Electronically modified polymer-supported cinchona phase-transfer catalysts for asymmetric synthesis of α-alkyl-α-amino acid derivatives

Article abstract of DOI:10.1246/cl.2008.436

Merrifield resin-supported hydrocinchonidinium salts containing particular functional groups that can participate in hydrogen bonding were prepared and evaluated as chiral phase-transfer catalysts using the asymmetric benzylation of glycine imine ester. These electronically modified Merrifield resin-supported phase-transfer catalysts generally provided better enantioselectivities compared to the unmodified ones. Copyright

Full text of DOI:10.1246/cl.2008.436

436
Chemistry Letters Vol.37, No.4 (2008)
Electronically Modified Polymer-supported Cinchona Phase-transfer Catalysts
for Asymmetric Synthesis of ꢀ-Alkyl-ꢀ-amino Acid Derivatives
Qinghua Shi,1 Yeon-Ju Lee,2 Hongrui Song,1 Maosheng Cheng,1 Sang-sup Jew,2
Hyeung-geun Park,ꢀ2 and Byeong-Seon Jeongꢀ3
1Shenyang Pharmaceutical University, Shenyang Wenhua road 103, P. R. China
2Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
3College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea
(Received February 4, 2008; CL-080128; E-mail: hgpk@snu.ac.kr, jeongb@ynu.ac.kr)
Merrifield resin-supported hydrocinchonidinium salts
PS-PTCs 3 in which hydrogen bonding inducing functional
groups are incorporated in O-supported polymer part.3c As part
of our ongoing studies towards the cinchona PS-PTCs, we herein
report the design and preparation of electronically modified
type-2 cinchona PS-PTCs 4b–4d and 5b–5d, and preliminary
evaluation of their capabilities using asymmetric phase-transfer
catalytic benzylation of 1.
containing particular functional groups that can participate in
hydrogen bonding were prepared and evaluated as chiral
phase-transfer catalysts using the asymmetric benzylation of
glycine imine ester. These electronically modified Merrifield
resin-supported phase-transfer catalysts generally provided
better enantioselectivities compared to the unmodified ones.
Newly designed type-2 cinchona PS-PTCs 4b–4d and
5b–5d along with reference compounds 4a and 5a were prepared
from (ꢂ)-hydrocinchonidine and the corresponding Merrifield
Cinchona alkaloid-derived quaternary ammonium salts have
been frequently employed as chiral phase-transfer catalysts
(PTCs) in the enantioselective phase-transfer catalytic alkylation
of glycine imine ester such as 1 affording a variety of optically
active natural and non-natural ꢀ-alkyl-ꢀ-amino acid deriva-
tives.1 In addition, considerable efforts have been made on the
immobilization of cinchona PTCs on various polymer supports.2
The most advantageous aspect to use a polymer-supported PTC
(PS-PTC) is that it can be readily recoverable and recyclable,
which makes PS-PTC more suitable for a large-scale production
than unsupported PTCs from both practical and economical
points of view (Chart 1).
Generally, natural cinchona alkaloids provide two sites for
polymer attachment, thus cinchona PS-PTCs can be categorized
into two types; type-1 PS-PTCs (O-supported PTCs) and type-2
PS-PTCs (N-supported PTCs). We have proposed that water
molecule-mediated internal hydrogen bonding between C(9)-
oxygen and special functional groups, such as 20-F, 20-CꢁN,
or 20-Nþ–Oꢂ, in Nþ(1)-arylmethyl moieties in cinchona PTCs
plays a critical role for enhancement of enantioselectivity in
the alkylation of 1.3a,3b Based on this fact, we recently reported
the design and preparation of a new class of type-1 cinchona
Br
O
N
OH
X
C
D
+
Y
4a-d
5a-d
6a, X-Y = C-H
6b, X-Y = C-F
6c, X-Y = C-CN
6d, X-Y = N+-O-
N
Hydrocinchonidine
OH
OH
A
B1
6a
O
HO
7
8
OH
CHO
OH
a, b
A
B1
6b
O
F
HO
F
MeO
HO
F
9
10
11
c
d
e
OH
OMe
OMe
CN
Br
HO
Br
MeO
Br
MeO
12
13
14
15
6c
OMe
f
A
B2
OMe
CN
O
CN
HO
16
17
g
OAc
OAc
h
g
N
i
N
N
N
HO
HO
O
AcO
AcO
O
18
19
OH
20
21
OH
A
B1
N
6d
O
O
N
HO
O
22
23
Asymmetric
PTC Alkylation
Ph
N
CO2t-Bu
Ph
N
CO2t-Bu
H2N
CO
2H
*
R
2
*
Ph
Ph
R
Scheme 1. Reagents and Conditions: (a) BBr3, CH2Cl2,
ꢂ78 ꢃC to rt, 1 h, 86%; (b) NaBH4, MeOH, rt, 10 min, 99%;
(c) HCHO, 20% KOH, 60 ꢃC, 6 h, 30%; (d) MeI, KOH, DMSO,
rt, 30 min, 97%; (e) CuCN, DMF, reflux, 8 h, 80%; (f) NaSEt,
DMF, reflux, 2 h, 60%; (g) m-CPBA, CHCl3, rt, 4 h, 94% for
19, 82% for 21; (h) Ac2O, reflux, 1 h, 90%; (i) 1 M HCl, acetone,
reflux, 8 h, 76%; (A) Merrifield resin (Br, 0.94 mmol/g), K2CO3,
DMF, reflux, 2 h, 96% for 8, 93% for 11, 94% for 17, 96% for 23;
(B1) Ph3P, CBr4, CH2Cl2, 0 ꢃC to rt, 24 h, 96% for 6a, 88%
for 6b, 94% for 6d; (B2) BBr3, CH2Cl2, ꢂ78 ꢃC to rt, 4 h,
99% for 6c; (C) CH2Cl2, rt, 24 h, 92% for 4a (0.59 mmol/g),
94% for 4b (0.54 mmol/g), 93% for 4c (0.57 mmol/g), 94%
for 4d (0.61 mmol/g); (D) allyl bromide, 50% KOH, CH2Cl2,
rt, 24 h, 95% for 5a (0.56 mmol/g), 99% for 5b (0.54 mmol/
g), 99% for 5c (0.56 mmol/g), 99% for 5d (0.59 mmol/g).
1
α-Amino acids
X
X
N+
N+
1
G
*
*
*
*
9
O
2'
O
R
N
N
Type-1
Type-2
Br
Br
N+
N+
O
X
X
Y
O
O
R
Y
N
N
3
4a, X-Y = C-H, R = H ; 5a, X-Y = C-H, R = allyl
4b, X-Y = C-F, R = H ; 5b, X-Y = C-F, R = allyl
4c, X-Y = C-CN, R = H ; 5c, X-Y = C-CN, R = allyl
4d, X-Y = N+-O-, R = H ; 5d, X-Y = N+-O-, R = allyl
X-Y = C-F
C-CN
N+-O-
Chart 1.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.4 (2008)
Table 1. Screening of reaction conditions
437
Table 2. Catalytic enantioselective phase-transfer benzylation
PS-PTC (20 mol %)
PhCH2Br (5 equiv)
4d (20 mol%)
PhCH2Br (5 equiv)
Ph
N
CO2t-Bu
Ph
N
CO2t-Bu
Ph
N
CO2t-Bu
Ph
N
CO2t-Bu
50% KOH (20 equiv)
base, solvent, temp.
Ph
Ph
PhMe-CHCl3 (7:3), 0 o
C
Ph
Ph
Ph
1
2
Ph
1
2
Entry Basea Solventb Temp/ꢃC Time/h Yieldc/% eed/%
Entry
PS-PTC
Time/h
Yield/%a
ee/%b
1
2
3
4
5
6f
7
8
A
B
C
C
C
C
D
C
E
F
E
F
G
G
G
G
0
ꢂ50
0
12
6
48
0e
69
—
86
83
90
89
85
90
1
2
3
4
5
6
7
8
4a
4b
4c
4d
5a
5b
5c
5d
b
26
28
26
24
24
26
20
24
89
89
88
92
90
92
88
89
80
84
88
90
78
82
91
89
44
36
24
40
120
60
90
89
92
92
75
87
0
0
0
0
ꢂ20
a
.
A: 3.0 equiv of solid KOH; B: 3.0 equiv of solid CsOH H2O; C: 20.0
aIsolated yield. Enantiopurity was determined by HPLC analysis
using a chiral column (Chiralcel OD-H) with hexanes/2-propanol
as eluents, and absolute configuration of 2 was assigned as S.
equiv of 50% KOH; D: 20.0 equiv of 50% NaOH. bE: toluene;
F: dichloromethane, G: toluene–chloroform (volume ratio = 7:3).
cIsolated yield. dEnantiopurity was determined by HPLC analysis
using a chiral column (Chiralcel OD-H) with hexanes/2-propanol as
eluents, and absolute configuration of 2 obtained from all experiments
was assigned as S by comparison of retention times of both enantiom-
100
98
96
94
92
90
88
86
84
82
80
30
28
26
24
22
20
18
16
14
12
10
e
ers determined previously. The imine moiety of the substrate 1 was
f
hydrolyzed to afford benzophenone. 10 mol % of 4d was used.
%
Time/h
resin-bound benzylic bromides 6a–6d as shown in Scheme 1.
The benzyl bromides 6 were obtained by bromination of benzyl
alcohol with Ph3P–CBr4 (for 8, 11, and 23) or benzylic methoxy
group with BBr3 (for 17). These Merrifield resin-supported pre-
cursors for bromination, 8, 11, 17, and 23, were prepared by O-
alkylation of phenolic oxygen of 7, 10, 16, and 22 with bromo-
Merrifield resin, respectively. Compound 7 was commercially
available, and 2-fluoro-intermediate 10 was obtained by
two-step sequence, demethylation and reduction, started from
2-fluoro-4-methoxybenzaldehyde (9). For the preparation of
2-cyano-intermediate 16, 3-bromophenol (12) was used as a
starting material which was treated with formaldehyde in 20%
KOH to afford hydroxymethylated compound 13, followed by
protection of two hydroxys with methyl groups. Converting
bromide to cyanide with copper cyanide, and subsequent
selective demethylation of the phenolic methoxy group with so-
dium ethanethiolate afforded 16. The 2-N-oxide intermediate 22
was prepared by four-step sequence from 5-hydroxy-2-methyl-
pyridine (18). 18 was first treated with 3-chloroperbenzoic acid
(m-CPBA) to give N-oxide 19 which was then transformed to
diacetoxypyridine compound 20 by acetic anhydride treatment.
Oxidation of pyridyl nitrogen with m-CPBA followed by hydro-
lysis of two acetoxy groups gave 22.
reaction time (h)
yield (%)
ee (%)
1
2
3
4
Number of use of PS-PTC 4d
Figure 1.
catalysts, 4a and 5a.
The examination of the reusability of PS-PTC was then car-
ried out with 4d under the same conditions used in Table 2
(Figure 1). PS-PTS 4d was recovered after the first benzylation,
and the recovered 4d was then employed in the second benzyla-
tion. No significant change was found in both chemical yield
and enantioselectivity, and this tendency was continued in the
additional two cycles.
In summary, we developed a series of new cinchona PS-
PTCs in which hydrogen bonding inducing functional group is
incorporated. All of the newly prepared PS-PTCs were found
to have an ability to catalyze the asymmetric alkylation of 1
under phase-transfer conditions in good chemical/optical yields.
This work was supported by the Grant (No. E00257) from
the Korea Research Foundation (2006).
The catalytic efficiency of the newly prepared PS-PTCs was
evaluated by catalytic asymmetric benzylation of 1 under the
phase-transfer conditions. As there are some factors influencing
enantioselectivity, such as catalyst, base, solvent, and reaction
temperature, we performed this reaction with PTC 4d under
different conditions as described in Table 1. 50% KOH base
provided the highest enantioselectivity and good chemical yield
in proper reaction time compared to other bases. It was also
found that both a mixed solvent of toluene–chloroform (7:3)
and 0 ꢃC of reaction temperature gave better results than others.
We next investigated the effect of the nature of catalyst on
the reaction under the optimal conditions (Entry 5 in Table 1).
As demonstrated in Table 2, all of the hydrogen bonding induc-
ing functional group incorporated catalysts, 4b–4d and 5b–5d,
showed enhanced enantioselectivities compared to the reference
References
1
a) M. J. O’Donnell, Acc. Chem. Res. 2004, 37, 506. b) T. Ooi,
K. Maruoka, Angew. Chem., Int. Ed. 2007, 46, 4222.
´
´
2
a) R. Chinchilla, P. Mazon, C. Najera, Tetrahedron: Asymmetry
2000, 11, 3277. b) B. Thierry, J.-C. Plaquevent, D. Cahard,
Tetrahedron: Asymmetry 2001, 12, 983. c) T. Danelli, R.
Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, G. Tocco,
Tetrahedron: Asymmetry 2003, 14, 461. d) R. Chinchilla, P.
´
´
Mazon, C. Najera, Adv. Synth. Catal. 2004, 346, 1186. e) X.
Wang, L. Yin, T. Yang, Y. Wang, Tetrahedron: Asymmetry
2007, 18, 108.
3
a) S.-S. Jew, M.-S. Yoo, B.-S. Jeong, I. Y. Park, H.-G. Park, Org.
Lett. 2002, 4, 4245. b) M.-S. Yoo, B.-S. Jeong, J.-H. Lee, H.-G.
Park, S.-S. Jew, Org. Lett. 2005, 7, 1129. c) Q. Shi, Y.-J. Lee,
M.-J. Kim, M.-K. Park, K. Lee, H. Song, M. Cheng, B.-S. Jeong,
H.-G. Park, S.-S. Jew, Tetrahedron Lett. 2008, 49, 1380.
Published on the web (Advance View) March 8, 2008; doi:10.1246/cl.2008.436