Convenient conditions for the enantioselective synthesis of α-methyl-α-amino acids with the use of Cinchona ammonium salts as phase-transfer organocatalysts

Article abstract of DOI:10.1002/ejoc.200700925

The enantioselective α-alkylation of 2-naphthalenecarbaldehyde aldimine alanine tert-butyl ester is carried out by using N-anthracenylmethyl ammonium salts from the simple and unmodified cinchonidine and cinchonine alkaloids as phase-transfer organocataly

Full text of DOI:10.1002/ejoc.200700925

FULL PAPER
DOI: 10.1002/ejoc.200700925
Convenient Conditions for the Enantioselective Synthesis of α-Methyl-α-amino
Acids with the Use of Cinchona Ammonium Salts as Phase-Transfer
Organocatalysts
Rafael Chinchilla,*[a] Carmen Nájera,*[a] and Francisco J. Ortega[a]
Dedicated to Prof. Jan-E. Bäckvall on the occasion of his 60th birthday
Keywords: Enantioselective synthesis / Phase-transfer catalysis / Amino acids / Ammonium salts / Organocatalysis
The enantioselective α-alkylation of 2-naphthalenecarbal-
dehyde aldimine alanine tert-butyl ester is carried out by
using N-anthracenylmethyl ammonium salts from the simple
and unmodified cinchonidine and cinchonine alkaloids as
phase-transfer organocatalysts, which affords (S)- and (R)-
enantioenriched α-methyl-α-amino acid (AMAA) derivatives
in 71–98% yield and 79–96%ee. The employed reaction con-
ditions, rubidium hydroxide as base and toluene/chloroform
as solvent at –20 °C, allows higher enantioselectivities to be
obtained than those previously obtained by using other Cin-
chona alkaloid-derived ammonium salts, even with a lower
catalyst loading (5 mol-%).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Phase-transfer catalysis (PTC) applied to the asymmetric
alkylation of amino acid derived Schiff bases by using chiral
phase-transfer organocatalysts is nowadays one of the most
simple and easy to scale up procedures for the enantioselec-
tive synthesis of α-amino acids.[7,8] Thus, the advent in the
early 1990s of the enantioselective alkylation of amino acid
imines under PTC conditions catalyzed by quaternized Cin-
chona alkaloids, pioneered by O’Donnell[9] by using ammo-
nium salts such as N-benzylated cinchonidinium chloride 1,
and further improved by Lygo[10] and Corey[11] by using N-
anthracenylmethylated analogues such as 2a and 2d, respec-
tively, allowed impressive degrees of enantioselectivity to be
introduced into the products by using a very simple pro-
cedure. This procedure allows reversal of the enantio-
selectivity by using the corresponding pseudoenantiomeric
cinchoninium-derived ammonium salts such as 3[9] or 4[12]
as organocatalysts.
Introduction
The enantioselective synthesis of natural and nonpro-
teinogenic amino acids is a topic of high interest due to
their remarkable pharmacological and conformational
properties, both as free amino acids and as components of
biologically active peptides. Among them, α-alkyl- and es-
pecially α-methyl-α-amino acids (AMAAs) are valuable
tools for restricting the conformational mobility of a pep-
tide backbone and promote particular structures in the de-
sign of peptides and proteins.[1] This effect can be of great
importance, for instance, in preventing the ability of amy-
loidogenic proteins, responsible for diseases such as Alzhei-
mer’s and Parkinson’s, from adopting a β-sheet conforma-
tion by interfering with the amyloid self-assembly process.[2]
Moreover, they can make peptides resistant to degrada-
tion,[3] and they are present in natural antibiotics[4] and act
as enzyme inhibitors.[5] The asymmetric synthesis of
These asymmetric PTC procedures have been mainly em-
AMAAs has been traditionally achieved by diastereoselec- ployed for the α-alkylation of benzophenone-derived gly-
tive α-alkylation of an enolate obtained from chiral alanine- cine Schiff base derivatives 5, although applications to the
derived templates.[6] However, more recently their enantio- enantioselective synthesis of AMAA derivatives by alky-
selective syntheses by employing easily available chiral cata- lation of aromatic aldehyde-derived alanine Schiff base de-
lysts has revealed clear synthetic advantages for large-scale rivatives 6 (R1 = Me) can also be found. This change in the
preparations.[7]
nature of the imine group from glycine to alanine is impor-
tant, as the benzophenone imine, used for the monoalkyl-
ation of glycine derivatives 5, does not allow a second alky-
lation process because of the decreased acidity of the α-
methine proton in the monoalkylated derivative.[13]
The enantioselective synthesis of α,α-dialkylamino acids
by subsequent α-alkylation of derivatives of type 6 is con-
[a] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante
Apdo. 99, 03080 Alicante, Spain
Fax: +34-965903549
E-mail: chinchilla@ua.es
cnajera@ua.es
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6034–6038

Enantioselective Synthesis of α-Methyl-α-Amino Acids
under PTC conditions with the use of common, simple, and
inexpensive cinchonidine and cinchonine ammonium salts
2a,d or 4 as organocatalysts can be considerably improved.
Simple changes in the reaction conditions and some fine
tuning of the catalysts were all that was needed. This in-
cluded the exchange of the chloride anion of 2a for tetra-
fluoroborate or hexafluorophosphate anions to afford 2b,c,
respectively, and exchange of the bromide anion of the O-
allylated derivatives to afford fluorinated derivatives 2e,f.[22]
In this work we describe that simple Cinchona catalysts 2
or 4 can be used for the efficient enantioselective alkylation
of imine alaninates under PTC conditions to afford enanti-
oenriched AMAA derivatives.
Results and Discussion
Initially, the model enantioselective PTC for α-ben-
zylation of (S)-alanine was performed on 4-chlorobenzaldi-
mine alanine tert-butyl ester 9a by using the simple and less
derivatized cinchonidium-derived ammonium salt 2a
(5 mol-%) as the organocatalyst (Table 1, Entry 1). We em-
ployed 50% aqueous KOH as a cheap base in a toluene/
chloroform (7:3) mixture as the solvent at 0 °C for 1 d.
These conditions afforded high selectivity in the enantiose-
lective α-alkylation of benzophenone glycine imines 6 when
these types of organocatalysts were used.[22] Jew and Park
had found that the use of this particular mixture of organic
solvents in this PTC alkylation process afforded high
enantioselectivities with the use of dimeric cinchonidinium
salts as organocatalysts.[23] The incorporation of a certain
amount of a more polar solvent to the toluene solution
probably allows higher solubility of the organocatalyst,
even at low temperatures, in the organic reaction phase.[24]
Thus, under these reaction conditions, 50% aqueous KOH,
sidered to be a more difficult process in comparison to the
α-monoalkylation of glycine derivatives 5; generally, lower
enantioselectivities are observed. Thus, the only example in
which a chiral ammonium salt was prepared directly from
a natural, simple, and cheap chiral source was reported by
O’Donnell who employed N-benzyl cinchoninium chloride
3 as a phase-transfer organocatalyst for the enantioselective
α-alkylation of 4-chlorobenzaldehyde-derived iminic alanin-
ate 6 (Ar = 4-ClC6H4, R1 = Me, R2 = tBu); however, low
ee values were obtained such as the 40%ee for the α-ben-
zylation reaction.[13] This result was improved up to 87%ee
by Lygo who used N-anthracenylmethyl dihydrocinchonid-
inium bromide 7 as a catalyst, which was obtained after
hydrogenation of cinchonidine and further N-quaterni-
zation.[14] Related to this hydrocinchonidine-incorporating
Table 1. Enantioselective benzylation of alanine imine derivatives 9
structure is trifluorinated catalyst 8, which was developed with the use of catalysts 2 under PTC conditions.
recently by Jew and Park. They obtained even higher
enantioselectivities in the α-alkylation of a 2-naphthyl ald-
imine Schiff base of alanine tert-butyl ester 6 (Ar = 2-naphth-
yl, R1 = Me, R2 = tBu) and achieved 95%ee for the ben-
zylation reaction.[15] Other non-Cinchona catalysts have
been used for the enantioselective synthesis of AMAA de-
rivatives by alkylation of alanine-derived imines 6 under
Entry
Aldimine Catalyst Product
Yield[a]
[%]
ee[b,c]
[%]
82[d]
74
75
60
51
51
82
PTC conditions, such as metal–salen complexes,[16,17] bi-
naphthol derivatives,[18] and C2-symmetric ammonium
salts.[19–21]
1
2
3
4
5
6
7
8
9a
9a
9a
9a
9a
9a
9b
9c
2a
2b
2c
2d
2e
2f
(S)-10aa
(S)-10aa
(S)-10aa
(S)-10aa
(S)-10aa
(S)-10aa
(S)-10ba
(S)-10ca
83
56
60
56
29
31
55
57
2a
2a
87
[a] Crude yield as determined by 1H NMR (300 MHz) spec-
troscopy. [b] Determined by chiral HPLC from the corresponding
N-benzoyl amides.[14] [c] Configuration assigned on the basis of the
relative reported retention times of the (R/S) isomers.[15] [d] A
87%ee was reported with the use of catalyst 7 (K2CO3/KOH, tolu-
Recently, we demonstrated that the enantioselectivity in
the alkylation reaction of benzophenone imine glycinates ene, r.t.).[14]
Eur. J. Org. Chem. 2007, 6034–6038
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R. Chinchilla, C. Nájera, F. J. Ortega
FULL PAPER
toluene/chloroform, 0 °C, a 82 % ee for corresponding Table 2. Enantioselective benzylation of alanine imine derivative 9c
with the use of catalyst 2a under PTC conditions.
AMAA derivative (S)-10aa was obtained (Table 1, Entry 1).
Attempts to improve this result by exchanging the chloride
anion of 2a for the tetrafluoroborate and hexafluorophos-
phate anions,[22] were not successful (Table 1, compare En-
try 1 with Entries 2 and 3). The use of Corey’s cinchonidine
ammonium salt 2d as the organocatalyst under these reac-
tion conditions gave a rather poor value of 60%ee (Table 1,
Entry 4), and even lower values were obtained with the use
of the corresponding tetrafluoroborate (2e) and hexafluoro-
phosphate (2f) salts (Table 1, compare Entry 4 with En-
tries 5 and 6).
After observing that the more simple catalyst 2a afforded
the highest degree of enantioselectivity, we next investigated
the influence of the aldimine group in the alanine derivative.
Thus, we performed the benzylation reaction on 2-thienyl
aldimine alanine tert-butyl ester 9b by using ammonium
salt 2a as the catalyst. No influence on the enantio-
selectivity was observed in comparison to that achieved
with 4-chlorobenzaldehyde-derived alanine ester 9a; the ee
value remained at 82% for (S)-10ba. (Table 1, compare En-
tries 1 and 7). However, when the alkylation substrate was
changed to 2-naphthyl aldimine alanine tert-butyl ester
7c,[15] the enantioselectivity for (S)-10ca rose from 82 up to
87%ee (Table 1, compare Entries 1 and 8).
When the best combination of substrate/catalyst was set-
tled, that is, 9c and 2a, we continued the optimization of
the benzylation reaction by changing the base in an attempt
to increase the enantioselectivity of the reaction. Thus, we
employed solid monohydrated cesium hydroxide in the tolu-
ene/chloroform mixture at 0 °C, but the ee values for ben-
zylated compound (S)-10ca dropped dramatically to 59%
(Table 2, compare Entries 1 and 2). However, the use of ru-
bidium hydroxide as the base[15] increased the yield to 83%
and the enantioselectivity to 90% for (S)-10ca (Table 2, En-
Entry Catalyst Base
[mol-%]
T
[°C]
t
[h]
Yield[a] ee[b]
[%]
[%]
1
2
3
4
5
6
7
8
5
5
5
5
5
2
1
5
50% aq. KOH
CsOH
RbOH
RbOH
RbOH
RbOH
RbOH
50% aq. KOH
0
0
0
–20
–35
–20
–20
–20
24
8
57
69
83
84
78
68
60
81
87
59
90
94
90
88
86
90
24
24
24
24
24
24
[a] Crude yield as determined by 1H NMR (300 MHz) spec-
troscopy. [b] Determined by chiral HPLC from the corresponding
N-benzoyl amides.[14]
base: product (S)-10ca was obtained with a 90%ee at
–20 °C with 5 mol-% of catalysts 2a (Table 2, Entry 8).
Once the best substrate (9c) organocatalyst (2a), and op-
timal reaction conditions (RbOH as base, toluene/chloro-
form as solvent at –20 °C) were chosen for the enantioselec-
tive PTC benzylation of 9c, we extended this methodology
to the preparation of enantioenriched AMAA derivatives
10c, and the results are shown in Table 3. In addition to the
use of cinchonidinium-derived ammonium salt 2a, we also
employed pseudoenantiomeric cinchonine-derived chloride
4a as the organocatalyst to obtain the corresponding
AMAA enantiomers. Thus, the use of cinchoninium salt 4a
as the organocatalyst in the enantioselective benzylation of
Table 3. Enantioselective alkylation of alanine imine derivative 9c
try 3). Moreover, when the reaction temperature was de- with the use of catalysts 2a and 4a under PTC conditions.
creased to –20 °C, the yield was similar but the ee value
increased to 94% (Table 2, Entry 4). This result is quite
interesting, as a similar enantioselectivity (95%ee) was ob-
tained in the benzylation of 9c when the more elaborate
trifluorobenzylated hydrocinchonidinium ammonium salt 8
Entry RBr
Catalyst Product Yield[a] ee[b,c]
was used as the organocatalyst under the same reaction
conditions (same base, toluene as solvent) but at –35 °C.[15]
In our case, a decrease in the reaction temperature down
to –35 °C was not beneficial and a lower enantioselectivity
(90%ee) was obtained (Table 2, Entry 5).
[%]
[%]
1
2
PhCH2Br
PhCH2Br
2a
4a
2a
4a
2a
4a
2a
4a
2a
4a
2a
4a
2a
4a
(S)-10ca
(R)-10ca
(S)-10cb
(R)-10cb
(S)-10cc
(R)-10cc
(S)-10cd
(R)-10cd
(S)-10ce
(R)-10ce
(S)-10cf
(R)-10cf
(S)-10cg
(R)-10cg
84
92
98
67
90
88
84
82
87
94
79
71
91
82
94
94
95
94
91
94
93
96
93
93
91
90
93
79
3
4
5
6
7
8
9
10
11
12
13
14
4-BrC6H4CH2Br
4-BrC6H4CH2Br
4-tBuC6H4CH2Br
4-tBuC6H4CH2Br
3-MeC6H4CH2Br
3-MeC6H4CH2Br
4-F3CC6H4CH2Br
4-F3CC6H4CH2Br
CH2=CHCH2Br
CH2=CHCH2Br
CHϵCCH2Br
It is remarkable that these reaction conditions produced
such enantioselectivities with the use of only a 5 mol-%
loading of phase-transfer organocatalyst 2a, as a 10 mol-%
loading has always been employed with Cinchona-related
ammonium salts.[13–15] Therefore, we also explored if the
amount of catalyst could be diminished even more. Thus,
when a 2 mol-% of 2a was used under the best reaction
conditions, an 88%ee of (S)-10ca was obtained; this value
dropped slightly to 86%ee when only 1 mol-% loading of
2a was employed (Table 2, compare Entries 4, 6 and 7). We
also explored the influence of lowering the reaction tem-
CHϵCCH2Br
[a] Crude yield as determined by 1H NMR (300 MHz) spec-
troscopy. [b] Determined by chiral HPLC from the corresponding
N-benzoyl amides.[14] [c] Configuration assigned on the basis of the
perature when using 50% aqueous potassium hydroxide as relative HPLC reported retention times of the (R/S) isomers.[15]
6036
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Eur. J. Org. Chem. 2007, 6034–6038

Enantioselective Synthesis of α-Methyl-α-Amino Acids
9c, under the optimized reaction PTC conditions, gave rise under phase-transfer conditions by using N-anthracenylme-
to a value of 94%ee for (R)-10ca, which is identical to that thyl ammonium salts from simple and easily available non-
achieved for its enantiomer (S)-10ca with the use of cin- derivatized OH-free Cinchona alkaloids cinchonidine and
chonidinium-derived organocatalyst 2a (Table 3, compare cinchonine organocatalysts. The most appropriate alky-
Entries 1 and 2). When 4-bromobenzyl bromide was used lation substrate is 2-naphthalenecarbaldehyde aldimine ala-
as the electrophile and cinchonidinium ammonium salt 2a nine tert-butyl ester, whereas rubidium hydroxide as base
as the organocatalyst, corresponding 4-bromobenzylalanine and a mixture of toluene/chloroform as solvent at –20 °C
ester derivative (S)-10cb was obtained with a 95%ee, are the most appropriate reaction conditions. Both AMAA
whereas a very similar value of 94%ee for its enantiomer enantiomers are accessible by using the cinchonidine or the
(R)-10cb was obtained with the use of cinchoninium-de- cinchonine-derived salts. This combination of ammonium
rived organocatalyst 4a (Table 3, compare Entries 3 and 4). salts and reaction conditions shows clear advantages when
4-Bromobenzylalanine ester derivative (R)-10cb can be em- compared to the previously reported procedure for the
ployed for the synthesis of a precursor of cell adhesion enantioselective alkylation of 2-naphthalenecarbaldehyde
BIRT-377 (11).[21]
aldimine alanine tert-butyl ester, as a lower loading (from
10 to 5 mol-%) of more simple an economical ammonium
salts are used at a higher temperature. The enantioselectivi-
ties of the obtained AMMA derivatives are in general the
highest achieved to date by using Cinchona-derived ammo-
nium salts as organocatalysts under phase-transfer condi-
tions.
Other α-benzylated alanine derivatives were obtained
with excellent enantioselectivities by following this method-
ology. Thus, when 4-tert-butylbenzyl bromide was used as
the electrophile and ammonium salt 2a as the organocata-
lyst, corresponding AMAA derivative (S)-10cc was ob-
tained with a 91%ee, whereas a higher value of 94%ee for
(R)-10cc could be achieved by using catalyst 4a (Table 3,
Entries 5 and 6). High enantioselectivities were also ob-
tained by using electrophiles such as 3-methylbenzyl and 4-
trifluoromethylbenzyl bromide, which gave rise to 93%ee
for both (S)-10cd and (S)-10ce when 2a was used as the
organocatalyst (Table 3, Entries 7 and 9). Their correspond-
ing enantiomers (R)-10cd and (R)-10ce could be prepared
in 96 and 93%ee by employing cinchoninium salt 4a as the
catalyst (Table 3, Entries 8 and 10).
Experimental Section
Enantioselective Alkylation of Aldimine Alanine Ester 9c with the
Use of Organocatalyst 2a or 4a Under PTC Conditions: A solution
of aldimine 9c (57 mg, 0.20 mmol), catalyst 2a or 4a (5.2 mg,
0.01 mmol), and the corresponding alkyl halide (1.0 mmol) dis-
solved in a mixture of toluene and CHCl3 (7:3, 1.5 mL) was cooled
to –20 °C. Rubidium hydroxide (102 mg, 1.0 mmol) was added, and
the mixture was stirred vigorously at –20 °C and monitored by
GLC. The suspension was diluted with water (10 mL) and extracted
with Et2O (3ϫ3 mL). The combined organic layer was dried with
MgSO4, filtered, and the solvents evaporated in vacuo to afford
crude products 10, which were analyzed by 1H NMR (300 MHz)
spectroscopy.
The enantioselectivity of the reaction was determined by chiral
When a nonactivated electrophile such as n-butyl iodide HPLC of the corresponding N-benzoyl derivatives,[14] and the abso-
lute stereochemistry was assigned on the basis of the relative reten-
tion times of the enantiomers described in the literature.[15] HPLC
reference racemic samples were prepared from corresponding race-
mic 10, which were obtained by using n-tetrabutylammonium bro-
mide as the PTC catalyst.
was used, no alkylation reaction was observed. However,
when allyl bromide was used as the electrophile with the
use of organocatalysts 2a and 4a, the ee value for the (S)
and (R) enantiomers, respectively, of corresponding al-
lylated alanine derivative 10cf was 91 and 90%, respectively
(Table 3, Entries 11 and 12). In addition, the use of propar-
gyl bromide as the electrophile and 2a as the organocatalyst Acknowledgments
gave (S)-10cg with 93%ee (Table 3, Entry 13). These values
We thank the financial support from the Spanish Ministerio de
can be considered quite high, as only 85%ee for (S)-10cf
and 84%ee for (S)-10cg were recently reported with the use
of organocatalyst 8 and the same base, but in toluene as
solvent at –35 °C.[15] In the case of the propargylation of
9c, the use of cinchoninium-derived organocatalyst 4a did
not give a comparable enantioselectivity to that obtained
for its enantiomer (S)-10cg, as (R)-10cg was obtained with
an ee value of only 79% (Table 3, Entry 14).
Educación y Ciencia (projects CTQ 2004-00808/BQU, Consolider
Ingenio 2010, and CSD2007-00006), the Generalitat Valenciana
(projects CTIOIB/2002/320, GRUPOS03/134, and GV05/144), and
the University of Alicante. F. J. O. thanks the University of Al-
icante for a predoctoral fellowship.
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Eur. J. Org. Chem. 2007, 6034–6038
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6037

R. Chinchilla, C. Nájera, F. J. Ortega
FULL PAPER
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