Enantioselective synthetic method for α-alkylserine via phase-transfer catalytic alkylation of 2-phenyl-2-oxazoline-4- carbonylcamphorsultam

Article abstract of DOI:10.1021/jo050197j

An enantioselective synthetic method for α-alkylserines by the phase-transfer catalytic alkylation of 2-phenyl-2-oxazoline-4- carbonylcamphorsultam (4a) was developed. The phase-transfer catalytic a-alkylation of 4a using P2-Et at -78 °C gave α-alkylation

Full text of DOI:10.1021/jo050197j

structures.4 A number of enantioselective synthetic meth-
ods have been reported for chiral R-alkylserines so far,
but only a few are practical.5
Enantioselective Synthetic Method for
r-Alkylserine via Phase-Transfer Catalytic
Alkylation of 2-Phenyl-2-oxazoline-4-
carbonylcamphorsultam
Recently, we reported a new synthetic method for (()-
R-alkylserines by the selective R-alkylation of tert-butyl
2-phenyl-2-oxazoline-4-carboxylate (1) in phase-transfer
catalytic conditions (Scheme 1).6 As a successive study,
the enantioselective version using chiral phase-transfer
catalysts was also disclosed.7 Both works showed that
the phase-transfer catalytic condition is very efficient for
the R-alkylation of the oxazoline-4-carboxylate system.
In this note, we report a new enantioselective synthetic
method for R-alkylserines via phase-transfer catalytic
alkylation8 of the oxazoline-4-carboxylate, possessing
camphorsultam as a chiral auxiliary (4a).
Jihye Lee, Yeon-Im Lee, Myoung Joo Kang,
Yeon-Ju Lee, Byeong-Seon Jeong, Jeong-Hee Lee,
Mi-Jeong Kim, Ji-yeon Choi, Jin-Mo Ku,
Hyeung-geun Park,* and Sang-sup Jew*
Research Institute of Pharmaceutical Science and College of
Pharmacy, Seoul National University, Seoul 151-742, Korea
hgpk@plaza.snu.ac.kr
Received January 31, 2005
The use of a chiral auxiliary, in conjunction with
benzophenone imine glycine derivatives, has been studied
by a number of groups.9 Among them, Oppolzer’s sultam
was mostly employed for the enantioselective synthesis
of R-amino acids (3).9a-c We adapted the camphorsultam
as a chiral auxiliary to tert-butyl 2-phenyl-2-oxazoline-
An enantioselective synthetic method for R-alkylserines by
the phase-transfer catalytic alkylation of 2-phenyl-2-oxazo-
line-4-carbonylcamphorsultam (4a) was developed. The phase-
transfer catalytic R-alkylation of 4a using P2-Et at -78 °C
gave R-alkylation (75∼99%, 90∼97% de), which could be
easily hydrolyzed to R-alkylserines.
(4) (a) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.;
Toyama, R.; Yoneta, M.; Chiba, K.; Hosino, Y.; Okumoto, T. J. Antibiot.
1994, 47, 216. (b) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki,
K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113.
(c) Omura, S.; Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.;
Fujita, S.; Nakagawa, A. J. Antibiot. 1991, 44, 117. (d) Yamashita, T.;
lijima, M.; Nakamura, H.; Isshiki, K.; Naganawa, H.; Hattori, S.;
Hamada, M.; Ishizuka, M.; Takeuchi, T. J. Antibiot. 1991, 44, 557. (e)
Kawatsu, M.; Yamashita, T.; Ishizuka, M.; Takeuchi, T. J. Antibiot.
1995, 48, 222.
The enantioselective synthesis of chiral compounds is
an extremely formidable challenge to the synthetic chem-
ist. Chiral R-alkylserines have been regarded as impor-
tant components in the fields of synthetic and medicinal
chemistry.1 As their quaternary carbon centers play an
important role for their preferable conformations in
peptide backbones,2 chiral R-alkylserines have been
frequently employed in the design of new peptidomimetic
drugs.3 In addition, several biologically active natural
products have R-alkylserine moieties or the related
(5) Previous synthetic methods of chiral R-alkylserines are cited in
ref 7.
(6) Park, H.-g.; Lee, J.; Kang, M. J.; Lee, Y.-J.; Jeong, B.-S.; Lee,
J.-H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.-h.; Jew, S.-s. Tetrahedron 2004,
60, 4243.
(7) Jew, S.-s.; Lee, Y.-J.; Lee, J.; Kang, M. J.; Jeong, B.-S.; Lee, J.-
H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.-h.; Ku, J.-M.; Park, H.-g. Angew.
Chem., Int. Ed. 2004, 43, 2382.
* Phone: 82-2-880-8264. Fax: 82-2-872-9129.
(1) (a) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225. (b)
Cativiela, C.; Diaz-de-Villegas, M. D. T. Tetrahedron: Asymmetry 1998,
9, 3517. (c) Cativiela, C.; Diaz-de-Villegas, M. D. T. Tetrahedron:
Asymmetry 2000, 11, 645.
(8) For our recent reports on the enantioselective phase-transfer
catalytic alkylation, see: (a) Jew, S.-s.; Jeong, B.-S.; Yoo, M.-S.; Huh,
H.; Park, H.-g. Chem. Commun. 2001, 1244. (b) Park, H.-g.; Jeong,
B.-S.; Yoo, M.-S.; Park, M.-K.; Huh, H.; Jew, S.-s. Tetrahedron Lett.
2001, 42, 4645. (c) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park,
M.-K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002,
41, 3036. (d) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-
g. Org. Lett. 2002, 4, 4245. (e) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.;
Lee, J.-H.; Park, B.-s.; Kim, M. G.; Jew, S.-s. Tetrahedron Lett. 2003,
44, 3497. (f) Lee, Y.-J.; Lee, J.; Kim, M.-J.; Kim, T.-S.; Park, H.-g.;
Jew, S.-s. Org. Lett. 2005, 7, 1557.
(2) (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.; Cavicchioni,
G.; Pre´cigoux, G.; Aubry, A.; Kamphius, J. Biopolymers 1993, 33, 1061.
(b) Karle, I. L.; Rao, R. B.; Prasad, S.; Kaul, R.; Balaram, P. J. Am.
Chem. Soc. 1994, 116, 10355. (c) Formaggio, F.; Pantano, M.; Crisma,
M.; Bonora, G. M.; Toniolo, C.; Kamphius, J. J. Chem. Soc., Perkin
Trans. 2 1995, 1097. (d) Benedetti, E. Biopolymers 1996, 40, 3. (e)
Karle, I. L.; Kaul, R.; Rao, R. B.; Raghothama, S.; Balaram, P. J. Am.
Chem. Soc. 1997, 119, 12048.
(3) (a) Barrett, G. C. Amino Acids, Peptides and Proteins; The
Chemical Society: London, 1980; Vol. 13, p 1. (b) Hunt, S. In Chemistry
and Biochemistry of the Amino Acids; Barrett, G. C., Ed.; Chapman
and Hall: London, 1985; p 55. (c) Richardson, J. S. Biophysik. J. 1992,
63, 1186. (d) Mickos, H.; Sundberg, K.; Luning, B. Acta Chem. Scand.
1992, 46, 989. (e) Gante, J. Angew. Chem., Int. Ed. 1994, 33, 1699.
(9) (a) Josien, H.; Martin, A.; Chassaing, G. Tetrahedron Lett. 1991,
32, 6547. (b) Josien, H.; Chassaing, G. Tetrahedron: Asymmetry 1992,
3, 1351. (c) Josien, H.; Lavielle, S.; Brunissen, A.; Saffroy, M.; Torrens,
Y.; Beaujouan, J.-C.; Glowinski, J.; Chassaing, G. J. Med. Chem. 1994,
37, 1586. (d) Guillena, G.; Najera, C. Tetrahedron: Asymmetry 1998,
9, 3935.
10.1021/jo050197j CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/13/2005
4158
J. Org. Chem. 2005, 70, 4158-4161

SCHEME 1
TABLE 1. Optimal Base Conditions for Phase-Transfer Catalytic Alkylationa
entry
base
KOH
solvent
temp (°C)
time
yieldb (%)
de %c (configuration)d
1
2
PhCH3
PhCH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
1 h
1 h
1 h
3 h
26
0
20 (4S)
50% KOH
BEMP
BEMP
BEMP
BTPP
BTPP
BTPP
P2-Et
3
83
87
0e
91 (4S)
92 (4S)
4
-20
-40
0
5
24 h
6
1 h
3 h
82
88
0e
93 (4S)
93 (4S)
7
-20
-40
0
8
24 h
9
5 min
75
80
85
95
65 (4S)
82 (4S)
93 (4S)
97 (4S)
10
11
12
P2-Et
-20
-40
-78
5 min
5 min
5 min
P2-Et
P2-Et
a Reaction was carried out with benzyl bromide (5 equiv), base (2 equiv), and tetrabutylammonium bromide (10 mol %) in toluene or
methylene chloride. b Isolated yields. c Diastereoselectivity was determined by HPLC analysis of the benzylated oxazoline methyl ester
from the hydrolysis of 6e with 1 N LiOH, followed by methylation with excess diazomethane using a chiral column (DAICEL Chiralcel
OD-H) with hexane/2-propanol (volume ratio ) 99:1) as the eluent solvent; in this case, it was established by analysis of the racemate,
of which the enantioisomers were fully resolved. d Absolute configuration for C(4) was determined by comparison of the optical rotation
of R-benzylserine from the acidic hydrolysis of 6e with the reported value.7 e 4a was recovered.
SCHEME 2a
and various bases (2.0 equiv). During our investigation,
the enantioselective synthesis of R-methylcysteine using
2-phenyl-2-thiazoline-4-carbonylcamphorsultam (4b) was
independently reported by the Singh group.12 The meth-
ylation of 4b using n-BuLi and CH3I at -78 °C in the
presence of HMPA in tetrahydrofuran, followed by hy-
drolysis, provided R-methylcysteine (49%, 95% ee). How-
ever, in our oxazoline system (4a), n-BuLi or LDA in tet-
rahydrofuran at -78 °C gave no major product but many
unidentifiable products, which were similarly obtained
even in the presence of HMPA. The oxazoline-4-carboxy-
late moieties might be very sensitive to strong base
conditions. Generally, strong base conditions gave â-elim-
ination or substitution as major products in an oxazoline
system,6,4i,13 whereas both t-BuLi and t-BuOK in tetrahy-
drofuran at 0 °C gave no reaction, suggesting that their
steric hindrance inhibits the R-hydrogen abstraction to
form the corresponding enolate intermediate.
a Reagents and conditions: (a) (1S)-(-)-2,10-camphorsultam,
Al(CH3)3, PhCH3, 60 °C, 30 h, 94%. (b) RX, n-Bu4N+Br- (10 mol
%), base, toluene or CH2Cl2. (c) (i) 1 N LiOH, THF, rt, 10 min; (ii)
6 N HCl, EtOH, reflux, 12 h.
In the case of phase-transfer catalytic conditions (Table
1), 50% KOH in the presence of n-Bu4N+Br- led only to
hydrolysis, affording 2-phenyl-2-oxazoline-4-carboxylic
acid and (1S)-(-)-2,10-camphorsultam, but solid KOH
provided R-benzylation (6e) in low chemical yield (26%)
with poor diastereoselectivity (20% de14).
To enhance the diastereoselectivity, we finally at-
tempted to use Schwesinger bases15 (neutral nitrogen
bases) for phase-transfer catalytic alkylation. Surpris-
ingly, BEMP (entry 3, 91% de), BTPP (entry 6, 93% de),
and P2-Et (entry 9, 65% de) all gave R-benzylated product
4-carboxylate (1) and investigated the optimal reaction
conditions for the diastereoselective R-alkylation.
Substrate 4a was easily prepared by the coupling of
methyl 2-phenyl-2-oxazoline-4-carboxylate (5)10 with (1S)-
(-)-2,10-camphorsultam in the presence of trimethyl-
aluminum in 94% yield (Scheme 2).11 To determine the
optimal alkylation conditions, the benzylation was per-
formed using 4a along with benzyl bromide (5.0 equiv)
(10) Compound 5 was prepared from ethyl benzimidate and serine
methyl ester on the basis of previous methods6,7 (95%).
(11) (a) Basha, A.; Lipton, M.; Weinreb. S. M. Tetrahedron Lett.
1977, 18, 4171. (b) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron
Lett. 1989, 30, 6009.
(12) Singh, S.; Rao, S. J.; Pennington, M. W. J. Org. Chem. 2004,
69, 4555.
(13) Blarer, S. J. Tetrahedron Lett. 1985, 26, 4055.
J. Org. Chem, Vol. 70, No. 10, 2005 4159

TABLE 2. Phase-Transfer Catalytic Alkylationa
a Alkyl halides were varied using the conditions described in entry 12 of Table 1. b Isolated yields. c Diastereoselectivity was determined
by HPLC analysis of the alkylated oxazoline methyl ester from the hydrolysis of 6 with 1 N LiOH, followed by methylation with excess
diazomethane using a chiral column (DAICEL Chiralcel OD-H or AD-H) with hexane/2-propanol as the eluent solvent; in this case, it was
established by analysis of the racemate, of which the enantioisomers were fully resolved. d Absolute configuration of C(4) was tentatively
assigned to be 4S on the basis of the absolute configuration of 6e (Table 1).7
SCHEME 3a
a Reagents and conditions: (a) tert-butyl acrylate, n-Bu4N+Br-, P2-Et, CH2Cl2, -78 °C, 95%. (b) (i) 1 N LiOH, THF, rt; (ii) 6 N HCl,
EtOH, reflux, 93% from 9.
(1S)-(-)-2,10-camphorsultam (94%), which could be re-
cycled to prepare the substrate 4a. The hydrolysis of
2-phenyl-2-oxazoline-4-benzyl-4-carboxylic acid with 6 N
HCl, followed by purification using ion-exchange resin,
afforded (S)-R-benzylserine in 95% yield.
Further investigations of the phase-transfer catalytic
alkylation with various alkyl halides were performed
using the above optimal reaction conditions (entry 12,
Table 1). As shown in Table 2, the active alkyl halides
6e in high yields at 0 °C. When the reaction temperature
(entries b-h) gave R-alkylation in high chemical yields
was decreased, BEMP and BTPP did not show any
with high diastereoselectivities (90-97% de), but ali-
significant increase of diastereoselectivity at -20 °C, and
no reaction was observed at -40 °C. In contrast, P2-Et
(14) Diastereomeric excess (de) of the alkylation products was
determined by the chiral HPLC analysis of the corresponding methyl
exhibited higher diastereoselectivities at lower reaction
temperatures. The best results were obtained using P2-
Et at -78 °C (entry 12, 95% yield, 97% de). The hydroly-
sis of 6e (97% de) with 1 N LiOH gave 2-phenyl-2-
oxazoline-4-benzyl-4-carboxylic acid (98%) along with
2-phenyl-2-oxazoline-4-alkyl-carboxylates. Representative procedure
for transformation to the methyl ester is explained in Supporting
Information.
(15) (a) Schwesinger, R. Chimia 1985, 39, 269. (b) Schwesinger, R.;
Schlemper, H. Angew. Chem., Int. Ed. 1987, 26, 1167.
4160 J. Org. Chem., Vol. 70, No. 10, 2005

phatic halides provided no R-alkylation except methyl
iodide (entry a), which might be due to the low reactivity.
The high chemical yields and high diastereoselectivities
indicated that the new synthetic method under phase-
transfer catalytic conditions is very efficient for the
asymmetric synthesis of R-alkylserines.
The optimized phase-transfer catalytic reaction was
also successfully applied to the Michael reaction for the
synthesis of (2S)-R-(hydroxymethyl)glutamic acid (10),
which is one of the most useful glutamate receptor
ligands (Scheme 3).16 The Michel addition of 4a with tert-
butyl acrylate using P2-Et in methylene chloride at -78
°C, followed by hydrolysis provided 10 (88% yield from
4a, 85% de).
FIGURE 1. Plausible transition-state structure of a tetrabu-
tylammonium (E)-enolate-A derived from 4a and n-Bu4N+Br-.
methylene chloride solution (0.30 mL) of 4a (50.0 mg, 0.129
mmol) and tetrabutylammonium bromide (4.16 mg, 0.013 mmol)
was added benzyl bromide (0.077 mL, 0.644 mmol). After the
reaction mixture was cooled to -78 °C, phosphazene base P2-
Et (0.086 mL, 0.257 mmol) was added, and the reaction mixture
was stirred at -78 °C until starting material had been consumed
(5 min). The reaction mixture was quenched with saturated NH4-
Cl solution, diluted with methylene chloride (20 mL), washed
with water (5 mL), dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by column chromatography
on silica gel (hexane/EtOAc ) 10:1) to afford 6e (58.5 mg, 95%
yield) as a white foamy compound. The diastereoselectivity was
determined by chiral HPLC analysis of the benzylated oxazoline
methyl ester from the hydrolysis of 6e with 1 N LiOH, followed
by methylation with excess diazomethane (DAICEL Chiralcel
OD-H, hexane/2-propanol ) 99:1, flow rate ) 1.0 mL/min, 23
°C, λ ) 254 nm, retention times; S (major) 18.0 min, R (minor)
37.5 min, 97% ee). The absolute configuration was determined
by comparison of the optical rotation of R-benzylserine from the
acid hydrolysis of 6e with the reported value.7
A plausible transition state in the catalytic alkylation
is proposed in Figure 1. Molecular modeling studies of
the enolate intermediates of 4a revealed that the (E)-
enolate-A (45.46 kcal/mol) is the most stable conformer
among the four possible conformers.17 Therefore, the (E)-
enolate-A anion forms an ionic binding intermediate with
the tetrabutylammonium cation, and the lower side of
the intermediate is shielded by the camphor moiety. In
consequence, electrophiles can only approach from above,
affording the (4S)-6 and (2S)-10 in accord with the
results.
In conclusion, we developed a new, efficient, asym-
metric synthetic methodology for R-alkylserine by the
diastereoselective phase-transfer catalytic alkylation of
2-phenyl-2-oxazoline-4-carbonylcamphorsultam (4a). The
easy preparation of substrate 4a, the high chemical yields
and diastereoselectivities, and the efficient recovery of
the chiral auxiliary could make this method very efficient
for the synthesis of chiral R-alkylserines.
General Procedure for the Hydrolysis of 6e. To a tet-
rahydrofuran solution (2 mL) of 4-benzyl-2-phenyl-2-oxazoline-
4-carbonylcamphorsultam 6e (50.0 mg, 0.105 mmol) was added
1 N LiOH (2 mL), and the reaction mixture was stirred for 10
min. After tetrahydrofuran was removed in vacuo, the residue
was extracted with EtOAc (5 mL). The removal of EtOAc in
vacuo gave (1S)-(-)-2,10-camphorsultam (21.3 mg, 94%). The
aqueous layer was acidified with 1 N HCl (2 mL) and extracted
with EtOAc (15 mL). The removal of solvent in vacuo gave
4-benzyl-2-phenyl-2-oxazoline-4-carboxylic acid. To an ethanol
solution (2 mL) of the acid was added 6 N HCl (2 mL), and the
reaction solution was refluxed for 12 h. After solvent was
removed in vacuo, the residue was purified by column chroma-
tography (5% NH4OH) using ion-exchange resin (Dowex 50WX8-
100) to give (S)-(+)-R-benzylserine as a white solid (18.9 mg, 93%
for two steps). [R]20 +16.0 (c 0.71, H2O) [lit.7 [R]20 +16.4 (c
Experimental Section
General Procedure for the Enantioselective Phase-
Transfer Catalytic Alkylation of 4a (Benzylation). To a
D
D
0.81, H2O)]. The physical and spectral properties were consistent
with the literature values.7
(16) (a) Zhang, J.; Flippen-Anderson, J. L.; Kozikowski, A. P. J. Org.
Chem. 2001, 66, 7555. (b) Choudhury, P. K.; Le Nguyen, B. K.; Laglois,
N. Tetrahedron Lett. 2002, 43, 463. (c) Kawasaki, M.; Namba, K.;
Tsujishima, H.; Sinada, T.; Ohfune, Y. Tetrahedron Lett. 2003, 44, 1235.
(17) Calculations were done using the program SYBYL 6.5 from
Tripos Software, Inc., St. Louis, MO. The four-enolate conformers were
minimized using Tripos force field parameters and the conjugate
gradient algorithm with a gradient convergence value of 0.005 kcal/
mol Å. Partial atomic charges were calculated using the Gasteiger-
Hu¨ckel method. The low-energy conformation was searched by the grid
search method.
Acknowledgment. This work was supported by a
grant (E00261) from the Korea Research Foundation
(2004).
Supporting Information Available: Representative ex-
perimental procedures, as well as spectroscopic characteriza-
tions of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO050197J
J. Org. Chem, Vol. 70, No. 10, 2005 4161