Enantioselective synthesis of aroylalanine derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01017-7

In this paper we report the development of a highly enantioselective method for the synthesis of aroylalanines. The approach described employs a protected 2-amino-4-bromopent-4-enoic acid, generated via the asymmetric phase-transfer catalyzed alkylation of a glycine imine, as a key intermediate. Suzuki coupling with an aryl boronic acid followed by ozonolysis of the resulting styrene provides efficient access to the aroylalanine derivatives. The utility of this methodology is illustrated by the synthesis of L-kynurenine along with several aroylalanine inhibitors of the kynurenine pathway.

Full text of DOI:10.1016/S0040-4039(03)01017-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4499–4502
Enantioselective synthesis of aroylalanine derivatives
Barry Lygo* and Benjamin I. Andrews
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
Received 21 March 2003; revised 7 April 2003; accepted 17 April 2003
Abstract—In this paper we report the development of a highly enantioselective method for the synthesis of aroylalanines. The
approach described employs a protected 2-amino-4-bromopent-4-enoic acid, generated via the asymmetric phase-transfer
catalyzed alkylation of a glycine imine, as a key intermediate. Suzuki coupling with an aryl boronic acid followed by ozonolysis
of the resulting styrene provides efficient access to the aroylalanine derivatives. The utility of this methodology is illustrated by
the synthesis of L-kynurenine along with several aroylalanine inhibitors of the kynurenine pathway. © 2003 Elsevier Science Ltd.
All rights reserved.
Aroylalanine derivatives 1 constitute an interesting
group of a-amino acids that have attracted considerable
interest in recent years. Much of this interest has arisen
as a consequence of studies into the kynurenine path-
way,1,2 a process that starts with the oxidative cleavage
In recent years it has been shown that a number of
aroylalanine derivatives are able to act as selective
inhibitors of enzymes involved in this pathway. For
example it has been demonstrated that o-methoxyben-
zoylalanine 1b preferentially inhibits kynurenine 3-
hydroxylase and m-nitrobenzoylalanine 1c is an
inhibitor of kynureninase (Scheme 1).2p,q,s,3 This high-
lights the need for synthetic methods that allow efficient
access to aroylalanine derivatives, and in this paper we
report the development of such an approach and its
application to the enantioselective synthesis of com-
pounds 1a–c.
of the essential amino acid
L-tryptophan to give
kynurenine 1a. This pathway appears to play an impor-
tant role in a variety of fundamental biological pro-
cesses, including neuronal excitability, antioxidant
status, and cell growth/cell division. The need to study
this pathway in more detail, coupled with the recogni-
tion that it could offer a means of treating a wide
variety of disorders,1 has led to significant interest in
the synthesis of kynurenine and related aroylalanine
derivatives.2
Over the past few years we4 have been concerned with
the development and application of the asymmetric
phase-transfer catalyzed alkylation of glycine imine 4.5,6
In particular we have focussed on alkylation conditions
that involve the use of aqueous hydroxide at room
temperature. These reaction conditions have proved
extremely convenient to use4,7 and are compatible with
a wide range of alkylating agents, however we have
found that alkylations involving a-haloketones (e.g.
a-bromoacetophenone, Scheme 2) generally result in
* Corresponding author.
Scheme 1. (i) Kynurenine 3-hydroxylase; (ii) kynureninase.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01017-7

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B. Lygo, B. I. Andrews / Tetrahedron Letters 44 (2003) 4499–4502
enantioselectivity of the reaction,4d however in this case
it appears that the latter salt is relatively insoluble in the
organic reaction phase (PhMe). This results in a reduc-
tion in the effective concentration of the catalyst, which
in turn results in a lowering of the enantioselectivity. To
overcome this problem we screened a range of different
dihydrocinchonidine-derived salts4a and found that use
of the O-benzyl derivative 9c resulted in high levels of
enantioselectivity (93–95% e.e.).
Scheme 2. (i) a-Bromoacetophenone, 9 M aq. KOH, PhMe,
O-benzyl-N-9-anthracenylmethyldihydrocinchonidinium bro-
mide 9c (10 mol%), rt.
Thus, asymmetric alkylation of imine 4 with 2,3-dibromo-
propene followed by imine hydrolysis and N-protection
gave the amino acid derivative 1011 in good overall yield
(Scheme 4). Using this approach, the enantiomeric excess
of crude 11 was found to be 94%.12
Scheme 3.
low yields of the desired product 5. This is primarily
because the a-bromoketone is prone to hydrolysis and
also readily participates in a base-mediated self conden-
sation leading to the formation of the cyclopropyl ketone
by-product 6.8 Recently it has been shown that careful
optimization of the reaction conditions can minimize
these problems and this has enabled an enantioselective
synthesis of the highly fluorescent amino acid 6-(2-
dimethylaminonaphthoyl) alanine to be developed.9 We
have been investigating an alternative solution to this
problem, one which avoids the involvement of a-haloke-
tones, and which allows installation of the aryl moiety
at a relatively late stage, thus facilitating the synthesis of
a range of aroylalanine derivatives from an advanced
intermediate.
Suzuki couplings involving amino acid 11 gave excellent
yields under standard conditions, and simple ozonolysis
followed by reductive work-up then gave the protected
aroylglycines 12 (Scheme 5). As can be seen this two-step
sequence is compatible with both electron rich and
electron deficient aryl functions and ortho-substituents in
the aromatic ring do not appear to cause any problems.
HPLC analysis on selected products established that this
sequence does not result in any loss of enantiomeric
excess, and thus confirmed that this is a highly enantiose-
lective route to protected aroylalanines.
In order to complete the synthesis of compounds 1a–c,
we investigated a number of deprotection methods.2u,13
It was found that this could best be achieved by heating
intermediates 12 in a mixture of chloroform and TFA.
Purification by ion-exchange chromatography then pro-
Our approach is centred on the potential utility of
2-amino-4-bromopent-4-enoic acid derivatives 7 as direct
precursors to aroylalanine derivatives 8. We envisaged
that the transformation of 7 into 8 should be possible via
Suzuki coupling10 followed by oxidative cleavage
(Scheme 3), and that this chemistry should be compatible
with a wide variety of aryl groups.
vided
and
L
-kynurenine 1a,
L
-o-methoxybenzoylalanine 1b
L
-m-nitrobenzoylalanine 1c in good overall yield
(Scheme 6). Compounds 1a–c had spectroscopic data in
agreement with that previously reported,2l,n,p confirming
their structural assignment.
For this strategy to be successful, efficient access to
amino acid derivatives 7 is required. To this end we
examined the utility of the asymmetric PTC alkylation
of imine 4 with 2,3-dibromopropene. Initially we
employed the quaternary ammonium salt 9a as the
precatalyst4d,e in the asymmetric alkylation reaction. This
salt was chosen as it usually leads to very high levels of
enantioselectivity and favours formation of the L-amino
acid stereochemistry. Unfortunately, in this instance,
although the desired stereoisomer was favoured, variable
levels of enantioselectivity (e.e.’s 41–60%) were obtained.
Under the alkylation conditions the precatalyst 9a is
converted into the O-alkyl derivative 9b. In most alkyla-
tions of this type this does not significantly effect the
Scheme 4. (i) 2,3-Dibromopropene, 9 M aq. KOH, PhMe,
CH2Cl2,
O-benzyl-N-9-anthracenylmethyldihydrocinchoni-
dinium bromide 9c (10 mol%), rt; (ii) 15% aq. citric acid, THF,
rt; Boc2O, Et3N, rt.

B. Lygo, B. I. Andrews / Tetrahedron Letters 44 (2003) 4499–4502
4501
Acknowledgements
We thank the EPSRC for funding.
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