDCl3) d 7.37–7.16
(m, 4H, HC11,10,9,8), 5.16 (dd, J = 13.3, 2.8 Hz, 1H, HC1), 4.94–4.74
(m, 2H, HC6,11b), 4.48 (AB, J = 17.4 Hz, 1H, HC3), 4.12 (AB,
0
0
J = 12.0 Hz, 2H, HC3 ), 1.90–1.79 (m, 2H, HC2 ), 1.70–1.51 (m, 2H,
HC2 ), 1.40–1.31 (m, 2H, HC3) ppm. 13C{1H} NMR (101 MHz, CDCl3)
0
0
d 174.2 (C12), 164.3 (C4), 138.9 (C6 ), 134.9 (C7a), 132.8 (C11a), 129.4
(C8), 128.5 (C8 ), 127.7 (C7 ), 127.6 (C9), 127.6 (C9 ), 127.1 (C10), 125.6
(C11), 76.7 (C4 ), 70.2 (C5 ), 55.0 (C11b), 49.1 (C3), 45.3 (C1), 40.1 (C1 ),
0
0
0
0
0
0
0
0
0
0
39.2 (C6), 31.7 (C3 ), 31.6 (C3 ), 28.8 (C7), 27.6 (C2 ), 27.4 (C2 ) ppm.
Minor rotamer (23.46%): 1H NMR (400 MHz, CDCl3): d 7.38–7.12
J = 17.4 Hz, 1H, HC3), 3.68 (tt, J = 10.8, 3.8 Hz, 1H, HC4 ), 3.06–2.78
0
0
0
0
0
0
(m, 9H, HC7 ,8 ,9,10,9 ,,), 4.91–4.70 (m, 3H, HC6,11b, 3), 4.57 (s, 2H, HC5 ),
(m, 4H, HC7,6,1,7), 2.45 (tt, J = 11.7, 3.3 Hz, 1H, HC1 ), 2.11 (d,
0
0
4.35 (d, J = 13.4 Hz, 1H, HC1), 3.88 (AB, J = 18.6 Hz, 1H, HC3), 3.44–
J = 12.5 Hz, 2H, HC3 ), 1.95–1.75 (m, 2H, HC2 ), 1.76–1.56 (m, 2H,
HC2 )., 1.43–1.27 (m, 2H, HC3 ) ppm. 13C{1H} NMR (101 MHz,
0
0
0
3.33 (m, 1H, HC4 ), 3.28 (t, J = 11.9 Hz, 1H, HC1), 3.03–2.75 (m, 3H,
0
0
HC7,6,7), 2.46 (t, J = 11.6 Hz, 1H, HC1 ), 2.20 (d, J = 12.0 Hz, 2H, HC3 ),
CDCl3) d 174.2 (C12), 164.4 (C4), 134.9 (C7a), 132.8 (C11a), 129.4
0
0
0
1.90–1.79 (m, 2H, HC2 ), 1.70–1.51 (m, 2H, HC2 ), 1.40–1.31 (m, 2H,
(C8), 127.6 (C9), 127.1 (C10), 125.6 (C11), 69.9 (C4 ), 55.1 (C11b),
HC3 ) ppm. 13C{1H} NMR (101 MHz, CDCl3) d 173.7 (C12), 165.5
49.2 (C3), 45.4 (C1), 39.8 (C1 ), 39.3 (C6), 34.8 (C3 ), 28.8 (C7), 27.6
0
0
0
0
0
0
0
(C4), 138.9 (C6 ), 135.6 (C7a), 132.0 (C11a), 129.8 (C8), 128.5 (C8 ),
(C2 ), 27.4 (C2 ) ppm.
Minor rotamer (32.89%): 1H NMR (400 MHz, CDCl3): d 7.37–
7.16 (m, 4H, HC9,10,8,11), 4.94–4.74 (m, 3H, HC6,11b,3), 4.37 (d,
J = 12.6 Hz, 1H, HC1), 3.91 (AB, J = 18.9 Hz, 1H, HC3), 3.68 (tt,
0
0
127.9 (C9), 127.7 (C7 ), 127.6 (C9 ), 127.1 (C10), 125.3 (C11), 76.7
0
0
0
(C4 ), 70.2 (C5 ), 55.9 (C11b), 49.8 (C1), 46.5 (C3), 40.1 (C1 ), 38.8 (C6),
31.7 (C3 ), 31.6 (C3 ), 29.2 (C7), 27.6 (C2 ), 27.4 (C2 ) ppm.
0
0
0
0
0
J = 10.8, 3.8 Hz, 1H, HC4 ), 3.31 (t, J = 11.9 Hz, 1H, HC1), 3.06–2.77
0
4.1.12. (R)-(ꢀ)-2-(cis-4-Hydroxycyclohexanecarbonyl)-1,2,3,6,7,
11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one ((R)-(ꢀ)-
cis-40-hydroxypraziquantel) 9a
(m, 3H, HC7, 6, 7), 2.59–2.51 (m, 1H, HC1 ), 2.11 (d, J = 12.5 Hz, 2H,
0
0
0
HC3 ), 1.95–1.75 (m, 2H, HC2 ), 1.76–1.56 (m, 2H, HC2 ), 1.43–1.27
(m, 2H, HC3 ) ppm. 13C{1H} NMR (101 MHz, CDCl3) d 173.8 (C12),
0
Compound 8a (150 mg, 0.36 mmol) was dissolved in ethanol
165.6 (C4), 135.7 (C7a), 132.1 (C11a), 129.8 (C8), 128.0 (C9), 127.1
0
(30 mL), 10% w/w Pd/C (38. 2 mg, 35.90
l
mol) was added and an
(C10), 125.3 (C11), 69.9 (C4 ), 55.9 (C11b), 49.8 (C1), 46.5 (C3), 39.8
0
0
0
0
atmosphere of hydrogen was introduced at room temperature.
The reaction mixture was stirred under hydrogen at 45 °C for 3 h
(Parr shaker hydrogenation apparatus); it was then cooled and fil-
tered through Celite, washed with ethanol (3 ꢂ 10 mL), and the
solvent was removed under reduced pressure. A white powder
(C1 ), 38.8 (C6), 34.8 (C3 ), 29.0 (C7), 27.8 (C2 ), 27.6 (C2 ) ppm.
(S)-(+)-cis-40-Hydroxypraziquantel 9c and (S)-(+)-trans-4 -
hydroxypraziquantel monohydrate 9d were obtained in a similar
manner, starting from (S)-(+)-praziquanamine 3b.
0
was obtained (114.2 mg, 92% yield). Mp 161.09 °C ½a D
ꢃ
¼ ꢀ148:0
4.2. X-ray crystal structure determinations
(c 1, CHCl3). IR mmax 3423, 2926, 2866, 1631, 1419, 1204 cmꢀ1
.
MS (EI) m/z (relative intensity, %) 328 (M+, 20), 201 (62), 185
The crystals of 2a, 4a, 8a, 8b, and 9b mounted on glass fiber
(15), 173 (48), 145 (60), 132 (100). HRMS (EI) Calcd for
were studied with an Oxford Diffraction Gemini ‘A’ diffractometer
C
C
19H24N2O3 (M+): m/z 328.1781, Found: 328.1793. Anal. Calcd for
with
a
CCD area detector; with radiation source of
19H24N2O3: C, 69.49; H, 7.37; N, 8.53. Found: C, 69.39; H, 7.37;
kMoK = 0.71073 Å for 4a, 8b, and 9b, and kCuK = 1.5418 Å for 2a
a
a
N, 8.68. For clarity, the NMR spectra of the two rotamers are de-
scribed separately.
and 8a using graphite-monochromatized radiation. CrysAlisPro
and CrysAlis RED software packages17 were used for data collection
and data integration. Data sets consisted of frames of intensity data
Major rotamer (73.49%): 1H NMR (400 MHz, CDCl3) d 7.32–7.13
(m, 4H, HC11,10,9,8), 5.15 (d, J = 12.8 Hz, 1H, HC1), 4.87–4.71 (m, 2H,
HC6,11b), 4.44 (AB, J = 17.3 Hz, 1H, HC3), 4.07 (AB, J = 17.3 Hz, 1H,
collected with a frame width of 1° in
x and a crystal-to-detector
distance of 55.00 mm. The double pass method of scanning was
used to exclude any noise. The collected frames were integrated
by using an orientation matrix determined from the narrow frame
scans. Final cell constants were determined by a global refinement;
collected data were corrected for absorbance by using analytical
numeric absorption correction18 using a multifaceted crystal mod-
el based on expressions upon the Laue symmetry using equivalent
reflections.
Structure solution and refinement were carried out with the
program(s): SHELXS9719 for molecular graphics: ORTEP-3 for Win-
dows;20 and the software used to prepare material for publication:
WinGX 1.80.05.21
0
HC3), 4.03 (s, 1H, HC4 ), 3.03–2.73 (m, 4H, HC7,6,1,7), 2.50 (t,
0
0
0
J = 11.2 Hz, 1H, HC1 ), 2.07–1.75 (m, 4H, HC2 ,3 ), 1.68–1.50 (m,
4H, HC3 ,2 ) ppm. 13C{1H} NMR (101 MHz, CDCl3) d 174.3 (C12),
0
0
164.4 (C4), 134.8 (C7a), 132.8 (C11a), 129.4 (C8), 127.6 (C9), 127.1
0
(C10), 125.6 (C11), 65.6 (C4 ), 55.1 (C11b), 49.2 (C3), 45.3 (C1), 39.8
0
0
0
0
(C1 ), 39.3 (C6), 32.1 (C3 ), 28.8 (C7), 23.3 (C2 ), 23.1 (C2 ) ppm.
Minor rotamer (26.51%): 1H NMR (400 MHz, CDCl3): d 7.32–
7.13 (m, 4H, HC9,10,8,11) 4.86–4.74 (m, 3H, HC6,11b,3), 4.34 (d,
0
J = 12.1 Hz, 1H, HC1), 4.03 (s, 1H, HC4 ), 3.86 (AB, J = 19.2 Hz, 1H,
HC3), 3.25 (t, J = 11.8 Hz, 1H, HC1), 3.02–2.73 (m, 3H, HC7,6,7),
0
0
0
2.60 (t, J = 10.5 Hz, 1H, HC1 ), 2.07–1.75 (m, 4H, HC2 ,3 ), 1.68–1.50
(m, 4H, HC3 ,2 ). 13C{1H} NMR (101 MHz, CDCl3) d 173.7 (C12),
Full-matrix least-squares refinement was carried out by mini-
0
0
165.7 (C4), 135.7 (C7a), 132.2 (C11a), 129.8 (C8), 127.8 (C9), 127.1
mizing (Fo2 ꢀ Fc2)2. All non-hydrogen atoms were refined aniso-
0
(C10), 125.3 (C11), 65.6 (C4 ), 55.9 (C11b), 49.8 (C1), 46.5 (C3), 39.8
tropically. The H atoms of the hydroxyl group and water
0
0
0
0
(C1 ), 38.8 (C6), 32.1 (C3 ), 28.8 (C7), 23.7 (C2 ), 23.3 (C2 ).
molecule were located in a difference Fourier map and refined iso-
tropically with Uiso(H) = 1.5 Ueq. The H atoms attached to C atoms
were placed in geometrically idealized positions and refined as
riding on their parent atoms, with C@H = 0.93–1.00 Å with
Uiso(H) = 1.2 Ueq(C) for methylene, methyne and aromatic groups,
and Uiso(H) = 1.5 Ueq(C) for methyl groups. CCDC 945871 for 2a,
945872 for 8b, 945874 for 8a, 945875 for 4a and 945876 for 9b
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/Com-
munity/Requestastructure/Pages/DataRequest.aspx?.
4.1.13. (R)-(ꢀ)-2-(trans-40-Hydroxycyclohexanecarbonyl)-1,2,3,
6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one mono-
hydrate, ((R)-(ꢀ)-trans-40-hydroxypraziquantel monohydrate) 9b
Following the procedure reported for the preparation of 9a and
starting with 8b (150 mg, 0.36 mmol) compound 9b was obtained
as
a
white powder (115.7 mg, 93% yield). Mp 98.66 °C
½ ꢃ ¼ ꢀ135:4 (c 1, CHCl3). IR mmax 3452, 3368, 3252, 2934, 2854,
a D
1648, 1631, 1495, 1457, 1437, 1423, 1070, 767 cmꢀ1. MS (EI) m/z
(relative intensity, %) 328 (M+, 41), 201 (100), 185 (19), 173 (20),

140
A. Cedillo-Cruz et al. / Tetrahedron: Asymmetry 25 (2014) 133–140
4.3. Cysticidal activity
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V. Lemus, M. Gutiérrez, N. Esturau, and R. I. Villar. We thank
Dr. E. Bratoeff for valuable comments on the work.
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