A new trimeric cinchona alkaloid as a chiral phase-transfer catalyst for the synthesis of asymmetric α-amino acids

Article abstract of DOI:10.1055/s-2005-872170

A new trimeric cinchona alkaloid, the quaternary ammonium salt, α,α′,α″-tris[O(9)-allylcinchonidinium-(4- methylphenoxymethyl)]benzene trichloride, has been synthesized and used as an efficient phase-transfer catalyst in asymmetric alkylation of N-(diphen

Full text of DOI:10.1055/s-2005-872170

PAPER
2927
A New Trimeric Cinchona Alkaloid as a Chiral Phase-Transfer Catalyst for
the Synthesis of Asymmetric a-Amino Acids
C
inchona Alkaloid
y
as
a
Chira
l
P
hase-Transf
a
e
r
C
atalystnar Siva,*a Eagambaram Muruganb
a
Department of Chemistry, Gandhigram Rural Institute-Deemed University, Gandhigram 624 302, TN, India
Department of Physical Chemistry, University of Madras, Guindy Campus, Chennai 600 025, TN, India
Fax +91(451)2453071; E-mail: ptcsiva@yahoo.co.in
b
Received 1 March 2005; revised 11 May 2005
Br–
Abstract: A new trimeric cinchona alkaloid, the quaternary ammo-
nium salt, a,a¢,a¢¢-tris[O(9)-allylcinchonidinium-(4-methylphen-
oxymethyl)]benzene trichloride, has been synthesized and used as
an efficient phase-transfer catalyst in asymmetric alkylation of N-
(diphenylmethylene)glycine tert-butyl ester with very good yield
(up to 97%) and high enantioselectivity (up to 98%).
+DC
Br–
OR
N
N
OR
N
CD+
N
N
1a R = H; 1b R = allyl
2a R = H; 2b R = allyl
Key Words: enantioselective, cinchona alkaloid, trimeric, Schiff
base, a-amino acid
1
2
3
CD+
CD+
CD+
3Br–
CD+
+DC
CD+
RO
CD =
Phase-transfer catalysis (PTC) is one of the most impor-
tant and useful methods in synthetic organic reactions be-
cause of easy reaction workup, mild reaction conditions,
inexpensive and environmental friendly reagents.1 In the
asymmetric version of PTC utilizing chiral phase-transfer
catalysts, however, it has not been extensively studied as
compared to general enantioselective catalysts. Since the
pioneering work of O’Donnel and his co-workers2 leading
to the development of highly practical enantioselective
synthesis using cinchona alkaloid quaternary ammonium
salts 1 (Figure 1), they are used as chiral PTC (CPTC) for
the synthesis of asymmetric a-amino acids. But the yield
and enantiomeric excess (ee) were found to be very poor.
Further, Corey3 and Lygo4 have studied this independent-
ly and reported greatly improved enantioselectivities and
chemical yields using cinchona-based anthracenyl-de-
rived catalyst system 2. Merrifield resin bound cinchonine
and cinchonidine catalysts have also been employed as an
insoluble chiral component.5 Some of the researchers
have reported on the use of non-cinchona asymmetric cat-
alysts, viz. spiroammonium6 and phosphonium salts,7
TADDOL,8 binaphthyl-derived amines,8b,9 various transi-
tion metal anchored Salen complexes10 and chiral metal
catalysts11 for the enantioselective alkylation of glycine
imines.
N
+DC
4
5
6
R = H, allyl
Figure 1 Cinchona alkaloid quaternary ammonium salts 1–6
early literature, we envisaged that attempts should be nec-
essarily made to synthesize new chiral phase-transfer cat-
alysts. Thus we prepared a,a¢,a¢¢-tris[cinchonidinium-(4-
methylphenoxymethyl)]benzene trichloride (9a) from
cinchonidine and 1,3,5-tris(4-chloromethylphenoxymeth-
yl)benzene (8).15 Cinchonidine (3.5 equiv) and 1,3,5-
tris(4-chloromethylphenoxymethyl)benzene were stirred
at 100 °C in ethanol–DMF (6:4) for 10 hours followed by
O(9)-allylation with allyl bromide and 50% aqueous KOH
to give a,a¢,a¢¢-tris[O(9)-allylcinchonium(4-methylphen-
oxymethyl)]benzene trichloride (9b) in 87% overall yield
(Scheme 1). The efficiency of the trimeric catalysts 9
were studied by enantioselective C-alkylation of N-
(diphenylmethylene)glycine tert-butyl ester (10) using 5
mol% of catalyst along with various alkyl halides and
20% aqueous NaOH in toluene–CH2Cl2 (8:2) at –10 °C
for about 15 hours. The enatioselectivities were measured
by chiral HPLC analysis of the alkylated imines 12.
Recently, Jew et al.12 (3–5), Park et al.13 (6) and Najera et
al.14 have reported dimeric and trimeric quaternary cin-
chona-based chiral catalysts derived from o-, m-, p-xylene
dibromide and mesitylene tribromide, respectively. These
have been used as chiral PTCs to obtain good ee’s but they
required a higher amount of aqueous NaOH (50%) which
is not environmentally acceptable. Taking in view all the
The attainment of higher chemical yield and enantiomeric
excess depends on various factors, such as the nature of
the electrophiles (steric and electronic), the structure of
the CPT catalysts, the nature of the counter ion associated
with the CPT catalysts, and the polarity of the solvents.
The inorganic base that is associated with the cation of the
catalysts (R4N+) and its concentration were influenced by
the formation of chiral quaternary ammonium hydroxide.
We analyzed these factors in some depth, with a view to
achieve an efficient alkylation of glycine imine 10 using
earlier reported procedures.
SYNTHESIS 2005, No. 17, pp 2927–2933
x
x.
x
x
.
2
0
0
5
Advanced online publication: 12.08.2005
DOI: 10.1055/s-2005-872170; Art ID: Z04605SS
© Georg Thieme Verlag Stuttgart · New York

2928
A. Siva, E. Murugan
PAPER
RO
ClH2C
N
O
N
O
CH3
(i) NBS,CCl4, Bz2O2
Cinchonidine/DMF–EtOH (6:4)
100 °C
(ii) 4-OH-C6H4CHO/THF
3Cl-
(iii) LiAlH4/Et2O
(iv) PCl3/THF
H3C
CH3
O
N
O
N
O
O
RO
ClH2C
CH2Cl
7
8
9
OR
N
N
9a R = H
allyl bromide, 50% KOH,
CH2Cl2, r.t.
9b R = allyl
Scheme 1 Schematic diagram for the synthesis of CPTC catalysts
(Table 1, entries 12a–f). The increased yield and enantio-
meric excess are strongly dependent on the optical induc-
tion of CPTC’s quaternary ammonium salts (R4N+) with
enolate of the Schiff base. Thus, tert-butyl substituted
benzyl bromide provided higher yield of the product
whereas p-nitrobenzyl bromide gave a lower yield and
enantiomeric excess (Table 1, entry 12e and 12f) due to
the N-benzyl group (electrophile = NO2) that diminishes
the p-interaction between the enolate of the substrate and
catalyst.
The Nature of Electrophiles
The alkylation of glycine imine 10 was carried out with
various substituted benzyl halides in the presence of cin-
chona-derived CPTC’s, viz. 9b in 20% aqueous NaOH
and a mixture of toluene and CH2Cl2 (8:2) at low temper-
ature (–10 °C) (Table 1, entries 12a–f). From the observed
results, the enantiomeric excess increases with increasing
bulkiness of the substituents on the benzyl moiety, i.e. t-
Bu > OCH3 > CF3 > CH3 > H > NO2, due to the higher op-
tical induction with the catalyst at the chiral environment
Table 1 Dependence of Enantioselection (%) on Variously Substituted Benzyl Bromide under CPTC Conditions
CH2Br
9b (5 mol%)
20% aq. NaOH
Ph
Ph
12a X = H
Ph
Ph
CO2t-Bu
N
CO2t-Bu
*
12b X = 4-CH3
12c X = 4-CF3
12d X = 4-OCH3
12e X = 4-NO2
12f X = 4-t-Bu
+
N
toluene–CH2Cl2 (8:2)
–10 °C
X
10
11
12
X
Entry
12a
12b
12c
12d
12e
12f
Electrophiles
H
Yield (%)a
ee (%)
65
Abs. Config.b
42
59
60
90
75
93
S
S
S
S
S
S
CH3
80
CF3
87
OCH3
NO2
91
58
t-Bu
95
a Isolated products were confirmed by 1H NMR and 13C NMR spectroscopy.
b Absolute configurations were determined by chiral HPLC.
Synthesis 2005, No. 17, 2927–2933 © Thieme Stuttgart · New York

PAPER
Cinchona Alkaloid as a Chiral Phase-Transfer Catalyst
2929
ate yield and ee’s were observed when toluene used as sol-
vent due to the poor solubility of the CPTC catalyst
(Table 3, entry 2). Catalyst decomposition was observed
when polar solvents were used for the alkylation of gly-
cine imine. Generally, the use of pure toluene as solvent is
not practical for the alkylation of glycine imine due to the
poor solubility of the catalyst. Hence, we have carried out
the alkylation reaction in the presence of a mixture of sol-
vents like toluene and CH2Cl2 (8:2), which can improve
the solubility as well as influence of the enantioselectivity
of the alkylated product (Table 3, entry 6). The addition of
dichloromethane to toluene in more than 20% diminished
the chemical yield and ee’s (Table 3, entries 3–5). The
enantioselectivity of the alkylation reaction is strongly de-
pendent on the addition of toluene to the reaction mixture.
The increase of toluene amount in the solvent ratio (8:2)
influenced the chemical yield (93%) and ee’s up to 95%
under CPTC conditions at lower concentration of base
(Table 3, entries 6–11).
Nature of the Inorganic Bases
Next we carried out the alkylation of glycine imine 10
with 4-tert-butylbenzyl bromide in the presence of vari-
ous inorganic bases like KOH, LiOH, Ca(OH)2 and
K2CO3 under CPTC condition. The other parameters such
as solvents and temperature were kept as constant. From
the results, it is very clear that the NaOH afforded better
results as compared to other bases (Table 2, entry 1–5)
due to weak ionic interaction of Na+ with the substrate.
The highest ee’s and yield were observed when 20%
aqueous NaOH solution was used (Table 2, entry 2). The
chemical yield as well as the ee’s were too low when
KOH, Ca(OH)2, LiOH and K2CO3 were used as bases
(Table 2, entries 1,3–5) due to strong ionic interaction be-
tween the quaternary ammonium salts of the CPTC’s and
substrates of the enolate anion (ion-pair interaction).
When the concentration of aqueous NaOH was increased
(more than 20%) decomposition of the catalyst occurred
(Table 2, entry 6–8). A similar observation was noticed by
O’Donnell et al.16 for the enantioselective alkylation of
ketimine in the presence of aqueous 50% NaOH as a base.
Table 3 Effect of Solvents on Alkylation of Glycine Imine under
CPTC Conditions
CH2Br
Table 2 Influence of Various Bases on Syntheses of a-Amino Acids
Ph
Ph
CO2t-Bu
Cat. 9b (5 mol%)
N
*
Ph
Ph
CO t-Bu
+
2
CH2Br
N
solvent,
20% aq. NaOH
–10 °C
Cat. 9b (5 mol%)
Ph
Ph
CO2t-Bu
Ph
Ph
t-Bu
N
*
aqueous base
t-Bu
11f
CO t-Bu
+
10
2
N
12f
toluene–CH2Cl2 (8:2)
–10 °C
t-Bu
11f
10
t-Bu
Entry
Solvent
CH2Cl2
toluene
Yield (%)a
ee (%)b
17 (S)
36 (S)
71 (S)
66 (S)
58 (S)
46 (S)
35 (S)
87 (S)
95 (S)
78 (S)
67 (S)
12f
Entry Aqueous Solution Yield (%)a ee (%)
(Base)
Abs. Config.b
1
2
9
39
65
57
49
38
19
87
93
82
76
1
2
3
4
5
6
7
8
KOH (20%)
NaOH (20%)
LiOH (20%)
Ca(OH)2 (20%)
K2CO3 (20%)
NaOH (30%)
NaOH (40%)
NaOH (50%)
45
93
58
27
23
68
60
42
59
95
38
25
46
83
68
41
S
S
S
S
S
S
S
S
3
toluene–CH2Cl2(1:1)
toluene–CH2Cl2 (4:6)
toluene–CH2Cl2 (3:7)
toluene–CH2Cl2 (2:8)
toluene–CH2Cl2 (1:9)
toluene–CH2Cl2 (9:1)
toluene–CH2Cl2 (8:2)
toluene–CH2Cl2 (7:3)
toluene–CH2Cl2 (6:4)
4
5
6
7
8
9
10
11
a Isolated products were confirmed by 1H NMR and 13C NMR spec-
troscopy.
b Absolute configurations were determined by chiral HPLC.
a Isolated products were confirmed by 1H NMR and 13C NMR spec-
troscopy.
b Absolute configurations were determined by chiral HPLC.
Effect of Solvents on Enantioselective Alkylation of
Glycine Imine
Effect of Temperature on Alkylation of Glycine Imine
The reactivity and also enantioselectivity of the CPTCs
are dependent on their solubility and stability in the organ-
ic solvent under the PTC conditions. The alkylation reac-
tions were carried out in the presence of various polar or
non-polar solvents, the selected solvent results are pre-
sented in Table 3. Lower yield of alkylation was observed
in pure CH2Cl2 as solvent because the solvent reacted with
the aqueous sodium hydroxide (Table 3, entry 1). Moder-
The observed yield and ee’s are strongly dependent on the
reaction temperature. Variation of the temperature also af-
fects the ion pair interaction between the enolate of the
substrate and quaternary ammonium of the CPTC’s. Some
selected results are presented in Table 4. The change in
temperature of the alkylation reaction was studied from
+30 to –30 °C. From the observed results, the higher yield
Synthesis 2005, No. 17, 2927–2933 © Thieme Stuttgart · New York

2930
A. Siva, E. Murugan
PAPER
and ee’s were obtained at –10 °C because at higher tem- In conclusion, the present study has shown that a-amino
perature the catalyst was decomposed. Hence the opti- acids can be successfully synthesized using two different
mum temperature for the alkylation reaction is –10 °C stable new trimeric cinchona-based chiral phase-transfer
(Table 4, entries 1–6). However no influence on the ee catalysts (CPTC) 9a and 9b. These two different new
was observed when the reaction temperature was lowered chiral PTC’s were structurally confirmed by various spec-
1
13
at –20 and –30 °C (Table 4, entries 5, 6) due to the lower tral techniques like FT-IR, H, C NMR and mass spec-
induction between the enolate of the substrate and cata- troscopy. The catalytic efficiency was studied by the
lyst. The same observation was reported by Park et al.13 alkylation of glycine imine and gave very good yields (up
for the synthesis of a-amino acids at a lower temperature to 97%) and ee’s (up to 98%) under phase-transfer catalyt-
of –20 °C in the presence of ortho-fluoro dimeric cincho- ic conditions. The applications of CPT catalyst 9 to other
na-derived phase-transfer catalysts.
enantioselective catalytic reactions are currently being
studied.
Table 4 Effect of Temperature on Enantioselective Alkylations of
Glycine Imine
All melting points are uncorrected. The IR spectra were recorded
CH2Br
1
using Shimadzu FT-IR 8300 instrument. The H and 13C NMR
Cat. 9b (5 mol%)
Ph
Ph
CO2t-Bu
spectra of all compounds in DMSO-d6 were recorded using Jeol
GSX (200, 300 and 400 MHz) NMR spectrometer. The mass spec-
tra were obtained on a using Jeol (HRMS) spectrometer. Column
chromatography was performed using silica gel (100–200 mesh
size). The enantioselectivities were determined by chiral HPLC
analysis using a chiral column (DAICEL Chiralcel OD).
Ph
Ph
N
*
CO2t-Bu
+
N
20% aq. NaOH
toluene–CH2Cl2
(8:2)
t-Bu
11f
10
t-Bu
–10 °C to +30 °C
12f
Entry
Temp (°C)
Yield (%)a
ee (%)b
59 (S)
68 (S)
76 (S)
95 (S)
89 (S)
77 (S)
1
2
3
4
5
6
30
67
73
79
93
87
78
1,3,5-Tris(bromomethyl)benzene
Mesitylene (4.0 g, 33.28 mmol), N-bromosuccinimide (22.65 g,
116.48 mmol), benzoyl peroxide (2.5 g) and CCl4 (75 mL) were tak-
en in a 250-mL round-bottomed flask. The reaction mixture was re-
fluxed in an oil bath for 12 h at 70 °C. Then the succinimide formed
was removed by filtration and the solvent was evaporated to give a
yellow colored solid; yield: 24.52 g (92%); mp 96 °C.
FT-IR (KBr): 686, 2956 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.26 (s, 6 H), 7.03 (s, 3 H).
20
10
–10
–20
–30
a Isolated products were confirmed by 1H NMR and 13C NMR spec-
troscopy.
1,3,5-Tris(4-chloromethylphenoxymethyl)benzene (8)
1,3,5-Tris(bromomethyl)benzene (3.0 g, 8.41 mmol), p-hydroxy-
benzaldehyde (3.59 g, 29.46 mmol, 3.5 equiv), THF (50 mL) and a
catalytic amount of K2CO3 were taken in a 250-mL round-bottomed
flask. The mixture was refluxed for 12 h at 80 °C. Then the solvent
was removed by distillation to give the crude 1,3,5-tris(4-methoxy-
benzaldehyde)benzene, which was recrystallized from EtOH; yield:
6.13 g (93%).
b Absolute configurations were determined by chiral HPLC.
We examined next the catalytic efficiency of the CPTCs 9
in phase-transfer alkylation of glycine imine 10 with a va-
riety of alkyl halides 13 to give the alkylated products 14.
Selected results are presented in Table 5. In the case of
alkylations, better results were obtained when 9b was
used as a catalyst (Table 5, entries 2, 4, 5, 7–9, 11–13).
The observed results show lower yield and ee’s when 9a
was used as a catalyst, due to the formation of hydrogen
bond between the C9-(OH) of the catalyst with the enolate
1,3,5-Tris(4-methoxybenzaldehyde)benzene
FT-IR (KBr): 1698 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.8 (s, 6 H), 6.8–7.32 (m, 15 H),
10.32 (s, 3 H).
The above aldehyde was reduced with EtOH in the presence of a
of the substrates (Table 5, entries 1, 3, 6 and 10). In all en- catalytic amount of LiAlH4 in Et2O (40 mL). The alcoholic com-
pound was treated with PCl3 in the presence of THF to give 1,3,5-
tries of the alkylation reactions, the absolute configuration
tris(4-chloromethylphenoxymethyl)benzene (8). It was purified by
was S. In addition, the reaction with 9-bromomethylan-
silica gel column chromatography using EtOH–benzene (30:70) as
an eluent; yield: 4.15 g (83%).
FT-IR (KBr): 722, 1058 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.46 (s, 6 H), 5.20 (s, 6 H), 6.67
thracene (entry 5), 4-bromomethyl-1H-indene (entry 8),
3-bromomethyl-1-(toluene-4-sulfonyl)-1H-indole (entry
9), 3-bromomethylthiophene (entry 12) and 2-naphthyl
bromide (entry 13) afforded the corresponding protected
(d, 6 H, J = 6.56 Hz), 7.10 (s, 3 H), 7.22 (d, 6 H, J = 6.56 Hz).
unnatural a-amino acids, which can be versatile interme-
diates of various unnatural a-amino acids, up to 98% ee. 13C NMR (50 MHz, CDCl3): d = 47.6, 72.3, 114.7, 125.2, 129.8,
130.5, 141.6, 160.4.
MS: m/z = 541.07 (M+).
In the case of our trimeric catalyst 9, it showed higher
chemical yield and ee’s than the previously reported cata-
lysts 412 and 613 under identical reaction conditions
(Table 5, entries 1, 2, 14 and 15) due to the minimization
of steric hindrance.
a,a¢,a¢¢-Tris[allylcinchonidinium(4-methylphenoxymeth-
yl)]benzene Trichloride
Compound 8 (0.88 g, 1.95 mmol), cinchonidine (1.72 g, 5.85 mmol,
3 equiv) and DMF–EtOH (6:4) were taken in a 100-mL round-bot-
Synthesis 2005, No. 17, 2927–2933 © Thieme Stuttgart · New York

PAPER
Cinchona Alkaloid as a Chiral Phase-Transfer Catalyst
2931
Table 5 Enantioselective Catalytic Phase-Transfer Alkylation of Glycine Imine
CPTC (5 mol%)
20% aq. NaOH
Ph
Ph
Ph
Ph
CO2t-Bu
CO2t-Bu
+
N
N *
R'
14
R'X
toluene–CH2Cl2 (8:2)
–10 °C
10
13
Entry
R¢X
Catalyst
9a
Time (h)
Yield (%)a
ee (%)
56
Abs. Config.b
1
2
3
4
5
PhCH2Br
PhCH2Br
CH2=CHCH2Br
CH2=CHCH2Br
Br
10.0
10.0
10.0
10.0
12.5
38
42
54
96
92
S
S
S
S
S
9b
65
9a
53
9b
86
9b
94
6
7
8
CH≡CCH2Br
CH≡CCH2Br
Br
9a
9b
9b
12.0
12.0
12.0
93
84
88
77
90
92
S
S
S
9
9b
10.0
92
89
S
Br
N
Ts
10
11
12
CH3I
CH3I
CH2Br
9a
9b
9b
7.5
7.5
6.5
90
92
89
85
95
98
S
S
S
S
13
14
15
2-NaphCH2Br
9b
6
7.0
10.0
10.0
97
31
53
96
53
61
S
S
S
PhCH2Br
PhCH2Br
4
a Isolated products were confirmed by 1H NMR and 13C NMR spectroscopy.
b Absolute configurations were determined by chiral HPLC.
tomed flask. The mixture was refluxed for 36 h at 100 °C. After
completion of reaction time, the solvent was removed by vacuum
distillation. The crude compound of 9a was purified by silica gel
column chromatography using acetone–hexane (30:70) as an elu-
ent; yield: 2.44 g (94%); mp 243 °C (dec.).
HRMS (FAB): m/z calcd for [C87H93N6O6]3+: 1318.7043; found:
1318.3894.
Anal. Calcd for C87H93Cl3N6O6: C, 73.33; H, 6.58; N, 5.90. Found:
C, 73.19; H, 6.52; N, 5.76.
FT-IR (KBr): 3487, 2934, 1245 cm–1.
a,a¢,a¢¢-Tris[O(9)-allylcinchonidinium(4-methylphenoxymeth-
yl)]benzene Trichloride
1H NMR (400 MHz, DMSO-d6): d = 1.48–1.53 (m, 1 H) 1.65 (t,
J = 8.60 Hz, 2 H), 1.70 (q, J = 11.8 Hz, 2 H), 2.77 (q, J = 12.4 Hz,
1 H), 3.24–3.30 (m, 4 H), 4.07–4.15 (m, 1 H), 4.48 (s, 2 H), 5.11 (d,
J = 13.0 Hz, 1 H), 5.16 (s, 2 H), 5.22 (q, 1 H), 5.40 (br s, 1 H), 6.03
(d, J = 15.44 Hz, 2 H), 6.72 (d, J = 16.48 Hz, 2 H), 6.93 (d,
J = 15.04 Hz, 2 H), 7.02 (d, J = 14.56 Hz, 1 H), 7.15 (s, 3 H), 7.41
(t, J = 10.32 Hz, 1 H), 7.47 (t, J = 7.1 Hz, 1 H), 7.76 (d, J = 9.36 Hz,
Compound 9, allyl bromide, aq 50% KOH and CH2Cl2 (30 mL)
were taken in a 100-mL round-bottomed flask. The reaction mixture
was stirred at r.t. for 24 h. Then the solvent was removed by vacuum
distillation and the crude product was purified by column chroma-
tography over silica gel using hexane–MeOH (60:40) as eluent;
yield: 1.31 g (87%).
1 H), 8.12 (d, J = 8.88 Hz, 1 H), 8.66 (d, J = 8.88 Hz, 1 H).
9b
13C NMR (100 MHz, DMSO-d6): d = –28.3, 30.2, 37.8, 38.4, 61.3,
65.2, 65.8, 69.4, 78.3, 79.4, 114.3, 114.7, 119.6, 123.2, 125.2,
125.5, 126.4, 127.8, 129.2, 130.6, 131.2, 140.2, 141.8, 143.6, 148.6,
149.8, 158.5.
Mp 231 °C (dec.).
FT-IR (KBr): 2967, 1256, 1087 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.34–1.40 (m, 1 H) 1.63 (t,
J = 6.66 Hz, 2 H), 1.75–1.82 (m, 2 H), 2.82–2.89 (m, 1 H), 3.22–
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A. Siva, E. Murugan
PAPER
3.29 (m, 4 H), 4.05 (t, J = 7.3 Hz, 2 H), 4.22 (q, J = 15.4 Hz, 1 H),
4.45 (s, 2 H), 5.12 (d, J = 15.12 Hz, 1 H), 5.17 (s, 2 H), 5.20 (q,
J = 13.6 Hz, 1 H), 5.43 (br s, 1 H), 5.55–5.60 (m, 1 H), 5.78 (d,
J = 16.84 Hz, 2 H), 6.04 (d, J = 14.2 Hz, 2 H), 6.65 (d, J = 15.96 Hz,
2 H), 6.87 (d, J = 15.96 Hz, 2 H), 7.12 (d, J = 12.96 Hz, 1 H), 7.18
(s, 3 H), 7.37 (t, J = 5.16 Hz, 1 H), 7.52 (t, J = 5.16 Hz, 1 H), 7.73
(d, J = 16.44 Hz, 1 H), 8.21 (d, J = 12.88 Hz, 1 H), 8.43 (d, J = 13.2
Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = –26.6, 33.4, 36.8, 38.4, 61.7,
65.5, 66.9, 69.7, 70.8, 78.3, 79.5, 114.3, 114.5, 115.7, 119.7, 122.2,
125.5, 125.8, 126.9, 127.2, 129.2, 131.6, 131.2, 135.4, 142.2, 143.8,
144.6, 147.8, 150.1, 155.6.
MS: m/z = 453.18 (M+).
tert-Butyl 3-(4-Methoxyphenyl)-2-diphenylmethyleneamino-
propanoate [(S)-12d]
Synthesized following the general procedure and according to the
reaction condition listed in Table 1; yield: 0.18 g, 90%; [a]D25 –17.3
(c = 0.2, CHCl3).
FT-IR (KBr): 3042, 2965, 1698, 1555, 1236, 786 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.32 (s, 9 H), 3.10 (s, 3 H), 3.24
(d, 2 H, J = 10.0 Hz), 4.45 (t, 1 H, J = 4.0 Hz), 7.02 (d, 2 H, J = 6.0
Hz), 7.38 (d, 2 H, J = 4.0 Hz), 7.47–7.85 (m, 10 H).
13C NMR (50 MHz, DMSO-d6): d = 24.5, 37.7, 62.3, 71.3, 120.2,
127.5, 129.4, 130.4, 131.9, 132.5, 133.7, 137.5, 141.6, 161.3, 179.0.
HRMS (FAB): m/z calcd for [C96H105N6O6]3+: 1438.8023; found:
1438.7896.
MS: m/z 415.18 (M+).
Anal. Calcd for C96H105Cl3N6O6: C, 74.62; H, 6.85; N, 5.44. Found:
C, 74.46; H, 6.61; N, 5.39.
HRMS: m/z calcd for C27H29NO3: 415.2397; found: 415.2186.
tert-Butyl 3-(4-Nitrophenyl)-2-diphenylmethyleneaminopro-
panoate [(S)-12e]
Synthesized following the general procedure and according to the
reaction condition listed in Table 1; yield: 0.16 g, 75%; [a]D25 –16.7
(c = 0.2, CHCl3).
FT-IR (KBr): 3055, 2910, 1725, 1560, 1467, 1223, 1075 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.15 (s, 9 H), 3.12 (d, 2 H,
J = 6.0 Hz), 4.25 (t, 1 H, J = 5.0 Hz), 7.23–7.66 (m, 14 H).
Alkylation of Glycine Imine 10; General Procedure
A solution of glycine imine 10 (0.5 mmol) in toluene–CH2Cl2 (8:2)
was treated sequentially with the appropriate catalyst 9 (5 mol%),
alkylating agent 11 or 13 (0.5 mmol), and 20% aq NaOH (0.5 mL)
(see Tables 1 and 5). The resulting mixture was stirred at –10 °C for
about 1–15 h. The aqueous layer was extracted with EtOAc (5 × 5
mL), and the combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to give the crude product 12 or
14. This was dissolved in THF (5 mL) and 15% aq citric acid (1.5
mL) was added. The mixture was stirred vigorously at r.t. for 1 h,
and then diluted with H2O (5 mL). The mixture was extracted with
Et2O (2 × 5 mL) to remove any excess alkylating agent and ben-
zophenone, then the aqueous layer was basified with K2CO3. Ex-
traction with EtOAc (3 × 5 mL) followed by drying (Na2SO4) and
concentration under reduced pressure gave the crude a-amino acid
tert-butyl ester, which can be generally purified by passing through
a plug of silica gel (Tables 1 and 5). The enantioselectivities were
measured by chiral HPLC analysis (DAICEL Chiralcell OD, hex-
ane–propan-2-ol, flow rate 0.5 mL/min, at 25 °C, l = 254 nm). The
absolute configuration was determined by comparison of the HPLC
retention time with the authentic sample synthesized by the earlier
reported procedure.2,3
MS: m/z = 430.18 (M+).
tert-Butyl 3-(4-tert-Butylphenyl)-2-diphenylmethyleneamino-
propanoate [(S)-12f]
Synthesized following the general procedure and according to the
reaction condition listed in Table 1; yield: 0.21 g, 93%; [a]D25 –28.2
(c = 0.2, CHCl3).
FT-IR (KBr): 3050, 2915, 1705, 1555, 1450, 1224, 1065 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.35 (s, 9 H), 2.16 (s, 9 H), 3.25
(d, 2 H, J = 8.4 Hz), 4.36 (t, 1 H, J = 6.4 Hz), 6.92–7.67 (m, 14 H).
13C NMR (50 MHz, DMSO-d6): d = 24.8, 28.4, 39.5, 65.7, 73.2,
76.4, 122.2, 128.9, 130.2, 131.5, 132.8, 134.7, 135.5, 141.6, 165.2,
185.1.
tert-Butyl 3-Phenyl-2-diphenylmethyleneaminopropanoate
[(S)-12a]
MS: m/z = 441.52 (M+).
Synthesized following the general procedure and according to the
reaction condition listed in Table 1; yield: 0.21 g, 42%; [a]D25 –13.4
(c = 0.2, CHCl3).
FT-IR (KBr): 3025, 2906, 1710, 1525, 1235 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.45 (s, 9 H), 3.25 (d, 2 H,
J = 8.4 Hz), 4.35 (t, 1 H, J = 4.0 Hz), 7.12–7.35 (m, 15 H).
tert-Butyl 3-(2-Allyl)-2-diphenylmethyleneaminopropanoate
[(S)-14, R¢ = CH2CH=CH2] (Table 5, Entry 4)
Synthesized following the general procedure and according to the
reaction condition listed in Table 5; yield: 0.15 g, 96%; [a]D25 –19.2
(c = 0.2, CHCl3).
FT-IR (KBr): 3065, 2926, 1720, 1629, 1245 cm–1.
13C NMR (50 MHz, DMSO-d6): d = 27.4, 37.6, 61.9, 73.0, 124.7,
1H NMR (300 MHz, DMSO-d6): d = 1.40 (s, 9 H), 2.65 (t, 2 H,
J = 5.7 Hz), 4.25 (t, 1 H, J = 6.6 Hz), 4.95 (d, 2 H, J = 8.4 Hz), 5.72
(m, 1 H), 7.15–7.60 (m, 10 H).
13C NMR (75 MHz, DMSO-d6): d = 28.3, 35.2, 57.4, 71.4, 114.6,
127.6, 128.5, 130.5, 137.8, 161.7, 175.9.
125.3, 128.4, 128.9, 129.5, 130.8, 137.5, 141.6, 160.8, 176.9.
MS: m/z = 385.19 (M+).
HRMS: m/z calcd for C26H27NO2: 386.2042; found: 386.1897.
MS: m/z = 321.41 (M+).
tert-Butyl 3-(4-Trifluoromethylphenyl)-2-diphenylmethylene-
aminopropanoate [(S)-12c]
Synthesized following the general procedure and according to the
reaction condition listed in Table 1; yield: 0.13 g, 60%; [a]D25 –14.3
(c = 0.2, CHCl3).
tert-Butyl 3-(9-Methylanthracenyl)-2-diphenylmethyleneami-
nopropanoate [(S)-14, R¢ = methylanthracenyl)] (Table 5, Entry
5)
FT-IR (KBr): 3076, 2904, 1732, 1610, 1230 cm–1.
Synthesized following the general procedure and according to the
reaction condition listed in Table 5; yield: 0.22 g, 92%; [a]D25 –21.3
(c = 0.2, CHCl3).
FT-IR (KBr): 3024, 2875, 1710, 1598, 1225 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.40 (s, 9 H), 3.70 (d, 2 H,
J = 5.16 Hz), 4.35 (t, 1 H, J = 6.0 Hz), 7.07–78.02 (m, 19 H).
1H NMR (300 MHz, DMSO-d6): d = 1.32 (s, 9 H), 3.25–3.29 (d, 2
H, J = 12.0 Hz), 4.32–4.38 (t, 1 H, J = 9.0 Hz), 7.05–7.09 (d, 2 H,
J = 12.0 Hz), 7.41–7.44 (d, 2 H, J = 9.0 Hz), 7.47–7.76 (m, 10 H).
13C NMR (75 MHz, DMSO-d6): d = 26.2, 37.3, 61.6, 73.2, 119.6,
125.3, 128.2, 128.6, 129.2, 130.5, 137.4, 143.8, 164.5, 178.2.
Synthesis 2005, No. 17, 2927–2933 © Thieme Stuttgart · New York

PAPER
Cinchona Alkaloid as a Chiral Phase-Transfer Catalyst
2933
13C NMR (50 MHz, DMSO-d6): d = 27.2, 33.5, 61.4, 73.5, 124.6,
125.3, 125.8, 126.2, 128.2, 128.6, 129.1, 130.2, 131.3, 132.3, 132.6,
137.4, 165.7, 182.6.
References
(1) For general reviews on asymmetric PTC, see:
(a) O’Donnell, M. J. Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley: New York, 2000. (b) Shioiri, T.;
Arai, S. Stimulating Concepts in Chemistry; Vogtle, F.;
Stoddart, J. F.; Shibaski, M., Eds.; Wiley: New York, 2000.
(c) Nelson, A. Angew. Chem. Int. Ed. 1999, 38, 1583.
(2) (a) O’Donnell, M. J.; Benett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353. (b) Lipkowitz, K. B.; Cavanaugh, M.
W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56,
5181. (c) O’Donnell, M. J.; Wu, S. Tetrahedron: Asymmetry
1992, 3, 591. (d) O’Donnell, M. J.; Wu, S.; Huffman, J. C.
Tetrahedron 1994, 50, 4507. (e) O’Donnell, M. J.; Delgado,
F.; Hostettller, C.; Schwesinger, R. Tetrahedron Lett. 1998,
39, 8775. (f) O’Donnell, M. J.; Delgado, F.; Pottorf, R.
Tetrahedron 1999, 55, 6347.
(3) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414. (b) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron
Lett. 1998, 39, 5347. (c) Corey, E. J.; Bo, Y.; Busch-
Peterson, J. J. Am. Chem. Soc. 1998, 120, 13000.
(4) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
8595. (b) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron
Lett. 1999, 40, 1389. (c) Lygo, B. Tetrahedron Lett. 1999,
40, 1389. (d) Lygo, B.; Crosby, J.; Peterson, J. A.
Tetrahedron Lett. 1999, 40, 8671.
(5) (a) Zhang, Z.; Wang, Y.; Hodge, P. React. Funct. Polym.
1999, 41, 37. (b) Chinchilla, R.; Mazon, P.; Najera, C.
Tetrahedron: Asymmetry 2000, 11, 3277.
(6) (a) Ooi, T.; Kameda, M. J. Am. Chem. Soc. 1999, 121, 6519.
(b) Ooi, T.; Tayama, E.; Doda, K.; Takeuchi, M.; Maruoka,
K. Synlett 2000, 1500. (c) Ooi, T.; Takeuchi, M.; Kameda,
M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.
(7) (a) Manabe, K. Tetrahedron Lett. 1998, 39, 5807.
(b) Manabe, K. Tetrahedron 1998, 54, 14456.
(8) (a) Belokon, Y. N.; Kotchetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Vyskocil, S.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 851. (b) Belokon, Y. N.; Kotchetkov,
K. A.; Churkina, T. D.; Ikonnikov, N. S.; Chesnokov, A. A.;
Larionov, A. V.; Singh, I.; Parmar, V. S.; Vyskocil, S.;
Kagan, H. B. J. Org. Chem. 2000, 65, 7041.
MS: m/z = 485.49 (M+).
tert-Butyl 3-(Inden-3-yl)-2-diphenylmethyleneaminopro-
panoate [(S)-12, R¢ = inden-3-yl] (Table 5, Entry 8)
Synthesized following the general procedure and according to the
reaction condition listed in Table 5; yield: 0.19 g, 88%; [a]D25 –26.4
(c = 0.2, CHCl3).
FT-IR (KBr): 3058, 2920, 1720, 1684, 1217 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.35 (s, 9 H), 3.22 (d, 2 H,
J = 13.8 Hz), 3.35 (d, 2 H, J = 11.4 Hz), 4.24 (t, 1 H, J = 7.83 Hz),
6.38 (dd, 2 H, J = 7.5, 8.1 Hz), 6.95 (t, 1 H, J = 7.4 Hz), 7.04 (dd, 2
H, J = 6.6, 7.4 Hz), 7.14–7.80 (m, 10 H).
13C NMR (75 MHz, DMSO-d6): d = 24.5, 29.2, 30.3, 62.4, 72.9,
121.4, 123.5, 125.8, 127.0, 128.4, 128.6, 129.0, 130.2, 134.2, 135.5,
137.7, 140.3, 163.4, 182.4.
MS: m/z = 423.12.
tert-Butyl 3-[(1-Toluene-4-sulfonyl)indol-3-yl]-2-diphenylmeth-
yleneaminopropanoate [(S)-12, R¢ = (1-toluenesulfonyl)indol-3-
yl] (Table 5, Entry 9)
Synthesized following the general procedure and according to the
reaction condition listed in Table 5; yield: 0.18 g, 92%; [a]D25 –19.2
(c = 0.2, CHCl3).
FT-IR (KBr): 3025, 2910, 1715, 1522, 1235 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.36 (s, 9 H), 2.44 (s, 3 H), 3.12
(d, 2 H, 8.07 Hz), 4.35 (t, 1 H, J = 5.20 Hz), 6.8 (s, 1 H), 7.22 (dd,
2 H, J = 7.92, 8.04 Hz), 7.52 (dd, 2 H, J = 7.5, 8.4 Hz).
13C NMR (75 MHz, DMSO-d6): d = 27.2, 38.6, 61.7, 73.4, 125.7,
127.3, 128.4, 128.9, 129.5, 130.7, 137.2, 140.6, 164.8, 172.9.
MS: m/z = 385.19 (M+).
HRMS: m/z calcd for C26H27NO2: 386.2042; found: 386.1897.
tert-Butyl 3-(Methyl)-2-diphenylmethyleneaminopropanoate
[(S)-12, R¢ = Me] (Table 5, Entry 11)
(9) (a) Belokon, Y. N.; Kotchetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Vyskocil, S.; Kagan, H. B. Tetrahedron:
Asymmetry 1999, 10, 1723. (b) Belokon, Y. N.; Kotchetkov,
K. A.; Churkina, T. D.; Ikonnikov, N. S.; Larionov, O. V.;
Harutyunyan, S. R.; Vyskocil, S.; North, M.; Kagan, H. B.
Angew Chem. Int. Ed. 2001, 40, 1948. (c) Casas, J.; Najera,
C.; Sansano, J. M.; Gonzalez, J.; Saa, J. M.; Vega, M.
Tetrahedron: Asymmetry 2001, 12, 699.
(10) (a) Belokon, Y. N.; North, M.; Kublitski, V. S.; Ikonokov, N.
S.; Krasik, P. E.; Maleev, V. L. Tetrahedron Lett. 1999, 40,
6105. (b) Belokon, Y. N.; Davies, R. G.; North, M.
Tetrahedron Lett. 2000, 41, 7245.
(11) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.;
Ohshima, T.; Shibasaki, T. Tetrahedron Lett. 2002, 43,
9539.
(12) Jew, S.; Jeong, B.; Yoo, M.; Park, H.; Huh, H. Chem.
Commun. 2001, 1244.
Synthesized following the general procedure and according to the
reaction condition listed in Table 5; yield: 0.14 g, 92%; [a]D25 –15.7
(c = 0.2, CHCl3).
FT-IR (KBr): d = 3022, 2919, 1710, 1520, 1233 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.40 (s, 9 H), 1.52 (d, 3 H,
J = 9.42 Hz), 4.17 (q, 1 H, J = 13.95 Hz), 6.8–7.45 (m, 10 H).
13C NMR (75 MHz, DMSO-d6): d = 17.8, 27.2, 55.6, 73.2, 128.4,
129.3, 130.5, 137.4, 155.4, 176.6.
MS: m/z = 309.38 (M+).
tert-Butyl 3-(3-Thiophenyl)-2-diphenylmethyleneaminopro-
panoate [(S)-12, R¢ = 3-thiophenyl] (Table 5, Entry 12)
Synthesized following the general procedure and according to the
reaction condition listed in Table 5; yield: 0.17 g, 89%; [a]D25 –27.3
(c = 0.2, CHCl3).
FT-IR (KBr): 3060, 2925, 1720, 1618, 1232 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.27 (s, 9 H), 3.27 (d, 2 H,
J = 7.8 Hz), 4.22 (t, 1 H, J = 7.02 Hz), 6.02 (s, 1 H).
(13) Park, H.; Jeong, B.; Yoo, M.; Park, M.; Huh, H.; Jew, S.
Tetrahedron Lett. 2001, 42, 4645.
(14) Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron:
Asymmetry 2002, 13, 927.
(15) Rajakumar, P.; Srisailas, M. Tetrahedron Lett. 2002, 43,
1909.
13C NMR (75 MHz, DMSO-d6): d = 29.3, 32.1, 62.4, 74.5, 121.5,
126.8, 128.2, 129.1, 129.7, 130.6, 137.2, 138.4, 165.4, 168.8.
MS: m/z = 391.29 (M+).
(16) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994,
50, 4507.
Synthesis 2005, No. 17, 2927–2933 © Thieme Stuttgart · New York