Analogs of the dopamine D4 receptor ligand FAUC 113 with planar- and central-chirality

Article abstract of DOI:10.1016/S0957-4166(02)00639-0

By employing yeast enzymes, natural amino acids and the Jacobsen's catalyst as sources of chirality, we have synthesized pyrazolo[1,5-a]pyridine derivatives with central- and planar-chirality as analogs of the dopamine D4 receptor ligand FAUC 113. In vitro binding experiments displayed enhanced D2 and D3 affinity for both enantiomers of the [2.2]paracyclophane 3. The C-methylpiperazine (R)-4a revealed excellent D4 selectivity.

Full text of DOI:10.1016/S0957-4166(02)00639-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2303–2310
Analogs of the dopamine D4 receptor ligand FAUC 113 with
planar- and central-chirality
Stefan Lo¨ber, Birgit Ortner, Laura Bettinetti, Harald Hu¨bner and Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19,
D-91052 Erlangen, Germany
Received 31 July 2002; accepted 27 September 2002
Abstract—By employing yeast enzymes, natural amino acids and the Jacobsen’s catalyst as sources of chirality, we have
synthesized pyrazolo[1,5-a]pyridine derivatives with central- and planar-chirality as analogs of the dopamine D4 receptor ligand
FAUC 113. In vitro binding experiments displayed enhanced D2 and D3 affinity for both enantiomers of the [2.2]paracyclophane
3. The C-methylpiperazine (R)-4a revealed excellent D4 selectivity. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
receptor ligands.3 Following these requirements, we
recently reported on the highly selective D4 receptor
partial agonist FAUC 113 revealing D4 affinity in the
low nanomolar range.4 Structural modification led to
the regioisomer FAUC 213 showing a full antagonist
profile.5 In contrast, introduction of a cyano substituent
into position 7 of the pyrazolo[1,5-a]pyridine moiety
(FAUC 327) significantly increased the intrinsic activ-
ity.6 As we are planning non-invasive investigations of
D4-neurotransmission by SPECT, we synthesized and
evaluated the radiolabelled 7-iodo analog 1.7 Although
stereocontrolled recognition processes have received
much attention in modern drug discovery, none of the
D4 receptor ligands of type A that were previously
described feature chiral information. Very recently, we
reported on the asymmetric synthesis and biological
effects of the first planar-chiral neuroreceptor ligands
(R)-2 and (S)-2 incorporating a hitherto unknown
indolocyclophane as a structural feature,8 when signifi-
cant dopamine receptor subtype specific stereodifferen-
tiation was observed.9
The successful cloning of the dopamine D4 receptor
subtype in the early 1990s1 marked the beginning of an
extensive search for subtype selective ligands. These
investigations were inspired by the assumption that
neurotransmission at the D4 receptor is associated with
the neuropathology of schizophrenia, attention-deficit
hyperactivity (ADHD), mood disorders and Parkin-
son’s disease.2 It is interesting to note that compounds
fulfilling the structural specifications of type A in par-
ticular (see Fig. 1) proved to be extremely potent D4
As an extension of these studies investigating the influ-
ence of the absolute configuration on the ligand recog-
nition at the dopamine receptors we designed a number
of central- and planar-chiral FAUC 113 analogs. Varia-
tions of the structural moieties of type A should be
performed by replacement of the chlorophenyl group
with the [2.2]paracyclophane system resulting in the
target compound 3 (Fig. 2). Introduction of a methyl
group into the piperazine moiety and its complete
exchange for alternative asymmetric scaffolds was envi-
sioned to give test compounds of type 4, 5 and 6 with
chirality resulting from stereogenic centers only.
Figure 1. Arylpiperazinyl substituted heteroarenes as potent
dopamine D4 receptor ligands.
* Corresponding author. Fax: +49-913-18522585; e-mail: gmeiner@
pharmazie.uni-erlangen.de
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00639-0

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S. Lo¨ber et al. / Tetrahedron: Asymmetry 13 (2002) 2303–2310
(H2, Pd/C). The cleavage was successful when following
the methodology described by Kanth and co-workers.12
Here, the benzylpiperazine was transformed into a car-
bamate by treatment with methyl chloroformate fol-
lowed by acid catalyzed release of the secondary amine
( )-10. Subsequent Mannich reaction of the
cyclophanylpiperazine with pyrazolo[1,5-a]pyridine 11
gave the desired compound ( )-3 possessing only
planar-chirality.
Due to the predicted formation of achiral aryne-type
intermediates, the aforementioned base-catalyzed ami-
nation reaction was not suitable for the preparation of
enantiopure piperazinyl cyclophanes (R)-3 and (S)-3.
Thus, we took advantage of our recently reported
amination sequence employing the cyclophanyl triflates
(R)-12 and (S)-12 as key intermediates, which can be
approached by kinetic resolution of 4-acet-
oxy[2.2]paracyclophane with lipase from Candida cylin-
dracea and subsequent sulfonylation9 (Scheme 2).
Figure 2. Analogs of FAUC 113 with central- and planar-
chirality.
We next tried to elaborate the palladium-promoted
amination. We succeeded when the triflates (R)-12 and
(S)-12 were treated with piperazinylmethyl substituted
pyrazolo[1,5-a]pyridine 14, which was obtained by car-
bamate cleavage of the Mannich base 13, in the pres-
ence of Pd2dba3 and dppf. Under these conditions, the
desired stereoisomers (R)-3 and (S)-3 could be isolated
in 42% yield from (R)-12 and (S)-12, respectively.
2. Chemistry
When benzylamine was employed as the nucleophile,
amination of dibromo[2.2]paracyclophane could be
accomplished by palladium-catalyzed coupling reac-
tion.10 Further amination reactions of [2.2]paracyclo-
phanyl bromides have not been described in the litera-
ture, yet. Our attempts to use Pd2dba3/P(tBu)3 as a
catalyst system for coupling of N-Boc protected piper-
azine to racemic 4-bromo[2.2]paracyclophane 7 failed,
when only traces of the amination product ( )-8 were
obtained (Scheme 1).
The synthesis of the methyl substituted derivatives of
FAUC 113 started from the enantiopure N-benzyl-
methylpiperazines (S)-15 and (S)-16, which were syn-
thesized from suitably protected alanine and glycine
precursors according to an ex-chiral pool procedure
reported by Kiely and co-workers13 (Scheme 3). Palla-
dium-catalyzed arylation with 1-bromo-4-chloroben-
zene furnished the 4-chlorophenyl piperazines (S)-17
and (S)-18 in 74 and 67% yield, respectively. After
Employing a palladium free, KOtBu-catalyzed proce-
dure,11 the cyclophanylpiperazine ( )-8 could be iso-
lated in 16% yield. Under the same reaction conditions
N-benzylpiperazine could be efficiently transformed
into the corresponding cyclophanyl derivative ( )-9
(64%). Surprisingly, the benzyl protecting group of
( )-9 could not be removed using standard conditions
Scheme 1. Reagents and conditions: (a) N-Boc-piperazine,
KOtBu, toluene, 130°C, 48 h (16%); (b) N-benzylpiperazine,
KOtBu, toluene, 130°C, 24 h (64%); (c) 1. ClCO2Me, reflux,
3 h; 2. conc. HCl, reflux, 16 h (65%); (d) CH2O, HOAc,
DCM, rt, 16 h (81%).
Scheme 2. Reagents and conditions: (a) CH2O, HOAc, DCM,
rt, 3 days (80%); (b) 4N HCl, dioxane, 0°C, 20 min. (90%); (c)
Pd2dba3, dppf, NaOtBu, toluene, 100°C, 24 h (42%).

S. Lo¨ber et al. / Tetrahedron: Asymmetry 13 (2002) 2303–2310
2305
Scheme 4. Reagents and conditions: (a) 4-chloroaniline, DCC,
HOBt, EtOAc, rt, 17 h (82%); (b) HCl, EtOAc, rt, 16 h (97%);
(c) 11, CH2O, Et2MeN, HOAc, CH2Cl2, rt, 16 h (88%); (d)
LiAlH4, THF, 0°C–rt, 4 h (62%).
Scheme 3. Reagents and conditions: (a) 1-Bromo-4-chloroben-
zene Pd2(dba)3, P(tBu)3, NaOtBu, toluene, 120°C, 5 h (74%
for 17, 67% for 18); (b) 1. ClCO2Me, rt, 1.5 h; 2. KOH,
MeOH, reflux, 72 h (81% for 19, 70% for 20); (c) 11, CH2O,
HOAc, CH2Cl2, rt, 16 h (71% for 4a, 81% for 4b).
cleavage of the benzyl protecting groups the corre-
sponding secondary amines (S)-19 and (S)-20 were
converted into the respective pyrazolo[1,5-a]pyridines
(S)-4a and (S)-4b. The enantiomers (R)-4a and (R)-4b
were prepared analogously starting from the respective
methylpiperazines (R)-15 and (R)-16.
The synthesis of the enantiopure 2-aminomethyl pyrro-
lidine framework, which was selected to serve as an
alternative diamine surrogate, started from Boc pro-
Scheme 5. Reagents and conditions: (a) H2O, 0°C–rt, 2 h (44%
of (S)-24); (b) MeNH2 (33% in EtOH), rt, 2 h (94%); (c)
Na(OAc)3BH, CH2Cl2, rt, 16 h (89%); (d) THF, 0°C–rt, 3 h
(89% for (S,S)-27, 89% for (R,S)-27).
tected
L-proline. DCC-mediated coupling with 4-
chloroaniline furnished the proline amide (S)-21
(Scheme 4). After cleavage of the protecting group, the
resulting secondary amine (S)-22 was transformed into
the pyrazolo[1,5-a]pyridine derivative (S)-23 using
Mannich conditions. Finally, reduction with LiAlH4
gave the desired test compound (S)-5 in 43% overall
yield. The enantiomer (R)-5 was prepared analogously
(Scheme 5). The enantiomeric integrity of the synthesis
was established by derivatization of (S)-26. Thus, cou-
pling of the secondary amine with (R)- or (S)-
phenylethylisocyanate gave the ureas (R,S)-27 or
(S,S)-27, respectively. 1H NMR spectra proved the
synthetic material to be enantiomerically pure. The
enantiomer (R)-6 was prepared analogously employing
(S,S)-Co(III)-salen as a catalyst.
starting from Boc-D-proline.
The enantiopure amino alcohol 6 was synthesized start-
ing from 4-chlorophenyloxymethyl oxirane 24. Apply-
ing Jacobsen’s hydrolytic kinetic resolution (HKR)14
methodology, ring-opening of the epoxide 2415 with 0.5
equiv. of H2O mediated by (R,R)-Co(III)-salen gave the
diol (R)-25 besides unreacted (S)-24, which was treated
with methylamine to obtain the 1,2-aminoalcohol (S)-
26. Finally, reductive alkylation with pyrazolo[1,5-a]-
pyridine-3-carbaldehyde16 gave the test compound (S)-6
3. Pharmacology
Both enantiomers of the test compounds 3, 4a, 4b, 5
and 6 were evaluated in vitro for their ability to dis-
place [3H]spiperone from the cloned human dopamine
17
receptors D2long, D2short
,
D318 and D419 being stably
expressed in CHO cells. D1 affinity was determined by

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S. Lo¨ber et al. / Tetrahedron: Asymmetry 13 (2002) 2303–2310
employing bovine striatal membrane preparations and
the D1 selective antagonist [3H]SCH 23390.20
Department of Organic Chemistry, University of Erlan-
gen-Nu¨rnberg. Optical rotations were measured with a
Perkin–Elmer 241 spectropolarimeter. THF and toluene
were freshly distilled from sodium benzophenone or
sodium, respectively. All reagents were of commercial
quality and used as purchased. Flash chromatography
was carried out with silica gel 60 (4.0–6.3 mm) eluting
with appropriate solution in the stated v:v proportions.
Analytical thin-layer chromatography (TLC) was per-
formed with silica gel plates on aluminium (silica gel 60
F254 from Merck).
The dopamine receptor binding profiles of the double-
layered test compounds (R)-3 and (S)-3 clearly indicate
a significant loss of D4 affinity when compared to
FAUC 113 (Table 1). On the other hand, ligand recog-
nition at the D2 and D3 subtypes increased 18- to
90-fold. The central chiral FAUC 113 analogs (R)-4a
and (R)-4b revealed Ki values at the D4 receptor in low
nanomolar range, when selectivity over D2long and
D2short was significantly enhanced in the case of (R)-4a.
Irrespective of the absolute configuration, displacement
of the piperazine moiety by aminomethylpyrrolidine or
a vicinal amino alcohol group resulting in the test
compounds 5 and 6, respectively, was not tolerated by
the D4 receptor.
5.2. 1-tert-Butyloxycarbonyl-4-[2.2]paracyclophan-4-
ylpiperazine, ( )-8
A suspension of ( )-7 (50 mg, 0.175 mmol), N-Boc-
piperazine (110 mg, 0.59 mmol) and KOtBu (66 mg,
0.59 mmol) and toluene (1 mL) was stirred in a sealed
tube at 130°C for 48 h. Saturated aqueous NaHCO3
solution was added and the aqueous layer was extracted
with Et2O. The combined organic layers were dried
(Na2SO4) and evaporated and the residue was purified
by flash chromatography (petroleum ether–EtOAc 4:1)
to afford ( )-8 as a colorless solid (36 mg, 16%): IR
Table 1. Dopamine receptor binding (Ki values [nM]) of
the pyrazolo[1,5-a]pyridines (R)-3, (S)-3, (R)-4a,b, (S)-
4a,b, (R)-5, (S)-5, (R)-6 and (S)-6 compared to the lead
structure FAUC 113a
Compd
D1
D2long
D2short D3
D4
1
(KBr): w 2925, 2852, 1697, 1415, 1170 cm−1; H NMR
(R)-3
(S)-3
5500
170
100
12000
40000
4900
130
84
6500
20000
4500
10000
18000
23000
43000
11000
4300
87
55
6100
11000
13000
5700
4500
4700
9900
14000
5000
117
100
47
6.2
30
3.9
2100
1800
970
(360 MHz, CDCl3): l 1.49 (s, 9H), 2.71 (ddd, 1H,
J=13.1, 10.0, 6.4 Hz), 2.80–3.74 (m, 15H), 5.72 (d, 1H,
J=1.7 Hz), 6.30 (dd, 1H, J=7.5, 1.8 Hz), 6.36 (dd, 1H,
J=7.8, 1.8 Hz), 6.43 (d, 1H, J=7.5 Hz), 6.45 (dd, 1H,
J=7.8, 1.8 Hz), 6.53 (dd, 1H, J=7.8, 1.7 Hz), 6.67 (dd,
1H, J=7.8, 1.8 Hz).
3400
1200
1700
7700
9100
7300
22000
6700
13000
12000
(S)-4a
(R)-4a
(S)-4b
(R)-4b
(R)-5
(S)-5
(R)-6
(S)-6
FAUC 113
6800
19000
19000
53000
24000
3200
5.3. 1-Benzyl-4-[2.2]paracyclophan-4-ylpiperazine, ( )-9
1300
3.1
A suspension of ( )-7 (200 mg, 0.699 mmol), N-ben-
zylpiperazine (176 mg, 1.00 mmol) and KOtBu (156
mg, 1.39 mmol) and toluene (2 mL) was stirred in a
sealed tube at 130°C for 24 h. Then, a saturated
solution of NaHCO3 was added and the aqueous layer
was extracted with Et2O. The combined organic layers
were dried (NaSO4) and evaporated and the residue was
purified by flash chromatography (petroleum ether–
EtOAc 4:1) to afford ( )-9 as a colorless solid (171 mg,
64%): mp 134°C; IR (KBr): w 2925, 2810, 1587, 1490,
a Data are based on the means of 2–3 experiments performed in
triplicate at eight concentrations.
4. Conclusion
In conclusion, we have synthesized a number of enan-
tiomerically pure FAUC 113 analogs featuring central-
or planar-chiral information. Radioligand binding stud-
ies demonstrated, that the affinity to the dopamine D2
and D3 receptor subtypes could be enhanced when the
chlorophenyl moiety is replaced by a [2.2]paracyclo-
phane group. Depending on the absolute configuration,
the incorporation of a stereogenic center into the piper-
azine substructure significantly influenced the D4 selec-
tivity.
1
1231, 737 cm−1; H NMR (360 MHz, CDCl3): l 2.59–
2.75 (m, 4H), 2.87–3.07 (m, 10H), 3.26 (ddd, 1H,
J=12.5, 9.3, 6.3 Hz), 3.37 (ddd, 1H, J=12.9, 9.4, 2.2
Hz), 3.59 (d, 1H, J=12.9 Hz), 3.63 (d, 1H, J=12.9 Hz),
5.70 (d, 1H, J=1.4 Hz), 6.26 (dd, 1H, J=7.6, 1.4 Hz),
6.34 (dd, 1H, J=7.8, 1.8 Hz), 6.39 (d, 1H, J=7.6 Hz),
6.44 (dd, 1H, J=7.8, 1.8, Hz), 6.52 (d, 1H, J=7.9 Hz),
6.69 (dd, 1H, J=7.9, 1.8 Hz), 7.23–7.40 (m, 5H); MS
m/z=382 [M+]. Anal. calcd for C27H30N2: C, 84.77; H,
7.90; N, 7.32. Found: C, 84.35; H, 7.94; N, 6.89%.
5. Experimental
5.1. General procedures
5.4. N-[2.2]Paracyclophan-4-ylpiperazine, ( )-10
A mixture of ( )-9 (50 mg, 0.131 mmol) and ClCO2CH3
(2 mL) was heated under reflux for 3 h. After removal
of the formic ester the residue was dissolved in conc
HCl (2 mL) and refluxed for 16 h. Then careful alkal-
ization with 2N NaOH and extraction with EtOAc the
combined organic layers were dried (Na2SO4) and evap-
Melting points were determined on a Bu¨chi 530 appara-
1
tus and are uncorrected. All H And 13C NMR spectra
were recorded in CDCl3 or DMSO-d6 solution with
Bruker AC spectrometers at 360 MHz as well as 90 and
63 MHz. Elemental analyses were performed by the

S. Lo¨ber et al. / Tetrahedron: Asymmetry 13 (2002) 2303–2310
2307
orated. The residue was purified by flash chromatogra-
phy (CH2Cl2–MeOH–EtMe2N 9:1:0.1) to afford ( )-10
amine as a colorless solid (25 mg, 65%): mp >200°C
decomposition; IR (KBr): w 3433, 2928, 2722, 1590,
rated NaHCO3 solution. The aqueous layer was washed
with ether several times. The combined organic layers
were dried (Na2SO4) and evaporated and the residue
was purified by flash chromatography (EtOAc) to
afford (R)-3 as a colorless solid (3.5 mg, 42%): mp
130°C; IR (KBr): w 2924, 2812, 1634, 1586, 1415, 730
1
1412, 742 cm−1; H NMR (360 MHz, CDCl3): l 2.76
(ddd, 1H, J=13.1, 9.9, 6.2 Hz), 2.86 (s, 1H), 2.91–3.53
(m, 15H), 5.84 (d, 1H, J=1.7 Hz), 6.36 (dd, 1H, J=7.6,
1.7 Hz), 6.42 (dd, 1H, J=7.8, 1.7 Hz), 6.46 (dd, 1H,
J=7.8, 1.7 Hz), 6.47 (d, 1H, J=7.8 Hz), 6.53 (dd, 1H,
J=7.8, 1.7 Hz), 6.68 (dd, 1H, J=7.6, 1.7 Hz); MS
m/z=292 [M+]. Anal. calcd for C20H24N2: C, 82.15; H,
8.27; N, 9.58. Found: C, 82.41; H, 7.94; N, 9.87%.
1
cm−1; H NMR (360 MHz, CDCl3): l 2.60–2.80 (m,
5H), 2.84–3.10 (m, 9H), 3.24 (ddd, 1H, J=12.7, 9.3, 6.2
Hz), 3.36 (ddd, 1H, J=12.8, 9.5, 2.3 Hz), 3.80 (s, 2H),
5.70 (d, 1H, J=1.7 Hz), 6.26 (dd, 1H, J=7.5, 1.7 Hz),
6.34 (dd, 1H, J=7.7, 1.7 Hz), 6.39 (d, 1H, J=7.5 Hz),
6.47 (dd, 1H, J=7.7, 1.7 Hz), 6.52 (dd, 1H, J=7.7, 1.7
Hz), 6.68 (dd, 1H, J=7.7, 1.7 Hz), 6.76 (ddd, 1H,
J=6.7, 6.7, 1.0 Hz), 7.12 (ddd, 1H, J=8.7, 6.7, 1.0 Hz),
7.66 (ddd, 1H, J=8.7, 1.0, 1.0 Hz), 7.94 (s, 1H), 8.46
(ddd, 1H, J=6.7, 1.0, 1.0 Hz); MS m/z=422 [M+].
Anal. calcd for C28H30N4: C, 79.59; H, 7.16; N, 13.26.
Found: C, 79.45; H, 7.19; N, 13.19%. [h]2D0=+11.4 (c
0.5, CHCl3). Starting from (S)-12 and 14, (S)-3 was
prepared under identical conditions [h]2D0=−10.4 (c 0.5,
CHCl3); HPLC: Chiralcel OD column, solvent
(petroleum ether–iPrOH 6:4), P=28 bar, flowrate=1.0
ml/min; Rt ((R)-3)=21.1 min, Rt ((S)-3)=17.8 min;
[e.e.]: (R)-3 >98%; (S)-3 >98%.
5.5. 4-(Pyrazolo[1,5-a]pyridin-3-ylmethyl)piperazinyl-1-
carboxylic acid tert-butyl ester, 13
A solution of pyrazolo[1,5-a]pyridine 11 (100 mg, 0.847
mmol), CH2O (68 mL of a 37% solution, 0.839 mmol),
tert-butyl piperazine-1-carboxylate (150 mg, 0.847
mmol) and HOAc (three drops) was stirred in CH2Cl2
(6 mL) at room temperature for 3 days. Saturated
aqueous NaHCO3 solution was added and the aqueous
layer was extracted with CH2Cl2. The combined organic
layers were dried (Na2SO4) and evaporated and the
residue was purified by flash chromatography (EtOAc–
MeOH 95:5) to afford 13 as a colorless solid (202 mg,
80%): mp 116°C; IR (KBr): w 2976, 2861, 1681, 1426,
5.8. (S)-1-Benzyl-4-(4-chlorophenyl)-2-methylpiperazine,
(S)-17
1
1240, 1126, 760 cm−1; H NMR (360 MHz, CDCl3): l
A mixture of (S)-15 (47.3 mg, 0.247 mmol), p-bromo-
chlorobenzene (70 mg, 0.365 mmol), NaOtBu (35 mg,
0.365 mmol) and Pd2(dba)3 (1.2 mg, 1.31 mmol) was
treated with a freshly prepared solution of P(tBu)3
0.021 mmol/l in toluene, 0.5 ml) under a nitrogen
atmosphere and heated in a sealed tube for 5 h at
120°C. After cooling to room temperature EtOAc was
added and the mixture was washed with saturated
NaHCO3 solution. The organic layer was dried
(Na2SO4) and evaporated and the residue was purified
by flash chromatography (petroleum ether–EtOAc 9:1)
to afford (S)-17 as a colorless solid: mp 78°C; 1H NMR
(360 MHz, CDCl3): l 1.23 (d, 3H, J=5.9 Hz), 2.29
(ddd, 1H, J=11.5, 11.0, 3.3 Hz), 2.61 (ddd, 1H, J=9.0,
5.9, 2.8 Hz), 2.68 (dd, 1H, J=10.9, 9.0 Hz), 2.81 (ddd,
1H, J=11.5, 3.6, 3.3 Hz), 2.84 (ddd, 1H, J=11.5, 11.0,
3.3 Hz), 3.20 (d, 1H, J=13.0 Hz), 3.31 (dddd, 1H,
J=11.5, 3.6, 3.3, 1.5 Hz), 3.38 (ddd, 1H, J=10.9, 2.8,
1.5 Hz), 4.10 (d, 1H, J=13.0 Hz), 6.78–6.84 (m, 2H),
7.15–7.21 (m, 2H), 7.23–7.37 (m, 5H); MS m/z=300
[M+]. Anal. calcd for C18H21ClN2: C, 71.87; H, 7.04; N,
9.31. Found: C, 72.05; H, 7.14; N, 9.26%. [h]2D0=+62.8
(c 1, CHCl3). Starting from (R)-15, (R)-17 was pre-
pared under identical conditions [h]2D0=−63.4 (c 1,
CHCl3).
1.45 (s, 9H), 2.34–2.49 (m, 4H), 3.35–3.48 (m, 4H), 3.70
(s, 2H), 6.74 (ddd, 1H, J=7.0, 6.5, 1.0 Hz), 7.09 (ddd,
1H, J=9.2, 6.5, 0.8 Hz), 7.59 (ddd, 1H, J=9.2, 1.0, 0.8,
Hz), 7.87 (s, 1H), 8.43 (ddd, 1H, J=7.0, 0.8, 0.8 Hz);
MS m/z=316 [M+]. Anal. calcd for C17H24N4O2: C,
64.53; H, 7.65; N, 17.71. Found: C, 64.89; H, 7.81; N,
18.20%.
5.6. N-Pyrazolo[1,5-a]pyridin-3-ylmethylpiperazine, 14
A mixture of 13 (182 mg, 0.607 mmol) was stirred in a
HCl solution (4N in dioxane) at 0°C for 20 min. Then,
the solvent was evaporated and the hydrochloride was
obtained. The residue was resolved in 2N NaOH and
extracted with CH2Cl2. The combined organic layers
were dried (Na2SO4) and evaporated to give 14 as a
colorless solid (110 mg, 90%): mp 61°C; IR (KBr): w
1
3854, 2923, 2819, 1635, 1471, 1129, 742 cm−1; H NMR
(360 MHz, CDCl3): l 2.49 (br s, 4H), 2.76–2.87 (m,
4H), 3.73 (s, 2H), 4.85 (s, 1H), 6.88 (ddd, 1H, J=7.0,
6.8, 1.0 Hz), 7.23 (ddd, 1H, J=9.0, 6.8, 1.0 Hz), 7.72
(ddd, 1H, J=9.0, 1.0, 1.0, Hz), 7.92 (s, 1H), 8.48 (ddd,
1H, J=7.0, 1.0, 1.0 Hz); MS m/z=216 [M+]. Anal.
calcd for C12H16N4: C, 66.64; H, 7.46; N, 25.90. Found:
C, 66.94; H, 7.41; N, 25.69%.
5.9. (S)-4-Benzyl-1-(4-chlorophenyl)-2-methylpiperazine,
(S)-18
5.7. (R)-3-(4-[2.2]Paracyclophan-4-ylpiperazin-1-
ylmethyl)pyrazolo[1,5-a]pyridine, (R)-3
Starting from (S)-16 (102 mg, 0.537 mmol), (S)-18 was
A solution of (R)-12 (7 mg, 0.019 mmol), 14 (4.2 mg,
0.019 mmol), NaOtBu (2.7 mg, 0.022 mmol), Pd2(dba)3
(0.5 mg, 0.55 mmol) and dppf (1.1 mg, 1.99 mmol) in
toluene (0.5 mL) was stirred at 100°C for 24 h. After
cooling to rt Et2O was added and extracted with satu-
prepared in 67% yield following the procedure
1
described for (S)-17 (Section 5.8): mp 109°C; H NMR
(360 MHz, CDCl3): l 1.06 (d, 3H, J=6.3 Hz), 2.34
(ddd, 1H, J=10.6, 9.9, 3.9 Hz), 2.46 (dd, 1H, J=11.0,
3.4 Hz), 2.60 (ddd, 1H, J=11.0, 3.5, 1.9 Hz), 2.82

2308
S. Lo¨ber et al. / Tetrahedron: Asymmetry 13 (2002) 2303–2310
(dddd, 1H, J=10.6, 3.7, 3.4, 1.9 Hz), 3.10 (ddd, 1H,
J=11.8, 9.9, 3.4 Hz), 3.16 (ddd, 1H, J=11.8, 3.9, 3.7
Hz), 3.47 (d, 1H, J=13.2 Hz), 3.58 (d, 1H, J=13.2 Hz),
3.80 (ddd, 1H, J=6.3, 3.5, 3.4 Hz), 6.78–6.84 (m, 2H),
7.16–7.21 (m, 2H), 7.23–7.29 (m, 1H), 7.30–7.39 (m,
4H); MS m/z=300 [M+]. Anal. calcd for C18H21ClN2:
C, 71.87; H, 7.04; N, 9.31. Found: C, 71.71; H, 6.89; N,
9.12%. [h]2D0=−23.1 (c 1, CHCl3). Starting from (R)-16,
(R)-18 was prepared under identical conditions [h]2D0=
+22.4 (c 1, CHCl3).
J=11.5, 11.2, 3.2 Hz), 2.60 (ddd, 1H, 10.0, 5.8, 3.4 Hz),
2.67 (dd, 1H, J=10.6, 10.0 Hz), 2.82 (ddd, 1H, J=11.6,
11.2, 3.4 Hz), 2.87 (ddd, 1H, J=11.5, 3.5, 3.4 Hz), 3.32
(dddd, 1H, J=11.6, 3.5, 3.2, 1.8 Hz), 3.39 (ddd, 1H,
J=10.6, 3.4, 1.8 Hz), 3.56 (d, 1H, J=13.7 Hz), 4.21 (d,
1H, J=13.7 Hz), 6.75 (ddd, 1H, J=6.9, 6.9, 1.2 Hz),
6.77–6.82 (m, 2H), 7.09 (ddd, 1H, J=8.9, 6.9, 1.1 Hz),
7.14–7.20 (m, 2H), 7.63 (ddd, 1H, J=8.9, 1.2, 1.1 Hz),
7.90 (s, 1H), 8.44 (ddd, 1H, J=6.9, 1.1, 1.1 Hz); MS
m/z=340 [M+]. Anal. calcd for C19H21ClN4: C, 66.95;
H, 6.21; N, 16.44. Found: C, 67.30; H, 6.28; N, 16.53%.
[h]2D0=+75.6 (c=1, CHCl3). Starting from (R)-19, (R)-
4a was prepared under identical conditions [h]2D0=−76.0
(c 1, CHCl3).
5.10. (S)-1-(4-Chlorophenyl)-3-methylpiperazine, (S)-19
A solution of (S)-17 (32 mg, 0.106 mmol) in methyl
chloroformate (1.0 ml) was stirred for 1.5 h at room
temperature. The mixture was evaporated and the
residue was treated with two pearls of KOH and
MeOH (2 ml). After refluxing for 3 days, the solvent
was evaporated. Addition of a saturated solution of
NaHCO3, extraction with CHCl3 and evaporation of
the dried (Na2SO4) organic layer gave the crude
product, which was purified by flash chromatography
(CH2Cl2–MeOH–EtMe2N 9:1:0.1) to give (S)-19 (18.1
mg, 81%) as a colorless solid: mp 67°C; IR (KBr): w
3256; 1H NMR (360 MHz, CDCl3): l 1.13 (d, 3H,
J=6.2 Hz), 1.54 (s, 1H), 2.33 (dd, 1H, J=11.7, 10.0
Hz), 2.68 (ddd, 1H, J=11.6, 11.6, 3.3 Hz), 2.97 (ddd,
1H, J=10.0, 6.4, 3.3 Hz), 3.02 (ddd, 1H, J=11.7, 11.6,
3.1 Hz), 3.11 (ddd, 1H, J=11.7, 3.3, 2.3 Hz), 3.43–3.49
(m, 2H), 6.81–6.87 (m, 2H), 7.17–7.22 (m, 2H); MS
m/z=210 [M+]. Anal. calcd for C11H15ClN2: C, 62.70;
H, 7.18; N, 13.29. Found: C, 63.20; H, 7.39; N, 13.47%.
[h]2D0=−4.3 (c 1, CHCl3). Starting from (R)-17, (R)-19
was prepared under identical conditions [h]2D0=+4.3 (c
1, CHCl3).
5.13. (S)-3-[4-(4-Chlorophenyl)-3-methylpiperazin-1-
ylmethyl]pyrazolo[1,5-a]pyridine (S)-4b
Starting from (S)-20 (11.5 mg, 0.055 mmol), (S)-4b was
prepared in 81% yield following the procedure
described for (S)-4a (Section 5.12): mp 137°C; IR
1
(KBr): w 1634 cm−1; H NMR (360 MHz, CDCl3): l
1.03 (d, 3H, J=6.5 Hz), 2.33 (ddd, 1 H, J=10.5 10.0,
3.6 Hz), 2.47 (dd, 1H, J=10.9, 3.3 Hz), 2.63 (ddd, 1H,
J=10.9, 3.4, 1.7 Hz), 2.84 (dddd, 1H, J=10.5, 3.6, 3.3,
1.7 Hz), 3.07 (ddd, 1H, J=11.9, 10.0, 3.3 Hz), 3.15
(ddd, 1H, J=11.9, 3.6, 3.6 Hz), 3.67 (d, 1H, J=13.4
Hz), 3.74 (d, 1H, J=13.4 Hz), 3.80 (ddd, 1H, J=6.5,
3.4, 3.3 Hz), 6.75 (ddd, 1H, J=6.7, 6.7, 1.0 Hz),
6.77–6.83 (m, 2H), 7.09 (ddd, 1H, J=8.8, 6.7, 1.0 Hz),
7.15–7.21 (m, 2H), 7.65 (ddd, 1H, J=8.8, 1.0, 0.9 Hz),
7.89 (s, 1H), 8.44 (ddd, 1H, J=6.7, 1.0, 0.9 Hz); MS
m/z=340 [M+]; [h]D20=−21.6 (c 1, CHCl3). Starting
from (R)-20, (R)-4b was prepared under identical con-
ditions [h]2D0=+21.0 (c 1, CHCl3).
5.11. (S)-1-(4-Chlorophenyl)-2-methylpiperazine, (S)-20
5.14. N-Boc-
L
-proline-4-chlorophenylamide, (S)-21
-proline (1.00 g, 4.65 mmol),
Starting from (S)-18 (50.5 mg, 0.168 mmol), (S)-20 was
A mixture of N-Boc-
L
prepared in 70% yield following the procedure
DCC (1.15 g, 5.58 mmol) and HOBt (0.75 g, 5.58
mmol) in EtOAc (10 ml) was stirred at room tempera-
ture for 1 h. After addition of 4-chloroaniline (0.85 g,
5.56 mmol), stirring was continued for 16 h followed by
addition of EtOAc (10 ml) and CHCl3 (10 ml). The
N,N%-dicyclohexylurea was separated by filtration and
the clear solution was evaporated. Purification by flash
chromatography (petroleum ether–EtOAc 3:7) afforded
(S)-21 as a colorless solid (0.87 g, 82%): mp 168°C; IR
1
described for (S)-19 (Section 5.10): mp 54°C; H NMR
(360 MHz, CDCl3): l 1.02 (d, 3H, J=6.5 Hz), 1.78 (s,
1H), 2.85 (ddd, 1H, J=12.1, 3.3, 0.7 Hz), 2.89–3.20 (m,
5H), 3.70 (ddd, 1H, J=6.5, 3.3, 3.3 Hz), 6.77–6.91 (m,
2H), 7.13–7.28 (m, 2H); MS m/z=210 [M+]. Anal.
calcd for C11H15ClN2: C, 62.70; H, 7.18; N, 13.29.
Found: C, 62.39; H, 7.30; N, 13.13%. [h]2D0=−32.0 (c 1,
CHCl3). Starting from (R)-18, (R)-20 was prepared
under identical conditions [h]2D0=+32.2 (c 1, CHCl3).
(KBr): w 3290, 1702, 1669 cm−1; H NMR (360 MHz,
1
CDCl3): l 1.48 (s, 9H), 1.57–1.69 (m, 1H), 1.88–1.99
(m, 2H), 2.45–2.62 (m, 1H), 3.30–3.51 (m, 2H), 4.40–
4.49 (m, 1H), 7.22–7.30 (m, 2H), 7.44–7.99 (m, 2H),
9.60 (br s, 1H); MS m/z 324 [M+]; [h]D20=−92.3 (c 1,
5.12. (S)-3-[4-(4-Chlorophenyl)-2-methylpiperazin-1-
ylmethyl]pyrazolo[1,5-a]pyridine, (S)-4a
A mixture of (S)-19 (10 mg, 0.048 mmol), 11 (11.2 mg,
0.095 mmol), formaldehyde (7.7 ml, 37% in H2O, 0.095
mmol) and HOAc (three drops) in CH2Cl2 (1.5 ml) was
stirred for 16 h at room temperature. After addition of
a saturated solution of NaHCO3 the organic layer was
separated, dried (Na2SO4) and evaporated. The crude
product was purified by flash chromatography (EtOAc)
to give (S)-4a (11.4 mg, 71%) as a colorless solid: mp
CHCl3). Starting from N-Boc-D-proline, (R)-21 was
prepared under identical conditions [h]2D0=+90.7 (c 1,
CHCl3).
5.15.
L
-Proline-4-chlorophenylamide hydrochloride, (S)-
22·HCl
A solution of (S)-21 (900 mg, 2.77 mmol) in EtOAc (8
ml) was treated with a saturated solution of HCl in
EtOAc (10 ml) and stirred for 16 h. Evaporation of the
1
110°C; IR (KBr): w 1634 cm−1; H NMR (360 MHz,
CDCl3): l 1.31 (d, 3H, J=5.8 Hz), 2.33 (ddd, 1 H,

S. Lo¨ber et al. / Tetrahedron: Asymmetry 13 (2002) 2303–2310
2309
solvent was followed by washing of the residue with
Et2O/EtOH (95/5) to give (S)-22·HCl (702 mg, 97%)
as a colorless solid: mp 190°C; IR (KBr): w 3249,
16.44. Found: C, 66.88; H, 6.20; N, 16.22%. [h]2D0=
−38.0 (c 1, CHCl3). Starting from (R)-23·HCl, (R)-5
was prepared under identical conditions [h]2D0=+37.0
(c 1, CHCl3).
1
3119, 1686, 1612 cm−1; H NMR (360 MHz, DMSO-
d6): l 1.98–2.02 (m, 3H), 2.36–2.47 (m, 1H), 3.20–3.31
(m, 2H), 4.38–4.45 (m, 1H), 7.39–7.45 (m, 2H), 7.66–
7.72 (m, 2H), 8.69 (br s, 1H), 10.01 (br s, 1H), 11.14
(br. S, 1H); MS m/z=224 [M+−HCl]. Anal. calcd for
C11H14Cl2N2O·0.1H2O: C, 50.25; H, 5.44; N, 10.65.
Found: C, 50.29; H, 5.43; N, 10.77%. [h]2D0=−33.0 (c
1, CHCl3). Starting from (R)-21, (R)-22·HCl was pre-
pared under identical conditions [h]2D0=+32.0 (c 1,
CHCl3).
5.18. (S)-2-(Chlorophenoxymethyl)oxirane, (S)-24
(R,R)-(salen)Co(III)OAc was prepared using the
(R,R)-(salen)Co(II) precatalyst21 (50 mg, 0.083 mmol),
which was dissolved in CH2Cl2 (0.5 ml) and treated
with HOAc (20 mg). After stirring for 10 min at
room temperature, the solvent was evaporated to give
a brown solid, which was used immediately without
further purification. So, a mixture of 2415 (2.0 g, 10.8
mmol) and (R,R)-(salen)Co(III)OAc (37 mg, 0.057
mmol) was cooled to 0°C, treated with H2O (0.110
ml, 6.1 mmol) and warmed to room temperature. The
progress of the conversion was monitored by HPLC
(RP18, MeOH/H2O 1:1, UV 225 nm). After 2 h, the
reaction was completed and the crude product was
purified by flash chromatography (petroleum ether–
EtOAc 2:3) to give (S)-24 (0.88 mg, 44%) as a color-
5.16. N-Pyrazolo[1,5-a]pyridin-3-ylmethyl-
L-proline-4-
chlorophenylamide, (S)-23
A solution of (S)-22·HCl (100 mg, 0.44 mmol), 11
(52 mg, 0.44 mmol) and EtMe2N (35 mg, 0.44 mmol)
in CH2Cl2 (4 ml) was treated with HOAc (0.30 ml)
and formaldehyde (37% in H2O, 44 ml) and stirred for
16 h at room temperature. Addition of a saturated
solution of NaHCO3 (10 ml) was followed by extrac-
tion with CHCl3. The organic layer was dried
(MgSO4) and evaporated. The crude product was
purified by flash chromatography (EtOAc) to give
(S)-23 (139 mg, 88%) as a colorless solid: mp 101–
1
less oil: H NMR (360 MHz, CDCl3): l 2.73 (dd, 1H,
J=4.5, 2.5 Hz), 2.90 (t, 1H, 4.5 Hz), 3.31–3.37 (m,
1H), 3.91 (dd, 1H, J=11.0, 6.0 Hz), 4.21 (dd, 1H,
J=11.0, 3.0 Hz), 6.81–6.88 (m, 2H), 7.21–7.27 (m,
2H); MS m/z=184 [M+]; [h]D20=+3.2 (c 1, CHCl3).
Starting from 24 and the (S,S)-(salen)Co(II) precata-
lyst,21 (R)-24 was prepared under identical conditions
[h]2D0=−3.2 (c 1, CHCl3).
1
102°C; IR (KBr): w 3269, 1684, 1513 cm−1; H NMR
(360 MHz, CDCl3): l 1.69–1.88 (m, 2H), 1.95–2.04
(m, 1H), 2.21–2.33 (m, 1H), 2.58 (ddd, 1H, J=10.0,
10.0, 6.5 Hz), 3.18 (ddd, 1H, J=9.0, 7.0, 2.0 Hz),
3.34 (dd, 1H, J=10.0, 3.5 Hz), 3.85 (d, 1H, J=13.5
Hz), 4.05 (d, 1H, J=13.5 Hz), 6.75 (ddd, 1H, J=7.0,
7.0, 1.5 Hz), 7.12 (ddd, 1H, J=9.0, 6.0, 1.0 Hz),
7.22–7.27 (m, 2H), 7.38–7.44 (m, 2H), 7.50 (br d, 1H,
J=9.0 Hz), 7.90 (s, 1H), 8.41 (br d, 1H, 7.0 Hz), 9.35
(br s, 1H); MS m/z=354 [M+]; [h]D20=−92.0 (c 1,
CHCl3). Starting from (R)-22·HCl, (R)-23 was pre-
pared under identical conditions [h]2D0=+94.0 (c 1,
CHCl3).
5.19. (S)-1-(4-Chlorophenoxy)-3-methylaminopropan-2-
ol, (S)-26
(S)-24 (300 mg, 1.60 mmol) was treated with a solu-
tion of methylamine (33% in EtOH, 5 ml) and stirred
for 2 h at room temperature. The solvent was evapo-
rated and the residue was crystallized from Et2O/
EtOH to give (S)-26 (0.33 g, 94%) as a colorless
solid: mp 69°C; IR (KBr): w 3444, 3289, 2896, 2846,
1492 cm−1; 1H NMR (360 MHz, CDCl3): l 2.48 (s,
3H), 2.71–2.83 (m, 2H), 3.94–3.97 (m, 2H), 4.03–4.08
(m, 1H), 6.81–6.87 (m, 2H), 7.21–7.27 (m, 2H); MS
m/z=215 [M+]; [h]D20=−5.0 (c 1, CHCl3). Starting
from (R)-24, (R)-26 was prepared under identical
conditions [h]2D0=+6.2 (c 1, CHCl3).
5.17. (S)-N-(4-Chlorophenyl)-N-(1-pyrazolo[1,5-a]-
pyridin-3-ylmethylpyrrolidin-2-ylmethyl)amine, (S)-5
LiAlH4 (1.0 M in THF, 0.270 ml) was added to a
precooled (0°C) solution of (S)-23 (90 mg, 0.25
mmol) in THF (5 ml). The mixture was warmed to
room temperature and stirred for 4 h. Treatment with
a saturated solution of NaHCO3 was followed by
extraction with CH2Cl2. The organic layer was dried
(MgSO4) and evaporated. The crude product was
purified by flash chromatography (EtOAc) to give
(S)-5 (54 mg, 62%) as a colorless oil: IR (NaCl): w
3349, 2962, 2805, 1634, 1601, 1500 cm−1; 1H NMR
(360 MHz, CDCl3): l 1.63–1.83 (m, 3H), 1.88–2.00
(m, 1H), 2.33 (q, 1H, J=9.0 Hz), 2.79–2.87 (m, 1H),
2.89–3.05 (m, 1H), 3.14–3.21 (m, 2H), 3.55 (d, 1H,
J=13.5 Hz), 4.06 (d, 1H, J=13.5 Hz), 4.35 (br s,
1H), 6.48–6.53 (m, 2H), 6.73 (ddd, 1H, J=7.0, 7.0,
1.5 Hz), 7.05 (ddd, 1H, J=9.0, 6.0, 1.0 Hz), 7.09–
7.14 (m, 2H), 7.46 (br d, 1H, J=9.0 Hz), 7.85 (s,
1H), 8.42 (br d, 1H, 7.0 Hz); MS m/z=340 [M+].
Anal. calcd for C19H21ClN4: C, 66.95; H, 6.21; N,
5.20. Determination of the enantiomeric purity of (S)-
26
(S)-Phenylethylisocyanate (8 mg, 0.054 mmol) was
added at 0°C to a solution of (S)-26 (10 mg, 0.047
mmol) in THF (1 ml). After stirring the mixture for 3
h, the solvent was evaporated and the unreacted
starting material was separated by flash chromatogra-
phy (petroleum ether–EtOAc 1:4) to give (S,S)-27.
The coupling was also carried out with (R)-
phenylethylisocyanate to give the appropriate
diastereomer (R,S)-27. Diagnostic signals: 1H NMR
(360 MHz, CDCl3) (S,S)-27: l 3.48–3.60 (m, 2H);
(R,S)-27: l 3.55 (d, 2H, J=4.5 Hz).

2310
S. Lo¨ber et al. / Tetrahedron: Asymmetry 13 (2002) 2303–2310
5.21. (S)-1-(4-Chlorophenoxy)-3-(N-methyl-N-(pyra-
zolo[1,5-a]pyridin-3-ylmethyl)amino)propan-2-ol, (S)-6
2. (a) McCracken, J. T.; Smalley, S. L.; McGough, J. J.;
Crawford, L.; Del’Homme, M. A.; Cantor, R. M.; Liu,
A.; Nelson, S. F. Mol. Psychiatr. 2000, 5, 531; (b)
Lichter, J. B.; Barr, C. L.; Kennedy, J. L.; Van Tol, H.
H. M.; Kid, K. K.; Livak, K. J. Hum. Biol. Genet. 1993,
2, 767.
3. For a review, see: Kulagowski, J. J.; Patel, S. Curr.
Pharm. Design 1997, 3, 355 and references cited therein.
4. Lo¨ber, S.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 1999, 9, 97.
A solution of (S)-26 (80 mg, 0.37 mmol) and pyra-
zolo[1,5-a]pyridine-3-carbaldehyde16 (60 mg, 0.41
mmol) in CH2Cl2 (5 ml) was treated with Na(OAc)3BH
(87 mg, 0.41 mmol) and stirred for 16 h at room
temperature. Addition of a saturated solution of
NaHCO3 was followed by extraction with CH2Cl2. The
organic layer was dried (MgSO4) and evaporated and
the crude product was purified by flash chromatogra-
phy (EtOAc) to give (S)-6 (115 mg, 89%) as a colorless
solid: mp 63°C; IR (KBr): w 3333, 2933, 2847, 1636,
5. Lo¨ber, S.; Hu¨bner, H.; Utz, W.; Gmeiner, P. J. Med.
Chem. 2001, 44, 2691.
6. Lo¨ber, S.; Aboul-Fadl, T.; Hu¨bner, H.; Gmeiner, P.
Bioorg. Med. Chem. Lett. 2002, 12, 633.
1
1492, 1245, 747 cm−1; H NMR (360 MHz, CDCl3): l
7. Prante, O.; Lo¨ber, S.; Hu¨bner, H.; Gmeiner, P.; Kuwert,
T. J. Labelled Compd. Radiopharm. 2001, 44, 849.
8. Ortner, B.; Waibel, R.; Gmeiner, P. Angew. Chem., Int.
Ed. 2001, 40, 1283.
2.31 (s, 3H), 2.54 (dd, 1H, J=12.5, 4.0 Hz), 2.66 (dd,
1H, J=12.5, 9.5 Hz), 3.76 (d, 1H, J=13.5 Hz), 3.88 (d,
1H, 13.5 Hz, J=13.5 Hz), 3.91 (d, 2H, J=5.0 Hz),
4.09–4.16 (m, 1H), 6.76 (ddd, 1H, J=9.0, 6.0, 1.0 Hz),
6.78–6.83 (m, 2H), 7.11 (ddd, 1H, J=9.0, 6.0, 1.0 Hz),
7.19–7.24 (m, 2H), 7.55 (br d, 1H, J=9.0 Hz), 7.88 (s,
1H), 8.44 (br d, 1H, J=7.0 Hz); MS m/z=345 [M+].
Anal. calcd for C18H20ClN3O2: C, 62.52; H, 5.83; N,
12.15. Found: C, 62.48; H, 5.83; N, 12.13%. [h]2D0=
−26.0 (c 0.5, CHCl3). Starting from (R)-26, (R)-6 was
prepared under identical conditions [h]2D0=+26.0 (c 0.5,
CHCl3).
9. Ortner, B.; Hu¨bner, H; Gmeiner, P. Tetrahedron: Asym-
metry 2001, 12, 3205.
10. Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. J.
Org. Chem. 1997, 62, 6462.
11. Beller, M.; Breindl, T. H.; Riermeier, T. H.; Eichberger,
M.; Trauthwein, H. Angew. Chem., Int. Ed. 1999, 37,
3389.
12. Kanth, J. V. B.; Reddy, C. K.; Periasamy, M. Synth.
Commun. 1994, 24, 313.
13. Kiely, J. S.; Priebe, S. R. Org. Prep. Proc. Int. 1990, 22,
761.
14. (a) Tokunanga, M.; Larrow, J. F.; Kakiuchi, F.; Jacob-
sen, E. N. Science 1997, 277, 936; (b) Furrow, M. E.;
Scott, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
6776.
15. Newman, M. S.; Fones, W.; Renoll, M. J. Am. Chem.
Soc. 1947, 69, 718.
16. Tanji, K.; Sasahara, T.; Suzuki, J.; Higashino, T. Hetero-
cycles 1993, 35, 915.
17. Hayes, G.; Biden, T. J.; Selbie, L. A.; Shine, J. J. Mol.
Endocrinol. 1992, 6, 920.
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macol. 1992, 225, 331.
Acknowledgements
The authors wish to thank Dr. H. H. M. Van Tol
(Clarke Institute of Psychiatry, Toronto), Dr. J.-C.
Schwartz and Dr. P. Sokoloff (INSERM, Paris) as well
as Dr. J. Shine (The Garvan Institute of Medical
Research, Sydney) for providing dopamine D4, D3 and
D2 receptor expressing cell lines, respectively. Thanks
are also due to Mrs. H. Szczepanek and Mrs. P.
Schmitt for skillful technical assistance. This work was
supported by the BMBF and the Fonds der Chemis-
chen Industrie.
19. Agashari, V.; Sanyal, S.; Buchwaldt, S.; Paterson, A.;
Jovanovic, V.; Van Tol, H. H. M. J. Neurochem. 1995,
65, 1157.
20. Hu¨bner, H.; Haubmann, C.; Utz, W.; Gmeiner, P. J.
Med. Chem. 2000, 43, 756.
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1991, 350, 610.
21. Both enantiomers of the (salen)Co(II) precatalyst are
commercially available from Aldrich.