Catalytic, asymmetric synthesis of α,α-disubstituted amino acids

Article abstract of DOI:10.1016/S0040-4039(03)00170-9

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.

Full text of DOI:10.1016/S0040-4039(03)00170-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2045–2048
Catalytic, asymmetric synthesis of a,a-disubstituted amino acids
b
a
a
a
b
Yuri N. Belokon’, Devayani Bhave, Daniela D’Addario, Elizabetta Groaz, Viktor Maleev,
a,
b
Michael North * and Armine Pertrosyan
a
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
b
A.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813 Moscow, Vavilov 28,
Russian Federation
Received 18 December 2002; accepted 17 January 2003
Abstract—Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of
amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the
process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>
valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the
reactions is presented. © 2003 Elsevier Science Ltd. All rights reserved.
a,a-Disubstituted amino acids are components of a
This reaction leads to a-methyl-a-amino acids with high
1
number of potential pharmaceuticals, and when incor-
enantiomeric excesses (up to 92%). Optimal results are
6
porated into peptides result in the formation of unusual
obtained using a para-chlorobenzylidene imine, and
2
conformations such as the 3 -helix. Whilst a number
the chemistry is compatible with the use of methyl ester
1
0
5
of chiral auxiliary based methods are available for the3
asymmetric synthesis of a,a-disubstituted amino acids,
a catalytic method would have significant financial and
practical advantages. In recent papers, we have shown
that copper(salen) complex 1 is capable of catalysing
the asymmetric alkylation of alanine enolates under
substrates. Lygo has shown that cinchona alkaloid
7
derivatives can be used to catalyse similar reactions,
and Maruoka has used synthetic, C -symmetric ammo-
2
nium salts to prepare both a-substituted and a,a-disub-
8
stituted amino acids with high enantiomeric excesses.
9
10
The use of TADDOL and NOBIN complexes to
accomplish the asymmetric alkylation of alanine eno-
lates has also been reported. Of these systems, only the
Maruoka catalyst has been demonstrated to work with
substrates derived from amino acids other than glycine
and alanine. In this paper, we report our results on the
extension of the methodology shown in Scheme 1 to
amino acids other than alanine.
4–6
very mild reaction conditions as shown in Scheme 1.
It was expected that the introduction of large sub-
stituents into the substrate would lead to a reduction in
the rate of the alkylation reaction which might result in
catalyst decomposition during the reactions. However,
initial results using N-benzylidene alanine isopropyl
ester as substrate and benzyl bromide as the alkylating
agent showed that under the standard reaction condi-
tions, the enantiomeric excess of the product did not
vary with % conversion (91% ee at 10–90% conversion).
This indicated that catalyst 1 was completely stable
during the reaction and hence that the longer reaction
times which may be required for more hindered sub-
strates should not result in the formation of product
with reduced enantiomeric excess.
Scheme 1. Reagents and conditions: (i) NaOH/R%X/1 (2
+
mol%), toluene, rt; (ii) H O .
3
Keywords: a,a-disubstituted amino acid; enolate alkylation; asymmet-
ric catalysis; copper(salen) complex.
*
Corresponding author. Tel.: +44-207-848-1164; fax: +44-870-131-
783; e-mail: michael.north@kcl.ac.uk
3
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00170-9

2
046
Y. N. Belokon’ et al. / Tetrahedron Letters 44 (2003) 2045–2048
To extend the scope of the chemistry shown in Scheme
, we first investigated the alkylation of the enolate
Leucine derivative 3 is a more hindered substrate which
contains a branch at the g-carbon. The alkylation of
this substrate was considerably more problematical
than the alkylation of compound 2 as shown in Table 1
1
derived from aminobutyric acid derivative 2. As shown
in Table 1 (entries 1–7), this slight increase in the size of
the side chain did have a detrimental effect upon both
the enantioselectivity and the rate of reaction. How-
ever, by increasing the reaction time to 2 days (compare
entries 3 and 4 or 5 and 6) or by increasing the
concentration of the alkylating agent (compare entries 5
and 7) where necessary, it was still possible to obtain
a-ethyl a-amino acids with 79–82% enantiomeric excess
(
entries 8–15). Under the standard conditions with ben-
zyl bromide as the alkylating agent, no reaction
occurred (entry 8). However, by increasing the amount
of catalyst to 10 mol% (entry 9) and the reaction time
to 7 days (entry 10), it was possible to obtain the
a-benzyl leucine derivative in moderate yield and enan-
tiopurity. The same conditions were also found to be
optimal when para-nitrobenzyl bromide was used as the
alkylating agent (entry 12), though in this case use of a
higher concentration of the alkylating agent allowed the
reaction time to be reduced to one day with only a
small reduction in enantioselectivity (entry 13). The
amount of catalyst could also be reduced to 2 mol%
with little change in the enantioselectivity, though at
the expense of a lower chemical yield (entry 14). The
smaller alkylating agent allyl bromide, also reacted with
substrate 3 in the presence of 10 mol% of the catalyst to
give a-allyl leucine in moderate yield but with only low
enantiomeric excess after one day (entry 15).
11
with both allylic and benzylic alkyl halides. All enan-
tiomeric excesses were determined by reaction of the
a,a-disubstituted amino esters with (S)-1-phenylethyl
isocyanate
and
subsequent
analysis
of
the
1
diastereomeric adducts by H NMR spectroscopy as
previously reported.
5
,6
The next amino acid to be studied as a substrate for the
alkylation reaction was phenylalanine since in this case
the side chain contains a branch at the b-position. The
results are shown in Table 1 (entries 16–24). Using the
standard amounts of alkylating agent and catalyst
(
entries 16 and 17), a moderate yield of a-allyl phenyl-
Table 1. Alkylation of amino acid derivatives 2–6
Entry
Substrate
Alkylating agent (equiv.)
Catalyst (mol%) Time (days)
Yield (%)
Enantiomeric excess (%)
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
5
5
5
6
6
6
Allyl bromide (1.2)
Allyl bromide (2.4)
Benzyl bromide (1.2)
Benzyl bromide (1.2)
para-Nitrobenzyl bromide (1.2)
para-Nitrobenzyl bromide (1.2)
para-Nitrobenzyl bromide (2.4)
Benzyl bromide (1.2)
Benzyl bromide (1.2)
Benzyl bromide (1.2)
para-Nitrobenzyl bromide (1.2)
para-Nitrobenzyl bromide (1.2)
para-Nitrobenzyl bromide (2.4)
para-Nitrobenzyl bromide (2.4)
Allyl bromide (1.2)
Allyl bromide (1.2)
Allyl bromide (1.2)
Allyl bromide (2.4)
Allyl bromide (4.8)
Allyl bromide (4.8)
Allyl bromide (1.2)
Allyl bromide (1.2)
Allyl bromide (1.2)
para-Nitrobenzyl bromide (1.2)
Allyl bromide (2.4)
Allyl bromide (2.4)
Benzyl bromide (2.4)
Benzyl bromide (1.2)
2
2
2
2
2
2
2
2
10
10
10
10
10
2
10
2
2
1
1
1
2
1
2
1
1
1
7
1
7
1
1
1
1
5
1
1
1
1
1
1
1
7
2
2
2
2
2
46
54
39
91
23
83
95
0
41
54
46
63
64
47
46
30
44
53
74
87
40
68
70
67
0
80
70
80
82
78
79
75
27
55
40
56
47
43
22
17
17
15
18
20
31
27
19
34
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2
2
10
10
25
50
10
2
10
10
2
0
0
69
45
46
42
47
25
para-Nitrobenzyl bromide (1.2)
1-Bromobut-2-yne
2
2

Y. N. Belokon’ et al. / Tetrahedron Letters 44 (2003) 2045–2048
2047
alanine was obtained after 1–5 days. By increasing the
concentration of the alkylating agent (entries 18 and
derivative 4 was hydrolysed to (+)-a-allyl phenylalanine
which is known to correspond to the (S)-enantiomer of
this compound.
13
19), it was possible to obtain the product in excellent
yield, but the enantiomeric excess of the a-allyl phenyl-
alanine never exceeded 20%. In contrast, use of 10 or 25
mol% of the catalyst (entries 21 and 22) raised the
enantiomeric excess of the product to around 30%,
though without increasing the chemical yield of the
product. A further increase in the amount of catalyst
used (to 50%; entry 23) was however severely detrimen-
tal to the enantioselectivity. Use of para-nitrobenzyl
bromide as the alkylating agent under conditions of
optimal enantioselectivity (entry 21) gave comparable
results (entry 24).
We have previously proposed that the alkylation of
amino ester enolates catalysed by complex 1 occurs as
4
shown in Figure 1 (R=H). In this model, the enolate
is coordinated to both the copper and sodium ions of a
bimetallic complex and is held orthogonal to the plane
of the salen ligand. The alkylation is directed by the
conformation of the cyclohexane ring, with reaction on
the re-face of the enolate being less hindered than
reaction on the si-face. This model works well for
4
glycine and alanine substrates, both of which are alkyl-
ated with high enantioselectivity. For other amino acid
derived substrates however, an additional factor needs
to be considered: rotation around the C ꢀC bond of
The most hindered naturally occurring a-amino acid is
valine, and as such, substrate 5 was felt to represent the
most demanding test of the methodology. However, all
attempts to alkylate substrate 5 were unsuccessful
a
b
the enolate. Thus, the R-group shown in Figure 1 could
be located over the re- (as shown) or si-face of the
enolate. The former is most likely since the R-group
will be repelled by the same features of the cyclohexane
ring that direct alkylation to the re-face of the enolate.
If the R-group is over the re-face of the enolate how-
ever, then it will hinder the approach of the electrophile
to the re-face and this will result in a lower enantiose-
lectivity during the alkylation. The overall rate of reac-
tion will also decrease as the size of the R-group
increases. Thus, the model correctly predicts both the
absolute configuration of the product, and the relation-
ship between the enantioselectivity and the size of the
amino acid side chain.
(
Table 1, entries 25–27). Based on these results, there
appears to be a relationship between the size of the side
chain present in the substrate, and both the enantiose-
lectivity and rate of the alkylation. As the side chain
increases in size, and particularly as it becomes
branched close to the a-position of the amino acid, the
enantioselectivity decreases and the reactions become
slower until with valine derived substrate 5, no reaction
occurs.
To test this hypothesis, we investigated the alkylation
of allylglycine derivative 6. In this case, for ease of
1
2
synthesis of the substrate, an unhalogenated imine
6
was used. Previous results suggest that this will lower
Another feature of these reactions that requires expla-
nation is the variation of rate of reaction/enantioselec-
tivity with catalyst concentration. Entries 16 and 21–23
of Table 1 show that for the allylation of substrate 4,
there is an optimal concentration of catalyst and higher
or lower concentrations give product with lower enan-
tiomeric excess. A similar effect is observed on the rate
of reaction during the alkylation of substrate 7 with
benzyl bromide (Fig. 2). The most likely explanation of
these effects is that the catalytically active, dimeric form
of the catalyst (Fig. 1) exists in equilibrium with higher
oligomers which are catalytically inactive. Thus,
increasing the concentration of the catalyst beyond the
the enantioselectivity of the process by up to 10%.
Never the less, as the allyl side chain in substrate 6 is
unbranched and intermediate in size between those of
substrates 2 and 3, it would be expected that the
enantioselectivity of the alkylations would be lower
than those observed for compound 2, but higher than
those observed for compound 3. When benzyl bromide
is used as the electrophile, the data in Table 1 show that
this trend is indeed followed (compare entries 4, 8, 9,
and 28). The enantiomeric excess observed with sub-
strate 3 exceeds that observed for substrate 6 only when
the amount of catalyst used is increased from 2 to 10
mol%. Similarly, when para-nitrobenzyl bromide was
used as the alkylating agent with 2 mol% of the catalyst
(
entries 6, 14, and 29), the enantioselectivities followed
the expected trend.
The absolute configuration of the major enantiomer of
the products formed in these reactions has in most
cases not been determined, but based on previous work
is expected to result from alkylation of the re-face of
the enolate of the substrate. Consistent with this, two
sets of reactions form the methyl ester of a-allyl phenyl-
alanine: entries 16–23 by the alkylation of a phenylala-
nine derivative with allyl bromide; and entry 28 by the
alkylation of an allylglycine derivative using benzyl
bromide. These two sets of reactions gave opposite
1
enantiomers of the product as determined by H NMR
analysis of their (S)-1-phenylethyl isocyanate adducts,
and the product formed by allylation of phenylalanine
Figure 1.

2
048
Y. N. Belokon’ et al. / Tetrahedron Letters 44 (2003) 2045–2048
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In summary, we have demonstrated that complex 1 will
catalyse the alkylation of enolates of a range of amino
acids, thus allowing the synthesis of enantiomerically
enriched a,a-disubstituted amino acids. There is a clear
relationship between the size of the side chain of the
amino ester substrate, and the enantioselectivity of the
process. This relationship is consistent with the model
that we have previously proposed to explain the nature
of the catalysis and the origin of the asymmetric induc-
tion. Work on the modification of the catalyst structure
to enhance the enantioselectivity of the alkylation of
amino acids with large side chains is currently in
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recorded by the EPSRC service at the University of
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