ASYMMETRIC SYNTHESIS OF CYCLOALIPHATIC α-AMINO ACIDS WITH A NORBORNANE SKELETON

Article abstract of DOI:10.1016/0957-4166(90)90038-C

The asymmetric synthesis of endo and exo 2-aminonorbornane-2-carboxylic acids is carried out via the Diels-Alder reaction between cyclopentadiene and (-)-menthyl N-acetyl-α,β-dehydroalaninate.It is shown that this dienophile is more reactive than the corresponding methyl ester, which opens the way for the use of chiral N-acetyl-α,β-dehydroalaninates as dienophiles in asymmetric Diels-Alder reactions.As high diastereofacial selectivity is obtained with what was previously considered a mediocre chiral auxiliary, the acetamido group must play an important role, which is discussed.

Full text of DOI:10.1016/0957-4166(90)90038-C

Tetrahedron: Asymmetry Vol. 1.
pp.379.388 1990
Printed in Great Britain
plc
ASYMMETRIC SYNTHESIS OF CYCLOALIPHATIC
a-AMINO ACIDS WITH A NORBORNANE SKELETON
Carlos Cativiela*, Pilar
A. Mayoral.
Department of Organic Chemistry.
de Ciencia de
50009
de
de
CSIC.
Spain.
(Received 12
1990)
Abstract: The asymmetric synthesis of
and exo
acids is
carried out via the Diels-Alder reaction between cyclopentadiene and (-)-menthyl N-acetyl-
It is shown that this dienophile is more reactive than the corresponding
methyl ester, which opens the way for the use of chiral
as
dienophiles in asymmetric Diels-Alder reactions. As high diastereofacial selectivity is obtained
with what was previously considered a mediocre chiral auxiliary, the acetamido group must
play an important role, which is discussed.
In spite of the interesting biological properties of cycloaliphatic amino acids possessing a norbornane skeleton
there is very little in the literature
with regard to the ion transport through biological membranes
the synthesis of these structures. The parent compounds,
acids, have been
As high levels of
obtained by Diels-Alder reaction of N-acyl-a$-dehydroalaninates and
diastereofacial selectivity have been achieved in asymmetric Diels-Alder reactions using chiral acrylates as
it is interesting to determine whether chiral N-acyl-a$-dehydroalaninates can be used as chiral
dienophiles in the asymmetric synthesis of the above-mentioned a-amino acids. We have recently
communicated our preliminary results in this field4 and we want now to report the complete work in the first
asymmetric synthesis of
acids, using (-)-menthyl N-acetyl-
as a chiral dienophile. Given that in most the asymmetric syntheses of a-amino acids,
a$-dehydroamino acid derivatives are used as the starting
this work opens the way for the use of
chiral N-acyl-a$-dehydroalaninates as reagents in asymmetric reactions, the aim of which is the
enantioselective synthesis of a-amino acids.
RESULTS AND DISCUSSION
The chiral dienophile, obtained by reaction of N-acetyl-a$-dehydroalaninate
with (-)-menthol
in the
was reacted with cyclopentadiene in toluene under several conditions
presence of
(Table 1).
379

380
C. CATIVIELA et al.
reaction between
N-acetyl-a$-dehydroalaninate (2) and cyclopentadiene
ratio
(1.1)
25
25
25
0
3
3
100
100
75
1
(0.5)
(1.1)
7
3
100
99
0
3
8
8
1
(0.5)
(1.1)
0
7
76
98
-20
-20
-45
-45
-70
25
25
25
25
25
0
5
5
100
98
(1.1)
6
7
99
22
10
22
10
23
93
22
46
54
138
68
99
30
AIC13 (1.1)
(1.1)
74
43
Alc13 (0.5)
(0.5)
20
90
98
28
52
18
AlC13 (1.1)
0
Alc13 (1.1)
(1.1)
-20
25
0
(1.1)
a. Determined by
b. No signals corresponding to
could be found.
In order to find a way of determining the results of the Diels-Alder reaction, the
and exo
methyl
cycloadducts were prepared by reaction of the corresponding
and exo
[obtained by Diels-Alder reaction of methyl
with cyclopentadiene, followed by column
with (-)-menthol
and exo thus
in the presence of timethylaluminium (Scheme 1). The mixtures of
+
+
obtained were analyzed by
Scheme shows the signals that can be used to determine the relative
amounts of these compounds. Given that the singlet corresponding to the acetamido group of (-)-menthyl
appears at 2.13 ppm, the results were determined by integration of the signals of
the acetamido group methyl corresponding to the different compounds present in the reaction mixture.

381
Cycloaliphatic a-amino acids
1. cpd
column chromatography
2.
13
(-)-menthol(Z)
_
5b
5a
4b
4a
-4-a
:
2.38 (dd,
0.75 (d,
0.70
2.32
6.04
6.10
(dd,
1.96
2.03
1.89
(s,
(s,
(s,
-5-a
-5-b
(m,
The mixture of cycloadducts obtained from the Diels-Alder reaction was separated into its
and exo
n-hexane = as an eluent), and the
components by means of column chromatography (diethyl ether
corresponding purified
and
were almost quantitatively transformed into the corresponding a-amino acids
by saponification, hydrogenation, acid hydrolysis of the acetamido group and elution through an
ionic exchange resin IR 45 OH (Scheme 2).

382
C.
(-)-menthol
+
1
I
1. cpd
2. column chromatography
5a
5b
4a
6a
8a
4b
6b
8b
KOH
KOH
7a
1.
6N
1.
6N
IR 45 OH
2. Amberlite
2. Amberlite IR 45 OH
The optical rotations of the a-amino acids
and
obtained were compared with those given in the
starting from a mixture of
(1% water) = -61.4
:
= 89 : 11 the optical rotation measured for
which gives
was
(1%
87.7 12.3 starting
water) =
from a mixture of
(1% water) = -24.7
:
= 90 : 10 the optical rotation measured for
was
(1% water) = -19.1 (
which gives
88.7 11.3. These results show that there is
no epimerization during the process and enabled us to determine the absolute configuration of the major
cycloadducts resulting from the Diels-Alder reaction. In the saponification step, the
recovered without loss of optical purity.
auxiliary
was

383
Cycloaliphatic a-amino acids
The rate of the Diels-Alder reaction depends on the nature of the Lewis acid used as a catalyst (Table
and is
faster with
.In fact, the use of this catalyst leads to high chemical yields in short reaction times, even at
low temperatures and using catalyst dienophile ratios lower than the equimolecular. It is well known* that
can form seven membered chelate complexes with dienophiles that have two carbonyl groups in suitable
positions. Whereas the coordination between (-)-menthyl
place at the most basic amido group
intermediate (Figure 1). This difference may account for the greater efficiency of
the reaction rate is affected in the same way by the nature of the catalyst, but the
So the (-)-menthyl is a more reactive dienophile, which
makes it possible to use chiral N-acetyl-a$-dehydroalaninates in asymmetric Diels-Alder reactions.
and
can coordinate both carbonyl groups to give a chelate
With methyl
must take
reaction is
As
the exo cycloadducts
are obtained in greater proportion and the exo
ratio is not
noticeably modified either by the nature of the catalyst, the catalyst
temperature.
dienophile ratio or the reaction
In the Diels-Alder reaction between (-)-menthyl acrylate and cyclopentadiene,
is the major
In comparison with the reaction carried out at
the same temperature, better selectivity is obtained in the reaction between
N-acetyl-a$-dehydroalaninate and cyclopentadiene, but the same face of the dienophile is shielded by the
chiral auxiliary and
and
are the major cycloadducts. The stereochemical control may be explained by the

384
C.
et al.
similarity to the model proposed for
where the carbonyl group is antiplanar the olefinic double
bond and synplanar to the alcoxy C-H group (Figure 1). Accordingly, the Re-face of the dienophile is shielded
by the isopropyl group of the chiral auxiliary and the attack of the diene on the Si-face leads to and It is
difficult to account for the better selectivity obtained with (-)-menthyl N-acetyl-a$-dehydroalaninate, but the
acetamido group must play an important role. It has been shown that, unlike methyl where the syn
enoate conformer is favoured by about 0.7
conformer is favoured by about 0.6
show a preference of about 1.3
in methyl N-acetyl-a$-dehydroalaninate the anti enoate
Nevertheless, the Lewis acid complexes of methyl acrylate
for the anti enoate
which is explained by steric
hindrance. In the case of N-acetyl-a$-dehydroalaninates, coordination with the acetamido group is preferred. It
is therefore difficult to believe that this coordination can substantially change the 0.6 preference for
the anti enoate conformer for steric reasons and, consequently, explain the better selectivity obtained.
Therefore, we suggest that there are two possible reasons why the preference for this conformer can be
increased. When is used as a catalyst, the anti enoate conformer would be greatly favoured by the
formation of the above-mentioned complex between the Lewis acid and the dienophile (Figure 1). In
the case of AlC13, the formation of a hydrogen bond between the N-H and the carbonyl of the ester group
(favoured by coordination at the acetamido group which must increase N-H
results.
would account for the
Furthermore, a higher diastereofacial selectivity is obtained in the exo approximation, which may be due to the
steric interaction between the methylenic protons of the cyclopentadiene and the (-)-menthol moiety of the
dienophile that is only present in the transition state leading to
A similar reason has been used to explain
the exo preference in the cycloaddition between cyclopentadiene and methyl
Further work to clarify the role of the acetamido group and improve the results by use of different chiral
auxiliaries is in progress
Acknowledgements:This work was made possible by the financial support of the
(Project number
Asesora de
y
Methyl
N-acetyl-a$-dehydroalaninate
Both compounds were prepared following the methods described in the
*
and
To a solution of (-)-menthyl
General
(133.5 mg, 0.5 mmol) in anhydrous toluene (15 ml) under an inert atmosphere was added the
catalyst. After 20 minutes stirring at the corresponding working temperature, a solution of freshly distilled
cyclopentadiene (198 mg, 3 mmol) in toluene (0.5 ml) was added and the reaction was for the time
reported in Table 1. The mixture was treated with (200 mg), the solution was filtered and the
solvent evaporated under vacuum to give a mixture, composition of which was analyzed by The
for Diels-Alder

385
Cycloaliphatic a-amino acids
reaction mixture can be separated into
column using diethyl ether n-hexane
and exo
and
by column chromatography on silica gel
as an eluent
Identification and characterization of
* Methyl
and Methyl
To an anhydrous toluene solution (100 ml) of methyl N-acetyl-+dehydroalaninate
kept in an inert atmosphere, a solution of (19 ml solution in mmol) was added dropwise.
After 20 minutes stirring at a solution of freshly -distilled cyclopentadiene (6.6 g, 100 mmol) in toluene
(5 ml) was added and the reaction was stirred at After 14 hours, the reaction was treated with
(2 g) until the was removed. The mixture was filtered and the solvent was evaporated
25mmol)
under reduced pressure. The rough was separated into
chromatography using ethyl acetate as an eluent to afford 1.3 g of
and exo
and
by column
(yield: 26%) and 2.3 g of
The corresponding
and exo
were identified by means of their
spectra and
melting points, which were in good agreement with the data described in the
* Transesteriflcation of and to give and
and
were prepared from the corresponding
and by
means of the following procedure:
To an anhydrous toluene solution (25 ml) of (-)-menthol
atmosphere, a solution of (2.25 ml solution 2N in hexanes, 5.5 mmol) was added
(780 mg, 5 mmol) kept in an inert
at 0°C.
After stirring at this temperature for 30 min., the ice-bath was removed and a solution of methyl
[or methyl
(1.57 g, 7.5 mmol)] in anhydrous toluene (5 ml) was added. The reaction was
refluxed for 4 days. After cooling, the reaction mixture was treated with (1 g), filtered and the
solvent evaporated under reduced pressure. The corresponding
[or
+
were
purified by column chromatography using diethyl ether n-hexane (9: 1) as an eluent.
= 0.70
0.75
1.98
0.81-0.95
1.86-2.04
4.45-4.70 (m,lH
6.30-6.38
6H
6H
+
0.96-1.85
+
2.32 (dd,lH
5.96 (bs,lH
2.38 (dd,lH
2.94
(m,
+ 2H
+
+
+
+
= 0.75
2.03
+ 3H
0.89
0.98-1.80
2.64
4.68 (ddd,lH
+
1.95-2.10 (m,lH
3.31 (bs,lH
2.70
2.88-2.98 (m, 2H
6.42 (m,
+
Found:
for
C 71.75, H 9.62, N 4.24
C 72.04, H 9.37, N 4.20 %
C 71.85, H 9.50, N 4.00%

386
C.
al.
Transformation of amido esters
and
into amino acids
acids
and
*
To a solution of
3 mmol) in
(10 ml) was added a solution of KOH (KOH 3N in
20 ml) and the reaction mixture
was refluxed for 2 days. The resulting solution was cooled and the solvent was evaporated. The residue was
diluted in water (30 ml) and washed with ether (3 x 15 ml). The aqueous layer was then at and
the white precipitate was filtered off. The filtrate was extracted with ether (20 ml) in a Soxhlet apparatus for 4
days. After extraction, the organic layer was dried over and evaporated under vacuum to afford
of (yield: 85%).
+
The ethereal layer obtained in the first extraction was evaporated and the (-)-menthol
by sublimation under vacuum without epimerization.
was recovered
(CDC13):
1.25 1.50
1.65
1.75
1.90
2.80
2.95 (bs,lH),
6.20 (dd,lH), 8.27
IR (nujol): 3325 cm-t (N-H), 1703 cm-t (C=O), 1620
(C=O).
Found:
for
C 61.81,
H
7.00, N 6.95 %
7.17
C 61.53, H 6.71,
N
*
acids
The reaction was performed using the same conditions described for
days for reaction, 2 days for continuous extraction, 350 mg of
Starting from
(999 mg, 3 mmol),
+
were obtained (yield: 60%).
(CDC13):
1.27
1.37
1.75
6.33
2.83
3.25 (bs,lH), 6.13
7.90
(C=O).
IR (nujol): 3353 cm-t (N-H), 1694 cm-t (C=O), 1620
Found:
for
C 61.27, H 6.47, N 6.92 %
C 61.53, H 6.71 , N 7.17
*
acids
A solution of
acids
(390 mg, 2 mmol)
in
(15 ml) was hydrogenated under atmospheric pressure with Palladium-Charcoal activated (10% Pd)
(50 mg) as a catalyst. The reaction was shaken overnight. The catalyst was then filtered and the solvent was
evaporated under reduced pressure to afford 390 mg of acids as a white solid (yield: 99%).
+
(DMSO):
1.05-1.85
8.18
(N-H), 1696
1.75
2.13 (bs,lH), 2.23
2.45
(nujol): 3332
(C=O), 1620
(C=O).
Found:
for
C 60.72, H 7.95 , N 6.90 %
C 60.90 , H 7.66 , N 7.10 %

387
a-amino acids
*
acids
The reaction was performed using the same conditions described for
Starting from
(390 mg,
2
mg of
+
were obtained (yield: 95%).
(DMSO): = 1.05-2.10
1.78
2.45
2.60
8.00
IR (nujol): 3353 cm-t (N-H), 1709 cm-t (C=O), 1614 cm-r
Found:
for
C 61.09, H 7.85, N 6.98 %
C 60.90, H 7.66, N 7.10 %
*
acids
acids
197 mg, 1 mmol) were suspended
in
5N (5 ml) and the solution was heated to
for 5 hours. After this time the solvent was
evaporated under vacuum and the remaining solid was dried under reduced pressure to yield the corresponding
amino acid hydrochlorides (130 mg, 93% yield).
The mixture of amino acid hydrochlorides was diluted in water (15 ml) and the solution was passed
through an Amberlite IR 45 column (0.5 g, OH- form). The column was eluted with water until the eluate was
neutral. After evaporation of the eluates, the remaining residue was dried under vacuum to yield the amino
acids
+
as a white solid.
When the synthetic route started from (-)-menthyl N-acetyl-a$-dehydroalaninate
with
as a catalyst and the reaction was carried out at the measurement by polarimetry of the mixture
of amino acids
major
+
gave an enantiomeric excess of 75.4%
(
(1% water) =
being the
‘H-NMR
= 0.45
1.98-2.10
(nujol): 3115
Found:
0.48
0.63
1.05
1.00
2.50-2.67
1654 cm-t
1463 cm-t
1381 cm-t
C 61.65, H 8.70, N 9.00 %
C 61.91 H 8.44, N 9.02 %
for
acids
The amino acids
+
were similarly prepared from the
2-exo-carboxylic acids
When the synthetic route started from (-)-menthyl N-acetyl-a$-dehydroalaninate
with
as a catalyst and the reaction was carried out at
of amino acids
major
the measurement by polarimetry of the mixture
+
gave an enantiomeric excess of 77.4% ([a]$ (1% water) = -19.1, being the
‘H-NMR
0.57 (d,lH), 0.64 (d,lH), 0.73
1.61 1.65
1581 cm-t
C 61.85, H 8.50, N 9.10 %
C 61.91 8.44, N 9.02 %
0.96 (dd,lH), 1.29
1378
1.33 (bs,lH),
1.54
(nujol): 3357
Found:
1522

388
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