Stereoselective synthesis of β2-amino acids by Michael addition of diorgano zinc reagents to nitro acrylates

Article abstract of DOI:10.1016/S0957-4166(02)00788-7

Phosphoramidite-derived copper(I) catalysts readily facilitate the enantioselective 1,4-addition of dialkyl zinc reagents to nitro acrylates. The resulting 2-substituted 3-nitro propionic acid esters can easily be transformed to β²-amino acids.

Full text of DOI:10.1016/S0957-4166(02)00788-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 189–191
Stereoselective synthesis of b2-amino acids by Michael addition
of diorgano zinc reagents to nitro acrylates
Uwe Eilitz, Frank Leßmann, Oliver Seidelmann and Volkmar Wendisch*
ChiroBlock Ltd., Andresenstrasse 1a, D-06766 Wolfen, Germany
Received 12 November 2002; accepted 21 November 2002
Abstract—Phosphoramidite-derived copper(I) catalysts readily facilitate the enantioselective 1,4-addition of dialkyl zinc reagents
to nitro acrylates. The resulting 2-substituted 3-nitro propionic acid esters can easily be transformed to b2-amino acids. © 2003
Elsevier Science Ltd. All rights reserved.
The synthesis of rare and unnatural amino acids in
their stereochemically pure form has been the subject of
intense research for decades. Because of their relevance
to many processes in living matter, b-amino acids con-
tinue to attract particular attention of many synthetic
The required zinc reagents are readily available. Many
dialkylzinc reagents can be purchased in bulk quanti-
ties, others, especially those containing functional
groups are accessible by the method of Knochel.30–32
Nitro acrylates can be made by standard procedures.33–35
chemists.1–5 While quite
a number of synthetic
approaches towards enantiopure a- and b3-amino acids
are known,6–11 facile synthesis routes to the 2-branched
b-amino acids are rare and limited to single com-
pounds.11–15 This fact contrasts the importance of those
compounds which were found to be essential sub-struc-
tures and building blocks in peptides and naturally
occurring compounds. Some of these molecules show
high cytostatic or anti-viral activity or exhibit other
unusual properties.16–18 The tumour suppressing crypto-
phycines from marine sponges are good examples.19–21
As far as the catalyst is concerned, we and others have
shown the value and suitability of copper(I) based
molecules for such 1,4-additions.24,36,37 While nitro
acrylates represent two-fold Michael acceptors, the
nitro group is known to be the strongest Michael
acceptor and hence should desirably direct the CꢀC
coupling to the C-2 atom.28,38,39
In order to check the scope and limitations of the
reaction between dialkylzinc reagents and nitro acryl-
ates, we tested several known ligands for the copper
ion, mainly phosphites and phorphoramidites.25,38,40,41
We found that all catalysts employed regioselectively
facilitate the reaction. Moderate enantioselectivities
were observed with most catalysts.
In our efforts to develop a synthesis route which allows
an economically feasible production of b2-amino acids,
we tried to avoid a diastereoselective approach with its
known drawbacks, especially for industrial applica-
tions.22,23 Instead we favoured a catalytic strategy based
on our and others experiences in the 1,4-addition of
dialkylzinc reagents to Michael acceptors.24–29 A retro
synthetic analysis prompted us to investigate the reac-
tion of dialkylzinc reagents with nitro acrylic acid esters
as Michael acceptors. The resulting 2-substituted 3-
nitro acrylates should be ideal intermediates for the
synthesis of the respective b2-amino acids.
Only the Feringa–type BINOL–based ligand 1 and its
enantiomer turned out to transfer the stereochemical
information efficiently. Enantiomeric excesses of up to
87% could be obtained.
* Corresponding author. Tel.: +49-3494-638323; fax: +49-3494-
638324; e-mail: wendisch@chiroblock.de
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00788-7

190
U. Eilitz et al. / Tetrahedron: Asymmetry 14 (2003) 189–191
low ee values. The probable coordination of solvent
molecules to the active complex has been discussed
earlier.42 Dialkyl ethers are the solvents most appropri-
ate with the cheap TBME being the solvent of choice.
The nature of the ester (R%) does not influence either the
yield or the enantiomeric excess of the product. Aiming
towards amino acids, the substrate should on the one
hand easily be saponified, while on the other hand, it
should boil at a low temperature, since a safe distilla-
tion of this potentially explosive substance is required
for purification: the methyl ester meets these require-
ments best.
Using ligand 1, we started with diethylzinc and nitro
acrylic acid methyl ester to investigate the influence of
the solvent on the reaction. Then we varied the ester R%
for the optimal solvent and finally other alkylzinc
reagents were tested for the most appropriate substrate.
Representative results, obtained with 0.5 mol%
catalyst† at –78°C are shown in Table 1.‡
In our first experiments, we restricted ourselves to three
dialkylzinc reagents. While both diethyl- and di-
isobutylzinc yield the respective products with an enan-
tiomeric excess of about 80%, dimethylzinc only
resulted in an enantiomeric excess of 18%. The reason
for this poor performance is likely to be the elevated
reaction temperature,§ which was necessary because of
the low reactivity of dimethylzinc in comparison to the
other alkylzinc reagents.
In contrast to the enantiomeric excess, the yields are
nearly independent from the reaction conditions
employed. The reaction proceeds with high regioselec-
tivity to give the desired product. As can be seen from
the data, solvents without donor atoms only give rise to
Each of the three 2-substituted 3-nitro propionic acid
esters can readily be transformed to the respective
b2-amino acid via catalytic hydrogenation and subse-
quent saponification.¶ The overall yield is 60–65%, cal-
culated for the nitro acrylates. No racemisation occurs
during these following reactions, as can be proved by
capillary zone electrophoresis using g-cyclodextrins as
geometric selectors. After one recrystallisation of the
hydrochlorides, the compounds are enantiomerically
pure (ee >98%).
Table 1. Yields and enantiomeric excesses of 2-substituted
3-nitro propionic acid esters with respect to solvent
(THF–tetrahydrofuran, DCM–dichlormethane, T–toluene,
DEE–diethylether, TBME–tertiary butyl methyl ether),
substrate and reagent
R
R%
Solvent
Yield (%)
ee (%)
Hence, the outlined reaction sequence is a promising
approach towards enantiomerically pure 2-branched b-
amino acids. Despite the required low temperatures, the
process is economically feasible. The high catalytic
efficiency, the cheap substrate and the availability of
several organozinc reagents are not the only reasons for
that finding. The tolerance of organozinc reagents to
functional groups in the alkyl chains and the fact that
one compound serves as a substrate for various prod-
ucts, increases the potential of this synthesis.
Ethyl
Methyl
DCM
T
THF
DEE
TBME
20
93
98
96
94
5
13
25
86
85
Ethyl
Methyl
tButyl
Benzyl
TBME
94
97
92
85
87
85
Methyla
Ethyl
Methyl
TBME
97
94
96
18
85
79
iButyl
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