Chemoenzymatic synthesis and binding affinity of novel (R)- and (S)-3-aminomethyl-1-tetralones, potential atypical antipsychotics

Article abstract of DOI:10.1016/j.bmcl.2003.11.064

A series of (R)- and (S)-3-aminomethyl-1-tetralones, conformationally constrained analogues of haloperidol, have been obtained by enzymatic resolution of the corresponding racemic 3-hydroxymethyl-1-tetralones using Pseudomonas fluorescens lipase. Their bi

Full text of DOI:10.1016/j.bmcl.2003.11.064

Bioorganic & Medicinal Chemistry Letters 14 (2004) 585–589
Chemoenzymatic synthesis and binding affinity of novel (R)- and
(S)-3-aminomethyl-1-tetralones, potential atypical antipsychotics
Yolanda Caro,a Marıa Torrado,a Christian F. Masaguer,a Enrique Ravina,a,*
Fernando Padın,b Jose Breab and Marıa I. Lozab
a
´
Departamento de Quımica Organica, Laboratorio de Quımica Farmaceutica (Drug Research & Development Group),
´
´
Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
´
b
´
Departamento de Farmacologıa, Facultad de Farmacia, Universidad de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
Received 3 October 2003; revised 18 November 2003; accepted 26 November 2003
Abstract—A series of (R)- and (S)-3-aminomethyl-1-tetralones, conformationally constrained analogues of haloperidol, have been
obtained by enzymatic resolution of the corresponding racemic 3-hydroxymethyl-1-tetralones using Pseudomonas fluorescens lipase.
Their binding affinities at dopamine D2 and serotonin 5-HT2A and 5-HT2C receptors were determined showing in some cases an
atypical antipsychotic profile with Meltzer’s ratio higher than 1.30.
# 2003 Elsevier Ltd. All rights reserved.
Schizophrenia is a complex disorder affecting approxi-
mately 1% of the population.1 Classical (typical) neuro-
leptics such as haloperidol (Fig. 1), are currently used
for the treatment of this disease, but their use is asso-
ciated with severe mechanism-related side effects,
including induction of acute extrapyramidal symptoms
(EPS),2 and they are ineffective against negative symp-
toms of schizophrenia. The clinical efficacy of classical
antipsychotics in the treatment of schizophrenia and
other psychotic disorders is directly related to their
ability to block dopamine D2 receptors in the brain;3
however, it has been reported that dopamine receptor
blockade in the striatum is closely associated with their
extrapyramidal side effects.4
of clozapine and other atypical antipsychotics such as
risperidone or olanzapine, the most important factor is
their relative affinities for D2 and 5-HT2A receptors.8
They proposed that the ratio pKi’s 5-HT2A/D2 between
pKi for 5-HT2A and pKi for D2 may be used to dis-
criminate atypical antipsychotics (ratio>1.12) from
classical antipsychotics (ratio<1.09). Experimental
and clinical studies seem to confirm the major role of
the 5-HT2A receptor for the atypical profile of the
antipsychotics.9
The introduction of clozapine for treatment-resistant
schizophrenia gave rise to a new group of atypical or
non-classical antipsychotics which have no EPS and are
effective against negative symptoms.5 These drugs exhi-
bit potent antagonism at multiple receptor subtypes
including serotonin and dopamine receptors, suggesting
the implication of the serotoninergic system in this
pathology.6 Meltzer et al.7 suggested that in the efficacy
Keywords: Aminomethyltetralones; Enzymatic resolution; Dopamine
receptors; Serotonin receptors; Antipsychotics.
* Corresponding author. Tel.: +34-981-594-628; fax: +34-981-594-
912; e-mail: qofara@usc.es
Figure 1. Some typical and atypical antipsychotics.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.11.064

586
Y. Caro et al. / Bioorg. Med. Chem. Lett. 14 (2004) 585–589
Additionally, many of the atypical antipsychotic agents
block not only 5-HT2A but other serotonin receptors,
particularly 5-HT2C receptors.10 It has been also sug-
gested that 5-HT2C receptor blockade is responsible for
reducing EPS.11 These findings have given cause for
5-HT2C receptor to be considered as a potential target in
the treatment of psychotic illnesses.12
(Æ)-1–3 were synthesized from the corresponding
benzaldehydes in a five step procedure (30–40% overall
yield) as described previously.16 Tosylation of the
hydroxyketones (Æ)-1–3 with p-toluenesulfonyl chlo-
ride in pyridine afforded the corresponding tosylates
(Æ)-4–6. Alkylation of the secondary amine a–d with
the tosylates (Æ)-4–6 gave the conformationally con-
strained aminobutyrophenones (Æ)-7a–d, (Æ)-8a–d and
(Æ)-9a–d.
Four decades after its introduction into the clinic, clo-
zapine remains the prototype of atypical antipsychotic
drugs and no currently available agents appear to have
the spectrum of efficacy of this drug. However, treat-
ment with clozapine is associated with an increased risk
of agranulocytosis,13 which strongly limits its therapeutic
use. Hence, the discovery of a more effective side effects
free therapy for the treatment of schizophrenia remains a
challenging research goal.
The synthesis of the optically pure aminobutyro-
phenones (+)- and (À)-7–9 was accomplished by
resolution of the intermediates (Æ)-1–3. Between the
different method of resolution we chose the lipase cata-
lyzed kinetic resolution methodology, which has proven
to have substantial advantages over conventional
chemistry-based methods.17 Preliminary studies carried
out with the hydroxytetralone (Æ)-1 were reported pre-
viously by us.18 The best results (Table 1) were achieved
using lipase from Pseudomonas fluorescens (PF) adsor-
bed on Celite119 in benzene, which yielded the hydroxy-
ketone (R)-(À)-1 (93% ee), and the acetate (S)-(+)-10
(91% ee). Accordingly, racemic hydroxymethyltetralones
(Æ)-2–3 were submitted to enzymatic kinetic resolution
using PF lipase adsorbed on Celite1 (Scheme 2) in dif-
ferent solvents.20 Optimized results are shown in Table
1. Resolution of alcohol (Æ)-2 afforded enantiomeri-
cally pure acetate (S)-(+)-11 in THF (E>200), while
enantiopure residual hydroxyketone (R)-(À)-2 could be
obtained when the reaction was carried out in vinyl
acetate (E=45). Complete resolution (E>200) of
hydroxymethyltetralone (Æ)-3 was accomplished with
vinyl acetate as solvent. In these compounds, lipase PF
reacts preferently with the (S) enantiomers to produce
the (S)-acetates. Finally, ester hydrolysis of (S)-(+)-10–
12 with LiOH afforded the corresponding hydroxy-
methyltetralones (S)-(+)-1–3 in 90% yield (Scheme 2).
The absolute configurations of (+)- and (À)-1–3 were
determined on the basis of the reported X-ray crystal-
lography of their tosylates.16,18
As part of a program aimed at developing potential
atypical antipsychotic compounds we have reported the
synthesis, pharmacological activity and molecular mod-
elling of aminoalkylbenzocycloalkanones (Fig. 2) which
are conformationally restricted butyrophenone analo-
gues of haloperidol.14 These compounds represent some
of our efforts on modulation of the butyrophenone sys-
tem with the aim of combining antagonism at 5-HT2
family and D2 receptors in a single molecule.15 The
known chiral discriminatory properties of drug–receptor
interactions have prompted us to further investigate
whether the receptor affinities of these compounds are
associated with absolute stereochemistry by means of
the preparation of these compounds as single enantio-
mers. Herein we describe the chemoenzymatic synthesis
of (R)- and (S)-6,7-dimethoxy-, 6-methoxy- or unsub-
stituted 3-aminomethyl-1-tetralones 7–9 (Scheme 1),
and their binding affinities on D2, 5-HT2A and 5-HT2C
receptors.
The target 3-aminomethyltetralones 7–9 were prepared
as shown in the Scheme 1. 3-Hydroxymethyltetralones
Tosylation of the enantiomerically pure alcohols fol-
lowed by nucleophilic displacement of the tosyl group
with amines c and d (Scheme 1) gave (R)-(À)-/(S)-(+)-
7–9c, and (R)-(À)-/(S)-(+)-7–9d, which hydrochloride
salts prove to be aceptable forms for binding assays.
The two-step transformations of (R)- and (S)-1–3 to
Figure 2. General formula of aminoalkylbenzocycloalkanones.
Scheme 1. (i) See ref 19; (ii) TsCl, Py (70–85%); (iii) HNRR (2 equiv), NMP (50–80%).

Y. Caro et al. / Bioorg. Med. Chem. Lett. 14 (2004) 585–589
587
Table 1. Enzymatic resolution of 3-hydroxymethyl-1-tetralones using PF lipase adsorbed on Celite1
Compd
Solventa
T (h)
Conversion (%)
Hydroxyketone (À)-1–3
Acetate (+)-10–12
Yield (%)
ee (%)c
Eb
Yield (%)
ee (%)c
1
2
2
3
Bencene
THF
VA
7.5
1.5
0.25
0.6
50
48
58
50
35
52
20
47
93
91
99.9
99.9
40
91
94
>200
45
43
75
45
99.9
72.5
99.9
VA
>200
a VA: vinyl acetate.
b Enantioselectivity was calculated from the formula E=ln[1Àc(1Àees)]/ln[1Àc(1+ees)].21
c Determined by chiral HPLC (Chiracel1 OD-H column, Daicel), except for acetate (+)-10, which was determined after alkaline hydrolysis to the
corresponding alcohol.22
Table 2. Binding affinities and selectivities for aminomethyltetralones
(Æ)-7a–d, (Æ)-8a–d and (Æ)-9a–d
Compd
pKia
5-HT Ki ratio
pKi ratio
5-HT2A 5-HT2C D2
2C/2A
5-HT2A/D2
(Æ)-7a
6.29
6.05
5.63
6.01
6.16
6.18
7.88
7.75
8.22
8.57
7.34
8.02
6.78
8.04
9.30
5.55
7.33
<5
5.48
5.34
<5
6.30
5.93
7.08
6.89
5.79
6.83
5.14
7.98
8.13
6.69
6.65
6.08
6.40
<5
5.5
0.05
—
3.4
6.7
0.94
0.91
0.93
0.94
—
(Æ)-8a
(Æ)-9a
(Æ)-7b
(Æ)-8b
(Æ)-9b
<5
—
—
(Æ)-7c
6.65
6.71
6.56
7.24
6.34
6.82
9.22
6.65
ndb
38.1
66.1
13.8
47.6
35.5
15.5
43.6
1.1
1.18
1.15
1.25
1.18
1.16
1.18
0.73
1.21
nd
(Æ)-8c
(Æ)-9c
(Æ)-7d
(Æ)-8d
(Æ)-9d
Haloperidol
Clozapine
Risperidone
Scheme 2. Enzymatic resolution of 3-hydroxymethyl-1-tetralones.
14.8
a Values are means of three separate experiments (s.e.m. less than 6%).
b nd=not determined.
(R)- and (S)-7–9, respectively, were achieved in 40–65%
overall yield.
The binding affinities of the racemic aminomethyl-
tetralones (Æ)-7a–d, (Æ)-8a–d and (Æ)-9a–d at the
5-HT2A, 5-HT2C, and dopamine D2 receptors are sum-
marized in Table 2.23 Aminomethyltetralones contain-
ralone ring in these series do not affect significantly to
the binding affinity at any of the receptors studied,
which suggests that their interaction with such receptors
is not significant.
ing
a piperazine (a or b, Scheme 1) fragment
(compounds (Æ)-7a,b, (Æ)-8a,b, and (Æ)-9a,b) show
modest or low affinity at the three receptors tested. In
general, these derivatives display receptor selectivity
(potent D2 relative to 5-HT2A affinity) similar to classi-
cal neuroleptics: the pKi ratios 5-HT2A/D2 (Meltzer’s
ratio) were lower than 1.09. Because of their low affinity
at D2 receptors, compounds (Æ)-8b and (Æ)-9b do not
possess interest as potential antipsychotics, though (Æ)-
9b could have interest as selective 5-HT2A compound.
Those compounds with higher 5-HT2A affinity and
Meltzer’s ratios (7c–d, 8c–d, and 9c–d) were synthesized
as pure enantiomers, and their binding affinities were
measured (Table 3). In general, all examples in this ser-
ies show excellent potency for the 5-HT2A receptor,
reaching pKi values as high as 8.83 (Ki=1.5 nM) for
compound (+)-8d. Also it is remarkable the increased
selectivity showed for some enantiomers at the 5-HT2A
receptor over the 5-HT2C and D2 receptors with respect
to the racemic compound. Thus, compounds (À)-7c,
In general, aminomethyltetralones bearing a substituted
piperidine moiety, i.e., (Æ)-7c,d, (Æ)-8c,d, and (Æ)-9c,d,
exhibited higher affinity (pKi>7.3 or Ki<50 nM) and
selectivity (Ki ratios >10) for the 5-HT2A receptor than
the mentioned piperazine group. With the exception of
the dimethoxy derivative (Æ)-9c, these compounds
showed higher affinity at D2 than at 5-HT2C receptors:
the trend of the binding potency displayed was
5-HT2A>D2>5-HT2C. Since all the compounds in this
group have a Meltzer’s ratio higher than 1.15, an atypi-
cal antipsychotic profile could be predicted for these
compounds. In general, the methoxy groups at the tet-
(À)-7d, and (+)-8d have particularly higher 5-HT2C
/
5-HT2A ratios than their corresponding racemates. The
same happens with the D2/5-HT2A ratios of (+)-8d and
(À)-9c versus (Æ)-8d and (Æ)-9c, respectively. Unfor-
tunately, the effective differences in affinity at the
5-HT2A, 5-HT2C, and D2 receptors for these corre-
sponding (R)/(S) pairs is insignificant, and it is not pos-
sible to establish a general rule that connect the
stereochemistry of the chiral centre with potency in any
of the receptors studied.

588
Y. Caro et al. / Bioorg. Med. Chem. Lett. 14 (2004) 585–589
Table 3. Binding affinities and selectivities for aminomethyltetralones
(+)- and (À)-7c–d, 8c–d and 9c–d
References and notes
1. Reynolds, G. P. Trends Pharmacol. Sci. 1992, 13, 116.
2. Martin, A. R. In Burger’s Medicinal Chemistry, 5th ed.;
Wolf, M. E., Ed.; Wiley-Interscience: New York, 1997;
Vol. 5, p 195.
Compd
pKia
5-HT Ki ratio
pKi ratio
5-HT2A 5-HT2C D2
2C/2A
5-HT2A/D2
(+)-7c
(À)-7c
7.63
8.23
7.95
7.79
7.36
8.25
7.53
8.20
8.83
7.58
7.79
8.14
6.78
8.04
9.30
6.31
6.11
5.96
6.01
6.24
6.78
6.18
6.08
6.29
6.08
6.85
6.85
5.14
7.98
8.13
6.47
6.98
6.27
6.42
6.50
6.00
6.67
7.19
6.30
6.36
6.97
6.79
9.22
6.65
ndb
20.9
131.8
97.7
60.3
13.2
29.5
22.4
131.8
346.7
31.6
8.7
1.18
1.18
1.27
1.21
1.13
1.37
1.13
1.14
1.40
1.19
1.11
1.20
0.73
1.21
nd
3. (a) Seeman, P.; Chou-Wong, M.; Tadesco, J.; Wong, K.
Nature 1976, 261, 717. (b) Peroutka, S. J.; Snyder, S. H.
Am. J. Psychiatry 1980, 173, 1518. (c) Hartman, D. S.;
Civelli, O. Progress in Drug Research 1997, 48, 173.
4. (a) Sanberg, P. R. Nature (London) 1980, 284, 472. (b)
Nowak, K.; Welsch-Kunze, S.; Kuschinsky, K. Naunyn-
Schmiedeberg’s Arch. Pharmacol. 1988, 337, 385.
5. (a) Fitton, A.; Heel, R. C. Drugs 1990, 40, 722. (b)
Schwarz, J. T.; Brotman, A. W. Drugs 1992, 44, 981. (c)
Rosenheck, R.; Cramer, J.; Xu, W.; Thomas, J.; Hender-
son, W.; Frisman, L.; Fye, C.; Charney, D. N. Engl. J.
Med. 1997, 337, 809.
(+)-8c
(À)-8c
(+)-9c
(À)-9c
(+)-7d
(À)-7d
(+)-8d
(À)-8d
(+)-9d
(À)-9d
19.5
43.5
1.1
Haloperidol
Clozapine
Risperidone
6. Sanders-Buch, E.; Mayer, S. E. In The Pharmacological
Basis of Therapeutics, 9th ed.; Hardman, J. G., Limbird,
L. E., Molinoff, P. B., Ruddon, R. W., Goodman, A.,
Eds.; McGraw-Hill: New York, 1996; p 249.
14.8
a Values are means of three separate experiments (s.e.m. less than 6%).
b nd=not determined.
7. (a) Meltzer, H. Y.; Matsubara, S.; Lee, J. C. Psycho-
pharmacol. Bull. 1989, 25, 390. (b) Roth, B. L.; Tandra,
S.; Burgess, L. H.; Sibley, D. R.; Meltzer, H. Y. Psycho-
pharmacology 1995, 120, 365. (c) Roth, B. L.; Meltzer,
H. Y.; Khan, N. Adv. Pharmacol. 1998, 42, 482.
8. Lowe, J. A., III Curr. Med. Chem. 1994, 1, 50.
9. (a) Van Oekelen, D.; Luyten, W. H. M. L.; Leysen, J. E.
Life Sci. 2003, 72, 2429. (b) Sipes, T. E.; Geyer, M. A.
Brain Res. 1997, 761, 97. (c) Okuyama, S.; Chaki, S.;
Kawashima, N.; Suzuki, Y.; Ogawa, S.; Kumagai, T.;
Nakazato, A.; Nagamine, M.; Yamaguchi, K.; Tomisawa,
K. Brit. J. Pharmacol. 1997, 121, 515.
10. Di Matteo, V.; Cacchio, M.; Di Giulio, C.; Di Giovanni,
G.; Esposito, E. Pharmacol. Biochem. Behav. 2002, 71,
607.
11. Reavill, C.; Kettle, A.; Holland, V.; Riley, G.; Blackburn,
T. P. Br. J. Pharmacol. 1999, 126, 572.
However, it is worth mentioning compounds (+)-8d
and (À)-9c as potential atypical antipsychotics, with a
Meltzer’s ratio of 1.40 and 1.37, respectively, both
higher than that of clozapine (1.21).24 Benzisox-
azolylpiperidine compound (+)-8d exhibits, at 5-HT2A
receptor, the highest affinity (pKi=8.83, Ki=1.5 nM)
and selectivity (>300-fold over 5-HT2C and D2 recep-
tors), while benzoylpiperidine derivative (À)-9c displays
high affinity at 5-HT2A receptor (pKi=8.25, Ki=5.6
nM), and 177-fold selectivity over D2 receptor
(pKi=6.00, Ki=1000 nM), and both compounds have
affinity and selectivity profiles at 5-HT2A receptor sig-
nificantly different than those of their counterparts.
Although methoxy groups have not afforded sig-
nificantly pharmacological advances, these groups open
a chemical access to a large range of substituents in the
aromatic portion of the tetralones, research in progress
now in our group.
12. Wood, M. D.; Heidbreder, C.; Reavill, C.; Ashby, C. R.,
Jr.; Middlemiss, D. N. Drug Dev. Res. 2001, 54, 88.
13. Lieberman, J. A.; Hohn, C. A.; Mikane, J.; Rai, K.; Pis-
ciotta, A. V.; Salz, B. L.; Howard, A. J. Clin. Psychiat.
1988, 49, 271.
14. (a) Cortizo, L.; Santana, L.; Ravina, E.; Orallo, F.; Fon-
tenla, J. A.; Castro, E.; de Ceballos, M. J. Med. Chem.
1991, 34, 2242. (b) Fontenla, J. A.; Osuna, J. A.; Rosa, E.;
Castro, E.; Loza, I.; G-Ferreiro, T.; Calleja, J. M.; Sanz,
F.; Rodriguez, J.; Fueyo, J.; Ravina, E.; Masaguer, C. F.;
Vidal, A.; de Ceballos, M. J. Med. Chem. 1994, 37, 2564.
(c) Brea, J.; Rodrigo, J.; Carrieri, A.; Sanz, F.; Cadavid,
M. I.; Enguix, M. J.; Villazon, M.; Mengod, G.; Caro, Y.;
Masaguer, C. F.; Ravina, E.; Centeno, N. B.; Carotti, A.;
Loza, M. I. J. Med. Chem. 2002, 45, 54 and references
cited therein.
In summary, we have described the synthesis and bind-
ing affinity of new 3-aminomethyltetralones as con-
formationally constrained analogues of haloperidol.
Those compounds with a more interesting binding pro-
file were prepared as single enantiomers by a che-
moenzymatic route using Pseudomonas fluorescens
lipase, and their binding affinities and selectivities at D2,
5-HT2A, and 5-HT2C receptors were examined. From
this effort have emerged the benzisoxazolylpiperidine
compound (+)-8d and the benzoylpiperidine derivative
(À)-9c as potential antipsichotic compounds, as a result
of their good affinities, selectivities and Meltzer’s ratios.
15. Ravina, E.; Masaguer, C. F. Curr. Med. Chem.: Central
Nervous System Agents 2001, 1, 43.
16. Caro, Y.; Torrado, M.; Masaguer, C. F.; Ravina, E. Tet-
rahedron: Asymmetry 2003, 14, 3689.
17. (a) Bornscheuer, U. T.; Kazlauskas, R. J. In Hydrolases
in Organic Synthesis: Regio- and Stereoselective Bio-
transformations; Wiley-VCH: Weinheim, 1999. (b) Carrea,
G.; Riva, S. Angew. Chem., Int. Ed. Engl 2000, 39, 2226.
18. Caro, Y.; Masaguer, C. F.; Ravina, E. Tetrahedron:
Asymmetry 2003, 14, 381.
Acknowledgements
´
This work was supported by Spanish Comision Inter-
ministerial de Ciencia y Tecnologıa (CICYT) under
´
Grants SAF98-0148-C04-04, SAF2002-04195-C03-01,
and SAF2002-04195-C03-02, by Xunta de Galicia under
19. Bianchi, D.; Cesti, P.; Battistel, E. J. Org. Chem. 1988, 53,
5531.
´
Grant PGIDT01-PXI20309PR, and by the Fundacio La
´
Marato de TV3.
20. General procedure: To
a solution of the hydroxy-
methyltetralone (Æ)-1–3 (1.0 mmol) in a solvent (Table

Y. Caro et al. / Bioorg. Med. Chem. Lett. 14 (2004) 585–589
589
1), vinyl acetate (55 mL, 0.6 mmol), and Pseudomonas
fluorescens lipase on Celite1 (100 mg) was added. The
mixture was stirred at room temperature, filtered through
Celite1 and concentrated in vacuo. The residue was pur-
ified by flash column chromatography (silica gel, EtOAc:
hexane, 1:3) to give the (R)-3-hydroxymethyltetralones
(À)-1–3 and the (S)-acetates (+)-10–12.
hexane–2-propanol 90:10, flow 0.3 mL/min, l 254 nm,
tR=112 min.
23. Methods for binding assays have been published in ref
14(c).
24. Data for selected compounds: (S)-(+)-8d: white solid, mp
162–163 ꢀC. [a]2D0=+23.3 (c 1.5, AcOEt). IR: 1667. 1H
NMR (CDCl3): d 2.04–2.45 (m, 10H); 2.65–2.84 (m, 2H);
2.95–3.11 (m, 4H); 3.85 (s, 3H); 6.72 (d, 1H, J=2.2); 6.81
(dd, 1H, J=8.7, 2.4); 7.04 (dt, 1H, J=8.8, 2.1); 7.19–7.24
(m, 1H); 7.69 (dd, 1H, J=8.7, 5.1); 7.97 (d, 1H, J=8.7).
MS (CI, m/z): 409 (MH+). Hydrochloride: mp 230 ꢀC
21. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294.
22. (R)-(À)-1: [a]2D0=À26.5 (c 1.0, AcOEt), 93% ee. Chir-
alcel1 OD-H, hexane–2-propanol 94:6, flow 0.5 mL/min,
l 254 nm, tR=49 min. (R)-(À)-2: [a]2D0=À36.3 (c 0.5,
AcOEt), 99.9% ee. Chiralcel1 OD-H, hexane:2-propanol
90:10, flow 0.3 mL/min, l 254 nm, tR=64 min. (R)-(À)-3:
[a]2D0=À53.0 (c 0.5, AcOEt), 99.9% ee. Chiralcel1 OD-H,
hexane–2-propanol 90:10, flow 0.3 mL/min, l 254 nm,
tR=104 min. (S)-(+)-11: [a]2D0=+31 (c 1.0, AcOEt),
99.9% ee. Chiralcel1 OD-H, hexane–2-propanol 90:10,
flow 0.3 mL/min, l 254 nm, tR=70 min. (S)-(+)-12:
[a]2D0=+40 (c 1.0, AcOEt), 99.9% ee. Chiralcel1 OD-H,
.
(decomp.). Anal. (C24H25FN2O3 HCl): C, H, N. (R)-(À)-
9c: white solid, mp 153–155 ꢀC. [a]D20=À39.6 (c 0.8,
1
AcOEt). IR: 1668. H NMR (CDCl3): d 1.87 (br.s, 4H);
2.05–2.47 (m, 6H); 2.58–2.75 (m, 2H); 2.88–3.06 (m,
3H); 3.12–3.24 (m, 1H); 3.88, 3.92 (s, 3H); 6.68 (s, 1H);
7.05–7.17 (t, 2H, J=8.5); 7.47 (s, 1H); 7.95 (dd, 2H,
J=8.7, 5.5). ꢀMS (CI, m/z): 426 (MH+). Hydrochloride:
1
.
.
mp 244–245 C. Anal. C25H28FNO4 HCl /2H2O: C, H,
N.