(1-Benzylpiperazin-2-yl)methanols: Novel EPC synthesis from (S)-serine and transformation into ligands for central nervous system receptors

Article abstract of DOI:10.1016/S0957-4166(01)00208-7

A novel three-step synthesis of 4-substituted-(1-benzylpiperazin-2-yl)methanols 5a-5c is described starting from the methyl ester of the proteinogenic amino acid (S)-serine, which involves the diastereomeric oxazolidine derivatives 11a-11c as key intermed

Full text of DOI:10.1016/S0957-4166(01)00208-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1293–1302
(1-Benzylpiperazin-2-yl)methanols: novel EPC synthesis from
(S)-serine and transformation into ligands for central nervous
system receptors
Stephan Bedu¨rftig, Manuela Weigl and Bernhard Wu¨nsch*
Pharmazeutisches Institut der Universita¨t Freiburg, Albertstraße 25, D-79104 Freiburg i. Br., Germany
Received 5 April 2001; accepted 4 May 2001
Abstract—A novel three-step synthesis of 4-substituted-(1-benzylpiperazin-2-yl)methanols 5a–5c is described starting from the
methyl ester of the proteinogenic amino acid (S)-serine, which involves the diastereomeric oxazolidine derivatives 11a–11c as key
intermediates. 5b and 5c were transformed into the chiral, non-racemic bicyclic lactams 14b and 14c via Swern oxidation followed
by Wittig reaction and subsequent hydrogenation. In the screening for central nervous system receptor affinity the butyl derivative
14b was found to have promising interaction with s1-receptors (Ki=345 nM). © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
proteinogenic amino acid (S)-serine was used as
homochiral starting material in analogy to our strategy
with the amino acid (2S,3R)-threonine.7 The (piperazin-
2-yl)methanols 5 were further transformed into chiral
non-racemic bicyclic lactams 14, which were investi-
gated for their ability to interact with CNS receptors
(NMDA-, m-, k-, and s-receptors) (Scheme 1).
2-Substituted piperazine derivatives display high
affinity for various receptors within the central nervous
system (CNS). Among these compounds is the (R)-
configured 1,4-diacylpiperazine 1 with a (pyrrolidin-1-
yl)methyl residue in position 2, representing one of the
most potent and selective k-receptor agonists (IC50=
0.018 nM).1 Using (R)-2-aminoadipic acid as the lead
structure, the potent and selective competitive N-
methyl- -aspartate (NMDA) antagonist 2—a phospho-
D
nopropyl substituted piperazine-2-carboxylic acid—has
been developed.2 A further example for a receptor
ligand with piperazine structure is the bis-urea deriva-
tive 3, which binds with high affinity at NK1 receptors
(substance P antagonist).3 In addition to their own
pharmacological properties, 2-substituted piperazines
are incorporated as substructures into several pharma-
cologically useful compounds, e.g. HIV-protease
inhibitors (Indivavir4) or PAF antagonists.5 Further-
more, 2-substituted piperazines serve as building blocks
for the synthesis of pharmacologically active piperazi-
nes, including 1–3 as well as racemic lactams 4, which
are of interest because of their nootropic activity (Fig.
1).6
Herein, we report a novel method for the synthesis of
homochiral (piperazin-2-yl)methanols 5, which are
selectively protected in position 1 with a benzyl group
and substituted with various residues in position 4. The
* Corresponding author. Fax: 0761/203-6321; e-mail: wuensch@
ruf.uni-freiburg.de
Figure 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00208-7

1294
S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
derivatives.9 Analogously, threonine methyl ester
reacted with benzaldehyde and chloroacetyl chloride to
yield the corresponding 3-(chloroacetyl)-2-phenyloxaz-
olidine derivative.7 However, condensation of the
hydrochloride of serine methyl ester, 6·HCl, with ben-
zaldehyde to give 7 and subsequent acylation with
chloroacetyl chloride provided only low 2–5% yields of
the stereoisomeric methyl oxazolidine-4-carboxylates 9.
Therefore, the reaction sequence was reversed and (S)-
6·HCl was acylated with chloroacetyl chloride to give
the chloroacetamide 8 (93%), which was condensed
with benzaldehyde dimethyl acetal to afford the
stereoisomeric oxazolidine derivatives cis-9 and trans-9.
[N.B. The stereodescriptors cis and trans are used to
characterize the relative configuration of the protons in
positions 2 and 4 of the oxazolidine ring system.] After
reaction of benzaldehyde dimethyl acetal with the
chloroacetamide 8, the mixed acetal 10 (mixture of
diastereomers) was obtained as a side product in vari-
able amounts (15–80%). The isolated mixed acetal 10
could be cyclized upon heating with a catalytic amount
of p-toluenesulfonic acid. However, the yield of the
oxazolidine derivatives 9 did not exceed 58% as a result
of decomposition of the mixed acetal 10 indicating that
the mixed acetal 10 is not the only intermediate during
the synthesis of the oxazolidines 9 from the chloro-
acetamide 8 and benzaldehyde dimethyl acetal (Scheme
2).
Scheme 1.
The syntheses of 2-substituted piperazine derivatives
starting with (R)- or (S)-serine is described in the
literature.1,5,8 The unique feature of our strategy is,
however, the simultaneous protection of both the
amino- and hydroxy-moiety of serine with benzalde-
hyde to generate a 1,3-oxazolidine ring system. The
reductive opening of the N/O-acetalic oxazolidine ring
system should generate the benzyl protective group in
position 1 and, at the same time, liberate the hydroxy
group in the side chain for further transformations
(compare Scheme 3).
2. Chemistry
Condensation of methyl esters of serine and threonine
with pivalaldehyde and subsequent acylation stereose-
lectively provided cis-configured N-acyloxazolidine
The stereoselectivity observed during the formation of
2-phenyloxazolidines 9 is strongly dependent on the
Scheme 2.

S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
1295
reaction conditions. Heating the chloroacetamide 8 with
benzaldehyde dimethyl acetal in CH2Cl2 (41°C) led to
the diastereomeric cis- and trans-oxazolidines 9 in a
ratio of ꢀ9:1. After heating the same components in
refluxing toluene trans-9 predominated in a ꢀ3:7 cis/
trans mixture. Obviously, trans-9 is the thermodynami-
cally more stable isomer, whereas the cis-isomer cis-9 is
formed under kinetic control. With regard to the stereo-
chemistry, the 3-(chloroacetyl)-2-phenyloxazolidines 9
differ significantly from the 2-tert-butyl substituted oxa-
zolidines described by Seebach et al.9
which were trapped without purification with the
Wittig reagent 12 to produce the a,b-unsaturated esters
1
Interpretation of the H NMR spectra of 9 was compli-
cated by the appearance of four sets of broad signals,
which are caused by slow rotation around the amidic N-
CꢀO bond. However, recording the 1H NMR spectra at
elevated temperature (DMSO, 90°C) unequivocally
demonstrated the existence of rotamers and facilitated
the interpretation of the spectra by the coalescence of
corresponding signals.
The chloroacetyl substituted oxazolidines 9 (mixture of
cis/trans diastereomers) reacted with simple primary
amines including benzylamine and butylamine as well as
further substituted amines like aminoacetaldehyde
dimethyl acetal to give the bicyclic piperazinediones 11
in good yields (Scheme 3). During these transformations
the diastereomeric ratio of the chloroacetamides 9 is con-
served leading to bicyclic piperazinediones 11 in the
same cis:trans diastereomeric ratio. The diastereoiso-
mers of 11 could be easily separated by flash chromatog-
raphy and the relative configuration of the cis-
configured benzyl substituted derivative cis-11a was
determined by a NOESY NMR experiment, which con-
firmed the neighborhood of the protons in positions 6
and 9. The analogous experiment performed with trans-
11a did not lead to enhancement of the C(6)H-signal
after irradiation at 6.25 ppm (C(9)H).
Scheme 3.
Heating the bicyclic piperazinediones 11 with excess
7,10
LiAlH4
afforded
the
(1-benzylpiperazin-2-
yl)methanols 5 with different substituents at position 4.
This transformation comprises reduction of both lactam
carbonyl moieties and concomitant reductive ring open-
ing of the oxazolidine ring system destroying the initially
generated stereogenic center. We demonstrated, that
both diastereomeric piperazinediones cis-11 and trans-
11 provided the same (1-benzylpiperazin-2-yl)methanol
5 within a comparable time and in the same yield. There-
fore, the preparation of 5 was usually performed using a
diastereomeric mixture of cis-11 and trans-11.
Syntheses of ( )-1,4-diazabicyclo[4.3.0]nonan-9-ones
with the general formula 4 have been reported.6,11 How-
ever, enantiomerically pure bicyclic lactams 4 have not
been described. Herein, we point out, that the (R)-con-
figured (1-benzylpiperazin-2-yl)methanols 5 can be used
as homochiral building blocks for the preparation of chi-
ral, non-racemic bicyclic lactams 14, which represent
alkyl analogues of the racemic nootropics 4 (Scheme 4).
Thus, the alcohols 5b and 5c were oxidized under Swern
conditions12 to afford the corresponding aldehydes,
Scheme 4.

1296
S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
13b and 13c as mixtures of cis- and trans-isomers,
respectively. Reaction of the a,b-unsaturated esters
13b and 13c with hydrogen in the presence of cata-
lytic Pd/C led to saturation of the double bond,
hydrogenolytic cleavage of the benzyl protective
group and subsequent intramolecular aminolysis to
provide the bicyclic lactams 14b and 14c. These trans-
formations correspond to the analogous reactions of
5. Experimental
5.1. General procedures
Unless otherwise noted, moisture sensitive reactions
were conducted under dry nitrogen. THF was distilled
from sodium/benzophenone ketyl immediately prior to
use. Petroleum ether used refers to the fraction boiling
at 40–60°C. Thin-layer chromatography (tlc): silica gel
60 F254 plates (Merck). Flash chromatography (fc):16
silica gel 60, 0.040–0.063 mm (Merck); parentheses
include: diameter of the column (cm), eluent, fraction
size (mL), Rf. Melting points: melting point apparatus
SMP 2 (Stuart Scientific), uncorrected. Optical rota-
tion: polarimeter 241 (Perkin–Elmer); 1.0 dm tube;
concentration c (g/100 mL); temperature 20°C. Ele-
mental analyses: Vario EL (Elementaranalysesysteme
GmbH). MS: MAT 312, MAT 8200, MAT 44 and
TSQ 7000 (Finnigan); EI=electron impact, CI=chem-
ical ionization. High resolution MS (HRMS): MAT
8200 (Finnigan). IR: IR spectrophotometer 1605 FT-
IR (Perkin–Elmer). (br=broad, m=medium, s=
( )-1,4-dibenzylpiperazine-2-carbaldehyde
providing
( )-bicyclic lactams 4 with sulfonyl and acyl residues
at N(4).6
3. Receptor binding studies
To investigate the binding at receptors within the cen-
tral nervous system, the homochiral bicyclic lactams
14b and 14c and the synthetic intermediate 13c were
screened with two concentrations (1 and 10 mM) for
their affinities to NMDA-, k-, m-, s1- and s2-recep-
tors. The following tritiated radioligands were
employed: (+)-MK-801 (PCP binding site of the
NMDA-receptor), U-69593 (k-receptor), DAMGO (m-
receptor), (+)-pentazocine (s1-receptor) and ditolyl-
guanidine in the presence of an excess of unlabelled
(+)-pentazocine (s2-receptor).13 In Table 1 the residual
binding of the respective radioligand at a test com-
pound concentration of 10 mM is summarized. With
exception of the s1-receptor affinity of 14b the resid-
ual binding of the radioligands in each experiment
exceeds 50%, indicating an IC50-value of greater than
10 mM.
1
strong.) H NMR (300 MHz), 13C NMR (75 MHz):
Unity 300 FT NMR spectrometer (Varian), l in ppm
related to tetramethylsilane, coupling constants are
given with 0.5 Hz resolution; the assignments of 13C
1
and of H NMR signals were supported by 2D NMR
techniques.
5.2. (+)-(2S)-Methyl 2-(2-chloroacetylamino)-3-hydroxy-
propanoate 8
The determination of the exact s1-receptor affinity13 of
the butyl substituted bicyclic lactam 14b by recording
the complete competition curves in triplicates led to a
Ki value of 345 nM (SEM 23 nM). Compared with
the antipsychotic agent BMY-14802,14 the s1-receptor
affinity of which has also been determined in our
assay [Ki=265 nM 32 nM (SEM)], 14b displays simi-
lar binding to s1-receptors.
A suspension of (S)-serine methyl ester hydrochloride9
6·HCl (10.0 g, 64.3 mmol) in CH2Cl2 (100 mL) was
cooled to −5°C. Triethylamine (17.9 mL, 128.6 mmol)
and subsequently a solution of chloroacetyl chloride
(4.9 mL, 61.1 mmol) in CH2Cl2 (15 mL) was added
dropwise. The reaction mixture was stirred for 1 h at
−5°C and for 1 h at room temperature. Precipitated
Et3N·HCl was filtered off, the solvent was evaporated
in vacuo and the residue was purified by flash chro-
matography (8 cm, ethyl acetate, 100 mL, Rf=0.38) to
4. Conclusion
yield 8 as a yellow, viscous oil (11.69 g, 93%). [h]589=
+30.8 (c=0.945, CH2Cl2); MS (EI): m/z (%)=196 (M,
1), 167/165 (M−OCH3, 16/50), 138/136 (M−CO2CH3,
25/75), 118 (M−ClCH2CO, 15), 79/77 (ClCH2CO, 12/
33), 59 (138/136−ClCH2CO, 9); IR (film): w (cm−1)=
3352 (br, OH), 2956 (m, C-H), 1740 (s, CꢀO ester),
1670 (s, CꢀO amide), 1536 (s, C-N), 1226 (s, C-O), 775
s1-Receptors bind several classes of psychoactive
agents including opioid-related compounds, phency-
clidine-related compounds and typical neuroleptics.15
Therefore, the bicyclic lactams 14, which differ from
the nootropics 4 by an alkyl residue at N(4), may have
potential in the treatment of psychiatric and neurode-
generative disorders.
1
(m, C-Cl); H NMR (CDCl3): l=2.48 (s broad, 1H,
OH), 3.82 (s, 3H, CO2CH3), 3.95 (dd, J=11.3/3.5 Hz,
Table 1. Residual binding (%) of the respective radioligand at a test compound concentration of 10 mM
Compound
NMDA
[(+)-MK-801]
k
m
s1
s2
(U-69593)
(DAMGO)
[(+)-Pentazocine]
Ditolylguanidine
13c
14b
14c
87%
83%
82%
90%
97%
96%
97%
102%
100%
79%
9.3%
84%
81%
58%
89%

S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
1297
1H, 3-H), 4.05 (dd, J=11.3/3.7 Hz, 1H, 3-H), 4.10 (s,
2H, CH2Cl), 4.65–4.70 (m, 1H, 2-H), 7.45 (s broad, 1H,
NH); calcd for C6H10ClNO4 (195.6) C, 36.84; H, 5.15;
N, 7.16. Found: C, 36.75; H, 5.40; N, 6.93%.
(PhCHOCH3, 12), 91 (benzyl, 37), 79/77 (ClCH2CO,
9/24), 65 (benzyl–C2H2, 3); MS (CI): m/z (%)=318/316
(MH+, 0.5/1). IR (film): w (cm−1)=2954 (m, C-H), 1744
(s, CꢀO ester), 1673 (s, CꢀO amide), 1442 (s, C-H), 1358
(m, C-O), 751 (m, C-Cl); 1H NMR (CDCl3): l=2.95 (s,
3×0.5H, OCH3 diastereomer 1), 2.96 (s, 3×0.5H, OCH3
diastereomer 2), 3.30 (dd, J=10.1/3.1 Hz, 0.5H, 3-H
diastereomer 1), 3.34 (dd, J=10.1/3.2 Hz, 0.5H, 3-H
diastereomer 2), 3.38 (s, 3×0.5H CO2CH3 diastereomer
1), 3.39 (s, 3×0.5H CO2CH3 diastereomer 2), 3.53 (dd,
J=10.1/3.2 Hz, 0.5H, 3-H diastereomer 1), 3.59 (dd,
J=10.0/3.1 Hz, 0.5H, 3-H diastereomer 2), 3.64–3.75
(m, 2H, CH2Cl), 4.26–4.37 (m, 1H, 2-H), 5.09 (s, 0.5H,
PhCH diastereomer 1), 5.10 (s, 0.5H, PhCH
diastereomer 2), 7.21–7.38 (m, 5H, arom.). The signal
for the proton of the NH group could not be detected;
calcd for C14H18ClNO5 (315.75): C, 53.25; H, 5.75; N,
4.44. Found: C, 52.81; H, 5.78; N, 4.47%.
5.3. (2R,4S)- and (2S,4S)-Methyl 3-chloroacetyl-2-
phenyl-1,3-oxazolidine-4-carboxylate cis-9 and trans-9
(a) Thermodynamic control: a solution of benzaldehyde
dimethyl acetal (2.3 mL, 15.3 mmol), 8 (1.0 g, 5.1 mmol)
and p-toluenesulfonic acid monohydrate (22 mg, 0.12
mmol) in toluene (20 mL) was heated under reflux for
2 h in a Dean–Stark trap. The reaction mixture was
concentrated to a volume of about 5 mL. After adding
Et2O (20 mL) to the cooled solution, the organic layer
was washed with a saturated solution of NaHCO3 (2×10
mL), water (10 mL) and brine (10 mL). The organic
layer was dried (Na2SO4), evaporated in vacuo and the
residue was separated by flash chromatography (5 cm,
CH2Cl2/ethyl acetate 9:1, 15 mL) to provide cis-9/trans-
9 (Rf=0.47) and 10 (Rf=0.29).
(b) Kinetic control: a solution of benzaldehyde dime-
thyl acetal (1.53 mL, 10.2 mmol) and 8 (2.0 g, 10.2
mmol) in CH2Cl2 (120 mL) was heated under reflux for
60 h. p-Toluenesulfonic acid monohydrate (4 mg, 0.02
mmol) was added to the cooled solution, and the
mixture was stirred under reflux for an additional 76 h.
The solvent was evaporated in vacuo and the residue
was separated by flash chromatography (6 cm, CH2Cl2/
ethyl acetate 9:1, 20 mL) to yield 9 (Rf=0.47) as pale
yellow, viscous oil (1.122 g, 39%) as a mixture of
cis-9/trans-9=9:1 and 10 (Rf=0.29) as pale yellow,
viscous oil (1.694 g, 56%).
cis-9/trans-9: Pale yellow, viscous oil (1.023 g, 71%). MS
(EI): m/z (%)=248 (M−Cl, 100), 224 (M−CO2CH3, 22),
206 (M−ClCH2CO, 58), 148 (2-phenyl-1,3-oxazolidine,
65), 105 (PhCHꢀO, 55), 91 (benzyl, 30), 65 (benzyl−
C2H2, 3); MS (CI): m/z (%)=286/284 (MH+, 20/70); IR
(film): w (cm−1)=2954 (m, C-H), 1747 (s, CꢀO ester),
1673 (s, CꢀO amide), 1423 (s, C-H), 1362 (m, C-O), 1212
(s, C-O), 759 and 701 (m, aryl-C-H); 1H NMR (CDCl3):
l=3.59 (d, J=13.3 Hz, 1H, CH2Cl), 3.67 (d, J=13.3
Hz, 1H, CH2Cl), 3.82 (s, 3×0.15H, OCH3, cis, rotamer
1), 3.84 (s, 3×0.70H, OCH3, trans), 3.87 (s, 3×0.15H,
OCH3, cis, rotamer 2), 4.03 (d broad, J=6.4 Hz, 0.15H,
5-H, cis, rotamer 2), 4.12 (dd, J=14.3/7.3 Hz, 0.70H,
5-H, trans), 4.13 (dd, J=9.5/3.4 Hz, 0.15H, 5-H, cis,
rotamer 1), 4.30 (dd, J=9.2/7.1 Hz, 2×0.15H, 5-H, cis),
4.30 (dd, J=14.3/12.0 Hz, 0.70H, 5-H, trans), 4.84–4.90
(m, 1H, 4-H), 6.16 (s broad, 0.70H, 2-H, trans), 6.37 (s,
0.15H, 2-H, cis rotamer 1), 6.49 (s, 0.15H, 2-H, cis
rotamer 2), 7.38–7.75 (m, 5H, arom.); 1H NMR
(DMSO, 27°C): l=3.70 (s, 3×0.15H, OCH3, cis,
rotamer 1), 3.75 (s, 3×0.70H, OCH3, trans), 3.77 (s,
3×0.15H, OCH3, cis, rotamer 2), 4.08–4.30 (m, 3H, 5-H
and CH2Cl(1H)), 4.44 (d broad, J=8.8 Hz, 0.70H,
CH2Cl, trans), 4.52 (dd, J=14.2/4.5 Hz, 0.30H, CH2Cl,
cis), 4.71–4.81 (m, 0.35H, 4-H, trans, rotamer 2), 4.91
(dd, J=6.4/2.6 Hz, 0.15H, 4-H, cis, rotamer 2), 5.07 (d,
J=5.8 Hz, 0.35H, 4-H, trans, rotamer 1), 5.19 (d, J=6.1
Hz, 0.15H, 4-H, cis, rotamer 1), 6.00 (s, 0.35H, 2-H,
trans, rotamer 1), 6.22 (s, 0.35H, 2-H, trans, rotamer 2),
6.25 (s, 0.15H, 2-H, cis, rotamer 1), 6.56 (s, 0.15H, 2-H,
(c) Synthesis of 9 from 10: a solution of 10 (4.163 g,
13.2 mmol) and p-toluenesulfonic acid monohydrate (81
mg, 0.43 mmol) in toluene (100 mL) was heated to
reflux for 2 h in a Dean–Stark trap. The reaction
mixture was concentrated to a volume of about 5 mL.
After addition of Et2O (30 mL) to the cooled solution,
the organic layer was washed with a saturated solution
of NaHCO3 (2×15 mL), water (15 mL) and brine (15
mL). The organic layer was dried (Na2SO4), evaporated
in vacuo and the residue was purified by flash chro-
matography (6 cm, CH2Cl2/ethyl acetate 9:1, 50 mL,
Rf=0.47). A mixture of cis-9/trans-9 was obtained as
pale yellow, viscous oil (2.18 g, 58%). Ratio cis-9/trans-
9=3:7.
5.4. (−)-(6S,9R)-4-Benzyl-9-phenyl-8-oxa-1,4-diazabi-
cyclo[4.3.0]nonane-2,5-dione cis-11a and (+)-(6S,9S)-4-
benzyl-9-phenyl-8-oxa-1,4-diazabicyclo[4.3.0]nonane-2,5-
dione trans-11a
1
cis, rotamer 2), 7.33–7.72 (m, 5H, arom.); H NMR
A solution of 9 (cis-9/trans-9=3:7, 1.0 g, 3.52 mmol),
benzylamine (0.38 mL, 3.52 mmol) and triethylamine
(0.49 mL, 3.52 mmol) in acetonitrile (200 mL) was
stirred under reflux for 48 h. Removal of the solvent in
vacuo followed by flash chromatography (5 cm, ethyl
acetate/petroleum ether 1:1, 20 mL) gave cis-11a (Rf=
0.38) and trans-11a (Rf=0.29).
(DMSO, 90°C): l=3.75 (s, 3H, OCH3), 4.14–4.31 (m,
4H, 5-H and CH2Cl2), 4.94–4.96 (m, 1H, 4-H), 6.16 (s,
0.70H, 2-H, trans), 6.37 (s, 0.30H, 2-H, cis), 7.37–7.56
(m, 5H, arom.); ratio of cis-9/trans-9=3:7; calcd for
C13H14ClNO4 (283.71): C, 55.04; H, 4.97; N, 4.94.
Found: C, 54.88; H, 5.13; N, 4.97%.
Compound 10: Pale yellow, viscous oil (0.105 g, 7%).
MS (EI): m/z (%)=249 (M−Cl−OCH3, 15), 248 (M−Cl−
HOCH3, 100), 206 (M−Cl−CO2CH3−CH3, 71), 121
cis-11a: Colorless solid (0.32 g, 29%; mp 79–80°C;
[h]589=−196.9
(c=0.645,
CH2Cl2);
C19H18N2O3
(322.36); HRMS: calcd 322.1317, found 322.1317 ( 0

1298
S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
ppm); MS (EI): m/z (%)=322 (M, 36), 231 (M−benzyl,
7), 175 (M−BnNCOCH, 4), 146 (BnNCOCH, 16), 105
(BnN, 34), 91 (benzyl, 100), 65 (benzyl−C2H2, 9); IR
(KBr): w (cm−1)=2891 (w, C-H), 1669 (s, CꢀO), 1448
(m, C-H), 1224 (m, C-O-C), 740 and 701 (m, aryl-C-H);
1H NMR (CDCl3): l=3.78 (d, J=16.6 Hz, 1H, 3-H),
4.06 (dd, J=16.6/1.4 Hz, 1H, 3-H), 4.21 (t, J=8.4 Hz,
1H, 7-H), 4.45 (td, J=7.3/1.4 Hz, 1H, 6-H), 4.46 (d,
J=14.6 Hz, 1H, PhCH2N), 4.58 (dd, J=8.4/7.2 Hz,
1H, 7-H), 4.76 (d, J=14.5 Hz, 1H, PhCH2N), 6.48 (s,
trans-11b: Pale yellow, viscous oil (0.9 g, 66%). [h]589=
−54.5 (c=1.14, CH2Cl2); C16H20N2O3 (288.35); HRMS:
calcd 288.1474, found 288.1473 (−0.1 ppm); MS (EI):
m/z (%)=288 (M, 88), 259 (M−CH2CH3, 8), 245 (M−
CH2CH2CH3, 6), 231 (M−butyl, 3), 211 (M−Ph, 16),
183 (211−CH2CH3, 23), 147 (2-phenyloxazolidin, 21),
105 (PhCO, 100), 77 (Ph, 62); IR (film): w (cm−1)=2958
(m, C-H), 1675 (s, CꢀO), 1437 (s, C-H), 1234 (m, C-O),
1
756 and 699 (m, aryl-C-H); H NMR (CDCl3): l=0.96
(t, J=7.3 Hz, 3H, CH2CH2CH2CH3), 1.36 (‘sext’, J=
7.4 Hz, 2H, CH2CH2CH2CH3), 1.57 (‘quint’, J=7.5
Hz, 2H, CH2CH2CH2CH3), 3.43 (dt, J=13.7/7.4 Hz,
1H, CH2CH2CH2CH3), 3.53 (dt, J=13.4/7.4 Hz, 1H,
CH2CH2CH2CH3), 3.80 (d, J=16.7 Hz, 1H, 3-H), 4.20
(dd, J=16.2/1.0 Hz, 1H, 3-H), 4.26 (t, J=7.9 Hz, 1H,
7-H), 4.42 (t, J=7.9 Hz, 1H, 7-H), 4.47 (td, J=8.2/1.2
Hz, 1H, 6-H), 6.25 (s, 1H, 9-H), 7.35–7.45 (m, 5H,
arom.).
1
1H, 9-H), 7.23–7.46 (m, 10H, arom.); H NOE: after
irradiation at l=6.48 ppm (9-H) a NOE was found at
l=4.21 ppm (7-H) and l=4.45 ppm (6-H).
trans-11a: Colorless solid (0.75 g, 66%); mp 114–115°C;
[h]589=+0.9 (c=0.505, CH2Cl2); calcd for C19H18N2O3
(322.36): C, 70.79; H, 5.63; N, 8.7. Found: C, 70.26; H,
5.64; N, 8.52%; MS (EI): m/z (%)=322 (M, 34), 231
(M−benzyl, 6), 175 (M−BnNCOCH, 3), 146
(BnNCOCH, 10), 105 (BnN, 30), 91 (benzyl, 100), 65
(benzyl−C2H2, 11); IR (KBr): w (cm−1)=2890 (w, C-H),
1674 (s, CꢀO), 1441 (m, C-H), 1234 (m, C-O), 737 and
700 (m, aryl-C-H); 1H NMR (CDCl3): l=3.80 (d,
J=17.0 Hz, 1H, 3-H), 4.09 (dd, J=17.0/1.2, 1H, 3-H),
4.32 (t, J=8.6 Hz, 1H, 7-H), 4.48 (t, J=8.6 Hz, 1H,
7-H), 4.54 (td, J=8.6/1.2 Hz, 1H, 6-H), 4.62 (d, J=
14.6 Hz, 1H, PhCH2N), 4.72 (d, J=14.5 Hz, 1H,
PhCH2N), 6.25 (s, 1H, 9-H), 7.29–7.38 (m, 10H,
arom.); 1H NOE: after irradiation at l=6.25 ppm
(9-H) an NOE was found at l=4.48 ppm (7-H). An
NOE at l=4.54 ppm was not detected.
5.6. (−)-(6S,9R)-4-(2,2-Dimethoxyethyl)-9-phenyl-8-oxa-
1,4-diazabicyclo[4.3.0]nonane-2,5-dione cis-11c and
(−)-(6S,9S)-4-(2,2-dimethoxyethyl)-9-phenyl-8-oxa-1,4-
diazabicyclo[4.3.0]nonan-2,5-dione trans-11c
A solution of 9 (cis-9/trans-9=3:7, 5.0 g, 17.6 mmol),
aminoacetaldehyde dimethyl acetal (1.9 mL, 17.6
mmol) and triethylamine (2.45 mL, 17.6 mmol) in
acetonitrile (400 mL) was stirred under reflux for 48 h.
Removal of the solvent in vacuo followed by flash
chromatography (8 cm, ethyl acetate/petroleum ether
9:1, 50 mL) gave cis-11c (Rf=0.27) and trans-11c
(Rf=0.18).
5.5. (−)-(6S,9R)-4-Butyl-9-phenyl-8-oxa-1,4-diazabi-
cyclo[4.3.0]nonane-2,5-dione cis-11b and (−)-(6S,9S)-4-
butyl-9-phenyl-8-oxa-1,4-diazabicyclo[4.3.0]nonane-2,5-
dione trans-11b
cis-11c: Pale yellow oil (1.46 g, 26%); [h]589=−180.5
(c=1.29, CH2Cl2); calcd for C16H20N2O5 (320.34): C,
59.99; H, 6.29; N, 8.74. Found: C, 59.71; H, 6.87; N,
8.74%; MS (EI): m/z (%)=289 (M−OCH3, 2), 105
(PhCHꢀO, 4), 91 (benzyl, 3), 75 (CH(OCH3)2, 100); MS
(CI): m/z (%)=321 (MH+, 4); IR (film): w (cm−1)=2942
(w, C-H), 2836 (w, O-CH3), 1673 (s, CꢀO), 1449 (m,
C-H), 1220 (m, C-O), 1076 (m, O-CH3), 733 and 699 (s,
A solution of 9 (cis-9/trans-9=3:7, 1.33 g, 4.7 mmol),
butan-1-amine (0.47 mL, 4.7 mmol) and triethylamine
(0.65 mL, 4.7 mmol) in acetonitrile (200 mL) was
refluxed for 48 h. Removal of the solvent in vacuo
followed by flash chromatography (6 cm, ethyl acetate/
ethanol, 5:1, 20 mL) gave cis-11b (Rf=0.65) and trans-
11b (Rf=0.55).
1
aryl-C-H); H NMR (CDCl3): l=3.33 (dd, J=13.9/5.3
Hz, 1H, CH2CH(OCH3)2), 3.41 (s, 3H, OCH3), 3.42 (s,
3H, OCH3), 3.75 (dd, J=13.9/5.1 Hz, 1H, CH2CH-
(OCH3)2), 4.00 (d, J=16.7 Hz, 1H, 3-H), 4.21 (dd,
J=8.3/7.6 Hz, 1H, 7-H), 4.36 (dd, J=16.5/1.6 Hz, 1H,
3-H), 4.43 (td, J=7.4/1.6 Hz, 1H, 6-H), 4.50 (t, J=5.1
Hz, 1H, CH(OCH3)2), 4.53 (dd, J=8.3/7.0 Hz, 1H,
7-H), 6.5 (s, 1H, 9-H), 7.35–7.5 (m, 5H, arom.).
cis-11b: Pale yellow, viscous oil (0.39 g, 29%), [h]589
=
−166.5 (c=0.895, CH2Cl2). C16H20N2O3 (288.35);
HRMS: calcd 288.1474, found 288.1473 (−0.1 ppm);
MS (EI): m/z (%)=288 (M, 100), 259 (M−CH2CH3,
10), 245 (M−CH2CH2CH3, 8), 231 (M−butyl, 7), 211
(M−Ph, 8), 183 (M−Ph–CH2CH3, 23), 147 (2-phenylox-
azolidin, 25), 105 (PhCO, 90), 77 (Ph, 26); IR (film): w
(cm−1)=2958 (m, C-H), 1670 (s, CꢀO), 1450 (s, C-H),
trans-11c: Pale yellow oil (3.4 g, 60%); [h]589=−48.0
(c=0.89, CH2Cl2); calcd C16H20N2O5 (320.34): C,
59.99; H, 6.29; N, 8.74. Found: C, 59.85; H, 6.47; N,
8.64%; MS (EI): m/z (%)=320 (M, 2), 289 (M−OCH3,
7), 105 (PhCHO, 5), 91 (benzyl, 5), 75 (CH(OCH3)2,
100); IR (film): w (cm−1)=2942 (w, C-H), 2835 (w,
O-CH3), 1681 (s, CꢀO), 1440 (m, C-H), 1079 (m, O-
1
1224 (m, C-O), 739 and 699 (m, aryl-C-H); H NMR
(CDCl3): l=0.95 (t, J=7.3 Hz, 3H, CH2CH2CH2CH3),
1.34 (‘sext’, J=7.4 Hz, 2H, CH2CH2CH2CH3), 1.55
(‘quint’, J=7.5 Hz, 2H, CH2CH2CH2CH3), 3.36 (dt,
J=13.8/7.4 Hz, 1H, CH2CH2CH2CH3), 3.52 (dt, J=
13.8/7.5 Hz, 1H, CH2CH2CH2CH3), 3.82 (d, J=16.8
Hz, 1H, 3-H), 4.19 (‘t’, J=8.1 Hz, 1H, 7-H), 4.23 (dd,
J=16.5/1.8 Hz, 1H, 3-H), 4.41 (td, J=7.4/1.5 Hz, 1H,
6-H), 4.54 (dd, J=8.5/7.3 Hz, 1H, 7-H), 6.49 (s, 1H,
9-H), 7.36–7.49 (m, 5H, arom.).
1
CH3), 733 and 699 (s, aryl-C-H); H NMR (CDCl3):
l=3.42 (s, 3H, OCH3), 3.43 (s, 3H, OCH3), 3.47 (dd,
J=14.0/5.0 Hz, 1H, CH2CH(OCH3)2), 3.70 (dd, J=
14.0/5.1 Hz, 1H, CH2CH(OCH3)2), 3.99 (d, J=17.1 Hz,
1H, 3-H), 4.25 (t, J=8.9 Hz, 1H, 7-H), 4.32 (dd,
J=17.1/1.2 Hz, 1H, 3-H), 4.42 (t, J=8.8 Hz, 1H, 7-H),

S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
1299
4.47 (td, J=8.7/1.2 Hz, 1H, 6-H), 4.52 (t, J=5.2 Hz,
1H, CH(OCH3)2), 6.27 (s, 1H, 9-H), 7.31–7.39 (m, 5H,
arom.).
cm, ethyl acetate/ethanol, 5:1, 20 mL, Rf=0.26) fur-
nished 5b as a pale yellow, viscous oil; (0.909 g, 74%);
[h]589=+19.4 (c=0.875, CH2Cl2); C16H26N2O (262.39);
HRMS: calcd for M−CH2OH (C15H23N2) 231.1861,
found 231.1861 ( 0 ppm); MS (EI): m/z (%)=233
(M−CH2CH3, 5), 231 (M−CH2OH, 100), 140
(butylpiperazine, 10), 91 (benzyl, 68), 65 (benzyl−C2H2,
6); MS (CI): m/z (%)=263 (MH+, 100); IR (film): w
(cm−1)=3393 (br, OH), 2954 (s, C-H), 2816 (s, C-OH),
1454 (m, C-H), 1153 (m, C-OH), 739 and 699 (s,
5.7. (+)-[(2R)-1,4-Dibenzylpiperazin-2-yl]methanol 5a
A solution of 11a (mixture of cis/trans isomers, 1.0 g,
3.1 mmol) in THF (80 mL) was added to a stirred
suspension of a LiAlH4 pellet (1.12 g, 29.5 mmol) in
THF (150 mL). The reaction mixture was heated to
reflux for 72 h. Under N2 atmosphere and cooling (ice
bath) water (1 mL), NaOH (3N, 1.0 mL) and again
water (1 mL) were successively added. The suspension
was refluxed for 30 min. After the mixture was cooled
to room temperature, the precipitate was filtered off
and the solvent removed under reduced pressure. The
residue was dissolved in CH2Cl2 (20 mL), the solution
was washed with NaOH (1N, 2×10 mL) and brine (10
mL), dried with Na2SO4 and evaporated in vacuo.
Purification of the residue by flash chromatography (3
cm, ethyl acetate, 15 mL, Rf=0.24) furnished 5a as a
1
aryl-C-H); H NMR (CDCl3): l=0.91 (t, J=7.3 Hz,
3H, CH2CH2CHCH3), 1.32 (‘sext’, J=7.3 Hz, 2H,
CH2CH2CH2CH3), 1.47 (‘quint’, J=7.4 Hz, 2H,
CH2CH2CH2CH3), 2.31 (‘t’, J=7.5 Hz, 2H,
CH2CH2CH2CH3), 2.31–2.39 (m, 1H, 3-H, 5-H or 6-H),
2.43–2.51 (m, 2H, 3-H, 5-H and/or 6-H), 2.58–2.69 (m,
3H, 2-H and 3-H, 5-H and/or 6-H), 2.93–3.01 (m, 1H,
3-H, 5-H or 6-H), 3.46 (d, J=13.3 Hz, 1H, PhCH2N),
3.61 (dd, J=11.4/1.9 Hz, 1H, CH2OH), 3.98 (d, J=
13.3 Hz, 1H, PhCH2N), 4.10 (dd, J=11.5/2.8 Hz, 1H,
CH2OH), 7.24–7.32 (m, 5H, arom.). The signal for the
proton of the OH group could not be detected; 13C
NMR (CDCl3): l=13.9 (1C, CH2CH2CH2CH3), 20.6
(1C, CH2CH2CH2CH3), 28.8 (1C, CH2CH2CH2CH3),
49.9, 52.6 and 56.4 (3C, C-3, C-5, C-6), 58.4 (1C,
PhCH2N), 58.3 (1C, CH2CH2CH2CH3), 58.5 (1C, C-2),
62.2 (1C, CH2OH), 127.0 (1C, C-4 arom.), 128.3 (2C,
C-3 and C-5 arom.), 128.8 (2C, C-2 and C-6 arom.),
138.4 (1C, C-1 arom.).
pale yellow, viscous oil, yield (0.524 g, 57%). [h]589
=
+30.0 (c=1.165, CH2Cl2); C19H24N2O (296.41) HRMS:
calcd for M−OCH3 (C18H21N2) 265.1705, found
265.1704 (−0.1 ppm); MS (EI): m/z (%)=265 (M−
CH2OH, 34), 174 (benzylpiperazine, 4), 146
(BnNCH2CHN, 19), 106 (BnNH, 13), 91 (benzyl, 100),
65 (benzyl−C2H2, 12); MS (CI): m/z (%)=297 (MH+,
100); IR (film): w (cm−1)=3381 (br, OH), 2937 (m,
C-H), 2811 (s, C-O), 1452 (m, C-H), 1147 (m, C-O), 738
1
and 700 (s, aryl-C-H); H NMR (CDCl3): l=2.35–2.54
5.9. (+)-[(2R)-1-Benzyl-4-(2,2-dimethoxyethyl)piperazin-
2-yl]methanol 5c
(m, 3H, 3-H, 5-H and/or 6-H), 2.57–2.70 (m, 3H, 2-H
and 3-H, 5-H and/or 6-H), 2.93–3.00 (m, 1H, 3-H, 5-H
or 6-H), 3.47 (d, J=13.1 Hz, 1H, PhCH2N1), 3.49 (s,
2H, PhCH2N4), 3.59 (dd, J=11.3/2.2 Hz, 1H, CH2OH),
3.99 (d, J=13.3 Hz, 1H, PhCH2N1), 4.05 (dd, J=11.5/
3.2 Hz, 1H, CH2OH), 7.22–7.34 (m, 10H, arom.). The
signal for the proton of the OH group could not be
detected; 13C NMR (CDCl3): l=49.8 and 52.3 (2C,
C-5, C-6), 55.9 (1C, C-3), 57.9 (1C, N1CH2Ph), 58.7
(1C, C-2), 61.9 (1C, CH2OH), 63.0 (1C, N4CH2Ph),
126.9 and 127.1 (2C, 2×C-4 arom.), 128.2 and 128.6 (4
C, 2×C-3 and 2×C-5 arom.), 128.8 and 129.0 (4 C,
2×C-2 and 2×C-6 arom.), 137.5 and 138.4 (2C, 2×C-1
arom.).
A solution of 11c (mixture of cis/trans isomers, 1.0 g,
3.1 mmol) in THF (80 mL) was added to a stirred
suspension of a LiAlH4 pellet (1.06 g, 27.9 mmol) in
THF (150 mL). The reaction mixture was heated under
reflux for 72 h. Under N2 atmosphere and cooling (ice
bath) water (1 mL), NaOH (3N, 1.0 mL) and further
water (1 mL) were successively added. The suspension
was stirred under reflux for 30 min. The mixture was
cooled to room temperature, the precipitate was filtered
off and the solvent removed under reduced pressure.
The residue was dissolved in CH2Cl2 (20 mL), the
solution was washed with NaOH (1N, 2×10 mL) and
brine (10 mL), dried with Na2SO4 and evaporated in
vacuo. Purification of the residue by flash chromatogra-
phy (3 cm, ethyl acetate/ethanol, 5:1, 10 mL, Rf=0.26)
furnished 5c as pale yellow, viscous oil (0.569 g, 62%);
[h]589=+21.9 (c=1.12, CH2Cl2); C16H26N2O3 (294.1);
HRMS: calcd for M−OCH3 (C15H23N2O2) 263.1759,
found 263.1760 (+0.1 ppm); MS (EI): m/z (%)=294
(M, 1), 263 (M−OCH3, 100), 219 (M−CH(OCH3)2, 34),
172 (263−benzyl, 20), 91 (benzyl, 41), 75 (CH(OCH3)2,
6); MS (CI): m/z (%)=295 (MH+, 100); IR (film): w
(cm−1)=3381 (br, O-H), 2944 (s, C-H), 2825 (s, OCH3),
1452 (m, C-H), 1128 (s, C-OH), 1070 (s, O-CH3), 735
5.8. (+)-[(2R)-1-Benzyl-4-butylpiperazin-2-yl]methanol
5b
A solution of 11b (mixture of cis/trans isomers, 1.0 g,
3.47 mmol) in THF (80 mL) was added to a stirred
suspension of a LiAlH4 pellet (1.01 g, 26.5 mmol) in
THF (150 mL). The mixture was stirred under reflux
for 72 h. Under N2 atmosphere and cooling (ice bath)
water (1 mL), NaOH (3N, 1.0 mL) and further water (1
mL) were successively added. The suspension was
stirred under reflux for 30 min. After the mixture was
cooled to room temperature, the precipitate was filtered
off and the solvent removed under reduced pressure.
The residue was dissolved in CH2Cl2 (20 mL), the
solution was washed with NaOH (1N, 2×10 mL) and
brine (10 mL), dried with Na2SO4 and evaporated.
Purification of the residue by flash chromatography (4
1
and 700 (m, aryl-C-H); H NMR (CDCl3): l=2.41–
2.46 (m, 2H, 3-H, 5-H and/or 6-H), 2.48 (dd, J=13.3/
5.3 Hz, 1H, CH2CH(OCH3)2), 2.53 (dd, J=13.3/5.3 Hz,
1H, CH2CH(OCH3)2), 2.57–2.70 (m, 3H, 2-H and 3-H,
5-H and/or 6-H), 2.74–2.79 (m, 1H, 3-H, 5-H or 6-H),
2.89–2.97 (m, 1H, 3-H, 5-H or 6-H), 3.35 (s, 6H,

1300
S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
2×OCH3), 3.46 (d, J=13.3 Hz, 1H, PhCH2N), 3.61 (dd,
J=11.5/2.1 Hz, 1H, CH2OH), 3.98 (d, J=13.3 Hz, 1H,
PhCH2N), 4.05 (dd, J=11.1/3.1 Hz, 1H, CH2OH), 4.52
(t, J=5.3 Hz, 1H, CH(OCH3)2), 7.25–7.35 (m, 5H,
arom.). The signal for the proton of the OH group
could not be detected; 13C NMR (CDCl3): l=49.9,
53.3 and 56.8 (3C, C-3, C-5, C-6), 53.3 (2C, 2×OCH3),
58.0 (1C, PhCH2N), 58.6 (1C, C-2), 59,7 (1C,
CH2CH(OCH3)2), 62.1 (1C, CH2OH), 102.3 (1C,
CH(OCH3)2), 127.0 (1C, C-4 arom.), 128.3 (2C, C-3
and C-5 arom.), 128.8 (2C, C-2 and C-6 arom.), 138.5
(1C, C-1 arom.).
OCH2CH3), 20.6 (1C, CH2CH2CH2CH3), 28.9 (1C,
CH2CH2CH2CH3), 50.8, 53.0 and 58.2 (3C, C-3, C-5,
C-6), 58.5 (1C, CH2CH2CH2CH3), 59.8 (0.85 C,
PhCH2N (E)-isomer), 60.0 (0.15 C, PhCH2N (Z)-iso-
mer), 60.1 (0.15 C, OCH2CH3 (Z)-isomer), 60.4 (0.85
C, OCH2CH3 (E)-isomer), 63.1 (1C, C-2), 121.9 (0.15
C, CHꢀCHCO2Et (Z)-isomer), 123.7 (0.85 C,
CHꢀCHCO2Et (E)-isomer), 126.9 (1C, C-4 arom.),
128.1 (2C, C-3 and C-5 arom.), 128.9 (2C, C-2 and C-6
arom.), 138.3 (1C, C-1 arom.), 148.8 (0.85 C,
CHꢀCHCO2OEt
(E)-isomer),
149.0
(0.15
C,
CHꢀCHCO2Et (Z)-isomer), 166.0 (1C, CO2Et).
5.10. (+)-Ethyl 3-[(2S)-1-benzyl-4-butylpiperazin-2-yl]-
prop-2-enoate 13b
5.11. (+)-Ethyl 3-[(2S)-1-benzyl-4-(2,2-dimethoxyethyl)-
piperazin-2-yl]prop-2-enoate 13c
To a stirred and cooled (−78°C) mixture of CH2Cl2 (20
mL) and oxalyl chloride (0.18 mL, 2.1 mmol), was
added dropwise a solution of dimethyl sulfoxide (0.3
mL, 4.2 mmol) in CH2Cl2 (10 mL). After stirring for 2
min at −78°C a solution of 5b (0.5 g, 1.9 mmol) in
CH2Cl2 (30 mL) was added within 5 min. The mixture
was stirred for an additional 15 min. Triethylamine
(1.32 mL, 9.55 mmol) was added and the reaction
mixture was stirred at −78°C for 5 min and then
allowed to warm to room temperature. The Wittig
reagent 12 (1.33 g, 3.82 mmol) dissolved in CH2Cl2 (30
mL) was added dropwise. The reaction mixture was
stirred for 5 h at room temperature. Water (30 mL) was
added, the organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3×15 mL). The
organic layers were combined, washed with brine (2×50
mL), dried (Na2SO4) and concentrated in vacuo. Flash
chromatography of the residue (5 cm, petroleum ether/
ethyl acetate, 1:3, 20 mL, Rf=0.45) afforded 13b
[(E)/(Z)=85:15], as a pale yellow oil (0.513 g, 81%);
[h]589=+36.3 (c=0.420, CH2Cl2); C20H30N2O2 (330.47);
HRMS: calcd 330.2307, found 330.2306 (−0.1 ppm);
MS (EI): m/z (%)=330 (M, 15), 285 (M−OCH2CH3, 3),
239 (M−benzyl, 41), 210 (M−benzyl–CH2CH3, 6), 140
(butylpiperazine, 2), 91 (benzyl, 100), 65 (benzyl−C2H2,
12); MS (CI): m/z (%)=331 (MH+, 100); IR (film): w
(cm−1)=2954 (s, C-H), 2808 (s, C-O), 1722 (s, CꢀO),
1654 (m, CꢀC), 1453 (m, C-H), 986 (w, H-CꢀC-H), 738
To a stirred and cooled (−78°C) mixture of CH2Cl2 (25
mL) and oxalyl chloride (0.32 mL, 3.7 mmol), was
added dropwise a solution of dimethyl sulfoxide (0.53
mL, 7.5 mmol) dissolved in CH2Cl2 (10 mL). After
stirring for 2 min at −78°C a solution of 5c (1.0 g, 3.4
mmol) in CH2Cl2 (50 mL) was added over 5 min. The
mixture was stirred for an additional 15 min and tri-
ethylamine (2.4 mL, 17 mmol) was added. The reaction
mixture was stirred at −78°C for 5 min. It was allowed
to warm to room temperature. The Wittig reagent 12
(2.37 g, 6.8 mmol) dissolved in CH2Cl2 (40 mL) was
added dropwise. The reaction mixture was stirred for 5
h at room temperature. Water (30 mL) was added, the
organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3×15 mL). The organic layers
were combined, washed with brine (2×50 mL), dried
(Na2SO4) and concentrated in vacuo. Flash chromatog-
raphy of the residue (6 cm, petroleum ether/ethyl ace-
tate 1:3, 20 mL, Rf=0.31) afforded 13c [(E)/(Z)=
85:15], as a pale yellow oil (0.814 g, 66%); [h]589=+29.3
(c=0.915, CH2Cl2); calcd for C20H30N2O4 (362.47): C,
66.27; H, 8.34; N, 7.73. Found: C, 66.09; H, 8.09; N,
7.87%; MS (EI): m/z (%)=362 (M, 15), 331 (M−OCH3,
20), 287 (M−CH(OCH3)2, 100), 196 (287−benzyl, 2),
175 (benzylpiperazine, 10), 91 (benzyl, 90), 75
(CH(OCH3)2, 30); IR (film): w (cm−1)=2942 (s, C-H),
2824 (s, O-CH3), 1719 (s, CꢀO), 1581 (m, CꢀC), 1451
(m, C-H), 1368 (m, C-O-Et), 1075 (s, O-CH3), 981 (m,
H-CꢀC-H), 736 and 701 (m, aryl-C-H); 1H NMR
(CDCl3): l=1.30 (t, J=7.2 Hz, 3H, OCH2CH3), 2.18–
2.34 (m, 3H, 3-H, 5-H and/or 6-H), 2.52 (d, J=5.3 Hz,
2H, CH2CH(OCH3)2), 2.70–2.79 (m, 3H, 3-H, 5-H and/
or 6-H), 3.12 (d, J=13.7 Hz, 0.85H, PhCH2N (E)-iso-
mer), 3.15 (td, J=8.8/2.9 Hz, 1H, 2-H), 3.34 (s, 3H,
OCH3), 3.35 (s, 3H, OCH3), 3.56 (d, J=13.5 Hz,
0.15H, PhCH2N (Z)-isomer), 3.87 (d, J=13.6 Hz,
0.15H, PhCH2N (Z)-isomer), 3.91 (d, J=13.4 Hz,
0.85H, PhCH2N (E)-isomer), 4.19 (q, J=7.1 Hz, 2×
0.15H, OCH2CH3 (Z)-isomer), 4.20 (q, J=7.1 Hz, 2×
0.85H, OCH2CH3 (E)-isomer), 4.49 (t, J=5.2 Hz, 1H,
1
and 700 (m, aryl-C-H); H NMR (CDCl3): l=0.89 (t,
J=7.2 Hz, 3H, CH2CH2CH2CH3), 1.28 (t, J=7.0 Hz,
3H, OCH2CH3), 1.29 (‘sext’, J=7.3 Hz, 2H,
CH2CH2CH2CH3), 1.44 (‘quint’, J=7.5 Hz, 2H,
CH2CH2CH2CH3), 2.03–2.23 (m, 3H, 3-H, 5-H and/or
6-H), 2.30 (t, J=7.6 Hz, 2H, CH2CH2CH2CH3), 2.67–
2.79 (m, 3H, 3-H, 5-H and/or 6-H), 3.09 (d, J=13.4
Hz, 0.85H, PhCH2N (E)-isomer), 3.11–3.18 (m, 1H,
2-H), 3.20 (d, J=13.4 Hz, 0.15H, PhCH2N (Z)-isomer),
3.84 (d, J=13.4 Hz, 0.15H, PhCH2N (Z)-isomer), 3.91
(d, J=13.4 Hz, 0.85H, PhCH2N (E)-isomer), 4.19 (q,
J=7.2 Hz, 2×0.15H, OCH2CH3 (Z)-isomer), 4.20 (q,
J=7.2 Hz, 2×0.85H, OCH2CH3 (E)-isomer), 5.90 (d,
J=12.0 Hz, 0.15H, CHꢀCHCO2Et (Z)-isomer), 6.06
(d, J=15.9 Hz, 0.85H, CHꢀCHCO2Et (E)-isomer), 6.32
(dd, J=12.4/8.2 Hz, 0.15H, CHꢀCHCO2Et (Z)-iso-
mer), 6.96 (dd, J=15.9/8.6 Hz, 0.85H, CHꢀCHCO2Et
(E)-isomer), 7.21–7.29 (m, 5H, arom.); 13C NMR
(CDCl3): l=13.9 (1C, CH2CH2CH2CH3), 14.2 (1C,
CH(OCH3)2), 5.91 (d,
J=11.9 Hz, 0.15H,
CHꢀCHCO2Et (Z)-isomer), 6.07 (d, J=15.9 Hz,
0.85H, CHꢀCHCO2Et (E)-isomer), 6.31 (dd, J=11.6/
9.2 Hz, 0.15H, CHꢀCHCO2Et (Z)-isomer), 6.96 (dd,
J=15.9/8.5 Hz, 0.85H, CHꢀCHCO2Et (E)-isomer),
7.21–7.33 (m, 5H, arom.); 13C NMR (CDCl3): l=14.2
(1C, OCH2CH3), 50.5, 53.3 and 58.8 (3C, C-3, C-5,

S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
1301
C-6), 53.4 and 53.6 (2C, 2×OCH3), 59.6 (1C,
CH2CH(OCH3)2), 59.7 (0.85 C, PhCH2N (E)-isomer),
59.9 (0.15 C, PhCH2N (Z)-isomer), 60.1 (0.15 C,
OCH2CH3 (Z)-isomer), 60.4 (0.85 C, OCH2CH3 (E)-
isomer), 62.7 (1C, C-2), 102.4 (1C, CH(OCH3)2), 122.0
(0.15 C, CHꢀCHCO2Et (Z)-isomer), 123.9 (0.85 C,
CHꢀCHCO2Et (E)-isomer), 126.9 (1C, C-4 arom.),
128.2 (2C, C-3 and C-5 arom.), 128.9 (2C, C-2 and C-6
arom.), 138.2 (1C, C-1 arom.), 148.5 (0.85 C,
8-H), 2.53 (dd, J=13.4/5.2 Hz, 1H, CH2CH(OCH3)2),
2.59 (dd, J=13.4/5.1 Hz, 1H, CH2CH(OCH3)2), 2.85–
2.95 (m, 2H, 2-H and 3-H), 3.04 (ddd, J=10.9/3.5/1.2
Hz, 1H, 5-H), 3.35 (s, 3H, OCH3), 3.36 (s, 3H, OCH3),
3.64 (dtd, J=10.7/7.1/3.6 Hz, 1H, 6-H), 3.92–3.98 (m,
1H, 2-H), 4.50 (t, J=5.2 Hz, 1H, CH(OCH3)2); 13C
NMR (CDCl3): l=22.1 (1C, C-7), 30.2 (1C, C-8), 39.5
(1C, C-2), 50.5 (1C, C-3), 53.5 (1C, OCH3), 53.6 (1C,
OCH3), 55.5 (1C, C-6), 59.7 (1C, CH2CH(OCH3)2),
60.7 (1C, C-5), 102.7 (1C, CH(OCH3)2), 173.2 (1C,
C-9).
CHꢀCHCO2Et
(E)-isomer),
149.0
(0.15
C,
CHꢀCHCO2Et (Z)-isomer), 166.0 (1C, CO2Et).
5.14. Receptor binding studies, general13
5.12. (−)-(6S)-4-Butyl-1,4-diazabicyclo[4.3.0]nonan-9-
one 14b
Homogenizer: Potter® S (B. Braun Biotech Interna-
tional). Ultraturrax: Euroturrax® T20 (Ika Labortech-
nik). Centrifuge: high speed cooling centrifuge model
J2-HS (Beckman). Filter: Whatman glass fiber filters
GF/B, presoaked in the medium described below before
use. Filtration was performed with a Brandel 24-well
cell harvester. Scintillation cocktail: Rotiscint Eco Plus
(Roth). Liquid scintillation analyzer: TriCarb 2100 TR
(Canberra Packard), counting efficiency 66%. All exper-
iments were carried out in triplicate. IC50 values were
determined from competition experiments with at least
six concentrations of test compounds and were calcu-
lated with the GraphPad Prism® 3.0 program (Graph-
Pad Software) by nonlinear regression analysis. Ki
values were calculated according to Cheng and Pru-
soff.17 The Ki values are given as mean value SEM
from three independent experiments.
Pd/C (10%, 88 mg) was added to a solution of 13b
(0.176 g, 0.56 mmol) in CH3OH (15 mL). The suspen-
sion was stirred under a H2 atmosphere (5 bar) at room
temperature for 12 h. The mixture was filtered through
a pad of Celite® AFA and the filtrate was concentrated
in vacuo. Flash chromatography (2 cm, ethanol, 2 mL,
Rf=0.29) of the residue yielded 14b as a pale yellow,
viscous oil (42 mg, 40%); [h]589=−32.5 (c=1.82,
CH2Cl2); C11H20N2O (196.29), HRMS: calcd 196.1576,
found 196.1575 (−0.1 ppm); MS (EI): m/z (%)=196
(M, 9), 153 (M−CH2CH2CH3, 100), 138 (M−CH2CH2-
CH2CH3, 8), 112 (ethylpiperazine, 3), 83 (piperazine, 4);
IR (film): w (cm−1)=2954 (s, C-H), 1678 (s, CꢀO), 1498
1
(m, C-H); H NMR (CDCl3): l=0.90 (t, J=7.3 Hz,
3H, CH2CH2CH2CH3), 1.31 (‘sext’, J=7.3 Hz, 2H,
CH2CH2CH2CH3), 1.45 (‘quint’, J=7.6 Hz, 2H,
CH2CH2CH2CH3), 1.52–1.60 (m, 1H, 7-H), 1.67 (t,
J=10.6 Hz, 1H, 5-H), 1.89 (dd, J=15.4/3.6 Hz, 1H,
3-H), 2.07–2.21 (m, 1H, 7-H), 2.32–2.40 (m, 4H, 8-H
and CH2CH2CH2CH3), 2.80–2.86 (m, 2H, 2-H and
3-H), 2.98 (ddd, J=10.9/3.5/1.5 Hz, 1H, 5-H), 3.62
(dtd, J=10.6/7.1/3.6 Hz, 1H, 6-H), 3.93–3.99 (m,
1H, 2-H); 13C NMR (CDCl3): l=13.9 (1C,
CH2CH2CH2CH3), 20.6 (1C, CH2CH2CH2CH3), 22.2
(1C, C-7), 28.8 (1C, CH2CH2CH2CH3), 30.2 (1C, C-8),
39.5 (1C, C-2), 51.9 (1C, C-3), 55.5 (1C, C-6), 58.1 (1C,
CH2CH2CH2CH3), 60.1 (1C, C-5), 173.2 (1C, C-9).
5.15. Performance of the s1-assay
For the s1-assay guinea pig brain membranes were
prepared as described in Ref. 13. The test was per-
formed with the radioligand [3H]-pentazocine (1036
GBq/mmol; NEN™ Life Science Products). The
thawed membrane preparation (about 150 mg of
protein) was incubated with various concentrations of
the test compound, 3 nM [3H]-pentazocine, and buffer
(50 mM Tris–HCl, pH 7.4) in a total volume of 500 mL
for 120 min at 37°C. The incubation was terminated by
rapid filtration through presoaked Whatman GF/B
filters (0.5% polyethylenimine in water for 2 h at 4°C)
using a cell harvester. After washing four times with 2
mL of cold buffer, 3 mL of scintillation cocktail was
added to the filters. After at least 8 h bound radioactiv-
ity trapped on the filters was counted in a liquid
scintillation analyzer. Nonspecific binding was deter-
mined with 10 mM haloperidol.
5.13. (−)-(6S)-4-(2,2-Dimethoxyethyl)-1,4-diazabicyclo-
[4.3.0]nonan-9-one 14c
Pd/C (10%, 25 mg) was added to a solution of 13c (84
mg, 0.23 mmol) in CH3OH (10 mL). The suspension
was stirred under a H2 atmosphere (balloon) at room
temperature for 5 h. The mixture was filtered through a
pad of Celite® AFA and the filtrate was concentrated in
vacuo. Flash chromatography (1 cm, ethanol, 2 mL,
Rf=0.33) of the residue yielded 14c as pale yellow
viscous oil, yield 34 mg (64%); [h]589=−27.9 (c=1.4,
CH2Cl2); C11H20N2O3 (228.29); HRMS: calcd for M−
OCH3 (C10H17N2O2) 197.1290, found 197.1290 ( 0
ppm); MS (EI): m/z (%)=228 (M, 5), 197 (M−OCH3,
4), 153 (M−CH(OCH3)2, 100), 138 (M−CH2CH-
(OCH3)2, 6), 75 (CH(OCH3)2, 7); IR (film): w (cm−1)=
2945 (m, C-H), 2833 (m, O-CH3), 1675 (s, CꢀO), 1458
Acknowledgements
Financial support of this work by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemis-
chen Industrie is gratefully acknowledged. Thanks are
also due to the Degussa AG, Janssen-Cilag GmbH, and
Bristol-Myers Squibb for donation of chemicals and
reference compounds.
1
(m, C-H), 1070 (m, O-CH3); H NMR (CDCl3): l=
1.49–1.62 (m, 1H, 7-H), 1.85 (t, J=10.8 Hz, 1H, 5-H),
2.03–2.19 (m, 2H, 3-H and 7-H), 2.34–2.39 (m, 2H,

1302
S. Bedu¨rftig et al. / Tetrahedron: Asymmetry 12 (2001) 1293–1302
1993, 4, 2389–2398; (d) Falorni, M.; Porcheddu, A.;
References
Giacomelli, G. Tetrahedron: Asymmetry 1996, 7, 1999–
2005; (e) Warshawsky, A. M.; Patel, M. V.; Chen, T.-M.
J. Org. Chem. 1997, 62, 6439–6440.
1. Naylor, A.; Judd, D. E.; Lloyd, J. E.; Scopes, D. I. C.;
Hayes, A. G.; Birch, P. J. J. Med. Chem. 1993, 36,
2075–2083.
2. Bra¨uner-Osborne, H.; Egebjerg, J.; Nielsen, E.; Madsen,
U.; Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43,
2609–2645.
9. Seebach, D.; Stucky, G.; Renaud, P. Chimia 1988, 42,
176–278.
10. Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J.
Org. Chem. 1961, 26, 2525–2528.
3. (a) Mills, S. G.; Wu, M. T.; MacCoss, M.; Budhu, R. J.;
Dorn, C. P.; Cascieri, M. A.; Sadowski, S.; Strader, C.
D.; Greenlee, W. J. Bioorg. Med. Chem. Lett. 1993, 3,
2707–2712; (b) Mills, S. G.; MacCoss, M.; Cascieri, M.
A.; Sadowski, S.; Patel, S.; Chapman, K. L.; Hutson, P.
H. Bioorg. Med. Chem. Lett. 1995, 5, 599–604.
4. Rossen, K.; Pye, P. J.; DiMichele, L. M.; Volante, R. P.;
Reider, P. Tetrahedron Lett. 1998, 39, 6823–6826.
5. Fukushi, H.; Mabuchi, H.; Terashita, Z.; Nishikawa, K.;
Sugihara, H. Chem. Pharm. Bull. 1994, 42, 551–559.
6. Manetti, D.; Ghelardini, C.; Bartolini, A.; Bellucci, C.;
Die, S.; Galeotti, N.; Gualtieri, F.; Romanelli, N. M.;
Scapecchi, S.; Teodori, E. J. Med. Chem. 2000, 43, 1969–
1974.
11. (a) Piwinski, J. J.; Wong, J. K.; Greene, M. J.; Kaminski,
J. J.; Colizzo, F.; Albanese, M. M.; Ganguly, A. K.;
Billah, M. M.; Anthes, J. C.; West, R. E. Bioorg. Med.
Chem. Lett. 1998, 8, 3469–3474; (b) Van den Branden, S.;
Compernolle, F.; Hoornaert, G. J. J. Chem. Soc., Perkin
Trans. 1 1992, 1035–1042.
12. Swern, D.; Mancuso, A. J. Synthesis 1981, 165–185.
13. Soukara, S.; Maier, C.; Predoiu, U., Ehret, A.; Jackisch,
R.; Wu¨nsch, B. J. Med. Chem. 2001, in press.
14. Drugs fut. 1995, 20, 821–822. Original monograph: Drugs
fut. 1987, 12, 752–755.
15. (a) Wlaker, J. M.; Bowen, W. D.; Walker, F. O.; Mat-
sumoto, R. R.; de Costa, B.; Rice, K. C. Pharmacol. Rev.
1990, 42, 355–402; (b) Kaiser, C.; Pontecorvo, M. J.;
Mewshaw, R. E. Neurotransmission 1991, 7, 1–5.
16. Still, W. S.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923–2925.
7. Soukara, S.; Wu¨nsch, B. Synthesis 1999, 1739–1746.
8. (a) Fischer, E.; Roesner, H. Liebigs Ann. Chem. 1910,
375, 199–206; (b) Falorni, M.; Giacomelli, G.; Satta, M.;
Coss, S. Synthesis 1994, 391–395; (c) Falorni, M.; Satta,
M.; Conti, S.; Giacomelli, G. Tetrahedron: Asymmetry
17. Cheng, Y.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22,
3099–3108.
.