Highly enantioselective synthesis of (R)-α-alkylserines via phase-transfer catalytic alkylation of o-biphenyl-2-oxazoline-4-carboxylic acid tert-butyl ester using cinchona-derived catalysts

Article abstract of DOI:10.1021/ol050228x

(Chemical Equation Presented) A highly enantioselective synthetic method for (R)-α-alkylserines was developed by the phase-transfer catalytic alkylation of obiphenyl-2-oxazoline-4-carboxylic acid tert-butyl ester (4i) using cinchona-derived phase-transfer

Full text of DOI:10.1021/ol050228x

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1557-1560
Highly Enantioselective Synthesis of
(R)- -Alkylserines via Phase-Transfer
Catalytic Alkylation of
r
o-Biphenyl-2-oxazoline-4-carboxylic Acid
tert-Butyl Ester Using Cinchona-Derived
Catalysts
Yeon-Ju Lee, Jihye Lee, Mi-Jeong Kim, Taek-Soo Kim, Hyeung-geun Park,* and
Sang-sup Jew*
Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul
National UniVersity, Seoul 151-742, Korea
hgpk@plaza.snu.ac.kr
Received February 3, 2005
ABSTRACT
A highly enantioselective synthetic method for (R)-r-alkylserines was developed by the phase-transfer catalytic alkylation of o-biphenyl-2-
oxazoline-4-carboxylic acid tert-butyl ester (4i) using cinchona-derived phase-transfer catalyst N(1)-(9-anthracenylmethyl)-O(9)-allyl-dihydrocin-
chonidinium bromide (up to 96% ee).
Chiral R-alkylserines have been regarded as important
components in the areas of the both synthetic and medicinal
chemistry.1 Their hydroxyl groups contribute to stabilize the
secondary structure in peptides by hydrogen bonding with
amide carbonyl groups, which makes R-alkylserines useful
in peptidomimetic drug design.2 There are also several bio-
logically active natural products, possessing chiral R-alkylserine
moieties.3 In addition, chiral R-alkylserines could be con-
verted to various useful synthetic building blocks via
chemical transformations.1 So far, a number of enantiose-
lective synthetic methods have been developed for chiral
R-alkylserines, but only a few are practical.4
(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. J. Am. Chem.
Soc. 1953, 75, 5867. (c) Hanessian, S.; Haskell, T. H. Tetrahedron Lett.
1964, 5, 2451. (d) Wirth, T. Angew. Chem., Int. Ed. 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.
(2) (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.
10.1021/ol050228x CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/18/2005

Very recently, we reported a very efficient enantioselective
synthetic method for (S)-R-alkylserines by the phase-transfer
catalytic alkylation5 of 2-phenyl-2-oxazoline-4-carboxylate
tert-butyl ester (4a) using chiral quaternary ammonium salts
(1,6 2,7 and 38).9 The previous study revealed that (S)-
binaphthyl quaternary ammonium salt 3 showed enantiose-
lectivity quite superior to that of the cinchona-derived
catalysts (1 and 2) (Scheme 1).9 Regardless of the excellent
substrates to form favorable binding intermediate with
cinchona-derived catalysts by the modification of 4a. As the
tert-butyl ester group of 4a was known as an essential group
for high enantioselectivity, the tert-butyl ester group was
retained and the phenyl group of 4a was modified to various
aromatic groups. Nine oxazoline tert-butyl esters (4a-i) were
prepared in two steps from the corresponding aromatic acids
(Scheme 2).
Scheme 2. Preparation of the Oxazoline tert-Butyl Ester
Scheme 1. Enantioselective PTC Alkylation for
(S)-R-Alkylserines Using 3
Substrates
enantioselective catalytic efficiency of 3, the high cost and
several steps involved in the preparation of 3 might make
this method less practical for industrial application. In this
letter, we report a new synthetic method for (R)-R-alkylserine
using cinchona-derived catalysts (1 and 2) by the modifica-
tion of oxazoline ester substrate 4a.
It was assumed that the enantioselectivity in phase-transfer
catalytic alkylation might depend on the favorable ionic
binding between quaternary ammonium salt catalysts and the
enolate of 4a. As shown in the previous studies, the
cinchona-derived catalysts (1 and 2) have a limit in enan-
tioselectivity compared to (S)-binaphthyl quaternary am-
monium salt 3.
The coupling of the aromatic acids and serine tert-butyl
ester by EDC, followed by the cyclization using DAST, gave
the corresponding oxazoline tert-butyl esters (4a-i) in high
yields (75-92%).
For the alkylation, we adapted the previous reaction
conditions except for solvent. The enantioselective phase-
transfer catalytic benzylation was performed using 10 mol
% catalyst (1 or 2) along with the prepared oxazoline tert-
butyl esters (4a-i), benzyl bromide (5.0 equiv), and solid
KOH (5.0 equiv) in methylene chloride at 0 °C for 2-8 h.
As shown in Table 1, the enantioselectivity dramatically
depended on the aromatic groups. There was no significant
electronic effect on the phenyl group, but the enantioselec-
tivity was variable with the position of substituents. The
ortho-substituted derivatives (entries 3 and 4, 4b; entries 9
and 10, 4e) still retained the enantioselectivity, but quite a
drop in enantioselectivity was observed in meta- and para-
substituted derivatives in both cases of electron-donating (4f)
and -withdrawing groups (4c and 4d). However, the bulky
aromatic analogues showed variable enantioselectivity. The
R-naphthyl derivative 4g (entries 13 and 14) exhibited much
higher enantioselectivity than 4a, but moderate enantiose-
lectivity was observed in the â-naphthyl analogue 4h (entries
15 and 16). The o-biphenyl analogue 4i (entry 17) showed
the highest enantioselectivity among the prepared oxazoline
esters. In the case of catalysts, catalyst 1 gave relatively lower
enantioselectivity than catalyst 2 in phenyl analogues
(4a-f) and â-naphthyl analogue (4h), but R-naphthyl (4g)
As part of our program for the practical synthesis of (R)-
R-alkylserine, we attempted to design new oxazoline ester
(3) (a) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.;
Toyama, R.; Yoneta, M.; Chiba, K.; Hosino, Y.; Okumoto, T. J. Antibiotics
1994, 47, 216. (b) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.;
Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiotics 1991, 44, 113. (c)
Omura, S.; Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita,
S.; Nakagawa, A J. Antibiotics 1991, 44, 117. (d) Yamashita, T.; lijima,
M.; Nakamura, H.; Isshiki, K.; Naganawa, H.; Hattori, S.; Hamada, M.;
Ishizuka, M.; Takeuchi, T. J. Antibiotics 1991, 44, 557. (e) Kawatsu, M.;
Yamashita, T.; Ishizuka, M.; Takeuchi, T. J. Antibiotics 1995, 48, 222.
(4) Previous synthetic methods of chiral R-alkylserines are cited in
ref 9.
(5) For recent reports for asymmetric phase-transfer catalytic reactions,
see: (a) Shioiri, T.; Arai, S. In Stimulating Concepts in Chemistry; Vogtle,
F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH: Germany, 2000; pp
123-143. (b) O’Donnell, M. J. In Catalytic Asymmetric Synthesis; Ojima,
I.; Wiley-VCH: New York, 2000; Chapter 10. (c) O’Donnell, M. J.
Aldrichim. Acta 2001, 34, 3.
(6) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
(b) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(7) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, H.-g. Org. Lett. 2002, 4,
4245.
(8) (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121,
6519. (b) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228. (c) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 5139.
(9) 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.
1558
Org. Lett., Vol. 7, No. 8, 2005

Table 1. Enantioselective Phase-Transfer Catalytic
Benzylationa
Table 2. Optimization of Phase-Transfer Catalytic
Benzylationa
time yieldb
% eec
(configurationd)
entry substrate catalyst
(h)
(%)
temp
(°C)
time
(h)
yieldb
(%)
% eec
entry
base
(configurationd)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
3
4
3
3
3
4
3
3
4
5
8
2
5
6
3
6
3
6
7
8
90
94
90
91
82
83
87
85
82
80
86
87
85
88
92
90
91
88
62
49 (R)
69 (R)
41 (R)
81 (R)
10 (R)
28 (R)
12 (R)
20 (R)
45 (R)
74 (R)
41 (R)
47 (R)
90 (R)
81 (R)
43 (R)
66 (R)
93 (R)
91 (R)
41 (S)
1
2
3
4
5
6
7
NaOH
KOH
KOH
0
0
-20
-40
0
-20
-40
16
6
20
120
2
90
91
87
86
79
83
90
32 (R)
93 (R)
90 (R)
80 (R)
68 (R)
84 (R)
96 (R)
KOH
CsOH
CsOH
CsOH
4
8
a Reaction conditions were the same as those in Table 1 except for the
base and reaction temperature. b Isolated yields. c Enantiopurity was deter-
mined by HPLC analysis of the benzylated oxazoline tert-butyl ester 5i-b
using a chiral column (DAICEL Chiralcel OD) with hexanes/2-propanol
(volume ratio ) 500:2.5) as a solvent; in this case, the enantiopurity was
established by analysis of the racemate, of which the enantioisomers were
fully resolved. d Absolute configuration was determined by comparison of
the optical rotation of R-benzylserine from the acidic hydrolysis of 5i-b
with the reported value.9
4f
4g
4g
4h
4h
4i
4i
4i
longer reaction time. This might be due to the slow reaction
rate at low temperature, which enhanced the non-PTC
a Reaction was carried out with 5.0 equiv of benzyl bromide and 5.0
equiv of solid KOH in the presence of catalyst (10 mol %) in methylene
chloride at 0 °C. b Isolated yields. c Enantiopurity was determined by HPLC
analysis of the benzylated oxazoline tert-butyl ester 5 using a chiral column
(DAICEL Chiralcel OD) with hexanes/2-propanol as a solvent; in this case,
the enantiopurity was established by analysis of the racemate, of which the
enantioisomers were fully resolved. d Absolute configuration was determined
by comparison of the optical rotation of R-benzylserine from the acidic
hydrolysis of 5 with the reported value.9
Table 3. Enantioselective Phase-Transfer Catalytic Alkylationa
and o-biphenyl analogues (4i) showed higher enantioselec-
tivity with catalyst 1 compared to catalyst 2. Notably, the
best catalyst in the previous report,9 3, gave poor enantiose-
lectivity in the alkylation of 4i, suggesting that the enolate
of 4i and 3 could not form a favorable binding intermediate
in phase-transfer catalytic alkylation. On the basis of the
cumulative results, the general tendency could be sum-
marized as follows: (1) The ortho substituents on the phenyl
group play a more important role for high enantioselectivity
than the corresponding meta and para substituents, but their
electronic properties are not important. (2) The ortho aromatic
moieties afford high enantioselectivity, and the increase of
enantioselectivity might be due to the enhanced favorable
binding affinity by the π,π-stacking interaction with catalysts.
(3) The sterically hindered oxazoline substrates gave higher
enantioselectivity in the presence of catalyst 1, but catalyst
2 shows higher enantioselectivity in relatively less hindered
oxazoline substrates.
Next, we focused our attention toward finding on optimal
base conditions using the best substrate, 4i. As shown in
Table 2, KOH gave the highest enantioselectivity (entry 2,
93% ee) among the alkali bases used at 0 °C, but the lower
reaction temperature gave lower enantioselectivity with a
a Reaction conditions were same as those for entry 7 of Table 2 except
for alkyl halides. b Isolated yields. c Enantiopurity was determined by HPLC
analysis of 5i using a chiral column (Chiralcel OD) with hexanes/2-propanol
as eluents. d Absolute configuration was assigned by the relative retention
times of both enantiomers determined previously.1-3
Org. Lett., Vol. 7, No. 8, 2005
1559

intermediate reaction pathway. In contrast, the decrease of
reaction temperature under CsOH base conditions could
increase the enantioselectivity, and the optimal temperature
was -40 °C. 4i and the above optimal reaction conditions
were chosen for further investigation of the enantioselective
phase-transfer catalytic alkylation with various alkyl ha-
lides. As shown in Table 3, very high enantioselectivities
(90-96% ee) were observed in the case of activated alkyl
halides, but unfortunately nonactivated alkyl halides did not
afford alkylation. The hydrolysis of 5i-b (96% ee) with 12
N HCl afforded optically active (R)-(+)-benzylserine in 98%
yield.9,10 As a merit for practicality, 6i could be recovered
(99%) after hydrolysis of 5i and recycled to prepare the
substrate 4i.
line substrates, o-biphenyl-2-oxazoline-4-carboxylic acid
tert-butyl ester showed the highest enantioselectivity
using catalyst 1. The easy preparation of substrate 4i, the
high enantioselectivity, and the very mild reaction condi-
tions could make this method very practical for (R)-R-
alkylserines.
Acknowledgment. This work was supported by a grant
(R01-2002-000-0005-0) from the Basic Research Program
of the KOSEF (2004).
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterizations of the new
catalysts. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we prepared new oxazoline tert-butyl
esters for the enantioselective synthesis of (R)-R-alkylserines
by the asymmetric phase-transfer catalytic alkylation using
cinchona-derived catalysts. Among the prepared oxazo-
OL050228X
(10) Clerici, F.; Gelmi, M. L.; Gambini, A. J. Org. Chem. 1999, 64,
5764.
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Org. Lett., Vol. 7, No. 8, 2005