(S)-(-)-α-Methylbenzylamine as chiral auxiliary in the synthesis of (+)-lortalamine

Article abstract of DOI:10.1007/s00706-008-0017-2

(+)-Lortalamine was synthesised using (S)-(-)-α-methylbenzylamine as a chiral auxiliary. The stereochemistry of an intermediate compound was established on the basis of X-ray crystallography, allowing unambiguous assignment of the absolute configuration.

Full text of DOI:10.1007/s00706-008-0017-2

Monatsh Chem (2009) 140:83–86
DOI 10.1007/s00706-008-0017-2
ORIGINAL PAPER
(S)-(2)-a-Methylbenzylamine as chiral auxiliary in the synthesis
of (+)-lortalamine
Jolanta Pawłowska Æ Krzysztof K. Krawczyk Æ
Krystyna Wojtasiewicz Æ Jan K. Maurin Æ
Zbigniew Czarnocki
Received: 5 February 2008 / Accepted: 2 June 2008 / Published online: 20 August 2008
Ó Springer-Verlag 2008
Abstract (?)-Lortalamine was synthesised using (S)-(-)-
a-methylbenzylamine as a chiral auxiliary. The stereo-
chemistry of an intermediate compound was established on
the basis of X-ray crystallography, allowing unambiguous
assignment of the absolute configuration.
been developed and introduced as a relatively safe anti-
depressant and antipsychotic drug (lortalamine, LM 1404)
[1, 2].
O
N
H
Cl
Keywords Drug research ꢀ Tetracyclic antidepressants ꢀ
Relative stereochemistry ꢀ Heterocycles ꢀ
X-ray structure determination
HN
O
(+)-1
Introduction
As a result of the presence of the rigid multi-ring system,
two stable enantiomers of lortalamine (1) are possible.
Interestingly, to date there are no reports of a stereoselective
preparation of non-racemic 1. The asymmetric synthesis of
pharmacologically valuable compounds using readily
available chiral inductors is one of the leading tasks in
synthetic organic chemistry, since it is well documented
that enantiomers usually exhibit different biological activity
and metabolic profiles. In this context, we decided to use
(S)-(-)-a-methylbenzylamine (2), which is widely known
as an effective chiral adjuvant [5, 6] and whose utility has
also been proven in our laboratory [7].
Considering the growing number of people suffering from
depressive illnesses, the development of efficient antide-
pressants seems to be a very important target for the
pharmaceutical industry. The search for possible lead
compounds with desired activity, which has been based
mainly on the monoamine theory of depression, has led in
recent decades to the discovery of several promising can-
didates [1–4]. Among them, the tetracyclic compound
(1R*,9R*,10S*)-6-chloro-12-methyl-2-oxa-12,15-diazatet-
racyclo[7.5.3.01,10.03,8]heptadeca-3,5,7-trien-16-one (1) has
J. Pawłowska ꢀ K. K. Krawczyk ꢀ K. Wojtasiewicz ꢀ
Z. Czarnocki (&)
Faculty of Chemistry, Warsaw University,
Pasteura 1, 02-093 Warsaw, Poland
e-mail: czarnoz@chem.uw.edu.pl
Results and discussion
It is known that the racemic hexahydrobezopyrano[3,2-c]
pyridine ring system can be prepared in a two-step
procedure from ethyl coumarin-3-carboxylate and 1-methyl-
4-piperidone [1, 2]. Since N-[(S)-a-methylbenzyl]-4-piperi-
done (3) can easily be obtained from commercially available
and relatively inexpensive compound 2 without loss of
J. K. Maurin
National Medicines Institute, Chełmska 30/34,
00-725 Warsaw, Poland
J. K. Maurin
Institute of Atomic Energy, 05-400 Otwock-Swierk, Poland
´
123

84
J. Pawłowska et al.
enantiomeric purity, we considered it as an interesting
chiral building block for the stereoselective synthesis of
lortalamine (1). Compound 3 was synthesised according to
the protocol described by Kuehne et al. [8]. Another
component, 5-chloro-3-carboxyethylcoumarin (4), can be
prepared in nearly quantitative yield in a Knoevenagel-type
condensation as proposed by Horning and Dimmig [9].
Compounds 3 and 4 suspended in absolute ethanol under-
went a condensation reaction in the presence of ammonium
acetate. The resulting b-ketoesters 5a and 5b were not
stable enough for spectroscopic characterisation, but their
presence can be assumed considering previous syntheses of
other lortalamine analogues [10]. We have already shown
that, in the preparation of des-chlorolortalamine and
4-chlorolortalamine, b-ketoesters were stable enough to
allow purification and characterisation [10]. In the case of
the synthesis of racemic lortalamine, according to Briet
et al. [1, 2], the condensation was followed directly by
acid-catalysed hydrolysis without purification of the inter-
mediates. The diastereoisomers 6a and 6b (Scheme 1)
were formed in 72% total yield and could be easily sepa-
rated via column chromatography on silica gel (6a was the
less polar isomer). HPLC analysis showed the diastereo-
meric ratio to be 49:51.
In the case of diastereomer 6b, we were able to obtain
a monocrystal suitable for X-ray structure analysis, which
proved unambiguously the stereochemistry of this com-
pound (Fig. 1). The characteristic feature of this crystal
structure is the hydrogen bonding N–HꢀꢀꢀO network
formed by the N–H and C=O groups of one of the lor-
talamine rings of adjacent molecules. These form a
system of anti-parallel hydrogen-bonded polar chains,
where the chains pass in the a-direction. The crystal was
a weak diffractor, which resulted in a low number of
observed data points [976 data points with I [ 2r(I)] and
hence higher R and wR factors. This might be interpreted
as the result of thermal motion, especially visible in an N-
substituent region.
The chiral auxiliary was then removed from compound
6a by hydrogenation with a Pd/C catalyst to give the
enantiopure 7a (Scheme 2), which was isolated in the form
of a hydrochloride in 61% yield. The hydrochloride salt
was both more prone to efficient purification by crystalli-
sation and more stable than the free amine. The amine 7a
was then N-methylated to give (?)-lortalamine ((?)-1).
The purity of this compound was proven by HPLC analysis
on a chiral stationary phase.
O
C2H5
Although we have already observed that the use of
(R)-(?)-1-(1-naphthyl)ethylamine in a similar reaction
sequence leading to lortalamine analogues gave consider-
ably better diastereoselectivity (up to 84:16) [10], we found
that, in the present sequence, the diastereoselectivity
increase (if any) was overshadowed by unfavourable
chromatographic properties of the isomers that precluded
their effective separation. Therefore, it seems that the use
of (S)-(-)-a-methylbenzylamine (2) was the optimal
choice.
Ph
Cl
CHO
O
O
+
H3C
O
OH
NH2
2
C2H5O
K2CO3, H2O/EtOH, reflux,
75%
MeOH, reflux,
95%
N
I
O
O
Cl
N
Ph
O
O
O
3
4
CH3 COO NH4,
EtOH, rt.
EtOOC
H
EtOOC
H
O
O
Cl
Cl
N
Ph
N
Ph
+
HN
O
HN
O
5a
5b
HCl, reflux,
72%
H
8
17
O
H
O
7
11
1'
Cl
Cl
9
N
3'
10
N
7'
6'
+
HN
HN
5
13
3
1
4'
O
4
14
O
5'
6a
6b
Fig. 1 Conformation of 6b and the numbering scheme. The non-
hydrogen atoms are shown as 30% probability ellipsoids
Scheme 1
123

(S)-(-)-a-Methylbenzylamine as chiral auxiliary in the synthesis of (?)-lortalamine
85
Scheme 2
HCHO/H2O,
EtOH, NaBH
O
Cl
NH2
O
H
H
CH3COOH, HCl,
Pd/C, H2, 61%
Ph
,
4
Cl
Cl
10°C, 68
%
N
HN
O
HN
(+)-1
O
7a
6a
eluent (TLC, silica plates, CHCl3:MeOH = 19:1, Rf =
0.50 for 6a and Rf = 0.45 for 6b). The pure diastereomers
6a and 6b were obtained in 35% and 37% yield,
respectively. The crystals of 6b, suitable for an X-ray
analysis were obtained by a slow evaporation from a
chloroform/diethyl ether mixture.
Experimental
The NMR spectra were recorded on a Varian Unity Plus
1
spectrometer operating at 500 MHz for H NMR and at
125 for 13C NMR with TMS as an internal standard. Mass
spectra were collected with an AMD 604 apparatus; high-
resolution mass spectra were acquired using LSIMS
(positive ion mode), GC/MS was performed on a HP 6890
with an HP 5973 mass detector (oven 280°C, injection
300°C, detector 300°C). A ChiraDex b-Dex120 30 m/
0.25 mm Supelco column was used for analytical enan-
tiomer separations. Optical rotation was measured on a
Perkin-Elmer 247 MC polarimeter. TLC analysis was
performed on Merck 60 silica gel glass plates and visual-
ised using iodine vapour. Column chromatography was
carried out at atmospheric pressure using Silica Gel 60
(230–400, Merck). HPLC analyses were performed on a
Knauer apparatus (model 64) with Eurochrom 2000 soft-
ware using 4 mm 9 250 mm silica (5 lm) column model
Li-Chrosorb Si-60 (Knauer) with a gradient ratio of
dichloromethane/methanol. Melting points were deter-
mined on a Boetius hot-plate microscope.
6a: M.p.: 122–128 °C (from CHCl3/Et2O); 1H NMR
(CDCl3): d = 7.34 - 7.29 and 7.25 - 7.22 (m, 5H, H-3’–
H-7’), 7.12 (dd, 1H, J1 = 8.5 Hz, J2 = 2.5 Hz, H-5), 7.03
(d, 1H, J = 2.5 Hz, H-7), 6.73 (d, 1H, J = 8.5 Hz, H-4),
6.57 (br.s, 1H, NH), 3.46 (apparent q, 1H, J = 4.0 Hz, H-
1’), 2.94-2.88 (br.m, 1H, H-9), 2.89-2.88 (br.d, 1H, H-11),
2.78 (ddAB, 1H, J1 = 17.3 Hz, J2 = 5.5 Hz, H-17), 2.79-
2.72 (br.m, 1H, H-10), 2.57 (ddAB, 1H, J1 = 17.3 Hz,
J2 = 1.5 Hz, H-17), 2.30–2.38 (br.m, 2H, H-13), 2.00 -
1.91 (br.m, 2H, H-11, H-14), 1.86 (br.t, 1H, J = 11.0 Hz,
H-14), 1.32 (br.d, 3H, J = 4.0 Hz, CH3) ppm; 13C NMR
(CDCl3): d = 170.7, 148.5, 128.7, 128.7, 128.4, 127.3,
127.0, 126.4, 124.8, 118.8, 81.6, 64.1, 48.6, 47.2, 41.9,
37.6, 36.2, 32.8, 18.7 ppm; ES (?): m/z (%) = 383 (100),
385 (40); [a]D = -29.3° cm3 g-1 dm-1 (c 1.2, CHCl3).
22
6b: M.p.: 165–170 °C (from CHCl3/Et2O); 1H NMR
(CDCl3): d = 7.30–7.21 (m, 5H, H-3’–H-7’), 7.11 (dd, 1H,
J1 = 8.5 Hz, J2 = 2.5 Hz, H-5), 6.96 (d, 1H, J = 2.5 Hz,
H-7), 6.82 (br.s, 1H, NH), 6.72 (d, 1H, J = 8.5 Hz, H-4),
3.36 (q, 1H, J = 6.0 Hz, H-10), 3.08 (br.d, 1H, J = 5.5 Hz,
H-11), 2.76–2.74 (br.m, 1H, H-9), 2.72 (ddAB, 1H,
J1 = 19.0 Hz, J2 = 5.0 Hz, H-17), 2.60–2.58 (br.m, 1H, H-
10), 2.51 (ddAB, 1H, J1 = 19.0 Hz, J2 = 4.0 Hz, H-17),
2.36–2.24 (m, 2H, H-13), 2.11–1.96 (br.m, 2H, H-11,
H-14), 1.72 (br.t, 1H, J = 11.2 Hz, H-14), 1.30 (d, 3H,
J = 6.0 Hz, CH3) ppm; 13C NMR (CDCl3): d = 170.9,
148.4, 128.6, 128.4, 128.4, 127.2, 127.0, 127.2, 126.2,
124.8, 118.7, 81.6, 64.4, 50.8, 45.3, 41.89, 37.5 36.3, 32.5,
X-ray data were collected applying a Kuma KM4 j-axis
single crystal diffractometer and the characteristic MoKa
radiation. These data were used consecutively to solve and
then refine the crystal structure using SHELXS97 and
SHELXL97 programs [11, 12].
(1R,9R,10S)-6-Chloro-12-[(10S)-phenyl-ethyl]-2-oxa-
12,15-diazatetracyclo[7.5.3.01,10.03,8]heptadeca-3,5,7-
trien-16-one (6a, C22H23ClN2O2) and (1S,9S,10R)-6-
chloro-12-[(10S)-phenyl-ethyl]-2-oxa-12,15-diazatetracyclo
[7.5.3.01,10.03,8]heptadeca-3,5,7-trien-16-one
(6b, C22H23ClN2O2)
A suspension containing 2.20 g N-[(S)-a-methylbenzyl]-4-
piperidone (3) (10.84 mmol), 2.70 g 5-chloro-3-carboeth-
oxycoumarin (4) (10.84 mmol) and 4.17 g ammonium
acetate (54.18 mmol) in 7 cm3 absolute ethyl alcohol was
stirred for 72 h at room temperature. After evaporation of
the solvent, 5 cm3 concentrated hydrochloric acid was
added and the mixture was heated at reflux for 45 min. The
volatiles were then evaporated and the residue (3.0 g) was
purified by column chromatography on silica gel using 3%
(v/v) methanol/chloroform mixture as eluent. The mixture
was then subjected to a column chromatography on silica
gel using 1% (v/v) methanol/chloroform mixture as an
19.9 ppm; [a]D = -98° cm3 g-1 dm-1 (c 1.2, CHCl3).
22
After mounting and centring a crystal of dimensions 0.3
9 0.26 9 0.2 mm3, the unit cell was found and data were
collected. Crystallographic data: orthorhombic crystal,
P212121 space group, a = 7.3850(15), b = 9.2730(19), c
3
˚
˚
= 33.589(7) A, a = b = c = 90°, V = 2300.2(8) A , Z =
4, F(000) = 808, l(MoKa) = 0.183 mm-1, T = 293(2) K,
4,139 reflections [976 with I [ 2r(I)], R = 0.0896. The
detailed structural data had been deposited with the Cam-
bridge Structural Data Centre under the number CCDC
225585.
123

86
J. Pawłowska et al.
(1R,9R,10S)-6-Chloro-2-oxa-12,15-diazatetracyclo
[7.5.3.01,10.03,8]heptadeca-3,5,7-trien-16-one
hydrochloride (7a, C14H16Cl2N2O2)
crystalline solid (TLC, silica plates, CHCl3:MeOH = 23:2,
Rf = 0.65). M.p.: 212–216 °C (from CHCl3); 1H NMR
(DMSO-d6):d = 8.61 (s, 1H, NH), 7.27 (d, 1H, J = 1.95 Hz,
H-7), 7.19 (dd, 1H, J1 = 8.79 Hz, J2 = 1.95 Hz, H-5), 6.83
To a solution containing 220 mg of the diastereomer 6a
(0.58 mmol) in 30 cm3 freshly distilled acetic acid,
1.3 cm3 conc. hydrochloric acid and 100 mg 10% Pd/C
were added. The flask was then filled with hydrogen under
a pressure of ca. 1.5 atm; hydrogenation proceeded for
80 h at 50 °C with vigorous stirring. The suspension was
then filtered through a thin layer of Celite. [CAUTION:
Activated hydrogenation catalysts are highly pyrophoric
and have to be handled with special care!] The solvent was
removed in vacuo and the residue was purified via column
chromatography on silica gel with 7% (v/v) MeOH in
CHCl3 to give 110 mg (61%) of the amine 7a hydrochlo-
ride as white crystals (TLC, silica plates, CHCl3:MeOH
= 17:3, Rf = 0.4). M.p.: [ 220 °C (decomposition, from
(d, 1H, J = 8.79 Hz, H-4), 2.94 (m, 1H, H-9), 2.76 (ddAB
,
1H, J1 = 17.6 Hz, J2 = 4.9 Hz, H-17), 2.73–2.69 (br.m, 1H,
H-13), 2.64 (dd, 1H, J1 = 10.7 Hz, J2 = 3.9 Hz, H-11), 2.32
(ddd, 1H, J1 = 13.7 Hz, J2 = 4.0 Hz, J3 = 2.0 Hz, H-14),
2.29 (ddAB, 1H, J1 = 17.6 Hz, J2 = 2.0 Hz, H-17), 2.14 (s,
3H, CH3), 2.11–2.07 (m, 2H, H-11, H-13), 1.78 (td, 1H,
J1 = 13.7 Hz, J2 = 4.0 Hz, H-14), 1.55 (t, 1H, J = 10.7 Hz,
H-10) ppm; 13C NMR (CDCl3): d = 169.9, 148.7, 128.8,
127.9, 126.2, 124.4, 118.4, 81.4, 54.2, 50.5, 45.3, 41.8, 36.0,
35.0, 31.6 ppm; [a]D = ?39.3° cm3 g-1 dm-1 (c 1.2,
22
MeOH); LSIMS (?): m/z (%) = 315 [M ? Na]? (25), 293
[M ? H]? (25), 269 (30), 258 (30), 199 (30) 106 (100), 93
(25).
1
CHCl3/MeOH); H NMR (DMSO-d6): d = 9.81 (s, 1H,
HCl), 9.55 (br.s, 1H, NH), 8.84 (s, 1H, NH), 7.34 (d, 1H,
J = 2.5 Hz, H-7), 7.25 (dd, 1H, J1 = 8.5 Hz, J2 = 2.5 Hz,
H-5), 6.90 (d, 1H, J = 9.0 Hz, H-4), 3.30 (br.d, 2H, H-13),
3.15–3.13 (br.m, 1H, H-10), 2.95 (m, 1H, H-11), 2.80
(ddAB, 1H, J1 = 17.3 Hz, J2 = 5.0 Hz, H-17), 2.68 (br.m,
1H, J = 10.0 Hz, H-14), 2.40 (dAB, 1H, J = 17.0 Hz, H-
17), 2.35-2.27 (br.m, 2H, H-9, H-11), 2.14 (m, H-14) ppm;
13C NMR (CDCl3): d = 169.5, 148.0, 129.2, 128.4, 125.2,
124.8, 118.8, 80.1, 48.4, 42.1, 41.4, 32.9, 31.4, 30.8 ppm;
Acknowledgment We acknowledge financial support from grant
PBZ-KBN-126/T09/2004/13.
References
1. Briet P, Berthelon JJ, Depin JC (1980) US Patent 4.201.783
2. Ding Y-S, Lin K-S (2005) Bioorg Med Chem 13:4658–4666
3. Sanger DJ, Depoortere R, Perrault G (1996) Behav Pharmacol
7:477–482
4. Depin JC, Betbeder-Matibet A, Bonhomme Y, Muller AJ,
Berthelon JJ (1985) Arzneim-Forsch/Drug Res 35 (II), 11:1655–
1662
22
[a]D = ?63.5° cm3 g-1 dm-1 (c 1.2, MeOH);
(+)-Lortalamine ((+)-1, C15H17ClN2O2)
(?)-Lortalamine ((?)-1, C15H17ClN2O2)Hydrochloride 7a
(110 mg, 0.35 mmol) was basified with a 15% solution of
NaOH, and extracted with CH2Cl2 (3x5 cm3). The solution
was dried over MgSO4, and the solvent was removed in
vacuo. A volume of 0.15 cm3 37% (w/v) formalin and
5 cm3 EtOH were added, followed by a portionwise
addition of 200 mg (5.26 mmol) NaBH4 at 10 °C. After
48 h of stirring at room temperature, the solvents were
removed in vacuo and 20 cm3 brine was added. The
product was extracted with CH2Cl2 (3x5 cm3). After
drying over MgSO4, the solvent was removed, and the
residue was purified by column chromatography on silica
gel using 2% (v/v) MeOH:CHCl3 to give 68 mg (68%) of
´
5. Juaristi E, Escalante J, Leon-Romo JL, Reyes A (1998) Tetra-
hedron Asymmetry 9:715–740
´
6. Juaristi E, Leon-Romo JL, Reyes A, Escalante J (1999) Tetra-
hedron Asymmetry 10:2441–2495
7. Ziołkowski M, Czarnocki Z, Leniewski A, Maurin JK (1999)
Tetrahedron Asymmetry 10:3371–3380
8. Kuehne ME, Matson PA, Bornman WG (1991) J Org Chem
56:513
9. Horning EC, Horning MG, Dimmig DA (1955) Org Synth Col-
lect III:165
10. Biała J, Czarnocki Z, Maurin JK (2002) Tetrahedron Asymmetry
13:1021
11. Sheldrick GM (1990) Acta Crystallogr A46:467–473
12. Sheldrick GM, SHELXL-97. Program for the refinement of
¨
crystal structures, University of Gottingen, Germany
´
123