Application of metal reagent to the asymmetric synthesis of α-αamino acids

Article abstract of DOI:10.1081/SCC-120005421

Using "mix-ligands" type chiral synthons containing metal ions, a,a-amino acids were obtained in "one-pot" reactions in moderate to high yields and ee% values.

Full text of DOI:10.1081/SCC-120005421

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
APPLICATION OF METAL REAGENT TO THE
ASYMMETRIC SYNTHESIS OF α,α-AMINO ACIDS
Ai-Guo Hu , Ling-Yun Zhang , Shan-Wei Wang & Ji-Tao Wang
To cite this article: Ai-Guo Hu , Ling-Yun Zhang , Shan-Wei Wang & Ji-Tao Wang (2002)
APPLICATION OF METAL REAGENT TO THE ASYMMETRIC SYNTHESIS OF α,α-AMINO
ACIDS, Synthetic Communications, 32:14, 2143-2147, DOI: 10.1081/SCC-120005421
To link to this article: http://dx.doi.org/10.1081/SCC-120005421
Published online: 18 Oct 2011.
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Date: 08 August 2017, At: 14:13

SYNTHETIC COMMUNICATIONS
Vol. 32, No. 14, pp. 2143–2147, 2002
APPLICATION OF METAL REAGENT
TO THE ASYMMETRIC SYNTHESIS OF
a,a-AMINO ACIDS
1
1,
2
Ai-Guo Hu, Ling-Yun Zhang, * Shan-Wei Wang,
1
,y
andJi-Tao Wang
1
Department of Chemistry and
Central Laboratory, Nankai University,
Tianjin 300071, P.R. China
2
ABSTRACT
Using ‘‘mix-ligands’’ type chiral synthons containing metal
ions, ꢀ,ꢀ-amino acids were obtained in ‘‘one-pot’’ reactions
in moderate to high yields and ee% values.
ꢀ
-Amino acids play important roles in chemistry and biology. The
availability of these compounds to optically pure form is critical in
both fundamental research and its applications. In the last three decades,
asymmetric synthesis of ꢀ-amino acids has attracted extensive attentions
[
1–15]
and stimulated the development of series of methodologies.
metallic compounds have many outstanding merits, they have been widely
used as synthetic tools in chemistry.
Organo-
[
16–18]
However, the application of
*
Current address: Department of Chemistry, UBC, Vancouver BC V6T 1Z1,
Canada.
y
Corresponding author. E-mail: hagmhsn@yahoo.com, wangjt@sun.nankai.edu.cn
2
143
DOI: 10.1081/SCC-120005421
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

2
144
HU ET AL.
organometallic compounds in the asymmetric synthesis of ꢀ-amino acids is
still rare. Herein, we report an asymmetric synthesis of ꢀ,ꢀ-amino acids
using chiral synthons containing metal ions.
A most commonly used ꢀ,ꢀ-amino acids, ꢀ-methylphenylalanine was
chosen as the target amino acid, and two tridentate-ligand-type compounds
1 and 2 were selected as the substrates. The alkylations of the substrates with
different kinds of electrophiles were conducted in THF in the presence of
one equivalent of metal salts (TiCl Á2THF) at a certain temperature using
4
LDA as base. The experimental results are listed in Table 1.
ꢀ
Scheme 1. Reagent and conditions: (i) LDA/THF (7–10 eq.), ꢂ60 C, electrophile,
Ar, then warm to certain temperature, 12 h; (ii) 6 N HCl, reflux, 10 h.
Table 1. Asymmetric Synthesis of ꢀ-Methylphenylalanine
Temperature
ꢀ
ee%
Conversion (Config.)
a
a
Entry Substrate Auxiliary Electrophile
( C)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
1
1
1
1
1
1
1
1
1
1
2
1
2
2
–
3
5
6
7
4
3
3
3
3
3
3
8
8
8
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnCl
BnOTs
MeI
À60 ꢁ 25
À60 ꢁ 25
À60 ꢁ 25
À60 ꢁ 25
À60 ꢁ 25
À60 ꢁ 25
À60 ꢁ 25
À60 ꢁ 0
5%
98%
60%
65%
38%
56%
67%
74%
24%
76%
67%
60%
n.d.
0
0
b
10% (R)
11% (S)
6% (S)
22% (R)
42% (R)
50% (R)
5% (R)
56% (R)
37% (R)
18% (S)
–
À60 ꢁ À20
À60 ꢁ 0
1
1
1
1
1
1
À60 ꢁ 0
À60 ꢁ 0
BnBr
MeI
MeI
À60 ꢁ 0
À60 ꢁ 0
65%
60%
55% (S)
74% (S)
À60 ꢁ À15
a
Detected on a chiral HPLC column (Chirex 3126), eluent: methanol: 2 mM
ꢀ
CuCl /H O, 30/70 (v/v), flow rate: 1 mL/min, temperature: 22 C, retention time:
2
2
b
S)-: 23.64 min, (R)-: 33.07min; TiCl
(
4
ꢁ2THF is absent.

ASYMMETRIC SYNTHESIS OF ꢀ,ꢀ-AMINO ACIDS
2145
Scheme 2. Structure of the chiral auxiliaries.
Starting from racemic substrate, enantiomeric enriched product could
only be obtained as both the chiral auxiliary and metal salt were present
(
Entries 1–2 vs others), which reveals that a complexing system of these two
components and substrate is formed in solution. In this complexing system,
metal ion fixes the substrate and chiral auxiliary together and transfers the
chiral induction.
The reactivity of the anionized Schiff base decreased dramatically in
the presence of metal salt (Entry 1 vs 2), which indicates that, on coordina-
tion, electron density flows to the metal ion and makes the Schiff base
substrate less nucleophilic. When chiral diol is present, the di-anions com-
plex with the metal ion, pushes electron density back to Schiff base sub-
strate, causes the Schiff base more reactive. As a result, the reactivity of the
intermediate is critically dependent on the complexing property of the diol.
For TADDOL derivatives 7, two bulky phenyl groups restricted the diol
from coordinating with the metal ion. The electron-donating effect is
reduced, and the reactivity is low (Entry 5). Other diols are free of this
steric hindrance, and the conversions are much higher.
The selectivity is affected by the size of the complexing ring and the
bulkiness of the ꢀ-substituents of the diol. The 1,4-diols (Entries 3–5), which
form a seven-membered ring, demonstrate significant flexibility and the
chiral induction are poor. While in the case of 1,2-diols (Entries 6–7),
much more rigid five-membered rings are formed, and the ee% values are
higher. The difference between 3 and 4 may be rationalized as that benzyl
group has much more spatial freedom compared to the cyclohexyl group
and minimized the chiral induction.
The temperature dependence of this reaction is evident. There exists an
optimal point (Entry 8 vs 7, 9) in this type of reactions at around zero
degree. At this temperature, both maximum conversion and selectivity are
reached. From the discussion so far, we learned that both conversion and
selectivity are related to the formation of complex. A plausible explanation
for this is: In solution, there exists equilibrium between the complexing ring

2
146
HU ET AL.
(
the intermediate) and the three free components. At the optimal point, the
coordination is rigid. At higher temperature, the coordinated system
becomes flexible, while at lower temperature, the chiral auxiliary is not
able to replace the chlorine atom of the metal salt. Both cases are unfavor-
able to conversion and selectivity.
Screening the electrophiles and the substrates, we found that the
higher the reactivity of the electrophile, the lower the selectivity, and an
inconclusive effect on the conversion was found (Entries 7, 10–11).
Methylation of phenylalanine substrate gives the same product (ꢀ-methyl-
phenylalanine) in opposite configuration, but the selectivity is quite low
(
Entry 12). The reason may be that methyl group is too small.
From the above discussion, it can be seen that the selectivity can be
improved when a chiral auxiliary bearing bulky ꢀ-substituents is used. To
[
19]
test this presumption, chiral 1,2-diol 8
was used as auxiliary.
Unfortunately, when 8 was introduced into the standard reaction con-
ditions, benzylation of alanine substrate didn’t occur (Entry 13). A reason-
able explanation for this is that the ꢀ-substituents of the diol are too large
and thus restrict the bulky benzyl group from attacking the substrate. We
then tested methylation of phenylalanine substrate. Using a smaller electro-
phile, (Entries 14–15), it works well.
In conclusion, a novel asymmetric synthesis of ꢀ,ꢀ-amino acids has
been developed. Using amino acid equivalent-Schiff base, metal salts and
chiral auxiliaries, the target amino acids can be obtained in one-pot reac-
tion. The optimization of this reaction is under progress.
EXPERIMENTAL
Synthesis of Schiff base 1: To a solution of 0.1 mol ꢀ-amino acid ester
in 200 mL CH Cl , 0.1 mole salicylaldehyde was added. The mixture was
2
2
refluxed for 5 h. The solvent was evaporated. After recrystallization in
ether/petroleum ether, the Schiff base was obtained in 85–93% yield.
General procedure of the alkylation: To a 1 : 1 : 1 solution of 1,
[
20]
ꢀ
TiCl Á2THF
and chiral auxiliary in THF cooled at À60 C, LDA was
4
introduced under Argon, the mixture was stirred for 30 min, and alkyl
halide was then added. The reaction mixture was warmed up to certain
temperature and stirred for 12 h, and then quenched with dilute HCl. The
chiral auxiliary was recovered without loss of chirality in this step. The
residue was refluxed with 6N HCl for 10 h and the target ꢀ,ꢀ-amino acid
were obtained. An aliquot portion was analyzed on a chiral column for the
determination of the yield and the ee% value.

ASYMMETRIC SYNTHESIS OF ꢀ,ꢀ-AMINO ACIDS
2147
ACKNOWLEDGMENT
This work is supported by National Natural Science Foundation of
China (29972026), Key Lab of the Elemento-organic Chemistry of China,
Key lab of the Shanghai Institute of Organic Chemistry.
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Received in Japan February 20, 2001