Diastereoselective synthesis of lortalamine analogs

Article abstract of DOI:10.1016/S0957-4166(02)00232-X

(R)-(+)-1-(1-Naphthyl)ethylamine was found to be a more effective chiral auxiliary in the asymmetric synthesis of lortalamine analogs than (S)-(-)-α-methylbenzylamine. Chiral, non-racemic ketones 6 and 7 were prepared and transformed into pairs of diaster

Full text of DOI:10.1016/S0957-4166(02)00232-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1021–1023
Diastereoselective synthesis of lortalamine analogs
Jolanta Biała,a Zbigniew Czarnockia,* and Jan K. Maurinb,c
aFaculty of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
bDrug Institute, Chełmska 30/34, 00-750 Warsaw, Poland
Institute of Atomic Energy, 05-400 Otwock-Swierk, Poland
c
´
Received 7 May 2002; accepted 9 May 2002
Abstract—(R)-(+)-1-(1-Naphthyl)ethylamine was found to be a more effective chiral auxiliary in the asymmetric synthesis of
lortalamine analogs than (S)-(−)-a-methylbenzylamine. Chiral, non-racemic ketones 6 and 7 were prepared and transformed into
pairs of diastereomeric intermediates of final lortalamine analogs. For one of them, the stereochemistry on the heterocyclic part
was established on the basis of X-ray crystallography. Enantiomerically pure (+)-des-chloro-lortalamine 2 was finally obtained.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Benzopyranopyridino-
and
pyrimidino-derivatives
Having been engaged in the asymmetric synthesis of
compounds of pharmacological interest, we recently
turned our attention to the possibility of the stereose-
lective construction of the lortalamine system. We first
selected a des-chloro analog 2 as our model synthetic
target. It is known that racemic compound 2 can be
prepared from ethyl coumarin-3-carboxylate 3 and 1-
methyl-4-piperidone in a two-step procedure.4 We
observed that when the chiral, non-racemic N-[(S)-a-
methylbenzyl]-4-piperidone 65 was used for this reac-
tion, an intermediate b-keto ester 86 as a relatively
unstable and inseparable diastereomeric mixture was
exhibit a wide variety of pharmacological activity,
including antipyretic, anti-inflammatory, analgesic, gas-
troprotective and antiplatelet activities.1 Additionally,
several
2-aryl-4-oxobenzopyrano[2,3-d]pyrimidines
have been shown to exhibit in vivo antitumor proper-
ties.2 Moreover, several examples of neurochemical
action have been reported in this group of compounds.3
Among them, the tetracyclic compound, (1R*,9R*,
10S*)-6-chloro-12-methyl-2-oxa-12,15-diazatetracyclo-
[7.5.3.01,10.03,8]heptadeca-3,5,7-trien-16-one) was devel-
oped and introduced as a relatively safe antidepressant
and antipsychotic drug (lortalamine 1, LM 1404).4
Interestingly, lortalamine 1 is sold as a racemate. There
are no reports available on either enantioselective syn-
thesis, or resolution of racemic mixtures of these types
of derivatives.
initially formed (Scheme 1). The structure of
8
remained unclear for us until we were able to obtain a
monocrystal of 107 that was suitable for X-ray crystal-
lographic analysis. Surprisingly, we found that in this
crystal, that belongs to the common non-centrosym-
metric space group P21, both diastereomeric molecules
were present in the unit cell (Fig. 1).7 Subsequent acid
hydrolysis and decarboxylation of 8 brought about the
formation of isomers 14a8 and 14b9 in a ratio of 48:52,
respectively.
In each of the series (8–13) both isomers could easily be
separated by column chromatography on silica gel but
a single-crystal X-ray analysis could be performed only
for diastereomer 15a.10 This allowed the assignment of
(1S,9S,10R) stereochemistry at the heterocyclic part of
the molecule (Fig. 2). In the case of pure diastereomer
* Corresponding author. Tel.: +48 22 822 02 11; fax: +48 22 822 59
96; e-mail: czarnoz@chem.uw.edu.pl
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00232-X

1022
J. Biała et al. / Tetrahedron: Asymmetry 13 (2002) 1021–1023
Scheme 1.
Figure 1. ORTEP diagram of compound 10. Two diastereomers are present in the unit cell.
Figure 2. X-Ray crystal structure of 15a.

J. Biała et al. / Tetrahedron: Asymmetry 13 (2002) 1021–1023
1023
Table 1. Diastereoselectivity of lortalamine analogs
129.29, 129.18, 128.58, 128.46, 127.36, 127.23, 124.98,
122.03, 121.87, 120.63, 117.52, 117.28, 83.34, 64.00, 63.77,
62.21, 61.36, 61.32, 53.57, 53.54, 51.10, 51.01, 50.50,
48.51, 47.43, 46.21, 37.28, 36.92, 35.61, 35.43, 18.69,
13.79; EI 70 eV m/z (%): 420 (65), 405 (80), 374 (20), 347
(45), 315 (35), 289 (25), 200 (50), 184 (25), 105 (100).
7. X-Ray intensity data for 10 and 15a: Measurements were
completed at T=293 K on a Kuma KM4CCD k-axis
formation13
Entry
Diastereomers
Yield (%)
Selectivity
1
2
3
4
5
6
14aa:14ba
15a:15b
16a:16b
17a:17b
18a:18b
19a:19b
89
91
78
92
95
77
48:52
62:38
40:60
29:71
23:77
84:16
,
diffractometer with Mo Ka radiation (u=0.71073 A).
2120 frames were collected at 0.9° intervals with a count-
ing time of 5 s for 15a (656 frames and 0.7° for 10,
respectively). The data were corrected for Lorentz and
polarization effects. No absorption corrections were
applied. The structures were solved by direct methods
from SHELXS11 and refined using SHELXL software.12
Crystal data for compound 10: C25H24Cl2N2O4, M=
487.36, monoclinic space group P21; a=12.910(3), b=
a a, less polar; b, more polar diastereomer on silica plate.
14a, the chiral auxiliary was subsequently removed by
hydrogenolysis over Pd/C and the secondary amine
thus formed was subsequently N-methylated using
formaldehyde–sodium borohydride to afford (+)-2 in
enantiomerically pure form.
,
14.020(3), c=12.920(3) A, i=91.00(3)°, V=2338.1(8)
,
3
A , Z=4 and Dcalcd=1.384 Mg/m3. Colorless crystal, v
(Mo Ka)=0.313 mm−1, F(000)=1016, 4727 reflections
collected. Least squares on F2 (all reflections), R=0.0633,
wR2=0.1795 (observed).
We observed that whereas the modification of the cou-
marin component affected the diastereomeric ratio
slightly (Table 1, entries 1–3), a more profound influ-
ence on the stereoselectivity could be noticed when a
more sterically demanding amine was applied as the
chiral auxiliary. Thus, when ketone 7 derived from
(R)-(+)-1-(1-naphthyl)ethylamine5 was used, we
observed an increase of the selectivity to around 23:77
or even 84:16 (Table 1, entries 4–6).
8. Selected data for 14a: [h]2D0=+31.6 (c 2.05, CHCl3); mp
156–157°C; 1H NMR (CDCl3, 500 MHz): l 7.30–6.78
(9H, m), 6.51 (1H, s), 3.41 (2H, ABq, J=13.5), 2.90 (2H,
br d, J=5.5 Hz), 2.79–2.70 (2H, m), 2.60 and 2.56 (1H,
two s), 2.36–2.32 (2H, m), 1.98–1.95 (1H, m), 1.92–1.86
(2H, m), 1.80 (1H, br s), 1.28 (3H, d, J=6.0 Hz); 13C
NMR (125 MHz, CDCl3): 171.22, 149.87, 144.58, 129.14,
128.63, 128.33, 127.31, 126.92, 123.28, 121.72, 117.32,
81.45, 64.06, 48.73, 47.46, 42.26, 38.04, 36.53, 32.83,
19.00; EI 70 eV 8 kV m/z (%): 348 (75), 333 (100), 243
(50), 271 (8), 200 (18), 105 (62), 91 (10), 77 (12); IR (KBr,
cm−1) 3450, 3200, 2800, 1680, 1580.
The preliminary results described above show that pop-
ular chiral, non-racemic 1-arylethyl amines may also
serve as good chiral inductors in the diastereoselective
synthesis of benzopyranopyridine derivatives.
9. Selected data for 14b: [h]2D3=−27 (c 2.0, CHCl3); mp
218–220°C; 1H NMR (CDCl3, 500 MHz): l 7.29–6.78
(9H, m), 6.56 (1H, s), 3.44 (2H, ABq, J=5.5), 2.76–2.70
(2H, m), 2.60–2.51 (2H, m), 2.39–2.24 (2H, m), 2.11 (1H,
d, J=13.5 Hz), 2.00 (1H, br s), 1.80–1.75 (1H, t, J=11.5
Hz), 1.33 (3H, d, =5.5 Hz); 13C NMR (125 MHz,
CDCl3): 171.18, 149.82, 129.15, 128.59, 128.40, 127.29,
126.97, 123.24, 121.70, 117.29, 81.37, 64.45, 51.14, 45.35,
42.20, 37.90, 36.53, 32.58, 20.01; EI 70 eV 8 kV m/z (%):
348 (85), 333 (100), 243 (60), 271 (10), 200 (25), 105 (65),
91 (10); IR (KBr, cm−1) 3400, 3200, 3000–2700, 1510.
10. Crystal data for compound 15a: C23H26N2O3, M=378.46,
References
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ethyl coumarin-3-carboxylate 3 (0.75 g, 3.4 mmol) and
ammonium acetate (1.32 g, 17.2 mmol) in anhydrous
ethanol (7 ml) was stirred for 90 h at room temperature.
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