An unusual base-dependent α-alkylation and β-elimination of tert-butyl 2-phenyl-2-oxazoline-4-carboxylate: Practical synthesis of (±)-α-alkylserines and tert-butyl benzamidoacrylate

Article abstract of DOI:10.1016/j.tet.2004.03.041

Practical synthesis of (±)-α-alkylserines and tert-butyl benzamidoacrylate from tert-butyl 2-phenyl-2-oxazoline-4-carboxylate (6) were developed. The α-alkylation and β-elimination of 6 are dramatically dependent upon base conditions. The phase-transfer catalytic condition bearing solid KOH in toluene gives α-alkylation (up to >99%), and t-BuOK in DMF gives β-elimination (98%).

Full text of DOI:10.1016/j.tet.2004.03.041

Tetrahedron 60 (2004) 4243–4249
An unusual base-dependent a-alkylation and b-elimination of
tert-butyl 2-phenyl-2-oxazoline-4-carboxylate: practical synthesis
of (6)-a-alkylserines and tert-butyl benzamidoacrylate
*
Hyeung-geun Park, Jihye Lee, Myoung Joo Kang, Yeon-Ju Lee, Byeong-Seon Jeong,
*
Jeong-Hee Lee, Mi-Sook Yoo, Mi-Jeong Kim, Sea-hoon Choi and Sang-sup Jew
Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, San 56-1,
Sinllim-dong, Kwanak-gu, Seoul 151-742, South Korea
Received 24 January 2004; revised 15 March 2004; accepted 15 March 2004
Abstract—Practical synthesis of (^)-a-alkylserines and tert-butyl benzamidoacrylate from tert-butyl 2-phenyl-2-oxazoline-4-carboxylate
(6) were developed. The a-alkylation and b-elimination of 6 are dramatically dependent upon base conditions. The phase-transfer catalytic
condition bearing solid KOH in toluene gives a-alkylation (up to .99%), and t-BuOK in DMF gives b-elimination (98%).
q 2004 Published by Elsevier Ltd.
1. Introduction
hydrolysis under acidic conditions can provide a-alkyl-
serines. However, it usually requires a strong base (LDA)
and low temperature conditions below 250 8C for alkyl-
ation, otherwise b-elimination (4) and the following
Michael addition (5) are predominant.7l In the case of
n-BuLi at 2100 8C, only the corresponding n-butyl ketone
can be prepared by substitution (Scheme 2).8 Herein,
we report the unusual base dependent a-alkylation and
b-elimination in the oxazoline ester and the practical
reaction conditions for the selective synthesis of (^)-a-
alkylserines and tert-butyl benzamidoacrylate.
a-Alkylserines have been extensively studied, due to their
important roles in the fields of synthetic and biological
chemistry.1 As their quaternary carbon centers induce
preferable conformations in peptide backbones,2 a-alkyl-
serine moieties have been employed in the design of
biologically active peptidomimetics.3 In addition, a-alkyl-
serines are frequently found in several biologically active
natural products, such as mycestericins,4 (þ)-lactacystin,5
and (þ)-conagenin,6 and a-alkylserines themselves are
useful synthetic building blocks via chemical transform-
ations.1 A number of synthetic methods7 have been reported
for a-alkylserines. Among them, the alkylation of phenyl-
oxazoline derivatives of serine esters is the most practical
(Scheme 1).7l
Scheme 1.
The oxazoline moiety can not only provides sufficient
acidity to the a-hydrogen of the ester group, but also acts as
an excellent protecting group for both the amino and
hydroxyl groups in the serine ester. The following
Scheme 2.
2. Results and discussion
Keywords: a-Alkylserines; Benzamidoacrylate; Phase-transfer catalytic
alkylation.
As part of our program for the conformational studies of
the peptidomimetics bearing a-alkylserines, we needed
*
Corresponding authors. Tel.: þ8228807871; fax: þ8228729129;
e-mail address: hgpk@plaza.snu.ac.kr
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.03.041

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H. Park et al. / Tetrahedron 60 (2004) 4243–4249
Scheme 3.
practical synthetic methods for the various a-alkylserines.
So we adapted the a-alkylation of 2-phenyl-2-oxazoline-4-
carboxylic ester and investigated the practical reaction
conditions. As shown in Scheme 3, we chose the tert-butyl
ester 6 as the substrate, which might reduce the ester
hydrolysis in the practical base conditions, such as mild
alkali bases at 0 8C or room temperature.
employ a phase-transfer catalytic reaction. Surprisingly,
solid KOH in the presence of a catalytic amount of
tetrabutylammonium bromide (TBAB, 5 mol%) in toluene
afforded 7f in a very high chemical yield (99%), without any
b-elimination (entry 10). The high chemical yield could be
produced even at room temperature (98%, entry 11). The
replacement of solid KOH with 50% aq. KOH reduced the
chemical yield, due to low reaction rate (entry 12). The
hydrolysis of 7f with 6 N-HCl, followed by the purification
using ion-exchange resin afforded (^)-a-benzylserine in
98% yield.4m,12 Further investigations of the phase-transfer
catalytic alkylation with various alkyl halides, using the
above optimal reaction conditions,13 were performed. As
shown in Table 2, all the active alkyl halides (entry c–m)
performed a-alkylation in very high yield, but aliphatic
halides (entry a and b) provided relatively lower chemical
yield, which might be due to the low reactivity. The high
chemical yields indicate that phase-transfer catalytic
condition is very efficient for the synthesis of (^)-a-
alkylserines.
Substrate 6 is easily prepared by coupling ethyl benzimidate
and serine tert-butyl ester in 98% yield.9 To determine the
optimal alkylation conditions, the benzylation was per-
formed using tert-butyl 2-phenyl-2-oxazoline-4-carboxylate
6 along with benzyl bromide (5 equiv.), and various bases
10
(5 equiv.) in tetrahydrofuran at 0 8C. K2CO3 (entry 1)
and DBU11 (entry 2), which have been applied in the
a-epimerization of oxazoline esters, unexpectedly gave no
a-alkylation and b-elimination product. Interestingly, in
the series of tert-butoxide bases, the relative ratio of 7f
(a-alkylation) to 8 and 9 (b-elimination) depended on the
cation, as shown in Table 1. The a-benzylation increased as
follows: Liþ.Naþ.Kþ (entries 3–5). We assume that the
enhanced covalent bond character of the enolate inter-
mediate might contribute to the increase in a-alkylation. In
the case of solid alkali hydroxides, although they are weak
bases as compared to alkali tert-butoxides, they delivered 7f
in modest chemical yields (83%–85%), except for LiOH
(entries 6–8). Notably, 40% aq. tetrabutylammonium
hydroxide gave only 7f without any b-elimination products,
although the chemical yield was low because of partial
hydrolysis (entry 9). These results finally prompted us to
After the optimization of the selective a-alkylation, we
focused our attention toward optimizing the b-elimination
condition for tert-butyl benzamidoacrylate 8, which is one
of the versatile synthetic intermediates. There have been a
few synthetic methods for benzamidoacrylates, but gener-
ally they need several steps or gave relatively low chemical
yields.14 In Table 1 (entry 3), tert-BuOK showed the most
promising possibility for the selective b-elimination, but
there was still some amount of dimeric side product 9 via
Table 1. Optimal conditions for the alkylation of 6a
No
Base
Solvent
Temperature (8C)
Time
7f Yieldb (%)
8 Yieldb (%)
9 Yieldb (%)
c
1
2
3
4
5
6
7
8
K2CO3
DBUc
DMF/t-BuOH
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
rt
rt
0
0
0
0
0
rt
0
0
rt
0
12 h
12 h
0
0
0
0
0
83
43
18
0
0
0
0
0
0
0
5
9
10
3
3
0
0
0
t-BuOK
t-BuONa
t-BuOL
KOH
2 min
2 min
2 min
0.75 h
1.25 h
5 day
10 min
3 h
18
57
83
85
25
38
99
98
32
NaOH
LiOH
9
40% aq. n-Bu4NOH
KOH/TBABd
10
11
12
PhCH3
PhCH3
PhCH3
KOH/TBABd
2 h
2 day
0
0
0
0
50% aq. KOH/TBABd
a
The reaction was carried out with 5.0 equiv. of benzyl bromide and 5.0 equiv. of base in tetrahydrofuran or toluene under the given conditions.
Isolated yields.
6 was recovered.
5 mol% of tetra-n-butylammonium bromide (TBAB) was used.
b
c
d

H. Park et al. / Tetrahedron 60 (2004) 4243–4249
4245
Table 2. Phase-transfer catalytic alkylationa
Entry
RX
Time (h)
Yieldb (%)
a
b
CH3I
CH3CH2I
2.5
1.0
65
52
c
d
e
0.4
0.4
0.4
.99
.99
.99
f
2.0
2.5
3.5
3.0
98
.99
99
g
h
i
98
j
1.0
92
k
l
0.2
1.0
80
96
m
0.5
95
a
The reaction was carried out with 5.0 equiv. of alkylating agent and 5.0 equiv. of solid KOH in toluene under the given conditions.
Isolated yields.
b
1,4-addition. To increase the selectivity for b-elimination,
various solvents were employed at the lower reaction
temperature (220 8C). As shown in Table 3, generally the
more polar aprotic solvent gave the higher selectivity for
b-elimination, which might be due to the stabilization of
the enolate intermediate by the solvation. Among the
solvents, DMF showed the best result in both the selectivity
and the chemical yield (98%), but no reaction was detected
in case of t-BuOH.
3. Conclusions
We founded the unusual base dependent a-alkylation and
b-elimination of tert-butyl 2-phenyl-2-oxazoline-4-carb-
oxylate (6). The a-alkylation and b-elimination are
dramatically dependent upon base conditions. The phase-
transfer catalytic condition in the presence of alkyl halides
could selectively give the corresponding a-alkylated
products in high yield. In case of t-BuOK, tert-butyl

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H. Park et al. / Tetrahedron 60 (2004) 4243–4249
Table 3. b-Elimination for benzamidoacrylatea
No
Solvent
8 Yieldb (%)
9 Yieldb (%)
1
2
3
4
THF
n-Hexane
DMF
t-BuOHc
91
50
98
0
2
8
0
0
a
The reaction was carried out with 1.1 equiv. of base in the corresponding solvent at 220 8C for 10 min.
Isolated yields.
6 was recovered.
b
c
benzamidoacrylate could be obtained in high yield by
4.2. General procedure for the phase-transfer catalytic
alkylations (7a-7m)
the selective b-elimination. The easy preparation of
substrate 6, the high chemical yields, and the very mild
reaction conditions could make these methods very prac-
tical for the synthesis of (^)-a-alkylserines and tert-butyl
benzamidoacrylate, which are very useful synthetic
intermediates.
To a toluene solution (0.80 mL) of 2-phenyl-2-oxazoline-4-
carboxylic acid tert-butyl ester 6 (50.0 mg, 0.200 mmol),
tetrabutylammonium bromide (3.2 mg, 0.01 mmol) and
KOH (56.1 mg, 1.00 mmol) was added the corresponding
alkyl halide (1.00 mmol) at 0 8C. The reaction mixture was
stirred at room temperature. After completion of the
reaction, the reaction mixture was diluted with ethyl acetate
(20 mL), washed with water (2£5 mL), dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc¼20:1) to afford the compounds 7a-7m.
4. Experimental
4.1. General
Infrared spectra were taken on a Perkin–Elmer 1710 FT-IR
spectrometer. Mass spectra were obtained on a VG Trios-2
4.2.1. 4-Methyl-2-phenyl-2-oxazoline-4-carboxylic acid
tert-butyl ester (7a). A pale yellow oil (34 mg, 65% yield);
1H NMR (300 MHz, CDCl3) d 8.01 (d, J¼7.3 Hz, 2H),
7.59–7.38 (m, 3H), 4.46 (d, J¼8.8 Hz, 1H), 4.11 (d, J¼
8.8 Hz, 1H), 2.30 (s, 3H), 1.47 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3) d 172.0, 164.7, 131.8, 128.7, 128.3,
127.0, 82.0, 76.2, 74.5, 27.9, 24.8 ppm; IR (KBr) 2978,
1729, 1645, 1452, 1287 cm21; MS (FAB) m/z 262 [MþH]þ;
HRMS calculated for C15H19NO3: 261.3163. Found:
262.1443 [MþH]þ.
1
GC-MS and JEOL JMS-700 instrument. H and 13C NMR
spectra were measured with a JEOL JNM-LA 300 and a
JEOL JNM-GCX 400 spectrometers using TMS as the
internal standard. Most reagents were obtained from
commercial suppliers and used without further purification
unless noted. Tetrahydrofuran was distilled from Na and
benzophenone, and methylenechloride from CaH2.
4.1.1. 2-Phenyl-2-oxazoline-4-carboxylic acid tert-butyl
ester (6). To a methylenechloride solution (60 mL) of
ethyl benzimidate hydrochloride (3.71 g, 20.0 mmol) and
L-serine tert-butyl ester hydrochloride (3.52 g, 20.0 mmol)
in methylenechloride was added triethylamine (5.58 mL,
40.0 mmol). The reaction mixture was refluxed for 2 h and
stirred for 10 h at room temperature. The reaction mixture
was diluted with methylenechloride (200 mL), washed with
sat. aq. NaHCO3 soln. (2£50 mL) and water (2£50 mL),
dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography
(silica gel, hexane/EtOAc¼9:1) to afford 6 (5.16 g, 98%
yield) as a white solid; mp: 42–45 8C; 1H NMR (300 MHz,
CDCl3) d 7.99 (d, J¼7.1 Hz, 2H), 7.53–7.36 (m, 3H), 4.84
(dd, J¼8.0, 10.5 Hz, 1H), 4.62–4.53 (m, 2H), 1.51 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3) d 170.3, 165.9, 131.6,
128.5, 128.1, 127.0, 82.0, 69.7, 69.3, 27.9 ppm; IR (KBr)
2979, 1734, 1644, 1453, 1364, 1298, 1222, 1156, 1089,
1026, 967, 846, 777, 696 cm21; MS (FAB) m/z 248
[MþH]þ; HRMS calculated for C14H17NO3: 247.1208.
Found: 248.1285 [MþH]þ.
4.2.2. 4-Ethyl-2-phenyl-2-oxazoline-4-carboxylic acid
tert-butyl ester (7b). A pale yellow oil (29 mg, 52%
1
yield); H NMR (300 MHz, CDCl3) d 7.99 (d, J¼8.3 Hz,
2H), 7.51–7.37 (m, 3H), 4.71 (d, J¼8.9 Hz, 1H), 4.21 (d,
J¼8.9 Hz, 1H), 1.95 (qd, J¼1.4, 7.5 Hz, 2H), 1.50 (s, 9H),
0.94 (t, J¼7.5 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) d
172.0, 164.1, 131.5, 128.5, 128.2, 127.4, 81.7, 78.9, 73.4,
31.0, 27.9, 8.0 ppm; IR (KBr): 2973, 2926, 1726, 1646,
1455, 1364, 1252, 1146, 1067, 1026, 971, 845, 778,
694 cm21; MS (ESI) m/z 276 [MþH]þ, 298 [MþNa]þ;
HRMS calculated for C16H21NO3: 275.1521. Found:
276.1600 [MþH]þ.
4.2.3. 4-Allyl-2-phenyl-2-oxazoline-4-carboxylic acid
tert-butyl ester (7c). A pale yellow oil (59 mg, .99%
1
yield); H NMR (300MHz, CDCl3) d 7.98 (d, J¼6.8 Hz,
2H), 7.52–7.38 (m, 3H), 5.80–5.66 (m, 1H), 5.20–5.13 (m,
2H), 4.70 (d, J¼8.8 Hz, 1H), 4.27 (d, J¼8.8 Hz, 1H), 2.76–
2.60 (m, 2H), 1.50 (s, 9H) ppm; 13C NMR (100 MHz,

H. Park et al. / Tetrahedron 60 (2004) 4243–4249
4247
CDCl3) d 171.3, 164.6, 131.9, 131.6, 128.6, 128.3, 127.2,
119.5, 82.0, 77.8, 73.1, 42.1, 27.9 ppm; IR (KBr) 2979,
1728, 1644, 1452, 1365, 1275, 1147, 1089, 1027, 978, 922,
846, 777, 696 cm21; MS (FAB) m/z 288 [MþH]þ; HRMS
calculated for C17H21NO3: 287.1521. Found: 288.1601
[MþH]þ.
(d, J¼9.1 Hz, 1H), 4.23 (d, J¼9.1 Hz, 1H), 3.35 (d, J¼
13.8 Hz, 1H), 3.18 (d, J¼13.8 Hz, 1H), 1.43 (s, 9H) ppm;
13C NMR (100 MHz, CDCl3) d 170.8, 165.0, 141.4, 131.8,
131.7, 131.1, 128.4, 128.2, 126.8, 118.7, 110.7, 82.5, 78.2,
73.3, 43.2, 27.8 ppm; IR (KBr) 2978, 2228, 1728, 1644,
1452, 1366, 1281, 1159, 1092, 979, 847, 759, 697 cm21
;
MS (FAB) m/z 363 [MþH]þ; HRMS calculated for
4.2.4. 4-(2-Methyl-allyl)-2-phenyl-2-oxazoline-4-carb-
oxylic acid tert-butyl ester (7d). A yellow oil (61 mg,
.99% yield); 1H NMR (300 MHz, CDCl3) d 7.95 (d,
J¼7.0 Hz, 2H), 7.45–7.34 (m, 3H), 4.85 (s, 1H), 4.82 (d,
J¼8.8 Hz, 1 H), 4.68 (s, 1H), 4.29 (d, J¼8.8 Hz, 1 H), 2.83
(d, J¼14.6 Hz, 1H), 2.53 (d, J¼14.6 Hz, 1H), 1.74 (s, 3H),
1.45 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) d 171.2,
164.2, 140.9, 131.5, 128.5, 128.2, 127.3, 114.3, 81.9, 77.9,
73.3, 45.5, 27.8, 23.9 ppm; IR (KBr) 2976, 2926, 1727,
1644, 1453, 1365, 1286, 1160, 1102, 978, 898, 846, 776,
695 cm21; MS (ESI) m/z 302 [MþH]þ, 324 [MþNa]þ;
HRMS calculated for C18H23NO3: 301.1678. Found:
302.1755 [MþH]þ.
C22H22N2O3: 362.1630. Found: 363.1696 [MþH]þ.
4.2.9. 4-(4-Fluoro-benzyl)-2-phenyl-2-oxazoline-4-carb-
oxylic acid tert-butyl ester (7i). A yellow caramel
1
(71 mg, 98% yield); H NMR (300 MHz, CDCl3) d 7.93
(d, J¼7.1 Hz, 2H), 7.51–7.37 (m, 3H), 7.26–7.21 (m, 2H),
6.96–6.88 (m, 2H), 4.63 (d, J¼8.8 Hz, 1H), 4.27 (d, J¼
8.8 Hz, 1H) 3.20 (dd, J¼13.9, 21.2 Hz, 2H), 1.47 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3) d 171.3, 164.7, 164.1
160.7, 131.9, 131.8, 131.6, 131.3, 128.5, 128.2, 127.1,
115.0, 114.8, 82.2, 78.6, 72.9, 42.3, 27.9 ppm; IR (KBr)
2978, 1726, 1644, 1510, 1366, 1279, 1224, 1160, 1101, 979,
846, 695 cm21; MS (FAB) m/z 356 [MþH]þ; HRMS
calculated for C21H22FNO3: 355.1584. Found: 356.1666
[MþH]þ.
4.2.5. 4-Prop-2-ynyl-2-phenyl-2-oxazoline-4-carboxylic
acid tert-butyl ester (7e). A pale yellow caramel (58 mg,
.99% yield); 1H NMR (300 MHz, CDCl3) d 7.97 (d,
J¼6.8 Hz, 2H), 7.51–7.36 (m, 3H), 4.85 (d, J¼8.8 Hz, 1H),
4.47 (d, J¼8.8 Hz, 1H) 2.95 (dd, J¼2.7, 16.7 Hz, 1H), 2.69
(dd, J¼2.7, 16.7 Hz, 1H), 1.95 (t, J¼2.7 Hz, 1H), 1.49 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3) d 170.0, 165.5,
131.8, 128.6, 128.2, 126.9, 82.5, 78.7, 77.4, 73.5, 71.0, 27.9,
27.8 ppm; IR (KBr): 2979, 1731, 1641, 1453, 1366, 1279,
1161, 1101, 978, 845, 695 cm21; MS (FAB) m/z 286
[MþH]þ; HRMS calculated for C17H19NO3: 285.1365.
Found: 286.1442 [MþH]þ.
4.2.10. 4-(4-tert-Butyl-benzyl)-2-phenyl-2-oxazoline-4-
carboxylic acid tert-butyl ester (7j). A pale yellow caramel
(73 mg, 92% yield); 1H NMR (300 MHz, CDCl3) d 8.05 (d,
J¼7.1 Hz, 2H), 7.51–7.36 (m, 3H), 7.26–7.16 (m, 4H),
4.67 (d, J¼8.9 Hz, 1H), 4.31 (d, J¼8.9 Hz, 1H), 3.22 (dd,
J¼13.8, 38.6 Hz, 2H), 1.46 (s, 9H), 1.26 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3) d 171.3, 164.5, 149.5, 132.5,
131.5, 129.9, 128.5, 128.1, 127.3, 125.0, 82.0, 78.9, 73.0,
42.8, 34.3, 31.2, 27.9 ppm; IR (KBr) 2964, 1723, 1644,
1454, 1365, 1278, 1161, 1091, 1025, 978, 847, 695 cm21
;
MS (FAB) m/z 394 [MþH]þ; HRMS calculated for
4.2.6. 4-Benzyl-2-phenyl-2-oxazoline-4-carboxylic acid
tert-butyl ester (7f). A pale yellow caramel (67 mg, 98%
C25H31NO3: 393.2304. Found: 394.2381 [MþH]þ.
1
yield); H NMR (300 MHz, CDCl3) d 7.94 (d, J¼7.1 Hz,
4.2.11. 4-(4-Methoxy-benzyl)-2-phenyl-2-oxazoline-4-
carboxylic acid tert-butyl ester (7k). A yellow oil
2H), 7.50–7.15 (m, 8H), 4.66 (d, J¼8.8 Hz, 1H), 4.31 (d,
J¼8.8 Hz, 1H), 3.25 (dd, J¼13.8, 46.7 Hz, 2H), 1.46 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3) d 171.3, 164.6, 135.6,
131.5, 130.3, 128.5, 128.1, 128.0, 127.2, 126.8, 82.1, 78.7,
72.8, 43.1, 27.8 ppm; IR (KBr) 2978, 1726, 1644, 1453,
1366, 1280, 1160, 1095, 978, 847, 697 cm21; MS (FAB)
m/z 338 [MþH]þ; HRMS calculated for C21H23NO3:
337.1678. Found: 338.1750 [MþH]þ.
1
(60 mg, 80% yield); H NMR (300 MHz, CDCl3) d 7.95
(d, J¼7.3 Hz, 2H), 7.50–7.36 (m, 3H), 7.17 (d, J¼8.5 Hz,
2H), 6.75 (d, J¼8.5 Hz, 2H), 4.65 (d, J¼8.8 Hz, 1H), 4.30
(d, J¼8.8 Hz, 1H), 3.72 (s, 3H), 3.19 (dd, J¼13.9, 17.8 Hz,
2H), 1.47 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) d
171.5, 164.5, 158.4, 131.5, 131.3, 128.6, 128.5, 128.2,
127.5, 113.5, 82.1, 78.9, 72.7, 55.1, 42.2, 27.9 ppm; IR
(KBr) 2929, 1726, 1643, 1513, 1455, 1365, 1252, 1160,
1091, 1033, 978, 846, 695 cm21; MS (FAB) m/z 368
[MþH]þ; HRMS calculated for C22H25NO4: 367.1784.
Found: 368.1856 [MþH]þ.
4.2.7. 4-(4-Trifluoromethylbenzyl)-2-phenyl-2-oxazo-
line-4-carboxylic acid tert-butyl ester (7g). A white solid
(82 mg, .99% yield); mp: 61–63 8C: 1H NMR (300 MHz,
CDCl3) d 7.94 (d, J¼7.1 Hz, 2H), 7.51–7.38 (m, 7H), 4.66
(d, J¼8.9 Hz, 1H), 4.26 (d, J¼8.9 Hz, 1H), 3.29 (dd, J¼
13.8, 25.1 Hz, 2H), 1.46 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) d 171.0, 165.0, 140.0, 131.8, 130.7, 129.3, 128.9,
128.5, 128.3, 127.0, 125.0, 82.5, 78.5, 73.2, 42.9, 27.8 ppm;
IR (KBr) 2979, 1728, 1645, 1452, 1366, 1327, 1281, 1163,
1121, 1066, 1023, 980, 849, 695 cm21; MS (FAB) m/z 406
[MþH]þ; HRMS calculated for C22H22F3NO3: 405.1552.
Found: 406.1634 [MþH]þ.
4.2.12. 4-(Naphthalene-2-ylmethyl)-2-phenyl-2-oxazo-
line-4-carboxylic acid tert-butyl ester (7l). A pale yellow
solid (75 mg, 96% yield); mp: 82–84 8C; 1H NMR
(300 MHz, CDCl3) d 7.95 (d, J¼7.3 Hz, 2H), 7.76–7.67
(m, 4H), 7.50–7.35 (m, 6H), 4.70 (d, J¼8.9 Hz, 1H), 4.38
(d, J¼8.9 Hz, 1H), 3.43 (s, 2H), 1.48 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3) d 171.4, 164.7, 133.3, 133.2, 132.3,
131.5, 129.0, 128.6, 128.5, 128.2, 127.6, 127.5, 127.4,
127.2, 125.8, 125.5, 82.2, 78.9, 72.8, 43.2, 27.9 ppm; IR
(KBr) 2977, 1726, 1643, 1452, 1365, 1280, 1159, 1092, 978,
846, 752, 696 cm21; MS (FAB) m/z 388 [MþH]þ; HRMS
calculated for C25H25NO3: 387.1834. Found: 388.1910
[MþH]þ.
4.2.8. 4-(4-Cyano-benzyl)-2-phenyl-2-oxazoline-4-carb-
oxylic acid tert-butyl ester (7h). A pale yellow needle
1
(73 mg, 99% yield); mp: 66–68 8C: H NMR (300 MHz,
CDCl3) d 7.91 (d, J¼8.5 Hz, 2H), 7.58–7.37 (m, 7H), 4.63

4248
H. Park et al. / Tetrahedron 60 (2004) 4243–4249
4.2.13. 4-(Anthracenyl-9-ylmethyl)-2-phenyl-2-oxazo-
line-4-carboxylic acid tert-butyl ester (7m). A yellow
solid (84 mg, 95% yield); mp: 102–104 8C; 1H NMR
(300 MHz, CDCl3) d 8.51–8.37 (m, 3H), 7.94–7.92 (m,
4H), 7.54–7.33 (m, 7H), 4.63–4.08 (m, 4H), 1.60 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3) d 172.5, 164.1, 131.5,
131.3, 131.2, 128.8, 128.3, 128.0, 127.8, 127.4, 127.0,
126.2, 125.5, 124.7, 82.3, 79.69, 72.0, 33.4, 27.9 ppm; IR
(KBr) 2977, 1723, 1645, 1451, 1230 cm21; MS (FAB) m/z
438 [MþH]þ; HRMS calculated for C29H27NO3: 437.1991.
Found: 438.2070 [MþH]þ.
Acknowledgements
This work was supported by a grant (01-PJ2-PG6-01NA01-
0002) from the Korea Health 21 R&D Project, Ministry of
Health and Welfare, Republic of Korea.
References and notes
1. (a) Wilson, E. M.; Snell, E. E. J. Biol. Chem. 1962, 237, 3180.
(b) Flynn, E. H.; Hinman, J. W.; Caron, E. L.; Woolf, D. O., Jr.
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T. H. Tetrahedron Lett. 1964, 5, 2451. (d) Wirth, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 225. (e) Cativiela, C.; Diaz-de-
Villegas, M. D. T. Tetrahedron: Asymmetry 1998, 9, 3517.
(f) Cativiela, C.; Diaz-de-Villegas, M. D. T. Tetrahedron:
Asymmetry 2000, 11, 645.
4.3. Dimeric Michael adduct: 4-(2-benzoylamino-2-tert-
butoxycarbonyl-ethyl)-2-phenyl-4,5-dihydro-oxazole-4-
carboxylic acid tert-butyl ester (9)
A yellow oil; 1H NMR (300 MHz, CDCl3) d 7.99–7.26 (m,
10H), 4.73 (d, J¼9.2 Hz, 1H), 4.61–4.54 (m, 1H), 4.27 (d,
J¼9.2 Hz, 1H), 2.62–2.25 (m, 2H), 1.42 (s, 9H), 1.35 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3) d 170.9, 170.6,
167.2, 165.3, 134.2, 133.7, 132.1, 131.4, 128.6, 128.2,
127.4, 126.9, 82.8, 81.6, 76.0, 74.4, 52.1, 39.1, 27.9,
27.8 ppm; IR (KBr) 2978, 1732, 1647, 1529, 1487, 1367,
1289, 1154 cm21; MS (FAB) m/z 495 [MþH]þ; HRMS
calculated for C28H34N2O6: 494.2417. Found: 495.2498
[MþH]þ.
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4.4. (6)-a-Benzylserine
To an ethanol solution (1.5 mL) of 4-benzyl-2-phenyl-2-
oxazoline-4-carboxylic acid tert-butyl ester 7f (500 mg,
1.48 mmol) was added 6 N-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-
exchange resin (Dowexw 50WX8-100) to give (^)-a-
benzylserine as a white solid (365 mg, 98%). Physical and
spectral properties were consistent with the literature
values.4m,12
3. (a) Barrett, G. C. Amino acids, peptides and proteins; The
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4.5. tert-Butyl benzamidoacrylate (8)
To a dimethylformamide solution (1.5 mL) of 2-phenyl-2-
oxazoline-4-carboxylic acid tert-butyl ester 6 (50.0 mg,
0.200 mmol) was added a dimethylformamide solution
(0.5 mL) of tert-BuOK (25 mg, 0.22 mmol) by dropwise
at 220 8C. The reaction mixture was stirred at 220 8C for
10 min. After completion of the reaction, the excess tert-
BuOK was quenched with a few drops of sat. aq. NH4Cl.
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diluted with ethyl acetate (50 mL), washed with water
(3£5 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The residue was purified by
column chromatography (silica gel, hexane/EtOAc¼5:1)
to afford 8 (49 mg, 98% yield) as a yellow needle; mp:
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(f) Obrecht, D.; Altorfer, M.; Lehmann, C.; Schonholzer, P.;
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1
66–68 8C; H NMR (300 MHz, CDCl3) d 8.58 (br, 1H),
7.83–7.80 (m, 2H), 7.53–7.40 (m, 3H), 6.69 (s, 1H), 5.88
(s, 1H), 1.53 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) d
165.6, 163.3, 134.4, 131.9, 128.7, 126.9, 107.8, 83.1, 60.4,
27.7 ppm; IR (KBr) 3418, 2976, 1677, 1519, 1370, 1338,
1159 cm21; MS (FAB) m/z 248 [MþH]þ; HRMS
calculated for C14H17NO3: 247.1208. Found: 248.1290
[MþH]þ.

H. Park et al. / Tetrahedron 60 (2004) 4243–4249
4249
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