Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80

Article abstract of DOI:10.1002/ardp.200400994

In order to find novel δ opioid receptor agonists, the pharmacophoric benzhydryl moiety of the lead compound SNC 80 (1) was dissected and the phenyl residues were attached to different positions of the 6,8-diazabicyclo[3.2.2] nonane core system (4). The position of the carboxamido group, the stereochemistry, the C3/C4 bond order and the kind and length of the spacer X were considered. The resulting compounds were compared with the four energetically most favourable conformations of SNC 80 by a multifit analysis. These calculations led to the structures 5-10, which fit best to SNC 80. Herein the synthesis of one of these compounds (9) is described. Starting from (S)-glutamate two alternative routes are detailed to obtain the key intermediate 14. A variation of the Dieckmann cyclization, which uses trapping of the first cyclization product with ClSiMe₃ provided the mixed acetal 20, which was carefully hydrolyzed to yield the bicyclic ketone 17. Stereoselective addition of phenylmagnesium bromide, dehydration, LiAlH₄ reduction and exchange of the N-6 residue afforded the designed compound 9. The affinities of 9 towards δ, μ, κ and ORL1 receptors were determined in receptor binding studies with radioligands. Only moderate receptor affinity was found.

Full text of DOI:10.1002/ardp.200400994

Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
DOI 10.1002/ardp.200400994
281
Molecular modeling directed synthesis of a bicyclic
analogue of the δ opioid receptor agonist SNC 80
Bettina Junga, Werner Englbergerb, and Bernhard Wünscha
a Institut für Pharmazeutische und Medizinische Chemie, Münster, Germany
b Grünenthal GmbH, Aachen, Germany
In order to find novel δ opioid receptor agonists, the pharmacophoric benzhydryl moiety of the lead
compound SNC 80 (1) was dissected and the phenyl residues were attached to different positions
of the 6,8-diazabicyclo[3.2.2]nonane core system (4). The position of the carboxamido group, the
stereochemistry, the C3/C4 bond order and the kind and length of the spacer X were considered. The
resulting compounds were compared with the four energetically most favourable conformations of
SNC 80 by a multifit analysis. These calculations led to the structures 5-10, which fit best to SNC 80.
Herein the synthesis of one of these compounds (9) is described. Starting from (S)-glutamate two
alternative routes are detailed to obtain the key intermediate 14. A variation of the Dieckmann cycliza-
tion, which uses trapping of the first cyclization product with ClSiMe3 provided the mixed acetal 20,
which was carefully hydrolyzed to yield the bicyclic ketone 17. Stereoselective addition of phenylmag-
nesium bromide, dehydration, LiAlH4 reduction and exchange of the N-6 residue afforded the designed
compound 9. The affinities of 9 towards δ, μ, κ and ORL1 receptors were determined in receptor
binding studies with radioligands. Only moderate receptor affinity was found.
Keywords: δ receptor agonists; ligand based molecular modeling; multifit analysis; bridged piperazines;
bicyclic SNC 80 analogues; Dieckmann cyclization
Received: October 15, 2004; Accepted: February 1, 2005 [FP994]
Introduction
in animal models and in man but their clinical use is limited
by strong diuresis, dysphoria and sedation [3, 4].
Strong analgesics (i.e. morphine) mediate their effects by
activating opioid receptors, which belong to the superfamily
of G-protein coupled receptors (GPR). They transmit their
information via Gi proteins inhibiting adenylyl cyclase,
opening Kϩ channels and closing Ca2ϩ channels. In the last
three decades the opioid receptor class has been subdivided
into three different subtypes named μ (MOP), κ (KOP) and
δ (DOP)opioid receptor. The recently identified ORL1 re-
ceptor (NOP) is also classified in the opioid receptor family.
The amino acid sequence of the ORL1 receptor is about
60% homologous to that of the μ, κ and δ receptors and
about 80% homologous in the 2nd, 3rd and 7th transmem-
brane domains [1]. However, nociceptin the endogenous
agonist of the ORL1 receptor induces hyperalgesia instead
of analgesia [2].
δ agonists also induce strong analgesia with no or little lia-
bility to induce the typical side effects of μ and κ agonists.
Moreover, they potentiate the analgesic effect of morphine
in subanalgesic doses [3]. Because of their antinociceptive
potency and the lack of side effects δ agonists are con-
sidered as safe analgesics [3,4]. In addition to their analgesic
activity δ agonists possess further pharmacological effects
e.g. immunoregulatory properties, antisecretory activity in
bronchial diseases and gastroprotective effects [4].
In literature some highly potent and selective non-peptide δ
agonists have been described. They are subdivided into
three major types: morphine derived compounds (e.g.
SIOM) isoquinoline derivatives (e.g. TAN 67) and pipera-
zine based compounds (e.g. SNC 80 (1), BW 373U86 (2))
[3, 4]. Intensive structure activity relationship studies based
on SNC 80 (1) showed that the carboxamido moiety [3]
and a cyclic amine [5] are required for strong δ receptor
interaction. Removal of the piperazine methyl groups de-
creased the δ receptor affinity [6] and replacement of the N-
allyl moiety by a proton or by alkyl or other alkenyl residues
resulted in less potent δ agonists [6].
The opioid analgesics used in clinical practice activate pre-
dominantly the μ receptor. However, their strong analgesic
activity is associated with undesirable side effects including
respiratory depression, physical dependency and consti-
pation. High affinity κ agonists also display analgesic effects
Correspondence: Bernhard Wünsch, Institut für Pharmazeutische
und Medizinische Chemie, Hittorfstrasse 58-62, 48149 Münster,
Germany. Phone: ϩ49 251 8333311, Fax: ϩ49 251 32144, e-mail:
wuensch@uni-muenster.de
In order to develop novel δ agonists derived from the
piperazine derivative SNC 80 (1) we replaced the mono-
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

282
Wünsch et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
cyclic piperazine ring by the conformationally restricted di-
azabicyclo [3.2.2]nonane system as shown in structure 4.
The benzhydryl moiety should be imitated by two separated
phenyl residues attached to different ring positions of the
bicyclic core system. The propano bridge of the bicyclic sys-
tem represents the methyl groups of SNC 80 (1). Several
variations of the bicyclic structure were considered: The po-
sition of the carboxamido group, the stereochemistry, the
binding order of the C3/C4 bond and the kind and the
length of the spacer X. Ligand based molecular modeling
should provide an idea, which of the possible variations
might have similar steric and electronic properties as 1.
lic compounds 4 were compared with SNC 80 (1). In order
to find energetically favorable conformations of the flexible
benzhydryl moiety of SNC 80 (1), a systematic confor-
mational analysis was performed. For this purpose, the
bonds indicated with a) and b) of 1 in Figure 1 were rotated
by increments of 30° and the resulting conformations were
minimized and filtered to select the nonrepetitive confor-
mations. The bond c) of the remaining eight conformations
was rotated by an increment of 10° and after minimizing
and filtering the resulting 12 conformations were ranked
according to their energy. These conformations were grouped
into four families (see Table 1) using the family option.
The conformation 4 (family 2) corresponds to the crystal
structure of the fluoro derivative 3 [7]. In Figure 2 the simi-
larity of conformation 4 of SNC 80 and the crystal structure
of the fluoro derivative 3 is shown.
Results
Molecular modeling
We assume that similarity of novel compounds to the lead
compound SNC 80 (1) corresponds with high δ receptor
affinity. Therefore in a molecular modeling study the bicyc-
Table 1. Calculated conformations of SNC 80 (1).
Conformation
Energy
[kcal/mol]
Family
1
2
3
4
5
6
7
8
9
15.7
16.1
16.4
17.5
18.5
19.1
19.3
19.5
20.1
21.0
21.3
21.5
1
1
1
2
3
3
3
3
3
4
4
4
10
11
12
Figure 1. Lead compounds 1Ϫ3 and designed bicyclic δ ago-
nists 4.
Figure 2. Conformation 4 of SNC 80 (1) (left) and the crystal structure of 3 (right).
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
A bicyclic analogue of δ opioid receptor agonist SNC 80
283
The conformations with the lowest energy (conformations
1-4 ϭ family 1,2) were chosen as templates and were com-
pared with the planned bicyclic analogues 4 by multifit
analysis that combines an atom-by-atom superposition with
an energy minimization [8]. The pharmacophoric elements
carboxamido moiety, allyl residue, the centroids of the
phenyl residues and both piperazine nitrogen atomes were
used as atom pairs for the superposition. The corresponding
superposed anchoring points of the lead compound SNC
80 (1) and the synthesized compound 9 are demonstrated
in Figure 3.
Therefore it represents the quality of the fit: the lower the
energy the better the fit. Careful analysis of the multifit en-
ergies of more than 100 superpositions led to the following
general rules:
1. Compounds with the N,N-diethylcarbamoylbenzyl resi-
due at the nitrogen atom generally revealed lower multifit
energies than the analogues with this residue in position 4.
The six compounds among this group with the lowest multi-
fit energy are shown in Table 2.
2. The most favorable configuration is (1S,4S,5R) for the 2-
benzyloxy derivatives (5, Xϭ CH2O) and (1S,4R,5S) for the
2-phenyl (7, X ϭ bond) and 2-benzyl derivatives (10, X ϭ
CH2). However, the enantiomers 6 and 8 of these com-
pounds do also give low multifit energies. The best configu-
ration for compounds with a C3/C4 double bond is (1S,5S)
(compound 9).
The superposition of the molecules was analyzed by calcu-
lating the multifit energy. The multifit energy is the energy
that is necessary to adjust two molecules to each other.
3. The benzyl derivatives (e.g. 10) yielded the highest multi-
fit energies in this group indicating low correlation with
SNC 80 (1).
The multifit energy of 112 calculated superpositions ranged
from 1.1 kcal/mol to 18.1 kcal/mol. Therefore, it was postu-
lated that the compounds in Table 2 represent good corre-
lates to the lead structure SNC 80 (1) displaying similar
pharmacological activities.
We started the project with the synthesis and pharmacologi-
cal evaluation of compound 9. Since 9 possesses a double
bond between C3 and C4, stereoisomers at C4 are not to be
Figure 3. Pharmacophoric elements.
Table 2. Ten superpositions with low multifit energy.
Compound
Fit on conformation
(Table 1)
Spacer
X
Configuration
C3/C4 bond
order
Multifit-energy
[kcal/mol]
5
6
2
4
4
4
4
1
3
1
2
4
-CH2O-
bond
bond
-CH2O-
bond
bond
-CH2O-
-CH2-
-CH2-
-CH2-
1S, 4S, 5R
1R, 4S, 5R
1S, 4R, 5S
1R, 4R, 5S
1S, 5S
1S, 4R, 5S
1S, 4S, 5R
1S, 4R, 5S
1S, 4R, 5S
1S, 4R, 5S
single
“
“
“
double
single
1.1
1.4
2.0
2.2
2.4
2.7
3.2
3.4
3.7
3.7
7
8
9
7
5
“
“
“
“
10
10
10
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

284
Wünsch et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
considered. The multifit energy of 2.4 kcal/mol resulting
from the superposition of 9 with conformation 4 of SNC 80
(1), which is shown in Figure 4, indicates a quite good corre-
lation.
Chemistry
The synthesis of the 6,8-diazabicyclononane 9 started with
the proteinogenic amino acid (S)-glutamate (11). (Scheme
1) Esterification of (S)-glutamate with methanol and chloro-
trimethylsilane (TMSCl) [9] furnished the dimethyl ester
12·HCl [10,11]. A one-pot reaction [12,13] comprising al-
lylation and subsequent chloroacetylation of the amino
moiety of 12 gave the N-allylchloroacetamide 13 only in
poor yields (25%). The reaction of 13 with 4-methoxyben-
zylamine combines a SN2 substitution with an intramolecu-
lar aminolysis leading to the monocyclic piperazinedione 14
in 17% yield over three steps from (S)-glutamate.
In order to improve the yield the reaction sequence was
changed: Chloroacetylation of 12·HCl followed by reaction
of the formed chloroacetamide 15 with 4-methoxybenzyl-
amine gave the piperazinedione 16, which was allylated
whith NaHMDS and allyl bromide to furnish the piperazi-
nedione 14 in 42% yield over 4 steps from (S)-glutamate
(Scheme 2).
A
Dieckmann analogous cyclization (Scheme 3) was
planned as the next step of the synthesis of the bicyclic scaf-
fold 17. However, reaction of 14 with LiHMDS or LDA
failed to give the bicyclic ketone 17. Surprisingly, the reac-
tion of 14 with phenylmagnesium bromide led to the bicyclic
ketone in 10% yield and the allyl derivative 18 (15%) which
results from a [3,3]-sigmatropic rearrangement. Careful
1
analysis of the H NMR spectrum of the LDA experiment
proved, that 18 had also been formed in this experiment.
Finally, the cyclization was successfully performed by trap-
ping of the intermediate product 19 formed by depro-
tonation with LiHMDS with chlorotrimethylsilane to fur-
nish the mixed methyl/silyl acetal 20 [14] that was carefully
hydrolyzed to obtain the ketone 17 in 88% yield.
Figure 4. Superposition of compound 9 (dark gray) with con-
formation 4 (gray) of SNC 80 (1).
Scheme 1. Synthesis of methyl 3-(dioxopiperazin-2-yl)propionate 14.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
A bicyclic analogue of δ opioid receptor agonist SNC 80
285
Scheme 2. Improved synthesis of 14.
Scheme 3. Dieckmann cyclization of 14 to afford 17.
The phenyl residue was introduced by a diastereoselective
Grignard reaction of the ketone 17 with phenylmagnesium
bromide (Scheme 4). The (2S)-configuration of the gener-
ated center of chirality was determined by a positive NOE
between the phenyl residue and one proton of the benzyl
CH2-moiety. Dehydratation of the tertiary alcohol 21 with
diphosphorpentoxide yielded the alkene 22.
(25) to yield the target compound 9. The building block
25 was synthesized by reaction of 4-(chloromethyl)benzoyl
chloride with diethylamine [16].
Receptor binding studies
The affinity of the bridged piperazine 9 towards δ, μ, κ, and
ORL1 receptors was investigated in receptor binding studies
using tritiated deltorphine II (δ), naloxone (μ), Cl-977 (κ),
and nociceptin (ORL1) as radioligands. CHO-K 1 cell lines
expressing the corresponding human opioid receptors were
employed as receptor material. The results of the receptor
binding studies are summarized in Table 3. At a test concen-
Reaction of the bicyclic piperazinedione 22 with LiAlH4 led
to reduction of both lactam carbonyl moieties to give 23.
Removal of the N-(4-methoxybenzyl) protective group with
CF3COOH [15] provided the secondary amine 24, which
was alkylated with 4-(chloromethyl)-N,N-diethylbenzamide
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

286
Wünsch et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
Scheme 4. Synthesis route to 9.
tration of 10 μM compound 9 shows less than 20% inhi-
bition of radioligand binding at δ, κ and ORL1 receptors.
Only moderate affinity toward μ receptors (Ki ϭ 6.18 μM)
was found.
rotational flexibility of the carbamoylbenzyl moiety. We as-
sume that the combination of enhanced conformational
flexibility of the N-6 benzyl residue with reduced confor-
mational flexibility of the C-4 phenyl residue is responsible
for low δ receptor interaction. Obviously, the pharmaco-
phoric phenyl residues cannot adopt an arrangement, which
imitates the benzhydryl moiety at the δ opioid receptor.
Table 3. Affinity of compound 9 towards δ, μ, κ, and ORL1
receptors.
Acknowledgments
Assay
Receptor affinity of compound 9
Financial support of this work by the Fonds der Chemi-
schen Industrie is gratefully acknowledged. Thanks are also
due to the Degussa AG for donation of chemicals.
δ (DOP)
15.2%†
([3H]-deltorphine II)
μ (MOP)
Ki ϭ 6.18 μM
15.3%†
([3H]-naloxone)
Experimental
Molecular modeling
κ (KOP)
([3H]-ClϪ977)
The molecular modeling studies were performed with Sybyl 6.8.ver-
sion of Tripos® on a silicon graphics IRIS workstation. All mol-
ecules were geometry optimized in vacuo (ε ϭ 1) with the im-
plemented Tripos force field using the quasi Newton algorithm
BFGS until the convergence criterion of 0.05 kcal//mol change in
energy between successive iterations was reached. The charges were
calculated by the Gasteiger Hückel method and the non bond inter-
ORL1 (NOP)
9.3%†
([3H]-nociceptin)
†
inhibition at a concentration of 10 μM of 9.
˚
action cut off was set at 50 A. For the conformational analysis we
Discussion
used the tool grid search. Multifit analyses were performed by the
˚
program multifit and with a spring constant of 2 kcal/mol·A.
Molecular modeling studies have demonstrated structural
similarity of the novel bicyclic piperazine 9 with the highly
potent δ agonist SNC 80 (1). After synthesis of 9 receptor
binding studies have revealed only moderate δ receptor af-
finity.
Chemistry
General
Thin layer chromatography (tlc): Silica gel 60 F254 plates (Merck).
Flash column chromatography (fc)[17]: Silica gel 60, 0.040Ϫ0.063
mm (Merck); parentheses include: Diameter of the column [cm],
eluent, fraction size [mL], Rf. Melting points: Melting point appa-
ratus SMP 3 (Stuart Scientific), uncorrected. Optical rotation:
Polarimeter 341 (Perkin Elmer); 1.0-dm tube; concentration
c [g/100 mL]; temperature 20°C. Elemental analyses: Vario EL
(Elementaranalysesysteme GmbH). MS: MAT GCQ (Thermo-
In the lead structure SNC 80 (1) the phenyl residues are
connected in a benzhydryl moiety. Compared with SNC 80
the conformational freedom of the phenyl residue in positon
4 of 9 is restricted by attachment to an sp2 hybridized car-
bon atom and the single bonds of the N-6 residue lead to
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
A bicyclic analogue of δ opioid receptor agonist SNC 80
287
Finnigan); TSQ 7000 (Thermo-Finnigan); LCQ MAT (Thermo
Finnigan); EI ϭ electron impact; CI ϭ chemical ionization, ESI ϭ
electrospray ionisation. IR: IR spectrophotometer 480Plus FT-
ATR-IR (Jasco). 1H NMR (400 MHz), 13C NMR (100 MHz):
Unity Mercury Plus 400 NMR spectrometer (Varian); δ in ppm
related to tetramethylsilane, coupling constants are given with
0.5 Hz resolution; the assignments of 13C and 1H NMR signals
were supported by 2D NMR techniques. HPLC: L-6200A
Intelligent pump Merck Hitachi, Variable Wavelength Monitor
Knauer, D-2000 Chromato Integrator Merck Hitachi, columns:
LiChroCART® 250-4 Merck with LiChrospher® 100 RP-8
endcapped (5 μm) and Hibar® RT 250-4 Merck with LiChrospher®
100 RP-18 (5 μm), injection volume: 20 μL, flow: 1 mL/min.
were added. The mixture was stirred at room temperature for 16 h.
2/3 of the solvent were removed in vacuo and the residue was filtered
and poured into 0.5 N HCl (60 mL). The mixture was extracted
four times with CH2Cl2 (60 mL), the organic layer was dried
(Na2SO4) and the solvent was removed in vacuo. The residue was
purified by flash column chromatography (3 cm, CH2Cl2/ethyl ace-
tate 1:1, 10 mL, Rf ϭ 0.39) to give a yellow oil, yield 1.4 g (70%).
b) Under N2 atmosphere a 1 M solution of sodium hexamethyldi-
silazane in THF (17.2 mL, 17.2 mmol) was added dropwise to a
cooled solution (Ϫ78°C) of 16 (5.0 g, 15.6 mmol) and tetrabutylam-
monium iodide (1.0 g, 2.70 mmol) in THF (150 mL). The mixture
was stirred at Ϫ78°C for 40 min, then a solution of allyl bromide
(6.75 mL, 78.0 mmol) in THF (15 mL) was added. The mixture
was stirred at Ϫ78°C for 1 h and then allowed to warm to room
temperature (2 h). Then water (100 mL) was added and the mixture
was extracted twice with CH2Cl2 (150 mL). The organic layer was
dried (Na2SO4) and the solvent was removed in vacuo. The residue
was purified by flash column chromatography (8 cm, petroleum
ether/ethyl acetate 3:7, 30 mL, Rf ϭ 0.23) to give a yellow oil, yield
3.5 g (67%). [α]589 ϭ ϩ20.44, (c 0.50, CH2Cl2). C19H24N2O5
(360.4). Calcd. C 63.3, H 6.71, N 7.77, found C 62.8, H 6.86,
N 7.57. MS (EI): m/z (%) ϭ 360 (M, 43), 239 (M Ϫ CH2PhOCH3,
30), 121 (CH2PhOCH3, 100). IR (neat): ν [cmϪ1] ϭ 2951 (w,
νC-Halip.), 1733 (m, νCϭOester) 1657 (s, νCϭOamide), 1244, 1171 (m,
νCOC), 769 (s, p-disubst. ar.). 1H NMR(CDCl3): δ (ppm) ϭ
1.97Ϫ2.06 (m, 1H, CH2CH2CO2CH3), 2.18Ϫ2.28 (m, 1H,
CH2CH2CO2CH3), 2.33Ϫ2.49 (m, 2H, CH2CH2CO2CH3),
3.43Ϫ3.53 (m, 1H, NCH2CHϭCH2), 3.65 (s, 3H, CO2CH3), 3.77
(d, J ϭ 18.0 Hz, 1H, OϭC-CH2N), 3.79 (s, 3H, OCH3), 3.89 (d,
J ϭ 18.0 Hz, 1H, OϭC-CH2N), 4.02 (dd, J ϭ 8.6/3.9 Hz, 1H,
CHNAllyl), 4.41 (d, J ϭ 14.1 Hz, 1H, CH2PhOCH3), 4.52Ϫ4.54
(m, 1H, NCH2CHϭCH2), 4.58 (d, J ϭ 14.1 Hz, 1H, CH2PhOCH3),
5.18Ϫ5.27 (m, 2H, NCH2CHϭCH2), 5.68Ϫ5.74 (m, 1H,
NCH2CHϭCH2), 6.86 (d, J ϭ 8.6 Hz, 2H, 3Ј-H and 5Ј-H
[H3COPh]), 7.18 (d, J ϭ 8.6 Hz, 2H, 2Ј-H and 6Ј-H [H3COPh]).
Dimethyl (S)-2-aminopentanedioate hydrochloride (12·HCl) [10, 11]
Chlorotrimethylsilane (75 mL, 594 mmol) was added dropwise dur-
ing 90 min to an ice cooled suspension of 11 (25.1 g, 171 mmol) in
methanol. The mixture was stirred for 16 h at room temperature.
Then the solvent and all volatile components were removed under
reduced pressure. The residue was suspended with methanol (50
mL) and the mixture was concentrated in vacuo. Then diethyl ether
(3 ϫ 60 mL) was added and the mixture was concentrated in vacuo
to yield a colorless solid, yield 35.4 g (98%), mp 85°C (reference
[11]: mp 88Ϫ90°C. [α]589 ϭ ϩ22.4, (c 0.53, 6 N HCl) (reference
[11]: [α]589 ϭ ϩ26.0 (c 5.0, H2O). IR (neat): ν [cmϪ1] 2878 (m,
ϩ
νCHaliph.), 1730 (s, νCϭO ester), 1505 (w, δNH ) 1441 (m, δCHaliph),
1209, 1144 (m, νCOC). 1H NMR (CDCl3): δ (3ppm) ϭ 2.29Ϫ2.41 (m,
2H, CH2CH2CO2CH3), 2.53Ϫ2.72 (m, 2H, CH2CH2CO2CH3), 3.61
(s, 3H, CH2CO2CH3), 3.76 (s, 3H, CHCO2CH3), 4.22Ϫ4.32 (t, J ϭ
6.3 Hz, 1H, CHCO2CH3), 8.65 (s, 3H, NH3ϩ).
Dimethyl (S)-2-[N-allyl-N-(2-chloroacetyl)amino]pentanedioate (13)
Under N2 atmosphere a solution of allyl bromide (2.5 mL, 28.9
mmol) in acetonitrile (7.5 mL) was added dropwise to an ice cooled
solution of 12·HCl (4.0 g, 18.9 mmol), triethylamine (5.3 mL, 38.0
mmol) and tetrabutylammonium iodide (1.3 g, 3.6 mmol) in aceto-
nitrile (100 mL). Then the mixture was stirred for 2 h at 0Ϫ5°C
and for 16 h at room temperature. Subsequently, the mixture was
cooled with ice and triethylamine (2.7 mL, 19.4 mmol) and a solu-
tion of chloroacetyl chloride (4.5 mL, 56.6 mmol) in acetonitrile (12
mL) was added. The mixture was stirred for 2 h at 0Ϫ5°C and for
1 h at room temperature. 2/3 of the solvent were removed in vacuo
and CH2Cl2 (50 mL) was added. The mixture was washed with 0.5
N HCl (50 mL) and 0.5 N NaOH (50 mL). The combined aqueous
layers were extracted with CH2Cl2 (3 ϫ 50 mL). The CH2Cl2 layer
was dried (Na2SO4) and the solvent was removed in vacuo. The
residue was purified by flash column chromatography (6 cm, petro-
leum ether/ethyl acetate 6:4, fractions 30 mL, Rf ϭ 0.42) to give a
yellow oil, yield 1.4 g (25%). C12H18ClNO5 (291.8). MS (CI) m/z
Dimethyl (S)-2-(2-chloroacetylamino)pentanedioate (15)
A solution of chloroacetyl chloride (9.3 mL, 117 mmol) in CH2Cl2
(60 mL) was added dropwise to an ice cooled solution of 12·HCl
(8.0 g, 37.8 mmol) in CH2Cl2 (240 mL). After 40 min a saturated
solution of sodium hydrogen carbonate (100 mL) was added and
the mixture was stirred at room temperature for 16 h. Then the
organic layer was separated and washed with 0.5 N NaOH (2 ϫ
150 mL). The aqueous layer was extracted with CH2Cl2 (2 ϫ 200
mL) and the combined organic layers were dried (Na2SO4) and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (8 cm, petroleum ether/ ethyl acetate 6:4, 30 mL, Rf ϭ 0.38) to
give 15 as a colorless oil, yield 6.8 g (71.6%). [α]589 ϭ ϩ18.1 (c 0.6,
CH2Cl2). C9H14ClNO5 (251.7). Calcd. C 42.9, H 5.61, N 5.56,
found C 42.6, H 5.86, N 5.35. MS (CI, NH3): m/z (%) ϭ 269 (M
ϩ NH4ϩ, 22), 254 (MHϩ (Cl37), 34), 252 (MHϩ (Cl35, 100). IR
(neat): ν (cmϪ1) ϭ 3317 (w, νN-H), 2956 (w, νC-H), 1733 (s, νCϭOester),
1667 (s, νCϭOamide), 1528 (m, δN-H), 1206, 1170 (s, νC-O). 1H NMR
(CDCl3): δ ϭ 2.00Ϫ2.44 (m, 4 H, CH2CH2CO2CH3), 3.68 (s, 3 H,
CO2CH3), 3.77 (s, 3 H, CHCO2CH3), 4.06 (s, 2H, ClCH2), 4.63
(ddd, J ϭ 15.7/5.5/2.4 Hz, 1H , CHCO2CH3), 7.22 (d, J ϭ 5.5 Hz,1
H, NH).
(%) ϭ 294 (MHϩ (Cl37), 34), 292 (MHϩ (Cl35), 100), 262 (M (Cl37
)
Ϫ OCH3, 10), 260 (M (Cl35) ϪOCH3, 43). IR (neat): ν [cmϪ1] ϭ
2954 (w, νC-Haliph.), 1732 (s, νCϭOester), 1656 (m, νCϭOamide), 1258,
1204,1 169 (m, νCOC). 1H NMR (CDCl3): δ (ppm) ϭ 1.95Ϫ2.15 (m,
1H, CH2CH2CO2CH3), 2.2Ϫ2.39 (m, 3H, CH2CH2CO2CH3), 3.61
(s, 3H, CO2CH3), 3.64 (s, 3H, CHCO2CH3) ,4.02 (s, 2H, ClCH2),
3.98Ϫ4.07 (m, 2H, NCH2CHϭCH2), 4.45Ϫ4.57 (m,1H,
CHCO2CH3), 5.17Ϫ5.23 (m, 2H, NCH2CHϭCH2), 5.76Ϫ5.89
(m, 1H, NCH2CHϭCH2).
Methyl (S)-[4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-yl]propano-
ate (16)
Methyl (S)-3-[1-allyl-4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-
yl]propanoate (14)
4-Methoxybenzylamine (4.6 mL, 35.6 mmol), triethylamine (5.0
mL, 36.1 mmol) and tetrabutylammonium iodide (0.88 g, 2.38
mmol) were added to a stirred solution of 15 (6.0 g, 23.8 mmol) in
acetonitrile (200 mL). The mixture was refluxed for 48 h. 2/3 of the
solvent were removed in vacuo. The residue was filtered, poured into
a) To a solution of 13 (1.5 g, 5.14 mmol) in acetonitrile (100 mL)
4-methoxybenzylamine (1.0 mL, 7.74 mmol), triethylamine (1.1 mL,
7.94 mmol) and tetrabutylammonium iodide (0.19 g, 0.514 mmol)
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

288
Wünsch et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
0.5 N HCl (200 mL), the mixture was extracted with CH2Cl2 (3 ϫ
200 mL), the organic layer was dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
(8 cm, petroleum ether/ethyl acetate/acetone 3:2:6, 30 mL, Rf ϭ
0.32) to give a colorless solid, yield 6.7 g (88%), mp 93-94°C.
[α]589 ϭ Ϫ14.7, (c 0.51, CH2Cl2). C16H20N2O5 (320.3). Calcd. C
60.0, H 6.29, N 8.74, found C 59.7, H 6.54, N 8.63. MS (EI): m/z
(%) ϭ 320 (M, 11), 288 (M ϪHOCH3, 2), 199 (M Ϫ CH2PhOCH3,
2), 121 (CH2PhOCH3, 100). IR (neat): ν [cmϪ1] 3267 (w, νN-H), 2963
(w, νC-Halip.), 1733 (m, νCϭOester) 1661(s, νCϭOamide), 1534 (w,
δN-Hamide), 1217, 1176 (m, νCOC), 785 (s, p-disubst. ar.). 1H
NMR(CDCl3): δ (ppm) ϭ 2.13Ϫ2.27 (m, 2H, CH2CH2CO2CH3),
2.41Ϫ2.53 (m, 2H, CH2CH2CO2CH3), 3.67 (s, 3H, CO2CH3), 3.78
(d, J ϭ 17.6 Hz, 1H, CH2PhOCH3), 3.79 (s, 3H, OCH3 ), 3.84 (d,
J ϭ 17.6 Hz, 1H, CH2PhOCH3), 4.12 (dd, J ϭ 6.3/3.5 Hz, 1H,
CHNH), 4.51 (s, 2H, OϭC-CH2N), 6.87 (d, J ϭ 8.6 Hz, 2H, 3Ј-H
and 5Ј-H [H3COPh]), 6.98 (s, 1H, NH), 7.18 (d, J ϭ 8.6 Hz, 2H,
2Ј-H and 6Ј-H [H3COPh]).
(CDCl3): δ (ppm) ϭ 0.01 (s, 9H, Si(CH3)3), 1.61Ϫ1.69 (m, 1H, 4-
H), 1.74Ϫ1.81 (m, 2H, 3-H ), 1.87Ϫ1.95 (m, 1H, 4-H) 3.03 (s, 3H,
OCH3), 3.61 (s, 3H, PhOCH3), 3.71 (dd, J ϭ 5.5/2.4 Hz, 1H, 5-H),
3.72 (s, 1H, 1-H), 3.79 (d, J ϭ 14.9 Hz, 1H, CH2PhOCH3), 3.80 (m,
2H, NCH2CHϭCH2), 4.99 (d, J ϭ 14.9 Hz, 1H, CH2PhOCH3),
5.03Ϫ5.07 (m, 2H, NCH2CHϭCH2), 5.52Ϫ5.62 (m, 1H,
NCH2CHϭCH2), 6.68 (d, Jϭ 8.6 Hz, 2H, 3Ј-H and 5Ј-H
[H3COPh]), 6.96 (d, J ϭ 8.6 Hz, 2H, 2Ј-H and 6Ј-H [H3COPh]).
13C NMR (CDCl3): δ (ppm) ϭ 24.7 (1C, C-4), 33.3 (1C, C-3), 47.6
(1C, NCH2CHϭCH2), 48.0 (1C, CH2PhOCH3), 49.0 (1C, OCH3),
55.2 (1C, PhOCH3), 58.3 (1C, C-5), 65.8 (1C, C-1), 98.6 (1C, C-2),
114.2 (2C, C-3Ј and C-5Ј[H3COPh]), 119.0 (1C, NCH2CHϭCH2),
127.9 (1C, C-1Ј[H3COPh]), 129.4 (2C, C-2Ј and C-6Ј [H3COPh]),
132.2 (1C, NCH2CHϭCH2), 159.2 (1C, C-4Ј [H3COPh]), 165.8 (1C,
CϭO), 168.6 (1C, CϭO).
(1S,5S)-6-Allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]-
nonane-2,7,9-trione (17)
Under N2 atmosphere a solution of 20 (1.12 g, 2.59 mmol) was
stirred at room temperature in a degassed mixture of THF/2 N HCl
(10:1, 50 mL) for 2 h. Subsequently, water (50 mL) was added and
the mixture was extracted with CH2Cl2 (3 ϫ 50 mL). The organic
layer was dried (Na2SO4) and the solvent was removed in vacuo.
Methyl (S)-3-[5-allyl-4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-yl]-
propanoate (18)
Under N2 atmosphere a solution of phenylmagnesium bromide pre-
pared from bromobenzene (0.064 mL, 0.61 mmol) and magnesium
tunings (0.015 g, 0.61 mmol) in THF (2 mL) was added to a cooled
(Ϫ78°C) solution of 14 (0.20 g, 0.55 mmol) in THF (20 mL). After
stirring at Ϫ78°C for 2 h and at room temperature for 1 h the
mixture was poured into an ice cooled saturated solution of NH4Cl
(30 mL). The mixture was extracted four times with CH2Cl2, the
organic layer was dried, the solvent was removed in vacuo and the
residue was purified by flash column chromatography (2 cm,
CH2Cl2 /ethyl acetate 7:3, 5 mL) to give 17 (Rf ϭ 0.31) as a colorless
solid, yield 18.8 mg (10%) and 18 (Rf ϭ 0.18) as a pale yellow oil,
yield 29.3 mg, (15%). 18: C19H22N2O5 (360.4). MS (ESI): m/z (%) ϭ
383 (M ϩ Naϩ, 100). IR (neat): ν [cmϪ1] ϭ 3233 (w, νN-H), 2951
(w, μnC-Haliph.), 1734 (m, νCϭOester), 1681 (m, νCϭOsec.amide), 1654
(m, νCϭOtert.amide), 1512 (m, δN-H),1245, 1174 (m, νCOC), 807 (w,
p-disubst. ar.). 1H NMR (CDCl3): δ (ppm) ϭ 2.13Ϫ2.38 (m, 2H,
CH2CH2CO2CH3), 2.33Ϫ2.45 (m, 2H, CH2CH2CO2CH3),
2.49Ϫ2.58 (m, 2H, CH2CHϭCH2), 3.60 (s, 3H, CO2CH3), 3.73 (s,
3H, OCH3), 3.83 (m, 1H, OϭC-CHN), 3.86 (d, J ϭ 14.5 Hz, 1H,
CH2PhOCH3), 4.14 (t, J ϭ 4.7 Hz, 1H, CHNH), 5.10 (m, 2H,
CH2CHϭCH2), 5.21 (d, J ϭ 14.5Hz, 1H, CH2PhOCH3), 5.62Ϫ5.74
(m, 1H, CH2CHϭCH2), 6.50 (s, 1H, NH), 6.80 (d, J ϭ 8.6 Hz, 2H,
3Ј-H and 5Ј-H [H3COPh]), 7.10 (d, J ϭ 8.6 Hz, 2H, 2Ј-H and
6Ј-H [H3COPh]).
Colorless solid, yield 0.85 g (100%), mp 195-196°C. [α]589
ϭ
ϩ120.29 (c 0.49, CH2Cl2). C18H20N2O4 (328.4). Calcd. C 65.8, H
6.14, N 8.53, found C 65.6, H 5.95, N 8.25. MS (EI): m/z (%) ϭ
329 (M, 100), 121 (CH2PhOCH3, 12). IR (neat): ν [cmϪ1] ϭ 3005
(w, νC-Harom.), 2955 (w, νC-Haliph.), 1724 (s, νCϭOketone), 1670 (s,
νCϭOamide), 1243, (m, νCOC), 828 (s, p-disubst. ar.).1H NMR
(CDCl3): δ (ppm) ϭ 1.99Ϫ2.13 (m, 1H, 4-H), 2.21Ϫ2.32 (m, 1H,
3-H ), 2.35Ϫ2.48 (m, 2H, 3ϪH, 4-H), 3.71 (s, 3H, PhOCH3), 3.81
(ddt, J ϭ 17.9/6.3/1.6 Hz, 1H, NCH2CHϭCH2), 3.99 (dd, 1H, J ϭ
6.3/1.6 Hz, 1H, 5-H), 4.11 (ddt,
J ϭ 17.9/6.3/1.6 Hz, 1H,
NCH2CHϭCH2), 4.20 (s, 1H, 1-H), 4.26 (d, J ϭ 14.1 Hz, 1H,
CH2PhOCH3), 4.76 (d, J ϭ 14.1 Hz, 1H, CH2PhOCH3) 5.16Ϫ5.24
(m, 2H, NCH2CHϭCH2 ), 5.61Ϫ5.73 (m, 1H, NCH2CHϭCH2),
6.76 (d, J ϭ 8.6 Hz, 2H, 3Ј-H and 5Ј-H [H3COPh]), 7.14 (d, J ϭ
8.6 Hz, 2H, 2Ј-H and 6Ј-H [H3COPh]). 13C NMR (CDCl3): δ
(ppm) ϭ 30.2 (1C, C-4), 36.9 (1C, C-3), 48.1 (1C, NCH2CHϭCH2),
49.4 (1C, CH2PhOCH3), 55.8 (1C, OCH3), 59.0 (1C, C-5), 72.1 (1C,
C-1), 114.7 (2C, C-3Ј and C-5Ј[H3COPh]), 120.2 (1C, NCH2CHϭ
CH2), 127.0 (1C, C-1Ј[H3COPh]), 130.5 (2C, C-2Ј and C-6Ј
[H3COPh]), 131.6 (1C, NCH2CHϭCH2), 159.7 (1C, C-
4Ј[H3COPh]), 163.2 (1C, CϭO), 167.1 (1C, CϭO), 200.2 (1C, Cϭ
Oketone).
(1S,2R,5S)-6-Allyl-2-methoxy-8-(4-methoxybenzyl)-2-(trimethyl-
(1S,2S,5S)-6-Allyl-2-hydroxy-8-(4-methoxybenzyl)-2-phenyl-6,8-
siloxy)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione (20)
diazabicyclo[3.2.2]- nonane-7,9-dione (21)
Under N2 atmosphere a 1 M solution of lithium hexamethyldi-
silazane in THF (13.5 mL, 13.5 mmol) was added dropwise to a
cooled solution (Ϫ78°C) of 14 (3.25 g, 9.02 mmol) in THF
(130 mL). After stirring at Ϫ78°C for 40 min, a solution of chloro-
trimethylsilane (4.1 mL, 32.5 mmol) in THF (10 mL) was added.
The mixture was stirred at Ϫ78°C for 1 h and at room temperature
for 2 h. Then a saturated solution of sodium hydrogen carbonate
(150 mL) was added and the mixture was extracted with CH2Cl2
(3 ϫ 150 mL). The organic layer was dried (Na2SO4), the solvent
was removed in vacuo and the residue was purified by flash column
chromatography (6 cm, petroleum ether/ethyl acetate 6:4, 30 mL,
Rf ϭ 0.27) to give a colorless solid, yield 3.4 g (88%), mp 93Ϫ94°C.
[α]589 ϭ ϩ22.07, (c 0.995, CH2Cl2). C22H32N2O5Si (432.6). Calcd.
C 61.1, H 7.46, N 6.48, found C 60.6, H 7.30, N 6.38. MS (EI): m/z
Under N2 atmosphere a solution of 17 (2.2 g, 6.7 mmol) in THF
(100 mL) was added to an ice-cooled solution of phenylmagnesium
bromide prepared from bromobenzene (4.2 mL, 40.0 mmol) and
magnesium tunings (1.0 g, 40.7 mmol) in THF (10 mL). After stir-
ring for 2 h at 0Ϫ5°C the mixture was poured into a cold saturated
solution of NH4Cl (200 mL). The mixture was extracted four times
with CH2Cl2 (150 mL), the organic layer was dried, the solvent was
removed in vacuo and the residue was purified by flash column chro-
matography (4 cm, petroleum ether/ethyl acetate 2:8, 20 mL, Rf ϭ
0.25) to give a yellow oil, yield 2.5 g (90%). [α]589 ϭ ϩ3.96, (c 1.0,
CH2Cl2). C24H26N2O4 (406.5). MS (EI): m/z (%) ϭ 406 (M, 25),
365 (M-allyl, 10), 285 (M-CH2PhOCH3), 121 (CH2PhOCH3, 100).
IR (neat): ν [cmϪ1] ϭ 3400 (w, νO-H), 2935 (w, νC-Haliph.),1664 (s,
νCϭOamide), 1244 (s, νCOC), 809 (w, p-disubst. ar.), 753 (m, mono-
subst. ar), 701 (s, monosubst. ar). 1H NMR (CDCl3): δ (ppm) ϭ
1.94Ϫ2.07 (m, 1H, 3-H), 2.13Ϫ2.21 (m, 2H, 4-H ), 2.48Ϫ2.60 (m,
1H, 3ϪH), 2.82 (d, J ϭ 14.7 Hz, 1H, CH2PhOCH3), 3.37 (s, 1H,
(%)
ϭ 432 (M, 33), 311 (M Ϫ CH2PhOCH3, 24), 121
(CH2PhOCH3, 100). IR (neat): ν [cm1] ϭ 2954 (w, νC-Halip.), 1679
(s, νCϭOamide), 1251 (s, νCOC), 832 (s, p-disubst. ar.). 1H NMR
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
OH), 3.70 (s, 3H, OCH3), 3.89 (dd, 15.3/6.1 Hz, 1H,
NCH2CHϭCH2), 3.94 (s, 1H, 1ϪH), 3.97(m, 1H, 5ϪH), 4.14 (dd,
J ϭ 15.3/6.1 Hz, 1H, NCH2CHϭCH2), 4.86 (d, J ϭ 14.7 Hz, 1H,
CH2PhOCH3), 5.16Ϫ5.26 (m, 2H, NCH2CHϭCH2), 5.68Ϫ5.83 (m,
1H, NCH2CHϭCH2), 6.66 (d, J ϭ 9.0 Hz, 2H, 3Ј-H and 5Ј-H
[H3COPh]), 6.73 (d, J ϭ 9.0 Hz, 2H, 2Ј-H and 6Ј-H [H3COPh]),
7.23Ϫ7.54 (m, 5H, aromat. H).
A bicyclic analogue of δ opioid receptor agonist SNC 80
289
J
ϭ
Rf ϭ 0.27) to give a colorless oil, yield 0.074 g (77%). C16H2ON2
(240.3). MS (ESI): m/z (%) ϭ 241 (MHϩ, 22). IR (neat): ν [cmϪ1] ϭ
3274 (w, νN-H), 3025 (w, νC-Harom), 2924 (w, νC-alliph), 1506 (m,
δN-H). 1H NMR (CDCl3): δ (ppm) ϭ 2.49Ϫ2.60 (m, 1H, 4ϪH),
2.85Ϫ2.98 (m, 1H, 4ϪH), 3.23Ϫ3.43 (m, 7H, NCH2CHϭCH2,
5ϪH, 7ϪH, 9ϪH), 5.08Ϫ5.20 (m, 2H, NCH2CHϭCH2), 5.79Ϫ5.92
(m, 2H, NCH2CHϭCH2, 3-H), 7.07Ϫ7.31 (m, 5H, arom.H).
(1S,5S)-6-Allyl-8-(4-methoxybenzyl)-2-phenyl-6,8-diazabicyclo-
4-[(1S,5S)-(8-Allyl-4-phenyl-6,8-diazabicyclo[3.2.2]non-3-en-6-
[3.2.2]non-2-en-7,9-dione (22)
ylmethyl]-N,N-diethylbenzamide (9)
Under N2 atmosphere potassium carbonate (39 mg, 0.28 mmol) and
25 [16] (0.47 mg, 0.21 mmol) were added to a solution of 24 (45
mg, 0.19 mmol) and tetrabutylammonium iodide (7.0 mg, 0.019
mmol) in acetonitrile (20 mL). The mixture was refluxed for 9 h,
filtered and the solvent was removed in vacuo. 1 M HCl (10 mL)
was added to the residue, the mixture was washed with ethyl acetate
(2 ϫ 10 mL), 2 M NaOH (10 mL) was added to the aqueous layer
and the mixture was extracted with CH2Cl2 (3 ϫ 15 mL). The
CH2Cl2 layer was dried (Na2SO4) and concentrated in vacuo. The
residue was purified by flash column chromatography (1 cm,
CH2Cl2/ methanol 9.5:0.5, 3 mL, Rf ϭ 0.07) to give a colorless oil,
yield 51 mg (63%). [α]589 ϭ ϩ70.1, (c 0.65, CH2Cl2). C28H35N3O
(429.6). MS (ESI): m/z (%) ϭ 430 (MHϩ, 100). IR (neat): ν
[cmϪ1] ϭ 3077 (w, νC-Harom.), 2972, 2878 (w, νC-Haliph.), 1631 (s,
νCϭOamide), 843 (w, p-disubst. ar.) 757, 699 (w, monosubst. ar.). 1H
NMR (CDCl3): δ (ppm) ϭ 0.93Ϫ1.23 (m, 6H, N(CH2CH3)2), 2.26
(dt, J ϭ 18.8/4.3 Hz, 1H, 2ϪH), 2.51Ϫ2.61 (m, 1H, 7Ϫ H),
2.70Ϫ2.81 (m, 1H, 2ϪH), 2.83Ϫ2.91 (m, 1H, 9ϪH), 3.04Ϫ3.12 (m,
1H, 1ϪH), 3.12Ϫ3.19 (m, 2H, N(CH2CH3)2), 3.21Ϫ3.27 (m, 2H,
NCH2CHϭCH2), 3.27Ϫ3.51 (m, 2H, 7ϪH, 9ϪH), 3.41Ϫ3.50 (m,
2H, N(CH2CH3)2), 3.50 (d, J ϭ 13.3 Hz, 1H, CH2PhOCH3),
3.53Ϫ3.56 (m, 1H, 5ϪH), 3.59 (d, J ϭ 13.3 Hz, 1H, CH2PhOCH3),
5.03Ϫ5.18 (m, 2H, NCH2CHϭCH2), 5.83Ϫ5.91 (m, 1H,
NCH2CHϭCH2), 5.91Ϫ5.96 (m, 1H, 3ϪH), 7.04Ϫ7.17 (m, 9H,
arom. H). 13C NMR (CDCl3): δ (ppm) ϭ 13.4 (1C, N(CH2CH3)2),
14.7 (1C, N(CH2CH3)2), 34.9 (1C, CϪ2), 39.6 (1C, N (CH2CH3)2),
43.8 (1C, N(CH2CH3)2), 52.9 (1C, C-1), 54.4 (1C, CϪ7), 56.4 (1C,
CϪ5), 57.5 (1C, CϪ9), 59.1 (1C, NCH2CHϭCH2), 60.1 (1C,
CH2PhOCH3), 117.5 (1C, NCH2CHϭCH2), 126.1 (2C, arom. C),
126.2 (2C, arom. C) 126.7 (1C, arom. C), 127.8 (1C, CϪ3), 128.4
(2C, arom. C), 129.0 (2C, arom. C), 135.9 (1C, CϪ4), 136.5 (1C,
NCH2CHϭCH2), 140.2 (1C, CϪ1Ј[phenyl]), 142.5 (1C, CϪ1Ј[ben-
zyl]), 143.7 (1C, CϪ 4Ј[benzyl]), 171.4 (1C, CϭO).
Under N2 atmosphere diphoshorpentoxide (3 g, 21 mmol) was ad-
ded to a solution of 21 (1.0 g, 2.46 mmol) in toluene (70 mL). The
mixture was heated at 90°C for 48 h, filtered and concentrated in
vacuo. The residue was purified by flash column chromatography (3
cm, petroleum ether/ethyl acetate 3:7, 10 mL, Rf ϭ 0.43) to give a
colorless solid, yield 0.54 g (67%), mp 142Ϫ143°C. [α]589 ϭ ϩ184.4,
(c 0.57, CH2Cl2). C24H24N2O3 (388.5). Calcd. C 74.2, H 6.23, N
7.21, found C 73.7, H 6.13, N 6.92. MS (EI): m/z (%) ϭ 388 (M,
41), 226 (M-allyl-CH2PhOCH3, 22), 121 (CH2PhOCH3, 100). IR
(neat): ν [cmϪ1] ϭ 3010 (w, νC-Harom), 2937 (w, νC-Haliph.), 1672 (s,
νCϭOamide), 1239, (w, νCOC), 811 (w, p-disubst ar.), 753, 699 (m,
1
monosubst. ar.). H NMR(CDCl3): δ (ppm) ϭ 2.67 (ddd, J ϭ 19.5/
4.3/2.7 Hz, 1H, 4-H), 2.79 (ddd, J ϭ 19.5/4.3/2.7 Hz, 1H, 4-H), 3.72
(s, 3H, OCH3), 4.02 (dddd,
J ϭ 15.2/6.3/1.56/1.2 Hz, 1H,
NCH2CHϭCH2,), 4.10 (ddd, J ϭ 4.3/2.7/1.2 Hz, 1H, 5ϪH), 4.18
(dddd, J ϭ 15.2/6.3/1.6/1.2 Hz, 1H, NCH2CHϭCH2), 4.34 (d, 14.7
Hz, 1H, CH2PhOCH3), 4.47 (d, J ϭ1.6 Hz, 1H, 1ϪH), 4.66 (d,
14.7 Hz, 1H, CH2PhOCH3), 5.24Ϫ5.30 (m, 2H, NCH2CHϭCH2),
5.70Ϫ5.74 (m, 1H, 3ϪH), 5.76Ϫ5.86 (m, 1H, NCH2CHϭCH2),
6.62 (d, J ϭ 8.6 Hz, 2H, 3Ј-H and 5Ј-H [H3COPh]), 6.97 (d, J ϭ 8.6
Hz, 2H, 2Ј-H and 6Ј-H [H3COPh]), 7.01Ϫ7.23 (m, 5H, aromat. H).
(1S,5S)-6-Allyl-8-(4-methoxybenzyl)-2-phenyl-6,8-diazabicyclo-
[3.2.2]non-2-ene (23)
Under N2 atmosphere lithium aluminium hydride (0.464 g, 12.2
mmol) was added to an ice-cooled solution of 22 (0.95 g, 2.45
mmol) in THF (90 mL). The mixture was stirred with ice-cooling
for 30 min and then refluxed for 6 h. Water (0.88 mL, 48.9 mmol)
was added dropwise, and the mixture was stirred at 0Ϫ5°C for 30
min and refluxed for 30 min. The mixture was filtered, the solvent
was removed in vacuo and the residue was purified by flash chroma-
tography (3 cm, CH2Cl2/methanol 9.5:0.5, 10 mL, Rf ϭ 0.15) to give
a yellow oil, yield 0.23 g (26%). [α]589 ϭ ϩ42.8 (c 0.48, CH2Cl2).
The purity of 9 was determined by HPLC: Method a): Hibar® RT
250-4 Merck with LiChrospher® 100 RP-18 (5 μm), MeOH/H2O ϭ
70:30 ϩ 0.1% NEt3; detection UV, λ ϭ 235 nm, tR ϭ 26 min,
98.9%. Method b): LiChroCART® 250-4 Merck with LiChrospher®
100 RP-8 endcapped (5 μm), CH3CN/H2O ϭ 50:50 ϩ 0.1%, NEt3;
detection UV λ ϭ 254 nm, tR ϭ 17 min, 99.0%.
C24H28N2O (360.5). MS (EI): m/z(%)
ϭ 360 (M, 55), 239
(MϪCH2PhOCH3, 100), 198 (MϪCH2PhOCH3 Ϫ allyl, 45), 121
(CH2PhOCH3, 22). IR (neat): ν [cmϪ1] ϭ 3024 (w, νC-Harom), 2930
(w, νC-Haliph.), 1510 (m, νCϭC), 1244 (m, νCOC), 830 (w, p-disubst.
ar.), 758, 699 (m, monosubst. ar). 1H NMR (CDCl3): δ (ppm) ϭ
2.26Ϫ2.38 (m, 1H, 4ϪH), 2.56Ϫ2.66 (m, 1H, 9ϪH), 2.74Ϫ2.88 (m,
1H, 4ϪH), 2.89Ϫ3.02 (m, 1H, 7ϪH), 3.08Ϫ3.20 (m, 1H, 5ϪH),
3.22Ϫ3.38 (m, 4H, 7ϪH, 8ϪH, NCH2CHϭCH2), 3.46 (d, J ϭ 12.9
Hz, 1H, CH2PhOCH3), 3.52 (d, J ϭ 12.9 Hz, 1H, CH2PhOCH3),
3.60 (m, 1H, 1ϪH), 3.70 (s, 3H, OCH3), 5.03Ϫ5.23 (m, 2H,
NCH2CHϭCH2), 5.85Ϫ6.01 (m, 2H, NCH2CHϭCH2, 3ϪH), 6.67
(d, J ϭ 8.6 Hz, 2H, 3Ј-H and 5Ј-H [H3COPh]), 6.97 (d, J ϭ 8.6 Hz,
2H, 2Ј-H and 6Ј-H [H3COPh]), 7.04Ϫ7.23 (m, 5H, aromat. H).
References
[1] G. Calo, R. Guerrini, A. Rizzi, S. Salvadori, D. Regoli, Br. J.
Pharmacol. 2000, 129, 1261Ϫ1283.
[2] H. Shinkai, T. Ito, T. Iidia, Y. Kitao, H. Yamada, I. Uchide, J.
Med. Chem. 2000, 43, 4667Ϫ4677.
(1S,5S)-6-Allyl-2-phenyl-6,8-diazabicyclo[3.2.2]non-2-ene (24)
[3] G. Dondio, S. Ronzoni, P. Petrillo, Exp. Opin. Ther. Patents
1997, 7, 1075Ϫ1098.
Under N2 atmosphere a solution of 23 (0.145 g, 0.4 mmol) in TFA
(40 mL) was refluxed for 48 h. Then, under ice-cooling 10 M KOH
solution (50 mL) was added dropwise. The mixture was extracted
with CH2Cl2 (5 ϫ 100 mL), the organic layer was dried (Na2SO4),
the solvent was removed in vacuo and the residue was purified by
flash chromatography (2 cm, CH2Cl2/methanol 8.5 : 1.5, 5 mL,
[4] G. Dondio, S. Ronzoni, P. Petrillo, Exp. Opin. Ther. Patents
1999, 9, 353Ϫ374.
[5] X. Zhang, K. C. Rice, S. N. Calderon, H. Kayakiri, L. Smith,
A. Coop, A. E. Jacobson, R. B. Rothman, P. Davis, C. M.
Dersch, F. Porreca, J. Med. Chem. 1999, 42, 5455Ϫ5463.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

290
Wünsch et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
[6] M. S. Furness, X. Zhang, A. Coop, A. E. Jacobson, R. B. Roth-
man, C. M. Dersch, H. Xu, F. Porreca, K. C. Rice, J. Med.
Chem. 2000, 43, 3193Ϫ3196.
[12] F. Paradisi, G. Porzi, S. Sandri, Tetrahedron: Asymmetry 2001,
12, 3319Ϫ3324.
[13] R. Kumareswaran, A. Hassner, Tetrahedron: Asymmetry 2001,
12, 2269Ϫ2276.
[14] M. Weigl, B. Wünsch, Org. Lett. 2000, 2, 1177Ϫ1179.
[15] G. M. Brooke, S. Mohammed, M. C. Whiting, Chem. Commun.
1997, 1511Ϫ1512
[7] S. N. Calderon, K. C. Rice, R. B. Rothman, F. Porreca, J. L.
Flippen-Anderson, H. Kayakiri, H. Xu, K. Becketts. L. E.
Smith, E. J. Bilsky, P. Davis, R. Hovarth, J. Med. Chem 1997,
40, 695Ϫ704.
[16] a) R. Meier, P. Müller, E. Woitun, R. Hurnaus, M. Mark, B.
Eisele, R. M. Budzinski, G. Hallermayer, Ger. Offen. 1995, DE
4407138; b) F. Karrer, Ger. Offen. 1974, DE 2418295; c) F.
Karrer, Ger. Offen. 1974, DE 2418343.
[17] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43,
2923Ϫ2925.
[8] Tripos® Sybyl force field manual version 6.6, 1999.
[9] D. Seebach, G. Stucky, P. Renaud, Chimia 1998, 42, 176Ϫ178.
[10] M. Weigl, B. Wünsch, Tetrahedron 2002, 58, 1173Ϫ1183.
[11] J. R. Rachele, J. Org. Chem. 1963, 28, 2898.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim