The structure of McN-5652

Article abstract of DOI:10.1016/S0968-0896(01)00117-1

The configuration of the diastereoisomers of 6-(4-methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline 1 (McN-5652) is determined and unequivocally assigned by NMR spectroscopy (NOE measurements) and an X-ray structural analysis of the trans diastereoisomer. The enantiomers of cis-1 are separated by preparative HPLC on a chiral phase. One of the enantiomers of cis-1 represents the precursor for imaging the serotonin 5-HT transporter with positron emission tomography (PET).

Full text of DOI:10.1016/S0968-0896(01)00117-1

Bioorganic & Medicinal Chemistry 9 (2001) 2105–2111
The Structure of McN-5652
Oliver Schulze,a,b Ulrich Schmidt,a Jurgen Voss,a,* Bruno Nebeling,b
Gunadi Adiwidjajac and Klaus Scharwachtera
aInstitut fur Organische Chemie der Universitat Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
¨
¨
bUniversitatsklinikum Hamburg-Eppendorf, Klinik und Poliklinik fur Radiologie, Abt. fur Nuklearmedizin, UKE-Zyklotron,
Luruper Chaussee 149, 22761 Hamburg, Germany
¨
¨
¨
cMineralogisch-Petrographisches Institut der Universitat Hamburg, Grindelallee 48, 20146 Hamburg, Germany
¨
Received 8 August 2000; accepted 9 April 2001
Abstract—The configuration of the diastereoisomers of 6-(4-methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline 1
(McN-5652) is determined and unequivocally assigned by NMR spectroscopy (NOE measurements) and an X-ray structural ana-
lysis of the trans diastereoisomer. The enantiomers of cis-1 are separated by preparative HPLC on a chiral phase. One of the
enantiomers of cis-1 represents the precursor for imaging the serotonin 5-HT transporter with positron emission tomography
(PET). # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
on these compounds there is still a lack of information
about the correct stereochemistry of the individual iso-
mers. The information that can be found in the literature
is misleading and contradictory,5,6 that is a cis-stereo-
isomer can be found in a scheme but in the text it is
called trans.6 Furthermore, to the best of our knowl-
edge, there has never been an unequivocal proof of the
correct identification of any isomer.
McN-5652-Z is a highly potent serotonin 5-HT trans-
porter uptake blocker. Its [11CH3] derivative allows the
visualization and evaluation of the serotonergic trans-
porter density by the method of positron emission
tomography (PET).1ꢀ4 These studies might reveal what
damage is caused to the brain by drug (MDMA, e.g.,
Ecstasy) abuse and whether the damaged brain can
regenerate after the drug abuse is stopped. The chemical
name of this compound is 6-(4-methylthiophenyl)-
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (1).
Due to the fact that this compound possesses two cen-
tres of asymmetry there are four stereoisomers (6S,
10bR)-1, (6R, 10bS)-1, (6S, 10bS)-1 and (6R, 10bR)-1
(Scheme 1). Regarding the position of the hydrogen
atoms at C-6 and C-10b the two enantiomeric pairs
should be called ‘cis’ or ‘trans’. Because it is known that
these four isomers possess different Ki values for the
serotonin 5-HT transporter uptake inhibition,3ꢀ7 it is
important to characterize their chemical configuration
correctly. Although a lot of work has been performed
*Corresponding author. Tel.: +49-428-38-2803; fax: +49-428-38-
5592; e-mail: voss@chemie.uni-hamburg.de
Scheme 1. The four stereoisomers of 1: two cis-enantiomers (top) and
two trans-enantiomers (bottom).
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00117-1

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O. Schulze et al. / Bioorg. Med. Chem. 9 (2001) 2105–2111
Results and Discussion
We were able to separate the pair of trans-enantiomers
from the pair of cis-enantiomers by preparative column
chromatography. The chemical purity of the diastereo-
isomers was verified by HPLC.
Since we are involved in the pharmacological studies
mentioned at the beginning, we were interested to syn-
thesize and to characterize definitely the four stereo-
isomers. We used the synthetic route published by
Maryanoff et al.,6 in which general procedures for the
preparation of 1 and numerous related compounds are
described. Here, we will report the details of our synth-
esis only for those steps in which we were deviating
from the literature. Furthermore, all spectroscopic data
of 1 and its precursors 3 and 5–8 (Scheme 2) are given,
which are lacking in ref 6.
Our structural assignment was firstly based on 1H NMR
spectroscopic and, in particular, NOE measurements.
The essential data are presented in Figures 1 and 2. The
interpretation is unequivocal. For example the double
dublet signal at d=3.65 ppm of trans-1, which
obviously belongs to H-10b, exhibits an NOE contact
with one of the two protons (d=2.69 ppm) at C-5. The
latter is, therefore, located in cis-position with respect to
H-10b and represents H-5b. The signal at d=3.43 ppm
thus represents H-5a, which exhibits an NOE contact
with H-6 (d=4.35 ppm). Consequently, H-5a and H-
10b and thus H-6 and H-10b exhibit trans-configura-
tions. This is only possible for the trans-diastereoisomer
of 1. The assignment is also supported by a coupling
constant of J5b,6=11 Hz revealing a trans-configuration
between these two protons, whereas J5a,6=6.4 Hz is
typical of a cis-configuration. Analogous reasoning
applies for the 1H NMR data of the cis-diastereoisomer,
although no suitable NOE contacts could be observed
in this case. The NOE spectra also revealed that the
ortho-positions of the 4-methylthiophenyl residue are
not equivalent, that is the dihedral angle C24–C23–C41–
C42 (crystallographic numbering, cf. Fig. 3) should
deviate significantly from 180ꢁ. Furthermore, the 4-
methylthiophenyl substituent is obviously not able to
rotate freely at room temperature.
Scheme 2. Reagents and conditions: (i) CHBr3, NaOH, LiBr, dioxane;
(ii) PhCOOEt, NaH, THF; (iii) NaBH4, EtOH; (iv) xylene, TsOH;
(v) H+, TFA; (vi) BH3ꢂ THF.
Fortunately, we could grow a suitable single crystal of
one diastereoisomer. An X-ray structural analysis of
this crystal proved the compound to be racemic trans-1
and thus confirmed our NMR and NOE results.
Figure 1. Chemical shifts (ppm) and coupling constants ($, Hz) of
trans-1.
Figure 2. Observed NOE contacts ($) in trans-1.

O. Schulze et al. / Bioorg. Med. Chem. 9 (2001) 2105–2111
2107
Nevertheless, we did not know, whether the cis- or the
trans-diastereoisomer was the more potent serotonin
uptake blocker. Comparison with an authentic sample
of the most active isomer proved, however, that it was
identical with our cis-diastereoisomer. In order to find
out which of the two cis-enantiomers was the previously
described (+)-enantiomer,5 we had to separate and
compare them with an authentic sample of the (+)-
McN-5652-Z enantiomer.8 Therefore, we developed a
separation on a chiral column. The chiralpak1 AD
material [amylose tris(3,5-dimethylphenyl)carbamate]
showed very good separation of the (+)/(ꢀ)-enantio-
mers. A representative chromatogram of the separation
of the cis-enantiomers is given in Figure 4. The (ꢀ)-
enantiomer was eluted first as compared with the
reference sample.
Since 1 is a compound of high physiological activity we
have, finally, performed a 3-D QSAR calculation based
on our X-ray structural data using the HyperChem1
software.9 The calculated data are compiled in Table 1.
Experimental
General procedures
Melting points were determined by the use of an Elec-
trothermal apparatus (values are corrected). IR spectra
were measured with an ATI Mattson Genesis spectro-
meter. NMR spectra were recorded with Bruker AMX
400 and DRX 500 spectrometers. Chemical shifts (ppm)
are related to Me4Si (1H and 13C). Coupling constants J
are given in Hz. Multiplicity abbreviations: multiplet
(m), singlet (s), dublet (d). Standard correlation techni-
ques were used for assignments. Mass spectra were
measured on Varian CH 7 (EI, 70 eV) and VG Analy-
tical 70-250 S (HRMS) apparatus. TLC was carried out
on E. Merck PF254 foils (detection: UV light, EtOH–
H2SO4 spray/200 ꢁC), and column chromatography on
E. Merck Kieselgel 60 (70–230 mesh). Solvents were
purified and dried according to standard laboratory
procedures.10 The purity of the separated diastereo-
isomers was analyzed with HPLC on nucleosil 100 3 C18,
125Â3 mm. The mobile phase was 50% acetonitrile/50%
water with 0.02 mol ammonium formate.
Figure 3. ORTEP view of the X-ray diffraction structure of racemic
trans-1 [only the (6R, 10bR)-enantiomer is shown] with atom num-
bering. Thermal ellipsoids are drawn at the 50% probability level.
The preparative separation of the (+)/(ꢀ)-enantiomers
was performed on a 250Â10 mm column packed with
chiralpak1 AD 25 mm. The mobile phase was 97%
n-hexane/3% 2-propanol/0.05% triethylamine.
Table 1. Theoretical QSAR parameters for trans-1
Partial charge
Surface area (approx.)
Surface area (grid)
Volume
Hydration energy
LogP
Refractivity
Polarizability
Mass
Net charge=0.00 e
428.20 A2
508.27 A2
850.66 A3
ꢀ1.04 kcal molꢀ1
1.44
100.02 A3
35.74 A3
295.44 amu
Figure 4. HPLC separation of the two enantiomers of cis-1.

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O. Schulze et al. / Bioorg. Med. Chem. 9 (2001) 2105–2111
Table 2. Crystal data and structure refinement for trans-1a
Diffractometer
Molecular formular
KappaCCD Nonius
C19H21NS
Molecular weight (g molꢀ1
Temperature (K)
Wavelength (A)
Scan mode
)
295.43
293(2)
0.7107, MoKa, graphite monochromated
Rotation ꢀ
Crystal system
Space group
Unit cell dimensions
Monoclinic
P21/c
a=17.278(1) A
b=5.661(1) A
c=25.069(1) A
a=g=90ꢁ
b=138.39(1)ꢁ
1628.3(3)
Volume (A3)
Z (molecules per cell)
4
1.205
0.192
632
Dcalcd (g cmꢀ3
)
Absorption coefficient (mmꢀ1
F(000)
Crystal size (mm)
)
0.39Â0.35Â0.32
y Range for data collection (ꢁ)
Index ranges
1.63–25.02
0ꢃhꢃ20; 0ꢃkꢃ6;-29ꢃlꢃ19
Reflections collected
Independent reflections
Reflections with Iꢄ2s(I)
Refinement method
7579
2810
2218
Full-matrix-block least-squares on F2
2
Function minimized
ꢁw(Fo2ꢀFc2)2,w ¼ 1=½ꢀ2ðF2oÞ þ ð0:1160PÞ þ 0:7813PŠ;
where P ¼ ðF2o þ 2Fc2Þ=3
Geom. and difmap
2810/0/245
H-Atom refinement
Data/restraints/parameters
Goodness-of-fit on F2
1.050
Final R indices [Iꢄ2s(I)]
Largest difference peak and hole (e Aꢀ3
R1=0.0556, wR2=0.1556
R1=0.0773, wR2=0.2012
0.248 and ꢀ0.336
R Indices (all data)
)
aFull crystallographic details, excluding structure features, have been deposited with the Cambridge Crystallographic Data Centre. These data may
be obtained, on request, from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Tel.: +44-1223-336408; fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk (deposition number CCDC-142696).
Table 3. Selected bond lengths (pm), bond angles (ꢁ) and torsion angles (ꢁ) of trans-1
S(5)ꢀC(44)
176.3 (3)
176.5 (4)
145.4 (4)
144.5 (4)
145.2 (5)
151.2 (7)
152.9 (5)
151.9 (7)
152.5 (4)
152.5 (4)
139.9 (4)
150.5 (4)
151.2 (4)
138.4 (4)
105.14 (17)
116.1 (3)
104.4 (3)
111.1 (3)
102.3 (3)
109.6 (2)
110.3 (3)
102.3 (3)
103.4 (4)
106.3 (3)
112.2 (3)
111.0 (2)
114.1 (2)
C(23)ꢀC(24)ꢀC(25)
C(24)ꢀC(25)ꢀC(26)
121.6 (2)
119.4 (3)
119.3 (3)
119.2 (3)
121.5 (2)
165.4 (4)
42.8 (4)
172.5 (3)
ꢀ68.5 (4)
ꢀ46.2 (3)
ꢀ172.1 (3)
ꢀ174.1 (3)
60.0 (3)
S(5)ꢀC(51)
N(21)ꢀC(13)
C(24)ꢀC(25)ꢀC(34)
N(21)ꢀC(22)
C(11)ꢀC(26)ꢀC(25)
N(21)ꢀC(26)
C(23)ꢀC(41)ꢀC(42)
C(11)ꢀC(12)
C(22)ꢀN(21)ꢀC(13)ꢀC(12)
C(26)ꢀN(21)ꢀC(13)ꢀC(12)
C(13)ꢀN(21)ꢀC(22)ꢀC(23)
C(26)ꢀN(21)ꢀC(22)ꢀC(23)
C(13)ꢀN(21)ꢀC(26)ꢀC(11)
C(22)ꢀN(21)ꢀC(26)ꢀC(11)
C(13)ꢀN(21)ꢀC(26)ꢀC(25)
C(22)ꢀN(21)ꢀC(26)ꢀC(25)
C(11)ꢀC(12)ꢀC(13)ꢀN(21)
C(12)ꢀC(11)ꢀC(26)ꢀN(21)
N(21)ꢀC(22)ꢀC(23)ꢀC(24)
N(21)ꢀC(22)ꢀC(23)ꢀC(41)
C(24)ꢀC(25)ꢀC(26)ꢀN(21)
C(26)ꢀC(11)ꢀC(12)ꢀC(13)
C(12)ꢀC(11)ꢀC(26)ꢀC(25)
C(22)ꢀC(23)ꢀC(24)ꢀC(25)
C(41)ꢀC(23)ꢀC(24)ꢀC(25)
C(22)ꢀC(23)ꢀC(41)ꢀC(42)
C(24)ꢀC(23)ꢀC(41)ꢀC(42)
C(23)ꢀC(24)ꢀC(25)ꢀC(26)
C(24)ꢀC(25)ꢀC(26)ꢀC(11)
C(11)ꢀC(26)
C(12)ꢀC(13)
C(22)ꢀC(23)
C(23)ꢀC(24)
C(24)ꢀC(25)
C(25)ꢀC(26)
C(23)ꢀC(41)
C(41)ꢀC(42)
ꢀ22.4 (5)
C(44)ꢀS(5)ꢀC(51)
C(13)ꢀN(21)ꢀC(22)
C(13)ꢀN(21)ꢀC(26)
C(22)ꢀN(21)ꢀC(26)
N(21)ꢀC(13)ꢀC(12)
N(21)ꢀC(22)ꢀC(23)
N(21)ꢀC(26)ꢀC(25)
N(21)ꢀC(26)ꢀC(11)
C(12)ꢀC(11)ꢀC(26)
C(11)ꢀC(12)ꢀC(13)
C(22)ꢀC(23)ꢀC(24)
C(22)ꢀC(23)ꢀC(41)
C(24)ꢀC(23)ꢀC(41)
30.3 (4)
40.9 (4)
169.9 (3)
ꢀ26.5 (4)
ꢀ4.7 (5)
152.3 (4)
ꢀ10.1 (4)
ꢀ137.4 (2)
113.2 (3)
ꢀ118.8 (3)
3.0 (4)
ꢀ144.5 (4)

O. Schulze et al. / Bioorg. Med. Chem. 9 (2001) 2105–2111
2109
X-ray structure analysis. The crystal data and a sum-
mary of experimental details for racemic trans-1 are
given in Table 2. Cell parameters were determined by
least-squares refinement of the angular settings of 159
centred reflections with ꢂ=9–25ꢁ. The structure was
solved by direct methods using the SIR-97 program,11
and refined by full-matrix-block least-squares on F2
using all data and the SHELXL-97 program.12Hydro-
gen positions were obtained in the mixed mode. Selected
bond lengths and angles are given in Table 3.
70.5 (CH, C2), 55.4 (CH2, C5), 33.4 (CH2, C3), 24.7
(CH2, C4).
2-Hydroxy-2-(4-methylthiophenyl)ethanoic acid (3). The
crude product obtained according to the literature6 was
treated with 1 N NaOH and the resulting sodium salt of
3 was filtered and washed intensively with diethyl ether.
Then aq HCl (20%) was added and the solution was
extracted with diethyl ether. After drying with MgSO4
and evaporation of the solventꢁracemic 3 waꢁs isolated as
a pale yellow solid, mp. 132 C (138–140 C).6 Yield:
98%. 1H NMR (400 M Hz, acetone-d6): d 10.27 (bs, 1H,
COOH), 7.43 (ddd, 2H, Har, J=8.6, 2.0, 2.0), 7.25 (ddd,
2H, Har, J=8.7, 2.1, 2.1), 5.21 (s, 1H, CH(OH)), 2.46 (s,
3H, SMe). 13C NMR (101 M Hz, acetone-d6): d=207.5
(acetone), 175.0 (Cq, COOH), 139.9 (Cq), 137.8 (Cq),
128.6 (2 CH), 127.3 (2 CH), 73.5 (CH, CH(OH)), 30.4
(acetone), 15.9 (CH3, SMe). IR (KBr): n=3439, 3053,
2925, 2638, 1708, 1597, 1493, 1433, 1408, 1381, 1349,
1321, 1286, 1255, 1231, 1195, 1185, 1093, 1073, 1013,
946, 919, 891, 858, 813, 759, 726, 688, 651, 576, 494, 435
cmꢀ1. MS (FAB): m/z (%) 199 (37, M++1), 198 (100,
M+), 181 (97, M++1ꢀH2O). C9H10O3S (198.2): calcd
C 54.53, H 5.08, S 16.18; found C 54.74, H 5.02, S
16.29.
1-[2-Hydroxy-2-(4-methylthiophenyl)]ethanoyl-2-phenyl-
pyrrolidine (7). Deviating from Maryanoff’s procedure,6
a catalytic amount of 4-toluenesulphonic acid was
added to the reaction mixture. After filtration through
silica gel the product crystallized from ethyl acetate as a
colourless solid, mp. 135 ꢁC. The mother liquor was
concentrated and again filtered through silica gel.
1
According to the H NMR spectrum the ratio of the
two diastereoisomers (total yield 83%) was 2.7:1. Major
1
diastereoisomer: H NMR (400 M Hz, CDCl3): d 7.35–
7.21 (m, 7H, 30-H, 40-H, 50-H, 2000-H, 3000-H, 5000-H, 6000-
H), 7.16–7.13 (m, 2H, 20-H, 60-H), 5.21 (dd, 1H, 2-H,
J=8.1, 2.5), 5.13 (s, 1H, 200-H), 4.12 (bs, 1H, OH), 3.83
(ddd, 1H, 5a-H, J=10.1, 8.1, 3.4), 3.07 (ddd, 1H, 5b-H,
J=10.0, 9.0, 7.1), 2.48 (s, 3H, SMe), 2.17–2.08 (m, 1H,
3a-H), 2.00–1.70 (m, 3H, 3b-H, 4a-H, 4b-H). 13C NMR
(101 M Hz, CDCl3): d 170.6 (Cq, C100), 142.2 (Cq, C10),
139.2, 135.4 (each Cq, C1000, C4000), 128.5, 128.3, 127.0,
126.8 (2:2:1:2, each CH, C30, C40, C50, C2000, C3000, C5000,
C6000), 125.3 (CH, C20, C60), 72.4 (CH, C200), 61.9 (CH,
C2), 46.8 (CH2, C5), 33.6 (CH2, C3), 23.4 (CH2, C4),
15.56 (S-CH3). Minor diastereoisomer: 1H NMR
(400 M Hz, CDCl3): d 7.02 (dddd, 1H, 40-H, J=7.2, 7.2
1.3, 1.3), 6.96 (dddd, 2H, 30-H, 50-H, J=7.2, 7.2, 0.8,
0.8), 6.78 (ddd, 2H, 3000-H, 5000-H or 2000-H, 6000-H, J=8.5,
1.9, 1.9), 6.74 (ddd, 2H, 3000-H, 5000-H or 2000-H, 6000-H,
J=8.5, 1.9, 1.9), 6.62 (dddd, 2H, 20-H, 60-H, J=7.2, 1.6,
1.6, 1.6), 5.09 (d, 1H, 2-H, J=7.5), 5.04 (s, 1H, 200-H),
4.12 (bs, 1H, OH), 3.83 (ddd, 1H, 5a-H, J=12.2, 10.0,
7.6), 3.69 (ddd, 1H, 5b-H, J=12.5, 8.7, 2.3), 2.33 (s, 3H,
SMe), 2.31–2.22 (m, 1H, 3a-H), 2.00–1.70 (m, 3H, 3b-H,
4a-H, 4b-H). 13C NMR (101 M Hz, CDCl3): d=171.9
(Cq, C100), 141.2 (Cq, C10), 138.0, 135.3 (each Cq, C1000,
C4000), 128.1, 128.0, 126.43, 126.38 (2:2:1:2, each CH,
C30, C40, C50, C2000, C3000, C5000, C6000), 125.1 (CH, C20,
C60), 72.2 (CH, C200), 61.2 (CH, C2), 47.6 (CH2, C5),
35.9 (CH2, C3), 20.5 (CH2, C4), 15.78 (S–CH3). Dia-
stereoisomeric mixture: IR (KBr): n=3400, 3254, 3081,
3063, 3028, 2979, 2946, 2922, 2882, 1827 (s), 1581, 1493,
1441, 1357, 1339, 1317, 1285, 1244, 1198, 1185, 1161,
1112, 1072, 1044, 1027, 1016, 992, 965, 955, 926, 898,
870, 850, 824, 803, 791, 772, 754, 700, 662, 629, 597, 563,
548, 532, 491, 463 cmꢀ1. MS (FAB): m/z (%) 328 (100,
M++1), 310 (34, M++1ꢀH2O). C19H21NO2S (327.4):
calcd C 69.69, H 6.46, N 4.28, S 9.79; found C 69.40, H
6.50, N 4.21, S 10.13.
2-Phenyl-D1-pyrroline (5). Purification of the crude
product was accomplished by distillation in vacuo to
yield the pure pyrroline which crystallized on standing.
1H NMR (400 M Hz, CDCl3): d 7.86–7.81 (m, 2H, 20-H,
60-H), 7.43–7.36 (m, 3H, 30-H, 40-H, 50-H), 4.06 (tt, 2H,
5a-H, 5b-H, J=7.4, 2.0), 2.93 (tt, 2H, 3a-H, 3b-H,
J=8.2, 2.0), 2.02 (m, 2H, Ha-H, 4b-H). 13C NMR
(101 M Hz, CDCl3): d 173.3 (Cq, C2), 134.6 (Cq, C10),
130.3 (CH, C20, C60), 128.4 (CH, C30, C50), 127.6
(CH, C40), 61.5 (CH2, C5), 34.9 (CH2, C3), 22.7 (CH2,
C4).
2-Phenylpyrrolidine (6). 1H NMR (400 M Hz, CDCl3): d
7.42–7.19 (m, 5H, 20-H, 30-H, 40-H, 50-H, 60-H), 4.12 (dd,
1H, 2-H, J=7.7, 7.7), 3.20 (ddd, 1H, 5a-H, J=10.2, 7.7,
5.4), 3.01 (ddd, 1H, 5b-H, J=10.2, 8.3, 6.7), 2.26 (br s,
1H, NH), 2.23–1.62 (m, 4H, 3a-H, 3b-H, 4a-H,0 4b-H).
13C NMR (101 M Hz, CDCl3): d 138.8 (Cq, C1 ) 129.1,
128.7, 127.2 (2:2:1, each CH, C20, C30, C40, C50, C60),

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O. Schulze et al. / Bioorg. Med. Chem. 9 (2001) 2105–2111
H), 1.86–1.77 (m, 1H, 1a-H). 13C NMR (101 M Hz,
CDCl3): d 141.2, 139.0, 137.5, 136.4 (each Cq, C6a,
C10a, C10, C40), 129.7 (CH, C20, C60 or C30, C50), 129.1
(CH, C7 or C10), 127.0 (CH, C20, C60 or C30, C50),
126.3 (CH, C8, C9), 125.3 (CH, C7 or C10), 63.8 (CH,
C10b), 57.9 (CH2, C5), 53.0 (CH2, C3), 44.6 (CH, C6),
30.7 (CH2, C1), 22.1 (CH2, C2), 16.0 (CH3, SMe). IR
(KBr): n=3064, 3035, 3022, 2968, 2924, 2914, 2881,
2870, 2781, 2740, 2725, 2673, 1597, 1491(s), 1448, 1431,
1408, 1371, 1346, 1327, 1284, 1261, 1234, 1215, 1203,
1180, 1163, 1134, 1109, 1092, 1061, 1036, 1016, 976,
953, 918, 868, 820, 785, 752, 721, 648, 633, 609, 584, 552,
480, 444 cmꢀ1. C19H21NS (295.4): calcd C 77.24, H 7.16, N
4.74, S 10.85; found C 77.14, H 7.36, N 4.26, S 10.69.
cis-1: 1H NMR (500 M Hz, CDCl3): d 7.19–7.12 (m,
6H), 7.09–7.05 (m, 1H), 6.88 (ddd, 1H, 20-H, J=7.7, 1.0,
1.0), 4.17 (dd, 1H, 6-H, J=5.3, 5.3), 3.61 (dd, 1H, 10b-
H, J=9.6, 6.9), 3.01 (dd, 1H, 5a-H or 5b-H, J=11.1,
5.6), 2.95 (ddd, 1H, 3a-H or 3b-H, J=10.2, 8.2, 3.1),
2.91 (dd, 1H, 5a-H or 5b-H, J=11.0, 5.1), 2.69 (ddd,
1H, 3a-H or 3b-H, J=8.9, 8.9, 8.9), 2.45 (s, 3H, MeS),
2.40–2.34 (m, 1H, 1-H or 2-H), 2.04–1.94 (m, 1H, 1-H
or 2-H), 1.91–1.80 (m, 2H, 1-H or 2-H). 13C NMR
(101 M Hz, CDCl3): d 143.1, 138.7, 137.2, 135.9 (each
Cq, C6a, C10a, C10, C40), 129.4, 129.3, 126.7, 126.2,
126.1, 125.8 (2:1:2:1:1:1, each CH, C7, C8, C9, C10, C20,
C30, C50, C60), 63.6 (CH, C10b), 56.1 (CH2, C5), 54.3
(CH2, C3), 45.6 (CH, C6), 30.5 (CH2, C1), 22.3 (CH2,
C2), 16.1 (CH3, SMe). IR (KBr): n=3070, 3060, 3018,
2964, 2939, 2922, 2873, 2785, 2731, 1651, 1601, 1491(s),
1448, 1439, 1404, 1375, 1348, 1323, 1292, 1215, 1163,
6-(4-Methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-
a]isoquinoline-5-one (8). According to a modified litera-
ture synthesis13 the amide 7 was cyclodehydrated with
concd H2SO4 in a trifluoroacetic acid (TFA) medium.
After stirring overnight at room temperature the reac-
tion mixture was quenched by addition of water and
extracted with CH2Cl2. The organic layer was washed
with water and brine, dried (MgSO4) and concentrated
to give 8 as a brown syrup. Yield: 92%. Diaster-
1
eoisomeric mixture: H NMR (400 M Hz): d 7.42–7.02
(m, 8H, 7-H, 8-H, 9-H, 10-H and 20-H, 30-H, 50-H, 60-
H), 4.89 (s, 1H, 6-H), 4.53 (dd, 1H, 10b-H, J=6.3, 9.1),
3.66–3.51 (m, 2H, 3a-H, 3b-H), 2.64–2.59 (m, 1H, 1a-
H), 2.42 (s, 3H, MeS), 2.14–2.09 (m, 1H, 2a-H), 1.98–
1.88 (m, 2H, 1b-H, 2b-H). 13C NMR (101 M Hz,
CDCl3): d 169.0 (Cq, C5), 137.7, 137.3, 135.9, 135.2
(each Cq, C6a, C10a, C10, C40), 131.9, 128.9, 128.6,
128.2, 127.9, 127.3, 124.8 (each CH, C7, C8, C9, C10
and C20, C30, C50, C60), 59.4 (CH, C10b), 54.0 (CH, C6),
45.8 (CH2, C3), 32.1 (CH2, C1), 23.4 (CH2, C2), 16.3
(SMe). IR: n=3435, 2972, 2949, 2920, 2879, 1647 (s,
CO), 1491(s), 1439, 1404, 1344, 1317, 1304, 1236, 1198,
1132, 1117, 1092, 1016, 966, 823, 752 cmꢀ1
.
(+)-McN-5652-Z. As mentioned above we separated
the two cis-enantiomers of 1 on a 250Â10 mm column
packed with chiralpak1 AD 25mm. The mobile phase
was 97% n-hexane/3% 2-propanol/0.05% triethyl-
amine. The flow rate was 4.7 mL minꢀ1. The capacity
factors were 1.12 for the (ꢀ)-enantiomer and 2.99 for
the (+)-enantiomer.
1161, 1093, 1016, 910, 812, 758, 731, 685 cmꢀ1
.
Acknowledgements
6-(4-Methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-
a]isoquinoline (1). This was obtained as described in ref
6. The diastereoisomers were separated by column
chromatography with ethyl acetate as mobile phase.
The pair of trans-enantiomers was eluted first (Rf=0.20,
ethyl acetate) and crystallized as a pale brown solid, mp.
79–81 ꢁC. The pair of cis-enantiomers followed
(Rf=0.07, ethyl acetate) and was isolated as a brown
syrup. The ratio of the diastereoisomers trans/cis was 5:1.
The authors thank the Bundesinstitut fur Arzneimittel
und Medizinprodukte (BfArM) for financial support
(Project No. Z12.01-68503-206). Professor Dr. A. Krebs
and Dr. V. Sinnwell, Univ. Hamburg, are gratefully
acknowledged for supporting our HPLC and NMR
studies. We thank J. Zessin, Forschungszentrum Ros-
sendorf, for providing an authentic sample of (+)-
McN-5652-Z.
1
trans-1: H NMR (500 M Hz, CDCl3): d 7.22–7.19 (m,
2H, Har), 7.19–7.15 (m, 1H, Har), 7.13–7.11 (m, 1H,
Har), 7.10–7.08 (m, 2H, Har), 7.08–7.04 (m, 1H, Har),
6.83 (ddd, 1H, H-20, J=7.8, 0.9, 0.9), 4.35 (dd, 1H, 6-H,
J=10.6, 6.4), 3.65 (dd, 1H, 10b-H, J=7.7, 7.7), 3.43
(dd, 1H, 5a-H, J=11.8, 6.4), 3.15 (ddd, 1H, 3a-H,
J=9.0, 7.8, 4.2), 2.69 (dd, 1H, 5b-H, J=11.3, 11.3), 2.57
(ddd, 1H, 3b-H, J=8.3, 8.3, 8.3), 2.47 (s, 3H, SMe),
2.49–2.42 (m, 1H, 1b-H), 2.00–1.87 (m, 2H, 2a-H, 2b-
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