Asymmetric synthesis of quaternary tetrahydroisoquinoline-3-carboxylic acid derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00075-2

A new route towards the asymmetric preparation of quaternary 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives has been developed. The key step involves an intramolecular Pictet-Spengler reaction of an oxazolidino ester.

Full text of DOI:10.1016/S0040-4039(01)00075-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2111–2113
Asymmetric synthesis of quaternary
tetrahydroisoquinoline-3-carboxylic acid derivatives
Vale´rie Alezra, Martine Bonin,* Laurent Micouin* and Henri-Philippe Husson
Laboratoire de Chimie The´rapeutique associe´ au CNRS et a` l’Universite´ Rene´ Descartes,
Faculte´ des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
Received 17 November 2000; accepted 12 January 2001
Abstract—A new route towards the asymmetric preparation of quaternary 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
derivatives has been developed. The key step involves an intramolecular Pictet–Spengler reaction of an oxazolidino ester. © 2001
Elsevier Science Ltd. All rights reserved.
The design of new unnatural conformationally
restricted a-amino acids has been a popular area of
endeavor in recent years.1 Incorporation of such deriva-
tives into peptidic or non-peptidic structures can usu-
ally bring new insights into SAR analysis, and lead to
the development of compounds with improved pharma-
cological profiles. Among the numerous constrained
believed to produce molecules with even more con-
strained conformations, examples of asymmetric prepa-
ration of derivatives 3 are still scarce.5
We recently reported a new method for the asymmetric
synthesis of a substituted quaternary serines based on
the diastereoselective functionalization of oxazolidine 4
(Scheme 1).6
analogs
reported
in
the
literature,
tetra-
hydroisoquinoline carboxylic acid (Tic) derivatives are
of particular interest, since they are able to restrain
conformational freedom around  torsion angles.2 For
instance, incorporation of Tic 1 into peptides led to d
opioid receptor antagonists,3 and compound 2 was used
as a molecular scaffold for the design of matrix metal-
loproteinases.4 Although a substitution of Tic is
During our studies, we noted that the acidic hydrolysis
of such oxazolidines proved to be troublesome, because
of the good stability of the transient iminium species.
We report in this paper the use of this iminium reactiv-
ity for the preparation of tetrahydroisoquinolines 6 via
intramolecular Pictet–Spengler reactions.7
Scheme 1.
* Corresponding authors. E-mail: bonin@pharmacie.univ-paris5.fr; micouin@pharmacie.univ-paris5.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00075-2

2112
V. Alezra et al. / Tetrahedron Letters 42 (2001) 2111–2113
Table 1.
Compound
R1
R2
R3
d.e. (%)a,b
Yield (%)a
7a
7b
7c
7d
7e
OMe
OMe
OMe
H
OMe
OMe
H
H
OMe
H
H
94
96
95
94
86
64
74
50
65
70
O-CH2-O
Cl
H
a Yield of diastereomer mixture.
b Determined by 1H NMR analysis of the crude reaction mixture.
Quaternary oxazolidines 7a–e were prepared from oxa-
zolidine 4 according to our reported procedure (Table
1).6 They were obtained with good diastereomeric
purity, except for compound 7e. In this case,
diastereomerically pure material could be obtained,
albeit in a moderate yield (47%) after chromatographic
separation. The absolute configuration of the newly
created asymmetric center was established according to
our previous results with standard electrophiles.6
unreactive under such experimental conditions (Scheme
2 and Table 2).
Cyclization yields proved to be irreproducible unless a
small amount of Et3N was added to the reaction mix-
ture. We found that protonation of the starting oxazo-
lidine nitrogen completely inhibits the Pictet–Spengler
cyclization. Addition of Et3N neutralizes uncontrolled
acidic traces in the reaction mixture, leading to repro-
ducible results.8
As already noticed, the best yields were obtained with
benzylic electrophiles bearing iodine as a leaving group.
They were prepared by halogen exchange or from the
corresponding alcohol starting with commercially avail-
able benzyl derivatives.
Compounds 8a–d proved to be quite unstable, and were
directly submitted to hydrogenolysis, leading to quater-
nary amino acids 6a–d.9
The rearrangement of oxazolidine 8a was not fully
regioselective, and an 80:20 mixture of para- and ortho-
substituted compounds was obtained. This mixture was
hydrogenolyzed and the expected amino acid 6a was
obtained as a single regioisomer after recrystallization.
Compounds 7a–d smoothly rearranged into the corre-
sponding tetrahydroisoquinolines 8a–d in the presence
of TiCl4. Hydrolysis of tert-butyl ester occurred during
the aqueous work-up. The chloro derivative 7e was
Scheme 2.

V. Alezra et al. / Tetrahedron Letters 42 (2001) 2111–2113
2113
Table 2.
4. Matter, H.; Schwab, W. J. Med. Chem. 1999, 42, 4506–
4523.
Compound
R1
R2
R3
Yield (%)a
5. (a) Chinchilla, R.; Galindo, N.; Najera, C. Synthesis 1999,
704–717; (b) Ma, D.; Ma, Z.; Kozokowski, A. P.;
Pshenichkin, S.; Wroblewski, J. T. Bioorg. Med. Chem.
Lett. 1998, 8, 2447–2450; (c) Seebach, D.; Dziadulewicz,
E.; Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs Ann.
Chem. 1989, 1215–1232; (d) Bajgrowicz, J.; El Achquar,
A.; Roumestant, M.-L.; Pigie`re, C.; Viallefont, P. Hetero-
cycles 1986, 24, 2165–2167.
6a
6b
6c
6d
OMe
OMe
OMe
H
OMe
OMe
H
H
OMe
H
30
70
96
78
O-CH2-O
a Overall isolated yield from 7.
6. Alezra, V.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche,
C.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 1737–1740.
7. For a similar strategy, see: Allin, S. M.; Northfield, C. J.;
Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1998, 39,
4905–4908.
In the case of compounds 8b–d, only one regioisomer
was obtained in good overall yield.
In conclusion, oxazolidine 4 proved to be a suitable
tool for the asymmetric elaboration of various quater-
nary tetrahydroisoquinoline carboxylic acids. The key
step involved an intramolecular Pictet–Spengler reac-
tion, which proceeded efficiently with activated phenyl
rings. Compounds 6a–d can be used as new scaffolds
for incorporation into peptides, and the alcohol func-
tion can be exploited for further functionalizations.
8. The commercial solution of TiCl4 (1 M in CH2Cl2) used
for the rearrangement may contain some acidic traces.
9. Typical procedure: Oxazolidine 8d (68 mg, 0.15 mmol) was
dissolved in anhydrous dichloromethane (5 mL) with tri-
ethylamine (11 mL, 0.07 mmol) under argon. A solution of
TiCl4 (1 M in CH2Cl2, 308 mL, 0.31 mmol) was added
dropwise and the reaction mixture was stirred for 3 h.
Water (5 mL) was then added, the organic layer was
extracted and the aqueous layer was washed twice with
dichloromethane. The combined organic layers were dried
over anhydrous MgSO4, filtered, and the solvent was
evaporated. The crude reaction mixture (66 mg) was dis-
solved in a 1:1 water/ethanol mixture (8 mL), Pd(OH)2
(20%, 35 mg) was added and the suspension was stirred
under a hydrogen atmosphere for 2.5 h. After filtration
and solvent evaporation, the crude reaction mixture was
purified (Dowex 50X8, 80–100 mesh, 10 g) to give 30 mg
of amino acid 6d (78%). Compound 6d (white solid):
Acknowledgements
One of us (V.A.) thanks the MENRT for a grant.
References
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[h]D=−25 (c=1.4, MeOH). H NMR (CD3OD, 300 MHz)
l ppm: 6.76 (s, 2H) 6.00 (br. s., 2H), 4.42 (d, J=15.4 Hz,
1H), 4.18 (d, J=15.4 Hz, 1H), 4.04 (d, J=11.5 Hz, 1H),
3.77 (d, J=11.5 Hz, 1H), 3.22 (d, J=16.6 Hz, 1H), 3.02
(d, J=16.6 Hz, 1H). 13C NMR (CD3OD, 75.5 MHz) l
ppm: 174.9, 148.9, 148.2, 126.7, 123.2, 109.7, 107.2, 102.5,
66.6, 64.9, 43.9, 32.4. MS (NH3): 252 (MH+).
.
.