One-pot synthesis of α-amino acids based on free radical-mediated carbon-carbon bond formation

Article abstract of DOI:10.1039/a807017b

The one-pot reaction of 2-hydroxy-2-methoxyacetic acid methyl ester with benzyloxyamine and an alkyl radical provided a convenient method for preparing the protected α-amino acids via a carbon-carbon bond formation by intermolecular carbon radical additio

Full text of DOI:10.1039/a807017b

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One-pot synthesis of á-amino acids based on free radical-mediated
carbon–carbon bond formation
Hideto Miyabe, Naoko Yoshioka, Masafumi Ueda and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
E-mail: taknaito@kobepharma-u.ac.jp
Received (in Cambridge) 8th September 1998, Accepted 16th October 1998
Table 1 One-pot synthesis of α-amino acid derivatives 3b–g and 8h
The one-pot reaction of 2-hydroxy-2-methoxyacetic acid
methyl ester with benzyloxyamine and an alkyl radical
provided a convenient method for preparing the protected
á-amino acids via a carbon–carbon bond formation by
intermolecular carbon radical addition to glyoxylic oxime
ether.
Entry
RI
Producta
Yieldb (%)
1
2
3
4
5
6
7
PriI
3b
3c
3d
3e
3f
3g
8h
74
71
72
86
49
57
46
BusI
c-HexylI
ButI
In recent years, much attention has been paid to the develop-
ment of concise and flexible synthetic approaches to α-amino
acids, allowing facile incorporation of functional groups and
structural variability. Multi-step synthetic routes to α-amino
acids are available,1 however, integration of multi-step chemical
reactions into a one-pot reaction is of great significance from
both economical and ecological points of view.2 Thus, the
development of one-pot approaches to α-amino acids is a new
subject of considerable interest.3 We recently reported the first
example of the preparation of amines and α-amino acids based
on the intermolecular carbon radical addition to oxime ethers.4–6
We now report a novel one-pot procedure for the synthesis of
α-amino acid derivatives by the condensation of an α-keto acid
derivative with alkoxyamine followed by the addition of an
alkyl radical to the resulting oxime ether.
BuiI
AcO(CH2)4I
Cl(CH2)3I
a The ethylated product 3a was obtained in ca. 5–10% yields (entries
1–4) or ca. 10–25% yields (entries 5–7). b Isolated yields.
MeO2C
NOBn
1 +
2
H
4
O2
•
Et •
MeO2C
NOBn
Et3B
As a preliminary experiment, we chose a combination of
commercially available 2-hydroxy-2-methoxyacetic acid methyl
ester 1, benzyloxyamine 2 and triethylborane as an ethyl radical
source and investigated the one-pot reaction under several con-
ditions (Scheme 1). Conventional condensation of 2-hydroxy-2-
Et
5
Et3B
BEt2
H2O
MeO2C
NOBn
MeO2C
NHOBn
Et
Et
MeO2C
OH
OMe
MeO2C
NHOBn
+
+
BnONH2
Et3B
6
3a
90%
Et
Scheme 2
1
2
3a
b : R = Pri
c : R = Bus
Scheme 1 Reagents and conditions: MgSO4, CH2Cl2, 25 ЊC.
MeO2C
OH
+
+
RI
BnONH2
d : R = c-Hexyl
e : R = But
methoxyacetic acid methyl ester 1 with benzyloxyamine 2 pro-
ceeded smoothly in the presence of MgSO4 to give the glyoxylic
oxime ether 4. To the reaction vessel was added Et3B and then
the reaction mixture was stirred at 25 ЊC. This quite simple pro-
cedure in one-pot afforded, as expected, the protected α-amino
acid 3a in 90% yield. The reaction proceeds as indicated in
Scheme 2. An ethyl radical, initially generated from Et3B and
O2, adds intermolecularly to the oxime ether group of 4, which
was generated in situ from 2-hydroxy-2-methoxyacetic acid
methyl ester 1 and benzyloxyamine 2, to form the intermediate
aminyl radical 5. Since Et3B acts not only as a radical initiator
but also as a terminator to trap the resulting aminyl radical 5,
the radical reaction cycle proceeds through the regeneration of
the ethyl radical and the formation of the adduct 6.7 The
desired ethylated α-amino acid 3a is obtained as a result of the
hydrolysis of the adduct 6.
In order to investigate the generality and practicality of this
one-pot reaction, the present procedure was successfully
extended to a three-component reaction using different radical
precursors, 7b–h, as shown in Scheme 3. As in the case of 3a, to
the reaction vessel containing the intermediate oxime ether
formed from a 1:1 mixture of 1 and 2 were successively added
PriI 7b, Bu3SnH and Et3B as a radical initiator. The iso-
OMe
1
2
7b–h
f : R = Bui
g : R = (CH2)4OAc
h : R = (CH2)3Cl
OBn
N
MeO2C
MeO2C
NHOBn
R
3b–h
8h
Scheme 3 Reagents and conditions: Bu3SnH, Et3B, MgSO4, CH2Cl2,
25 ЊC.
propylated α-amino acid derivative 3b was obtained in 74%
yield (Table 1, entry 1). Not only a secondary alkyl but also the
bulky tert-butyl radical worked well under similar reaction con-
ditions (entries 1–4). Modest chemical yields were obtained in
the reactions using primary alkyl radicals because of the com-
petitive formation of a significant amount of the ethylated
product 3a as a by-product, which would be formed by the
reaction with the ethyl radical generated from Et3B (entries
5–7). As we were expecting that the addition of functionalized
radicals would make products more useful building blocks, as
J. Chem. Soc., Perkin Trans. 1, 1998, 3659–3660
3659

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exemplified by the recent progress in the fields of combinatorial
chemistry and drug discovery, we investigated the reaction
employing bifunctional halides as an alkyl radical precursor. As
was expected from the nature of the radical reaction, alkyl
iodides containing an ester moiety or a chlorine atom under-
went smooth radical addition reactions to give the correspond-
ingly functionalized α-amino acid derivatives 3g and 8h (entries
6 and 7). In the case of 1-chloro-3-iodopropane 7h, the proline
derivative 8h was obtained as a result of the concomitant
intramolecular N-alkylation of 3h which was preformed by the
one-pot reaction of the chloropropyl radical.
Acknowledgements
We thank the Ministry of Education, Science, Sports and
Culture of Japan and the Science Research Promotion Fund of
the Japan Private School Promotion Foundation for research
grants.
References
1 (a) R. M. Williams, Synthesis of Optically Active α-Amino Acids,
Pergamon Press, Oxford, 1989; (b) R. O. Duthaler, Tetrahedron, 1994,
50, 1539.
The advantages of this one-pot procedure are that the tedi-
ous isolation of the intermediate oxime ether is unnecessary
and the crucial radical addition proceeds under very mild
conditions to give C-alkylated products with high levels of
regioselectivity. Therefore, the radical addition approach com-
plements the nucleophilic addition of organometallic reagents
giving a mixture of C- and N-alkylated products.8,9
In addition to the previously reported multi-step synthesis of
amines and α-amino acids via alkyl radical addition to oxime
ethers, the newly found one-pot procedure disclosed a broader
aspect of the potentiality of an alkyl radical addition to oxime
ethers, thus establishing the one-pot synthesis as a simple and
useful methodology for the construction of various types of
α-amino acid derivatives.
2 (a) P. A. Tempest, S. D. Brown and R. W. Armstrong, Angew. Chem.,
Int. Ed. Engl., 1996, 35, 640; (b) G. H. Posner, Chem. Rev., 1986, 86,
831.
3 (a) N. A. Petasis and I. A. Zavialov, J. Am. Chem. Soc., 1997, 119,
445; (b) N. A. Petasis, A. Goodman and I. A. Zavialov, Tetrahedron,
1997, 53, 16463.
4 (a) H. Miyabe, R. Shibata, C. Ushiro and T. Naito, Tetrahedron
Lett., 1998, 39, 631; (b) H. Miyabe, C. Ushiro and T. Naito, Chem.
Commun., 1997, 1789; (c) H. Miyabe, R. Shibata, M. Sangawa,
C. Ushiro and T. Naito, Tetrahedron, 1998, 54, 11431.
5 Oxime ethers are well known to be excellent radical acceptors because
of the extra stabilisation of the intermediate aminyl radical provided
by the adjacent oxygen atom. See H. Miyabe, M. Torieda, K. Inoue,
K. Tajiri, T. Kiguchi and T. Naito, J. Org. Chem., 1998, 63, 4397 and
references cited therein.
6 For a related example, high 1,3-stereoinduction in radical additions
to glyoxylate imines has recently been reported. See M. P. Bertrand,
L. Feray, R. Nouguier and L. Stella, Synlett, 1998, 780.
7 K. Nozaki, K. Oshima and K. Utimoto, Bull. Chem. Soc. Jpn., 1991,
64, 403.
8 (a) Y. Yamamoto and W. Ito, Tetrahedron, 1988, 44, 5415; (b)
T. Kolasa, S. K. Sharma and M. J. Miller, Tetrahedron, 1988,
44, 5431; (c) J.-C. Fiaud and H. B. Kagan, Tetrahedron Lett., 1971,
1019; (d) J.-C. Fiaud and H. B. Kagan, Tetrahedron Lett., 1970,
1813.
9 For recent examples, the nucleophilic addition of allylic zinc reagents
to glyoxylic oxime ethers proceeds regioselectively to give the C-
alkylated products. See (a) S. Hanessian and R.-Y. Yang, Tetrahedron
Lett., 1996, 37, 8997; (b) S. Hanessian and R.-Y. Yang, Tetrahedron
Lett., 1996, 37, 5273.
General procedure
To a solution of 2-hydroxy-2-methoxyacetic acid methyl ester 1
(80 mg, 0.67 mmol) in CH2Cl2 (1 cm3) were added benzyl-
oxyamine 2 (82.4 mg, 0.67 mmol) in CH2Cl2 (0.5 cm3) and
MgSO4 (10 mg) under a nitrogen atmosphere at 25 ЊC. After the
reaction mixture was stirred at the same temperature for 1 day,
RI 7 (3.35 mmol), Bu3SnH (0.45 cm3, 1.68 mmol) and Et3B (1.0
M in hexane, 1.68 cm3, 1.68 mmol) were added. After being
stirred at the same temperature for 15 min, the reaction mix-
ture was diluted with saturated aqueous NaHCO3 and then
extracted with CH2Cl2. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. Purification
of the residue by preparative TLC (hexane–AcOEt 15:1, two
repeats) followed by preparative TLC (chloroform) afforded the
α-amino acid derivatives 3.
Communication 8/07017B
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J. Chem. Soc., Perkin Trans. 1, 1998, 3659–3660