Solid-phase synthesis of α-alkylserines via phase-transfer catalytic alkylation of polymer-supported 2-phenyl-2-oxazoline-4-carboxylate

Article abstract of DOI:10.1016/j.tet.2009.08.052

Described is the development of a new solid-phase synthetic method for α-alkylserines in which phase-transfer catalytic alkylation of polymer-supported 2-phenyl-2-oxazoline-4-carboxylate (12) is the key step. The easy preparation of the polymer-supported

Full text of DOI:10.1016/j.tet.2009.08.052

Tetrahedron 65 (2009) 8839–8843
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solid-phase synthesis of a-alkylserines via phase-transfer catalytic alkylation
of polymer-supported 2-phenyl-2-oxazoline-4-carboxylate
Jihye Lee a, Min Woo Ha a, Taek-Soo Kim a, Mi-Jeong Kim a, Jin-Mo Ku a, Sang-sup Jew a,
,
b,
*
Hyeung-geun Park a , Byeong-Seon Jeong
*
a Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2009
Received in revised form 21 August 2009
Accepted 21 August 2009
Available online 26 August 2009
Described is the development of a new solid-phase synthetic method for a-alkylserines in which phase-
transfer catalytic alkylation of polymer-supported 2-phenyl-2-oxazoline-4-carboxylate (12) is the key
step. The easy preparation of the polymer-supported substrate 12, the high chemical yield (up to 93%), and
the mild cleavage conditions could make this method very practical for the synthesis of a-alkylserines.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
prompted many researchers to apply PTC-mediated-solution-phase
reactions to solid-phase versions by using solid-supported-PTCs3 or
solid-supported substrates.4 As representative works on the poly-
mer-supported substrates (Fig. 1), O’Donnell and Scott developed
Since the pioneering work based on solid-supported resins by
Merrifield in 1963, solid-phase synthesis has been popularly ap-
plied to various synthetic methods, especially peptide synthesis.1
Ease of purification, fast synthetic processes, and automation have
granted this method an important role in combinatorial chemistry
and parallel synthesis for new drug development. A rapid growth of
the synthetic method using a phase-transfer catalyst (PTC) for the
efficient solid-phase synthetic methods for a-alkyl-a-amino acids
and peptides by the phase-transfer alkylation of resin-bound
N-(diphenylmethylene)glycine esters (ester linkage) 1.4 We recently
reported solid-phase synthetic methods for nonnatural
a-alkyl-
a-amino acids using resin-bound N-(benzylidene)glycine esters
preparation of unnatural
a
-amino acids in the last decade2 has
(imine linkage) 2 under phase-transfer catalytic alkylation condi-
tions.5 In this article, we report a new solid-phase synthetic system
for a-alkylserines using polymer-supported oxazoline-4-carboxylic
Solution-phase synthesis
acid derivatives.
O
O
O
PTC
Hydrolysis
alkylation
Ph
N
Ph
N
H2N
H2N
*
R
*
R
Ot-Bu
Ot-Bu
OH
Ph
Ph
2. Results and discussion
Solid-phase synthesis
We recently developed the efficient, novel substrate, 2-phenyl-
2-oxazoline-4-carboxylic acid tert-butyl ester (3), for the catalytic
O
O
O
PTC
Polymer
Ph
N
alkylation
detachment
Hydrolysis
*
R
enantioselective synthesis of
a-serine derivatives under phase-
Polymer
O
OH
OH
transfer conditions (Scheme 1).7
Ph
1
PTC
Polymer
O
N
alkylation
detachment
Asymmetric
PTC alkylation
Polymer
C
H2N
CO2t-Bu
CO2t-Bu
R
*
R
N
N
O
*
Ot-Bu
Hydrolysis
2
O
3
4
Figure 1. Phase-transfer catalytic synthesis of
a-amino acids.
H+
Hydrolysis
H2N
CO2H
R
*
OH
α-alkylserines
* Corresponding authors. Tel.: þ82 2 880 7871; fax: þ82 2 872 9129 (H.-G.P.); tel.:
þ82 53 810 2814; fax: þ82 53 810 4654 (B.-S.J.).
Scheme 1. Synthesis of a-alkylserines via solution-phase PTC alkylation.
E-mail addresses: hgpk@snu.ac.kr (H.-g. Park), jeongb@ynu.ac.kr (B.-S. Jeong).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.052

8840
J. Lee et al. / Tetrahedron 65 (2009) 8839–8843
Table 1
As part of our program for the conformational study of peptides
containing -alkylserines that can affect their conformations via
intramolecular hydrogen bonding,6 the solid-phase synthetic sys-
tem was needed for practical preparation of various -alkylserine
derivatives. Based on our previous solid-phase synthetic ap-
proaches5 and the O’Donnell and Scott’s method,4 both a 2-phenyl-
2-oxazoline linkage 5 and ester linkage 7 were designed, re-
spectively (Scheme 2).
Screening and optimization of reaction conditions for solid-phase alkylation via
a
phase-transfer catalysisa
O
O
a
n-Bu4NBr
N
O
N
O
PhCH2Br, base
O
M
M
Ph
Ph
CH2Ph
solvent, temp
O
12
13c
CO2Me
CH2Ph
N
O
NaOMe, MeOH
reflux, 6 h
Ph
O
O
R
PTC
alkylation
N
O
N
O
*
Ot-Bu
Ot-Bu
14c
Entry
Base (equiv)
Solvent
Temp
Time (h)
Yieldb (%)
5
6
1
2
3
4
5
Solid-KOH (5.0)
50% KOH (5.0)
50% CsOH (5.0)
BTPP (2.0)
PhMe
PhMe
PhMe
CH2Cl2
CH2Cl2
rt
rt
rt
24
24
24
24
12
dc
dc
dc
92
α-Alkylserines
0 ꢀ
rt
C
BTPP (2.0)
93
O
O
a
PTC
alkylation
Reaction was carried out with 5 equiv of benzyl bromide and 0.05 equiv of
tetrabutylammonium bromide.
N
O
N
*
O
O
b
R
Isolated yields for the two steps.
Some of the substrate was hydrolyzed.
O
c
7
8
Scheme 2. Solid-phase synthetic strategy of
a-alkylserines.
Table 2
Solid-phase catalytic alkylation of 12 under phase-transfer conditionsa
First,oxazoline-linkedresin-boundsubstrate5waspreparedfrom
carboxypolystyrene resin (4.5 mmol/g) and serine tert-butyl ester by
the reported methods.7d Coupling of the resin and serine tert-butyl
ester using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDC$HCl), followed by cyclization with dimethylamino-
sulfur trifluoride (DAST), gave the corresponding resin-bound
oxazoline tert-butyl ester 5. For evaluation of its suitability as a sub-
strate, catalytic benzylation of 5 under phase-transfer conditions in
the presence of tetrabutylammonium bromide, a PTC, followed by
hydrolysis with 6 M aq HCl was performed. However, unfortunately,
O
n-Bu4NBr
NaOMe
MeOH
reflux
6 h
CO2Me
R
N
O
N
O
electrophile
O
M
13
Ph
Ph
BTPP, CH2Cl2
rt, 12 h
12
14
Entry
1
Electrophile
Product
Yieldb (%)
85
CO2Me
N
Br
14a
Ph
Ph
O
CO2Me
N
O
onlyatraceamountof
various conditions.
a-benzylserinewasobtainedineverytrialwith
2
3
14b
14c
87
93
Br
Next, our attention was turned toward the ester linkage as in 7.
The ester-linked polymer-supported substrate 12 was prepared
from serine methyl ester HCl (9) in three steps with 42% overall yield
(Scheme 3). Coupling of 9 with ethyl benzimidate hydrochloride,
followed by hydrolysis with 1 M aq LiOH in THF gave 2-phenyl-2-
CO2Me
CO2Me
N
O
Ph
Ph
Br
N
O
.
NH HCl
1M-LiOH
HCl H2N
HO
CO2Me
Br
CO2Me
N
Ph
OEt
THF
4
5
14d
14e
92
92
Ph
rt, 0.5 h
93%
Me
Et3N, CH2Cl2
reflux, 3 h
90%
O
9
10
Me
CO2Me
N
O
O
Ph
Ph
Merrifield resin
KF, DMF
Br
CO2H
N
N
O
Ph
O
Ph
50 oC, 24 h
F
O
50%
12
0.47 mmol/g
F
11
CO2Me
N
O
O
R
n-Bu4NBr (5 mol%)
NaOMe
MeOH
N
Br
R-X, base
O
6
14f
91
90
Ph
O
solvent, temp
reflux
6 h
13
CO2Me
CO2Me
N
O
O
Ph
H2N
CO2H
R
CO2Me
N
7
14g
6M-HCl
reflux
MeO
Ph
R
O
OH
α-alkylserines
-alkylserines via solid-phase PTC alkylation.
a
Reaction was carried out with 5 equiv of electrophile, 2 equiv of BTPP, and
0.05 equiv of tetrabutylammonium bromide.
14
Scheme 3. Synthesis of
b
a
Isolated yields for the two steps.

J. Lee et al. / Tetrahedron 65 (2009) 8839–8843
8841
oxazoline-4-carboxylic acid (11). O-Alkylation of 11 with Merrifield
resin using potassium fluoride base in DMF at 50 ꢀC provided ester
linkage substrate 12.
Catalytic phase-transfer benzylations of 12 were performed using
5 mol % of tetrabutylammonium bromide, along with benzyl bro-
mide (5 equiv) under various kinds of bases and solvent conditions
(Table 1). Chemical yields were calculated with methyl 4-benzyl-2-
phenyl-2-oxazoline-4-carboxylate (14c, R¼CH2Ph) released by the
methanolysis of the benzylated product 13c (R¼CH2Ph) with cata-
lytic amount of sodium methoxide in methanol.
solution-phase synthetic version (i.e., the benzylation of 3).7b Only
42% enantiomeric excess was the highest one even with 1.0 equiv of
the best PTC 18. We speculate that the tert-butyl group of the
oxazoline-4-carboxylate system in solution-phase system might be
more sensitive compared to the N-(diphenylmethylene)glycinate
regarding enantioselectivity.
3. Conclusion
An efficient, new solid-phase synthetic method for a-alkylserines
The catalytic phase-transfer benzylation was dramatically de-
pendent on the base conditions. While none of the alkali bases
employed in toluene led any benzylation (entries 1–3), tert-buty-
liminotris(pyrrolidino)phosphorane (BTPP),7e a strong non-metal-
lic, non-ionic, and low-nucleophilic phosphazene base, gave high
chemical yields (entry 4, 92% and entry 5, 93%) insensitive to re-
action temperature. The benzylated product 14c could be success-
was developed. Catalytic phase-transfer alkylation of the Merrifield
resin-supported 2-phenyl-2-oxazoline-4-carboxylate (12) smoothly
afforded the alkylated products in high chemical yields under mild
reaction conditions. A phosphazene base, BTPP was found to be
effective to make the alkylation possible, while alkali hydroxides
were not. The ease in the preparation of the polymer-bound sub-
strate, high chemicalyields, and mild reaction conditions could make
fully hydrolyzed in 6 M aq HCl to give
a-benzylserine in 98% yield.
this method suitable for the combinatorial synthesis of a-alkylser-
Further investigation for scope and limitation of this solid-phase
synthetic system with several alkyl halides under optimal reaction
conditions (entry 5 in Table 1) was performed. As shown in Table 2,
high chemical yields (85–93%) were observed in allylic and benzylic
halides, but less active aliphatic halides provided poor results (data
not shown). The optimized solid-phase alkylation system was
successively applied to the Michael addition as well (entry 7, 90%).
We then turned our attention toward asymmetric version by
employing chiral PTCs instead of tetrabutylammonium bromide.
Representative four kinds of quaternary ammonium salts (15,8 16,9
17,10 1811) were employed as chiral PTCs for enantioselective phase-
transfer catalytic benzylations of 12. As shown in Table 3, relatively
low enantioselectivity was obtained, even in the case of catalyst 18,
which gave quite high enantioselectivity in the corresponding
ines. In addition, preliminary attempt on the asymmetric alkylation
of 12 with several representative chiral PTCs indicates that an in-
tensive systematic investigation will be required to search the best-
fit chiral catalyst for this solid-phase synthetic system.
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR-300E and
Perkin–Elmer 1710 FT spectrometer. Nuclear magnetic resonance
(1H NMR and 13C NMR) spectra were measured on a JEOL JNM-LA
300 [300 MHz (1H), 75 MHz (13C)] spectrometer and JEOL JNM-GSX
400 [400 MHz (1H), 100 MHz (13C) spectrometer, using CHCl3-d or
CH3OH-d or H2O-d as a solvent, and were reported in parts per
million relative to CHCl3-d (
4.80) for 1H NMR and relative to the CHCl3-d (
d (
49.15) or H2O-d (NA) resonance for 13C NMR. Coupling con-
d
7.24) or CH3OH-d (
d 4.87) or H2O-d
Table 3
(d
d
77.23) or CH3OH-
Asymmetric version of the solid-phase catalytic benzylation under phase-transfer
conditionsa
d
stants (J) in 1H NMR are in hertz. Low-resolution mass spectra (MS)
were recorded on a VG Trio-2 GC–MS spectrometer. Melting points
were measured on a Buchi B-540 melting point apparatus. For thin-
layer chromatography (TLC) analysis, Merck precoated TLC plate
(silica gel 60 GF254, 0.25 mm) was used. For column chromatog-
raphy, Merck Kieselgel 60 (70–230 mesh) was used.
O
chiral PTC
PhCH2Br
NaOMe
MeOH
CO2Me
CH2Ph
N
O
N
O
*
O
M
13c
Ph
Ph
BTPP, CH2Cl2
0 °C, 24 h
reflux
6 h
12
14c
HCD
HCD HCD
HCD
F
F
F
F
4.2. 2-Phenyl-2-oxazoline-4-carboxylic acid methyl ester (10)
F
F
Br
To a CH2Cl2 solution (60 mL) of ethyl benzimidate$HCl (3.71 g,
20.0 mmol) and L-serine methyl ester HCl (3.11 g, 20.0 mmol) was
F
15
16
17
N
added triethylamine (5.58 mL, 40.0 mmol), and the mixture was
refluxed for 3 h. The reaction mixture was diluted with CH2Cl2
(200 mL), washed with saturated NaHCO3 solution (2ꢁ50 mL) and
water (2ꢁ50 mL), dried over anhydrous MgSO4, filtered, and con-
centrated. The residue was purified by column chromatography
(silica gel, hexane/EtOAc¼9:1) to afford 9 (3.69 g, 90% yield) as
HCD =
Br
N+
F
O
F
N
18
colorless caramel. 1H NMR (300 MHz, CDCl3):
d
7.96 (d, J¼7.3 Hz,
2H), 7.52–7.34 (m, 3H), 4.91 (t, J¼14.6 Hz, 1H), 4.71–4.49 (m, 2H),
3.76 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
171.5, 166.1, 131.7,
Entry
PTC (equiv)
Yieldb (%)
eec (%)
Config.d
d
1
2
3
4
5
15 (0.1)
16 (0.1)
17 (0.1)
18 (0.05)
18 (1.0)
65
84
72
85
87
0
4
17
20
42
d
R
R
S
128.4, 128.2, 126.8, 69.4, 68.4, 52.6 ppm; IR (KBr) 2954, 1742, 1643,
1447, 1362, 1298, 1210, 1089, 972, 780, 698 cmꢂ1; MS (FAB) m/z 206
[MþH]þ; HRMS calculated for C11H11NO3: 205.0739; found:
206.0811 [MþH]þ.
S
a
Reaction condition was the same as Table 2, except catalyst and reaction
temperature.
4.3. 2-Phenyl-2-oxazoline-4-carboxylic acid (11)
b
Isolated yields for the two steps.
Enantiopurity was determined by HPLC analysis of 14c using a chiral column
c
To a THF solution (60 mL) of 2-phenyl-2-oxazoline-4-carboxyl-
ate methyl ester (10) (3.69 g, 18.0 mmol) was added 1 M LiOH so-
lution (60 mL, 60.0 mmol), and the mixture was stirred for 0.5 h at
(Chiralcel OD) with hexanes/2-propanol as the eluent.
d
Absolute configuration was assigned by comparison of the specific optical
rotation of a
-benzylserine from the hydrolysis of 14c with the literature value.7b

8842
J. Lee et al. / Tetrahedron 65 (2009) 8839–8843
room temperature. The reaction mixture was concentrated, acidi-
fied with 1 M HCl solution, extracted with EtOAc (4ꢁ200 mL), dried
over anhydrous MgSO4, filtered, and concentrated to afford 11 as
a white solid (3.20 g, 93% yield). 1H NMR (300 MHz, DMSO-d6):
244 [MþH]þ; HRMS calculated for C14H14NO3: 243.0895; found:
244.0974 [MþH]þ.
4.6.3. 4-Benzyl-2-phenyl-2-oxazoline-4-carboxylic acid methyl ester
d
7.95–7.92 (m, 2H), 7.65–7.51 (m, 3H), 4.94–4.88 (m, 1H), 4.67–4.56
(14c). Pale yellow oil (25.9 mg, 93%). 1H NMR (300 MHz, CDCl3):
(m, 2H) ppm; 13C NMR (100 MHz, DMSO-d6):
d
175.1, 169.0, 134.1,
d
8.00–7.97 (m, 2H), 7.53–7.12 (m, 8H), 4.76 (ABq, J¼9.0 Hz,1H), 4.41
131.7, 130.5, 130.4, 72.3, 70.0 ppm; IR (KBr) 3437, 2417, 1717, 1631,
1496, 1450, 1377, 1321, 1239, 1111, 1028, 955, 783, 701, 419 cmꢂ1; MS
(FAB) m/z 192 [MþH]þ; HRMS calculated for C10H9NO3: 191.0582;
found: 192.0658 [MþH]þ.
(ABq, J¼9.0 Hz, 1H), 3.78 (s, 3H), 3.36 (ABq, J¼13.8 Hz, 1H), 3.21
(ABq, J¼13.8 Hz,1H) ppm; 13C NMR (100 MHz, CDCl3):
d 173.0,164.9,
134.9, 131.7, 130.2, 128.5, 128.3, 128.2, 127.0, 126.9, 78.5, 72.6, 52.7,
43.5 ppm; IR (KBr): 2923, 1737, 1644, 1496, 1451, 1362, 1268, 1213,
1094, 1027, 979, 698 cmꢂ1; MS (FABþ): m/z 296 [MþH]þ; HRMS
calculated for C18H18NO3: 295.1208; found: 296.1287 [MþH]þ.
4.4. Merrifield resin-supported 2-phenyl-2-oxazoline-4-
carboxylate (12)
4.6.4. 4-(4-Methylbenzyl)-2-phenyl-2-oxazoline-4-carboxylic
methyl ester (14d). Colorless caramel (26.9 mg, 92%). 1H NMR
(300 MHz, CDCl3): 7.94–7.91 (m, 2H), 7.48–7.35 (m, 3H), 7.09–7.01
acid
To a DMF solution (30 mL) of 2-phenyl-2-oxazoline-4-carboxy-
lic acid (11) (1.35 g, 7.05 mmol) were added Merrifield resin (5.0 g,
0.94 mmol/g, purchased from BEADTECH in Korea) and potassium
fluoride (0.82 g, 14.1 mmol). The reaction mixture was vigorously
shaken at 50 ꢀC for 24 h. The resin was then filtered and succes-
sively washed with DMF, 50% aq DMF solution, water, 50% aq
MeOH, and finally MeOH. Pale yellow resin 12 was obtained after
drying in vacuo (50%, 0.47 mmol/g). IR (KBr) 3435, 3024, 2919,1638,
d
(m, 4H), 4.71 (ABq, J¼9.0 Hz, 1H), 4.34 (ABq, J¼9.0 Hz, 1H), 3.79 (s,
3H), 3.24 (s, 2H), 2.26 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
173.2, 194.9, 136.6, 131.9, 131.7, 130.1, 129.0, 128.5, 128.2, 127.1,
78.8, 72.6, 52.7, 43.2, 21.0 ppm; IR (KBr): 2923, 1737, 1644, 1514,
1449, 1362, 1266, 1212, 1091, 1026, 979, 814, 777, 695 cmꢂ1; MS
(FABþ): m/z 310 [MþH]þ; HRMS calculated for C19H20NO3:
309.1365; found: 310.1443 [MþH]þ.
1491, 1448, 1024, 754, 697, 537 cmꢂ1
.
4.6.5. 4-(4-Fluorobenzyl)-2-phenyl-2-oxazoline-4-carboxylic acid methyl
ester (14e). Pale yellow caramel (27.2 mg, 92%). 1H NMR (300 MHz,
4.5. General procedure for solid-phase alkylation of the solid-
supported substrate 12
CDCl3):
d 7.92–7.89 (m, 2H), 7.50–7.35 (m, 3H), 7.19–7.14 (m, 2H),
6.94–6.86 (m, 2H), 4.69 (ABq, J¼9.0 Hz,1H), 4.31 (ABq, J¼9.0 Hz,1H),
3.78 (s, 3H), 3.26 (d, J¼13.7 Hz, 1H), 3.15 (d, J¼13.7 Hz, 1H) ppm; 13C
To a mixture of the Merrifield resin-supported 2-phenyl-2-
oxazoline-4-carboxylate (12) (200 mg, 0.47 mmol/g) and tetrabutyl-
ammonium bromide (1.5 mg, 0.0047 mmol) in CH2Cl2 were added
BTPP (0.057 mL, 0.188 mmol) and electrophile (0.47 mmol) at 25 ꢀC.
The reaction mixture was stirred for 12 h. The resin was then fil-
tered and washed with a series of solvents: CH2Cl2, water, and
methanol. Pale yellow alkylated resin 13 was obtained after drying
in vacuo. A mixture of 13 and sodium methoxide (0.51 mg,
0.0094 mmol) in methanol was refluxed for 6 h. The reaction
mixture was filtered and washed with MeOH and CH2Cl2. The
filtrate was then concentrated. The residue was diluted with CH2Cl2
(50 mL), washed with water (2ꢁ10 mL), dried over anhydrous
MgSO4, filtered, and concentrated. The residue was purified by
column chromatography on silica gel (hexanes/EtOAc¼10:1) to af-
ford 14.
NMR (100 MHz, CDCl3): d 173.1, 165.1, 131.9,131.8, 131.7, 130.8, 130.7,
128.5, 128.3, 126.9, 115.2, 115.0, 78.5, 72.7, 52.8, 42.7 ppm; IR (KBr):
2954, 1737, 1644, 1604, 1510, 1447, 1362, 1268, 1221, 1100, 1025, 980,
844, 783, 695 cmꢂ1; MS (FABþ): m/z 314 [MþH]þ; HRMS calculated
for C18H17FNO3: 313.1114; found: 314.1192 [MþH]þ.
4.6.6. 4-Naphthalen-2-ylmethyl-2-phenyl-2-oxazoline-4-carboxylic
acid methyl ester (14f). Pale yellow caramel (29.6 mg, 91%). 1H NMR
(300 MHz, CDCl3): d 7.93–7.90 (m, 2H), 7.77–7.65 (m, 4H), 7.49–7.33
(m, 6H), 4.75 (ABq, J¼9.0 Hz, 1H), 4.41 (ABq, J¼9.0 Hz, 1H), 3.80 (s,
3H), 3.45 (d, J¼13.7 Hz, 1H), 3.39 (d, J¼13.7 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3): d 173.2,165.1,133.3,132.7,132.4,131.7,129.1,128.5,
128.4, 128.3, 127.8, 127.6, 127.5, 127.0, 126.0, 125.7, 78.8, 72.6, 52.8,
43.7 ppm; IR (KBr): 2924, 1736, 1643, 1446, 1362, 1265, 1214, 1092,
1025, 980, 822, 749, 696 cmꢂ1; MS (FABþ): m/z 346 [MþH]þ; HRMS
calculated for C22H20NO3: 345.1365; found: 346.1443 [MþH]þ.
4.6. Spectroscopic characterization of the alkylated
compounds 14
4.6.7. 4-(2-Methoxycarbonyl-ethyl)-2-phenyl-2-oxazoline-4-carboxy-
4.6.1. 4-Allyl-2-phenyl-2-oxazoline-4-carboxylic acid methyl ester
lic acid methyl ester (14g). Pale yellow oil (24.6 mg, 90%). 1H NMR
(300 MHz, CDCl3): d 7.97–7.93 (m, 2H), 7.51–7.36 (m, 3H), 4.73 (ABq,
(14a). Pale yellow oil (19.6 mg, 85%). 1H NMR (300 MHz, CDCl3):
d
7.97–7.94 (m, 2H), 7.50–7.36 (m, 3H), 5.75–5.61 (m, 1H), 5.19–5.12
(m, 2H), 4.76 (ABq, J¼9.0 Hz, 1H), 4.30 (ABq, J¼9.0 Hz, 1H), 3.79 (s,
3H), 2.75–2.29 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
173.0,
J¼9.2 Hz, 1H), 4.26 (ABq, J¼9.2 Hz, 1H), 3.78 (s, 3H), 3.63 (s, 3H),
2.51–2.32 (m, 3H), 2.21–2.12 (m, 1H) ppm; 13C NMR (100 MHz,
d
CDCl3): d 173.2,173.0,165.3,132.0,129.6,128.7,128.3, 64.2, 68.6, 52.9,
164.9, 131.8, 131.5, 128.6, 128.3, 127.0, 120.0, 77.6, 73.0, 52.8,
42.3 ppm; IR (KBr): 2925, 2854, 1738, 1643, 1450, 1363, 1269, 1217,
1093, 1027, 980, 925, 698 cmꢂ1; MS (FABþ): m/z 246 [MþH]þ;
HRMS calculated for C14H16NO3: 245.1052; found: 246.1130
[MþH]þ.
51.8, 33.2, 28.8 ppm; IR (KBr): 2924, 2852, 1737, 1645, 1448, 1365,
1267, 1105, 1026, 981, 780, 698 cmꢂ1; MS (FABþ): m/z 292 [MþH]þ;
HRMS calculated for C15H18NO5: 291.1107; found: 292.1185 [MþH]þ.
4.7. Hydrolysis of 14c: a-benzylserine
4.6.2. 4-Propagyl-2-phenyl-2-oxazoline-4-carboxylic acid methyl
To an ethanol solution (1.5 mL) of 4-benzyl-2-phenyl-2-oxazo-
line-4-carboxylic acid tert-butyl ester 14c (500 mg, 1.48 mmol) was
added 6 M HCl (1.5 mL) and the reaction mixture was refluxed for
24 h. After the solvent was removed in vacuo, the residue was
purified by column chromatography (5% aq NH4OH) using ion-ex-
ester (14b). Pale yellow caramel (20.0 mg, 87%). 1H NMR (300 MHz,
CDCl3):
d
7.96–7.93 (m, 2H), 7.50–7.36 (m, 3H), 4.89 (ABq, J¼9.2 Hz,
1H), 4.50 (ABq, J¼9.2 Hz, 1H), 3.80 (s, 3H), 2.97 (ABq, J¼16.7 Hz, 1H),
2.73 (ABq, J¼16.7 Hz, 1H), 1.97 (t, J¼3.5 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3):
d
171.7, 165.8, 131.9, 128.7, 128.3, 126.8, 78.3, 77.2,
change resin (DowexÒ 50WX8-100) to give (ꢃ)-
a-benzylserine as
73.4, 71.3, 53.1, 28.0 ppm; IR (KBr): 3295, 2955, 1740, 1642, 1450,
a white solid (283 mg, 98%). Physical and spectral properties were
1364, 1269, 1215, 1098, 1026, 980, 777, 696 cmꢂ1; MS (FABþ): m/z
consistent with the literature values.7a Chiral 14c (42% ee, entry 5 in

J. Lee et al. / Tetrahedron 65 (2009) 8839–8843
8843
4. (a) O’Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070;
(b) Scott, W. L.; Zhou, C.; Fang, Z.; O’Donnell, M. J. Tetrahedron Lett. 1997,
38, 3695; (c) O’Donnell, M. J.; Lugar, C. W.; Pottorf, R. S.; Zhou, C. Tetra-
hedron Lett. 1997, 38, 7163; (d) Griffith, D. L.; O’Donnell, M. J.; Pottorf, R. S.;
Scott, W. L.; Porco, J. A., Jr. Tetrahedron Lett. 1997, 38, 8821; (e) Dorminguez,
E.; O’Donnell, M. J.; Scott, W. L. Tetrahedron Lett. 1998, 39, 2167; (f) O’Donnell,
M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347; (g) O’Donnell, M. J.;
Delgado, F.; Drew, M.; Pottorf, R. S.; Zhou, C.; Scott, W. L. Tetrahedron Lett.
1999, 40, 5831; (h) O’Donnell, M. J.; Delgado, F.; Dorminguez, E.; Blas, J. D.; Scott,
W. L. Tetrahedron: Asymmetry 2001, 12, 821; (i) Scott, W. L.; Delgado, F.; Lobb, K.;
Pottorf, R. S.; O’Donnell, M. J. Tetrahedron Lett. 2001, 42, 2073; (j) O’Donnell, M. J.;
Alsiana, J.; Scott, W. L. Tetrahedron Lett. 2003, 44, 8403.
Table 3) also was hydrolyzed by the same procedure to afford
enantiomerically enriched (S)-(þ)-
a-benzylserine as a white solid.
þ16.4 (c 0.81, H2O)]. The physical
20
20
[
a]
þ6.7 (c 0.50, H2O) [lit.7b
[a
]
D
D
and spectral properties were consistent with the literature values.7b
Acknowledgements
This work was supported by the SRC/ERC program of MOST/
KOSEF (R11-2007-107-02001-0).
5. (a) Park, H.-g.; Kim, M. J.; Park, M.-k.; Jung, H.-j.; Lee, J.; Choi, S.-h.; Lee, Y.-J.;
Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Ku, J.-M.; Jew, S.-s. J. Org. Chem. 2005, 70,
1904; (b) Kim, M. J.; Jew, S.-s.; Park, H.-g.; Jeong, B.-S. Eur. J. Org. Chem. 2007,
2490.
References and notes
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