A practical asymmetric synthesis of α-methyl α-amino acids using a chiral cu-salen complex as a phase transfer catalyst

Article abstract of DOI:10.1016/S0040-4039(00)01247-8

The asymmetric C-alkylation of N-benzylidene alanine methyl ester has been achieved using a copper(II) (salen) complex as an asymmetric phase transfer catalyst and provides a practical synthesis of α-methyl α-amino acids with up to 86% enantiomeric excess. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01247-8

Tetrahedron Letters 41 (2000) 7245±7248
A practical asymmetric synthesis of a-methyl a-amino acids
using a chiral Cu±salen complex as a phase transfer catalyst
Yuri N. Belokon',b R. Gareth Daviesa and Michael Northa,*
aDepartment of Chemistry, King's College, Strand, London WC2R 2LS, UK
bA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813 Vavilov 28,
Moscow, Russia
Received 9 June 2000; revised 11 July 2000; accepted 20 July 2000
Abstract
The asymmetric C-alkylation of N-benzylidene alanine methyl ester has been achieved using a copper(II)
(salen) complex as an asymmetric phase transfer catalyst and provides a practical synthesis of a-methyl
a-amino acids with up to 86% enantiomeric excess. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: phase transfer; catalysis; copper; asymmetric synthesis; amino acid.
Most asymmetric catalysts are based on transition metal complexes since the coordination
geometry of the transition metal can ®x the relative positions of the reactants, and the variable
oxidation state of transition metals may facilitate the chemical transformation.1 One notable
exception to this trend is asymmetric phase transfer catalysis which until recently has been
dominated by derivatives of cinchona alkaloids,2,3 and more recently by other quaternary
ammonium salts.4 However, even this area has succumbed to metal catalysis. In 1998, Belokon',
Kagan and co-workers reported the use of sodium taddolate5 as a catalyst for the asymmetric
alkylation of alanine enolates (Scheme 1), and subsequently reported the use of sodium salts of
2-hydroxy-20-amino-1,10-binaphthyl derivatives for the same reaction.6 Subsequently, we were
able to show that nickel(II) or optimally copper(II) complexes of salen (2a,b) could function as
asymmetric phase transfer catalysts, with just 1 mol% of the catalyst being sucient to produce
a,a-disubstituted a-amino acids with >90% enantiomeric excess.7
Scheme 1.
* Corresponding author. E-mail: michael.north@kcl.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01247-8

7246
The chemistry shown in Scheme 1 is an attractive test for asymmetric phase transfer catalysis
since the products are a-methyl a-amino acids which are components of a wide range of
pharmaceutically active compounds.8 However, to date it has always been necessary to use the
iso-propyl 1a or tert-butyl esters 1b of the substrates, the syntheses of which are not trivial and
which add considerable cost to any attempt to exploit this chemistry commercially. It would be
highly desirable to develop the chemistry shown in Scheme 1 using the methyl ester substrate 1c.
For cinchona alkaloid-catalyzed reactions, it is known that the steric bulk of the ester is
important for ecient asymmetric induction;9 however, this would not necessarily be the case for
catalysis involving metal salen complexes. In this manuscript, we report that it is indeed possible
to prepare a-methyl a-amino acids using a copper salen catalyst and substrate 1c.
Our ®rst attempts to alkylate imine 1c with benzyl bromide using copper complex 2b (2 mol%)
as catalyst gave methyl a-methyl-phenylalaninate with moderate enantiomeric excess10 (45±50%),
but in very poor yield (25%). After considerable experimentation, it was discovered that the low
yields were being caused by two factors: (1) hydrolysis of the alkylated imines within the reaction
mixture; and (2) the surprisingly high water solubility (even at pH >7) of methyl a-methyl-
phenylalaninate. The ®rst of these problems was circumvented by introducing a re-esteri®cation
step with methanol and acetyl chloride as part of the reaction, and the second problem was
avoided by developing a non-aqueous work-up in which silica gel was used to hydrolyze the imine
and absorb metal residues, giving methyl (S)-a-methyl-phenylalaninate in 91% isolated yield and
with 81% enantiomeric excess10 12 (Scheme 2). Under these optimized conditions, no unalkylated
material was isolated, which implies that the formation of the enolate of 1c is signi®cantly faster
than the hydrolysis of the methyl ester since it is unlikely that sodium hydroxide could form a
dienolate under the reaction conditions. The reaction was also found to exhibit an unusual
temperature e€ect: optimal yields and enantiomeric excesses were obtained at room temperature
with both higher (64ꢀC; 21% yield, 52% ee) and lower (^78ꢀC; 77% yield, 60% ee) temperatures
being detrimental.
Scheme 2.
Having optimized the reaction conditions, the alkylation of 1c with a range of other electrophiles
was investigated, and the results are given in Table 1. Benzylic alkyl halides generally reacted with
1c in good yields and with moderate to good enantioselectivities. The only exception to this was
4-methoxybenzyl chloride which, under the standard conditions, gave a low chemical yield. This

7247
Table 1
problem was caused by a reaction between the particularly reactive alkylating agent and sodium
hydroxide, and could be circumvented by changing the base to sodium hydride. Allylic bromides
also gave good chemical yields and enantiomeric excesses, but propargyl bromide gave a much
lower enantiomeric excess, probably due the small size of the electrophile, and simple alkyl
halides or tri¯ates were totally unreactive.
The methyl esters could be hydrolyzed to give the corresponding amino acids simply by
re¯uxing in dilute hydrochloric acid as illustrated for the allyl bromide adduct which was
hydrolyzed to (S)-a-allyl alanine in 84% yield. Alternatively, it is possible to modify the work-up
of the alkylation to give the free amino acid directly. Thus, for a reaction using benzyl bromide,
omission of steps 2 and 3 (Scheme 2), ®ltration and evaporation of the toluene solvent followed
by overnight re¯ux in 2M hydrochloric acid removed both of the protecting groups. Extraction of
organic by-products with dichloromethane followed by evaporation of the aqueous solution then
gave almost pure a-methyl phenylalanine which could be puri®ed by dissolution in isopropanol,
®ltration through alumina and evaporation to give (S)-a-methyl phenylalanine in 76% overall
yield from 1c.
Our work on the mechanism, optimization, and applications of this novel type of asymmetric
phase transfer catalysis is continuing and further results will be reported in due course.
Acknowledgements
The authors thank King's College London for a postdoctoral fellowship (to R.G.D.) and the
EPSRC mass spectrometry service (Swansea) for high resolution mass measurements.
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7248
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equiv.). The reaction was then stirred at room temperature overnight under an argon atmosphere. The resulting
suspension was diluted with methanol (3 ml) and acetyl chloride (0.5 ml) was added slowly. The mixture was
stirred for a further 6 hours before the solvents were removed in vacuo. The residue was added to a silica gel
column and eluted with EtOAc:EtOH to yield the amino-ester.