Synthesis of novel chiral phase-transfer catalysts and their application to asymmetric synthesis of α-amino acid derivatives

Article abstract of DOI:10.1055/s-0029-1216736

To investigate the electronic and steric influences on enantioselectivities of asymmetric phase-transfer reactions, a series of chiral quaternary ammonium salts were synthesized from cinchona alkaloids and 2-chloromethylbenzimidazole or 1-chloromethyl ben

Full text of DOI:10.1055/s-0029-1216736

LETTER
1311
Synthesis of Novel Chiral Phase-Transfer Catalysts and Their Application to
Asymmetric Synthesis of a-Amino Acid Derivatives
C
hira
l
Phase-Transfer
C
e
atalysts for
i
S
ynthesis of
H
a
-Amino
A
cid
D
e
e
rivative
s
, Quanjun Wang, Qiaofeng Wang, Bangle Zhang, Xiaoli Sun, Shengyong Zhang*
Department of Chemistry, School of Pharmacy, The Fourth Military Medical University,
17 West Changle Road, 710032, Xi’an Shaanxi Province, P. R. of China
Fax +86(29)84776945; E-mail: syzhang@fmmu.edu.cn
Received 29 December 2008
was introduced as an effective unit for masking the nitro-
Abstract: To investigate the electronic and steric influences on
enantioselectivities of asymmetric phase-transfer reactions, a series
of chiral quaternary ammonium salts were synthesized from cincho-
na alkaloids and 2-chloromethylbenzimidazole or 1-chloromethyl
gen face. Much better results were obtained by replacing
the phenyl group with the bulkier anthracenyl moiety,
which led to substantially improved enantioselectivities
benzotriazole. Using one of the cinchonine-derived alkaloid cata- (up to 99.5% ee). Obviously, it is very essential to adjust
lysts, enantioselective alkylations of N-(diphenylmethylene) gly-
cine tert-butyl ester were efficiently carried out with various alkyl
halides to give products in high enantiomeric excess (94–99% ee).
steric hindrance effect of the catalysts for high enantio-
meric induction. However, since asymmetric alkylation of
glycine imines is an ion-pair-mediated reaction, the elec-
tronic properties of the PTC catalyst may also play a very
Key words: asymmetric catalysis, alkylation, amino acids, phase-
transfer catalysis, cinchona alkaloids
important role in the transformation. Based on this consid-
eration, we designed and synthesized new chiral quaterna-
ry ammonium salts from cinchona alkaloids which can
Asymmetric alkylation of glycine imines using quaterna-
ry ammonium salts as phase-transfer catalysts (PTC) has
emerged as a promising transformation because it pro-
vides a simple and easily scalable procedure for synthesis
of various naturally occurring and synthetic amino acids.1
Typical chiral PTC catalysts developed for this reaction in
the last two decades mainly focused on quaternary ammo-
nium salts derived from cinchona alkaloids2 and binaph-
thyl.3
maintain the space bulk and change the electronic charac-
teristic of the catalyst. Therefore, various PTC catalysts
were prepared from cinchona alkaloids and 2-chlorome-
thyl benzimidazole or 1-chloromethylbenzotriazole, re-
spectively (Figure 1). Herein the preliminary result of
their catalytic performance is disclosed.
Cl–
N+
N+
C2-Symmetric chiral spiro binaphthol ammonium salts
derivatives developed by the Maruoka group have been
successfully applied to the highly efficient, catalytic enan-
tioselective synthesis of various amino acids under mild
phase-transfer conditions,3a,b while these catalysts are ex-
pected to be expensive (not derived from the chiral pool
and often require multistep syntheses).1a Cinchona alka-
loids quaternary ammonium salts could be easily prepared
from cheap commercial natural products, which evoked
our greater interests to further study on them. We found
that subtle changes in structure of the ammonium salts
catalyst often lead to major improvements in the levels of
enantioselectivity. In 1989, O’Donnell first introduced N-
benzyl cinchona alkaloid salts as phase-transfer catalysts
(first generation) in the asymmetric alkylation of N-diphe-
nyl methylene glycine tert-butyl ester, which obtained the
corresponding product in 66% ee.4 The second generation
of catalysts, the N-alkyl O-alkyl cinchona alkaloid salts,
were reported in 1994,5 which gave improvement of enan-
tioselectivities (up to 81% ee). Finally, the third genera-
tion of catalyst was described independently by Lygo6 and
Corey7 in 1997, in which a 9-anthracenylmethyl group
8R
9S
8S
9R
Cl–
R
R
HO
OH
N
N
1a,b
cinchonine-derived
2a,b
cinchonidine-derived
OMe
Cl–
OMe
N+
8R
9S
N+
8S
Cl–
R
9R
R
HO
OH
N
N
3a,b
4a,b
quinidine-derived
quinine-derived
N
N
b
R =
N
a
R =
CH2
N
N
H
H2C
Figure 1 Cinchona-derived phase-transfer catalysts
Cinchona alkaloids, cinchonine, cinchonidine, quinidine,
or quinine and 2-chloromethylbenzimidazole or 1-chlo-
romethylbenzotriazole, were stirred at 110 °C in toluene
for three hours followed by recrystallization with diethyl
SYNLETT 2009, No. 8, pp 1311–1314
x
x.
x
x.
2
0
0
9
Advanced online publication: 22.04.2009
DOI: 10.1055/s-0029-1216736; Art ID: W20008ST
© Georg Thieme Verlag Stuttgart · New York

1312
W. He et al.
LETTER
ether to give the corresponding cinchona alkaloid cata- known, in the asymmetric phase-transfer catalytic reac-
lysts 1a–4a8 and 1b–4b9 in 85–93% yields. First, all the tion using cinchona-derived catalysts with free OH group,
quaternary ammonium salts were screened for the effec- the active catalyst was the O-alkylation of the cinchona
tiveness on the enantioselective phase-transfer benzyla- alkaloid quaternary ammonium salt, which was formed in
tion of N-(diphenylmethylene) glycine tert-butyl ester situ during the asymmetric alkylation.5 In our case, cata-
using 10 mol% of catalysts. Different factors influencing lysts 1a–4a have an additional NH group, which may in-
the enantioselectivities including solvent and temperature duce both N-alkylation and O-alkylation in situ during the
were also investigated (Table 1).
catalytic alkylation of 5, and the new active compounds
with larger steric bulk may decrease the catalytic activi-
ties. This can also explain the reaction phenomena oc-
curred at low temperature. When using 1a at –20 °C, the
yield decreased dramatically even with much longer time.
We further investigated the influence of solvent on enan-
tioselectivities using the optimal catalyst 1b. CH2Cl2 gave
the excellent ee (99%) as compared to toluene (75% ee)
and toluene–CH2Cl2 (7:3; 83% ee). In Et2O, excellent ee
could also be obtained, but the yield was unsatisfactory.
Table 1 Asymmetric Phase-Transfer Catalytic Benzylation Using
Cinchona-Derived Catalystsa
Ph
Ph
BnBr, catalyst (10 mol%)
solvent, KOH, K2CO3
N
N
*
Ph
CO2t-Bu
Ph
CO2t-Bu
Bn
5
6e
Entry Catalyst Solvent
Temp Time Yield ee
(°C) (h)
(%)b (%)c
Configd
Using the catalyst 1b, we also examined the scope and
limitations of the enantioselective phase-transfer alkyla-
tion of 5 with various alkyl halides with the aids of finely
powdered and dried mixture of K2CO3 and KOH. Table 2
indicates that high yields (82–92%) and enantioselectivi-
ties (94–99% ee) were achieved in the alkylation with 8
alkyl halides.10 The alkylated imines 6 could be further
transformed to the corresponding amino acids11 by acidic
hydrolysis via the known procedure.7
1
2
1a
2a
3a
4a
2b
1b
1b
1b
1b
1b
1b
1a
3b
4b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
20
20
20
20
20
20
20
24
24
24
24
12
12
18
12
12
15
24
36
12
12
70
65
60
61
90
55
65
79
91
85
80
20
73
69
95
90
R
S
3
73
R
S
4
68
5
96
S
6
99
R
R
R
R
R
R
R
R
S
In conclusion, novel simple cinchona alkaloid ammonium
salt catalysts and their catalytic performance were demon-
strated. These catalysts, which maintained the steric bulk
to mask the nitrogen face and an additional nitrogen atom
7
toluene
75
8
toluene–CH2Cl2 20
83
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
0
99
Table 2 Asymmetric Phase-Transfer Catalytic Alkylation Using
Various Alkyl Halides and Catalyst 1ba
10
11
12
13
14
>99
>99
95
Ph
Ph
-20
-20
20
N
RX, catalyst 1b (10 mol%)
N
*
Ph
CO2t-Bu
Ph
CO2t-Bu
CH2Cl2, KOH, K2CO3
R
5
6
75
Entry RX
ProductTime Yield ee
Configd
20
73
(h)
(%)b (%)c
a Conditions: 5/BnBr/catalyst = 1:1.2:0.1 (mmol).
b Isolated yield.
1
2
3
4
5
6
7
8
MeI
6a
6b
6c
6d
6e
6f
9
87
85
86
92
91
83
82
86
97
96
94
98
99
98
99
97
R
R
R
R
R
R
R
R
c Enantiomeric excess was determined by HPLC analysis using a
Chiralcel OD column with hexane–i-PrOH as eluent.
d Assigned by comparison with the sign of the specific rotation given
in the literature.
EtI
15
11
12
12
14
12
18
n-BuI
CH2=CHCH2Br
BnBr
As we can see, the absolute configuration of the product
was highly dependent upon the absolute configuration of
the C8- and C9-positions of the cinchona alkaloids. Not
surprisingly, the pseudoenantiomeric catalyst pairs gave
opposite enantioselectivity in the alkylation reaction. The
quaternary ammonium salts derived from quinine and qui-
nidine, with the additional methoxy group, gave lower ee,
as compared with the catalysts derived from cinchone and
2-Nap-CH2Br
4-t-BuBnBr
4-F3CBnBr
6g
6h
a Conditions: 5/RX/1b = 1:1.2:0.1 (mmol); reaction temperature:
20 °C.
cinchonidine. Generally speaking, both the conversions b Isolated yield.
c Enantiomeric excess was determined by HPLC analysis using a
and the enantioselectivities using 1b–4b were higher than
those of 1a–4a. We think the difference of activities and
ee may due to their chemical structures. As already
Chiralcel OD column with hexane–i-PrOH as eluent.
d Assigned by comparison with the sign of the specific rotation given
in the literature.
Synlett 2009, No. 8, 1311–1314 © Thieme Stuttgart · New York

LETTER
Chiral Phase-Transfer Catalysts for Synthesis of a-Amino Acid Derivatives
1313
5.93 (m, 1 H), 5.30–5.23 (m, 3 H), 4.85 (m, 1 H), 4.71 (t,
J = 5.2 Hz, 1 H), 4.07 (t, J = 11.2 Hz, 1 H), 3.97 (t, J = 8.5
Hz, 1 H), 3.07 (m, 1 H), 2.62 (m, 1 H), 2.35–1.78 (m, 4 H),
0.87 (m, 1 H). MS: m/z (%) 425 ([M–Cl]+, 5), 424 (10), 293
(40), 159 (20), 132 (100). Anal. Calcd for C27H29ClN4O: C,
70.34; H, 6.34; N, 12.15. Found: C, 70.32; H, 6.30; N, 12.18.
Compound 2a: white solid (prepared from cinchonidine);
yield 90%; mp 175–176 °C. [a]D25 –34 (c 0.5, EtOH). IR
(KBr): 3423, 3238, 2960, 1641, 1620, 1591, 1508, 1456, 746
cm–1. 1H NMR (400 MHz, CDCl3): d = 8.86 (d, J = 4.4 Hz,
1 H), 7.89 (d, J = 8.3 Hz, 1 H), 7.79 (d, J = 4.6 Hz, 1 H),
7.64–7.01 (m, 7 H), 6.77 (s, 1 H), 6.57–6.46 (m, 1 H), 6.14
(d, J = 13.8 Hz, 1 H), 5.46–5.24 (m, 2 H), 5.02 (m, 2 H), 4.72
(d, J = 13.6 Hz, 1 H), 4.05 (s, 1 H), 3.63–3.50 (m, 2 H), 2.68
(d, J = 5.0 Hz, 1 H), 2.20 (s, 1 H), 2.07–1.85 (m, 4 H), 1.24
(m, 1 H), 1.11 (m, 1 H). MS: m/z (%) = 425 (5) [M – Cl]+,
424 (10), 293 (55), 159 (15), 136 (40), 132 (100). Anal.
Calcd for C27H29ClN4O: C, 70.34; H, 6.34; N, 12.15. Found:
C, 70.37; H, 6.31; N, 12.14.
in the five-membered ring, showed good activities in the
asymmetric alkylation of glycine imines. Among these
catalysts, the N-benzimidazolemethyl cinchonine quater-
nary ammonium salt 1b showed the highest catalytic ac-
tivity (94–99% ee) in the alkylation of 5. The advantages
of this novel catalyst such as its simple structure, the low-
er preparation cost, high catalytic efficiency, and easily
recovering process imply it may be a potential practical
catalyst in industrial synthetic processes for natural and
unnatural chiral a-amino acids. Further detailed catalytic
mechanism and applications to other various phase-trans-
fer catalytic reactions using 1b are currently being inves-
tigated.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Compound 3a: pink solid (prepared from quinidine); yield
90%; mp 210–212 °C (dec.); [a]D25 +112 (c 0.2, EtOH). IR
(KBr): 3425, 2935, 1624, 1512, 1437, 1242, 1028, 743 cm–1.
1H NMR (400 MHz, CD3OD): d = 8.78 (d, J = 4.6 Hz, 1 H),
8.03 (d, J = 9.4 Hz, 1 H), 7.92 (d, J = 4.8 Hz, 1 H), 7.74–7.13
(m, 6 H), 6.76 (d, J = 1.7 Hz, 1 H), 6.12–6.03 (m, 1 H), 5.35–
5.27 (m, 3 H), 5.08 (d, J = 10.0 Hz, 1 H), 4.76 (t, J = 10.0 Hz,
1 H), 4.15 (t, J = 9.0 Hz, 1 H), 3.97 (s, 3 H), 3.90 (m, 2 H),
3.42 (m, 1 H), 2.79 (m, 1 H), 2.41 (t, J = 2.0 Hz, 1 H), 2.31
(s, 1 H), 1.89–1.98 (m, 4 H), 1.03 (m, 1 H). MS: m/z (%) =
455 (5) [M – Cl]+, 454 (10), 324 (35), 189 (20), 136 (100).
Anal. Calcd for C28H31ClN4O2: C, 68.49; H, 6.36; N, 11.41.
Found: C, 68.52; H, 6.33; N, 11.37.
Compound 4a: pink solid (preapred from quinine); yield
85%, mp 170–172 °C (dec.); [a]D25 –50 (c 0.2, CH2Cl2). IR
(KBr): 3403, 1622, 1510, 1242, 1028, 748 cm–1. 1H NMR
(400 MHz, CDCl3): d = 8.74 (d, J = 4.4 Hz, 1 H), 7.97 (d,
J = 9.1 Hz, 1 H), 7.79 (d, J = 4.4 Hz, 1 H), 7.66–7.17 (m, 6
H), 6.90 (s, 1 H), 6.59 (s, 1 H), 5.80 (d, J = 13.0 Hz, 1 H), 5.
51–5. 40 (m, 2 H), 5.17 (d, J = 7.1 Hz, 1 H), 5.00 (m, 2 H),
4.06 (d, J = 6.3 Hz, 2 H), 3.94 (t, J = 8.5 Hz, 1 H), 3.61 (s, 3
H), 3.29 (m, 1 H), 2.68 (d, J = 4.4 Hz, 1 H), 2.34 (s, 1 H),
2.26–1.83 (m, 4 H), 1.20 (m, 1 H). MS: m/z (%) = 455 (10)
[M – Cl]+, 454 (15), 123 (80), 136 (40), 132 (100). Anal.
Calcd for C28H31ClN4O2: C, 68.49; H, 6.36; N, 11.41. Found:
C, 68.54; H, 6.40; N, 11.39.
Acknowledgment
National Natural Science Foundation of China (20702063,
20572131, 20842007) is gratefully acknowledged.
References and Notes
(1) (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506.
(b) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
(c) Vachon, J.; Lacour, J. Chimia 2006, 60, 266.
(d) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107,
5656. (e) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679.
(2) (a) Thierry, B.; Plaquevent, J. C.; Cahard, D. Tetrahedron:
Asymmetry 2001, 12, 983. (b) Lygo, B.; Crosby, J.;
Lowdon, T. R.; Wainwright, P. G. Tetrahedron 2001, 57,
2391. (c) Park, H.; Jeong, B.; Yoo, M.; Park, M.; Huh, H.;
Jew, S. Tetrahedron Lett. 2001, 42, 4645. (d) Lygo, B.;
Andrews, B. I.; Crosby, J.; Peterson, J. A. Tetrahedron Lett.
2002, 43, 8015.
(3) (a) Ooi, T.; Kameda, M.; Maruok, K. J. Am. Chem. Soc.
2003, 125, 5139. (b) Kitamura, M.; Shirakawa, S.;Maruoka,
K. Angew. Chem. Int. Ed. 2005, 44, 1549. (c) Hashimoto,
T.; Tanaka, Y.; Maruoka, K. Tetrahedron: Asymmetry 2003,
14, 1599. (d) Han, Z.; Yamaguchi, Y.; Kitamura, M.;
Maruoka, K. Tetrahedron Lett. 2005, 46, 8555.
(4) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am.Chem. Soc.
1989, 111, 2353.
(9) Procedure for the synthesis of 1b–4b
To a suspension of the cinchona alkaloid (10 mmoL) in 40
mL toluene was added 1-chloromethylbenzotriazole(10.5
mmoL), and the mixture was stirred at reflux for 3 h (TLC
with CH2Cl2–MeOH = 15:1). The solvent was evaporated
under reduced pressure. The pure product was attained by
chromatography using CH2Cl2–MeOH as eluent.
(5) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994,
50, 4507.
(6) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
8595.
(7) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
(8) Procedure for the Synthesis of 1a–4a
Compound 1b: white solid (prepared from cinchonine);
yield 85%; mp 170–172 °C; [a]D25 +148 (c 0.5, EtOH). IR
(KBr): 3424, 2949, 1631, 1505, 1510, 1456, 1418, 1289, 764
cm–1. 1H NMR (300 MHz, CDCl3): d = 8.81–8.79 (m, 1 H),
8.73 (d, J = 7.9 Hz, 1 H), 8.65 (d, J = 8.1 Hz, 1 H), 8.04–8.01
(m, 1 H), 7.97–7.87 (m, 3 H), 7.73–7.61 (m, 1 H), 7.45–7.38
(m, 2 H), 6.86 (s, 1 H), 5.76–5.73 (m, 1 H), 5.22–5.14 (m, 2
H), 4.98–4.83 (m, 1 H), 4.86–4.75 (m, 1 H), 4.08–3.87 (m, 1
H), 3.81–3.75 (m, 1 H), 3.70–3.54 (m, 2 H), 2.95–2.89 (m, 1
H), 2.63–2.54 (m, 1 H), 2.31–1.89 (m, 5 H), 1.29–1.26 (m, 1
H). Anal. Calcd for C26H28ClN5O: C, 67.59; H, 6.11; N,
15.16. Found: C, 67.54; H, 6.16; N, 15.20. ESI-MS: 426
[M – Cl]+.
To a suspension of cinchona alkaloid (10 mmoL) in toluene
(40 mL) was added 2-chloromethylbenzimidazole (10.5
mmoL), and the mixture was stirred at reflux for 3 h (TLC
with CH2Cl2–MeOH = 15:1). The mixture was cooled to r.t.
and filtered. The solids were collected and recrystallized in
Et2O to afford the pure product.
Compound 1a: white solid (prepared from cinchonine);
yield 93%; mp 182–183 °C; [a]D25 +68 (c 0.5, EtOH). IR
(KBr): 3425, 2947, 1637, 1510, 1458, 1402, 746 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.87 (d, J = 4.6 Hz, 1 H),
7.83–7.80 (m, 2 H), 7.51–7.45 (m, 3 H), 7.27–7.16 (m, 4 H),
6.70–6.67 (m, 2 H), 6.60 (s, 1 H), 6.30 (d, J = 13.8 Hz, 1 H),
Compound 2b: white solid (prepared from cinchonidine);
yield 89%; mp 230–240 °C (dec.); [a]D25 –154 (c 0.5, EtOH).
Synlett 2009, No. 8, 1311–1314 © Thieme Stuttgart · New York

1314
W. He et al.
LETTER
IR (KBr): 3398, 3243, 2955, 1629, 1498, 1455, 760 cm–1. 1H
NMR (300 MHz, CDCl3): d = 8.82–8.81 (m, 1 H), 8.69 (d,
J = 7.8 Hz, 1 H), 8.45–8.41 (m, 1 H), 7.95–7.77 (m, 4 H),
7.49–7.37 (m, 3 H), 7.20 (s, 1 H), 6.79 (s, 1 H), 5.42–5.31
(m, 1 H), 5.13–5.08 (m, 1 H), 4.98 (d, J = 10.2 Hz, 1 H),
4.26–4.23 (m, 1 H), 3.69–3.56 (m, 2 H), 3.22–3.19 (m, 1 H),
2.52 (s, 1 H), 1.72–1.57 (m, 1 H), 1.09–1.01 (m, 1 H), 2.11–
1.93 (m, 5 H). Anal. Calcd for C26H28ClN5O: C, 67.59; H,
6.11; N, 15.16. Found: C, 66.94; H, 6.20; N, 15.19. ESI-MS:
426 [M – Cl]+.
Compound 3b: white solid (prepared from quinidine); yield
88%; mp 190–195 °C (dec.); [a]D25 +149 (c 0.5, EtOH). IR
(KBr): 3428, 2946, 1623, 1508, 1460, 1239 cm–1. 1H NMR
(300 MHz, CD3Cl): d = 8.63 (d, J = 8.1 Hz, 1 H), 8.46 (d,
J = 4.2 Hz, 1 H), 7.83–7.78 (m, 4 H), 7.40–7.37 (m, 2 H),
7.21–7.11 (m, 1 H), 6.87 (s, 1 H), 5.80–5.68 (m, 1 H), 5.15–
5.10 (m, 2 H), 4.87–4.80 (m, 1 H), 4.25–4.22 (m, 2 H), 3.85
(s, 3 H), 3.66–3.57 (m, 1 H), 3.06–3.03 (m, 1 H), 2.55–2.35
(m, 3 H), 2.33–2.31 (m, 1 H), 2.17 (t, J = 12.0 Hz, 1 H),
1.87–1.71 (m, 3 H), 1.25–1.21 (m, 1 H). ESI-MS: 456.6
[M – Cl]+. Anal. Calcd for C27H30ClN5O2: C, 65.91; H, 6.15;
N, 14.23. Found: C, 65.89; H, 6.19; N, 14.21.
Compound 4b: white solid (prepared from quinine); yield
90%; mp 160–162 °C; [a]D25 –122 (c 0.5, EtOH). IR (KBr):
3421, 1621, 1506, 1460, 1352, 1235 cm–1. 1H NMR (300
MHz, CDCl3): d = 8.68 (s, 1 H), 8.65 (d, J = 4.5 Hz, 1 H),
7.95–7.93 (m, 1 H), 7.91 (d, J = 3.3 Hz, 1 H), 7.78 (d, J = 4.2
Hz, 1 H), 7.66–7.64 (m, 1 H), 7.56 (d, J = 13.5Hz, 1 H), 7.47
(t, J = 7.2 Hz, 1 H), 7.36 (d, J = 7.5 Hz, 1 H), 6.97 (s, 1 H),
5.46–5.34 (m, 1 H), 5.07 (br s, 1 H), 4.96–4.91 (m, 2 H),
4.14–4.11 (m, 2 H), 3.98 (s, 3 H), 3.71 (t, J = 11.4 Hz, 1 H),
3.13 (d, J = 11.4 Hz, 1 H), 2.77–2.52 (m, 4 H), 2.19–2.18 (m,
1 H), 2.08–1.99 (m, 2 H), 1.98–1.85 (m, 1 H), 1.27–1.25 (m,
1 H). ESI-MS: 456.6 [M – Cl]+. Anal. Calcd for
C27H30ClN5O2: C, 65.91; H, 6.15; N, 14.23. Found: C, 65.94;
H, 6.20; N, 14.29.
(10) Representative Procedure for Enantioselective Catalytic
Alkylation of 5 under Phase-Transfer Conditions
To a mixture of N-(diphenylmethylene) glycine tert-butyl
ester (5, 295 mg, 1 mmol) and chiral catalyst 1b (46.2mg, 0.1
mmol) in CH2Cl2 (10 mL) was added BnBr (205 mg, 1.2
mmol). Then a finely powdered and dried mixture of K2CO3
(138 mg, 1 mmol) and KOH (56 mg, 1 mmol) was added to
the reaction mixture. The resulting suspension was then
vigorously stirred at 20 °C till the reaction was complete
(TLC, PE–EtOAc = 20:1). The suspension was diluted with
CH2Cl2 (10 mol), washed with H2O (2 × 30 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification of
the residue by flash column chromatography on SiO2 (PE–
EtOAc = 20:1 to 10:1) afforded the desired product 6e (258
mg, 91% yield) as a colorless oil. The ee was determined
by chiral HPLC analysis [DAICEL Chiralcel OD, hexane–
i-PrOH (98:2), flow rate = 0.4 mL/min, 23 °C, l = 259 nm;
tR (R, major) = 12.2 min; tR (S, minor) = 15.5 min, 99% ee].
The absolute configuration was determined by comparison
of the HPLC retention time with the authentic sample
synthesized by the reported procedure.
(11) Acidic Hydrolysis of Alkylated Imine 6e to the
Corresponding (R)-Phenylalanine
The crude alkylated imine 6e was treated by refluxing 4 h
in HCl (4 mL, 6 mol/L), followed by neutralization of the
amine hydrochloride using propylene oxide (0.8 mL) in
EtOH. After being filtrated and washed with precooled Et2O
and EtOH, the (R)-phenylalanine was attained in 75% yield,
[a]D25 +32 (c 1.0, H2O), lit. [a]D25 +33.7 (c 2.0, H2O).
Synlett 2009, No. 8, 1311–1314 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.