Asymmetric synthesis of potent and selective σ1 receptor ligands with tetrahydro-3-benzazepine scaffold

Article abstract of DOI:10.1002/ejoc.201200927

A new strategy for the synthesis of tetrahydro-3-benzazepinones 6 by reductive amination of keto acid 3 and subsequent carbonyl diimidazole (CDI) mediated cyclization was developed. Use of enantiomerically pure (R)-1-phenylethylamine led to the formation of diastereomeric lactams (R _α-R)-6d and (R_α-S)-6e in a 80:20 ratio. Diastereoselective alkylation of (R_α-R)-6d, BH ₃-mediated reduction and exchange of the N-phenylethyl substituent provided enantiomerically pure tetrahydro-3-benzazepines with various substituents in the 1-, 3-, and 4-positions. High I₁ affinity was achieved with a benzyl, cyclohexylmethyl, or 1-phenylethyl moiety at the N-atom. Whereas (R)-configuration of the N-substituent is crucial for high I₁ affinity, the configuration of the 3-benzazepine ring system does not influence the I₁ affinity considerably. Introduction of additional substituents in the 1-position led to almost complete loss of σ₁ affinity. Potent σ₁ ligands show high selectivity against the σ₂ subtype and the NMDA receptor. The key step in the synthesis of enantiomerically pure tetrahydro-3-benzazepines is the diastereoselective, consecutive, three-step transformation of keto acids into lactams. Relationships between the structure and the σ₁ affinity are elaborated.

Full text of DOI:10.1002/ejoc.201200927

Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
FULL PAPER
DOI: 10.1002/ejoc.201200927
Asymmetric Synthesis of Potent and Selective σ1 Receptor Ligands with
Tetrahydro-3-benzazepine Scaffold
Soumya Sarkar,[a] Dirk Schepmann,[a] Jens Köhler,[a] Roland Fröhlich,[b] and
Bernhard Wünsch*[a]
Keywords: Drug discovery / Reduction / Amination / Asymmetric synthesis / Diastereoselectivity / Receptors
A new strategy for the synthesis of tetrahydro-3-benzazep-
inones 6 by reductive amination of keto acid 3 and subse-
quent carbonyl diimidazole (CDI) mediated cyclization was
developed. Use of enantiomerically pure (R)-1-phenylethyl-
amine led to the formation of diastereomeric lactams (Rα-R)-
6d and (Rα-S)-6e in a 80:20 ratio. Diastereoselective alkyl-
ation of (Rα-R)-6d, BH3-mediated reduction and exchange of
the N-phenylethyl substituent provided enantiomerically
pure tetrahydro-3-benzazepines with various substituents in
the 1-, 3-, and 4-positions. High σ1 affinity was achieved with
a benzyl, cyclohexylmethyl, or 1-phenylethyl moiety at the
N-atom. Whereas (R)-configuration of the N-substituent is
crucial for high σ1 affinity, the configuration of the 3-benz-
azepine ring system does not influence the σ1 affinity con-
siderably. Introduction of additional substituents in the 1-po-
sition led to almost complete loss of σ1 affinity. Potent σ1 li-
gands show high selectivity against the σ2 subtype and the
NMDA receptor.
cation of a protein containing 223 amino acids with a mo-
lecular weight of 25.3 kDa.[9] According to a postulated
model, the σ1 receptor contains two transmembrane do-
mains with both the amino and carboxy termini located on
the intracellular side of the membrane.[10] In contrast to the
σ1 receptor, the σ2 receptor has not yet been cloned and
only little is known about its structural features. Photoaffin-
ity labeling experiments led to the identification of a protein
with a molecular weight of 18–21 kDa.[11]
The σ1 receptor is considered to play a crucial role in
controlling the activity of a variety of ion channels (e.g.,
K+, Na+, Ca2+ channels) and neurotransmitter systems
(e.g., glutamate, dopamine, acetylcholine systems). There-
fore, ligands interacting with σ1 receptors possess a poten-
tial for the treatment of neuropsychiatric disorders includ-
ing schizophrenia, depression, Alzheimer’s disease, and
pain, as well as alcohol and cocaine abuse.[12–15] The high
density of σ1 receptors in some human tumor cell lines (e.g.,
breast, lung, prostate cancer cell lines) could be exploited
for tumor diagnosis and therapy.[16,17]
Introduction
In 1976 Martin and co-workers postulated the σ receptor
as an opioid receptor subtype because the psychotomimetic
effects of (Ϯ)-N-allylnormetazocine (SKF-10,047) could
not be explained by activation of μ-opioid or κ-opioid re-
ceptors.[1] However, the selectivity of the σ receptor for dex-
trorotatory benzomorphan enantiomers[2] and the fact that
most of the effects of σ ligands neither in vivo nor in vitro
were blocked by the classical opioid antagonists naloxone
and naltrexone, led to reclassification of the σ receptor.[3,4]
In 1984 the σ receptor was considered to be identical to
the phencyclidine (PCP) binding site at the NMDA recep-
tor.[5,6] However, this classification had to be corrected as
well because some ligands exist (e.g., haloperidol) that exhi-
bit high affinity towards the σ receptor but no affinity
towards the PCP binding site of the NMDA receptor.[7]
Further research showed conclusively that σ receptors are
a unique nonopioid and non-PCP but haloperidol-sensitive
class of receptors containing two subtypes, which are
termed σ1 and σ2 receptors.[8]
Recently, we have reported on the synthesis of racemic
2,3-disubstituted tetrahydro-3-benzazepines 1 by micro-
wave-assisted condensation of keto acids with various pri-
mary amines as a key step. In particular, 3-benzazepines 1
with a small substituent at the 2-position and a lipophilic
substituent at the N-atom showed σ1 affinities in the low
nanomolar range. Moreover, high selectivity against the σ2
subtype was observed. As an example, 3-benzazepine 1a,
bearing a benzyl moiety at the N-atom and a small methyl
group in the 2-position (1a; R1 = Bn, R3 = CH3), represents
a very potent σ1 ligand (Ki = 12 nm) with more than 20-
fold selectivity over the σ2 subtype[18] (Figure 1).
The σ1 receptor has a specific drug selectivity pattern
and a characteristic distribution within the central nervous
system as well as in some organs of the periphery. Cloning
of the σ1 receptor subtype from rat brain led to the identifi-
[a] Institut für Pharmazeutische und Medizinische Chemie der
Westfälischen Wilhelms-Universität Münster,
Hittorfstraße 58-62, 48149 Münster, Germany
Fax: +49-251-8332144
[b] Organisch-Chemisches Institut der Westfälischen Wilhelms-
Universität Münster,
Correnstr. 40, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200927.
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S. Sarkar, D. Schepmann, J. Köhler, R. Fröhlich, B. Wünsch
FULL PAPER
Figure 1. Design of σ1 ligands based on the tetrahydro-3-benzazep-
ine scaffold.
To investigate the influence of the N-substituent and the
stereochemistry on the σ1 and σ2 receptor affinity, we
planned to synthesize enantiomerically pure 3-benzazepines
of type 2 with and without an additional substituent R2 in
the 3-benzazepine scaffold. Herein, we wish to report a new Scheme 1. Reagents and conditions: (a) R-NH2, NaBH(OAc)3,
CH2Cl2, room temp., 20 h. (b) CDI, THF, reflux, 5 h, 30% (6a),
and efficient method for the synthesis of enantiopure 3-
40% (6b), 50% (6c). (c) BH3·THF, THF, room temp., 16 h, 45%
benzazepines 2 with high enantiomeric excess. Since we
(7a), 40% (7b), 35% (7c).
have shown that the corresponding butyl (1b; R1 = Bn, R3
= Bu) and phenyl derivatives (1c; R1 = Bn, R3 = Ph) re-
sulted in rather low σ1 affinities (Ki Ͼ 400 and 1500 nm,
a ratio (Rα-R)-6d/(Rα-S)-6e of 78:22. In CH2Cl2 the ratio
respectively)[18] compared with the methyl derivative 1a, we
was slightly increased to 80:20 (20 °C) and 82:18 (0 °C),
focused herein on 3-benzazepines 2 with a methyl moiety in
the 4-postion. Furthermore, the σ1 and σ2 receptor affin-
ities of the synthesized ligands were determined in competi-
however, reduction of the temperature also decreased the
total yield from 45% (20 °C) to 32% (0 °C). In subsequent
experiments the crucial reductive amination step was per-
tive receptor binding assays leading to the identification of
formed at ambient temperature to obtain good yields of the
novel structure-affinity relationships.
products in high diastereoselectivity.
Synthesis
The synthesis of 2,3-disubstituted 3-benzazepines 7
started from methyl keto acid 3, which was obtained by
reaction of o-phenylenediacetic acid with an excess of
MeLi[19] (Scheme 1). The keto acid 3 was converted into 3-
benzazepinones 6a–c by a three-step, consecutive pro-
cedure. First, keto acid 3 was condensed with primary
amines to give imines 4, which were reduced by NaBH-
(OAc)3. The resulting amino acid intermediates 5a–c were
cyclized upon heating with two equivalents of carbonyl di-
imidazole (CDI) to yield 3-benzazepinones 6a–c with
various N-substituents. Finally, reduction of 6a–c with
BH3·THF provided tetrahydro-3-benzazepines 7a–c.
Scheme 2. Reagents and conditions: (a) 1. (R)-1-phenylethylamine,
NaBH(OAc)3, CH2Cl2, room temp., 20 h; 2. CDI, THF, reflux, 5 h,
ratio (Rα-R)-6d/(Rα-S)-6e 80:20, isolated yields 40% [(Rα-R)-6d],
5% [(Rα-S)-6e]. (b) BH3·THF, THF, room temp., 16 h, 60% [(Rα-
In the receptor binding studies the racemic tetrahydro-3-
benzazepine 7b with a benzyl moiety at the N-atom re-
vealed high σ1 receptor affinity. Therefore, the enantiomers
of 7b should be prepared and pharmacologically evaluated.
Additionally, the enantiomers of 7c were envisaged due to
the similarity in space and electronic differences of the cy-
clohexylmethyl moiety compared to the benzyl group. For
R)-7d], 50% [(Rα-S)-7e]. The corresponding enantiomers were syn-
thesized in the same manner using (S)-1-phenylethylamine.
After flash chromatographic separation of the dia-
this purpose, the keto acid 3 was reductively aminated with stereomeric lactams (Rα-R)-6d and (Rα-S)-6e, reduction
enantiomerically pure (R)-configured 1-phenylethylamine with BH3·THF provided the enantiomerically pure tetra-
and NaBH(OAc)3 to afford the amino acid intermediate hydro-3-benzazepines (Rα-R)-7d and (Rα-S)-7e in 60 and
that was cyclized with CDI to yield the diastereomeric lact- 50% yield, respectively, based on diastereomerically pure
ams (Rα-R)-6d and (Rα-S)-6e (Scheme 2) The ratio of dia- lactams (Rα-R)-6d and (Rα-S)-6e. The enantiomers (Sα-S)-
stereomers was dependent on the reductive amination of 7d and (Sα-R)-7e were prepared in similar fashion. In con-
keto acid 3. Therefore, various solvents (e.g., THF, CH2Cl2) clusion, this reductive amination protocol using enantio-
and temperatures (–20 to +20 °C) were investigated to at- merically pure 1-phenylethylamine to establish the chiral
tain an optimal diastereoselectivity during this key transfor- center represents a considerable improvement over the ox-
mation. Performing the reductive amination in THF led to azolidine strategy using phenylglycinol, which provided the
2
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Asymmetric Synthesis of σ1 Receptor Ligands
diastereomers in 1:1 ratio.[20–22] Moreover, the direct con-
densation of 1-phenylethylamine with keto acid 3 at 120 °C
led to the formation of indanone derivatives.[18]
The absolute configuration of the newly formed center
of chirality of (Rα-R)-7d and (Rα-S)-7e could not be deter-
mined by NMR experiments. Therefore, (Rα-R)-7d was
recrystallized from a mixture of CH2Cl2 and n-hexane to
provide crystals suitable for X-ray crystal structure analysis
(Figure 2). The X-ray crystal structure analysis reveals the
same configuration for both centers of chirality. Since the
configuration of the N-substituent is defined by the starting
material to be (R), the (R)-configuration is assigned to the
newly formed center of chirality in the 2-position.
Figure 3. HPLC analysis of (Rα-R)-7d and (Sα-S)-7d. (A) Artificial
mixture of (Rα-R)-7d and (Sα-S)-7d in the ratio 25:75; (B) Analysis
of (Rα-R)-7d after reduction of (Rα-R)-6d with BH3·THF leading
to an er of more than 98:2. HPLC: Daicel Chiralcel OJ-H (5 μm);
injection volume 5.0 μL; flow rate: 1.00 mL/min; detection at λ =
206 nm; eluent isohexane/2-propanol, 90:10.
Figure 2. Single X-ray crystal structure analysis of (Rα-R)-7d.
Since the enantiomerically pure 3-benzazepines (Rα-R)-
7d and (Sα-S)-7d [prepared in the same manner starting
with (S)-1-phenylethaylamine] were used for the synthesis
of enantiomerically pure 3-benzazepines 7 with various N-
substituents, a chiral HPLC method was developed to de-
termine the enantiomeric purity. The separation of the
enantiomers was performed with a Daicel Chiralcel OJ-H
column and an isocratic elution (isohexane/2-propanol,
90:10). Figure 3 (A) shows the baseline separation of an
artificial mixture of (Rα-R)-7d and (Sα-S)-7d (25:75). The
same analysis performed with the synthetic products
(Rα-R)-7d and (Sα-S)-7d resulted in a ratio of enantiomers
of more than 98:2, respectively (Figure 3, B).
Recently it was shown that oxazolidine annulated 3-
benzazepinones can be alkylated in the 1-position with high
diastereoselectivity.[21–23] Therefore, the diastereoselective
alkylation of (Rα-R)-6d bearing the chiral 1-phenylethyl
substituent at the nitrogen atom was investigated. Thus,
(Rα-R)-6d was deprotonated with LHMDS at –78 °C and
subsequently trapped with methyl or ethyl iodide
Scheme 3. Reagents and conditions: (a) LHMDS, CH3I or C2H5I,
THF, –78 °C, 20 h, 51% [(Rα-R,R)-8a], 60% [(Rα-R,R)-8b].
(b) BH3·THF, THF, room temp., 16 h, 79% [(Rα-R,R)-9a], 56%
[(Rα-R,R)-9b]. The corresponding enantiomers were synthesized in
the same manner starting with (Sα-S)-6d.
The relative configuration of the alkylated products (Rα-
(Scheme 3). According to GC–MS analysis, only one dia- R,R)-8a and (Rα-R,R)-8b was determined by NOE experi-
stereomer was formed, respectively, indicating high dia- ments. For example, the cis-configuration of the proton in
stereoselectivity (dr Ͼ 99:1) of this transformation. The the 1-position and the methyl moiety in the 4-position of
monoalkylated 3-benzazepines (Rα-R,R)-8a and (Rα-R,R)- (Rα-R,R)-8b was shown by a positive NOE interaction, i.e.,
8b were isolated as single diastereomers in 51–76% yield. the signal at δ = 1.41 ppm (CH3) was increased after irradi-
Reduction of the lactams (Rα-R,R)-8a and (Rα-R,R)-8b ation at δ = 3.49 ppm (1-H) and vice versa. This cis-config-
with BH3·THF yielded the enantiomerically pure trisubsti- uration directly leads to the absolute (R)-configuration of
tuted 3-benzazepines (Rα-R,R)-9a and (Rα-R,R)-9b. The the newly formed chiral center in the 1-position. The (1R)-
enantiomers (Sα-S,S)-9a and (Sα-S,S)-9b were prepared in configuration indicates that the methyl moiety in the 4-posi-
the same manner.
tion of the 3-benzazepinone (Rα-R)-6d directs the attack of
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S. Sarkar, D. Schepmann, J. Köhler, R. Fröhlich, B. Wünsch
FULL PAPER
the electrophile on the enolate to the opposite side (Re-face with isohexane/2-propanol, 90:10) as described for the sepa-
attack). ration of (Rα-R)-7d and (Sα-S)-7d. According to this chiral
To introduce further N-substituents, the 1-phenylethyl HPLC analysis, 1.5% of (S)-7b was present in the enanti-
moiety of (Rα-R)-7d and (Rα-R,R)-9b was removed hydro- omer (R)-7b (Ͼ 97%ee). The enantiomer (S)-7b showed an
genolytically (H2, Pd/C) to produce the secondary amines even higher enantiomeric excess of 99%ee. This result led
(R)-10 and (R,R)-11 (Scheme 4). Subsequent alkylation to the conclusion that neither racemization nor epimeri-
with benzyl bromide or cyclohexylmethyl bromide led to zation had occurred during the synthesis of the enantiomer-
the enantiomerically pure di- and trisubstituted tetrahydro- ically pure products 7b and its analogues 7c and 12.
3-benzazepines (R)-7b,c and (R,R)-12. The enantiomers (S)-
7b,c and (S,S)-12 were obtained in the same manner.
Receptor Affinity
The affinities of racemic and enantiomerically pure tetra-
hydro-3-benzazepines 7, 9 and 12 towards σ1 and σ2 recep-
tors were determined in competitive receptor binding stud-
ies. [3H]-(+)-Pentazocine and [3H]-(+)-di-o-tolylguanidine
were the competitors used in the σ1 and σ2 assays, respec-
tively. Because di-o-tolylguanidine also interacts with σ1 re-
ceptors, an excess of non-tritiated (+)-pentazocine was
added to mask σ1 sites. Guinea pig brain and rat liver prep-
arations served as receptor sources in the σ1 and σ2 assays,
respectively.[24–28] The Ki values given in Table 1 represent
mean values ϮSEM (standard error of the mean) of three
independent experiments. Competition curves of com-
Scheme 4. Reagents and conditions: (a) H2, Pd/C, CH3OH, room
temp., 4–6 h. (b) Bn-Br or C6H11CH2-Br, NEt3, CH3CN, 42–55%.
The corresponding enantiomers were synthesized in the same man-
ner starting with (Sα-S)-7d and (Sα-S,S)-9b.
pounds leading to Ki values greater than 250 nm in the first
experiment were not repeated (n = 1). Because some σ li-
gands also interact with the phencyclidine binding site of
the NMDA receptor and vice versa,[29,30] the affinities of
The enantiopurity of the enantiomers (R)-7b and (S)-7b the 3-benzazepines towards the PCP binding site of the
was determined by chiral HPLC analysis using the same NMDA receptor were also determined in competition ex-
method (Daicel Chiralcel OJ-H column, isocratic elution periments. [3H]-(+)-MK-801 served as radioligand and
Table 1. Affinities of racemic and enantiomerically pure tetrahydro-3-benzazepines towards σ1 and σ2 receptors.
R1
R2
Ki ϮSEM [nm][a]
σ1
σ1/σ2 selectivity
σ2
7a
Butyl
CH2Ph
CH2Ph
CH2Ph
H
H
H
H
H
H
H
H
325
79Ϯ18
257
57Ϯ6.3
217Ϯ130
48Ϯ8.5
108Ϯ13
290
Ͼ1000
101Ϯ22
19Ϯ10
Ͼ1000
Ͼ1000
Ͼ1000
Ͼ1000
Ͼ1000
Ͼ1000
n.d.
0.25
21
18
17
1.5
16
18
Ͼ2
4
0.07
–
–
–
–
7b[18]
12Ϯ5.6
3.2Ϯ0.6
13Ϯ2.0
31Ϯ9.3
6.6Ϯ0.33
16Ϯ8.4
520Ϯ123
24Ϯ9.0
270Ϯ79
Ͼ1000
Ͼ1000
Ͼ1000
Ͼ1000
496
(R)-7b
(S)-7b
(R)-7c
CH2C6H11
CH2C6H11
CH(CH3)Ph
CH(CH3)Ph
CH(CH3)Ph
CH(CH3)Ph
CH(CH3)Ph
CH(CH3)Ph
CH(CH3)Ph
CH(CH3)Ph
CH2Ph
(S)-7c
(Rα-R)-7d
(Sα-S)-7d
(Rα-S)-7e
(Sα-R)-7e
(Rα-R,R)-9a
(Sα-S,S)-9a
(Rα-R,R)-9b
(Sα-S,S)-9b
(R,R)-12
(S,S)-12
H
H
CH3
CH3
C2H5
C2H5
C2H5
C2H5
Ͼ2
–
–
13
0.6
CH2Ph
Ͼ1000
(+)-Pentazocine
Haloperidol
Di-o-tolylguanidine
5.7Ϯ2.2
6.3Ϯ1.6
89Ϯ29
78Ϯ2.3
58Ϯ18
[a] Generally, the Ki values were determined in triplicate (n = 3). For compounds showing very low affinity (Ki Ͼ 250 nm) in the first
experiment, repetitions were not performed (n = 1); n.d. = not determined.
4
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Asymmetric Synthesis of σ1 Receptor Ligands
membrane preparations from pig brain cortex as receptor dines in the ratio 50:50. Alkylation of (Rα-R)-6d took place
material in this assay.[31]
with very high diastereoselectivity, indicating that the rigid
The data in Table 1 clearly indicate that 3-benzazepine oxazolidine annulated 3-benzazepine scaffold is not re-
7a with an aliphatic butyl substituent at the N-atom shows quired for high diastereoselectivity. The novel 3-benzazep-
only low σ1 affinity. However, replacement of the butyl sub- ine building blocks were exploited for the preparation of
stituent with the benzyl substituent resulted in the very po- enantiomerically pure 3-benzazepines. Very potent σ1 li-
tent σ1 ligand 7b (Ki = 12 nm).[18] The σ1 receptor protein gands were obtained by introduction of a benzyl, a cyclo-
is able to discriminate between the enantiomers of 7b and hexylmethyl, or a methyl-substituted benzyl moiety at the
7c. Surprisingly, the (R)-configured enantiomer of the N- N-atom. Whereas the configuration of the N-substituent is
benzyl derivative (R)-7b and the (S)-configured enantiomer crucial for high σ1 receptor affinity, the configuration of the
of the N-cyclohexylmethyl derivative (S)-7c are preferably 3-benzazepine ring is less important. Introduction of fur-
bound by the σ1 receptor.
ther substituents in the 1-position of the 3-benzazepine ring
Introduction of an additional methyl moiety in the α- eliminates the σ1 affinity almost completely. The enantio-
position of the N-benzyl substituent provided the four merically pure 3-benzazepine (Sα-R)-7e, showing high σ2 af-
stereoisomeric 1-phenylethyl derivatives 7d and 7e. In this finity and selectivity over the σ1 subtype, represents a prom-
series of compounds the configuration of the N-(1-phenyle- ising starting point for the development of potent and selec-
thyl) moiety is crucial for high σ1 affinity. Whereas the 3- tive σ2 ligands.
benzazepines (Rα-R)-7d and (Rα-S)-7e with (R)-configura-
tion in the α-position reveal high σ1 affinities, the corre-
sponding (Sα)-configured stereoisomers (Sα-S)-7d and (Sα-
R)-7e are 10–30-fold less active. The configuration of the Experimental Section
chiral center in the 4-position of the 3-benzazepine scaffold
General: Unless otherwise mentioned, THF was dried with sodium/
appears to be less important for interaction with the σ1 re-
benzophenone and was freshly distilled before use. Thin-layer
ceptor.
chromatography (TLC) was performed with Silica gel 60 F254
plates (Merck); given Rf values refer to TLC. Flash chromatog-
raphy was performed with silica gel 60, 40–64 μm (Macherey–Na-
gel); parentheses include: diameter of the column, length of col-
An additional methyl or ethyl substituent in the 1-posi-
tion of the 3-benzazepine system (9 and 12) eliminated the
σ1 (and σ2) receptor affinity almost completely, on condi-
tion that the configuration in the 1- and 4-position is the umn, fraction size, eluent, Rf value. Melting points were determined
with a melting point apparatus SMP 3 (Stuart Scientific), and are
uncorrected. IR spectra were recorded with an IR spectrophotome-
same (like configuration). Clearly even a small substituent
in the 1-position of the 3-benzazepine ring with like-config-
uration is not tolerated by the σ1 (and σ2) receptor protein.
Most of the investigated 3-benzazepines show high selec-
tivity for the σ1 receptor over the σ2 receptor. The most
potent σ1 ligands of this series [(R)-7b, (S)-7b, (S)-7c,
(Rα,R)-7d] also represent the most selective derivatives.
Whereas the racemic N-butyl derivative 7a reveals a slight
preference for the σ2 receptor, the enantiomerically pure
1
ter 480Plus FT-ATR-IR (Jasco). H NMR (400 MHz), 13C NMR
(100 MHz) spectra were recorded with a Mercury plus 400 spec-
trometer (Varian); δ in ppm relative to tetramethylsilane; coupling
constants are given with 0.5 Hz resolution. Where necessary, the
1
assignment of the signals in the H NMR and 13C NMR spectra
1
1
was performed by using H-1H and H-13C COSEY NMR spectra
as well as NOE difference spectroscopy. Optical rotation [α] was
determined with a Polarimeter 341 (Perkin–Elmer); length 1 dm,
phenylethyl derivative (Sα,R)-7e interacts predominantly wavelength 589 nm (sodium D line); the unit of the specific rotation
[α]lT [deg mL dm–1 g–1] is omitted; concentration of the sample c
[g/100 mL] and the solvents used are given in brackets. MS (EI or
ESI) spectra were recorded with a MicroTof (Bruker Daltronics,
with the σ2 subtype. Moreover, the very low Ki value of
19 nm (σ2) represents a promising starting point for the de-
velopment of a novel potent and selective class of σ2 li-
Bremen), which was calibrated with sodium formate clusters before
gands.
measurement. HPLC method for determination of the product pu-
At a test compound concentration of 1 μm, 3-benzazep-
rity: Merck Hitachi Equipment. UV detector: L-7400; autosam-
ines 7, 9 and 12 did not compete significantly with the ra-
pler: L-7200; pump: L-7100; degasser: L-7614; Method for the de-
termination of compound purity: column: LiChrospher 60 RP-se-
dioligand [3H]-(+)-MK-801. Therefore, the affinity towards
the PCP binding site of the NMDA receptor is rather low
(IC50 Ͼ 1 μm).
lect B (5 μm), 250–4 mm cartridge; flow rate: 1.00 mL/min; injec-
tion volume: 5.0 μL; detection at λ = 210 nm for 30 min; solvents:
(A) water plus 0.05% (v/v) trifluoroacetic acid; (B) acetonitrile plus
0.05% (v/v) trifluoroacetic acid: gradient elution: 0–4 min (90% A),
4–29 min (gradient from 90 to 0% A), 29–31 min (0% A), 31–
31.5 min (gradient from 0 to 90% A), 31.5–40 min (0% A). Chiral
HPLC method for determination of the enantiomeric excess: all
except Rheodyne 7125i are Merck–Hitachi equipment; diode array
detector: L-7455; pump: L-6200A; degasser: L-7614; injection:
Rheodyne 7125i; column: Daicel Chiralcel OJ-H (5 μm) 250–
4.6 mm; precolumn: Daicel Chiralcel OJ-H (5 μm) 10–4 mm; injec-
tion volume: 5.0 μL; flow rate: 1.00 mL/min; detection at λ =
206 nm; solvents: isohexane/2-propanol, 90:10. Gas liquid
Conclusion
Reductive amination of methyl keto acid 3 with (R)-1-
phenylethylamine and subsequent cyclization of the inter-
mediate amino acid led to the diastereomeric 3-benzazepi-
nones (Rα-R)-6d and (Rα-S)-6e in the ratio 80:20. This rep-
resents a considerable improvement over the condensation
of 3 with phenylglycinol, producing diastereomeric oxazoli- chromatography (GLC) was performed with a Shimadzu GC-17A
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
S. Sarkar, D. Schepmann, J. Köhler, R. Fröhlich, B. Wünsch
FULL PAPER
gas chromatograph equipped with a SE-54 capillary column
(30 mϫ0.32 mm, 0.25 μm film thickness) by the CS-Chromatog-
raphy Service using the following program: N2 carrier gas, injection
temperature 250 °C, detector temperature 300 °C; temperature pro-
gram: start temperature 40 °C, heating rate 10 °C/min, end tem-
perature 280 °C for 5 min.
δ = 13.9 (1 C, CH2CH2CH2CH3), 20.2 (1 C, CH3), 20.4 (1 C,
CH2CH2CH2CH3), 30.6 (1 C, CH2CH2CH2CH3), 40.1 (1 C,
CH2CH2CH2CH3), 43.7 (1 C, C-5), 45.9 (1 C, C-1), 53.4 (1 C, C-
4), 126.9, 127.0, 129.2, 129.3 (4 C, Ph-CH), 134.2, 135.9 (2 C, Ph-
C), 169.9 (1 C, C=O) ppm. HRMS (ESI): m/z calcd. for
C15H21NONa 254.1515; found 254.1514. Purity (HPLC): 98.5%
(tR = 19.1 min).
General Procedures
3-Benzyl-4-methyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(6b):[18]
Synthesis of Lactams 6. General Procedure A: Under N2, primary
amine (1 equiv.) was added to a solution of methyl keto acid 3
(1 equiv.) in CH2Cl2 (6 mL). After stirring for 30 min at room
temp., NaBH(OAc)3 (2 equiv.) was added and the reaction mixture
was stirred for 20 h at room temp. The mixture was extracted with
NaHCO3 solution (3ϫ10 mL) and the aqueous layer was extracted
with CH2Cl2 (3ϫ15 mL). The organic layer was dried (Na2SO4),
concentrated in vacuo, and the residue was dissolved in THF
(20 mL). CDI (2 equiv.) was added and the reaction mixture was
heated to reflux for 5 h. The reaction mixture was concentrated in
vacuo, the residue was dissolved in EtOAc (10 mL) and the solution
was washed with water. The aqueous layer was extracted with
EtOAc (3ϫ15 mL), the organic layer was dried (Na2SO4), concen-
trated in vacuo and the residue was purified by flash chromatog-
raphy.
Following the General Procedure A, methyl keto acid 4 (113 mg,
0.59 mmol) was treated with benzylamine (64 μL, 0.59 mmol) and
NaBH(OAc)3 (250 mg, 1.18 mmol). The crude product was further
reacted with CDI (191 mg, 1.18 mmol). After complete transforma-
tion, the crude product was purified by flash chromatography [d =
3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc, 80:20, Rf = 0.34
(cyclohexane/EtOAc, 60:40)]. Colorless solid; m.p. 90 °C; yield
62 mg (40%). C H NO (265.3 g/mol). FTIR (ATR, film): ν =
˜
18 19
2928 (aliphatic C–H), 1635 (C=O) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.23 (d, J = 6.6 Hz, 3 H, CH3), 2.88 (dd, J = 15.6,
9.4 Hz, 1 H, 5-H), 3.13 (dd, J = 15.6, 4.4 Hz, 1 H, 5-H), 3.83 (d, J
= 15.2 Hz, 1 H, 1-H), 3.88–3.96 (m, 1 H, 4-H), 4.09 (d, J = 15.2 Hz,
1 H, 1-H), 4.20 (d, J = 15.6 Hz, 1 H, NCH2Ph), 5.07 (d, J =
15.5 Hz, 1 H, NCH2Ph), 6.97–7.28 (m, 9 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 20.4 (1 C, CH3), 39.9 (1 C, C-5), 43.5 (1
C, C-1), 48.1 (1 C, C-4), 52.9 (1 C, NCH2Ph), 126.9, 127.0, 127.1,
127.2, 128.4, 129.2, 129.3 (9 C, Ph-CH), 134.1, 136.0, 138.2 (3 C,
Ph-C), 170.8 (1 C, C=O) ppm. HRMS (ESI): m/z calcd. for
C18H19NONa 288.1359; found 288.1347. Purity (HPLC): 97.6%
(tR = 19.2 min).
Monoalkylation of Lactams 6d. General Procedure B: Under N2,
LHMDS (1 m in THF, 1.2 equiv.) was added to a cooled (–78 °C)
solution of lactam 6d (1.0 equiv.) in THF (6 mL). After stirring for
1 h at –78 °C, methyl iodide or ethyl iodide (1.2 equiv.) was added
and the solution was further stirred for 3 h at –78 °C. Saturated
NaCl solution (10 mL) was added to hydrolyze excess LHMDS and
the mixture was extracted with EtOAc (3ϫ10 mL). The organic
layer was washed with NaCl solution (10 mL) and water (10 mL)
and the aqueous layer was extracted with EtOAc (2ϫ10 mL). The
combined organic layers were dried (Na2SO4), filtered, the solvent
was evaporated in vacuo, and the residue was purified by flash
chromatography.
3-Cyclohexylmethyl-4-methyl-1,3,4,5-tetrahydro-3-benzazepin-2-one
(6c): Following the General Procedure A, methyl keto acid 3
(132 mg, 0.69 mmol) was treated with cyclohexylmethylamine
(89 μL, 0.69 mmol) and NaBH(OAc)3 (292 mg, 1.38 mmol). The
crude product was further reacted with CDI (224 mg, 1.38 mmol).
After complete transformation, the crude product was purified by
flash chromatography [d = 3 cm, l = 20 cm, V = 25 mL, cyclohex-
ane/EtOAc, 80:20, Rf = 0.33 (cyclohexane/EtOAc, 60:40)]. Color-
less viscous oil; yield 93 mg (50%). C18H25NO (271.4 g/mol). FTIR
Reduction of Lactams 6 and 8. General Procedure C: BH3·THF
complex (1 m in THF, 2 equiv.) was added to lactam 6 or 8
(1 equiv.) dissolved in THF (5 mL) and the mixture was stirred for
16 h at room temp. 1 m NaOH (3ϫ5 mL) was added, the aqueous
layer was extracted with EtOAc (3ϫ10 mL), the organic layers
were dried (Na2SO4), concentrated in vacuo, and the residue was
purified by flash chromatography.
(ATR, film): ν = 2921 (aliphatic C–H), 1631 (C=O) cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 0.67–0.85 (m, 2 H, CH2), 0.95–1.09 (m, 3
H, CH2), 1.14 (d, J = 6.6 Hz, 3 H, CH3), 1.30–1.59 (m, 6 H, CH2),
2.63 (dd, J = 13.6, 7.9 Hz, 1 H, NCH2), 2.84 (dd, J = 15.5, 9.1 Hz,
1 H, 5-H), 3.17 (dd, J = 15.4, 4.5 Hz, 1 H, 5-H), 3.56 (dd, J = 13.6,
6.8 Hz, 1 H, NCH2), 3.66 (d, J = 15.2 Hz, 1 H, 1-H), 3.74–3.84 (m,
1 H, 4-H), 3.89 (d, J = 15.2 Hz, 1 H, 1-H), 6.97–7.26 (m, 4 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.3 (1 C, CH3),
25.8, 25.9, 26.5, 30.6, 30.8 (5 C, CH2), 36.9 (1 C, CH2), 39.9 (1 C,
C-5), 43.9 (1 C, C-1), 52.0 (1 C, CH2), 53.9 (1 C, C-4), 126.9, 127.0,
129.1 (4 C, Ph-CH), 134.6, 136.0 (2 C, Ph-C), 170.5 (1 C,
C=O) ppm. HRMS (ESI): m/z calcd. for C18H25NONa 294.1828;
found 294.1824. Purity (HPLC): 90.0% (tR = 20.7 min).
Synthetic Procedures
Compound 3: Prepared by reaction of o-phenylenediacetic acid with
an excess of methyllithium.[19]
3-Butyl-4-methyl-1,3,4,5-tetrahydro-3-benzazepin-2-one (6a): Fol-
lowing General Procedure A, methyl keto acid
3 (203 mg,
1.10 mmol) was treated with butylamine (108 μL, 1.10 mmol) and
NaBH(OAc)3 (466 mg, 2.20 mmol). The crude product was further
reacted with CDI (356 mg, 2.20 mol). After complete transforma-
tion, the crude product was purified by flash chromatography [d =
3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc, 80:20, Rf = 0.29
(cyclohexane/EtOAc, 60:40)]. Colorless viscous oil; yield 73 mg
(R)-4-Methyl-3-[(R)-1-phenylethyl]-1,3,4,5-tetrahydro-3-benzazepin-
2-one [(Rα-R)-6d] and (S)-4-Methyl-3-[(R)-1-phenylethyl]-1,3,4,5-
tetrahydro-3-benzazepin-2-one [(Rα-S)-6e]: Following the General
Procedure A, methyl keto acid 3 (90 mg, 0.47 mmol) was treated
with (R)-1-phenylethylamine (60 μL, 0.47 mmol) and NaBH(OAc)
3 (199 mg, 0.94 mmol). The crude product was further reacted with
CDI (152 mg, 0.94 mmol). After complete transformation, the
crude product was purified by flash chromatography (d = 3 cm, l
= 20 cm, V = 25 mL, cyclohexane/EtOAc, 80:20).
(30%). C H NO (231.3 g/mol). FTIR (ATR, film): ν = 2957 (ali-
˜
15 21
phatic C–H), 1622 (C=O) cm–1. H NMR (400 MHz, CDCl3): δ =
1
0.79 (t, J = 7.3 Hz, 3 H, CH2CH2CH2CH3), 1.07–1.22 (m, 5 H,
CH2CH2CH2CH3/CH3), 1.32–1.44 (m, 2 H, CH2CH2CH2CH3),
2.86 (dd, J = 15.6, 9.3 Hz, 1 H, 5-H), 2.98 (dt, J = 13.5, 7.6 Hz, 1
H, CH2CH2CH2CH3), 3.14 (dd, J = 15.6, 4.0 Hz, 1 H, 5 H), 3.45
(dt, J = 13.5, 7.5 Hz, 1 H, CH2CH2CH2CH3), 3.63 (d, J = 15.4 Hz,
1 H, 1-H), 3.80–3.90 (m, 1 H, 4-H), 3.94 (d, J = 15.4 Hz, 1 H, 1-
H), 6.94–7.18 (m, 4 H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
(Rα-R)-6d: Colorless viscous oil; yield 52 mg (40%); Rf = 0.36
23
(cyclohexane/EtOAc, 60:40); [α]
= +104.4 (c = 0.12, CH2Cl2).
589
C H NO (279.4 g/mol). FTIR (ATR, film): ν = 2930 (aliphatic
˜
19 21
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
Asymmetric Synthesis of σ1 Receptor Ligands
C–H), 1620 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.30
(d, J = 7.0 Hz, 3 H, CH3), 1.50 (d, J = 7.1 Hz, 3 H, NCHCH3Ph),
2.56 (dd, J = 16.0, 6.0 Hz, 1 H, 5-H), 2.65 (dd, J = 16.0, 6.2 Hz, 1
1), 37.4 (1 C, C-4), 56.4 (1 C, C-2), 126.5, 126.7, 128.6, 128.7 (4 C,
Ph-CH), 138.2, 140.1 (2 C, Ph-C) ppm. HRMS (ESI): m/z calcd.
for C15H23NH 218.1903; found 218.1885. Purity (HPLC): 95.1%
H, 5-H), 3.41–3.52 (m, 1 H, 4-H), 3.71 (d, J = 15.5 Hz, 1 H, 1-H), (tR = 15.5 min).
3.97 (d, J = 15.5 Hz, 1 H, 1-H), 5.90 (q, J = 7.1 Hz, 1 H,
3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (7b):[18] Fol-
NCHCH3Ph), 6.81–7.19 (m, 9 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.9 (1 C, CH3), 22.4 (1 C, NCHCH3Ph), 40.0 (1 C,
C-1), 44.6 (1 C, C-5), 47.1 (1 C, C-4), 52.0 (1 C, NCHCH3Ph),
126.7, 126.8, 127.1, 127.5, 128.2, 129.1, 129.9 (9 C, Ph-CH), 133.4,
135.9, 140.6 (3 C, Ph-C), 171.4 (1 C, C=O) ppm. HRMS (ESI): m/z
calcd. for C19H21NONa 302.1515; found 302.1509. Purity (HPLC):
95.0% (tR = 20.8 min).
lowing the General Procedure C, 6b (35 mg, 0.13 mmol) was re-
duced with BH3·THF complex (1 m in THF, 0.26 mL, 0.26 mmol)
and the crude product was purified by flash chromatography [d =
2 cm, l = 15 cm, V = 10 mL, cyclohexane/EtOAc, 90:10, Rf = 0.56
(cyclohexane/EtOAc, 60:40)]. Colorless viscous oil; yield 14 mg
(40%). C H N (251.4 g/mol). FTIR (ATR, film): ν = 2975 (ali-
˜
18 21
phatic C–H) cm–1. H NMR (400 MHz, CDCl3): δ = 0.76 (d, J =
1
(Rα-S)-6e: Colorless viscous oil; yield 9 mg (5%); Rf = 0.39 (cyclo-
6.7 Hz, 3 H, CH3), 2.50–2.62 (m, 2 H, 1-H/5-H), 2.66–2.76 (m, 2
H, 4-H/5-H), 3.10–3.17 (m, 2 H. 2-H/4-H), 3.30 (d, J = 14.2 Hz, 1
H, 1-H), 3.73 (d, J = 13.8 Hz, 1 H, NCH2Ph), 3.79 (d, J = 13.8 Hz,
1 H, NCH2Ph), 6.89–7.37 (m, 9 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 12.7 (1 C, CH3), 35.8 (1 C, C-5), 41.9 (C-
1), 47.5 (1 C, C-4), 54.2 (1 C, C-2), 59.1 (1 C, NCH2Ph), 126.1,
126.3, 127.0, 128.5, 128.8, 130.3 (9 C, Ph-CH), 139.6, 140.3, 142.3
(3 C, Ph-C) ppm. HRMS (ESI): m/z calcd. for C18H21NH 252.1747;
found 252.1783. Purity (HPLC): 96.6% (tR = 15.4 min).
23
hexane/EtOAc, 60:40); [α]
= +60.7 (c = 0.10, CH2Cl2).
589
C H NO (279.4 g/mol). FTIR (ATR, film): ν = 2971 (aliphatic
˜
19 21
C–H), 1632 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.84
(d, J = 7.0 Hz, 3 H, CH3), 1.39 (d, J = 7.1 Hz, 3 H, NCHCH3Ph),
2.83 (dd, J = 16.2, 5.9 Hz, 1 H, 5-H), 3.17 (dd, J = 16.2, 5.2 Hz, 1
H, 5-H), 3.57–3.70 (m, 1 H, 4-H), 3.75 (d, J = 16.0 Hz, 1 H, 1-H),
4.00 (d, J = 16.0 Hz, 1 H, 1-H), 5.79 (q, J = 7.0 Hz, 1 H,
NCHCH3Ph), 6.91–7.31 (m, 9 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 15.9 (1 C, CH3), 20.4 (1 C, NCHCH3Ph), 40.6 (1 C,
C-1), 44.9 (1 C, C-5), 48.1 (1 C, C-4), 52.8 (1 C, NCHCH3Ph),
126.8, 126.9, 127.3, 127.7, 128.3, 129.7, 130.2 (9 C, Ph-CH), 132.8,
135.5, 140.8 (3 C, Ph-C), 170.8 (1 C, C=O) ppm. HRMS (ESI): m/z
calcd. for C19H21NONa 302.1515; found 302.1512. Purity (HPLC):
90.3% (tR = 20.0 min).
(R)-3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
[(R)-
7b]: A mixture of 3-benzazepine (Rα-R)-7d (48 mg, 0.18 mmol), Pd/
C (10 wt.-%) and methanol (6 mL) was stirred at room temp. under
a H2 atmosphere (balloon) for 4–6 h. The reaction mixture was
filtered using a Celite bed and the solvent was removed under re-
duced pressure to obtain secondary amine (R)-10. The residue was
dissolved in CH3CN (6 mL) and Et3N (124 μL, 0.90 mmol) and
benzyl bromide (107 μL, 0.90 mmol) were added. The mixture was
stirred at room temp. for 2 h, then the reaction mixture was concen-
trated in vacuo and the residue was purified by flash chromatog-
raphy [d = 2 cm, l = 15 cm, V = 10 mL, cyclohexane/EtOAc, 90:10,
(S)-4-Methyl-3-[(S)-1-phenylethyl]-1,3,4,5-tetrahydro-3-benzazepin-
2-one [(Sα-S)-6d] and (R)-4-Methyl-3-[(S)-1-phenylethyl]-1,3,4,5-
tetrahydro-3-benzazepin-2-one [(Sα-R)-6e]: Following the General
Procedure A, methyl keto acid 3 (87 mg, 0.45 mmol) was treated
with (S)-1-phenylethylamine (58 μL, 0.45 mmol) and NaBH-
(OAc)3 (190 mg, 0.90 mmol). The crude product was further re-
acted with CDI (146 mg, 0.90 mmol). After complete transforma-
tion, the crude product was purified by flash chromatography (d =
3 cm, l = 20 cm, V = 25 mL, cyclohexane/EtOAc, 80:20).
Rf = 0.56 (cyclohexane/EtOAc, 60:40)]. Colorless viscous oil; yield
23
21 mg (45%). C18H21N (251.4 g/mol). [α]
= +15.5 (c = 0.30,
589
CH2Cl2). HRMS (ESI): m/z calcd. for C18H21NH 252.1747; found
252.1721. Purity (HPLC): 95.2% (tR = 16.2 min). Chiral HPLC:
Ratio of (R)-7b/(S)-7b = 98.5:1.5 (tR = 11.16 min).
Compound (Sα-S)-6d: Colorless viscous oil; yield 52 mg (40%); Rf
23
= 0.36 (cyclohexane/EtOAc, 60:40); [α]
= –101.1 (c = 0.11,
589
(S)-3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine [(S)-7b]:
As described for (R)-7b, a mixture of 3-benzazepine (Sα-S)-7d (50,
0.19 mmol), Pd/C (10 wt.-%) and methanol (6 mL) was stirred un-
der H2, and subsequently benzylated with benzyl bromide (113 μL,
CH2Cl2). HRMS (ESI): m/z calcd. for C19H21NONa 302.1515;
found 302.1504. Purity (HPLC): 91.0% (tR = 20.8 min). The ana-
lytical and spectroscopic data of (Sα-S)-6d are in accordance with
those of the enantiomer (Rα-R)-6d.
0.95 mmol) and Et3N (132 μL, 0.95 mmol) in CH3CN (6 mL). Col-
23
orless viscous oil; yield 26 mg (55%); [α]
= –17.8 (c = 0.30,
Compound (Sα-R)-6e: Colorless viscous oil; yield 9 mg (5%); Rf =
0.39 (cyclohexane/EtOAc, 60:40); [α]25839 = –59.8 (c = 0.10, CH2Cl2).
HRMS (ESI): m/z calcd. for C19H21NONa 302.1515; found
302.1511. Purity (HPLC): 92.0% (tR = 20.1 min). The analytical
and spectroscopic data of (Sα-R)-6e are in accordance with those
of the enantiomer (Sα-R)-6e.
589
CH2Cl2). HRMS (ESI): m/z calcd. for C18H21NH 252.1747; found
252.1731. Purity (HPLC): 96.0% (tR = 16.0 min). Chiral HPLC:
Ratio of (R)-7b/(S)-7b = 0.5:99.5 (tR = 7.67 min). The analytical
and spectroscopic data of (S)-7b are in accordance with those of
the enantiomer (R)-7b.
3-Butyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (7a): Follow-
ing the General Procedure C, 6a (34 mg, 0.15 mmol) was reduced
with BH3·THF complex (1 m in THF, 0.30 mL, 0.30 mmol) and the
crude product was purified by flash chromatography [d = 2 cm, l
= 10 cm, V = 10 mL, cyclohexane/EtOAc, 90:10, Rf = 0.53 (cyclo-
hexane/EtOAc, 60:40)]. Colorless viscous oil; yield 14 mg (45%).
3-Cyclohexylmethyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(7c): Following the General Procedure C, 6c (60 mg, 0.22 mmol)
was reduced with BH3·THF complex (1 m in THF, 0.44 mL,
0.44 mmol) and the crude product was purified by flash chromatog-
raphy [d = 2 cm, l = 15 cm, V = 10 mL, cyclohexane/EtOAc, 90:10,
Rf = 0.54 (cyclohexane/EtOAc, 60:40)]. Colorless viscous oil; yield
C H N (217.4 g/mol). FTIR (ATR, film): ν = 2960 (aliphatic C–
20 mg (35%). C H N (257.4 g/mol). FTIR (ATR, film): ν = 2918
˜
18 27
˜
15 23
H) cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.69–0.94 (m, 5 H, (aliphatic C–H) cm–1. H NMR (400 MHz, CDCl3): δ = 0.71 (d, J
CH2CH2CH2CH3), 1.13–1.32 (m, 5 H, CH3/CH2CH2CH2CH3), = 6.7 Hz, 3 H, CH3), 0.75–1.83 (m, 11 H, CH2), 2.25–2.34 (m, 2
1.45–1.76 (m, 2 H, CH2CH2CH2CH3), 2.46–2.79 (m, 3 H, 1-H/4- H, NCH2), 2.50–2.60 (m, 2 H, 1-H/5-H), 2.66–2.76 (m, 2 H, 2-H/
H/5-H), 2.85–2.98 (m, 2 H, 4-H/5-H), 3.09–3.24 (m, 1 H, 1-H), 5-H), 2.95–3.05 (m, 2 H, 4-H), 3.20 (d, J = 14.3 Hz, 1 H, 1-H),
1
3.37–3.49 (m, 1 H. 2-H), 6.92–7.12 (m, 4 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): 13.8, 13.9, 20.8, 20.9 (4 C,
CH2CH2CH2CH3), 25.1 (1 C, CH3), 29.7 (1 C, C-5), 31.6 (1 C, C-
6.91–7.06 (m, 4 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.3 (1 C, CH3), 26.2, 26.3, 26.9, 31.9, 32.0 (5 C, CH2), 35.3 (1 C,
CHCH2), 36.4 (1 C, C-5), 41.4 (C-1), 48.4 (1 C, C-4), 54.8 (1 C, C-
δ
=
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
S. Sarkar, D. Schepmann, J. Köhler, R. Fröhlich, B. Wünsch
FULL PAPER
2), 61.2 (1 C, NCH2), 125.8, 126.0, 128.6, 130.0 (4 C, Ph-CH), X-ray Crystal Structure Analysis of (Rα-R)-7d: Formula C19H23N;
134.1, 137.4 (2 C, Ph-C) ppm. HRMS (ESI): m/z calcd. for M = 265.38; colorless crystal, 0.20ϫ0.10ϫ0.05 mm; a = 5.3639(2),
b = 8.4673(4), c = 33.8116(18) Å; V = 1535.65(12) Å3; ρcalc
C18H27NH 258.2216; found 258.2209. Purity (HPLC): 93.5% (tR
17.2 min).
=
=
1.148 gcm–3; μ = 4.940 mm–1; empirical absorption correction
(0.908 Յ T Յ 0.976); Z = 4; orthorhombic; space group P212121
(No. 19); λ = 1.54178 Å; T = 223(2) K, ω and φ scans, 11654 reflec-
tions collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å–1, 2705 indepen-
dent (Rint = 0.049) and 2410 observed reflections [IϾ2σ(I)], 184
refined parameters, R = 0.039, wR2 = 0.092, max. (min.) residual
electron density 0.14 (–0.13)eÅ–3, hydrogen atoms calculated and
refined as riding atoms.
(R)-3-Cyclohexylmethyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benz-
azepine [(R)-7c]: A mixture of 3-benzazepine (Rα-R)-7d (50 mg,
0.19 mmol), Pd/C (10 wt.-%) and methanol (6 mL) was stirred at
room temp. under a H2 atmosphere (balloon) for 4–6 h. The reac-
tion mixture was filtered using a Celite bed and the solvent was
removed under reduced pressure to obtain secondary amine (R)-
10. The residue was dissolved in CH3CN (6 mL) and Et3N (132 μL,
0.95 mmol) and cyclohexylmethyl bromide (131 μL, 0.95 mmol)
were added. The mixture was heated to reflux for 5 h, then the
reaction mixture was concentrated in vacuo and the residue was
purified by flash chromatography [d = 2 cm, l = 15 cm, V = 10 mL,
cyclohexane/EtOAc, 90:10, Rf = 0.54 (cyclohexane/EtOAc, 60:40)].
CCDC-869710 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; Fax: +44(1223)336-033, E-mail: deposit@ccdc.cam.
ac.uk].
Colorless viscous oil; yield 24 mg (50%). C18H27N (257.4 g/mol).
23
[α]
= +1.1 (c = 0.20, CH2Cl2). HRMS (ESI): m/z calcd. for
589
(S)-2-Methyl-3-[(S)-1-phenylethyl]-2,3,4,5-tetrahydro-1H-3-benz-
azepine [(Sα-S)-7d]: Following the General Procedure C, (Sα-S)-6d
(30 mg, 0.11 mmol) was reduced with BH3·THF complex (1 m in
THF, 0.22 mL, 0.22 mmol) and the crude product was purified by
flash chromatography [d = 2 cm, l = 10 cm, V = 10 mL, cyclohex-
C18H27NH 258.2216; found 258.2201. Purity (HPLC): 95.0% (tR
17.3 min).
=
(S)-3-Cyclohexylmethyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazep-
ine [(S)-7c]: As described for (R)-7c, a mixture of 3-benzazepine
(Sα-S)-7d (50 mg, 0.19 mmol), Pd/C (10 wt.-%) and methanol
(6 mL) was stirred under H2, and subsequently alkylated with cy-
clohexylmethyl bromide (131 μL, 0.95 mmol) and Et3N (132 μL,
ane/EtOAc, 90:10, Rf = 0.58 (cyclohexane/EtOAc, 60:40)]. Color-
23
less solid; m.p. 68–70 °C; yield 17 mg (60%); [α]
= –31.0 (c =
589
0.17, CH2Cl2). HRMS (ESI): m/z calcd. for C19H23NH 266.1903;
found 266.1911. Purity (HPLC): 98.7% (tR = 16.4 min). Ratio of
(Rα-R)-7d/(Sα-S)-7d Ͻ 2:98 (tR = 6.29 min). The analytical and
spectroscopic data of (Sα-S)-7d are in accordance with those of the
enantiomer (Rα-R)-7d.
0.95 mmol) in CH3CN (6 mL). Colorless viscous oil; yield 23 mg
23
(48%); [α] = –1.9 (c = 0.20, CH2Cl2). HRMS (ESI): m/z calcd.
589
for C18H27NH 258.2216; found 258.2211. Purity (HPLC): 96.6%
(tR = 17.4 min). The analytical and spectroscopic data of (S)-7c are
in accordance with those of the enantiomer (R)-7c.
(S)-2-Methyl-3-[(R)-1-phenylethyl]-2,3,4,5-tetrahydro-1H-3-benz-
azepine [(Rα-S)-7e]: Following the General Procedure C, (Rα-S)-6e
(30 mg, 0.11 mmol) was reduced with BH3·THF complex (1 m in
THF, 0.22 mL, 0.22 mmol) and the crude product was purified by
flash chromatography [d = 2 cm, l = 10 cm, V = 10 mL, cyclohex-
ane/EtOAc, 90:10, Rf = 0.60 (cyclohexane/EtOAc, 60:40)]. Color-
= +14.0 (c = 0.22,
CH Cl ). C H N (265.4 g/mol). FTIR (ATR, film): ν = 2926 (ali-
˜
2 2 19 23
(R)-2-Methyl-3-[(R)-1-phenylethyl]-2,3,4,5-tetrahydro-1H-3-benz-
azepine [(Rα-R)-7d]: Following the General Procedure C, (Rα-R)-6d
(32 mg, 0.12 mmol) was reduced with BH3·THF complex (1 m in
THF, 0.24 mL, 0.24 mmol) and the crude product was purified by
flash chromatography [d = 2 cm, l = 10 cm, V = 10 mL, cyclohex-
23
less viscous oil; yield 14 mg (50%); [α]
589
ane/EtOAc, 90:10, Rf = 0.58 (cyclohexane/EtOAc, 60:40)]. Color-
23
less solid; m.p. 68–70 °C; yield 18 mg (60%); [α]
= +29.0 (c =
589
phatic C–H) cm–1. H NMR (400 MHz, CDCl3): δ = 0.76 (d, J =
6.8 Hz, 3 H, CH3), 1.38 (d, J = 6.6 Hz, 3 H, NCHCH3Ph), 2.50
(dd, J = 14.3, 6.2 Hz, 1 H, 5-H), 2.56 (dd, J = 14.7, 6.4 Hz, 1 H,
1-H), 2.65–2.75 (m, 1 H, 4-H), 2.92 (dd, J = 12.5, 5.6 Hz, 1 H, 4-
H), 3.13–3.23 (m, 1 H, 5-H), 3.27–3.39 (m, 1 H, 2-H), 3.45 (d, J =
14.7 Hz, 1 H, 1-H), 3.94 (q, J = 6.6 Hz, 1 H, NCHCH3Ph), 6.97–
7.43 (m, 9 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.8
(1 C, CH3), 22.1 (1 C, NCHCH3Ph), 36.3 (1 C, C-5), 42.2 (1 C, C-
1), 42.8 (1 C, C-4), 51.1 (1 C, C-2), 60.6 (1 C, NCHCH3Ph), 126.0,
126.2, 126.8, 127.4, 128.5, 128.7, 130.2 (9 C, Ph-CH), 139.7, 142.3,
146.8 (3 C, Ph-C) ppm. HRMS (ESI): m/z calcd. for C19H23NH,
266.1903; found 266.1895. Purity (HPLC): 97.3% (tR = 16.8 min).
1
0.17, CH Cl ). C H N (265.4 g/mol). FTIR (ATR, film): ν = 2968
˜
2
2
19 23
1
(aliphatic C–H) cm–1. H NMR (400 MHz, CDCl3): δ = 0.73 (d, J
= 6.7 Hz, 3 H, CH3), 1.26 (d, J = 6.6 Hz, 3 H, NCHCH3Ph), 2.39
(dd, J = 14.6, 6.1 Hz, 1 H, 5-H), 2.47 (dd, J = 14.4, 6.1 Hz, 1 H,
1-H), 2.63 (dd, J = 13.3, 11.2 Hz, 1 H, 4-H), 2.81 (dd, J = 13.5,
6.3 Hz, 1 H, 4-H), 3.00 (dd, J = 13.7, 11.5 Hz, 1 H, 5-H), 3.22–
3.30 (m, 1 H, 2-H), 3.39 (d, J = 14.4 Hz, 1 H, 1-H), 3.83 (q, J =
6.6 Hz, 1 H, NCHCH3Ph), 6.90–7.37 (m, 9 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.5 (1 C, CH3), 21.8 (1 C,
NCHCH3Ph), 35.6 (1 C, C-5), 41.5 (1 C, C-1), 44.5 (1 C, C-4), 50.1
(1 C, C-2), 60.7 (1 C, NCHCH3Ph), 126.0, 126.3, 126.8, 127.4,
128.5, 128.6, 130.3 (9 C, Ph-CH), 139.6, 142.6, 147.4 (3 C, Ph-
C) ppm. HRMS (ESI): m/z calcd. for C19H23NH 266.1903; found
266.1897. Purity (HPLC): 99.4% (tR = 16.5 min). Chiral HPLC:
Ratio of (Rα-R)-7d/(Sα-S)-7dϾ 98:2 (tR = 7.35 min).
(R)-2-Methyl-3-[(S)-1-phenylethyl]-2,3,4,5-tetrahydro-1H-3-benz-
azepine [(Sα-R)-7e]: Following the General Procedure C, (Sα-R)-6e
(40 mg, 0.14 mmol) was reduced with BH3·THF complex (1 m in
THF, 0.28 mL, 0.28 mmol) and the crude product was purified by
flash chromatography [d = 2 cm, l = 10 cm, V = 10 mL, cyclohex-
For the X-ray crystal structure analysis, (Rα-R)-7d was recrys-
tallized from CH2Cl2/n-hexane. Data sets were collected with a
Nonius KappaCCD diffractometer. Programs used: data collection,
COLLECT (Nonius B. V., 1998); data reduction Denzo-SMN;[32]
absorption correction, Denzo;[33] structure solution SHELXS-
97;[34] structure refinement SHELXL-97[35] and graphics, XP (Bru-
kerAXS, 2000). Thermal ellipsoids are shown with 50% probability,
R-values are given for observed reflections, and wR2 values are
given for all reflections. The Flack parameter was refined to
–0.1(8).
ane/EtOAc, 90:10, Rf = 0.60 (cyclohexane/EtOAc, 60:40)]. Color-
25
less viscous oil; yield 16 mg (42%); [α]
= –12.3 (c = 0.32,
589
CH2Cl2). HRMS (ESI): m/z calcd. for C19H23NH, 266.1903; found
266.1893. Purity (HPLC): 98.3% (tR = 16.9 min). The analytical
and spectroscopic data of (Sα-R)-7e are in accordance with those
of the enantiomer (Rα-S)-7e.
(1R,4R)-1,4-Dimethyl-3-[(R)-1-phenylethyl]-1,3,4,5-tetrahydro-3-
benzazepin-2-one [(Rα-R,R)-8a]: Following the General Procedure
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
Asymmetric Synthesis of σ1 Receptor Ligands
B, (Rα-R)-6d (68 mg, 0.24 mmol) was alkylated with methyl iodide
(18 μL, 0.29 mmol). The crude product was purified by flash
chromatography [d = 2 cm, l = 20 cm, V = 10 mL, cyclohexane/
(1R,4R)-1,4-Dimethyl-3-[(R)-1-phenylethyl]-2,3,4,5-tetrahydro-1H-
3-benzazepine [(Rα-R,R)-9a]: Following the General Procedure C,
(Rα-R,R)-8a (40 mg, 0.13 mmol) was reduced with BH3·THF com-
plex (1 m in THF, 0.26 mL, 0.26 mmol) and the crude product was
purified by flash chromatography [d = 2 cm, l = 10 cm, V = 10 mL,
EtOAc, 85:15, Rf = 0.46 (cyclohexane/EtOAc, 60:40)]. Colorless
22
solid; m.p. 87–89 °C; yield 36 mg (51%); [α]
= +8.0 (c = 0.4,
589
CH Cl ). C H NO (293.4 g/mol). FTIR (ATR, film): ν = 2928 cyclohexane/EtOAc, 90:10, Rf = 0.59 (cyclohexane/EtOAc, 60:40)].
˜
2
2
20 23
(aliphatic C–H), 1635 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): Colorless solid; m.p. 75–76 °C; yield 30 mg (79%); [α] = +36.2
23
589
δ = 1.39 (d, J = 6.7 Hz, 3 H, CH3), 1.45 (d, J = 7.2 Hz, 3 H, CH3), (c = 0.60, CH Cl ). C H N (279.4 g/mol). FTIR (ATR, film): ν
˜
2
2
20 25
1.57 (d, J = 6.8 Hz, 3 H, CH3), 2.63 (dd, J = 14.8, 7.4 Hz, 1 H, 5-
H), 2.75 (dd, J = 14.8, 9.7 Hz, 1 H, 5-H), 3.28–3.41 (m, 1 H, 4-H), 0.85 (d, J = 6.0 Hz, 3 H, CH3), 1.08 (d, J = 7.1 Hz, 3 H, CH3),
= 2970 (aliphatic C–H) cm–1. 1H NMR (400 MHz, CDCl3): δ =
3.78 (q, J = 6.8 Hz, 1 H, 1-H), 5.75 [q, J = 7.1 Hz, 1 H, NCH(CH3)
Ph], 6.37–7.30 (m, 9 H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 12.4 (1 C, CH3), 17.2 (1 C, CH3), 25.3 (1 C, CH3), 40.9 (1 C,
1.20 (d, J = 6.7 Hz, 3 H, CH3), 2.36 (dd, J = 13.2, 6.9 Hz, 1 H, 5-
H), 2.57 (dd, J = 14.1, 5.5 Hz, 1 H, 2-H), 2.66 (dd, J = 13.2, 4.1 Hz,
1 H, 5-H), 2.70–2.80 (m, 1 H, 1-H), 3.21–3.37 (m, 2 H, 2-H/4-
C-1), 46.9 (1 C, C-5), 48.9 (1 C, C-4), 51.9 [1 C, NCH(CH3)Ph], H), 3.69 [q, J = 7.0 Hz, 1 H, NCH(CH3)Ph], 6.87–7.33 (m, 9 H,
126.5, 126.7, 127.1, 127.2, 128.0, 128.9 (9 C, Ph-CH), 134.8, 137.0,
140.8 (3 C, Ph-C), 174.1 (1 C, C=O) ppm. HRMS (ESI): m/z calcd.
for C20H23NOH 294.1852; found 294.1854. Purity (HPLC): 94.8%
(tR = 21.3 min). GLC: tR = 10.4 min.
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 7.0 (1 C, CH3), 17.2
(2 C, CH3/CH3), 40.2 (1 C, C-1), 41.9 (1 C, C-5), 50.0 (2 C, C-2/
C-4), 59.3 [1 C, NCH(CH3)Ph], 124.6, 125.2, 125.3, 126.4, 126.9,
129.3 (9 C, Ph-CH), 136.9, 144.5, 145.9 (3 C, Ph-C) ppm. HRMS
(ESI): m/z calcd. for C20H25NH 280.2060; found 280.2049. Purity
(HPLC): 95.2% (tR = 18.0 min).
(1S,4S)-1,4-Dimethyl-3-[(S)-1-phenylethyl]-1,3,4,5-tetrahydro-3-
benzazepin-2-one [(Sα-S,S)-8a]: Following the General Procedure B,
(Sα-S)-6d (88 mg, 0.31 mmol) was alkylated with methyl iodide
(23 μL, 0.37 mmol). The crude product was purified by flash
chromatography [d = 2 cm, l = 20 cm, V = 10 mL, cyclohexane/
(1S,4S)-1,4-Dimethyl-3-[(S)-1-phenylethyl]-2,3,4,5-tetrahydro-1H-3-
benzazepine [(Sα-S,S)-9a]: Following the General Procedure C, (Sα-
S,S)-8a (50 mg, 0.17 mmol) was reduced with BH3·THF complex
(1 m in THF, 0.34 mL, 0.34 mmol) and the crude product was puri-
fied by flash chromatography [d = 2 cm, l = 10 cm, V = 10 mL,
cyclohexane/EtOAc, 90:10, Rf = 0.59 (cyclohexane/EtOAc, 60:40)].
Colorless solid; m.p. 75–76 °C; yield 38 mg (79%); [α]25839 = –38.2 (c
= 0.60, CH2Cl2). HRMS (ESI): m/z calcd. for C20H25NH 280.2060;
found 280.2050. Purity (HPLC): 98.9% (tR = 18.2 min). The ana-
lytical and spectroscopic data of (Sα-S,S)-9a are in accordance with
those of the enantiomer (Rα-R,R)-9a.
EtOAc, 85:15, Rf = 0.46 (cyclohexane/EtOAc, 60:40)]. Colorless
22
solid; m.p. 87–89 °C; yield 51 mg (55%); [α]
= –7.5 (c = 1.0,
589
CH2Cl2). HRMS (ESI): m/z calcd. for C20H23NOH 294.1852;
found 294.1855. Purity (HPLC): 97.1% (tR = 21.2 min). The ana-
lytical and spectroscopic data of (Sα-S,S)-8a are in accordance with
those of the enantiomer (Rα-R,R)-8a.
(1R,4R)-1-Ethyl-4-methyl-3-[(R)-1-phenylethyl]-1,3,4,5-tetrahydro-
3-benzazepin-2-one [(Rα-R,R)-8b]: Following the General Procedure
B, (Rα-R)-6d (0.64 mg, 0.23 mmol) was alkylated with ethyl iodide
(22 μL, 0.28 mmol). The crude product was purified by flash
chromatography [d = 2 cm, l = 20 cm, V = 10 mL, cyclohexane/
(1R,4R)-1-Ethyl-4-methyl-3-[(R)-1-phenylethyl]-2,3,4,5-tetrahydro-
1H-3-benzazepine [(Rα-R,R)-9b]: Following the General Procedure
C, (Rα-R,R)-8b (34 mg, 0.11 mmol) was reduced with BH3·THF
complex (1 m in THF, 0.22 mL, 0.22 mmol) and the crude product
was purified by flash chromatography [d = 2 cm, l = 10 cm, V =
EtOAc, 85:15, Rf = 0.54 (cyclohexane/EtOAc, 60:40)]. Colorless
22
viscous oil; yield 42 mg (60%); [α] = +16.8 (c = 0.30, CH2Cl2).
589
C H NO (307.4 g/mol). FTIR (ATR, film): ν = 2966 (aliphatic
10 mL, cyclohexane/EtOAc, 90:10, Rf = 0.64 (cyclohexane/EtOAc,
˜
21 25
C–H), 1641 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.02 (t,
60:40)]. Colorless viscous oil; yield 18 mg (56%); [α] = +40.4 (c
23
589
J = 7.3 Hz, 3 H, CH2CH3), 1.41 (d, J = 6.7 Hz, 3 H, CH3), 1.46 = 0.18, CH Cl ). C H N (293.5 g/mol). FTIR (ATR, film): ν =
˜
2
2
21 27
1
(d, J = 7.2 Hz, 3 H, CH3), 1.85–1.96 (m, 1 H, CH2CH3), 2.34–2.46 2968 (aliphatic C–H) cm–1. H NMR (400 MHz, CDCl3): δ = 0.59
(m, 1 H, CH2CH3), 2.63 (dd, J = 14.8, 7.2 Hz, 1 H, 5-H), 2.75 (dd, (t, J = 7.4 Hz, 3 H, CH2CH3), 0.77 (d, J = 5.7 Hz, 3 H, CH3), 1.22
J = 14.8, 9.9 Hz, 1 H, 5-H), 3.30–3.40 (m, 1 H, 4-H), 3.49 (dd, J (d, J = 6.7 Hz, 3 H, CH3), 1.41–1.56 (m, 1 H, CH2CH3), 1.62–1.78
= 8.3, 5.9 Hz, 1 H, 1-H), 5.79 [q, J = 7.1 Hz, 1 H, NCH(CH3)Ph], (m, 1 H, CH2CH3), 2.33–2.57 (m, 3 H, 1-H/2-H/5-H), 2.68 (dd, J
6.38–7.23 (m, 9 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = = 13.1, 3.4 Hz, 1 H, 5-H), 3.24–3.41 (m, 2 H, 2-H/4-H), 3.65 [q, J
12.9 (1 C, CH2CH3), 17.5 (1 C, CH3), 20.3 (1 C, CH2CH3), 25.3 (1
= 7.0 Hz, 1 H, NCH(CH3)Ph], 6.83–7.84 (m, 9 H, ArH) ppm. 13C
C, CH3), 41.1 (1 C, C-1), 47.0 (1 C, C-5), 50.0 (1 C, C-4), 51.7 [1 NMR (100 MHz, CDCl3): δ = 12.7 (2 C, CH2CH3/CH3), 24.4 (2
C, NCH(CH3)Ph], 123.4, 126.6, 126.9, 127.3, 127.4, 128.2, 129.2 (9
C, Ph-CH), 137.4, 140.3, 140.9 (3 C, Ph-C), 173.6 (1 C, C=O) ppm.
HRMS (ESI): m/z calcd. for C21H25NOH 308.2009; found
C, CH2CH3/CH3), 43.0 (1 C, C-1), 49.4 (2 C, C-2/C-5), 50.6 (1 C,
C-4), 61.1 [1 C, NCH(CH3)Ph], 124.6, 125.2, 125.3, 126.4, 126.9,
129.3 (9 C, Ph-CH), 136.9, 144.5, 145.9 (3 C, Ph-C).HRMS (ESI):
m/z calcd. for C21H27NH 294.2216; found 294.2207. Purity
(HPLC): 95.0% (tR = 19.1 min).
308.2006. Purity (HPLC): 90.4 % (tR = 21.6 min). GLC: tR
=
10.5 min.
(1S,4S)-1-Ethyl-4-methyl-3-[(S)-1-phenylethyl]-1,3,4,5-tetrahydro-3-
benzazepin-2-one [(Sα-S,S)-8b]: Following the General Procedure B,
(1S,4S)-1-Ethyl-4-methyl-3-[(S)-1-phenylethyl]-2,3,4,5-tetrahydro-
1H-3-benzazepine [(Sα-S,S)-9b]: Following the General Procedure
(Sα-S)-6d (92 mg, 0.33 mmol) was alkylated with ethyl iodide C, (Sα-S,S)-8b (65 mg, 0.21 mmol) was reduced with BH3·THF
(32 μL, 0.40 mmol). The crude product was purified by flash
chromatography [d = 2 cm, l = 20 cm, V = 10 mL, cyclohexane/
complex (1 m in THF, 0.42 mL, 0.42 mmol) and the crude product
was purified by flash chromatography [d = 2 cm, l = 10 cm, V =
EtOAc, 85:15, Rf = 0.54 (cyclohexane/EtOAc, 60:40)]. Colorless
10 mL, cyclohexane/EtOAc, 90:10, Rf = 0.64 (cyclohexane/EtOAc,
22
23
viscous oil; yield 77 mg (76%); [α] = –15.4 (c = 0.30, CH2Cl2).
60:40)]. Colorless viscous oil; yield 40 mg (65%); [α] = –41.7 (c
589
589
HRMS (ESI): m/z calcd. for C21H25NOH 308.2009; found
308.2008. Purity (HPLC): 96.8% (tR = 22.0 min). The analytical
and spectroscopic data of (Sα-S,S)-8b are in accordance with those
of the enantiomer (Rα-R,R)-8b.
= 0.20, CH2Cl2). HRMS (ESI): m/z calcd. for C21H27NH 294.2216;
found 294.2201. Purity (HPLC): 97.2% (tR = 18.6 min). The ana-
lytical and spectroscopic data of (Sα-S,S)-9b are in accordance with
those of the enantiomer (Rα-R,R)-9b.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
S. Sarkar, D. Schepmann, J. Köhler, R. Fröhlich, B. Wünsch
FULL PAPER
(1R,4R)-3-Benzyl-1-ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benz-
azepine [(R,R)-12]: A mixture of 3-benzazepine (Rα-R,R)-9b
(35 mg, 0.12 mmol), Pd/C (10 wt.-%) and methanol (6 mL) was
stirred at room temp. under a H2 atmosphere (balloon) for 4–6 h.
The reaction mixture was filtered using a Celite bed and the solvent
was removed under reduced pressure to obtain secondary amine
(R,R)-11. The residue was dissolved in CH3CN (6 mL) and Et3N
(83 μL, 0.60 mmol) and benzyl bromide (71 μL, 0.60 mmol) were
added. The mixture was stirred at room temp. for 2 h, then the
reaction mixture was concentrated in vacuo and the residue was
purified by flash chromatography [d = 2 cm, l = 15 cm, V = 10 mL,
as standard, and subsequently the preparation was frozen (–80 °C)
in 1.5 mL portions containing about 1.5 mg protein/mL.
The σ1 Assay:[26–28] The test was performed with the radioligand
[3H]-(+)-pentazocine (42.5 Ci/mmol; Perkin–Elmer). The thawed
membrane preparation (about 75 μg of the protein) was incubated
with various concentrations of test compounds, 2 nm [3H]-(+)-pen-
tazocine, and buffer (50 mm TRIS, pH 7.4) in a total volume of
200 μL for 180 min at 37 °C. The incubation was terminated by
rapid filtration through the presoaked filtermats by using the cell
harvester. After washing each well five times with 300 μL of water,
the filtermats were dried at 95 °C. Subsequently, the solid scintil-
lator was put on the filtermat and melted at 95 °C. After 5 min,
the solid scintillator was allowed to solidify at room temp. The
bound radioactivity trapped on the filters was counted in the scin-
tillation analyzer. The nonspecific binding was determined with 10
μm unlabeled (+)-pentazocine. The Kd value of the radioligand
[3H]-(+)-pentazocine is 2.9 nm.[37]
cyclohexane/EtOAc, 90:10, Rf = 0.63 (cyclohexane/EtOAc, 60:40)].
23
Colorless viscous oil; yield 14 mg (42%); [α] = +17.3 (c = 0.20,
589
CH Cl ). C H N (279.4 g/mol). FTIR (ATR, film): ν = 2957 (ali-
˜
2
2
20 25
1
phatic C–H) cm–1. H NMR (400 MHz, CDCl3): δ = 0.69 (t, J =
7.3 Hz, 3 H, CH3), 0.79 (d, J = 3.7 Hz, 3 H, CH3), 1.63–1.82 (m,
2 H, CH2CH3), 2.42–2.58 (m, 3 H, 2-H/5-H), 2.76–2.86 (m, 1 H,
1-H), 3.03–3.14 (m, 1 H, 4-H), 3.36 (d, J = 12.7 Hz, 1 H, 5-H),
3.62 (d, J = 13.2 Hz, 1 H, NCH2Ph), 3.52 (d, J = 13.2 Hz, 1 H,
NCH2Ph), 6.81–7.40 (m, 9 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 12.9 (2 C, CH3), 24.4 (1 C, CH2CH3), 43.0 (1 C, C-2/
C-5), 51.2 (1 C, C-1), 54.7 (1 C, C-4), 60.9 (1 C, NCH2Ph), 126.0,
126.2, 126.9, 128.3, 128.9, 131.1 (9 C, Ph-CH), 138.3, 140.9, 144.6
(3 C, Ph-C) ppm. HRMS (ESI): m/z calcd. for C20H25NH 280.2060;
found 280.2061. Purity (HPLC): 95.1% (tR = 18.5 min).
Membrane Preparation for the σ2 Assay:[24–28] Two rat livers were
cut into small pieces and homogenized with a potter (500–800 rpm,
10 up-and-down strokes) in 6 volumes of cold 0.32 m sucrose. The
suspension was centrifuged at 1200 g for 10 min at 4 °C. The super-
natant was separated and centrifuged at 31000 g for 20 min at 4 °C.
The pellet was resuspended in buffer (50 mm TRIS, pH 8.0) and
incubated at room temp. for 30 min. After the incubation, the sus-
pension was centrifuged again at 31000 g for 20 min at 4 °C. The
final pellet was resuspended in buffer, the protein concentration
was determined according to the method of Bradford[36] using bo-
vine serum albumin as standard, and subsequently the preparation
was frozen (–80 °C) in 1.5 mL portions containing about 2 mg pro-
tein/mL.
(1S,4S)-3-Benzyl-1-ethyl-4-methyl-2,3,4,5-tetrahydro-1H-3-benz-
azepine [(S,S)-12]: As described for (R,R)-12b, a mixture of 3-
benzazepine (Sα-S,S)-9b (40 mg, 0.14 mmol), Pd/C (10 wt.-%) and
methanol (6 mL) was stirred under H2, and the resulting secondary
amine (S,S)-11 was benzylated with benzyl bromide (83 μL,
0.70 mmol) and Et3N (97 μL, 0.70 mmol) in CH3CN (6 mL). Col-
23
The σ2 Assay:[26–28] The test was performed with the radioligand
[3H]-di-o-tolylguanidine (50 Ci/mmol; ARC). The thawed mem-
brane preparation (about 100 μg of the protein) was incubated with
various concentrations of test compounds, 3 nm [3H]-di-o-tolyl-
guanidine, 500 nm (+)-pentazocine and buffer (50 mm TRIS, pH
8.0) in a total volume of 200 μL for 180 min at room temp. The
incubation was terminated by rapid filtration through the pre-
soaked filtermats using a cell harvester. After washing each well
five times with 300 μL of water, the filtermats were dried at 95 °C.
Subsequently, the solid scintillator was put on the filtermat and
melted at 95 °C. After 5 min, the solid scintillator was allowed to
solidify at room temp. The bound radioactivity trapped on the fil-
ters was counted in the scintillation analyzer. The nonspecific bind-
ing was determined with 10 μm unlabeled ditolylguanidine. The Kd
value of the radioligand [3H]-ditolylguanidine is 17.9 nm.[38]
orless viscous oil; yield 20 mg (53%); [α]
= –19.8 (c = 0.60,
589
CH2Cl2). HRMS (ESI): m/z calcd. for C20H25NH 280.2060; found
280.2091. Purity (HPLC): 95.7% (tR = 18.4 min). The analytical
and spectroscopic data of (S,S)-12 are in accordance with those of
the enantiomer (R,R)-12.
Receptor Binding Studies
Materials and General Procedures: Guinea pig brains and rat livers
were commercially available (Harlan–Winkelmann, Germany). Ho-
mogenizer: Elvehjem Potter (B. Braun Biotech International). Cen-
trifuge: High-speed cooling centrifuge model Sorvall RC-5C plus
(Thermo Finnigan). Filter: Printed Filtermat Type A (Perkin–El-
mer), presoaked in 0.5% aqueous polyethylenimine for 2 h at room
temp. before use. The filtration was carried out with a MicroBeta
FilterMate-96 Harvester (Perkin–Elmer). The scintillation analysis
was performed using Meltilex (Type A) solid scintillator (Perkin–
Elmer). The solid scintillator was melted on the filtermat at a tem-
perature of 95 °C for 5 min. After solidification of the scintillator
at room temp., the scintillation was measured using a MicroBeta
Trilux scintillation analyzer (Perkin–Elmer). The overall counting
efficiency was 20%.
Determination of the Affinity to the Phencyclidine Binding Site of
the NMDA Receptor: The preparation of the membranes from pig
brain cortex and the performance of the assay with [3H]-MK-801
were done according to the literature.[31]
Data Analysis: Typically, all experiments were carried out in tripli-
cate using standard 96-well-multiplates (Diagonal). The IC50 values
were determined in competition experiments with six concentra-
tions of the test compounds and were calculated with the program
GraphPad Prism 3.0 (GraphPad Software) by nonlinear regression
analysis. The Ki values were calculated according to Cheng and
Prusoff.[39] The Ki values are given as mean values ϮSEM from
three independent experiments.
Membrane Preparation for the σ1 Assay:[24–28] Five guinea pig
brains were homogenized with the potter (500–800 rpm, 10 up-and-
down strokes) in 6 volumes of cold 0.32 m sucrose. The suspension
was centrifuged at 1200ϫ g for 10 min at 4 °C. The supernatant
was separated and centrifuged at 23500ϫ g for 20 min at 4 °C.
The pellet was resuspended in 5–6 volumes of buffer (50 mm TRIS,
pH 7.4) and centrifuged again at 23500 g (20 min, 4 °C). This pro-
cedure was repeated twice. The final pellet was resuspended in 5–6
volumes of buffer, the protein concentration was determined ac-
cording to the method of Bradford[36] using bovine serum albumin
Supporting Information (see footnote on the first page of this arti-
1
cle): H, 13C NMR and NOE difference spectra of the newly syn-
thesized compounds.
10
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Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
Asymmetric Synthesis of σ1 Receptor Ligands
[18] S. Sarkar, S. M. Husain, D. Schepmann, R. Fröhlich, B.
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We wish to thank the NRW Graduate School of Chemistry for a
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Nordrhein-Westfalen (NRW) and the Westfälische Wilhelms-Uni-
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Received: July 13, 2012
Published Online: ᭿
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11

Job/Unit: O20927
/KAP1
Date: 11-09-12 16:47:11
Pages: 12
S. Sarkar, D. Schepmann, J. Köhler, R. Fröhlich, B. Wünsch
FULL PAPER
Asymmetric Synthesis
S. Sarkar, D. Schepmann, J. Köhler,
R. Fröhlich, B. Wünsch* ................. 1–12
Asymmetric Synthesis of Potent and Selec-
tive σ1 Receptor Ligands with Tetrahydro-
3-benzazepine Scaffold
The key step in the synthesis of enantio-
merically pure tetrahydro-3-benzazepines is
the diastereoselective, consecutive, three-
step transformation of keto acids into lact-
ams. Relationships between the structure
and the σ1 affinity are elaborated.
Keywords: Drug discovery / Reduction /
Amination / Asymmetric synthesis / Dia-
stereoselectivity / Receptors
12
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0