Asymmetric synthesis of 1-substituted tetrahydro-3-benzoazepines

Article abstract of DOI:10.1016/j.tetasy.2005.06.007

In order to develop a new asymmetric synthesis of enantiomerically pure 1-substituted tetrahydro-3-benzoazepines 3, the synthesis of diastereomerically pure oxazolo[3]benzoazepinone 4 has been performed. The stereochemical information of the key intermedi

Full text of DOI:10.1016/j.tetasy.2005.06.007

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2199–2202
Asymmetric synthesis of 1-substituted tetrahydro-3-benzoazepines
Ursula Wirt,a Roland Frohlichb and Bernhard Wunscha,*
¨
¨
aInstitut fu¨r Pharmazeutische und Medizinische Chemie der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster,
Hittorfstraße 58-62, D-48149 Mu¨nster, Germany
bOrganisch-Chemisches Institut der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster, Corrensstr. 40, D-48149 Mu¨nster, Germany
Received 15 September 2004;revised 6 June 2005;accepted 7 June 2005
Dedicated to Prof. Dr. C. Herdeis on the occasion of his 60th birthday
Abstract—In order to develop a new asymmetric synthesis of enantiomerically pure 1-substituted tetrahydro-3-benzoazepines 3, the
synthesis of diastereomerically pure oxazolo[3]benzoazepinone 4 has been performed. The stereochemical information of the key
intermediate 4 originates from the chiral auxiliary (R)-phenylglycinol. The tricyclic ring system of 4 allows the stereoselective intro-
duction of a benzyl residue at the 6-position to obtain benzyl derivative 15 with a diastereoselectivity of 95.1:4.9. The relative con-
figuration of the main product 15 was determined by X-ray crystal structure analysis. Reductive degradation of diastereomerically
pure 15 led to enantiomerically pure (R)-1-benzyl-3-benzoazepine 17.
ꢀ 2005 Elsevier Ltd. All rights reserved.
10
1. Introduction
1
9
NH
NH
H3C
NH
The NMDA receptor belongs to a group of excitatory
ionotropic glutamate receptors and is activated by N-
methyl-D-aspartate. The NMDA receptor is involved
in a variety of complex physiological processes such as
learning and memory. However, overstimulation causes
acute and chronic neurodegenerative disorders including
excitotoxicity, epilepsy, AlzheimerÕs or ParkinsonÕs dis-
ease.1 The tetracyclic MK-801 1 represents a non-com-
petitive NMDA receptor antagonist (Ki = 1.2 nM)
interacting with the PCP binding site within the cation
channel.2 Formal cleavage of the C9a/C10 bond of
MK-801 results in tetrahydroisoquinoline 2, also bind-
ing at the NMDA receptor. The enantiomers of 2 dis-
play considerable differences of their NMDA receptor
interaction: (S)-2: Ki = 35.4 nM, (R)-2: Ki = 3756 nM.3
1-Substituted 3-benzoazepines 3 are also potent NMDA
receptor antagonists. However, only racemic mixtures
have been investigated4 (see Fig. 1).
CH3
R
1
(–)-3
2
Figure 1.
Only a few methods for the synthesis of enantiomeri-
cally pure tetrahydro-3-benzoazepines have been re-
ported.5–8 Davies et al. elaborated a diastereoselective
intramolecular Friedel–Crafts alkylation of a chiral
Cr(CO)3-complex leading to enantiomerically pure
1-phenyltetrahydro-3-benzoazepines.5,6 The intramolecular
Friedel–Crafts acylation of N-(phenethyl)amino acids
provided 2-substituted tetrahydro-3-benzoazepines.7
Tietze et al. described an intramolecular Heck reaction,
which led to enantiomerically pure 3-benzoazepines.8
These methods belong to the class of chiral pool synthe-
sis. An asymmetric synthesis using a chiral auxiliary has
not been detailed. Furthermore, the already described
methods do not allow the systematic variation of the
3-benzoazepine substitution pattern. In order to investi-
gate the relationship between substituted 3-benzoaze-
pines and their NMDA receptor affinity, we were
interested in a method, which would allow a flexible
Since our interest has been focused on the NMDA
receptor affinity of 3-benzoazepine enantiomers, we in-
tended to develop an asymmetric synthesis of enantio-
merically pure 1-substituted 3-benzoazepines.
*
Corresponding author. Tel.: +49 251 8333311;fax: +49 251
8332144;e-mail: wuensch@uni-muenster.de
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.007

2200
U. Wirt et al. / Tetrahedron: Asymmetry 16 (2005) 2199–2202
H
H
O
O
H
H
N
NH
N
O
O
R
R
H
H
4
3
5
Figure 2.
substitution of the 3-benzoazepine scaffold. Therefore,
we planned a novel asymmetric synthesis of 1-substi-
tuted tetrahydro-3-benzoazepines 3. Tricyclic oxazolo[3]-
benzoazepinone 4 represents the key intermediate of the
projected synthesis. After deprotonation, diastereoselec-
tive alkylation should provide diastereomerically pure
products 5, which should yield after reductive cleavage
the enantiomerically pure 1-substituted 3-benzoazepines
3. The chiral information of 4 originates from (R)-phen-
ylglycinol (see Fig. 2).
duced by the reaction of anhydride 7 with enantiomeri-
cally pure (R)-phenylglycinol to give amido acid 8.10 For
the synthesis of the oxazolo[3]benzoazepinone 4, the car-
boxylic acid had to be reduced to the oxidation level of
an aldehyde. Since the direct reduction of the ester 9
failed to give an aldehyde, a reduction/oxidation proce-
dure was performed. For this purpose, the primary alco-
hol of 9 was protected with triisopropylsilyl chloride11 to
afford silyl ether 10. Reduction of 10 with LiBH4 yielded
alcohol 11, which was oxidised by Dess-Martin-Period-
inane12 to provide the desired aldehyde 12. Next, the
alcohol protecting group was cleaved with MeOH/HCl
resulting in the simultaneous protection of the aldehyde
moiety to give dimethyl acetal 13. Finally amido acetal
13 was cyclised with a catalytic amount of HCl to obtain
oxazolo[3]benzoazepinone 4 in 61% yield. A small
amount (7%) of side product 14, which was the main
product after heating of 13 in toluene, could be isolated
by flash chromatography. A further product could not
be isolated. Even careful HPLC analysis and NMR
experiments did not reveal the diastereomer of 4.
An analogous oxazolo[3]benzoazepine has been synthes-
ised by condensation of 2-[4,5-dimethoxy-2-(2-oxopro-
pyl)phenyl]acetic acid with (S)-phenylglycinol. Alkyla-
tion of this intermediate is not described.9
2. Results and discussion
The synthesis of the oxazolo[3]benzoazepinone 4 was
performed as shown in Scheme 1 by starting from com-
mercially available o-phenylenediacetic acid 6. In the
first step, dicarboxylic acid 6 was transformed into
anhydride 7. Then, the chiral information was intro-
The relative configuration of 4 was determined by the
nuclear Overhauser effect. Saturation of the proton at
COOH
H
O
N
a
COOH
COOH
OH
b
O
O
O
6
8
7
COOCH3
COOCH3
H
H
N
N
Si
c
d
OH
O
O
O
9
10
OH
CHO
H
N
H
N
Si
Si
e
f
O
O
O
O
11
12
OCH3
OCH3
H
H
HO
N
O
N
11a
3 H
OH
g
h
H
N
+
O
6
O
O
14
4
13
Scheme 1. Reagents and conditions: (a) SOCl2 1.0 equiv, toluene, 110 ꢁC, 18 h, 86%;(b) ( R)-phenylglycinol 1.0 equiv, Et3N 1.0 equiv, CH2Cl2, rt,
4 h, 85%;(c) TMS-Cl 3.0 equiv, MeOH abs., 0 ꢁC, 18 h, 83%;(d) triisopropylsilyl chloride 1.2 equiv, imidazole 2.5 equiv, DMF, rt, 18 h, 91%;(e)
LiBH4 4.0 equiv, THF abs., rt, 18 h, 94%;(f) Dess-Martin-Periodinane 1.15 equiv, CH 2Cl2, rt, 30 min, 71%;(g) 1% methanolic HCl, rt, 3 h, 75%;(h)
CHCl3/H+, rt, 5 h, 61% 4, 7% 14.

U. Wirt et al. / Tetrahedron: Asymmetry 16 (2005) 2199–2202
2201
the 11a-position (5.06 ppm) resulted in intensifying of
the signals of the phenyl protons. An increase of the
signal at 5.40 ppm (3-H) was not observed, indicating
a trans-arrangement of these protons. Thus, the configu-
ration of the novel stereogenic centre at the 11a-position
is (S).13
The relative configuration of alkylation product 15 was
determined by X-ray crystal structure analysis (see Fig.
3). As shown in Figure 3, the benzyl moiety and the
phenyl residue are trans configured. In several publica-
tions, highly diastereoselective alkylations of pyrrolidine,
piperidine and piperazine derivatives using the chiral
auxiliary phenylglycinol have already been described.15–17
In order to introduce alkyl substituents at the 6-posi-
tion, oxazolo[3]benzoazepinone 4 was deprotonated
with LDA (1.1 equiv) and subsequently alkylated with
benzyl bromide (1.0 equiv). The alkylation product 15
was isolated in 76% yield (Scheme 2).14 Careful HPLC
and LC/MS analysis of the crude alkylation product re-
vealed a diastereomeric ratio of 95.1:4.9. For further
transformations, 15 was purified by flash chromatogra-
phy to yield a product with 99.85% de.
The desired enantiomerically pure 1-benzyl tetrahydro-
3-benzoazepine 17 was obtained by reductive degrada-
tion of 15 with LiAlH4/AlCl3 and debenzylation with
ammonium formate Pd/C (Scheme 3).18 HPLC and
LC/MS analysis of 15 and 16 show that the LiAlH4
reduction proceeded without any epimerisation. Per-
forming the reductive degradation with diastereomeri-
cally pure 15 led to diastereomerically pure 16 and the
desired enantiomerically pure (R)-1-benzyl-3-benzoaze-
pine 17.
H
H
O
O
a
3. X-ray crystal structure analysis for 15
H
H
N
N
6
O
O
Formula C25H23NO2, M = 369.44, colourless crystal
0.45 · 0.20 · 0.15 mm,
4
H
a = 8.925(1),
˚
b = 13.894(1),
,
3
c = 16.015(1) A, V = 1985.9(3) A , qcalc = 1.236 g cmÀ3
˚
15
l = 6.13 cmÀ1, empirical absorption correction (0.770 6
Scheme 2. Reagents and conditions: (a) benzyl bromide 1.0 equiv,
LDA 1.1 equiv, THF abs., N2, 0 ꢁC, 4 h, 76%.
T 6 0.914), Z = 4, orthorhombic, space group P212121
˚
(No. 19), k = 1.54178 A, T = 223 K, x and u scans,
N
C
O
Figure 3. ORTEP-plot of X-ray crystal structure analysis of 15.
H
O
HO
H
H
NH
N
N
b
a
O
H
H
H
17
15
16
Scheme 3. Reagents and conditions: (a) AlCl3 0.92 equiv, LiAlH4 2.78 equiv, THF abs., N2, 0 ꢁC, 1.5 h, 80%;(b) HCOONH 4 10 equiv, Pd/C (10%),
MeOH, 80 ꢁC, 2.5 h, 74%.

2202
U. Wirt et al. / Tetrahedron: Asymmetry 16 (2005) 2199–2202
5. Coote, S. J.;Davies, S. G.;Middlemiss, D.;Naylor, A.
Tetrahedron Lett. 1989, 30, 3581–3584.
6. Coote, S. J.;Davies, S. G.;Middlemiss, D.;Naylor, A.
Tetrahedron: Asymmetry 1990, 1, 33–56.
7. Kawase, M.;Motohashi, N.;Niwa, M.;Nozaki, M.
Heterocycles 1997, 6, 1121–1129.
8999 refleÀct1ions collected ( h,
k,
3242 independent (Rint = 0.042) and
l), [(sinh)/
˚
k] = 0.59 A
,
2864 observed reflections [I P 2r(I)], 254 refined param-
eters, R = 0.040, wR2 = 0.106, max. residual electron
density 0.20 (À0.14) eAÀ3, Flack parameter 0.3(3),
˚
hydrogens calculated and refined as riding atoms.
8. Tietze, L. F.;Burkhardt, O.;Henrich, M. Liebigs Ann.
1997, 1407–1413.
Data set was collected with a Nonius KappaCCD dif-
fractometer. Programs used: data collection COLLECT
(Nonius B. V., 1998), data reduction Denzo-SMN,19
absorption correction SORTAV,20,21 structure solution
SHELXS-97,22 structure refinement SHELXL-97
(Sheldrick, G. M. Universita¨t Go¨ttingen, 1997), graph-
ics SCHAKAL (Keller, E. Universita¨t Freiburg, 1997).
9. Meyers, A. I.;Downing, S. V.;Weiser, M. J. J. Org. Chem.
2001, 66, 1413–1419.
10. The yields refer to fc purified compounds. All new
compounds gave satisfactory analytical and spectroscopic
data.
11. Cunico, R. F.;Bedell, L. J. Org. Chem. 1980, 45, 4797–
4798.
12. Speicher, A.;Bomm, V.;Eicher, T. J. Prakt. Chem. 1996,
338, 588–590.
13. NMR data of compound 4: H NMR (400 MHz, CDCl3)
Crystallographic data (excluding structure factors) for
the structure reported herein, have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication CCDC-249401. Copies of the data
can be obtained free of charge on application to The
Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: int. code +44 (0) 1223 336033, e-mail:
deposit@ccdc.cam.ac.uk].
1
d 3.33–3.41 (m, 2H, CH2 CHON);3.74 (dd, J = 8.8/7.2 Hz,
1H, OCH2CH);3.85 (d, J = 16.4 Hz, 1H, CH2C@O);3.96
(d, J = 16.4 Hz, 1H, CH2C@O);4.46 (t, J = 8.4 Hz, 1H,
OCH2CH);5.06 (dd, J = 7.0/5.1 Hz, 1H, CH2CHNO);
5.40 (t, J = 7.6 Hz, 1H, OCH2CH);7.17–7.31 (m, 9H, Ar).
14. The NMR data of compound 15: 1H NMR (400 MHz,
CDCl3) d 3.11 (dd, J = 14.1/7.0 Hz, 1H, CH2CHC@O);
3.21 (dd, J = 15.3/5.1 Hz, 1H, CH2CHNO);3.43 (dd,
J = 15.6/3.9 Hz, 1H, CH2CHNO);3.60 (dd, J = 16.3/
8.1 Hz, 1H, OCH2CH);3.59 (dd, J = 13.4/7.0 Hz, 1H,
CH2CHC@O);4.04 (t, J = 7.0 Hz, 1H, CH2CHC@O);
4.29 (t, J = 8.2 Hz, 1H, OCH2CH);5.14 (t, J = 4.3 Hz, 1H,
CH2CHNO);5.22 (t, J = 8.3 Hz, 1H, OCH2CH);6.95–
7.23 (m, 14H, Ar).
Acknowledgements
Financial support by the Fonds der Chemischen Indust-
rie is gratefully acknowledged. Thanks are also due to
the Degussa AG for donation of chemicals.
´
15. Amat, M.;Llor, N.;Herna ndez, A.;Bosch, J. Tetra-
hedron: Asymmetry 1996, 7, 977–980.
16. Schanen, V.;Cherrier, M.-P.;de Melo, S. J.;Quiron, J.-C.;
Husson, H.-P. Synthesis 1996, 833–837.
17. Amat, M.;Pshenichnyi, G.;Bosch, J.;Molins, E.;Mira-
vitlles, C. Tetrahedron: Asymmetry 1996, 7, 3091–
3094.
18. Burgess, L. E.;Meyers, A. I. J. Org. Chem. 1992, 57, 1656–
1662.
19. Otwinowski, Z.;Minor, W. Methods Enzymol. 1997, 276,
307–326.
References
1. Bra¨uner-Osborne, H.;Egebjerg, J.;Nielsen, E. O.;Mad-
sen, U.;Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43,
2609–2645.
2. Ho¨fner, G.;Wanner, K. Th. J. Rec. Sign. Transd. Res.
1996, 16, 297.
3. Sherriffs, H. J.;Shirakawa, K.;Kelly, J. S.;Olverman, H.
J.;Kuno, A.;Okubo, M.;Butcher, S. P. Eur. J. Pharma-
col. 1993, 247, 319–324.
4. Krull, O.;Wu nsch, B. Bioorg. Med. Chem. 2004, 12, 1439–
1451.
20. Blessing, R. H. Acta Cryst. 1995, A51, 33–37.
21. Blessing, R. H. J. Appl. Cryst. 1997, 30, 421–426.
22. Sheldrick, G. M. Acta Cryst. 1990, A46, 467–
473.
¨