Asymmetric synthesis of α-amino acids using polymer-supported Cinchona alkaloid-derived ammonium salts as chiral phase-transfer catalysts

Article abstract of DOI:10.1016/S0957-4166(00)00317-7

Cinchonidine and cinchonine have been N-alkylated with Merrifield resin and employed as chiral phase-transfer catalysts for the enantioselective alkylation of enolates from N-(diphenylmethylene)glycine esters with activated electrophiles (up to 90% ee). T

Full text of DOI:10.1016/S0957-4166(00)00317-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3277–3281
Asymmetric synthesis of a-amino acids using
polymer-supported Cinchona alkaloid-derived ammonium
salts as chiral phase-transfer catalysts
Rafael Chinchilla, Patricia Maz o´ n and Carmen N a´ jera*
Departamento de Qu ´ı mica Org a´ nica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 8 August 2000; accepted 11 August 2000
Abstract
Cinchonidine and cinchonine have been N-alkylated with Merrifield resin and employed as chiral
phase-transfer catalysts for the enantioselective alkylation of enolates from N-(diphenylmethylene)glycine
esters with activated electrophiles (up to 90% ee). The use of the polymer-supported cinchonidine
ammonium salt afforded the corresponding (S)-isomers, whereas the (R)-isomers were obtained using
related cinchonine-supported polymers. © 2000 Elsevier Science Ltd. All rights reserved.
The synthesis of optically active a-amino acids using a simple and easily scalable procedure
1
remains an important synthetic challenge nowadays. In spite of all the available synthetic
methods, frequently based on the alkylation of an array of chiral templates, it is doubtful that
the future of the industrial enantioselective preparation of a-amino acids will follow these
routes, the preparation of large-scale amounts of the template being generally rather cumber-
some and too expensive. However, the enantioselective synthesis of a-amino acids employing
easily available and re-usable chiral catalysts presents clear advantages for large-scale synthesis.
A simple and easily scaleable methodology is phase-transfer catalysis (PTC) using ammonium
2
salts as phase-transfer agents. The use of chiral alkaloid-derived ammonium salts allows the
asymmetric synthesis of optically active a-amino acids. Thus, the ee’s obtained by O’Donnell in
his pioneering works using tetralkylammonium halides, derived from Cinchona alkaloids, as
3
4
5
PTC catalysts in a two-phase system were subsequently improved by Corey and Lygo. In
6
7
addition, chiral spiro ammonium salts with a binaphthyl structure and also TADDOL or
NOBIN and derivatives have been used as chiral PTC catalysts in the alkylation of glycine
8
derivatives. With all these antecedents, a further step in the development of this asymmetric PTC
methodology would be anchoring the catalysts to a solid support. That method would allow an
easy separation from the reaction mixture once the reaction has finished and also the possibility
of re-using the same catalysts.
*
Corresponding author. Fax: +34-96-5903549; www.ua.es/dept.quimorg; e-mail: cnajera@ua.es
0
957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00317-7

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R. Chinchilla et al. / Tetrahedron: Asymmetry 11 (2000) 3277–3281
Supported Cinchona alkaloids have previously been used as catalysts. Thus, alkaloid–acrylo-
9
10
11
nitrile copolymers, alkaloid-crosslinked polymers and polymer supported alkaloids have been
employed as catalysts for asymmetric Michael additions. In addition, bis-Cinchona alkaloid–
12a
ethylene glycol dimethacrylate–methyl methacrylate and bis-Cinchona alkaloid–methyl meth-
1
2b
13
14
acrylate copolymers, as well as PEG, and silica gel supported Cinchona alkaloids have been
12,13
14
used as catalysts in asymmetric dihydroxylation
and aminohydroxylation reactions. More-
over, polystyrene-supported quaternary ammonium salts derived from Cinchona and Ephedra
alkaloids have been previously employed as catalysts for asymmetric Michael addition reactions
10a
of b-ketoesters to methyl vinyl ketone or thio-p-cresol to cyclohex-2-enone, although with low
ee’s (up to 27%). In this communication we report the use of these polystyrene-supported
ammonium salts derived from cinchonidine 1 and cinchonine 2 as chiral PTC catalysts for the
asymmetric synthesis of a-amino acids.
Catalysts 1 and 2 were prepared by reaction of Merrifield resin (crossliked with 1% of
divinylbenzene, 200–400 mesh, 1.7 mmol Cl/g) with an excess (2 equiv.) of cinchonidine or
cinchonine, respectively, in refluxing toluene. After filtration and washing thoroughly with ether,
polymer-supported quaternary ammonium chlorides 1 and 2 were obtained. The increase in the
initial resin weight and the presence of new bands in the IR spectra attributable to the alkaloid
structure showed the incorporation of the alkaloid cinchonine to the resin.
Polymer 1 was used as an insoluble PTC catalyst in the triphase alkylation reaction of
glycine-derived N-(diphenylmethylene)glycine alkyl esters 3 with benzyl bromide in a system
formed by toluene and a 25% aqueous NaOH solution at room temperature (Table 1, entries
1
5
16
1
–4). The enantioselectivity of the reaction was measured by chiral GLC analysis of the
17
corresponding N-trifluoroacetamide amido esters. When the ethyl or isopropyl ester deriva-
1
8
tives 3a or 3b were employed as starting materials under the same reaction conditions,
alkylated compounds 4aa or 4ba were obtained in 44 or 66% ee, respectively (Table 1, entries 1
and 2). However, when the reaction was carried out with the commercially available tert-butyl
derivative 3c, the reaction time was considerably longer (36 h) and product 4ca was obtained in
5
8% ee (Table 1, entry 4). Thus, derivative 3b was chosen as the starting material for the
alkylation reactions. When the reaction of 3b was performed at 0°C (bath temperature) a
significant increase in the obtained ee of 4ba was observed (90% ee, Table 1, entry 3).
In order to determine the absolute configuration of the alkylated products 4, compound 4ba
was hydrolyzed under refluxing 6N HCl to give phenylalanine in 70% overall yield after
treatment of the initially obtained hydrochloride with propylene oxide in refluxing ethanol. The
19
negative sign of the specific rotation of this isolated a-amino acid compared with the literature
allowed assignment of the (S)-configuration obtained when using cinchonidine-supported
ammonium chloride 1 as catalyst. When the reaction of 3b was performed employing
cinchonine-supported ammonium salt 2 as catalyst, compound 4ba was obtained with the
opposite configuration (Table 1, entry 5), thus allowing the preparation of the corresponding
enantiomeric (R)-series.

R. Chinchilla et al. / Tetrahedron: Asymmetry 11 (2000) 3277–3281
3279
Table 1
Enantioselective alkylation of glycine derivatives 3
Different benzyl bromides were employed as electrophiles (Table 1, entries 7–14), some of
them with activated or inactivated aromatic rings, although showing no significant influence
on the obtained ee’s. When other activated electrophiles such as allyl iodide and propargyl
bromide were employed with polymer 1 as the catalyst, the corresponding derivatives 4bf and
4
bg were obtained, respectively, although with low ee’s (Table 1, entries 15 and 16). The
(
S)-configuration of 4bf was assigned by the relative retention times of the (R/S)-isomers
1
7
reported in the literature. When unactivated electrophiles such as butyl iodide were used as
electrophiles, no alkylation reaction took place.
Other solvents such as dichloromethane, acetonitrile or tert-butyl methyl ether were
attempted, but in all cases the obtained ee’s were lower. Moreover, the use of other bases such
as aqueous solutions of KOH or CsOH lowered the obtained ee’s. When compound 4ba was
prepared using LiOH as a base, the obtained ee’s were similar to when using NaOH, although
the reaction was slower and the yield was only 15%. When catalyst 1 was employed, lowering

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R. Chinchilla et al. / Tetrahedron: Asymmetry 11 (2000) 3277–3281
the reaction temperature to 0°C (bath temperature) always produced an increase in the obtained
ee.
The recovered catalysts could be reused without appreciable loss of activity. Thus, once the
reaction of 3b with benzyl bromide was performed at room temperature (Table 1, entry 2) and
recycled catalyst 1 was employed again, the preparation of the corresponding alkylated
compound 4ba in almost identical yield and ee was allowed. Further studies on the applications
of these and related polymer-supported catalysts to other asymmetric synthesis will be reported
in due course.
Acknowledgements
This work has been supported by the DGES of the Spanish Ministerio de Educaci o´ n y
Cultura (MEC) (PB97-0123) and the Generalitat Valenciana (GV99-33-1-02).
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the electrophile (1.2 mmol) and aqueous 25% solution of NaOH (4 mL). The suspension was vigorously stirred
and monitored by GLC. When the reaction was finished, the mixture was filtered and the solid was washed with
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2
4
1
1
1
6. Chirasil-LVal (Chrompack), 1 min 85°C, 2°/min to 180°C. Reference racemic samples were prepared under the
same reaction conditions but using tetrabutylammonium bromide as phase-transfer catalyst.
7. Obtained after HCl/Et O hydrolysis of the imine function and further reaction with trifluoroacetic anhydride
2
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20
1
9. (S)-Phenylalanine: [h] =−34.5 (c 1; H O) (Dictionary of Organic Compounds; Chapman & Hall: New York,
D 2
1
982).
.