Improved conditions for the asymmetric synthesis of α-amino acids using Cinchona-derived anthracenylmethyl ammonium salts as chiral phase-transfer organocatalysts

Article abstract of DOI:10.1016/j.tetasy.2006.12.004

Cinchonidine and cinchonine-derived monomeric anthracenylmethyl ammonium salts bearing different counter-anions are used as chiral organocatalysts in the enantioselective alkylation of a benzophenone-imine tert-butyl glycinate under phase-transfer conditi

Full text of DOI:10.1016/j.tetasy.2006.12.004

Tetrahedron: Asymmetry 17 (2006) 3423–3429
Improved conditions for the asymmetric synthesis of a-amino
acids using Cinchona-derived anthracenylmethyl ammonium
salts as chiral phase-transfer organocatalysts
*
´
Rafael Chinchilla, Carmen Najera and Francisco J. Ortega
Departamento de Quı´mica Orga´nica and Instituto de Sı´ntesis Orga´nica (ISO), Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
Received 30 November 2006; accepted 4 December 2006
Available online 11 January 2007
Abstract—Cinchonidine and cinchonine-derived monomeric anthracenylmethyl ammonium salts bearing different counter-anions are
used as chiral organocatalysts in the enantioselective alkylation of a benzophenone-imine tert-butyl glycinate under phase-transfer con-
ditions. Generally, an improvement of the enantioselectivity is observed when the counterions are tetrafluoroborate and hexafluorophos-
phate using 50% aqueous KOH as the base and toluene/chloroform as the solvent. The enantioselectivities achieved are comparable and
frequently higher, even working under simpler and less-strict reaction conditions and with lower organocatalyst loading, than those
reported previously.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
guanidinium salts,13f binaphthyl-derived amines,13b,14 and
salen-metal complexes15 have also been used.
The asymmetric synthesis of a-amino acids has always been
always considered as a synthetic challenge due to their bio-
logical properties, therefore boosting the development of
many methodologies.1 Especially interesting from an
industrial point of view are those which include the use
of a catalyst, and amongst them the phase-transfer cataly-
sis (PTC)2 applied to the asymmetric alkylation of glycine
and alanine Schiff bases is probably the most simple and
easy to scale up. Thus, the enantioselective alkylation of
amino acid imines under PTC conditions catalyzed by salts
from Cinchona alkaloids3 pioneered by O’Donnell with
benzylated ammonium salts, such as the cinchonidine-
derived 14 and its pseudoenantiomeric cinchonine-derived
counterpart 2,4f and improved by Lygo (3a)5 and Corey
(3d)6 by changing the benzyl by an anthracenylmethyl
group, allowed high degrees of enantioselection using a
very simple procedure to be achieved. Encouraged by these
results, dimeric,7 trimeric,8 dendrimeric9 Cinchona alka-
loid-derived catalysts and even polymer-supported Cin-
chona-derived species have been developed.10 In addition,
catalysts such as spiro ammonium11 and phosphonium
salts,12 TADDOL13a,b and other tartaric derivatives,13c–e
Cl-
Cl-
N
N
+
+
OH
HO
N
N
1
2
X-
N
+
OR
N
3d, R = Allyl, X = Br
3e, R = Allyl, X = BF4
3f, R = Allyl, X = PF6
3a, R = H, X = Cl
3b, R = H, X = BF4
3c, R = H, X = PF6
Amongst this array of PTC catalysts, and considering
large-scale use, the cinchonidine-derived monomeric
ammonium salts developed by Lygo5 (3a) and Corey6
(3d) are the most simple, easily available, and economical.
*
Corresponding author. Tel.: +34 96 5903728; fax: +34 96 5903549;
e-mail: cnajera@ua.es
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.004

3424
R. Chinchilla et al. / Tetrahedron: Asymmetry 17 (2006) 3423–3429
Table 1. Enantioselective benzylation of glycine imine 4 under reported
and new PTC conditions
Comparing their performance in the alkylation of tert-
butyl N-(diphenylmethylene)glycinate, the cinchonidine-
derived ammonium salt 3a has been used in the synthesis
of (S)-a-amino acid derivatives under liquid–liquid PTC
condition with economical bases, such as KOH and at
room temperature, although the higher ee’s achieved are
only close to 90%. Ammonium salt 3d affords generally
higher ee’s than 3a (even higher than 99%), although these
results were achieved under solid–liquid PTC conditions,
using relatively expensive CsOH as a base and low reaction
temperatures (generally at or below ꢀ60 ꢁC) in CH2Cl2 as a
solvent. In spite of the use of this rather strict reaction
conditions, the asymmetric alkylation of tert-butyl N-
(diphenylmethylene)glycinate using 3d as a PTC catalysts
has frequently been used in the preparation of many a-ami-
no acids of interest.16
PhCH2Br
Ph
N
CO2tBu
Ph
N
CO2tBu
catalyst, conditions
Ph
Ph
Ph
4
(S)-5a
Entry
Catalyst
R
Cond.a t (h) Yieldb (%) eec (%)
No.
X
1
2
3
4
5
6
3a
3a
3a
3d
3d
3d
H
H
H
Cl
Cl
A
B
3
3
3
23
1.5
70
50
73
90
86
93
91
91
90
91
93
95
Cl Bd
Allyl Br
Allyl Br
Allyl Br Bd
C
B
3
a Conditions A: 10 mol % cat., 50% aq KOH, toluene, 25 ꢁC (reported in
Ref. 5a: 18 h, 68%, 91% ee); Conditions B: 5 mol % cat., 50% aq KOH,
toluene/CHCl3 (7/3 v/v), 25 ꢁC; Conditions C: 10 mol % cat., CsOHÆ
H2O, CH2Cl2, ꢀ78 ꢁC (reported in Ref. 6a: 23 h, 87%, 94% ee).
b Crude yield determined by 1H NMR (300 MHz).
c Determined by chiral GLC from the corresponding trifluoroacetamides
(see Experimental).
d The reaction was performed at 0 ꢁC.
Recently, a certain influence of the counter anion accompa-
nying the chiral ammonium salt in the enantioselectivity of
this reaction has been observed in a two-center tartrate-
derived bis-ammonium salt,17 this influence being even
larger when using the dimeric cinchonidinium and cinchon-
inium salts developed by our group,18 as well as in enantio-
selective Michael addition reactions.19 These observations
are especially interesting, as an improvement in the enantio-
selectivity of these chiral PTC catalysts can be achieved just
by changing their accompanying counterion, which is more
simple and straightforward than by modifying their struc-
tural features. A subsequent question is, if a counter-anion
exchange in the more simple monomeric salts 3a and 3d,
perhaps also combined with a modification of the reaction
conditions, would positively affect their performance as
chiral PTC catalysts. Thus, an anion-exchanged salt from
the less-derivatized 3a might be more suitable for achieving
the high enantioselectivities required, whereas an
exchanged salt from its allylated derivative 3d could keep
its high-performing properties although avoiding the use
of strict reaction conditions.
insolubility of the catalysts in the organic reaction phase.
This problem has been observed in related PTC alkylations
carried out in toluene, resulting in a reduction in the effec-
tive concentration of the catalyst which therefore gives a
lower enantioselection.20
The reaction of glycinate 4 with benzyl bromide under PTC
conditions using cinchonidine-derived chloride salt 3a as a
catalyst under Conditions B at room temperature or at
0 ꢁC gave 91% and 90% ee, respectively, of the correspond-
ing benzylated product (S)-5 in 3 h reaction time (Table 1,
entries 2 and 3), which was similar than the results we ob-
tained for this catalyst when using Conditions A5a with a
much longer reaction time (Table 1, entry 1). In addition,
the allylated cinchonidine bromide 3d gave rise in our
hands to a 94% ee of (S)-5a under Conditions C during
23 h (Table 1, entry 4).6a However, a quite similar 93% ee
could be obtained in 1.5 h working at room temperature
under Conditions B (Table 1, entry 5). This value increased
to 95% ee by lowering the reaction temperature down to
0 ꢁC (Table 1, entry 6). It can be concluded that Conditions
B at 0 ꢁC can afford similar enantioselectivities in much
lower reaction times than the previously described Condi-
tions A or C and with lower catalyst loading. Therefore,
for this benzylation reaction, the O-allylated salt 3d is a
more efficient catalyst than 3a.
2. Results and discussion
The cinchonidine-derived ammonium salts 3a and 3d where
employed as chiral PTC catalysts (5 mol %) in the model
benzylation reaction of tert-butyl N-(diphenylmethylene)-
glycinate 4 to give the corresponding enantiomerically
enriched benzylated compound (S)-5a. The first experi-
ments focused on a comparison between the enantioselec-
tivities achieved under the previously reported conditions
(Table 1, Conditions A and C) and others considered
appropriate for further developments (Table 1, Conditions
B). The base selected was the economical 50% aqueous
KOH. The solvent employed was a mixture of toluene/
chloroform (7/3 v/v) at room temperature or at 0 ꢁC with
a 5% mol of the phase-transfer catalyst. The use of this par-
ticular mixture of organic solvents for this liquid–liquid
PTC alkylation process was found to give the highest
enantioselectivities originally by Jew and Park using
dimeric cinchonidinium salts as catalysts and working at
temperatures of 0 and ꢀ20 ꢁC.7a The incorporation of a
certain amount of a more polar solvent than the toluene
allows lowering the reaction temperature avoiding a possible
After determining the suitability of the new reaction condi-
tions for performing the model benzylation reaction with, at
least, comparable enantioselectivities, the next step was to
investigate the influence of the counter anion of the catalyst
in the enantioselectivity of the reaction under Conditions B
at 0 ꢁC, which gave good enantioselectivities while keeping
a non-strict and easy-handling methodology. The tetrafluo-
roborate and hexafluorophosphate anions were considered
appropriate for exchanging the chloride anion of cinchoni-
dine-derived ammonium salt 3a and the bromide anion of
3d, as they have proven to give rise to a better enantioselec-

R. Chinchilla et al. / Tetrahedron: Asymmetry 17 (2006) 3423–3429
3425
tion,17–19 probably because they can form less tight ionic
pairs than chloride or bromide, thus allowing an easier
and rapid complexation of the chiral ammonium cation
with the glycine-derived enolate. Thus, the chloride anion
of 3a was exchanged by the tetrafluoroborate and the hexa-
fluorophosphate anions, after the reaction of 3a with
2.5 equiv of sodium tetrafluoroborate or potassium hexaflu-
orophosphate, respectively, in acetonitrile as a solvent for
1 day at room temperature. After the addition of ether
and filtration, the resulting solids were washed with water
and dried to give the corresponding salts 3b and 3c in
98% and 97% yields, respectively. Similarly the O(9)-allyl-
ated tetrafluoroborate and hexafluorophosphate cinchoni-
dine-derived salts 3e and 3f were prepared in 96% and
94% yields, respectively, now starting from the O-allylated
bromide 3b. Tetrafluoroborates 3b and 3e and hexafluoro-
phosphates 3c and 3f showed infrared spectra revealing
new strong absorption bands around 1060 3b and 3e and
840 (3c and 3f) cmꢀ1, corresponding to the tetrafluorobo-
rate and hexafluorophosphate anions, respectively.
and 3f also proved interesting. Thus, under Conditions B
at 0 ꢁC, the enantioselectivity achieved was 96% when the
exchanged O-allylated tetrafluoroborate 3e was used as a
catalyst, whereas for (S)-5a a 96% ee was obtained when
the O-allylated hexafluorophosphate 3f was used (Table
2, entries 5 and 6). This value increased to 97% ee when
the temperature was lowered to ꢀ20 ꢁC.
Taking into account the above mentioned consideration of
cinchonine-derived ammonium salts as pseudoenantiomers
of their cinchonidine counterparts, and a simple way of
achieving an opposite enantioselection,4f a cinchonine-de-
rived series of PTC catalysts 6 bearing different counterions
were also prepared following the same methodology as de-
scribed above. Thus, starting from chloride 6a, tetrafluoro-
borate 6b, and hexafluorophosphate 6c were prepared in
90% and 87% yields, respectively, whereas O-allylated bro-
mide 6d gave rise to the corresponding salts 6e and 6f in
82% and 85% yields, respectively; these anion exchanges
were also confirmed by IR spectroscopy.
The results obtained in the benzylation of glycinate 4 using
these exchanged salts are shown in Table 2, where the
reported values included in Table 1 for 3a and 3d are
included for a rapid comparison (Table 2, entries 1 and
4). Thus, the reaction of glycinate 4 using the cinchonidine-
derived exchanged tetrafluoroborate salt 3b as a catalyst
under Conditions B, afforded (S)-5a with an enantioselec-
tivity raised up to 94% (Table 2, entry 2) when compared
with its counterpart 3a (Table 2, entry 1); no influence
when lowering the temperature down to ꢀ20 ꢁC was ob-
served. A similar improvement in the final enantioselection
was detected when hexafluorophosphate 3c was employed
as a catalyst under Conditions B, (S)-5a with 95% ee (Table
2, entry 3) being obtained.
X-
N
+
RO
N
6d, R = Allyl, X = Br
6e, R = Allyl, X = BF4
6f, R = Allyl, X = PF6
6a, R = H, X = Cl
6b, R = H, X = BF4
6c, R = H, X = PF6
The use of these cinchonine-derived ammonium salts 6 as
PTC catalysts for the standard model benzylation reaction
under Conditions B at 0 ꢁC afforded, as expected, the (R)-
5a product. Thus, when chloride 6a was used as a catalyst,
a 93% ee of (R)-5a was obtained (Table 2, entry 7). This
The results observed when working with the new O-allyl-
ated cinchonidine-derived exchanged ammonium salts 3d
Table 2. Enantioselective benzylation of glycine imine 4 under PTC conditions
PhCH2Br
Ph
N
CO2tBu
Ph
N
CO2tBu
*
3 or 6 (5 mol%)
50% aq. KOH,
PhMe/CHCl3, 0 ºC
Ph
Ph
Ph
5a
4
Entry
Catalyst
R
Time (h)
Product
No.
X
No.
Yielda (%)
S/R Ratiob
ee (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
H
H
H
Allyl
Allyl
Allyl
H
H
H
Cl
3
2
2.5
3
2.5
1
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(R)-5a
(R)-5a
(R)-5a
(R)-5a
(R)-5a
(R)-5a
73
80
60
93
83
84
94
94
93
86
75
73
95/5
97/3
97.5/2.5
97.5/2.5
98/2
98/2
3.5/96.5
1/99
3/97
4/96
90
94
95
95
96
96
93c
98
94
92
92
95
BF4
PF6
Br
BF4
PF6
Cl
BF4
PF6
Br
BF4
PF6
6a
6b
6c
6d
6e
6f
10
24
24
6
23
20
10
11
12
Allyl
Allyl
Allyl
4/96
2.5/97.5
a Crude yield determined by 1H NMR (300 MHz).
b Determined by chiral GLC from the corresponding trifluoroacetamides (see Experimental).
c Literature values under Conditions A: 10 mol % cat., 18 h, 63%, 89% ee (Ref. 5a).

3426
R. Chinchilla et al. / Tetrahedron: Asymmetry 17 (2006) 3423–3429
value could be increased up to 98% ee when using the tet-
rafluoroborate counterpart 6b as a catalyst (Table 2, entry
8), although close to the enantioselection obtained using
the exchanged hexafluorophosphate 6c (Table 2, entry 9).
These values were clearly higher than these reported with
catalyst 6a under Conditions A (see footnote c in Table
2). When the O-allylated cinchonine-derived bromide 6d
was used as a catalyst, 92% ee of the benzylated product
was obtained, an identical value when using the exchanged
tetrafluoroborate 6e (Table 2, entries 10 and 11). However,
when hexafluorophosphate 6f was used, a higher 95% ee
for (R)-5a was obtained, a value similar than to when using
its cinchonidine pseudoenantiomeric counterpart 3f was ob-
tained, although in a longer reaction time (Table 2, entry
12).
performed using allyl bromide as the electrophile and
cinchonidine-derived chloride 3a as the PTC catalyst under
these reaction conditions, a 95% ee of the corresponding
allylated compound (S)-5b was obtained (Table 3, entry
2), which is a rather high value, when taking into account
that the use of catalyst 3a under Conditions A is reported
to afford an 88% ee for (S)-5b (Table 3, entry 1).5a When
this allylation reaction was performed using the exchanged
tetrafluoroborate 3b, the enantioselectivity dropped to
92%. However, a maximum value of 98% ee was achieved
using hexafluorophosphate 3c as a catalyst (Table 3, entries
3 and 4). When the O-allylated cinchonidine-derived bro-
mide catalyst 3d was employed for this allylation reaction,
the enantioselection for the corresponding (S)-5b was only
85%, which is lower than the 97% ee previously reported
using Conditions C6a (Table 3, entries 5 and 6). However,
in this case, the use of the exchanged tetrafluoroborate
and hexafluorophosphate O-allylated salts 3e or 3f allowed
an increase in the initially rather low enantioselection up to
a 96% ee for both catalysts (Table 3, entries 7 and 8).
The next step was extending the study of the PTC alkyl-
ation reaction of glycinate 4 with the anion-exchanged cat-
alysts to other activated and non-activated electrophiles
under Conditions B at 0 ꢁC. Thus, when the reaction was
Table 3. Enantioselective alkylation of glycine imine 4 under PTC conditions
RHal
Ph
N
CO2tBu
Ph
N
CO2tBu
3 (5 mol%), 50% aq. KOH
PhMe/CHCl3, 0 ºC
Ph
Ph
R
(S)-5
4
Entry
Catalyst
R
RHal
Time (h)
Product
S/R Ratiob
Ref.
5a
No.
X
No.
Yielda (%)
ee (%)
1c
2
3
4
5d
6
7
8
9e
10
11
12
13c
14
15
16d
17
18
19f
20
21c
22g
23
24
25
26
27
28
3a
3a
3b
3c
3d
3d
3e
3f
H
H
H
H
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
H
Cl
Cl
BF4
PF6
Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
2-O2NC6H4CH2Br
2-O2NC6H4CH2Br
2-O2NC6H4CH2Br
2-O2NC6H4CH2Br
CH3I
CH3I
CH3I
CH3I
CH3I
CH3I
CH3I
CH3I
18
3.5
5
5
22
3
5
(S)-5b
(S)-5b
(S)-5b
(S)-5b
(S)-5b
(S)-5b
(S)-5b
(S)-5b
(S)-5c
(S)-5c
(S)-5c
(S)-5c
(S)-5d
(S)-5d
(S)-5d
(S)-5d
(S)-5d
(S)-5d
(S)-5d
(S)-5d
(S)-5e
(S)-5e
(S)-5e
(S)-5e
(S)-5e
(S)-5e
(S)-5e
(S)-5e
76
93
84
81
87
80
96
73
92
88
90
81
41
55
52
71
50
58
44
47
67
49
41
64
56
86
85
80
94/6
97.5/2.5
96/4
88
95
92
98
97
85
96
96
92.5
90
94
94
89
89
89
97
90
93
93
92
68
76
81
81
78
80
79
86
99/1
98.5/1.5
92.5/7.5
98/2
98/2
96.25/3.75
95/5
6a
21
Br
BF4
PF6
Br
5.5
3d
3d
3e
3f
n.r.
12
12
12
3
24
24
28
24
23
28
24
18
8
8
8
8
8
8
27
Br
BF4
PF6
Cl
Cl
PF6
Br
97/3
97/3
3a
3a
3c
3d
3d
3e
3e
3f
95.5/5.5
94.5/5.5
94.5/5.5
98.5/1.5
95/5
96.5/3.5
96.5/3.5
96/4
84/16
88/12
90.5/9.5
90.5/9.5
89/11
5a
6a
H
H
Allyl
Allyl
Allyl
Allyl
Allyl
H
H
H
H
H
Br
BF4
BF4
PF6
Cl
Cl
Cl
BF4
PF6
Br
BF4
PF6
3a
3a
3a
3b
3c
3d
3e
3f
BrCH2CO2t-Bu
BrCH2CO2t-Bu
BrCH2CO2t-Bu
BrCH2CO2t-Bu
BrCH2CO2t-Bu
BrCH2CO2t-Bu
BrCH2CO2t-Bu
BrCH2CO2t-Bu
5e
Allyl
Allyl
Allyl
90/10
89.5/10.5
93/7
a Crude yield determined by 1H NMR (300 MHz).
b Determined by chiral GLC from the corresponding trifluoroacetamides (see Experimental).
c Literature results under Conditions A.
d Literature results under Conditions C.
e Literature results under Conditions C at ꢀ30 ꢁC.
f The reaction was performed at ꢀ20 ꢁC.
g The reaction was carried out at 25 ꢁC.

R. Chinchilla et al. / Tetrahedron: Asymmetry 17 (2006) 3423–3429
3427
When 2-nitrobenzyl bromide was used as the electrophile in
the presence of the O-allylated cinchonidine-derived bro-
mide catalyst 3d, benzylated compound (S)-5c was obtained
in a 90% ee (Table 3, entry 10). This value was increased up
to 94% ee when the exchanged ammonium salts 3e and 3f
were used as the catalysts (Table 3, entries 11 and 12). This
enantioselection was higher than that reported for (S)-5c
employing Conditions C but working at ꢀ30 ꢁC (92.5%
ee, Table 3, entry 9), in a synthesis of enantiomerically
enriched 3-amino-3,4-dihydro-1H-quinolin-2-one, a useful
building block in the synthesis of many biologically active
compounds.21
organocatalyst, and tuning the catalyst efficiency by means
of an anion exchange from chloride or bromide to tetra-
fluoroborate and hexafluorophosphate, can give shorter
reaction times, better yields, and higher enantioselectivities.
4. Experimental
4.1. General
All the reagents and solvents employed were of the best
grade available and used without further purification.
The ammonium salts 3a,5a 3d,6a 6a,5a and 6d4e were pre-
pared as described. Melting points are uncorrected. IR
data were collected on a Nicolet Impact 400D-FT spec-
trometer and only diagnostic bands are given. The 1H
NMR spectra were recorded on a Bruker AC-300 at
300 MHz, using CDCl3 as a solvent and TMS as the inter-
nal standard. The enantiomeric excesses of products 5 were
determined by GLC analyses of the corresponding N-triflu-
oroacetamide esters, obtained after 15% aq citric acid
hydrolysis of imines 5 and further reaction with trifluoro-
acetic anhydride22 (Crownpack Chirasil-L-Val column,
25 m · 0.25 mm i.d.; conditions for 5a, 5c, 5d, and 5e:
P = 85 kPa, 1 min 85 ꢁC, 2 ꢁC/min to 180 ꢁC; conditions
for 5b: P = 50 kPa, 1 min 105 ꢁC, 1 ꢁC/min to 180 ꢁC).
GLC reference racemic samples were prepared from the
corresponding racemic 5, which were obtained using
tetra-n-butylammonium bromide as a phase-transfer cata-
lyst. The absolute configuration was determined by the sign
of the specific rotation of phenylalanine, obtained by the
hydrolysis of (S)-5a under refluxing 6M HCl and treatment
with propylene oxide.23
The use of a non-activated electrophile, such as methyl
iodide, gave, as expected, longer reaction times and lower
yields. When chloride salt 3a was used as PTC catalysts
under Conditions B at 0 ꢁC, the corresponding (S)-5d was
obtained in an 89% ee, an identical value to that detected
when the usually enantioselection-increasing tetrafluoro-
borate salt 3c was employed (Table 3, entries 14 and 15).
This was also identical to the reported value observed under
Conditions A5a (Table 3, entry 13). In addition, when the
O-allylated cinchonidine-derived bromide 3d was used as
a catalyst, a 90% ee of the corresponding methylated prod-
uct (S)-5d was obtained. This value could be increased
slightly up to 93% and 92% ee when the exchanged tetra-
fluoroborate and hexafluorophosphate salts 3e and 3f,
respectively, were employed. No difference when lowering
the reaction temperature was detected (Table 3, entries
17–20). This methylation reaction has been previously re-
ported using bromide 3d as a catalyst, reaching up to 97%
ee, although working at ꢀ60 ꢁC6a (Table 3, entry 16).
More polar alkylating reagents, such as tert-butyl bromo-
acetate, are considered ‘difficult’ electrophiles for this type
of alkylation reactions, usually giving lower enantioselectiv-
ities, probably as a consequence of an increased rate of the
non-catalyzed background reaction.5e Thus, the use of bro-
mide 3a under Conditions A is reported to afford the corre-
sponding product (S)-5e in only 68% ee5e (Table 3, entry
21). However, just the use of Conditions B at room temper-
ature allowed us to raise this value to 76% ee (Table 2, entry
22), whereas the enantioselectivity achieved was an 81% ee
using chloride 3a or the exchanged tetrafluoroborate 3b
under Conditions B at 0 ꢁC, the hexafluorophosphate 3c
giving place to a 78% ee (Table 2, entries 23–25). The O-allyl-
ated bromide 3d or tetrafluoroborate 3e performed similarly
under Conditions B at 0 ꢁC, to afford the alkylated product
in 80% and 79% ee, respectively, whereas a remarkable 86%
ee could be achieved when using hexafluorophosphate 3f as
a catalyst (Table 3, entries 22–26).
4.2. Preparation of cinchonidine-derived ammonium salts 3b,
3c, 3e, and 3f
To a suspension of 3a (500 mg, 0.96 mmol) or 3d (581 mg,
0.96 mmol) in acetonitrile (9 mL) was added sodium tetra-
fluoroborate (2.4 mmol, 263 mg) or potassium hexafluoro-
phosphate (2.4 mmol, 442 mg). The reaction mixture was
stirred at room temperature for 24 h. After this time, the
solvent was removed and the mixture diluted with water
(10 mL) and extracted with CH2Cl2 (3 · 5 mL). The com-
bined organic extracts were dried over MgSO4 and evapo-
rated in vacuo to give a crude product, which was washed
with water and Et2O. Filtration and drying afforded 3b
(539 mg, 98%) and 3c (587 mg, 97%) from 3a, and 3e
(564 mg, 96%) and 3f (605 mg, 94%) from 3d. The 1H
NMR of these products were identical to those reported
for the starting materials.
3. Conclusions
4.2.1. N-9-Anthracenylmethylcinchonidinium tetrafluoro-
25
We can conclude that the enantioselectivity of the alkyl-
ation reaction of iminic glycinates under PTC conditions
using the common, simple, and inexpensive monomeric
cinchonidine and cinchonine-derived ammonium salts can
be improved, considerably, by using sometimes less-strict
reaction conditions. Thus, using 50% aqueous KOH in tol-
uene/chloroform as a solvent, lowering the loading of
borate 3b. Mp 173 ꢁC, ½aꢁD ¼ ꢀ316 (c 0.7, acetone),
IR (KBr) m 3419, 1060, 745 cmꢀ1
.
4.2.2. N-9-Anthracenylmethylcinchonidinium hexafluoro-
25
phosphate 3c. Mp 167 ꢁC, ½aꢁD ¼ ꢀ190 (c 0.5, acetone), IR
(KBr) m 3522, 839, 557 cmꢀ1
.

3428
R. Chinchilla et al. / Tetrahedron: Asymmetry 17 (2006) 3423–3429
4.2.3. O(9)-Allyl-N-anthracenylmethylcinchonidinium tetra-
Alicante for financial support. F.J.O. thanks the Universi-
dad de Alicante for a grant.
25
fluoroborate 3e. Mp 145 ꢁC, ½aꢁD ¼ ꢀ154 (c 0.5,
acetone), IR (KBr) m 1460, 1066, 743 cmꢀ1
.
4.2.4. O(9)-Allyl-N-anthracenylmethylcinchonidinium hexa-
25
References
fluorophosphate 3f. Mp 159 ꢁC, ½aꢁD ¼ ꢀ189 (c 0.8, ace-
tone), IR (KBr) m 1462, 839, 557 cmꢀ1
.
1. (a) Williams, R. M. Synthesis of Optically Active Amino
Acids; Pergamon Press: Oxford, 1989; (b) Stammer, C. H.
Tetrahedron 1990, 46, 2231–2254; (c) Heimgartner, H. Angew.
Chem., Int. Ed. Engl. 1991, 30, 238–264; (d) Williams, R. M.;
Hendrix, J. A. Chem. Rev. 1992, 92, 889–917; (e) Duthaler, R.
O. Tetrahedron 1994, 50, 1540–1650; (f) Burgess, K.; Ho,
K.-K.; Mye-Sherman, D. Synlett 1994, 575–583; (g) Bailey, P.
D.; Clayson, J.; Boa, A. N. Contemp. Org. Synth. 1995, 173–
187; (h) North, M. Contemp. Org. Synth. 1996, 323–343; (i)
Studer, A. Synthesis 1996, 793–815; (j) Seebach, D.; Sting, A.
R.; Hoffmann, M. Angew. Chem., Int. Ed. 1996, 35, 2708–
2748; (k) Wirth, T. Angew. Chem., Int. Ed. 1997, 36, 225–227;
4.3. Preparation of cinchonine-derived ammonium salts 6b,
6c, 6e, and 6f
To a suspension of 6a (500 mg, 0.96 mmol) or 6d (581 mg,
0.96 mmol) in acetonitrile (9 mL) was added sodium tetra-
fluoroborate (2.4 mmol, 263 mg) or potassium hexafluoro-
phosphate (2.4 mmol, 442 mg). The reaction mixture was
stirred at room temperature for 24 h. After this time, the
solvent was removed and the mixture diluted with water
(10 mL) and extracted with CH2Cl2 (3 · 5 mL). The com-
bined organic extracts were dried over MgSO4 and evapo-
rated in vacuo to give a crude which was washed with water
and Et2O. Filtration and drying afforded 6b (495 mg, 90%)
and 6c (527 mg, 87%) from 6a, and 6e (482 mg, 82%) and 6f
´
(l) Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron:
´
Asymmetry 1998, 9, 3517–3599; (m) Cativiela, C.; Dıaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645–732;
´
(n) Abellan, T.; Chinchilla, R.; Galindo, N.; Guillena, G.;
´
Najera, C.; Sansano, J. M. Eur. J. Org. Chem. 2000, 2689–
1
´
2697; (o) Najera, C. Synlett 2002, 1388–1403.
(547 mg, 85%) from 6d. The H NMR of these products
2. (a) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer
Catalysis, 3rd ed.; VCH: Weinheim, 1993; (b) Starks, C.
M.; Liotta, C. L.; Halpern, M. Phase-Transfer Catalysis;
Chapman & Hall: New York, 1994; (c) Handbook of Phase-
Transfer Catalysis; Sasson, Y., Neumann, R., Eds.; Blackie
Academic & Professional: London, 1997; (d) Phase-Transfer
Catalysis; Halpern, M. E., Ed. ACS Symposium Series 659;
American Chemical Society: Washington, DC, 1997; (e)
Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583–1585; (f)
Makosza, M. Pure Appl. Chem. 2000, 72, 1399–1403.
3. (a) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961–998; (b)
Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028; (c)
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518–525;
(d) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506–517; (e)
Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005.
4. (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353–2355; (b) Lipkowitz, K. B.; Cavanaugh,
M. W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56,
5181–5192; (c) O’Donnell, M. J.; Wu, S. Tetrahedron:
Asymmetry 1992, 3, 591–594; (d) O’Donnell, M. J.; Wu, S.;
Huffman, J. C. Tetrahedron 1994, 50, 4507–4518; (e) O’Don-
nell, M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55,
6347–6362; (f) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3–
15.
5. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
8595–8598; (b) Lygo, B.; Crosby, J.; Peterson, J. A. Tetra-
hedron Lett. 1999, 40, 1385–1388; (c) Lygo, B. Tetrahedron
Lett. 1999, 40, 1389–1392; (d) Lygo, B.; Crosby, J.; Peterson,
J. A. Tetrahedron Lett. 1999, 40, 8671–8674; (e) Lygo, B.;
Crosby, J.; Lowdon, T. R.; Peterson, J. A.; Wainwright, P. G.
Tetrahedron 2001, 57, 2403–2409; (f) Lygo, B.; Andrews, B.
I.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 2002, 43,
8015–8018; (g) Lygo, B.; Allbutt, B. Synlett 2004, 326–328.
6. (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414–12415; (b) Corey, E. J.; Noe, M. C.; Xu, F.
Tetrahedron Lett. 1998, 39, 5347–5350; (c) Horikawa, M.;
Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40,
3843–3846.
were identical to those reported for the starting materials.
4.3.1. N-9-Anthracenylmethylcinchoninium tetrafluoro-
25
borate 6b. Mp 194 ꢁC, ½aꢁD ¼ þ250 (c 1.0, CHCl3), IR
(KBr) m 3448, 1062, 743 cmꢀ1
.
4.3.2. N-9-Anthracenylmethylcinchoninium hexafluorophos-
25
phate 6c. Mp 179 ꢁC, ½aꢁD ¼ þ166 (c 0.9, acetone),
IR (KBr) m 3545, 839, 558 cmꢀ1
.
4.3.3. O(9)-Allyl-N-anthracenylmethylcinchoninium tetra-
25
fluoroborate 6e. Mp 159 ꢁC, ½aꢁD ¼ þ193 (c 0.7,
CHCl3), IR (KBr) m 1461, 1060, 744 cmꢀ1
.
4.3.4. O(9)-Allyl-N-anthracenylmethylcinchoninium hexaflu-
25
orophosphate 6f. Mp 165 ꢁC, ½aꢁD ¼ þ152 (c 0.7,
acetone), IR (KBr) m 1462, 835, 558 cmꢀ1
.
4.4. Enantioselective phase-transfer alkylations. General
procedure
To a mixture of 4 (74 mg, 0.25 mmol) and chiral catalyst 5
or 6 (0.0125 mmol) in a 7:3 v/v mixture of toluene and
CHCl3 (1.5 mL) was added 50% aqueous KOH
(0.140 mL, 1.25 mmol) and the corresponding alkyl halide
(1.25 mmol). The reaction mixture was stirred vigorously
at 0 ꢁC and monitorized by GLC. The suspension was
diluted with H2O (10 mL) and extracted with EtOAc
(3 · 3 mL). The organics were dried over MgSO4, filtered,
and evaporated in vacuo, affording crude products 5 which
were analyzed and identified by their 1H NMR data
(5a,b,d,e5e and 5c21).
Acknowledgements
7. (a) Jew, S.; Jeong, B.; Yoo, M.; Huh, H.; Park, H. Chem.
Commun. 2001, 1244–1245; (b) Park, H.; Jeong, B.; Yoo, M.;
Lee, J.; Park, M.; Lee, Y.; Kim, M.; Jew, S. Angew. Chem.,
´
We thank the Spanish Ministerio de Ciencia y Tecnologıa
(CTQ2004-00808/BQU), the Generalitat Valenciana
(GRUPOS03/134 and GV05/144) and the Universidad de
´
Int. Ed. 2002, 41, 3036–3038; (c) Chinchilla, R.; Mazon, P.;

R. Chinchilla et al. / Tetrahedron: Asymmetry 17 (2006) 3423–3429
3429
´
Najera, C. Tetrahedron: Asymmetry 2002, 13, 927–931; (d)
Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43,
9535–9537; (e) Kowtoniuk, W. E.; MacFarland, D. K.;
Grover, G. N. Tetrahedron Lett. 2005, 46, 5703–5705; (f)
Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagas-
awa, K. Angew. Chem., Int. Ed. 2002, 41, 2832–2834.
Park, H.; Jeong, B.; Yoo, M.; Lee, J.; Park, B.; Kim, M.; Jew,
S. Tetrahedron Lett. 2003, 44, 3497–3500; (e) Siva, A.;
Murugan, E. J. Mol. Catal. A: Chem. 2005, 241, 111–117.
8. (a) Park, H.; Jeong, B.; Yoo, M.; Park, M.; Huh, H.; Jew, S.
Tetrahedron Lett. 2001, 42, 4645–4648; (b) Siva, A.; Mur-
ugan, E. Synthesis 2005, 2927–2933.
9. (a) Mazon, P.; Chinchilla, R.; Najera, C.; Guillena, G.;
Kreiter, R.; Klein Gebbink, R. J. M.; van Koten, G.
Tetrahedron: Asymmetry 2002, 13, 2181–2185; (b) Guillena,
G.; Kreiter, R.; van de Coevering, R.; Klein Gebbink, R. J.
14. (a) Belokon’, Y. N.; Kotchetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Vyskocil, S.; Kagan, H. B. Tetrahedron:
Asymmetry 1999, 10, 1723–1728; (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, 1948–1951;
´
´
´
´
´
´
´
M.; van Koten, G.; Mazon, P.; Chinchilla, R.; Najera, C.
(c) Casas, J.; Najera, C.; Sansano, J. M.; Gonzalez, J.; Saa, J.
M.; Vega, M. Tetrahedron: Asymmetry 2001, 12, 699–702.
15. (a) Belokon’, Y. N.; North, M.; Kublitski, V. S.; Ikonnikov,
N. S.; Krasik, P. E.; Maleev, V. L. Tetrahedron Lett. 1999, 40,
6105–6108; (b) Belokon’, Y. N.; Davies, R. G.; North, M.
Tetrahedron Lett. 2000, 41, 7245–7248; (c) Belokon’, Y. N.;
Bhave, D.; D’Addario, D.; Groaz, E.; North, M.; Tag-
liazucca, V. Tetrahedron 2004, 60, 1849–1861.
Tetrahedron: Asymmetry 2003, 14, 3705–3712.
10. (a) Yongmei, W.; Zhengpu, Z.; Zhen, W.; Jiben, M.; Hodge,
P. Chin. J. Polym. Sci. 1998, 16, 356–361; (b) Zhengpu, Z.;
Yongmei, W.; Zhen, W.; Hodge, P. React. Funct. Polym.
´
´
1999, 41, 37–43; (c) Chinchilla, R.; Mazon, P.; Najera, C.
Tetrahedron: Asymmetry 2000, 11, 3277–3281; (d) Thierry, B.;
Plaquevent, J.-C.; Cahard, D. Tetrahedron: Asymmetry 2001,
12, 983–986; (e) Thierry, B.; Perrard, T.; Audouard, C.;
Plaquevent, J.-C.; Cahard, D. Synthesis 2001, 1742–1746; (f)
Thierry, B.; Plaquevent, J.-C.; Cahard, D. Tetrahedron:
Asymmetry 2003, 14, 1671–1677; (g) Danelli, T.; Annunziata,
R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco, G.
Tetrahedron: Asymmetry 2003, 14, 461–467; (h) Chinchilla,
16. (a) Jotterand, N.; Pearce, D. A.; Imperiali, B. J. Org. Chem.
2001, 66, 3224–3228; (b) Boisnard, S.; Carbonnelle, A.-C.;
Zhu, J. Org. Lett. 2001, 3, 2061–2064; (c) Boeckmann, R. K.,
Jr.; Clark, T. J.; Shook, B. C. Org. Lett. 2002, 4, 2109–2112;
(d) Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J. J. Org.
Chem. 2003, 68, 9835–9838; (e) Shults, M. D.; Pearce, D. A.;
Imperiali, B. J. Am. Chem. Soc. 2003, 125, 10591–10597; (f)
Armstrong, A.; Scutt, J. N. Chem. Commun. 2004, 510–511;
(g) De Paolis, M.; Chen, X.; Zhu, J. Synlett 2004, 729–731;
(h) Lin, L. S.; Lanza, T. J.; Castonguay, L. A.; Kamenecka,
T.; McCauley, E.; Van Riper, G.; Egger, L. A.; Mumford, R.
A.; Tong, X.; MacCoss, M.; Schmidt, J. A.; Hagmann, W. K.
Bioorg. Med. Chem. Lett. 2004, 14, 2331–2334; (i) Srinivasan,
J. M.; Burks, H. E.; Smith, C. R.; Viswanathan, R.; Johnston,
J. N. Synthesis 2005, 330–333; (j) Chen, X.; Chen, J.; De
Paolis, M.; Zhu, J. J. Org. Chem. 2005, 70, 4397–4408; (k)
Lepine, R.; Zhu, J. Org. Lett. 2005, 7, 2981–2984; (l) Van
Rompaey, K.; Ballet, S.; Tomboly, C.; De Wachter, R.;
Vanommeslaeghe, K.; Biesemans, M.; Willem, R.; Tourwe,
D. Eur. J. Org. Chem. 2006, 2899–2911; (m) Couturier, C.;
Schlama, T.; Zhu, J. Synlett 2006, 1691–1694.
´
´
R.; Mazon, P.; Najera, C. Molecules 2004, 9, 349–364; (i)
Chinchilla, R.; Mazon, P.; Najera, C. Adv. Synth. Catal.
´
´
2004, 346, 1186–1194.
11. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519–6520; (b) Ooi, T.; Tayama, E.; Doda, K.;
Takeuchi, M.; Maruoka, K. Synlett 2000, 1500–1502; (c) Ooi,
T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228–5229; (d) Ooi, T.; Uematsu, Y.;
Maruoka, K. Adv. Synth. Catal. 2002, 344, 288–291; (e)
Ooi, T.; Uematsu, Y.; Maruoka, K. Tetrahedron Lett. 2004,
45, 1675–1678; (f) Kano, T.; Konishi, S.; Shirakawa, S.;
Maruoka, K. Tetrahedron: Asymmetry 2004, 15, 1243–1245;
(g) Shirakawa, S.; Yamamoto, K.; Kitamura, M.; Ooi, T.;
Maruoka, K. Angew. Chem., Int. Ed. 2005, 44, 625–628; (h)
Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem.,
Int. Ed. 2005, 44, 1549–1551; (i) Han, Z.; Yamaguchi, Y.;
Kitamura, M.; Maruoka, K. Tetrahedron Lett. 2005, 46,
8555–8558; (j) Ooi, T.; Takeuchi, M.; Kato, D.; Uematsu, Y.;
Yamada, E.; Sakai, D.; Maruoka, K. J. Am. Chem. Soc. 2005,
127, 5073–5083.
17. (a) Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Fukuta,
Y.; Nemoto, T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
11206–11207; (b) Ohshima, T.; Shibuguchi, T.; Fukuta, Y.;
Shibasaki, M. Tetrahedron 2004, 60, 7743–7754.
´
´
18. Chinchilla, R.; Mazon, P.; Najera, C.; Ortega, F. J. Tetra-
12. (a) Manabe, K. Tetrahedron Lett. 1998, 39, 5807–5810; (b)
Manabe, K. Tetrahedron 1998, 54, 14456–14476.
hedron: Asymmetry 2004, 15, 2603–2607.
´
´
19. Chinchilla, R.; Mazon, P.; Najera, C.; Ortega, F. J. Arkivoc
13. (a) Belokon’, Y. N.; Kotchetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, A. V.;
2005, vi, 222–232.
20. Lygo, B.; Andrews, B. I. Tetrahedron Lett. 2003, 44, 4499–
´
Parmar, V. S.; Kumar, R.; Kagan, H. B. Tetrahedron:
4502.
Asymmetry 1998, 9, 851–857; (b) Belokon’, Y. N.; Kotchet-
21. Hulin, B.; Lopaze, M. G. Tetrahedron: Asymmetry 2004, 15,
kov, K. A.; Churkina, T. D.; Ikonnikov, N. S.; Chesnokov,
1957–1958.
´
A. A.; Larionov, A. V.; Singh, I.; Parmar, V. S.; Vyskocil, S.;
22. Oppolzer, W.; Moretti, R.; Zhou, C. Helv. Chim. Acta 1994,
77, 2363–2380.
Kagan, H. B. J. Org. Chem. 2000, 65, 7041–7048; (c)
Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Oshima,
T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539–9543; (d)
20
23. (S)-Phenylalanine: ½aꢁD ¼ ꢀ34:5 (c 1, H2O) Dictionary of
Organic Compounds; Chapman & Hall: New York, 1982.