Asymmetric synthesis of (S)-β2-homoarylglycines

Article abstract of DOI:10.1002/1099-0690(200007)2000:13<2459::AID-EJOC2459>3.0.CO;2-D

The synthesis of racemic N-phthalyl β²-homoarylglycines 5 and their asymmetric transformation have been investigated. The key step is the stereoselective addition of the (R)-pantolactone to the corresponding prochiral ketene 7.

Full text of DOI:10.1002/1099-0690(200007)2000:13<2459::AID-EJOC2459>3.0.CO;2-D

FULL PAPER
Asymmetric Synthesis of (S)-β2-Homoarylglycines
[a]
[a]
[a]
[a]
`
`
Monique Calmes,* Francoise Escale, Christele Glot, Marc Rolland, and
¸
Jean Martinez[a]
Keywords: β-Amino acids / Asymmetric synthesis / Peptidomimetics / Ketenes / (R)-Pantolactone / Deracemization
The synthesis of racemic N-phthalyl β2-homoarylglycines 5
and their asymmetric transformation have been investigated.
The key step is the stereoselective addition of the (R)-panto-
lactone to the corresponding prochiral ketene 7.
Introduction
most of them, corresponds to their first asymmetric syn-
thesis.
β-Amino acids and their derivatives are an important
class of compounds in the development of peptidomimet-
ics[1] and functionalized β-lactams.[2] They also show inter-
esting pharmacological effects in their free form.[3]
Many methods have been reported for the synthesis of
racemic β-amino acids, but only recently have enantiomer-
ically pure compounds been prepared.[4] However, these
syntheses concern principally β3-substituted compounds 1
(Scheme 1), the preparation of β2-substituted analogs 2 still
remaining a challenge.
Results and Discussion
Prior to carrying out the stereoselective transformation
(Scheme 3), racemic 3-amino-2-aryl propanoic acid deriva-
tives (that are racemic β2-homoarylglycines) had to be pre-
pared with the amine function fully protected in order to
avoid NH addition to the ketene. We developed a conveni-
ent method (Scheme 2) that directly produced adequate N-
protected substrates starting from various aryl acetic acid
benzyl esters 3 (easily prepared from the cheap commer-
cially available corresponding acid) and N-(bromome-
thyl)phthalimide.
Alkylation of 3d was achieved in good yield (70% after
purification) using the same experimental conditions as
those previously used for the preparation of the racemic N-
phthalyl-β2-homophenylglycine, i.e. deprotonation in THF
at low temperature (Ϫ78 °C) by using lithium diisopropyla-
mide as base and DMPU[10] as co-solvent. The same condi-
tions applied to 3a؊c, where the phenyl group contains a
fluoro- or one or two methoxy substituents, led to the cor-
responding esters in only moderate yields (35Ϫ40%), even
if another additive such as LiCl was used. On the other
hand, 4a, 4b, and 4c were obtained in good yield (75, 78,
Scheme 1
The usual way to prepared β2-substituted compounds in-
volves diastereoselective alkylation of an enolate derived
from β-alanine, the synthesis of the latter being the limiting
step.[5] An elaborate synthesis[6] using a palladium catalyzed
asymmetric allylic substitution and a modified Curtius re-
action as key steps to introduce nitrogen has also been pro-
posed. Recently, enantiomerically pure β2-homophenylgly-
cine has been obtained by acylation of metallated phenyl-
acetonitrile with sultam carbonyl chloride.[7]
It has been shown in previous studies[8,9] concerning de-
racemization reactions, that the asymmetric transformation
of racemic mixtures involving prochiral ketenes was a
simple, convenient and effective reaction. We have recently
successfully applied this method for the preparation of β-
amino acids and described a convenient access to (S)-β2-
homophenylglycine.[9e] Extending our investigations, we
wish now to report our results concerning the preparation
of optically active β2-homoarylglycines 9a؊d which, for
[a]
Laboratoire des Aminoacides, LAPP, UMR-CNRS 5810,
´
Universite de Montpellier,
Place E. Bataillon, 34095 Montpellier cedex 05, France
E-mail: monique@univ-montp2.fr
Fax: (internat.) ϩ33 04 67 14 48 66
Scheme 2. Synthesis of rac-5a؊d
Eur. J. Org. Chem. 2000, 2459Ϫ2466
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
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`
M. Calmes, F. Escale, C. Glot, M. Rolland, J. Martinez
FULL PAPER
and 68% yields, respectively after purification) in THF at Table 1. Reaction conditions, yields and (S,R)/(R,R) ratio in the
diastereoselective addition of (R)-pantolactone to aryl ketenes
7a؊d
low temperature (Ϫ78 °C) when lithium hexamethyldisil-
azane was used as the base. The benzyl ester was then easily
cleaved by hydrogenolysis without degradation of the
phthalyl group affording the N-phthalyl-3-amino-2-arylpro-
panoic acids 5a؊d as racemic mixtures, quantitatively.
According to the considered methodology, the asymmet-
ric transformation of 5 involves the stereoselective addition
of a chiral alcohol to the N-phthalyl-3-aminomethyl-2-aryl
ketene (7) (Scheme 3). This reaction was performed in THF
with (R)-pantolactone, a very efficient commercially avail-
able chiral auxiliary, used as the chiral alcohol.
Entry Ester NR3
1.1 equiv.
Ketene
ROH
Yield (S,R)/(R,R)
room temp. T [°C]
[%]
1
8a NEt3
1 h
room temp. 75 22:78
room temp. 88 84:16
room temp. 85 90:10
80 90:10
room temp. 55 75:25
2
8a Quinuclidine 1 h
8a Quinuclidine 2 h
8a Quinuclidine 2 h
3
4
0
5
8b NEt3
8b NEt3
8b NEt3
1 h
1 h
2 h
6
0
0
0
76 80:20
78 92:8
70 60:40
7
8
8b Quinuclidine 1 h
9
8c NEt3
1 h
1 h
1 h
1 h
room temp. 60 87:13
10
11
12
13
14
15
8c NEt3
0
0
0
0
82 84:16
60 73:27
68 79:21
85 94:6
8c NEt2Me
8c NMe2Et
8c Quinuclidine 1 h
8d NEt3
1 h
room temp. 65 55:45
room temp. 88 92:8
8d Quinuclidine 1 h
The data in Table 1 show that it was preferable to use the
tricyclic tertiary amine quinuclidine rather than triethylam-
ine, except in the case of 6b (entries 3, 7, 13, and 15). It is
also clear that the formation rate and the stability of ket-
enes are dependent on the substitution of the phenyl side
chain of the amino acid. The optimum results were ob-
tained for 8a and 8b for which the time for ketene formation
had been increased from one to two hours (entries 2, 3 and
6, 7). In addition, when the reaction was carried out at 0
°C instead at room temperature, we observed for 8b and 8c
an improvement in both yield and stereoselectivity (entries
5, 6 and 9, 10).
Scheme 3. Stereoselective synthesis of 9a؊d
Although the reaction was not totally diastereoselective,
the optically pure N-phthalyl pantolactonyl esters 8a؊d
could be easily obtained by recrystallisation of the corre-
sponding optically-enriched mixture. The (αS,3ЈR) config-
uration of the main esters form 8a؊c was ascertained from
the X-ray diffraction patterns (Figures 1Ϫ3).[12] In the case
of 8d, that crystallized as fine needles, the X-ray method
could not be applied.
The ketene 7 was obtained in situ by dehydrochlorination
of the corresponding acyl chloride 6, which was obtained
from 5 by treatment at room temperature with oxalyl chlor-
ide. The tertiary base, used in excess, both catalyzed the
diastereoselective addition of an alcohol to a ketene and
increased the stereoselectivity.[9,11] Ketene formation and al-
cohol addition occurred in a one pot procedure.
In the first attempt, we used the same experimental con-
ditions as previously employed for the preparation of the
N-phthalyl-β2-homophenylglycine, i.e. generation of the ke-
tene at room temperature by treatment of the acid chloride
6 with triethylamine, followed one hour later by the addi-
tion of the (R)-pantolactone at the same temperature. Un-
der these experimental conditions, moderate to modest
chemical yields and/or stereoselectivities were obtained, de-
pending on the nature of the amino acid aryl side chain
(Table 1, entries 1, 5, 9, and 14). However, the generation
of the ketene must occur at room temperature, since when
a lower temperature (0 °C to Ϫ20 °C) was used the ketene
was only partly produced. Indeed, at lower temperatures,
by trapping the ketene with CH3OD only a small amount of
the corresponding Cα deuterated methyl ester was formed.
Figure 1. ORTEP drawing of ester (αS,3ЈR)-8a
Hydrolysis[9c,9d] under acidic conditions of the diastereo-
To improve chemical yields and stereoselectivities, we merically pure N-phthalyl pantolactonyl esters afforded
tested various tertiary amines, reaction times, and temper- the corresponding β2-homoarylglycines 9a؊d. The enantio-
atures for each β-amino acid. The most representative re- meric excesses of 9a؊d were determined by NMR analysis
sults are recorded in Table 1.
after derivatization with Marfey’s reagent (1-fluoro-2,4-di-
2460
Eur. J. Org. Chem. 2000, 2459Ϫ2466

Asymmetric Synthesis of (S)-β2-Homoarylglycines
FULL PAPER
Experimental Section
Tetrahydrofuran (THF) was freshly distilled under argon from so-
dium and benzophenone; triethylamine (NEt3) was distilled from
KOH and ninhydrin; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim-
idinone (DMPU) was stirred with CaH2 for 1 h and then distilled
at reduce pressure before use. Thin layer chromatography (tlc) was
carried out on silica gel (60 F254, Merck 5715) and the spots located
with UV light or iodine vapor (eluent A: hexane/AcOEt 9:1; eluent
B: hexane/AcOEt 8:2; eluent C: hexane/diethyl ether 2:8; eluent D:
hexane/AcOEt 8:3; eluent E: CH2Cl2). (R)-Pantolactone (chemical
and enantiomeric purities Ͼ 99%) was purchased from Fluka
Chemical Co. All other chemicals were commercially pure com-
pounds. Ϫ Melting points were determined with a Büchi apparatus
and are uncorrected. Ϫ Optical rotations were measured with a
PerkinϪElmer, model 241 polarimeter. Ϫ IR spectra were recorded
with a FT-IR PerkinϪElmer, model 1000 spectrometer. Ϫ HPLC
analysis were performed with a Waters model 510 with variable
detector. Ϫ 1H NMR spectra were recorded with a Bruker AC 250
or A DRX 400 spectrometer. Data are reported as follows: chem-
ical shifts (δ) in ppm with respect to TMS, multiplicity (s ϭ singlet,
d ϭ doublet, t ϭ triplet, q ϭ quadruplet, m ϭ multiplet, br ϭ
broad), coupling constants (J) in Hz. Ϫ The ESI mass spectra were
recorded with a platform II quadrupole mass spectrometry (Micro-
mass, Manchester, UK) fitted with an electrospray source and the
voltages were set at 3.5 kV for the capillary and 30 V for the cone.
The Fast Atom Bombardment mass spectra were recorded with a
SX102 type spectrometer, Jeol Ltd., Tokyo, Japan and 3-nitro-
benzyl alcohol was used as matrix. Diastereoisomeric ratios of 8
were determined from crude products from 1H NMR spectra
(CDCl3) by integration of the 3Ј-CH signal of the pantolactonyl
moiety of the couple of diastereoisomers and/or by HPLC [column
chirasphere (Merck), 25 cm ϫ 4 mm, flow: 1 mL/min, hexane/2-
propanol: condition A: 95:5, condition B: 90:10]. Ϫ To obtain ra-
cemic samples of pantolactonyl esters 8, (SR)-5 was esterified with
(R)-pantolactone in the presence of dicyclohexylcarbodiimide
(DCC) and 4-dimethylaminopyridine (DMAP). HPLC and NMR
data of compounds 8 were deduced from comparison of the data of
the racemic mixtures and optically enriched compounds obtained.
Racemization during acid hydrolysis of 8 was controlled by 1H
NMR analysis ([D6]DMSO) after derivatization with Marfey’s re-
Figure 2. ORTEP drawing of ester (αS,3ЈR)-8b
Figure 3. ORTEP drawing of ester (αS,3ЈR)-8c
nitrophenyl-5-(S)-alanine amide).[13] The stereochemistry of
8a؊c allowed us to establish the (S) configuration for the
compounds 9a؊c.
To define the absolute configuration of the 3-amino-2-(α-
naphthyl)propanoic acid 9d, we prepared its N-tert-bu-
tyloxycarbonyl (Boc) derivative 9d-Boc, since the physical
data of the (R) enantiomer have been recently reported by
Bower et al.[6b] To our surprise, comparison of the specific
rotation values suggested that the (R) enantiomer of 9d-
Boc was formed, whereas we expected the (S) enantiomer.
However, in the study of Bower et al.[6b] the specific rota-
tion value of another compound, the (R)-3-amino-2-phenyl-
agent
[FDAA
ϭ
1-fluoro-2,4-dinitrophenyl-5-(S)-alanine
amide].[13] Marfey’s reagent induces an adequate chemical shift
propanoic acid, is given as opposite to that previously re- NMR non-equivalence of aromatic protons of the two diastereoiso-
ported by Wyatt et al.[5e] after determination of the absolute
mers formed from racemic 3-amino-2-arylpropanoic acids, allowing
satisfactory enantiomeric excess determination.
configuration by an unambiguous X-ray crystallographic
analysis. So, since in our case compounds 8a؊d have all
been prepared starting from similar compounds by using
the same reaction scheme, it is reasonable to assume that
8d, like 8a؊c, has the (αS,3ЈR) configuration thus affording
(S)-9d.
General Procedure for the Preparation of Benzyl Arylacetates (3):
Benzyl arylacetates 3 were prepared from the corresponding aryl-
acetic acid and benzyl alcohol as previously described in the literat-
ure.[14]
Benzyl (4-Methoxyphenyl)acetate (3a): Following the general pro-
cedure from (4-methoxyphenyl)acetic acid (1.66 g, 10.00 mmol), 3a
(2.30 g, 9.30 mmol, 93% yield), was obtained as an oil; tlc (eluent
D) Rf ϭ 0.42. Ϫ IR (KBr): ν˜ ϭ 3028 w, 2934 m, 2849 w,1731 s,
1509 m, 1259 s, 1165 s, 1080 m. Ϫ 1H NMR (CDCl3): δ ϭ 3.65
[s, 2 H, (CH3O)C6H4CH2CO], 3.80 (s, 3 H, OCH3), 5.16 (s, 2 H,
OCH2C6H5), 6.90 [d, J ϭ 8.7 Hz, 2 H, C6H4(OCH3)], 7.28 [d, J ϭ
8.7 Hz, 2 H, C6H4(OCH3)], 7.42 (m, 5 H, C6H5). Ϫ FAB-MS; m/z
(%): 256 (15) [Mϩ·], 135 (30), 121 (20), 109 (52), 91 (100). Ϫ
C16H16O3 (256.3) calcd. C 75.07, H 6.30; found C 75.12, H 6.38.
Conclusion
In this work, we have established syntheses of some opti-
cally active β2-homoarylglycine derivatives, which for most
of them correspond to their first asymmetric preparation.
This asymmetric transformation by stereoselective addition
of the (R)-pantolactone to prochiral ketenes proved to be a
simple and convenient method for the preparation of par-
ticularly interesting β2-substituted β-amino acids.
Benzyl (4-Fluorophenyl)acetate (3b): Following the general proce-
dure from (4-fluorophenyl)acetic acid (1.54 g, 10.00 mmol), 3b
Eur. J. Org. Chem. 2000, 2459Ϫ2466
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M. Calmes, F. Escale, C. Glot, M. Rolland, J. Martinez
FULL PAPER
(2.22 g, 9.10 mmol, 91% yield), was obtained as an oil; tlc (eluent 5.00 mmol), 4a (1.49 g, 3.60 mmol, 72% yield), was obtained as a
B) Rf ϭ 0.58. Ϫ IR (KBr): ν˜ ϭ 3066 w, 2924 m, 2849 w, 1731 s, colourless solid after chromatography, (eluent E) Rf ϭ 0.34. Ϫ m.p.
1
1509 m, 1221 m, 1160 m. Ϫ H NMR (CDCl3): δ ϭ 3.65 (s, 2 H,
148 °C. Ϫ IR (KBr): ν˜ ϭ 2990 w, 2952 m, 2830 w, 1773 m, 1707s,
1613 m, 1509 m. Ϫ H NMR (CDCl3): δ ϭ 3.75 (s, 3 H, 0CH3),
1
FϪC6H4CH2CO), 5.14 (s, 2 H, OCH2C6H5), 7.02 (t, J1 ϭ J2
ϭ
8.7 Hz, 2 H, C6H4F), 7.25 (dd, J ϭ 8.7 Hz and J ϭ 6.8 Hz, 2 H,
4.16 (m, 3 H, CHϪCH2ϪN and CHϪCH2ϪN), 5.02 (d, J ϭ
C6H4F), 7.35 (m, 5 H, C6H5). Ϫ FAB-MS; m/z (%): 245 (6) [(M ϩ 12.4 Hz, 1 H, HCHC6H5), 5.08 (d, J ϭ 12.4 Hz, 1 H, HCHC6H5),
H)ϩ], 154 (5), 137 (8), 109 (43), 91 (100). Ϫ C15H13FO2 (244.3) 6.75 [d, J ϭ 10.3 Hz, 2 H, C6H4(OCH3)], 7.20 [m, 7 H, C6H5 and
calcd. C 73.84, H 5.37; found C 73.76, H 5.43.
C6H4(OCH3)], 7.67 (m, 2 H, H-phthalyl), 7.75 (m, 2 H, H-
phthalyl). Ϫ ESI-MS; m/z (%): 415.9 (50) [(M ϩ H)ϩ], 269.9 (100).
Ϫ C25H21NO5 (415.4) calcd. C 72.36, H 5.10, N 3.38; found C
72.16, H 5.26, N 3.28.
Benzyl (3,4-Dimethoxyphenyl)acetate (3c): Following the general
procedure from (3,4-dimethoxyphenyl)acetic acid (1.96 g,
10.00 mmol), 3c (2.72 g, 9.50 mmol, 95% yield), was obtained as
an oil; tlc (eluent C) Rf ϭ 0.63. Ϫ IR (CH3CN): ν˜ ϭ 2985 w, 2943
m, 2830 w, 1736 s, 1514 s,.1259 s, 1235 m, 1141 s. Ϫ 1H NMR
(RS)-Benzyl 2-(4-Fluorophenyl)-3-phthalimidopropanoate (4b): Fol-
lowing method B from benzyl (4-fluorophenyl)acetate (1.21 g,
(CDCl3): δ ϭ 3.61 [s, 2 H, (CH3O)2C6H3CH2CO]), 3.82 (s, 3 H, 5.00 mmol), 4b (1.51 g, 3.70 mmol, 75% yield), was obtained as a
OCH3), 3.86 (s, 3 H, OCH3), 5.13 (s, 2 H, OCH2C6H5), 6.81 [s, 3 colourless solid after chromatography, (eluent E) Rf ϭ 0.65. Ϫ m.p.
H, C6H3(OCH3)2], 7.38 (m, 5 H, C6H5). Ϫ FAB-MS; m/z (%): 286 107 °C. Ϫ IR (KBr): ν˜ ϭ 3047 w, 2924 m, 2849 w, 1773 m, 1731 s,
(60) [Mϩ·], 209 (5), 151 (73), 91 (100). Ϫ C17H18O4 (286.3) calcd. 1707 s, 1603 m, 1509 m. Ϫ 1H NMR (CDCl3): δ ϭ 4.18 (m, 3
C 71.39, H 6.34; found C 71.30, H 6.45.
H, CHϪCH2ϪN and CHϪCH2ϪN), 5.08 (d, J ϭ 12.3 Hz, 1 H,
HCHC6H5), 5.12 (d, J ϭ 12.3 Hz, 1 H, HCHC6H5), 6.94 (t, J1 ϭ
J2 ϭ 8.7 Hz, 2 H, C6H4F), 7.24 (m, 7 H, C6H5 and C6H4F), 7.63
(m, 2 H, H-phthalyl), 7.71 (m, 2 H, H-phthalyl). Ϫ ESI-MS; m/z
(%): 404.3 (100) [(M ϩ H)ϩ], 312.9 (72). Ϫ C24H18FNO4 (403.4)
calcd. C 71.53, H 4.50, N 3.48; found C 71.45, H 4.38, N 3.25.
Benzyl (α-Naphthyl)acetate (3d): Following the general procedure
from (α-naphthyl)acetic acid (1.86 g, 10.00 mmol), 3d (2.48 g,
9.00 mmol, 90% yield), was obtained as an oil; tlc (eluent A) Rf ϭ
0.38. Ϫ IR (CH3CN): ν˜ ϭ 3056 m, 3028 m, 2934 m, 1736s, 1514
w, 1259 m, 1141 s. Ϫ 1H NMR (CDCl3): δ ϭ 4.18 (s, 2 H,
C10H7CH2CO), 5.21 (s, 2 H, OCH2C6H5), 7.35 (m, 5 H, C6H5), (RS)-Benzyl
2-(3,4-Dimethoxyphenyl)-3-phthalimidopropanoate
7.50 (m, 2 H, H-naphthyl); 7.57 (m, 2 H, H-naphthyl), 7.90 (m, 2
H, H-naphthyl), 8.07 (m, 1 H, H-naphthyl). Ϫ FAB-MS; m/z (%):
(4c): Following method B from benzyl (3,4-dimethoxyphenyl)ace-
tate (1.43 g, 5.00 mmol), 4c (1.38 g, 3.10 mmol, 62% yield), was ob-
276 (25) [Mϩ·], 199 (5), 141 (66), 91 (100). Ϫ C19H16O2 (276.33) tained as a colourless solid after chromatography, (eluent E) Rf ϭ
calcd. C 82.69, H 5.84; found C 82.52, H 5.96.
0.35. Ϫ m.p. 144 °C. Ϫ IR (KBr): ν˜ ϭ 2988 w, 2934 m, 2839 m,
1769 m, 1736 s, 1712 s, 1594 m, 1514 m. Ϫ 1H NMR (CDCl3): δ ϭ
3.77 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.20 (m, 3 H,
CHϪCH2ϪN and CHϪCH2ϪN), 5.07 (d, J ϭ 12.3 Hz, 1 H,
HCHC6H5), 5.13 (d, J ϭ 12.3 Hz, 1 H, HCHC6H5), 6.80 [m, 3 H,
C6H3(OCH3)2], 7.22 (m, 5 H, C6H5), 7.68 (m, 2 H, H-phthalyl),
7.77 (m, 2 H, H-phthalyl). Ϫ ESI-MS; m/z (%): 446.1 (100) [(M ϩ
H)ϩ]. Ϫ C26H23NO6 (445.5) calcd. C 70.18, H 5.21, N 3.15; found
C 70.10, H 5.34, N 3.18.
General Procedure for the Preparation of (RS)-Benzyl 2-Aryl-3-
phthalimidopropanoates (4). ؊ Method A: A solution of n-butyl-
lithium (2.5 ) in hexane (2.4 mL, 6.00 mmol) was added dropwise
over 5 min to a stirred solution of diisopropylamine (0.91 mL,
6.50 mmol) in dry THF (12 mL) at Ϫ78 °C under an argon atmo-
sphere.
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(3.5 mL) was added in one portion, and the mixture was then
stirred at Ϫ78 °C for 1 h. A solution of 3 (5.00 mmol) in THF
(7 mL) was then added over 10 min, keeping the temperature below
Ϫ78 °C during the addition. After 1 h stirring at Ϫ78 °C, the N-
(RS)-Benzyl 2-(α-Naphthyl)-3-phthalimidopropanoate (4d): Follow-
ing method A from benzyl (α-naphthyl)acetate (1.38 g, 5.00 mmol),
(bromomethyl)phthalimide (1.44 g, 6.00 mmol) was added drop- 4d (1.52 g, 3.50 mmol, 70% yield), was obtained as a colourless
wise in dry THF (9 mL) at the same temperature. The mixture was
stirred for an additional 1 h at Ϫ78 °C, and then warmed slowly
to room temperature. After 16 h stirring at room temperature the
reaction mixture was quenched with 1  HCl (60 mL), and then
extracted with diethyl ether (3 ϫ 100 mL). The combined ether
extracts were washed with water, dried (Na2SO4), and concentrated
in vacuo to afford a yellowish solid. The solid was then purified by
chromatography on silica gel to give 4 as colourless crystals.
solid after chromatography, (eluent E) Rf ϭ 0.59. Ϫ m.p. 129 °C.
Ϫ IR (KBr): ν˜ ϭ 3056 m, 2934 m, 1773 m, 1736 s, 1709 s, 1594 w,
1500 m. Ϫ H NMR (CDCl3): δ ϭ 4.15 (dd, J ϭ 6.7 Hz and J ϭ
13.8 Hz, 1 H, HCHϪN), 4.53 (dd, J ϭ 8.8 Hz and J ϭ 13.8 Hz, 1
H, HCHϪN), 5.13 (s, 2 H, CH2C6H5), 5.23 (dd, J ϭ 6.7 Hz and
J ϭ 8.8 Hz, 1 H, CHϪCH2ϪN), 7.18 (m, 5 H, C6H5), 7.50 (m, 4
H, H-naphthyl), 7.70 (m, 2 H, H-phthalyl), 7.85 (m, 4 H, H-naph-
thyl and H-phthalyl), 8.30 (m, 1 H, H-naphthyl). Ϫ ESI-MS; m/z
(%): 436.1 (100) [(M ϩ H)ϩ]. Ϫ C28H21NO4 (435.5) calcd. C 77.31,
H 4.87, N 3.22; found C 77.23, H 4.92, N 3.35.
1
Method B: A solution of n-butyllithium (2.5 ) in hexane (2.4 mL,
6.00 mmol) was added dropwise over 5 min to a stirred solution of
hexamethyldisilazane (1.37 mL, 6.50 mmol) in dry THF (12 mL) at
General Procedure for the Preparation of (RS)-2-Aryl-3-phthalimi-
Ϫ78 °C under argon and the mixture was then stirred for 1 h at dopropanoic Acids (5): (RS)-Benzyl 2-aryl-3-phthalimidopro-
Ϫ78 °C. A solution of 3 (5.00 mmol) in THF (7 mL) was then
added over 10 min, keeping the temperature below Ϫ78 °C during
the addition. After stirring the mixture for 1 h at Ϫ78 °C, the N-
(bromomethyl)phthalimide (1.44 g, 6.00 mmol), was added drop-
wise in dry THF (9 mL) at the same temperature. The mixture was
stirred for an additional 1 h at Ϫ78 °C, and then warmed slowly
to room temperature. After 16 h stirring at room temperature, the
reaction was treated as described in method A.
panoates 4 (1.50 mmol) were added to a cooled (Ϫ20 °C) solution
of 20% palladium hydroxide on charcoal (0.01 g) in ethyl acetate
(4 mL). The mixture was then stirred for 5Ϫ6 h at room temper-
ature under H2 (the reaction was monitored by tlc). After filtration
through Celite, concentration of the filtrate yielded the expected
compounds 5.
(RS)-2-(3-Methoxyphenyl)-3-phthalimidopropanoic Acid (5a): Fol-
lowing the general procedure from (RS)-benzyl 2-(4-methoxy-
(RS)-Benzyl 2-(4-Methoxyphenyl)-3-phthalimidopropanoate (4a): phenyl)-3-phthalimidopropanoate (0.63 g, 1.50 mmol), 5a (0.45 g,
Following method B from benzyl (4-methoxyphenyl)acetate (1.23 g,
1.40 mmol, 97% yield), was obtained as a colourless solid, m.p.
2462
Eur. J. Org. Chem. 2000, 2459Ϫ2466

Asymmetric Synthesis of (S)-β2-Homoarylglycines
FULL PAPER
186° C. Ϫ IR (KBr): ν˜ ϭ 3500Ϫ2500 br, 2952 w, 2839 w, 1773 m,
General Procedure for the Diastereoselective Addition of (R)-Panto-
1707 s, 1509 m, 1179 m, 709 m. Ϫ H NMR (CDCl3): δ ϭ 3.74 (s, lactone to Aryl Phthalimidomethyl Ketenes (7): To a stirred solution
1
3 H, OCH3), 4.24 (m, 3 H, CH2ϪN and CHϪCH2ϪN), 6.80 [d, of (RS)-2-aryl-3-phthalimidopropanoic acid chlorides
6
J ϭ 8.7 Hz, 2 H, C6H4(OCH3)], 7.23 [d, J ϭ 8.7 Hz, 2 H, (0.60 mmol) in 5 mL of anhydrous THF cooled to 0° C under ar-
C6H4(OCH3)], 7.68 (m, 2 H, H-phthalyl), 7.77 (m, 2 H, H-
phthalyl). Ϫ ESI-MS; m/z (%): 326.2 (45) [(M ϩ H)ϩ], 307.9 (15),
gon, was added 1.1 equivalents of NR3 in THF (0.3 mL). After t1
hours stirring at room temperature, a solution of 1.2 equivalents of
280 (100). Ϫ C18H15NO5 (325.3) calcd. C 66.52, H 4.65, N 4.31; (R)-pantolactone in 0.3 mL of THF was added. After t2 hours at
found C 66.58, H 4.55, N 4.42.
T °C (monitoring the reaction by tlc), a 1  citric acid solution
(5 mL) was added at 0 °C and the solution was extracted with Ac-
OEt (3 ϫ 10 mL). The organic layer was washed successively with
water, sodium bicarbonate solution and dried with sodium sulfate.
Evaporation in vacuo yielded the pantolactonyl esters 8.
(RS)-2-(4-Fluorophenyl)-3-phthalimidopropanoic Acid (5b): Follow-
ing the general procedure from (RS)-benzyl 2-(4-fluorophenyl)-3-
phthalimidopropanoate (0.60 g, 1.50 mmol), 5b (0.42 g, 1.40 mmol,
92% yield), was obtained as a colourless solid, m.p. 175° C. Ϫ IR
(KBr): ν˜ ϭ 3500Ϫ2500 br, 2950 w, 2924 w, 1769 m, 1707 s, 1500
m, 1221 m, 716 m. Ϫ 1H NMR (CDCl3): δ ϭ 4.27 (m, 3 H, CH2ϪN
4Ј,4Ј-Dimethyl-γ-butyrolacton-3Ј-yl 2-(4-Methoxyphenyl)-3-phthal-
imidopropanoate (8a): Following the general procedure (NR3
ϭ
and CHϪCH2ϪN), 6.96 (t, J1 ϭ J2 ϭ 8.6 Hz, 2 H, C6H4F), 7.30 quinuclidine, t1 ϭ 2 h; t2 ϭ 5 h; T ϭ room temp.) from (RS)-2-(4-
(dd, J ϭ 8.6 Hz and J ϭ 5.2 Hz, 2 H, C6H4F), 7.68 (m, 2 H, H-
phthalyl), 7.76 (m, 2 H, H-phthalyl). Ϫ ESI-MS; m/z (%): 313.9
methoxyphenyl)-3-phthalimidopropanoic acid chloride (0.20 g,
0.60 mmol), (αS,3ЈR)-8a (0.24 g, 80% de) was obtained as a crude
(82) [(M ϩ H)ϩ], 296.1 (65), 268.2 (45). Ϫ C17H12FNO4 (313.3) product, which after purification by column chromatography (silica
calcd. C 65.24, H 3.86, N 4.47; found C 65.13, H 3.75, N 4.52.
gel, ethyl acetate/hexane 1:1) yielded (αS,3ЈR)-8a as a colourless
solid (0.19 g, 75% yield, 80% de). Crystallisation from a mixture of
ethyl acetate and hexane gave optically pure (αS,3ЈR)-8a (0.11 g,
45% yield, Ͼ99% de). Ϫ m.p. 130 °C; [α]2D0 ϭ Ϫ95 (c ϭ 2 in
CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 2943 m, 2896 m, 2830 m, 1798 s, 1775
s, 1745 s, 1717 s, 1613 m, 1504 m, 1151 m, 717 s. Ϫ ESI-MS; m/z
(%): 438.1 (100) [(M ϩ H)ϩ], 308.2 (18), 280.0 (22). Ϫ C24H23NO7
(437.4) calcd. C 65.97, H 5.31, N 3.21; found C 65.91, H 5.16,
N 3.21.
(RS)-2-(3,4-Dimethoxyphenyl)-3-phthalimidopropanoic Acid (5c):
Following the general procedure from (RS)-benzyl 2-(3,4-dime-
thoxyphenyl)-3-phthalimidopropanoate (0.67 g, 1.50 mmol), 5c
(0.46 g, 1.40 mmol, 96% yield), was obtained as a white solid, m.p.
149 °C. Ϫ IR (KBr): ν˜ ϭ 3500Ϫ2500 br, 2952 w, 2924 w, 2839 w,
1760 m, 1707 s, 1584 m, 1514 m, 718 m. Ϫ 1H NMR (CDCl3): δ ϭ
3.80 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 4.23 (m, 3 H, CH2ϪN
and CHϪCH2ϪN), 6.74 [d, J ϭ 8.0 Hz, 1 H, C6H3(OCH3)2], 6.84
[s, 1 H, C6H3(OCH3)2], 6.87 [d, J ϭ 8.0 Hz, 1 H, C6H3(OCH3)2], Main Diastereoisomer (αS,3ЈR)-8a: HPLC (condition B): ret.
7.66 (m, 2 H, H-phthalyl), 7.71 (m, 2 H, H-phthalyl). Ϫ ESI-MS; time ϭ 39.6 min. Ϫ 1H NMR (CDCl3): δ ϭ 1.01 (s, 3 H, 4ЈϪCH3),
m/z (%): 356.1 (64) [(M ϩ H)ϩ], 309.9 (100). Ϫ C19H17NO6 (355.3)
calcd. C 64.29, H 4.83, N 3.95; found C 64.20, H 4.90, N 3.83.
1.13 (s, 3 H, 4Ј-CH3), 3.76 ( s, 3 H, OCH3), 3.91 (d, J ϭ 8.9 Hz, 1
H, 5Ј-HCH), 3.95 (d, J ϭ 8.9 Hz, 1 H, 5Ј-HCH), 4.12 (dd, J ϭ
7.4 Hz and J ϭ 13.6 Hz, 1 H, HCHϪN), 4.27 (dd, J ϭ 7.4 Hz
and J ϭ 13.6 Hz, 1 H, HCHϪN), 4.43 [t, J1 ϭ J2 ϭ 7.4 Hz, 1 H,
HCϪC6H4(OCH3)], 5.30 (s, 1 H, 3Ј-CH), 6.77 [d, J ϭ 8.7 Hz, 2 H,
C6H4(OCH3)], 7.24 [d, J ϭ 8.7 Hz, 2 H, C6H4(OCH3)], 7.70 (m, 2
H, H-phthalyl), 7.77 (m, 2 H, H-phthalyl).
(RS)-2-(α-Naphthylphenyl)-3-phthalimidopropanoic Acid (5d): Fol-
lowing the general procedure from (RS)-benzyl 2-(α-naphthyl)-3-
phthalimidopropanoate (0.65 g, 1.50 mmol), 5d (0.48 g, 1.40 mmol,
92% yield), was obtained as a colourless solid, m.p. 164° C. Ϫ IR
(KBr): ν˜ ϭ 3500Ϫ2500 br, 2945 w, 2924 w, 1764 m, 1740 s, 1707 s,
1
1688 m, 1537 m, 1198 m, 720 m. Ϫ H NMR (CDCl3): δ ϭ 4.16 Minor Diastereoisomer (αR,3ЈR)-8a: HPLC (condition B): ret.
1
(dd, J ϭ 7.3 Hz and J ϭ 13.8 Hz, 1 H, HCHϪN), 4.48 (dd, J ϭ
time ϭ 36.7 min. Ϫ H NMR (CDCl3): δ ϭ 0.75 (s, 3 H, 4Ј-CH3),
8.3 Hz and J ϭ 13.8 Hz, 1 H, HCHϪN), 5.20 (dd, J ϭ 7.3 Hz and 1.01 (s, 3 H, 4Ј-CH3), 3.76 (s, 3 H, OCH3), 3.94 (s, 2 H, 5Ј-CH2),
J ϭ 8.3 Hz, 1 H, CHϪCH2ϪN), 7.50 (m, 10 H, H-naphthyl and
H-phthalyl), 8.19 (m, 1 H, H-naphthyl). Ϫ ESI-MS; m/z (%): 345.9
4.21 (d, J ϭ 8.4 Hz, 1 H, HCHϪN), 4.22 (d, J ϭ 7.3 Hz, 1 H,
HCHϪN), 4.46 [dd, 7.3 Hz and 8.4 Hz, H,
J
ϭ
J
ϭ
1
(85) [(M ϩ H)ϩ], 328.1 (100), 299.9 (58). Ϫ C21H15NO4 (345.4) HCϪC6H4(OCH3)], 5.34 (s, 1 H, 3Ј-CH), 6.77 [d, J ϭ 8.7 Hz, 2 H,
calcd. C 73.11, H 4.38, N 4.06; found C 73.03, H 4.44, N 3.95.
C6H4(OCH3)], 7.24 [d, J ϭ 8.7 Hz, 2 H, C6H4(OCH3)], 7.70 (m, 2
H, H-phthalyl), 7.77 (m, 2 H, H-phthalyl).
General Procedure for the Preparation of (RS)-2-Aryl-3-phthalimi-
dopropanoic Acid Chlorides (6): A mixture of the (RS)-2-aryl-3- 4Ј,4Ј-Dimethyl-γ-butyrolacton-3Ј-yl 2-(4-Fluorophenyl)-3-phthalimi-
phthalimidopropanoic acid (1 equiv.) and oxalyl chloride (10
equiv.) was stirred under argon at 30 °C for 12 h. Evaporation of
excess oxalyl chloride yielded the corresponding (RS)-2-aryl-3-
phthalimidopropanoic acid chloride 6 that was used without fur-
ther purification in the following step.
dopropanoate (8b): Following the general procedure (NR3 ϭ NEt3,
t1 ϭ 2 h; t2 ϭ 15 h; T ϭ 0 °C) from (RS)-2-(4-fluorophenyl)-3-
phthalimidopropanoic acid chloride (0.20 g, 0.60 mmol), (αS,3ЈR)-
8b (0.23 g, 84% de) was obtained as a crude product, which after
purification by column chromatography (silica gel, ethyl acetate/
hexane 3:7) yielded (αS,3ЈR)-8b as a colourless solid (0.18 g, 72%
yield, 84% de). Crystallisation from diethyl ether gave optically pure
General Procedure for the Preparation of the Racemic Pantolactonyl
Esters (8): To (RS)-2-aryl-3-phthalimidopropanoic acids
5
(αS,3ЈR)-8b (0.14 g, 52% yield, Ͼ99% de); m.p. 127 °C. Ϫ [α]2D0
ϭ
(1.0 mmol), (R)-pantolactone (0.13 g, 1.00 mmol) and 4-(dimethyl-
amino)pyridine (0.12 g, 1 equiv) in 6 mL of CH2Cl2 was added 1
equiv. of dicyclohexylcarbodiimide (0.21 g) at 0° C. The mixture
was then stirred at room temp. for an additional 12 h. The resulting
mixture was filtered and washed successively with saturated aque-
ous solutions of citric acid (3 ϫ 6 mL) and saturated NaHCO3
solution (3 ϫ 6 mL), dried with Na2SO4, and concentrated in va-
cuo. The racemic mixtures (αS,3R)/(αR,3R) of the pantolactonyl
esters 8 were analyzed by NMR and HPLC.
Ϫ90 (c ϭ 2 in CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3056 w, 2943 m, 2877
m, 1788 s, 1750 s, 1712 s, 1610 m, 1504 m, 1160 m, 727 s. Ϫ ESI-
MS; m/z (%): 426.2 (100) [(M ϩ H)ϩ], 296 (28), 267.8 (6). Ϫ
C23H20FNO6 (425.4) calcd. C 65.00, H 4.74, N 3.30; found C 64.83,
H 4.63, N 3.28.
Main Diastereoisomer (αS,3ЈR)-8b: HPLC (condition B): ret.
1
time ϭ 29.8 min. Ϫ H NMR (CDCl3): δ ϭ 1.01 (s, 3 H, 4Ј-CH3),
1.14 (s, 3 H, 4Ј-CH3), 3.97 (d, J ϭ 9.0 Hz, 1 H, 5Ј-HCH), 3.99 (d,
Eur. J. Org. Chem. 2000, 2459Ϫ2466
2463

`
M. Calmes, F. Escale, C. Glot, M. Rolland, J. Martinez
FULL PAPER
J ϭ 9.0 Hz, 1 H, 5Ј-HCH), 4.18 (dd, J ϭ 8.6 Hz and J ϭ 13.6 Hz, Main Diastereoisomer (αS,3ЈR)-8d: HPLC (condition B): ret.
1
1 H, HCHϪN), 4.28 (dd, J ϭ 7.2 Hz and J ϭ 13.6 Hz, 1 H,
HCHϪN), 4.46 (dd, 7.2 Hz and 8.6 Hz, H,
time ϭ 32.6 min. Ϫ H NMR (CDCl3): δ ϭ 0.89 (s, 3 H, 4Ј-CH3),
1.08 (s, 3 H, 4Ј-CH3), 3.97 (s, 2 H, 5Ј-CH2), 4.25 (dd, J ϭ 6.7 Hz
J
ϭ
J
ϭ
1
HCϪC6H4F), 5.27 (s, 1 H, 3Ј-CH), 6.95 (t, J1 ϭ J2 ϭ 8.6 Hz, 2 H, and J ϭ 13.8 Hz, 1 H, HCHϪN), 4.59 (dd, J ϭ 8.9 Hz and J ϭ
C6H4F), 7.30 (dd, J ϭ 8.6 Hz and J ϭ 5.2 Hz, 2 H, C6H4F), 7.64
(m, 2 H, H-phthalyl), 7.73 (m, 2 H, H-phthalyl).
13.8 Hz, 1 H, HCHϪN), 5.34 (s, 1 H, 3Ј-CH), 5.39 (dd, J ϭ 6.7 Hz
and J ϭ 8.9 Hz, 1 H, HC-naphthyl), 7.50 (m, 3 H, H-naphthyl),
7.63 (m, 3 H, H-naphthyl and H-phthalyl), 7.82 (m, 4 H, H-naph-
thyl and H-phthalyl), 8.20 (d, J ϭ 8.4 Hz, 1 H, H-naphthyl).
Minor Diastereoisomer (αR,3ЈR)-8b: HPLC (condition B): ret.
1
time ϭ 27.2 min. Ϫ H NMR (CDCl3): δ ϭ 0.71 (s, 3 H, 4Ј-CH3),
Minor Diastereoisomer (αR,3ЈR)-8d: HPLC (condition B): ret.
time ϭ 30.20 min. Ϫ 1H NMR (CDCl3): δ ϭ 0.47 (s, 3 H, 4Ј-CH3),
0.93 (s, 3 H, 4Ј-CH3), 3.85 (d, J ϭ 8.9 Hz, 1 H, 5Ј-HCH), 4.05 (d,
J ϭ 8.9 Hz, 1 H, 5Ј-HCH), 4.19 (dd, J ϭ 6.5 Hz and J ϭ 13.9 Hz,
1 H, HCHϪN), 4.52 (dd, J ϭ 8.7 Hz and J ϭ 13.9 Hz, 1 H,
HCHϪN), 5.38 (s, 1 H, 3Ј-CH), 5.40 (dd, J ϭ 6.5 Hz and J ϭ
8.7 Hz, 1 H, HC-naphthyl), 7.50 (m, 3 H, H-naphthyl); 7.63 (m, 3
H, H-naphthyl and H-phthalyl); 7.82 (m, 4 H, H-naphthyl and H-
phthalyl); 8.20 (d, J ϭ 8.4 Hz, 1 H, H-naphthyl).
0.99 (s, 3 H, 4Ј-CH3), 3.91 (s, 2 H, 5Ј-CH2), 4.21 (d, J ϭ 8.0 Hz, 2
H, CH2ϪN), 4.45 (t, J ϭ 8.0 Hz, 1 H, HCϪC6H4F), 5.31 (s, 1 H,
3Ј-CH), 6.95 (t, J1 ϭ J2 ϭ 8.6 Hz, 2 H, C6H4F), 7.30 (dd, J ϭ
8.6 Hz and J ϭ 5.2 Hz, 2 H, C6H4F), 7.64 (m, 2 H, H-phthalyl),
7.73 (m, 2 H, H-phthalyl).
4Ј,4Ј-Dimethyl-γ-butyrolacton-3Ј-yl
2-(3,4-Dimethoxyphenyl)-3-
phthalimidopropanoate (8c): Following the general procedure
(NR3 ϭ quinuclidine, t1 ϭ 1 h; t2 ϭ 15 h; T ϭ 0 °C) from (RS)-2-
(3,4-dimethoxyphenyl)-3-phthalimidopropanoic
acid
(0.22 g,
General Procedure for the Hydrolysis of 4Ј,4Ј-Dimethyl-γ-butyrolac-
ton-3Ј-yl 2-Aryl-3-phthalimidopropanoate (8): A mixture of the
pantolactonyl esters 8 (0.50 mmol), acetic acid (1.4 mL) and a 6 
HCl solution (14 mL) was heated under reflux until completion of
the hydrolysis (4Ϫ5 h), monitoring the reaction by tlc. The mixture
was allowed to warm to room temperature and the volatile prod-
ucts were distilled at reduced pressure. Water (15 mL) was added to
the residue and the mixture was washed with AcOEt (3 ϫ 15 mL).
Concentration in vacuo of the aqueous layer followed by propylene
oxide treatment yielded the free amino acids 9.
0.60 mmol), (αS,3ЈR)-8c (0.25 g, 88% de) was obtained as a crude
product, which after purification by column chromatography (silica
gel, ethyl acetate/hexane 1:1) yielded (αS,3ЈR)-8c (as a colourless
solid (0.19 g, 70% yield, 88% de). Crystallisation from diethyl ether
yielded optically pure (αS,3ЈR)-8c (0.15 g, 55% yield, Ͼ99% de);
m.p. 124 °C; [α]2D0 ϭ Ϫ99 (c ϭ 2 in CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 2967
m, 2952 m, 2917 m, 1787 s, 1740 s, 1712 s, 1594 m, 1509 m, 1151
m, 717 s. Ϫ ESI-MS; m/z (%): 935.0 (13), 468.2 (100) [(M ϩ H)ϩ],
337.9 (12), 309.9 (20). C25H25NO8 (467.5) calcd. C 64.30, H 5.40,
N 3.00; found C 64.20, H 5.46, N 3.11.
(S)-(؊)-3-Amino-2-(4-methoxyphenyl)propanoic Acid (9a): From
(αS,3ЈR)-8a (0.22 g, Ͼ99% de), (S)-9a (0.08 g, 85% yield, 95% ee)
was obtained as a solid m.p. Ͼ260 °C. Ϫ [α]2D0 ϭ Ϫ89 (c ϭ 2 in 0.1
 HCl). Ϫ IR (KBr): ν˜ ϭ 3000Ϫ2500 br, 2190 m, 1556 s, 1514 s,
1258 m, 1030 m, 830 s. Ϫ 1H NMR (D2O): δ ϭ 3.16 (dd, J ϭ
7.5 Hz and J ϭ 12.8 Hz, 1 H, HCHϪN), 3.34 (dd, J ϭ 7.5 Hz
and J ϭ 12.8 Hz, 1 H, HCHϪN), 3.65 [t, J1 ϭ J2 ϭ 7.5 Hz, 1 H,
HCϪC6H4(OCH3)], 3.74 (s, 3 H, OCH3), 6.92 (d, J ϭ 8.5 Hz, 2 H,
H arom.), 7.18 (d, J ϭ 8.5 Hz, 2 H, H arom.). Ϫ ESI-MS; m/z (%):
196.1 (100) [(M ϩ H)ϩ], 178.1 (48), 149.9 (26). Ϫ C10H13NO3
(195.2) calcd. C 61.60, H 6.72, N 7.18; found C 61.68, H 6.63,
N 7.10.
Main Diastereoisomer (αS,3ЈR)-8c: HPLC (condition B): ret.
time ϭ 58.8 min. Ϫ H NMR (CDCl3): δ ϭ 1.01 (s, 3 H, 4Ј-CH3),
1
1.13 (s, 3 H, 4Ј-CH3), 3.81 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3),
3.96 (d, J ϭ 9.0 Hz, 1 H, 5Ј-HCH), 3.98 (d, J ϭ 9.0 Hz, 1 H, 5Ј-
HCH), 4.25 (dd, J ϭ 7.3 Hz and J ϭ 8.0 Hz, 2 H, CH2ϪN), 4.44
(dd, J ϭ 7.3 Hz and J ϭ 8.0 Hz, 1 H, HCϪC6H3(OCH3)2), 5.31 (s,
1 H, 3Ј-CH), 6.74 [d, J ϭ 8.4 Hz, 1 H, C6H3(OCH3)2], 7.84 [s, 1
H, C6H3(OCH3)2], 7.87 [d, J ϭ 8.4 Hz, 1 H, C6H3(OCH3)2], 7.69
(m, 2 H, H-phthalyl), 7.78 (m, 2 H, H-phthalyl).
Minor Diastereoisomer (αR,3ЈR)-8c: HPLC (condition B): ret.
1
time ϭ 55.5 min. Ϫ H NMR (CDCl3): δ ϭ 0.77 (s, 3 H, 4Ј-CH3),
1.04 (s, 3 H, 4Ј-CH3), 3.81 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3),
3.95 (s, 2 H, 5Ј-CH2), 4.19 (dd, J ϭ 8.0 Hz and J ϭ 13.8 Hz, 1 H,
HCHϪN), 4.27 (dd, J ϭ 8.0 Hz and J ϭ 13.8 Hz, 1 H, HCHϪN),
4.46 [t, J1 ϭ J2 ϭ 8.0 Hz, 1 H, HCϪC6H3(OCH3)2], 5.36 (s, 1 H,
3Ј-CH), 6.74 [d, J ϭ 8.4 Hz, 1 H, C6H3(OCH3)2], 7.84 [s, 1 H,
C6H3(OCH3)2], 7.87 [d, J ϭ 8.4 Hz, 1 H, C6H3(OCH3)2], 7.69 (m,
2 H, H-phthalyl), 7.78 (m, 2 H, H-phthalyl).
(S)-(؊)-3-Amino-2-(4-fluorophenyl)propanoic Acid (9b): From
(αS,3ЈR)-8b (0.21 g, Ͼ99% de), (S)-9b (0.07 mg, 82% yield, 92% ee)
was obtained as a solid m.p. Ͼ260 °C. Ϫ [α]2D0 ϭ Ϫ 78 (c ϭ 2 in
0.1  HCl). Ϫ IR (KBr): ν˜ ϭ3000Ϫ2500 br, 2100 m, 1551 s, 1500
s, 1382 m, 830 s. Ϫ 1H NMR (D2O): δ ϭ 3.18 (dd, J ϭ 7.3 Hz and
J ϭ 12.8 Hz, 1 H, HCHϪN), 3.36 (dd, J ϭ 7.3 Hz and J ϭ 12.8 Hz,
1 H, HCHϪN), 3.70 (t, J1 ϭ J2 ϭ 7.3 Hz, 1 H, HCϪC6H4F), 7.06
(t, J1 ϭ J2 ϭ 8.5 Hz, 2 H, C6H4F), 7.23 (dd, J ϭ 5.5 Hz and J ϭ
8.5 Hz, 2 H, C6H4F). Ϫ ESI-MS; m/z (%): 183.9 (100) [(M ϩ H)ϩ],
166.1 (8), 138.1 (5). Ϫ C9H10FNO2 (183.2) calcd. C 59.07, H 5.51,
N 7.65; found C 59.19, H 5.63, N 7.50.
4Ј,4Ј-Dimethyl-γ-butyrolacton-3Ј-yl 2-(α-Naphthyl)-3-phthalimido-
propanoate (8d): Following the general procedure (NR3 ϭ quinuclid-
ine, t1 ϭ 1 h; t2 ϭ 5 h; T ϭ room temperature) from (RS)-2-(α-
naphthylphenyl)-3-phthalimidopropanoic acid (0.22 g, 0.60 mmol),
(αS,3ЈR)-8d (0.26 g, 84% de) was obtained as a crude product, (S)-(؊)-3-Amino-2-(3,4-dimethoxyphenyl)propanoic Acid (9c): From
which after purification by column chromatography (silica gel,
ethyl acetate/hexane 1:1) yielded (αS,3ЈR)-8d as a colourless solid
(0.2 g, 72% yield, 84% de). A second column chromatography (si-
(αS,3ЈR)-8c (0.23 g, Ͼ99% de), (S)-9c (0.09 g, 84% yield, 94% ee)
was obtained as a solid m.p. Ͼ260 °C. Ϫ [α]2D0 ϭ Ϫ75 (c ϭ 2 in 0.1
 HCl). Ϫ IR (KBr): ν˜ ϭ 3000Ϫ2500 br, 2180 w, 1731 w, 1632 m,
1
lica gel CH2Cl2/ethyl acetate 9.5:0.5) yielded optically pure 1552 s, 1514 s, 1030 m, 830 m. Ϫ H NMR (D2O): δ ϭ 3.30 (dd,
(αS,3ЈR)-8d (0.14 g, 52% yield, Ͼ99% de); m.p. 88 °C. Ϫ [α]2D0
ϭ
J ϭ 7.4 Hz and J ϭ 12.6 Hz, 1 H, HCHϪN), 3.50 (dd, J ϭ 7.4 Hz
Ϫ115 (c ϭ 2 in CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3047 w, 2962 m, 2915 and J ϭ 12.6 Hz, 1 H, HCHϪN), 3.79 [t, J1 ϭ J2 ϭ 7.4 Hz, 1 H,
m, 2868 m, 1789 s, 1744 s, 1710 s, 1453 m, 717 m. Ϫ ESI-MS; m/z HCϪC6H3(OCH3)2], 3.89 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3),
(%): 458.3 (100) [(M ϩ H)ϩ], 328.2 (22), 300.1 (12). C27H23NO6 7.05 (m, 3 H, H arom.). Ϫ ESI-MS; m/z (%): 451.2 (8), 225.9 (100)
(457.5) calcd. C 70.96, H 5.07, N 3.06; found C 70.64, H 4.91,
N 2.99.
[(M ϩ H)ϩ], 207.9 (25), 179.8 (18). Ϫ C11H15NO4 (225.2) calcd. C
58.72, H 6.70, N 6.23; found C 58.66, H 6.78, N 6.17.
2464
Eur. J. Org. Chem. 2000, 2459Ϫ2466

Asymmetric Synthesis of (S)-β2-Homoarylglycines
(S)-(؊)-3-Amino-2-(α-naphthyl)propanoic Acid
FULL PAPER
(9d):
From
residual electron density in the final difference map was located
3
˚
(αS,3ЈR)-8d (0.23 g, Ͼ99% de), (S)-9d (0.08 mg, 79% yield, 94% ee) between Ϫ0.10 and 0.10 eA .
was obtained as a solid m.p. Ͼ260 °C. Ϫ [α]2D0 ϭ Ϫ 90 (c ϭ 0.8 in
Crystal Data for (αS,3ЈR)-8c: C25H25NO8 M ϭ 467.5, monoclinic,
space group P21, Z ϭ 2, a ϭ 11.560(1), b ϭ 8.400 (1), c ϭ 13.954(1)
0.1  HCl). Ϫ IR (KBr): ν˜ ϭ 3000Ϫ2500 br, 1735 m, 1551 s, 1504
1
m, 1367 m, 750 m. Ϫ H NMR ([D6]DMSO): δ ϭ 3.15 (dd, J ϭ
A, V ϭ 1318.1(4) A , dcalcd. ϭ 1.29 mg cmϪ3, λ(Mo-Kα) ϭ 0.71073
3
˚
˚
˚
4.8 Hz and J ϭ 12.8 Hz, 1 H, HCHϪN), 3.57 (dd, J ϭ 9.2 Hz and
J ϭ 12.8 Hz, 1 H, HCHϪN), 4.77 (dd, J ϭ 4.8 Hz and J ϭ 9.2 Hz,
1 H, HC-naphthyl), 7.48 (d, J ϭ 7.0 Hz, 1 H, H-naphthyl), 7.62
(m, 3 H, H-naphthyl), 8.05 (d, J ϭ 8.0 Hz, 1 H, H-naphthyl), 8.26
(d, J ϭ 8.4 Hz, 1 H, H-naphthyl). Ϫ ESI-MS; m/z (%): 216.0 (100)
[(M ϩ H)ϩ], 198.6 (18), 169.9 (12). Ϫ C13H13NO2 (215.3) calcd. C
72.63, H 6.09, N 6.51; found C 72.68, H 6.15, N 6.42.
A, µ ϭ 0.088 mmϪ1. Intensity data were measured with a
EnrafϪNonius Kappa CCD diffractometer using graphite-mono-
chromate Mo-Kα radiation and the ϕ-scan technique up to θ ϭ
25.41; 2742 collected reflections, 2742 unique (Rint ϭ 0.062) of
which 2547 were considered as observed having I Ն 1σ(I). The
hydrogen atoms are in the theoretical positions. Refinement was
carried out by minimizing the function w(F2o Ϫ |Fc|2)2, R ϭ 0.076
and wR2 ϭ 0.097 goodness of fit 1.428. The residual electron den-
sity in the final difference map was located between Ϫ0.27 and 0.30
(S)-(؊)-3-(tert-butoxycarbonylamino-(α-naphthyl)propanoic
Acid
(10d): 3-Amino-2-(α-naphthyl)propanoic acid 9d (0.06 g,
0.30 mmol), 0.65 mmol of aqueous 1  NaOH (0.65 mL), (Boc)2O
(0.09 g, 0.40 mmol) and THF (1 mL) were stirred at room temper-
ature for 48 h. The mixture was then diluted with water (1 mL) and
washed with diethyl ether (3 ϫ 1 mL). The aqueous extract was
acidified to pH 4 and extracted with diethyl acetate. The organic
layer was dried (Na2SO4) and after concentration in vacuo a col-
ourless solid was obtained (0.06 g, 65% yield); m.p. 139 °C. Ϫ
3
˚
eA . Computer program: maXus.
Crystallographic data (excluding structure factors) for the struc-
tures reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
no. CCDC-136875 and with the International Union of Cry-
stallography (refGS1061).[12] Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [Fax: (internat.) ϩ 44(1223)336Ϫ033; E-mail:
deposit@ccdc.cam.ac.uk].[12]
1
[α]2D0 ϭ Ϫ128 (c ϭ 1.2 in CHCl3). Ϫ H NMR (CDCl3) (some of
the signals were doublet up probably due to the presence of rota-
mers) δ ϭ 1.38 and 1.52 [s, 9 H, NHCO2C(CH3)3], 3.46 and 3.64
(m, 2 H, CH2ϪNHBoc), 4.63 and 4.75 (m, 1 H, CH-naphthyl),
5.10 (br, 1 H, NHBoc), 7.46 (m, 4 H, H-naphthyl), 7.78 (m, 2 H,
H-naphthyl), 8.16 (d, J ϭ 8.4 Hz, 1 H, H-naphthyl).
Acknowledgments
We thank Dr J. Daunis for his support and helpful discussions.
General Procedure for the Preparation of FDAA Derivatives:[13] To
an aqueous solution of 5.0 µmol of the β-amino acid (9a؊d) was
added 200 µL of 1% acetone solution of FDAA [1-fluoro-2,4-di-
nitrophenyl-(5S)-alanine amide] (2 mg, 7.2 µmol) followed by 40
µL of 1  NaHCO3 (40.0 µmol). The mixture was heated at 30Ϫ40
°C for 1 hour with frequent mixing. After cooling to room temper-
ature, 40 µL of 1  HCl (40.0 µmol) was added. The mixture was
concentrated and dried in vacuo over phosphorus pentoxide. The
residue dissolved in 0.5 mL of [D6]DMSO was analysed by 1H
NMR and the enantiomeric excess of the β-amino acid was deter-
mined using aromatic proton signals of the DFAA derivative.
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the final difference map was located between Ϫ0.19 and 0.16 eA .
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[7]
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3
˚
˚
11.1026(2), c ϭ 20.3200(6) A, V ϭ 2158.3(2) A , dcalcd. ϭ 1.31 mg
cmϪ3, λ(Mo-Kα) ϭ 0.71 A, µ ϭ 0.1 mmϪ1. Intensity data were
˚
measured with a EnrafϪNonius Kappa CCD diffractometer using
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nique up to θ ϭ 25.41; 2379 collected reflections, 2362 unique
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`
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`
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Ϫ
[9d]
|Fc|2)2, R ϭ 0.033 and wR2 ϭ 0.052 goodness of fit 1.220. The
Ϫ
M. Calmes, J. Daunis, N. Mai, Tetrahedron 1997, 53,
`
Eur. J. Org. Chem. 2000, 2459Ϫ2466
2465

`
M. Calmes, F. Escale, C. Glot, M. Rolland, J. Martinez
FULL PAPER
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[12]
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Received November 18, 1999
[O99636]
2466
Eur. J. Org. Chem. 2000, 2459Ϫ2466