Asymmetric synthesis of α-substituted propynyl amines. Application to the preparation of a polysubstituted dihydroisoindoline framework

Article abstract of DOI:10.1016/S0040-4039(01)00356-2

A new route towards the asymmetric preparation of α-substituted propynylamines has been developed. The key step involved a diastereoselective addition of diethylalkynylaluminum to oxazolidines derived from R-(-)-phenylglycinol. The use of this reaction for the rapid preparation of a polysubstituted isoindoline framework is described.

Full text of DOI:10.1016/S0040-4039(01)00356-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3171–3173
Asymmetric synthesis of a-substituted propynyl amines.
Application to the preparation of a polysubstituted
dihydroisoindoline framework
Je´roˆme Blanchet, 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 2 March 2001; accepted 3 March 2001
Abstract—A new route towards the asymmetric preparation of a-substituted propynylamines has been developed. The key step
involved a diastereoselective addition of diethylalkynylaluminum to oxazolidines derived from R-(−)-phenylglycinol. The use of
this reaction for the rapid preparation of a polysubstituted isoindoline framework is described. © 2001 Elsevier Science Ltd. All
rights reserved.
Enantiopure a-substituted propargylamines are useful
synthetic intermediates.1 Among them, propynyl amines
are particularly interesting since they can be further
functionalized with the help of the unique acetylide
reactivity.2 Asymmetric synthesis of such derivatives
has recently been investigated by Tabor’s group, and
involved the nucleophilic ring-opening of chiral non-
racemic tetrahydro-oxazines with protected acetylenic
Grignard reagents under Lewis acidic conditions.3 This
strategy led to the corresponding propargylic amines in
moderate to good enantioselectivities, but required the
use of 4 equiv. of the expensive trimethylsilylacetylene.
pounds. The use of dialkylalkynyl alanes proved to be
essential to get high diastereoselectivities and chemical
yields without requiring low temperature conditions.4
We report in this paper our work on the preparation of
a-substituted propynyl amines using mixed organoalu-
minum compounds as nucleophiles, and their transfor-
mation into polysubstituted dihydroisoindolines.
Oxazolidines 3 were prepared as previously described
and used without any purification for the alkynylation
step (Scheme 1). Unprotected diethylethynylaluminum
was prepared by a simple transmetallation from the
inexpensive, commercially available sodium acetylide
with diethylaluminum chloride.5 Compounds 4a–g were
obtained in good overall yield, with moderate to good
diastereoselectivity6 (Table 1).
We recently described a new route towards the asym-
metric synthesis of a-substituted propargylic amines,
based on the diastereoselective opening of chiral non-
racemic oxazolidines by mixed organoaluminum com-
Ph
OH
Ph
Ph
Ph
OH
OH
N
a
c
N
O
b
NH
NH2
Ar
R
Ar
R
Ar
1
2
3
4
Scheme 1. Reagents and conditions: (a) ArCHO, NaBH4, MeOH, 12 h; (b) RCHO, MgSO4, CH2Cl2, D, 1 h; (c) HCꢀCAlEt2
(3 equiv.), toluene, −10°C.
* 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)00356-2

3172
J. Blanchet et al. / Tetrahedron Letters 42 (2001) 3171–3173
Table 1.
after 76 h in toluene at 50°C. Under these conditions,
compound 4f led to cycloadduct 7f as a single
diastereomer and the diastereomeric mixture of com-
pounds 4e led to diastereomerically pure adduct 7e
after chromatographic purification.
Compound Ar
R
Yield (%)a d.e. (%)b
4a
4b
4c
4d
4e
4f
Ph
Ph
Me
92c
66
79
66
CH2CH2Ph 84
Ferrocenyl Me
Ferrocenyl CH2CH2Ph 64
2-Furyl
2-Furyl
2-Furyl
80c
Cycloadducts could be hydrogenated and N-depro-
tected in the same step in a quantitative yield, leading
to perhydroisoindoline 8e from 7e. Reduction of the
most hindered double bound of isopropyl-substituted
derivative 7f did not occur under the same conditions.
82
72
\97
\97
Me
iPr
Ph
81c
87
66
4g
a Overall yield of diastereomerically pure compound from 1.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Yield of diastereomeric mixture.
Relative configuration of compound 8e could be estab-
lished by NOE experiments, showing that hydrogena-
tion occurred from the less hindered face of the trans
bicyclic cycloadduct. The excellent diastereoselectivity
of the IMDAF reaction can be explained by the
reversibility of this reaction, leading to the most stable
trans compound under thermodynamic conditions.8
The absolute configuration of the newly created asym-
metric center was established according to our previous
results with mixed organoaluminum compounds as
nucleophiles.4
As previously observed, the methylene ferrocenyl pro-
tective group can be easily removed without any race-
mization (Scheme 2).
In conclusion, unprotected diethylethynylaluminum
reacts in an efficient and diastereoselective manner with
chiral non-racemic oxazolidines, leading to a-substi-
tuted propynyl amines. These synthetic intermediates
can be used for the preparation of more elaborate
molecules. As an example, polysubstituted isoindolines
derivatives could be obtained in enantiomerically pure
form via a highly stereoselective intramolecular Diels–
Alder reaction. These isoindolines can act as chiral
building blocks for the elaboration of biologically
active compounds.
Moreover, propynyl amines 4 can be further functional-
ized using the terminal acetylenic reactivity. As an
example, compounds 4e,f could be selectively O-pro-
tected and C-carboxymethylated without any epimer-
ization (Scheme 3). Compounds 6e,f were not purified
at this step, since they rapidly underwent an
intramolecular furyl Diels–Alder (IMDAF) cycloaddi-
tion.7 Completion of this reaction could be obtained
Ph
OH
Ph
OH
N
5% TFA in CH2Cl2
Et3SiH
HN
71 %
Fc
Me
Me
5:1 d.r.
5:1 d.r.
4c
5
Scheme 2.
Ph
Ph
OMe CO2Me
OH
a
N
N
O
O
R
4e R = Me
4f R = iPr
6e R = Me
6f R = iPr
R
b
Ph
c
c
O
O
O
NH
NH
N
H
Me
OMe
R
CO2Me
CO2Me
CO2Me
8f quant.
7e R = Me 44% from 4e
7f R = iPr 59% from 4f
8e quant.
Scheme 3. Reagents and conditions: (a) (i) NaH, MeI, THF, 3 h, (ii) MeLi, ClCOOMe, 30 min; (b) toluene, 50°C, 72 h; (c) H2,
Pd/C, MeOH, 8 h.

J. Blanchet et al. / Tetrahedron Letters 42 (2001) 3171–3173
3173
Acknowledgements
(20 mL, 1 M in hexane, 20 mmol) was slowly added
sodium acetylide (7.4 mL, 18% wt. slurry in xylene, 4
equiv.) under argon. The resulting mixture was stirred for
2 h at rt, cooled at −10°C and oxazolidine 3f (1.82 g, 6.73
mmol) in toluene (10 mL) was dropwise added. After
stirring for 1 h, the solution was transferred to a 1 M
Rochelle salts water solution (50 mL). The aqueous layer
was extracted twice with diethylether (50 mL) and the
combined organic layers were washed with a saturated
NaCl aqueous solution, dried over magnesium sulfate and
evaporated. The crude reaction mixture was purified by
column chromatography (silica gel, 9/1 cyclohexane/ethyl
acetate) to furnish 1.83 g of 4f (91%, 87% from phenylgly-
cinol 1). Compound 7f (colorless oil): [h]D=+55 (c 0.8,
CHCl3). 1H NMR (CDCl3, 300 MHz) l ppm: 7.28 (m,
6H), 6.29 (dd, J=3.3, 1.9 Hz, 1H), 6.14 (d, J=3.3 Hz,
1H), 4.02 (m, 3H), 3.89 (d, J=15.4 Hz, 1H), 3.79 (d,
J=15.4 Hz, 1H), 3.13 (dd, J=10.1, 2.2 Hz, 1H), 2.55 (br
s, 1H), 2.29 (d, J=2.2 Hz, 1H), 1.68 (m, 1H), 0.93 (d,
J=6.6 Hz, 3H), 0.80 (d, J=6.6 Hz, 3H). 13C NMR
(CDCl3, 75.5 MHz) l ppm: 153.7, 141.6, 138.8, 128.8,
127.9, 127.3, 110.2, 107.9, 83.1, 73.9, 66.9, 61.9, 61.9, 59.8,
43.5, 32.0, 20.3, 19.6. MS (NH3): 298 (MH+).
One of the authors (J.B.) would like to thank the MRT
for the award of a grant.
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