(S)-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) acetic acid as a solid supported chiral auxiliary in the asymmetric synthesis of β2-homoarylglycines

Article abstract of DOI:10.1016/S0957-4166(03)00178-2

Diastereoselective additions of the resin-supported (S)-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) acetic acid to phthalimidomethyl aryl ketenes allow solid phase preparation of β²-homoarylglycines with reasonable degrees of stereoselectivity.

Full text of DOI:10.1016/S0957-4166(03)00178-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1223–1228
(
S)-(3-Hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) acetic acid as
a solid supported chiral auxiliary in the asymmetric synthesis of
2
b -homoarylglycines
Rhalid Akkari, Monique Calm e` s,* Delphine Di Malta, Fran c¸ oise Escale and Jean Martinez
Laboratoire des Aminoacides, Peptides et Prot e´ ines, UMR-CNRS 5810-Universit e´ s Montpellier I et II, UM II,
Place E. Bataillon, 34095 Montpellier cedex 5, France
Received 20 January 2003; accepted 18 February 2003
Abstract—Diastereoselective additions of the resin-supported (S)-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) acetic acid to
2
phthalimidomethyl aryl ketenes allow solid phase preparation of b -homoarylglycines with reasonable degrees of stereoselectivity.
©
2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Solid-phase synthesis of small molecules has been rec-
ognized as an efficient tool to prepare chemical
1
2–4
libraries. However, asymmetric reactions on a solid
support have not been widely explored so far except
when a solid supported chiral reagent or catalyst was
2
3
During the last few years, the preparation of enantio-
used. The use of a supported chiral auxiliary is an
attractive approach since it allows simple isolation of
the desired non-racemic compound, easy elimination of
by-products and excess reagents, and facile separation
and recovery of the chiral material.
6
6
,7
,8
pure b-amino acids has gained considerable attention.
They are components of a variety of natural products
and show interesting pharmacological properties in
9
free form or as their cyclized derivatives (b-lactam).
Although numerous methodologies have emerged to
5
prepare enantiomerically pure b-amino acids in solu-
We have recently described the preparation of a new
3
enantiomerically pure auxiliary 1 with a carboxylic
function that allowed its attachment to an amine-func-
tionalized insoluble polymer to form 2. Its efficiency as
a polymer-supported chiral auxiliary has been first
demonstrated by asymmetric transformation of two
tion, these syntheses principally concern b -substituted
compounds 3 but the preparation of enantiomerically
2
10
pure b -substituted analogs 4 still remain a challenge.
11
We have previously found that stereoselective addi-
5
racemic aryl propionic acids via ketene formation.
tion of the chiral alcohol 5 to a prochiral ketene was a
*
0
Corresponding author. Fax: 04 67 14 48 66; e-mail: monique@ampir1.univ-montp2.fr
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00178-2

1
224
R. Akkari et al. / Tetrahedron: Asymmetry 14 (2003) 1223–1228
2
convenient method for the synthesis of (S)-b -
homoarylglycines 4 (R=aryl). As part of our program
directed toward the development of asymmetric solid-
phase reactions, we decided to examine this method for
the solid-phase preparation of these compounds using
the polymer-supported chiral auxiliary 2. To our
knowledge, there are no examples to date of asymmet-
The four step reaction sequence involved during the
asymmetric transformation of rac-4b–d are: (a) attach-
ment of the chiral auxiliary to the solid support after
removal of the Fmoc group of the linker; (b)
diastereoselective addition of the supported alcohol to
the ketene generated in solution by treatment with a
tertiary amine of the corresponding acyl chloride; (c)
benzhydrylamine bond cleavage; (d) acid hydrolysis of
both the ester and the phtalimido group to yield enan-
2
ric preparation of b -amino acids using an insoluble
polymer.
2
tioenriched b -homoarylglycines 4 (Scheme 1).
2
. Results and discussion
The key step of this reaction sequence, i.e. diastereose-
lective addition of the supported chiral auxiliary (S)-2
to the ketene, was carried out in a similar manner to
that developed by our group for the solid phase asym-
2
The starting b -amino acids were rac-2-phenyl-3-
phthalimidopropanoic acid: rac-4b, rac-2-(4-fluoro-
phenyl)-3-phthalimidopropanoic acid: rac-4c, and rac-
1
1
metric transformation of a-arylpropionic acids. This
consisted in the addition of an excess of the preformed
intermediate ketene to the supported chiral auxiliary
suspended in THF in the presence of the tertiary amine
catalyst at the selected temperature (Table 1). The
mixture was then left overnight at the same tempera-
ture. The excess of the tertiary base used both catalyzed
the diastereoselective addition of the auxiliary to the
2
-(3,4-dimethoxyphenyl)-3-phthalimidopropanoic acid:
rac-4d. The phthalimido group, which totally protected
the amine function, avoids the NH addition to the
intermediate ketene. The N-protected compounds 4b–d
were obtained directly, as previously described, start-
ing from the corresponding aryl acetic acid benzyl
esters and N-(bromomethyl) phthalimide.
11
13
ketene and increased the stereoselectivity.
1
2
We used a rink amide resin since the benzhydrylamine
bond created between the chiral auxiliary and the poly-
mer was stable under the employed reaction conditions
and it could be selectively cleaved after reaction of the
ketene with the supported chiral auxiliary.
The intermediate ketenes were generated using different
optimized experimental conditions as both their forma-
tion rate and their stability are dependent on the substi-
tution of the phenyl side chain of the amino acid (Table 1).
Scheme 1. Reagents: (a) piperidine, DMF; (b) (S)-1, BOP, DIEA, DMF; (c) PhtNCH (Ar)CꢀCꢀO, NR , THF; (d) TFA, CH Cl ;
2
3
2
2
(
e) 6N HCl/AcOH–propylene oxide.
Table 1.
Ester
Ar
NR3
t1, ketene room temp.
ROH T°C
Yield % ()a
(S,R)/(S,S)
7b
7c
7d
C H
4-F-C H4
3,4-(CH O) C H
NEt3
NEt3
Quinuclidine
1 h
2 h
2 h
Room temp.
0°C
Room temp.
95 (65)
98 (68)
90 (63)
93/7
92/8
85/15
6
5
6
3
2
6
3
a
After chromatography on silica gel.

R. Akkari et al. / Tetrahedron: Asymmetry 14 (2003) 1223–1228
1225
After cleavage of the benzhydrylamine bond, the corre-
3.2. General procedure for the diastereoselective addi-
sponding crude esters 7b–d were obtained in high
tion of the supported chiral auxiliary (S)-2 to phthal-
1
4
yields and with good diastereoselectivities (Table 1).
imidomethyl aryl ketenes
The diastereoisomeric ratios of 7b–d were determined
1
from crude products from H NMR spectra by integra-
To a stirred solution of (RS)-3-phthalimido-2-aryl-
propanoic acid chlorides (2.70 mmol, 3.0 equiv.) in 20
ml of anhydrous THF cooled to 0°C and under argon,
tion of the CH-3 signal of the ester moiety of the
15
couple of diastereoisomers and/or by HPLC.
was slowly (5 min) added 3.3 equiv. of NR in 5 ml of
3
1
1
Hydrolysis of the esters 7b–d under acidic conditions
THF (2.97 mmol). After t1 hours stirring at room
temperature, the resulting ketene was added at the
selected temperature T°C to the solvent-swollen sup-
ported chiral alcohol (1.24 g, 0.90 mmol) in 20 ml of
anhydrous THF. The suspension was stirred for 18 h at
the same temperature and the solution was removed
from the resin by filtration. After washing with THF
(3×30 ml), CH Cl2 (3×30 ml), CH Cl /CH OH (8/2)
afforded, after propylene oxide treatment, the corre-
2
sponding free (R)-b -homoarylglycines: (R)-4b–d. The
(
R) configuration was assigned by comparison of the
11
specific rotation values of 4 with the literature data
indicating that in each case the (S,R) esters 7 were
mainly formed when using the supported auxiliary (S)-
(
3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)
acetic
2
2
2
3
acid.
(3×30 ml), CH Cl (3×30 ml), diethyl ether (3×30 ml)
2
2
the expected resin 6 was dried under reduced pressure.
These results demonstrate that the polymer-bound chi-
ral auxiliary (S)-2 has significant potential in the asym-
3
.3. Preparation of the supported 3-phthalimido-2-
metric
preparation
on
solid
phase
of
phenylpropionic acid 6b
2
b -homoarylglycines using ketene chemistry. Both
stereoselectivity and chemical yields are comparable to
those obtained in the corresponding solution reactions.
This method represents the first solid-phase protocol
The supported 3-phthalimido-2-phenylpropionic acid
6
b (1.48 g, 0.9 mmol), was obtained following the
general procedure (NR =NEt (414 ml, 2.97 mmol, 3.3
2
3
3
for the asymmetric preparation of b -aminoacids.
equiv.), t =1 h; T°C=room temperature) from (RS)-3-
1
phthalimido-2-phenylpropanoic acid chloride (846 mg,
2
.7 mmol, 3.0 equiv.).
3. Experimental
3
.4. Preparation of the supported 3-phthalimido-2-(4-
fluorophenyl)propionic acid 6c
3
.1. General
The supported 3-phthalimido-2-(4-fluorophenyl)pro-
pionic acid 6c (1.50 g, 0.9 mmol), was obtained follow-
ing the general procedure (NR =NEt (414 ml, 2.97
All reagents were used as purchased from commercial
suppliers without further purification except triethyl-
amine (NEt ) which was distilled from KOH and nin-
3
3
mmol, 3.3 equiv.), t =2 h; T°C=0°C) from (RS)-3-
3
1
hydrin. Solvents were dried and purified by
conventional methods prior to use; THF was freshly
distilled under argon from sodium and benzophenone.
Melting points were determined with a Kofler Heizbank
apparatus and are uncorrected. Optical rotations were
phthalimido-2-(4-fluorophenyl)propanoic acid chloride
(895 mg, 2.7 mmol, 3.0 equiv.).
3
.5. Preparation of the supported 3-phthalimido-2-(3,4-
dimethoxyphenyl)propionic acid 6d
1
measured with a Perkin–Elmer 341 polarimeter. H or
1
3
1
13
C NMR spectra (DEPT, H/ C 2D-correlations)
The supported 3-phthalimido-2-(3,4-dimethoxyphenyl)-
were recorded with a Bruker A DRX 400 spectrometer.
Data are reported as follows: chemical shifts (l) in ppm
with respect to TMS, coupling constants (J) in Hz. The
ESI mass spectra were recorded with a platform II
propionic acid 6d (1.54 g, 0.9 mmol), was obtained
following the general procedure (NR =quinuclidine
3
(
330 mg, 2.97 mmol, 3.3 equiv.), t =2 h; T°C=room
1
temperature)
from
(RS)-3-phthalimido-2-(3,4-
quadrupole
mass
spectrometer
(Micromass,
dimethoxyphenyl)propanoic acid chloride (1.0 g, 2.7
mmol, 3.0 equiv.).
Manchester, UK) fitted with an electrospray source.
HPLC analysis were performed with a Waters model
5
10 instrument with variable detector at 214 nm using:
column A: reversed phase Nucleosil C , 5m, (250×10
mm), flow: 1 ml/min, H O/CH CN/0.1% TFA gradient
3.6. General procedure for the benzhydrylamine bond
hydrolysis of the resin 6
18
2
3
0
“100% (15 min) and 100% (4 min); column B: Chira-
sphere, 5m, (250×10 mm), flow: 1 ml/min, hexane/2-
propanol, 90/10.
To the resin 6 (0.9 mmol) was added 50 ml of a solution
of 5% TFA in dry CH Cl and the suspension was
2
2
stirred for 40 min. The solution was removed from the
resin by filtration and the resin was washed with
CH Cl2 (3×30 ml), CH Cl /CH OH (8/2) (3×30 ml),
The chiral auxiliary: (S)-3-hydroxy-4,4-dimethyl-2-
oxopyrrolidin-1-yl) acetic acid, its attachment on a rink
resin, the (RS)-3-phthalimido-2-arylpropanoic acids
and the (RS)-3-phthalimido-2-aryl propanoic acid chlo-
2
2
2
3
CH Cl2 (3×30 ml). A second cleavage was realized
2
using the same conditions. Evaporation of the com-
bined filtrates in vacuo afforded the expected ester 7.
5
,11
rides were prepared as previously described.

1
226
R. Akkari et al. / Tetrahedron: Asymmetry 14 (2003) 1223–1228
3
3
.7. (1-Carbamoylmethyl-4,4-dimethyl-2-oxopyrrolidinyl)
-phthalimido-2-phenylpropionate 7b
The main diastereoisomer (S,R)-7c: HPLC: column B
1
rt 121.9 min H NMR (CDCl ) l 0.90 (s, 3H, CH -C),
3
3
1
.06 (s, 3H, CH -C), 3.05 (d, J=9.5 Hz, 1H, HCH-5),
3
Following the general procedure from the supported
-phthalimido-2-phenylpropionic acid 6b (1.48 g), com-
3.19 (d, J=9.5 Hz, 1H, HCH-5), 3.79 (s, 2H, N-CH2-
CO), 4.05 (dd, J=8.1 Hz and J=13.7 Hz, 1H, HCH-
N), 4.20 (dd, J=8.1 Hz and J=13.7 Hz, 1H, HCH-N),
4.37 (t, J =J =8.1 Hz, 1H, HC-C H F), 5.13 (s, 1H,
3
pound (S,R)-7b (396 mg, 86% d.e., 95% yield) was
obtained as a crude product which after purification by
column chromatography (silica gel, CH Cl /MeOH/
1
2
6
4
CH-3), 5.84 (br, 1H, CO-HNH), 6.43 (br, 1H, CO-
HNH), 6.88 (t, J =J =8.6 Hz, 2H, C H F), 7.24 (dd,
2
2
AcOH 9.5/0.5/0.1 or ethyl acetate alone) yielded (S,R)-
1
2
6
4
7
b as a white solid (271 mg, 86% d.e., 65% yield); mp
J=8.6 Hz and J=5.2 Hz, 2H, C H F), 7.60 (m, 2H,
6 4
13
2
0
7
0–72°C; [h] =+21 (c 2 in AcOEt); HPLC: column A
H-phthalyl), 7.69 (m, 2H, H-phthalyl); C NMR
(CDCl ) l 21.57 (CH -C), 25.53 (CH -C), 38.07 (C-
D
+
rt 10.3 min; MS (ESI) m/z: 464.3 [(M+H) ], 928.5.
3
3
3
(
CH ) ), 40.63 (CH -N), 46.83 (N-CH -CO), 48.89
3 2 2 2
The main diastereoisomer (S,R)-7b: HPLC: column B
(HC-C H F), 58.72 (CH -5), 78.72 (CH-3), 116.12 (d,
6
4
2
1
rt 115.1 min; H NMR (CDCl ) l 0.90 (s, 3H, CH -C),
J=21.6 Hz), 123.77, 130.55 (d, J=8.4 Hz), (CH-
arom.), 131.13, 132.03 (C-arom.), 134.55 (CH-arom.),
162.81 (CF, d, J=247 Hz), 168.29, 170.31, 171.20
(CO).
3
3
1
3
.04 (s, 3H, CH -C), 3.05 (d, J=9.6 Hz, 1H, HCH-5),
.15 (d, J=9.6 Hz, 1H, HCH-5), 3.74 (d, J=16.1, 1H,
3
N-HCH-CO), 3.83 (d, J=16.1 Hz, 1H, N-HCH-CO),
4
4
4
.03 (dd, J=8.0 Hz and J=13.7 Hz, 1H, HCH-N),
.26 (dd, J=8.0 Hz and J=13.7 Hz, 1H, HCH-N),
.39 (t, J =J =8.0 Hz, 1H, HC-C H ), 5.10 (s, 1H,
The minor diastereoisomer (S,S)-7c has the following
15,16
HPLC and NMR physical data:
HPLC: column B
1
2
6
5
1
CH-3), 6.02 (br, 1H, CO-HNH), 6.48 (br, 1H, CO-
HNH), 7.17 (m, 3H, C H ), 7.27 (m, 2H, C H ), 7.58
rt 145.3 min; H NMR (CDCl )) l 0.63 (s, 3H, CH -C),
3 3
0.97 (s, 3H, CH -C), 2.96 (d, J=9.5 Hz, 1H, HCH-5),
6
5
6
5
3
13
(
m, 2H, H-phthalyl), 7.68 (m, 2H, H-phthalyl);
C
3.19 (d, J=9.5 Hz, 1H, HCH-5), 3.75 (s, 2H, N-CH2-
CO), 4.11 (dd, J=8.1 Hz and J=13.7 Hz, 1H, HCH-
N), 4.18 (dd, J=8.1 Hz and J=13.7 Hz, 1H, HCH-N),
4.38 (t, J =J =8.1 Hz, 1H, HC-C H F), 5.21 (s, 1H,
NMR (CDCl ) l 21.54 (CH -C), 25.66 (CH -C), 38.01
3
3
3
(
C-(CH ) ), 40.70 (CH -N), 46.85 (N-CH -CO), 49.72
3 2 2 2
(
HC-C H ), 58.81 (CH -5), 78.88 (CH-3), 123.72,
6 5 2
1
2
6
4
1
1
1
28.53, 128.77, 129.20 (CH-arom.), 132.14 (C-arom.),
34.47 (CH-arom.), 135.39 (C-arom.), 168.34, 170.46,
71.26 (CO).
CH-3), 5.84 (br, 1H, CO-HNH), 6.38 (br, 1H, CO-
HNH), 6.87 (t, J =J =8.6 Hz, 2H, C H F), 7.21 (dd,
1
2
6
4
J=8.6 Hz and J=5.2 Hz, 2H, C H F), 7.60 (m, 2H,
6
4
1
3
H-phthalyl), 7.69 (m, 2H, H-phthalyl); C NMR
(CDCl ) l 21.10 (CH -C), 25.21 (CH -C), 38.59 (C-
The minor diastereoisomer (S,S)-7b has the following
HPLC and NMR physical data:
rt 133.7 min; H NMR (CDCl ) l 0.58 (s, 3H, CH -C),
3
3
3
15,16
HPLC: column B
(CH ) ), 40.09 (CH -N), 46.83 (N-CH -CO), 48.46
3 2 2 2
1
(HC-C H F), 58.52 (CH -5), 78.30 (CH-3), 116.16 (d,
3
3
6
4
2
0
.95 (s, 3H, CH -C), 2.97 (d, J=9.2 Hz, 1H, HCH-5),
.18 (d, J=9.2 Hz, 1H, HCH-5), 3.74 (d, J=16.1, 1H,
J=21.6 Hz), 123.77, 130.55 (d, J=8.4 Hz), (CH-
arom.), 131.13,, 132.03 (C-arom.), 134.47 (CH-arom.),
162.81 (CF, d, J=247 Hz), 168.29, 170.70, 171.51
(CO).
3
3
N-HCH-CO), 3.83 (d, J=16.1 Hz, 1H, N-HCH-CO),
4
4
4
.10 (dd, J=8.5 Hz and J=13.7 Hz, 1H, HCH-N),
.22 (dd, J=8.5 Hz and J=13.7 Hz, 1H, HCH-N),
.37 (t, J =J =7.8 Hz, 1H, HC-C H ), 5.18 (s, 1H,
3.9. (1-Carbamoylmethyl-4,4-dimethyl-2-oxopyrrolidinyl)
3-phthalimido-2-(3,4-dimethoxyphenyl) propionate 7d
1
2
6
5
CH-3), 6.06 (br, 1H, CO-HNH), 6.40 (br, 1H, CO-
HNH), 7.17 (m, 3H, C H ), 7.27 (m, 2H, C H ), 7.58
6
5
6
5
13
(
m, 2H, H-phthalyl), 7.68 (m, 2H, H-phthalyl);
C
Following the general procedure from the supported
3-phthalimido-2-(3,4-dimethoxyphenyl)propionic acid
6d (1.54 g), compound (S,R)-7d (424 mg, 70% de, 90%
yield) was obtained as a crude product which after
purification by column chromatography (silica gel,
ethyl acetate) yielded (S,R)-7d as a pale yellow solid
NMR (CDCl ) l 21.47 (CH -C), 25.33 (CH -C), 38.20
3
3
3
(
C-(CH ) ), 40.76 (CH -N), 46.85 (N-CH -CO), 49.72
3 2 2 2
(
HC-C H ), 58.07 (CH -5), 78.64 (CH-3), 123.72,
6 5 2
1
1
1
28.43, 128.84, 129.10 (CH-arom.), 132.14 (C-arom.),
34.36 (CH-arom.), 135.37 (C-arom.), 168.23, 170.31,
71.32 (CO).
2
0
(330 mg, 70% d.e., 63% yield); mp 95–98°C; [h] =+18
D
(
(
c 2 in AcOEt); HPLC: column A rt 9.76 min; MS
+
ESI) m/z: 524.4 [(M+H) ].
3
3
.8. (1-Carbamoylmethyl-4,4-dimethyl-2-oxopyrrolidinyl)
-phthalimido-2-(4-fluorophenyl)propionate 7c
1
The main diastereoisomer (S,R)-7d: H NMR (CDCl ):
3
l 0.89 (s, 3H, CH -C), 1.03 (s, 3H, CH -C), 3.02 (d,
3
3
Following the general procedure from the supported
-phthalimido-2-(4-fluorophenyl)propionic acid 6c (1.5
J=9.5, 1H, HCH-5), 3.17 (d, J=9.5 Hz, 1H, HCH-5),
3.72 (s, 3H, OCH ), 3.74 (s, 3H, OCH ), 3.78 (d,
3
3
3
g), compound (S,R)-7c (425 mg, 84% de, 98% yield)
was obtained as a crude product which after purifica-
tion by column chromatography (silica gel, ethyl ace-
tate) yielded (S,R)-7c as a white solid (295 mg, 84%
J=10.0 Hz, 1H, N-HCH-CO), 3.82 (d, J=10.0 Hz,
1H, N-HCH-CO), 4.06 (dd, J=8.1 Hz and J=13.7 Hz,
1H, HCH-N), 4.20 (dd, J=8.1 Hz and J=13.7 Hz, 1H,
HCH-N), 4.32 (t, J =J =8.1 Hz, 1H, HC-
1
2
2
0
d.e., 68% yield). Mp 83–84°C; [h] =+25 (c 2 in
C H (OCH ) ), 5.12 (s, 1H, CH-3), 6.19 (br, 1H, CO-
D
6 3 3 2
AcOEt); HPLC: column A rt 10.4 min; MS (ESI) m/z:
HNH), 6.66 (m, 2H, CO-HNH and C H (OCH ) ),
6 3 3 2
6.78 (m, 2H, C H (OCH ) ), 7.59 (m, 2H, H-phthalyl),
6 3 3 2
+
4
82.3 [(M+H) ], 963.4.

R. Akkari et al. / Tetrahedron: Asymmetry 14 (2003) 1223–1228
1227
1
3
7
(
(
5
1
1
.68 (m, 2H, H-phthalyl); C NMR (CDCl ) l 21.53
H.; Da, C. S.; Wang, H. S.; Su, W.; Wang, R.; Chan, A.
S. C. J. Org. Chem. 2000, 65, 295–296; Mandoli, A.; Pini,
D.; Agostini, A.; Salvadori, P. Tetrahedron: Asymmetry
2000, 11, 4039–4042; Chinchilla, R.; Mazon, P.; Najera,
C. Tetrahedron: Asymmetry 2000, 11, 3277–3281; Altava,
B.; Burguete, M. I.; Collado, M.; Garcia-Verdugo, E.;
Luis, S. V.; Salvador, R. V.; Vincent, M. J. Tetrahedron
Lett. 2001, 42, 1673–1675; Hallman, K.; Moberg, C.
Tetrahedron: Asymmetry 2001, 12, 1475–1478; Thierry,
B.; Plaquevent, J.-C.; Cahard, D. Tetrahedron: Asymme-
try 2001, 12, 983–986.
3
CH -C), 25.45 (CH -C), 38.07 (CH -N), 40.49 (C-
3 3 2
CH ) ), 46.68 (N-CH -CO), 49.23 (HC-C H (OCH ) ),
3 2 2 6 3 3 2
6.14, 56.25 (OCH ) 58.71 (CH -5), 78.69 (CH-3),
3 2
11.50, 111.72, 121.23, 123.75 (CH-arom.), 127.60,
32.05 (C-arom.), 134.52 (CH-arom.), 149.06, 149.30
(
C-arom.), 168.43, 170.73, 171.59 (CO).
The minor diastereoisomer (S,S)-7d has the following
1
5,16 1
NMR physical data:
H NMR (CDCl ): l 0.69 (s,
3
3
1
3
1
H, CH -C), 0.94 (s, 3H, CH -C), 2.91 (d, J=9.5 Hz,
3
3
H, HCH-5), 3.17 (d, J=9.5 Hz, 1H, HCH-5), 3.72 (s,
H, OCH ), 3.74 (s, 3H, OCH ), 3.78 (d, J=10.0 Hz,
H, N-HCH-CO), 3.82 (d, J=10.0 Hz, 1H, N-HCH-
CO), 4.04 (dd, J=8.1 Hz and J=13.7 Hz, 1H, HCH-
N), 4.23 (dd, J=8.1 Hz and J=13.7 Hz, 1H, HCH-N),
3
. For recent applications of synthetic solid-supported aux-
iliary, see: Moon, H.-S.; Schore, N. E.; Kurth, M. J. J.
Org. Chem. 1992, 57, 6088–6089; Moon, H.-S.; Schore,
N. E.; Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915–
3
3
8918; Shuttleworth, S. J.; Allin, S. M. Tetrahedron Lett.
4
(
.32 (t, J =J =8.1 Hz, 1H, HC-C H (OCH ) ), 5.21
1 2 6 3 3 2
1996, 37, 8023–8026; Purandare, A. V.; Natarajan, S.
Tetrahedron Lett. 1997, 38, 8777–8780; Phoon, C. W.;
Abell, C. Tetrahedron Lett. 1998, 39, 2655–2658; Winkler,
J. D.; McCoull, W. Tetrahedron Lett. 1998, 39, 4935–
s, 1H, CH-3), 6.19 (br, 1H, CO-HNH), 6.66 (m, 2H,
CO-HNH and C H (OCH ) ), 6.78 (m, 2H,
C H (OCH ) ), 7.59 (m, 2H, H-phthalyl), 7.68 (m, 2H,
H-phthalyl); C NMR (CDCl ) l 21.07 (CH -C), 25.08
6
3
3 2
6
3
3 2
1
3
3
3
4936; Faita, G.; Paio, A.; Quadrelli, P.; Rancati, F.;
(
CH -C), 38.62 (CH -N), 40.00 (C-(CH ) ), 46.68 (N-
3 2 3 2
Seneci, P. Tetrahedron Lett. 2000, 41, 1265–1269; Gor-
don, K.; Bolger, M.; Khan, N.; Balasubramanian, S.
Tetrahedron Lett. 2000, 41, 8621–8625; Miyabe, H.; Kon-
ishi, C.; Naito, T. Org. Lett. 2000, 2, 1443–1445; Faita,
G.; Paio, A.; Quadrelli, P.; Rancatiand, F.; Seneci, P.
Tetrahedron 2001, 57, 8313–8322; Nakamura, S.;
Uchiyama, Y.; Ishikawa, S.; Fukinbara, R.; Watanabe,
Y.; Toru, T. Tetrahedron Lett. 2002, 43, 2381–2383.
CH -CO), 48.61 C H (OCH ) ), 56.14, 56.25 (OCH ),
8.51 (CH -5), 78.24 (CH-3), 111.42, 111.72, 121.34,
23.75 (CH-arom.), 127.89, 132.07, 134.51 (C-arom.),
34.52 (CH-arom.), 149.06, 149.30 (C-arom.), 171.09,
71.21, 172.04 (CO).
2
6
3
3 2
3
5
1
1
1
2
3
.10. General procedure for the hydrolysis of (1-Car-
bamoylmethyl-4,4-dimethyl-2-oxopyrrolidinyl)-3-phthal-
imido-2-arylpropanoate 7
4. For recent examples of stereoselective reactions on solid
support, see: Ojima, I.; Tsai, C.-Y.; Zhang, Z. Tetra-
hedron Lett. 1994, 35, 5785–5788; Reggelin, M.; Brenig,
V. Tetrahedron Lett. 1996, 37, 6851–6852; Rotella, D. P.
J. Am. Chem. Soc. 1996, 118, 12246–12247; Wipf, P.;
Henninger, T. C. J. Org. Chem. 1997, 62, 1586–1587;
Panek, J. S.; Zhu, B. J. Am. Chem. Soc. 1997, 119,
12022–12023; Delpiccolo, C. M. L.; Mata, E. G. Tetra-
hedron: Asymmetry 2002, 13, 905–910.
A mixture of the esters 7 (0.50 mmol), acetic acid (1.4
ml) and a 6N HCl solution (14 ml) was refluxed until
completion of the hydrolysis (4–5 h), monitoring the
reaction by TLC. The mixture was allowed to warm to
room temperature and the volatile products were dis-
tilled at reduced pressure. Water (15 ml) was added to
the residue and the mixture was washed with AcOEt
5. Akkari, R.; Calm e` s, M.; Mai, N.; Rolland, M.; Martinez,
J. J. Org. Chem. 2001, 66, 5859–5965.
(
3×15 ml). After concentration in vacuo of the aqueous
layer the remaining chiral auxiliary was solubilized in
refluxing acetone while the insoluble collected by filtra-
tion yielded the free aminoacids (R)-4b–d after propyl-
ene oxide treatment.
6
. Juaristi, E. Enantioselective synthesis of i-Aminoacids;
Wiley-VLH, John Wiley & Sons: New York, 1997; pp.
1–66.
7
. (a) Cole, D. C. Tetrahedron 1994, 50, 9517–9582; (b)
Juaristi, E. Aldrichimica Acta 1994, 27 (1), 3–11; (c)
Sewald, N. Amino Acids 1996, 11, 397–408; (d) Cardillo,
G.; Tomasini, C. Chem. Soc. Rev. 1996, 117–128; (e)
Abdel-Magid, A. F.; Cohen, J. H.; Marayanoff, C. A.
Curr. Med. Chem. 1999, 6, 955–970; (f) Juaristi, E.;
L o´ pez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983–1004; (g)
Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991–8035 and
references cited therein.
The characterization of compounds 4b–d has been
11
reported in previous papers.
References
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1
0. The usual way to prepare b -substituted compounds
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11
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14. As previously in solution and probably due to a low
stability of the intermediates involved, a rapid chro-
matography on silica gel of the crude esters 7b–d was
necessary to obtain pure compounds.
15. To obtain equimolar diastereomeric samples of 7b–d,
(SR)-4b–d were first esterified with the supported chiral
alcohol in the presence of dicyclohexylcarbodiimide
1
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7
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(DCC) and 4-dimethylaminopyridine (DMAP) in CH Cl
and then the benzhydrylamine bond was cleaved using
the conventional method.
2 2
3
35–360.
1. (a) Calm e` s, M.; Escale, F. Tetrahedron: Asymmetry 1998,
, 2845–2850; (b) Calm e` s, M.; Escale, F.; Glot, C.; Rol-
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1
16. HPLC and NMR data of the minor diastereoisomers
9
7b–d were deduced from comparison of the data of the
15
equimolar diastereomeric mixtures and diastereomeri-
cally enriched compounds.
2