Optical resolution by preferential crystallization of (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid and its use in synthesizing optically active 2-amino-2-methyl-3-phenylpropanoic acid.

Article abstract of DOI:10.1248/cpb.50.1362

To synthesize optically active 2-amino-2-methyl-3-phenylpropanoic acid (1), (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid [(RS)-2] was first optically resolved using cinchonidine as a resolving agent to yield optically pure (S)- and (R)-2 in yields of about 70%, based on half of the starting amount of (RS)-2. Next, the racemic structure of (RS)-2 was examined based on melting point, solubility, IR spectrum, and binary and ternary phase diagrams, with the aim of optical resolution by preferential crystallization of (RS)-2. Results indicated that the (RS)-2 exists as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization yielded (S)- and (R)-2 with optical purities of about 90%, which were fully purified by recrystallization. After O-tosylation of (S)- and (R)-2, reduction by zinc powder and sodium iodide gave (R)- and (S)-1, respectively.

Full text of DOI:10.1248/cpb.50.1362

1362
Chem. Pharm. Bull. 50(10) 1362—1366 (2002)
Vol. 50, No. 10
Optical Resolution by Preferential Crystallization of
(RS)-2-Benzoylamino-2-benzyl-3-hydroxypropanoic Acid and Its Use in
Synthesizing Optically Active 2-Amino-2-methyl-3-phenylpropanoic Acid
Tadashi SHIRAIWA,* Masahiro SUZUKI, Yoshio SAKAI, Hisashi NAGASAWA, Kazuhiro TAKATANI,
Daisuke NOSHI, and Kenji YAMANASHI
Unit of Chemistry, Faculty of Engineering and High Technology Research Center, Kansai University; Yamate-cho, Suita,
Osaka 564–8680, Japan. Received May 22, 2002; accepted July 12, 2002
To synthesize optically active 2-amino-2-methyl-3-phenylpropanoic acid (1), (RS)-2-benzoylamino-2-benzyl-
3-hydroxypropanoic acid [(RS)-2] was first optically resolved using cinchonidine as a resolving agent to yield op-
tically pure (S)- and (R)-2 in yields of about 70%, based on half of the starting amount of (RS)-2. Next, the
racemic structure of (RS)-2 was examined based on melting point, solubility, IR spectrum, and binary and
ternary phase diagrams, with the aim of optical resolution by preferential crystallization of (RS)-2. Results indi-
cated that the (RS)-2 exists as a conglomerate at room temperature, although it forms a racemic compound at
the melting point. The optical resolution by preferential crystallization yielded (S)- and (R)-2 with optical puri-
ties of about 90%, which were fully purified by recrystallization. After O-tosylation of (S)- and (R)-2, reduction
by zinc powder and sodium iodide gave (R)- and (S)-1, respectively.
Key words a-methylphenylalanine; N-benzoyl-a-benzylserine; optical resolution; preferential crystallization
a,a-Disubstituted a-amino acids, such as 2-amino-2- alanine (DL-4) to the corresponding oxazolone [(RS)-5], and
methyl-3-phenylpropanoic acid (1; a-methylphenylalanine) then treatment of (RS)-5 with aqueous formaldehyde in the
and 2-amino-2-benzyl-3-hydroxypropanoic acid (a-benzyl- presence of pyridine.6) When (RS)-3 was refluxed for 15—
serine), are known as enzyme inhibitors and as conforma- 30 min in 5 mol dmϪ3 hydrochloric acid, (RS)-2-amino-3-ben-
tional modifiers in physiologically important peptides.1) For zoyloxy-2-benzylpropanoic acid hydrochloride [(RS)-6] was
example, the dipeptide that is synthesized from optically ac- obtained in yields of 65—83%. (RS)-3 was hydrolyzed under
tive 1 and N-benzoylglycine is a substrate for carboxypepti- alkaline conditions to give (RS)-2.
dase A.2) (R)- and (S)-1 have been synthesized by conversion
We first attempted the optical resolution of (RS)-2 by sep-
of optically active 2-methylaziridine-2-carboxylic acid,3) by aration of the diastereoisomeric salts with optically active
reduction of optically active N-benzoyl derivative (2) of a- amines such as cinchonidine (7), a-methylbenzylamine, and
benzylserine,4) and by alkylation of the Schiff’s base, formed 2-amino-1-(4-nitrophenyl)-1,3-propanediol. Of these amines,
from benzaldehyde and DL-alanine ester, using enantiopure 2- only 7 formed a good crystalline salt with 2. The salt of (S)-2
hydroxy-2Ј-amino-1,1Ј-binaphthyl as the catalyst.5) Among with 7 [(S)-2·7 salt] was crystallized as a less-soluble di-
the reagents which are employed in the above syntheses, op- astereoisomeric salt and the more-soluble (R)-2·7 salt was
tically active 2 is seemed to be easily obtained by optical res- obtained from the filtrate. After treating these salts with hy-
olution of its racemate, which is synthesized from L-pheny- drochloric acid, the obtained (S)- and (R)-2 were recrystal-
lalanine (L-Phe).4,6) Therefore, we attempted to obtain opti- lized from ethanol to give optically pure (S)- and (R)-2 in
cally active 1 via optical resolution of (RS)-2.
yields of about 70%, based on half of the starting amount of
Preferential crystallization and separation of a di- (RS)-2.
astereoisomeric mixture have been well employed for optical
Since the (S)- and (R)-2 partially resolved by the dia-
resolution.7) Although (RS)-2 has been optically resolved by stereoisomeric method were recrystallized from ethanol to
separation of the diastereoisomeric salts with quinine to ob- give optically pure (S)- and (R)-2, (RS)-2 was postulated to
tain optically active 2,4) the optical resolution by preferential exist as a conglomerate. (RS)-2 has a lower melting point
crystallization of (RS)-2 have not yet been reported. Race- than (S)-2; (RS)-2, 161 °C; (S)-2, 173 °C. Although the melt-
mates exist in the forms of racemic compounds, racemic ing-point binary phase diagram suggested that (RS)-2 forms
solid solutions, and conglomerates (racemic mixtures), a racemic compound, as shown in Fig. 1,7) its IR spectrum
among which only conglomerates can be optically resolved was identical to that of (S)-2. In addition, (RS)-2 was more
by preferential crystallization.7) Since we found that (RS)-2 soluble than (S)-2 at 10 °C; solubility of (RS)-2, 10.773 g
exists as a conglomerate at room temperature, (RS)-2 was (100 ml of ethanol)Ϫ1; solubility of (S)-2, 6.025 g (100 ml of
subjected to optical resolution by preferential crystallization. ethanol)Ϫ1. The solubility ternary phase diagram at 10 °C
The obtained (R)- and (S)-2 were attempted to be reduced by (Fig. 2) suggests that (RS)-2 can exist as a conglomerate at
zinc powder and sodium iodide to give optically active 1 room temperature, even a racemic compound at the melting
(Chart 1).4,6,8)
point.
Thus, (RS)-2 was tried to optically resolve by preferential
crystallization at 10 °C in ethanol. To optimize conditions,
Results and Discussion
(RS)-5-Benzoylamino-5-benzyl-4-oxo-1,3-dioxane [(RS)- the optical resolution was conducted by stirring 140—170%
3] was synthesized starting from L-Phe by N-benzoylation of supersaturated solutions for 20—60 min, as shown in Figs. 3
L-Phe, followed by dehydration of the N-benzoyl-DL-phenyl- and 4 and summarized in Table 1; (S)-2 (0.050 g) was em-
* To whom correspondence should be addressed. e-mail: shiraiwa@ipcku.kansai-u.ac.jp
© 2002 Pharmaceutical Society of Japan

October 2002
1363
Chart 1. Synthetic Route to Optically Active 2-Amino-2-methyl-3-phenylpropanoic Acid (1)
(a) benzoyl chloride, OHϪ; (b) acetic anhydride, 95 °C; (c) pyridine, 37 wt% aq. formaldehyde; (d) 5 mol dmϪ3 hydrochloric acid, reflux; (e) i) 2 mol dmϪ3 aqueous sodium hy-
droxide, dioxane, ii) 2 mol dmϪ3 hydrochloric acid; (f) optical resolution; (g) i) tosyl chloride, pyridine; (h) zinc powder, sodium iodide, dimethylformamide, 120 °C; (i) i)
5 mol dmϪ3 hydrochloric acid, reflux, ii) triethylamine (pH 7), methanol.
Fig. 3. Relationship between the Amount of Crystallization and Degree of
Supersaturation in the Optical Resolution of 2-Benzoylamino-2-benzyl-3-
hydroxypropanoic Acid [(RS)-2]
Fig. 1. Melting-Point Binary Phase Diagram of 2-Benzoylamino-2-ben-
zyl-3-hydroxypropanoic Acid (2)
Conditions: (RS)-2, 3.016—3.663 g (140—170% supersaturation); seed crystals,
0.050 g of (S)-2; solvent, 20 ml of ethanol; stirring time, 30 min; temperature, 10 °C.
Amount of crystallization: ᭺ (S)-2; ᭹ (R)-2.
YE (g)ϭ[Yield (g)ϫOP (%)/100]Ϫ0.050,
DR (%)ϭYE (g)ϫ100/(1/2)[amount of (RS)-2 (g)Ϫ2.155],
AC(R) (g)ϭ(1/2)[Yield (g)ϪYE (g)Ϫ0.050],
AC(S) (g)ϭYE (g)ϩAC(R) (g),
where the solubility of (RS)-2 is 2.155 g in 20 cm3 of ethanol
at 10 °C and Yield is the sum of the amounts of the crystal-
lized 2 and seed crystals (0.050 g). OP is the optical purity of
the obtained (S)-2 and was calculated on the basis of the re-
ported specific rotation of (R)-2; (R)-2, [a]D20 ϩ70.0° (cϭ1,
methanol);4) (S)-2, [a]D20 Ϫ69.5° (cϭ1, methanol).4) The yield
of enantiomer [YE (g)] is the amount of crystallized optically
pure (S)-2 and corresponds to the theoretical yield of opti-
cally pure (S)-2 obtained by separation from partially re-
solved (S)-2.
Fig. 2. Solubility Ternary Phase Diagram of 2-Benzoylamino-2-benzyl-3-
hydroxypropanoic Acid (2)
Conditions: temperature, 10 °C; solvent, ethanol.
ployed as seed crystals. The yield of enantiomer [YE (g)], de-
gree of resolution [DR (%)] of (S)-2 obtained, and the
amounts of crystallization [AC(S) and AC(R) (g)] were calcu-
lated from
When the 140—170% supersaturated solutions were em-
ployed, the amount of crystallization of the seeded (S)-2 in-

1364
Vol. 50, No. 10
creased with increasing degree of supersaturation, after a res- 20—60 min (Fig. 4). The unseeded (R)-2 began to crystallize
olution time of 30 min (Fig. 3). On the other hand, rapid crys- rapidly at 50 min, but did not during the first 40 min. There-
tallization of the unseeded (R)-2 was not observed in the op- fore, the optical resolution at 40 min gave (S)-2 with an opti-
tical resolutions for the 140—155% supersaturated solutions cal purity of 89% in the highest degree of resolution (70%).
(Fig. 3), although (R)-2 crystallized rapidly from the 160 and
Next, successive optical resolution was attempted by stir-
170% supersaturated solutions. Thus, the optical resolution ring the 155% supersaturated solution as the initial solution
for the 155% supersaturated solution at 30 min gave (S)-2 for 40 min (Table 2). The degrees of resolution [DR (%)] of
with an optical purity of 85% in the highest degree of resolu- (S)- and (R)-2 obtained were calculated from
tion (58%). Furthermore, the optical resolution for the 155%
DR (%)ϭYE (g)ϫ100/[operation amount of (S)- or (R)-2 (g)Ϫ1.077],
supersaturated solution was carried out at resolution times of
where the operation amount is the amount of (S)- or (R)-2 in
the solution used in the optical resolution and those in runs
2—4 in Table 2 were calculated based on the yields and opti-
cal purities of the (S)- or (R)-2 obtained in runs 1—3, respec-
tively. The half amount for solubility of (RS)-2 is 1.077 g in
20 cm3 of ethanol at 10 °C.
The optical resolution afforded (S)- and (R)-2 with optical
purities of about 90% in degrees of resolution of 70—81%
and the partially resolved (S)- and (R)-2 could be purified by
simple recrystallization.
The O-tosyl derivatives of (S)- and (R)-2 [(S)- and (R)-8]
were subjected to reductive removal of their tosyloxy groups
with zinc powder and sodium iodide, via the iodide interme-
diates (9), to give the N-benzoyl derivative of optically active
1 (10).4,8) Thus (R)- and (S)-1 were afforded from (S)- and
(R)-2, after hydrolysis of (R)- and (S)-10, respectively, as
Fig. 4. Relationship between the Amount of Crystallization and Resolu- shown in Chart 1.
tion Time in the Optical Resolution of (RS)-2-Benzoylamino-2-benzyl-3-hy-
droxypropanoic Acid [(RS)-2]
Experimental
General Specific rotations were measured at 589 nm and 20 °C with a
Horiba Seisakusho SEPA-300 auto polarimeter equipped with a quartz cell
with a 5.00 cm path length. IR spectra were obtained in the range of 4000—
Conditions: (RS)-2, 3.340 g (155% supersaturation); seed crystals, 0.050 g of (S)-2;
solvent, 20 ml of ethanol; stirring time, 20—60 min; temperature, 10 °C. Amount of
crystallization: ᭺ (S)-2; ᭹ (R)-2.
Table 1. Preferential Crystallization of (RS)-2-Benzoylamino-2-benzyl-3-hydroxypropanoic Acida)
Degree of
supersaturation
(%)
(S)-2 obtained
Resolution time
(RS)-2 (g)
(min)
Yieldb) (g)
Specific rotationc) (°)
DRd) (%)
140
145
150
155
155
155
155
155
160
165
170
3.016
3.124
3.232
3.340
3.340
3.340
3.340
3.340
3.447
3.555
3.663
30
30
30
20
30
40
50
60
30
30
30
0.183
0.267
0.343
0.302
0.463
0.527
0.611
0.823
0.593
0.918
1.257
Ϫ62.3
Ϫ53.2
Ϫ61.8
Ϫ57.0
Ϫ59.7
Ϫ62.0
Ϫ51.9
Ϫ25.3
Ϫ45.0
Ϫ22.6
Ϫ8.5
26
32
47
33
58
70
68
41
51
35
14
a) Conditions: seed crystals, 0.050 g of (S)-2; solvent, 20 ml of ethanol; temperature, 10 °C. b) The Yield is the sum of the amounts of crystallized 2 and seed crystals.
c) [a]D20 (cϭ1.00, methanol). d) DR: degree of resolution.
Table 2. Successive Optical Resolution by Preferential Crystallization of (RS)-2-Benzoylamino-2-benzyl-3-hydroxypropanoic Acida)
Operation amounts of (S)- and (R)-2b) (g)
(S)- or (R)-2 obtained
Added amount of
Resolution time
(min)
Run
(RS)-2 (g)
(S)-2
(R)-2
Yieldc) (g)
Specific rotationd) (°) DRe) (%)
1
2
3
4
3.340
0.480
0.680
0.640
1.670
1.463
1.779
1.494
1.670
1.880
1.561
1.847
40
40
30
20
(S) 0.527
(R) 0.733
(S) 0.689
(R) 0.682
Ϫ62.0
ϩ65.5
Ϫ63.1
ϩ62.8
70
79
81
73
a) Conditions: seed crystals, 0.050 g of (S)- or (R)-2; solvent, 20 ml of ethanol; temperature, 10 °C. b) The operation amounts in runs 2—4 were calculated from the results
in runs 1—3. c) The Yield is the sum of the amounts of crystallized 2 and seed crystals. d) [a]D20 (cϭ1.00, methanol). e) DR: degree of resolution.

October 2002
1365
400 cmϪ1 with a Perkin-Elmer Model 1600 FT-IR spectrometer by the KBr
disk method. 1H- and 13C-NMR spectra were recorded on a JNM-FX270 FT
Ϫ70.0° (cϭ1.00, methanol) (lit.,4) [a]D20 Ϫ69.5° (cϭ1.00, methanol)). Anal.
Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.15; H, 5.71;
N, 4.65.
1
NMR system (270 MHz for H and 67.5 MHz for 13C) in deuterium oxide
(D2O), 0.5 mol dmϪ3 solution of sodium deuteroxide (NaOD) in D2O, or
deuterium chloroform-d (CDCl3) with sodium 3-(trimethylsilyl)propane-1-
sulfonate (DSS) or tetramethylsilane (TMS) as an internal standard. Chemi-
cal shifts were reported in d units downfield from DSS or TMS. Melting
points were measured with a Yanaco MP-500 D micro melting point appara-
tus.
(R)-2: Yield, 20.5 g (68.4%); mp 171—173 °C (lit.,4) 176—177 °C); [a]D20
ϩ70.0° (cϭ1.00, methanol) (lit.,4) [a]D20 ϩ70.0° (cϭ1.00, methanol)). Anal.
Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.16; H, 5.66;
N, 4.70.
Optical Resolution by Preferential Crystallization of (RS)-2-Benzoyl-
amino-2-benzyl-3-hydroxypropanoic Acid [(RS)-2] (RS)-2 (3.016—
3.663 g) was dissolved in 20 ml of ethanol at 40 °C and the solution was
gradually cooled to 10 °C over a period of 1 h and then seeded with 0.050 g
of (S)-2. After stirring the mixture with a blade (0.70 cm width; 2.0 cm
length) at 100 rpm at 10 °C for 30 min, the crystallized (S)-2 was quickly
collected by filtration and thoroughly dried.
Optical resolution was carried out for the 155% supersaturated solution
(3.340 g of (RS)-2 in 20 ml of ethanol) by stirring for 20—60 min at 10 °C in
a manner similar to that described above.
Successive Optical Resolution of (RS)-2-Benzoylamino-2-benzyl-3-hy-
droxypropanoic Acid [(RS)-2] (RS)-2 (3.340 g) was dissolved in 20 ml of
ethanol at 40 °C. The solution was gradually cooled to 10 °C over a period of
1 h and then seeded with 0.050 g of (S)-2. After stirring the mixture at 10 °C
for 40 min, (S)-2 (0.527 g) was quickly collected by filtration and thoroughly
dried (run 1 in Table 2). (RS)-2 (0.480 g) was dissolved in the filtrate at
40 °C and then the resulting solution was gradually cooled to 10 °C. (R)-2
(0.050 g) was added as seed crystals and then the mixture was stirred for
40 min. (R)-2 (0.733 g) was collected by filtration and dried (run 2 in Table
2). The filtrate was treated in a manner similar to that described above; the
detailed conditions for runs 3 and 4 are given in Table 2.
A mixture of (S)-2 (2.30 g) with an optical purity of 64% in 8 ml of
ethanol was vigorously stirred at 10 °C for 5 h. Then the purified (S)-2
(1.37 g) was collected by filtration and dried; [a]D20 Ϫ70.0° (cϭ1.00,
methanol). (R)-2 (2.31 g) with an optical purity of 67% was treated with 7 ml
of ethanol, in a manner similar to that for (S)-2, to give optically pure (R)-2
in a yield of 1.49 g; [a]D20 ϩ70.0° (cϭ1.00, methanol).
Cinchonidine (7) was purchased from Wako Pure Chemicals Ind.; [a]D20
Ϫ109° (cϭ1.00, ethanol). Compound DL-4 was prepared reacting L-Phe with
benzoyl chloride under alkaline conditions; mp 187—189 °C (lit,9) 187—
188 °C). L-Phe was purchased from Wako Pure Chemicals Ind.
(RS)-5-Benzoylamino-5-benzyl-4-oxo-1,3-dioxane [(RS)-3] A solution
of DL-4 (202 g, 750 mmol) in acetic anhydride (650 g, 6.37 mol) was stirred
at 95 °C for 1 h. After evaporation of the solution in vacuo at 75 °C, followed
by addition of pyridine (90 ml) and 380 ml of 37 wt% aqueous formaldehyde
to the residue, the mixture was stirred at room temperature for 12 h and was
then poured into 1 l of water. The precipitated (RS)-3 was collected by filtra-
tion, washed with water, and dried. After dissolving the crude (RS)-3 (190 g)
in 500 cm3 of methanol on heating, followed by being allowed to stand the
solution at 5 °C overnight, the precipitated (RS)-3 was collected by filtration
and dried. Yield, 121 g (51.8%); mp 176—179 °C (lit,6) 176—178 °C). IR
n
max (KBr) cmϪ1: 3404, 1726, 1651, 1522, 1489, 1458, 1227, 996, 734, 704.
1H-NMR (CDCl3) d: 7.66—7.63 (2H, m, aromatic H), 7.52—7.26 (8H, m,
aromatic H), 6.63 (1H, s, –NH–), 5.67 (1H, d, Jϭ5.1 Hz, 2-HH), 5.48 (1H, d,
Jϭ5.1 Hz, 2-HH), 4.27 (1H, d, Jϭ11.4 Hz, 6-HH), 4.17 (1H, d, Jϭ11.4 Hz,
6-HH), 3.55 (1H, d, Jϭ13.9 Hz, Ph–CHH–), 3.23 (1H, d, Jϭ13.9 Hz,
Ph–CHH–). 13C-NMR (CDCl3) d: 169.5 (4-CϭO), 166.8 (Ph–CO–NH–),
133.6 (aromatic C), 132.7 (aromatic C), 132.3 (aromatic C), 130.4 (aromatic
C), 129.3 (aromatic C), 128.7 (aromatic C), 128.2 (aromatic C), 127.0 (aro-
matic C), 94.9 (2-C), 87.5 (6-C), 57.9 (5-C), 41.1 (Ph–CH2–). Anal. Calcd
for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.22; H, 5.47; N,
4.47.
(RS)-2-Amino-3-benzoyloxy-2-benzylpropanoic Acid [(RS)-6] After
refluxing (RS)-3 (6.28 g, 20.0 mmol) in 50 ml of 5 mol dmϪ3 hydrochloric
acid for 15 min, the precipitated (RS)-6 was collected by filtration, washed
with small amounts of water and then methanol, and dried.11) Yield, 4.87 g
(S)- and (R)-2-Benzoylamino-2-benzyl-3-tosyloxypropanoic Acid [(S)-
and (R)-8] Tosyl chloride (38.1 g, 0.200 mol) was added to a solution of
(S)-2 (5.99 g, 20.0 mmol) in 25 ml of pyridine at 0 °C. After being allowed to
stand at 5 °C for 3 d, the solution was poured on ice-water (150 ml). The
mixture was extracted with chloroform (4ϫ50 ml) and then the organic layer
was washed with water (3ϫ50 ml), 1 mol dmϪ3 hydrochloric acid (3ϫ50 ml),
and then water (3ϫ50 ml). After dried over magnesium sulfate, the organic
layer was evaporated to dryness in vacuo to give crude the (S)-8, which was
recrystallized from ethyl acetate (50 ml) and hexane (250 ml). (R)-8 was pre-
pared from (R)-2, in a similar manner to (S)-8.
1
(83.0%), mp 191—194 °C. H-NMR (NaOD) d: 7.90—7.83 (2H, m, aro-
matic H), 7.60—7.24 (8H, m, aromatic H), 3.89 (1H, d, Jϭ10.7 Hz, 3-HH),
3.54 (1H, d, Jϭ10.8 Hz, 3-HH), 3.04 (1H, d, Jϭ13.3 Hz, Ph–CHH), 2.69
(1H, d, Jϭ13.3 Hz, Ph–CHH–). Anal. Calcd for C17H18NO4Cl: C, 60.81; H,
5.40; N, 4.17. Found: C, 60.77; H, 5.33; N, 4.17.
(RS)-2-Benaoylamino-2-benzyl-3-hydroxypropanoic Acid [(RS)-2]
After adding 2 mol dmϪ3 aqueous sodium hydroxide (25 ml) to a suspension
of (RS)-3 (12.2 g, 38.7 mmol) in 25 ml of dioxane, followed hy stirring the
solution at room temperature for 1 h, the dioxane was evaporated in vacuo at
60 °C. The aqueous layer was acidified with 2 mol dmϪ3 hydrochloric acid
and then the mixture was stirred in an ice bath for 1 h. The precipitated (RS)-
2 was collected by filtration and then was recrystallized from ethanol
(3.3 ml gϪ1). Yield, 10.4 g (89.2%); mp 158—161 °C (lit.,4) 159—161 °C).
IR nmax (KBr) cmϪ1: 3379, 3194, 1729, 1635, 1527, 1417, 1239, 1204, 1093,
1073, 728, 694, 631. 1H-NMR (NaOD) d: 7.65—7.19 (10H, m, aromatic H),
4.51 (1H, d, Jϭ11.1 Hz, 3-HH), 4.10 (1H, d, Jϭ11.3 Hz, 3-HH), 3.51 (1H,
d, Jϭ13.2 Hz, Ph–CHH), 3.18 (1H, d, Jϭ13.2 Hz, Ph–CHH–). 13C-NMR
(NaOD) d: 161.8 (1-COOH), 154.2 (Ph–CO–NH–), 121.6 (aromatic C),
119.3 (aromatic C), 117.0 (aromatic C), 114.7 (aromatic C), 113.8 (aromatic
C), 113.3 (aromatic C), 111.7 (aromatic C), 111.6 (aromatic C), 67.2 (3-C),
62.7 (2-C), 36.4 (Ph–CH2–). Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72;
N, 4.68. Found: C, 68.07; H, 5.76; N, 4.64.
(S)-8: Yield, 7.82 g (86.2%); mp 97—100 °C (lit.,4) 98—99 °C); [a]D20
Ϫ119° (cϭ1.00, methanol) (lit.,4) [a]D20 Ϫ117.4° (cϭ1.00, methanol)). IR
1
nmax (KBr) cmϪ1: 1826, 1657, 1359, 1182, 1004, 984, 756, 698, 670. H-
NMR (CDCl3) d: 7.79—7.10 (14H, m, aromatic H), 4.45 (1H, d, Jϭ9.9 Hz,
3-HH), 4.37 (1H, d, Jϭ10.0 Hz, 3-HH), 3.12 (1H, d, Jϭ13.2 Hz, Ph–CHH),
3.04 (1H, d, Jϭ13.4 Hz, Ph–CHH–), 2.39 (3H, s, –CH3). 13C-NMR (CDCl3)
d: 176.0 (1-COOH), 161.4 (Ph–CO–NH–), 144.9 (aromatic C), 132.7 (aro-
matic C), 132.2 (aromatic C), 129.9 (aromatic C), 129.6 (aromatic C), 128.4
(aromatic C), 128.2 (aromatic C), 128.1 (aromatic C), 127.9 (aromatic C),
127.8 (aromatic C), 127.7 (aromatic C), 127.4 (aromatic C), 124.9 (aromatic
C), 73.6 (3-C), 70.5 (2-C), 39.2 (Ph–CH2–), 21.6 (–CH3). Anal. Calcd for
C24H23NO6S: C, 63.56; H, 5.11; N, 3.09. Found: C, 63.82; H, 4.94; N, 3.22.
(R)-8: Yield, 8.16 g (90.0%); mp 98—99 °C; [a]D20 ϩ119° (cϭ1.00,
methanol). Anal. Calcd for C24H23NO6S: C, 63.56; H, 5.11; N, 3.09. Found:
C, 63.91; H, 4.99; N, 3.12. The 1H-, 13C-NMR and IR spectra of (R)-8 were
virtually identical to those of (S)-8.
Optical Resolution of (RS)-2-Benzoylamino-2-benzyl-3-hydroxy-
propanoic Acid [(RS)-2] by Separation of Diastereoisomeric Salts with
Cinchonidine (7) (RS)-2 (59.9 g, 0.200 mol) and 7 (58.9 g, 0.200 mol)
were dissolved in 390 ml of ethanol on heating. After stirring the solution in
an ice bath for 6 h, the precipitated (S)-2·7 salt was collected by filtration;
yield, 58.8 g; [a]D20 Ϫ124° (cϭ1.00, methanol). The filtrate was evaporated
to dryness in vacuo at 30 °C to give the (R)-2·7 salt as the residue; yield,
56.6 g; [a]D20 Ϫ11.0° (cϭ1.00, methanol). After stirring each suspension of
(S)-2·7 salt (59.2 g) and (R)-2·7 salt (56.3 g) in 1 mol dmϪ3 hydrochloric
acid (3.4 ml gϪ1) in an ice bath for 30 min, the precipitated (S)- and (R)-2
were collected by filtration in yields of 28.5 and 27.1 g; (S)-2, [a]D20 Ϫ65.0°
(cϭ1.00, methanol); (R)-2, [a]D20 ϩ61.8° (cϭ1.00, methanol). The obtained,
respectively, (S)- and (R)-2 were recrystallization from ethanol (5.7 ml gϪ1).
(S)-2: Yield, 22.1 g (73.8%); mp 172—173 °C (lit.,4) 176—177 °C); [a]D20
(R)- and (S)-2-Benzoylamino-2-methyl-3-phenylpropanoic Acid [(R)-
and (S)-10] After stirring a mixture of (S)-8 (4.54 g, 10.0 mmol), sodium
iodide (6.49 g, 50.0 mmol), and zinc powder (6.54 g, 100 mmol) in 50 ml of
dimethylformamide at 120 °C for 10 h, excess of sodium iodide and zinc
powder was removed by filtration. The filtrate was evaporated to dryness in
vacuo at 70 °C and then the residue was dissolved in 100 ml of ethyl acetate.
The solution was washed with 0.5 mol dmϪ3 hydrochloric acid (3ϫ50 ml)
and then water (3ϫ50 ml). After dried over magnesium sulfate, the organic
layer was evaporated to dryness in vacuo at 65 °C to give (R)-10 as the vis-
cous residue. (S)-10 was prepared from (R)-8, in a similar manner to (R)-10.
1
(R)-10: Yield, 2.12 g (74.9%). H-NMR (CDCl3) d: 7.68—7.13 (10H, m,
aromatic H), 3.63 (1H, d, Jϭ13.8 Hz, 3-HH), 3.41 (1H, d, Jϭ13.5 Hz, 3-
HH), 1.80 (3H, s, –CH3). 13C-NMR (CDCl3) d: 175.9 (1-COOH), 167.3
(Ph–CO–NH–), 136.1 (aromatic C), 134.2 (aromatic C), 131.1 (aromatic C),

1366
Vol. 50, No. 10
129.5 (aromatic C), 128.6 (aromatic C), 127.9 (aromatic C), 127.7 (aromatic of (RS)- and (S)-2 were measured at 10 °C similarly to the method described
C), 126.5 (aromatic C), 126.3 (aromatic C), 61.2 (2-C), 40.4 (3-C), 23.0 above. The solid 2 was filtered off, thoroughly dried, and the specific rotation
(–CH3).
was measured. The amounts of (R)- and (S)-2 in the solution were calculated
(S)-10: Yield, 2.05 g (72.4%). The 1H- and 13C-NMR spectra of (S)-10 based on the solubility of 2 and the specific rotation of the solid 2.
were virtually identical to those of (R)-10.
In preparation of the melting-point binary phase diagram, the melting
(R)- and (S)-2-Amino-2-methyl-3-phenylpropanoic Acid [(R)- and (S)-
points of the mixtures composed of (RS)- and (S)-2 were measured; after
1] The crude (R)-10 (5.67 g, 20.0 mmol) was refluxed in 100 ml of dissolving (RS)- and (S)-2 in an appropriate ratio in methanol, the mixtures
5 mol dmϪ3 hydrochloric acid for 10 h. After removing benzoic acid by filtra- were obtained by evaporating the solutions to dryness in vacuo. The melt-
tion, the filtrate was evaporated to dryness in vacuo at 70 °C to give (R)-1 ing-point binary phase diagram was prepared from the temperatures at the
hydrochloride, which was dissolved in 100 ml of methanol and then the solu- beginning and end of melting.
tion was adjusted with triethylamine to pH 7. The precipitated (R)-1 was col-
lected by filtration, washed with methanol, and dried. The obtained (R)-1
(3.47 g) was recrystallized from 50 ml of water.
Acknowledgments This research was financially supported by the Kan-
sai University Grant-in-Aid for the Faculty Joint Research Program, 2002.
(S)-1 was prepared from (S)-10, in a similar manner to (R)-1.
(R)-1: Yield, 3.16 g (82.1%); mp 277—279 °C (decomp) (lit.,4) 262— References and Notes
263 °C (decomp)); [a]D20 ϩ20.2° (cϭ1.00, water) (lit., [a]D20 ϩ19.0°
(cϭ0.51, water);3) [a]D20 ϩ6.3° (cϭ1.03, water);4) [a]D ϩ20.5° (cϭ1,
water)10)). IR nmax (KBr) cmϪ1: 3034, 1624, 1583, 1455, 1398, 1367, 1266,
1) Ohfune Y., Horikawa M., J. Syn. Org. Chem., 55, 982—993 (1997).
2) Lee M., Kim D. H., Bioorg. Med. Chem., 8, 815—823 (2000).
3) Davis F. A., Liu H., Reddy G. V., Tetrahedron Lett., 37, 5473—5476
(1996).
1
745, 702. H-NMR (D2O) d: 7.40—7.36 (3H, m, aromatic H), 7.28—7.25
(2H, m, aromatic H), 3.30 (1H, d, Jϭ14.3 Hz, 3-HH), 2.98 (1H, d,
Jϭ14.3 Hz, 3-HH), 1.55 (3H, s, –CH3). 13C-NMR (D2O) d: 176.7 (1-
COOH), 134.9 (aromatic C), 130.6 (aromatic C), 129.6 (aromatic C), 128.5
(aromatic C), 62.9 (2-C), 43.5 (3-C), 23.2 (–CH3). Anal. Calcd for
C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.14; H, 7.14; N, 7.53.
(S)-1: Yield, 3.09 g (80.3%); mp 276—279 °C (decomp); [a]D20 Ϫ20.1°
(cϭ1.00, water). Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 67.14; H, 7.14; N, 7.53. The 1H-, 13C-NMR, and IR spectra of (S)-
1 were virtually identical to those of (R)-1.
4) Olma A., Polish J. Chem., 70, 1442—1447 (1996).
5) Belokon Y., Kochetkov K. A., Churkina T. D., Ikonnikov N. S.,
Vyskocil S., Kagan H. B., Tetrahedron; Asymmetry, 10, 1723—1728
(1999).
6) Kaminski Z. J., Leplawy M. T., Zabrocki J., Synthesis, 1973, 792—793
(1973).
7) Eliel E. L., Wilen S. H., Mander L. N., “Stereochemistry of Organic
Compounds,” John Wiley and Sons, New York, 1994, pp. 297—464.
8) Fujimoto Y., Tatsuno T., Tetrahedron Lett., 1976, 3325—3326 (1976).
9) “Amino Acids and Peptides,” ed. Davies J. S., Chapman and Hall, Lon-
don, New York, 1985, p. 261.
Solubility and Phase Diagrams (RS)-2 (5.395 g) or (S)-2 (2.698 g) was
dissolved in 20 ml of ethanol at 50 °C. After vigorously stirring the solution
at 10 °C for 10 h, the precipitated 2 was rapidly collected by filtration and 10) Georg G. I., Guan X., Kant J., Tetrahedron Lett., 29, 403—406 (1988).
thoroughly dried. The solubility at 10 °C was calculated on the basis of the 11) (RS)-6 obtained by refluxing for 20 min: Yield, 4.09 g (72.5%); mp
weight of 2. Solubility: (RS)-2, 10.773 g (100 ml of ethanol)Ϫ1; (S)-2, 6.025 g
190—192 °C. (RS)-6 obtained by refluxing for 30 min: Yield, 3.93 g
(65.9%); mp 191—193 °C.
(100 ml of ethanol)Ϫ1
Preparating a solubility ternary phase diagram, the solubilities of mixtures
.