Synthesis of new racemic α,α-diaminocarboxylic ester derivatives

Article abstract of DOI:10.3390/molecules15129354

New racemic methyl or ethyl a-aminoglycinate derivatives were synthesized by N-alkylation of amines (aniline, 4-methylaniline, 2-methylaniline, 2,4-dimethoxyaniline, 2-nitroaniline, 4-chloro-2-fluoroaniline, 2-naphthylamine, benzylamine, N,N-dibenzylamine

Full text of DOI:10.3390/molecules15129354

Molecules 2010, 13, 9354-9363; doi:10.3390/molecules15129354
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of New Racemic α,α-Diaminocarboxylic
Ester Derivatives
Mabrouk El Houssine, Elachqar Abdelrhani, Alami Anouar 1,* and El Hallaoui Abdelilah
Laboratoire de Chimie Organique Fès, Faculté des Sciences Dhar El Mahraz, Université Sidi Mohamed
Ben Abdellah, Morocco
* Author to whom correspondence should be addressed; E-Mail: alamianouar@yahoo.fr;
Tel.: 212-5-35-73-3171; Fax: 212-5-35-73-3171.
Received: 26 October 2010; in revised form: 19 November 2010/ Accepted: 25 November 2010/
Published: 17 November 2010
Abstract: New racemic methyl or ethyl α-aminoglycinate derivatives were synthesized by
N-alkylation of amines (aniline, 4-methylaniline, 2-methylaniline, 2,4-dimethoxyaniline,
2-nitroaniline,
4-chloro-2-fluoroaniline,
2-naphthylamine,
benzylamine,
N,N-dibenzylamine, and cyclohexylamine) with methyl or ethyl α-azidoglycinate.
Keywords: amine; N-alkylation; methyl α-azidoglycinate; α-amino acids
1. Introduction
Amino acids are the fundamental building blocks of peptides and proteins and play essential roles in
living organisms. Because of the physiological importance of α-amino acids, innumerable studies for
their chemistry and synthesis have been published [1-4]. Along with the elucidation of their
distributions, origins and physiological functions, the D-amino acids have been recognized as the
candidates for novel physiologically active substances and/or marker molecules of diseases [5-6].
Since the end of last century, the studies of amino acids have changed to focusing on their
biochemistry, physiology and medical activities such as apoptosis inducing, platelet
aggregation-inhibiting/inducing, antimicrobial, anti-HIV.
The synthesis of amino acids was a very important development [7]. Their applications can be found
currently in several domains: biochemistry, enzymology [8-11], medicine (antibiotics, antiepileptics,
antivirals, antiprotozoals, cardiovascular, atherosclerosis, renal failure and diabetes, neuroexciters
[12-26]), agrochemical industry (herbicides, fungicides, regulation of plant growth), in addition to their

Molecules 2010, 15
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important utility as chiral auxiliaries in asymmetric synthesis [27,28]. The development of simple,
efficient and highly selective methods for widely used organic compounds from readily available
reagents is one of the major challenges in organic synthesis. Among these, C-N bond formation is one of
the most important transformations. The reactions of amines have been a topic of immense research
interest due to their synthetic utility [29-33] and biological activity [34]. Amines are widely used as
intermediates to prepare solvents, fine chemicals, agrochemicals, pharmaceuticals and as
polymerization catalysts [35-37].
Diaminoacids are important non-protein amino acids, usually components of both natural and
synthetic bioactive compounds [38]. In fact, they are currently well recognized as key structural moieties
in a variety of biologically active molecules [39,40].
The literature [41-49] reports different methods of alkylation, among which phase transfer catalysis,
the N-alkylation by microwaves, and the Mitsunobu reaction with organic azides have proved to be
efficient key intermediates in organic synthesis for the construction of heterocyclic systems by
cycloaddition reactions, while the substitution of the azide group has received much less attention.
Continuing our investigations on the use of organic azides [50,51], we report in this paper another part of
our investigations concerning the preparation of new α,α-diaminocarboxylic esters derivatives with the
aim of providing access to new active biomolecules.
2. Results and Discussion
Our strategy is based on the N-alkylation of amines with methyl or ethyl α-azidoglycinate 1 (R = CH3) or
1’ (R = C2H5) (Scheme 1). Azide derivatives 1 and 1’ were prepared using Achamlale’s version of the
Steglich reaction [52] and [53,54]. The title compounds are stable and can be stored for an unlimited
amount of time without any signs of decomposition. Methyl or ethyl α-bromoglycinate also can be used
and give satisfactory results; the azide 1 (R = CH3) or 1’ (R = C2H5) are used especially for their stability.
Scheme 1. N-alkylation of different amines, with methyl or ethyl α-azidoglycinate 1
(R = CH3) or 1’ (R = C2H5).
H
N
O
H
N
O
NuH / rt
Diisopropylethylamine/Acetone
C
C
OR
OR
O
N3
O
Nu
1 - 1'
2 - 11
R = CH3, C2H5
NH2
NH2
NH2
NH2
NH2
NH2
CH3
OCH3
F
NO2
Nu-H
=
;
;
;
;
;
CH3
OCH3
Cl
H
N
NH2
CH2
NH2
NH2
;
;
;

Molecules 2010, 15
9356
As shown in Scheme 1, the N-alkylation reactions of various amine nucleophiles (aniline,
4-methylaniline, 2-methylaniline, 2,4-dimethoxyaniline, 2-nitroaniline, 4-chloro-2-fluoroaniline,
2-naphthylamine, benzylamine, N,N-dibenzylamine, and cyclohexylamine) with N-benzoylated methyl
or ethyl α-azido-glycinates 1 (R = CH3) or 1’ (R = C2H5) were performed in dry acetone for 48 h at room
temperature in the presence of diisopropylethylamine (DIPEA). The products 2-11 were obtained in
1
good to high chemical yields (62-92%) and were characterized by MS, H-NMR and 13C-NMR
spectroscopy. The results are summarized in Table 1.
Table 1. Synthesis of new methyl or ethyl α-aminoglycinates derivatives 2-11.
m.p.
(°C)
Reaction Yield δHα
Time (h) (%) (ppm)
Entry Nu-H
Product
1
2
Aniline
Methyl 2-benzamido-2-(phenylamino)acetate (2)
Methyl 2-benzamido-2-(p-tolylamino)acetate (3)
124-126 48
80
6.22
4-methylaniline (R =
Me)
140-142 48
90
6.14
3
4
4-methylaniline (R = Et) Ethyl 2-benzamido-2-(p-tolylamino)acetate (3’)
164-166 48
128-130 48
80
90
6.11
6.22
2-methylaniline
Methyl 2-benzamido-2-(o-tolylamino)acetate (4)
Methyl
5
6
2,4-dimethoxy-aniline
2-benzamido-2-(2,4-dimethoxyphenylamino)acetate
170-172 48
86.5
90
6.15
6.20
(5)
Methyl
4-chloro-2-fluoro-aniline 2-benzamido-2-(4-chloro-2-fluorophenylamino)acetate 152-154 48
(6)
7
8
9
2-nitroaniline
2-naphthylamine
Benzylamine
Ethyl 2-benzamido-2-(2-nitrophenylamino)acetate (7)
Ethyl 2-benzamido-2-(2-naphthylamino)acetate (8)
Methyl 2-benzamido-2-(benzylamino)acetate (9)
Methyl 2-benzamido-2-(N,N-dibenzylamino)acetate
(10)
173-174 48
210-212 48
104-106 48
86
62
76
6.82
6.25
5.56
10
11
N,N-dibenzyl-amine
130-132 48
84
92
5.58
5.72
2-amino-cyclohexane
Methyl 2-benzamido-2-(cyclohexylamino)acetate (11) 182-184 48
Comparing these results with only the work done by our team [41,50,51], we see that we obtained
almost identical results. The molecule 2 used for previous work as a reference model. In continuation of
that work, we studied herein the influence of donors and withdrawing groups on the the aromatic ring of
the aniline moiety on the NMR chemical shifts of these systems. In molecule 2 used as a reference, the
proton on the carbon α to the carboxylate group appears as a doublet at 6.22 ppm. When the aromatic
ring bears a donor group in positions 2 or 4 (entries 2, 3 and 4), the chemical shift of the α-proton does
not undergo any major changes (δCH = 6.14-6.20 ppm).
It should be noted that in the 1H-NMR spectrum of pure product 6 the α-proton at 6.20 ppm appears as
a multiplet. The chemical shift is practically the same as that of the α-proton in the reference molecule 2,
and the splitting is probably due to the opposite effects (+ M) and (− I) of the two halogen atoms (fluorine
in position 2 and chlorine in position 4) on the aromatic ring.
In molecule 7, the α-proton multiplet underwent a deshielding of 6.22 to 6.82 ppm due to the presence
of an electron withdrawing group [with inductive and mesomeric effects (− I, − M)] at the ortho position
of the aromatic aniline system. In the case of benzylamine, dibenzylamine and cyclohexylamine as
N-alkylation reagents, the chemical shift of the α-hydrogen undergoes a shielding of about 0.60 ppm

Molecules 2010, 15
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(6.22 to 5.62 ppm) compared to molecule 2 used as a reference model (products 9, 10 and 11). This can
be justified by the electrondonor effect (+ I) of the benzyl and cyclohexyl groups.
In conclusion, this method provides a convenient method and easy procedure for the preparation of new
methyl or ethyl α-aminoglycinate derivatives starting from the appropriate azide derivatives 1 (R = CH3)
or 1’ (R = C2H5). The N-alkylation of various amines (aniline, 4-methylaniline, 2-methylaniline,
2,4-dimethoxyaniline, 2-nitroaniline, 4-chloro-2-fluoroaniline, 2-naphthylamine, benzylamine,
N,N-dibenzylamine, and cyclohexylamine) with azide occurred under very mild conditions and led after
a reaction time of about 48 h to the desired products in very satisfactory yields (Table 1).
The nucleophilic nature of the reagents has an immediate influence on the α-hydrogen acidity and its
possible effect the reactivity of the α,α-diamino acids.
3. Experimental
3.1. General
Melting points were determined with an Electrothermal melting point apparatus and are uncorrected.
NMR spectra (1H, 13C) were recorded on a Bruker AM 300 (operating at 300.13 MHz for 1H, at 75.47
MHz for 13C) spectrometer (Centre Universitaire Régional d’Interface, Fès). NMR data are listed in ppm
13
and are reported relative to tetramethylsilane (1H, C); residual solvent peaks being used as internal
standard. All reactions were followed by TLC. TLC analyses were carried out on 0.25 mm thick precoated
silica gel plates (Merck Fertigplatten Kieselgel 60F254) and spots were visualised under UV light or by
exposure to vaporised iodine. Mass spectra were recorded by electrospray on a micromass ESl Platform
II (Université Montpellier II, France) and on a PolarisQ Ion Trap GC/MSn Mass Spectrometer (Centre
Universitaire
Régional
d’Interface,
Fès).
Methyl
α-azidoglycinate
1
(R = CH3) or 1’ (R = C2H5) was prepared using Achamlale’s method [53,54].
3.2. Typical Procedure for N-Alkylation
To a stirred solution of amine (2.86 mmol) and diisopropylethylamine (3.12 mmol) in dry acetone
(10 mL), α-azidoglycinate (2.6 mmol) was added. The mixture was stirred at room temperature and the
reaction was followed by TLC (Kiesegel Merck 60F524). The solvent was evaporated under reduced
pressure. The residue was quenched with saturated aqueous solution of ammonium chloride (20 mL) and
extracted with dichloromethane(20 mL × 3). The organic phase was dried in sodium sulfate (Na2SO4)
and the solvent was removed under reduced pressure. The product was purified by column
chromatography on silica gel using ether/hexane as eluant to afford pure N-alkylated product.
Methyl 2-benzamido-2-(phenylamino)acetate (2): Yield 80%; Solid, m.p. 124-126 °C (ether/hexane); Rf
= 0.75 (ether); 1H-NMR (CDCl3, ppm): δ = 7.80 (m, 2H, Harom), 7.56-7.49 (m, 4H, Harom), 7.15-7.09 (m,
2H, NHamid + Harom), 6.79-6.68 (m, 3H, Harom), 6.22 (d, 1H, Hα, 8 Hz), 4.91 (br s, 1H, NH), 3.87 (s, 3H,
OCH3); 13C-NMR (CDCl3, ppm): δ = 170.0, 166.7 (CO), 146.2, 133.7, 132.2 (2C), 129.4, 128.8 (2C),
127.9 (2C), 118.0, 113.5 (2C) (C6H5 aromatic carbons), 60.9(-CH-), 53.0 (CH3O); MS (electrospray)
m/z: 285.2 (M + 1, 9%), 164 (100%), 104 (21%); (Formula: C16H16N2O3).

Molecules 2010, 15
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Methyl 2-benzamido-2-(p-tolylamino)acetate (3): Yield 90%; Solid, m.p. 140-142 °C (ether/hexane); Rf
= 0.67 (ether); 1H-NMR (CDCl3, ppm): δ = 7.76 (m, 2H, Harom), 7.52-7.40 (m, 3H, Harom), 7.02 (m, 2H,
NHamid + Harom), 6.77-6.67 (m, 3H, Harom), 6.14 (d, 1H, Hα, 7.8 Hz), 4.90 (br s, 1H, NH), 3.86 (s, 3H,
OCH3), 2.24 (s, 3H, CH3); 13C-NMR (CDCl3, ppm): δ = 170.5, 167.2 (CO), 141.6, 133.2, 132.1, 130.0
(2C), 129.0, 128.7 (2C), 127.2 (2C), 114.2 (2C) (C6H5 aromatic carbons), 61.1 (-CH-), 53.4 (OCH3),
20.5 (CH3); EIMS m/z: 298 (M+., 12% ), 239 (88%), 122 (38%), 105 (100%), 77 (59%); (Formula:
C17H18N2O3).
Ethyl 2-benzamido-2-(p-tolylamino)acetate (3’): Yield 80%; Solid, m.p. 164-166 °C (ether/hexane);
Rf = 0.72 (ether); 1H-NMR (CDCl3, ppm): δ = 7.75 (m, 2H, NHamid + Harom), 7.52-7.40 (m, 3H, Harom),
7.02 (m, 2H, NHamid + Harom), 6.82-6.69 (m, 3H, Harom), 6.11 (d, 1H, Hα, 7.9Hz), 4.90 (br s, 1H, NH),
13
4.32 (q, 2H, OCH2, 7.05Hz), 2.25 (s, 3H, CH3), 1.33 (t, 3H, CH3, 7.05Hz); C-NMR (CDCl3, ppm):
δ = 170.0, 167.3 (CO), 141.7, 133.4, 132.0, 130.0 (2C), 128.9, 128.6 (2C), 127.1 (2C), 114.3 (2C) (C6H5
aromatic carbons), 62.6 (-CH-), 61.3 (CH3CH2O), 20.5 (CH3), 14.9 (CH3CH2O); MS (electrospray) m/z:
313.2 (M + 1, 11.81 %); 239.1 (88.58%), 192.1 (11.82%), 136.1(37.80%), 118.0 (59.06%), 105.0
(100%); (Formula: C18H20N2O3).
Methyl 2-benzamido-2-(o-tolylamino)acetate (4): Yield 90%; Solid, m.p. 128-130 °C (ether/hexane); Rf
= 0.62 (ether); 1H-NMR (CDCl3, ppm): δ = 7.85 (m, 2H, Harom), 7.56-7.41 (m, 3H, Harom), 7.15-7.09 (m,
2H, NHamid + Harom), 6.79-6.68 (m, 3H, Harom), 6.22 (d, 1H, Hα, 8 Hz), 5.05 (br s, 1H, NH), 3.88 (s, 3H,
OCH3), 2.24 (s, 3H, CH3); 13C-NMR (CDCl3, ppm): δ = 170.6, 167.2 (CO), 142.2, 133.2, 132.2, 130.6,
128.7 (2C), 127.4, 127.2 (2C), 123.1, 119.2, 111.3 (C6H5 aromatic carbons), 60.7 (-CH-), 53.4 (OCH3),
17.5 (CH3); EIMS m/z: 298 (M+.,14% ), 239 (87%), 122 (64%), 105 (100%), 77 (69%); (Formula:
C17H18N2O3).
Methyl 2-benzamido-2-(2,4-dimethoxyphenylamino)acetate (5): Yield 86.5%; Solid, m.p. 170-172 °C
(ether/hexane); Rf = 0.69 (ether); 1H-NMR (CDCl3, ppm): δ = 7.78 (m, 2H, Harom), 7.55-7.30 (m, 3H,
Harom), 6.90-6.38 (m, 4H, NHamid + Harom), 6.15 (d, 1H, Hα, 7.8Hz), 5.10 (br s, 1H, NH), 3.85 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 3.74 (s, 3H, OCH3); 13C-NMR (CDCl3, ppm): δ = 170.5, 167.2 (CO), 153.7,
148.7, 133.4, 132.0, 128.6 (2C), 127.8, 127.4 (2C), 112.9, 103.9, 99.3 (C6H5 aromatic carbons), 61.3
(-CH-), 55.6, 55.5, 53.2 (OCH3); MS (electrospray) m/z: 345.2 (M + 1, 17.45%), 224.2 (79.19%), 192.2
(3.36%), 164.3 (11.41%); (Formula: C18H20N2O5).
Methyl 2-benzamido-2-(4-chloro-2-fluorophenylamino)acetate (6): Yield 90%; Solid, m.p. 152-154 °C
(ether/hexane); Rf = 0.87 (ether); 1H-NMR (CDCl3, ppm): δ = 7.78 (m, 2H, Harom), 7.62-7.41 (m, 3H,
Harom), 7.05-6.85 (m, 4H, NHamid + Harom), 6.20 (m, 1H, Hα), 5.15 (br s, 1H, NH), 3.85 (s, 3H, OCH3);
13C-NMR (CDCl3, ppm): δ = 169.8, 167.3 (CO), 152.6, 132.9, 132.3, 131.5, 128.8 (2C), 127.3 (2C),
124.9, 123.7, 115.7, 114.6 (C6H5 aromatic carbons), 60.0 (-CH-), 53.5 (OCH3); MS (electrospray) m/z:
361.1 (6.41%), 359.1 (16.99%), 337.1 (M + 1, 7.05%), 218.2 (32.05%), 216.2 (100%), 122.3 (58.33%);
(Formula: C16H14ClFN2O3).

Molecules 2010, 15
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Ethyl 2-benzamido-2-(2-nitrophenylamino)acetate (7): Yield 86%; Solid, m.p. 173-174 °C
(ether/hexane); Rf = 0.83 (ether); 1H-NMR (CDCl3, ppm): δ = 8.85 (br s, 1H, NHamid), 8.25-6.92 (5m,
9H, Harom), 6.82 (m, 1H, Hα), 6.45 (br s, 1H, NH), 4.35 (q, 2H, OCH2, 7.1Hz), 1.35 (t, 3H, CH3, 7.1Hz);
13C-NMR (CDCl3, ppm): δ = 168.5, 167.1 (CO), 142.0, 136.6, 133.6, 132.9, 132.4, 128.8 (2C), 127.2
(2C), 126.8, 117.8, 115.1 (C6H5 aromatic carbons), 63.1 (-CH-); 59.3 (CH3CH2O); 14.0 (CH3CH2O);
MS (electrospray) m/z: 366.2 (26.75%), 344.1 (M + 1, 17.52%), 223.2 (47.77%), 206.2 (57.96%), 105.3
(100%); (Formula: C17H17N3O5).
Ethyl 2-benzamido-2-(naphthalen-2-ylamino)acetate (8): Yield 62%; Solid, m.p. 210-212 °C
(ether/hexane); Rf = 0.67 (ether); 1H-NMR (CDCl3, ppm): δ = 7.85 (m, 2H, Harom), 7.71-7.64 (m, 3H,
Harom), 7.51-7.25 (m, 6H, Harom), 7.07 (m, 2H, NHamid + Harom), 6.87 (d, 1H, NH, 8.0Hz), 6.25 (d, 1H, Hα,
8.0Hz), 4.35 (q, 2H, OCH2, 7.1Hz), 1.34 (t, 3H, CH3, 7.1Hz); MS (electrospray) m/z: 697.3 (2M+1,
4.17%), 349.2 (M + 1, 8.01%), 154.3 (3.21%), 228.1 (100%); (Formula: C21H20N2O3).
Methyl 2-benzamido-2-(benzylamino)acetate (9): Yield 76%; Solid, m.p. 104-106 °C (ether/hexane);
6.97 (m, 1H, NH), 5.56 (d, 1H, Hα, 7.5Hz), 3.87 (d, 2H, CH2, 9.8 Hz), 3.79 (s, 3H, OCH3); 13C-NMR
(CDCl3, ppm): δ = 170.8, 167.4 (CO), 139.2, 133.4, 132.1, 128.7 (2C), 128.5 (2C), 128.3 (2C), 127.3,
127.1 (2C) (C6H5 aromatic carbons), 65.0 (-CH-), 53.0 (OCH3), 49.2 (CH2); EIMS m/z: 298.8 (M+.,
100%), 239 (25%), 178 (67%), 105 (31%), 91 (24%), 77 (10%); (Formula: C17H18N2O3).
Methyl 2-benzamido-2-(N,N-dibenzylamino)acetate (10): Yield 84%; Solid, m.p. 130-132 °C (ether/
1
hexane); Rf = 0.82 (ether); H-NMR (CDCl3, ppm): δ = 7.87 (d, 1H, NHamid, 7.3 Hz), 7.50 (m, 15H,
Harom), 5.58 (d, 1H, Hα, 7.3 Hz), 3.95 (br s, 4H, NCH2), 3.85 (s, 3H, OCH3); 13C-NMR (CDCl3, ppm): δ
= 170.4, 167.9 (CO), 139.6 (2C), 133.2, 132.2, 129.0 (4C), 128.8 (4C), 128.6 (2C), 128.3 (2C), 127.0
(2C) (C6H5 aromatic carbons), 66.5 (-CH-); 54.1 (2C) (CH2), 52.7 (OCH3); EIMS m/z: 389.9 (M + 1,
25.20% ), 388.9 (M+., 100% ), 329.3 (68.50%), 268.3 (93.70%), 196.2 (41.73%), 105.2 (22.05%), 77.3
(55.91%); (Formula: C24H24N2O3).
Methyl 2-benzamido-2-(cyclohexylamino)acetate (11): Yield 92%; Solid, m.p. 182-184 °C (ether/
hexane); Rf = 0.6 (ether); 1H-NMR (CDCl3, ppm): δ = 8.02-7.99 (m, 2H, NHamid + Harom), 7.56-7.46 (m,
13
4H, Harom), 5.72 (d, 1H, Hα, 6.18Hz), 3.87 (s, 3H, OCH3), 2.83-0.87 (m, 12H, Hcyc + NH); C-NMR
(CDCl3, ppm): δ = 170.9, 167.4 (CO), 133.4, 132.0, 128.7 (2C), 127.4 (2C) (C6H5 aromatic carbons),
63.0 (-CH-), 56.0 (OCH3), 52.7 (-CHCH2-), 32.5 (2C), 26.3 (2C), 25.2 (CH2); EIMS m/z: 289.1 (M+.,
14.29% ), 231.2 (100% ), 170.2 (47.62% ), 105.4 (88.10% ), 77.4 (28.17% ); (Formula: C16H22N2O3).
Acknowledgements
We thank the CNR for financial support of this work (PROTARS D13/03, Morocco).
References and Notes
1. Duthaler, R.O. Recent developments in the stereoselective synthesis of alpha-amino acids.
Tetrahedron 1994, 50, 1539-1650.

Molecules 2010, 15
9360
2. Beller, M.; Eckert, M. Amidocarbonylation-an efficient route to amino acid derivatives. Angew.
Chem. 2000, 39, 1011-1027.
3. Palacios, F.; Alonso, C.; de los Santos, J.M. Synthesis of β-aminophosphonates and phosphinates.
Chem. Rev. 2005, 105, 899-932.
4. Jin, L.; Song, B.; Zhang, G.; Xu, R.; Zhang, S.; Gao, X.; Hu, D.; Yang, S. Synthesis, X-ray
crystallographic
analysis,
and
antitumor
activity
of
N-(benzothiazole-2-yl)-1-(fluorophenyl)-O,O-dialkyl-α-aminophosphonates. Bioorg. Med. Chem.
Lett. 2006, 16, 1537-1543.
5. Pollegioni, L.; Piubelli, L.; Sacchi, S.; Pilone, M.S.; Molla, G. Physiological functions of D-amino
acid oxidases: from yeast to humans. Cell. Mol. Life Sci. 2007, 64, 1373-1394.
6. Sacchi, S.; Bernasconi, M.; Martineau, M.; Mothet, J.P.; Ruzzene, M.; Pilone, M.S.; Pollegioni, L.;
Molla, G. pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid
oxidase: effect on schizophrenia susceptibility. J. Biol. Chem. 2008, 283, 22244-22256.
7. Haemers, A.; Mishra, L.; Van Assche, I.; Bolleart, W. Asymmetric synthesis of amino acids by
enantio- and diastereodifferentiating reactions. Die Pharmazie 1989, 44, 97-109.
8. Mikolajczyk, M. Acyclic and cyclic aminophosphonic acids: asymmetric syntheses mediated by
chiral sulfinyl auxiliary. J. Organomet. Chem. 2005, 690, 2488-2496.
9. Meyer, F.; Laaziri, A.; Papini, A.M.; Uziel, J.; Juge, S. A novel phosphorus-carbon bond formation
by ring opening with diethyl phosphite of oxazolines derived from serine. Tetrahedron 2004, 60,
3593-3597.
10. Rodrigues, R.S.; da Silva, J.F.; Boldrini-FranÇa, J.; Fonseca, F.P.P.; Otaviano, A.R.;
Henrique-Silva, F.; Magro, A.J.; Braz, A.S.K.; dos Santos, J.I.; Homsi-Brandeburgo, M.I.; Fontes,
M.R.M.; Fuly, A.L.; Soares, A.M.; Rodrigues, V.M. Structural and functional properties of
Bp-LAAO, a new L-amino acid oxidase isolated from Bothrops pauloensis snake venom.
Biochimie 2009, 91, 490-501.
11. Samel, M.; Tõnismägi, K.; Rönnholm, G.; Vija, H.; Siigur, J.; Kalkkinen, N.; Siigur, E. L-Amino
acid oxidase from Naja naja oxiana venom. Comp. Biochem. Physiol. 2008, B 149, 572-580.
12. Leite, A.L.; Lima, R.S.; Moreira, D.R.M.; Cardoso, M.V.; Brito, A.C.G.; Santos, L.M.F.;
Hernandes, M.Z.; Kiperstok, A.C.; Lima, R.S.; Soares, M.B.P. Synthesis, docking, and in vitro
activity of thiosemicarbazones, aminoacyl-thiosemicarbazides and acyl-thiazolidones against
Trypanosoma cruzi. Bioorg. Med. Chem. 2006, 14, 3749-3757.
13. Moreira, D.R.; Leite, A.C.L.; Ferreira, P.M.; da Costa, P.M.; Costa Lotufo, L.V.; de Moraes, M.O.;
Brondani, D.J.; Pessoa, Cdo. O. Synthesis and antitumour evaluation of peptidyl-like derivatives
containing the 1,3-benzodioxole system. Eur. J. Med. Chem. 2007, 42, 351-357.
14. Ciscotto, P.; Machado de Avila, R.A.; Coelho, E.A.F.; Oliveira, J.; Diniz, C.G.; Farǐas, L.M.; de
Carvalho, M.A.R.; Maria, W.S.; Sanchez, E.F.; Borges, A., Chavez-Olőrtegui, C. Antigenic,
microbicidal and antiparasitic properties of an L-amino acid oxidase isolated from Bothrops
jararaca snake venom. Toxicon 2009, 53, 330-341.
15. Becker, S.S.; Russell, P.T.; Duncavage, J.A.; Creech, C.B. Current issues in the management of
sinonasal methicillin-resistant Staphylococcus aureus. Curr. Opin. Otolaryngol. Head Neck Surg.
2009, 17, 2-5.

Molecules 2010, 15
9361
16. Li, R.; Zhu, S.W.; Wu, J.B.; Wang, W.Y.; Lu, Q.M.; Clemetson, K.J. L-Amino acid oxidase from
Naja atra venom activates and binds to human platelets. Acta Biochim. Biophys. Sin. (Shanghai)
2008, 40, 19-26.
17. Alves, R.M.; Antonucci, G.A.; Paiva, H.H.; Cintra, A.C.O.; Franco, J.J.; Mendonça-Franqueiro,
E.P.; Dorta, D.J.; Giglio, J.R.; Rosa, J.C.; Fuly, A.L.; Dias-Baruffi, M.; Soares, A.M.; Sampaio,
S.V. Evidence of aspase mediated apoptosis induced by L-amino acid oxidase isolated from
Bothrops atrox snake venom. Comp. Biochem. Physiol. 2008, A 151, 542-550.
18. Trouet, A.; Passioukov, A.; Van Derpoorten, K.; Fernandez, AM.; Baurain, R. Abarca-Quinones, J,
Lobl, TJ.; Oliyai, C.; Shochat, D.; Dubois, V. Extracellularly tumor-activated prodrugs for the
selective chemotherapy of cancer: application to doxorubicin and preliminary in vitro and in vivo
studies. Cancer Res. 2001, 61, 2843-2846.
19. Wei, X.L.; Wei, J.F.; Li, T.; Qiao, L.Y.; Liu, Y.L.; Huang, T.; He, S.H. Purification,
characterization and potent lung lesion activity of an L-amino acid oxidase from Agkistrodon
blomhoffii ussurensis snake venom. Toxicon 2007, 50, 1126-1139.
20. Sant’Ana, C.D.; Menaldo, D.L.; Costa, T.R.; Godoy, H.; Muller, V.D.; Aquino, V.H.;
Albuquerque, S.; Sampaio, S.V.; Monteiro, M.C.; Stábeli, R.G.; Soares, A.M. Antiviral and
antiparasite properties of an L-amino acid oxidase from the snake Bothrops jararaca: cloning and
identification of a complete cDNA sequence. Biochem. Pharmacol. 2008, 76, 279-288.
21. Moore, J.D.; Sprott, K.T.; Hanson, P.R. Conformationally constrained α-Boc-aminophosphonates
via transition Metal-Catalyzed/Curtius rearrangement strategies. J. Org. Chem. 2002, 67, 8123-8129.
22. Stábeli, R.G.; Sant’Ana, C.D.; Ribeiro, P.H.; Costa, T.R.; Ticli, F.K.; Pires, M.G.; Nomizob, A.;
Albuquerque, S.; Malta-Neto, N.R.; Marins, M.; Sampaio, S.V.; Soares, A.M.; Cytotoxic L-amino
acid oxidase from Bothrops moojeni: biochemical and functional characterization. Int. J. Biol.
Macromol. 2007, 41, 132-140.
23. Leite, A.C.L.; Silva, K.P.; Souza, I.A.; Janete, M.A.; Dalci, J. Synthesis, antitumour and
antimicrobial activities of new peptidyl derivativescontaining the 1,3-benzodioxole system. Eur. J.
Med. Chem. 2004, 39, 1059-1065.
24. Samel, M.; Vija, H.; Rönnholm, G.; Siigur, J.; Kalkkinen, N.; Siigur, E. Isolation and
characterization of an apoptotic and platelet aggregation inhibiting L-amino acid oxidase from
Vipera berus berus (common viper) venom. Biochim. Biophys. Acta 2006, 1764, 707-714.
25. Tőnismägi; K.; Samel, M.; Trummal, K.; Rőnnholm, G.; Siigur, J.; Kalkkinen, N.; Siigur, E.
L-Amino acid oxidase from Vipera lebetina venom: isolation, characterization, effects on platelets
and bacteria. Toxicon 2006, 48, 227-237.
26. Ande, S.R.; Fussi, H.; Knauer, H.; Murkovic, M.; Ghisla, S.; Fröhlich, K.U.; Macheroux, P.
Induction of apoptosis in yeast by L-amino acid oxidase from the Malayan pit viper Calloselasma
rhodostoma. Yeast 2008, 25, 349-357.
27. Reider, P.J.; Eichen Conn, R.S.; Davis, P.; Grenda, V.J.; Zambito, A.J.; Grabowski, E.J.J. Synthesis
of (R)-serine-2-d and its conversion to the broad sprectrum antibiotic fludalanine.
J. Org. Chem. 1987, 52, 3326-3334.
28. Saravanan, P.; Corey, E.J.
A
short, stereocontrolled, and practical synthesis of
alpha-methylomuralide, a potent inhibitor of proteasome function. J. Org. Chem. 2003, 68,
2760-2764.

Molecules 2010, 15
9362
29. Wang, M.; Gould, S.J. Biosynthesis of capreomycin. 2. Incorporation of L-serine, L-alanine, and
L-2,3-diaminopropionic acid. J. Org. Chem. 1993, 58, 5176-5180.
30. Shen, H.; Xie, Z. Titanacarborane mediated C-N bond forming/breaking reactions. J. Organomet.
Chem. 2009, 694, 1652-1657.
31. Mohammad, N.S.R.; Ali, K.N. Somayeh, B.; Mohammad, A.F.; Abdolkarim, Z.; Abolfath, P.
One-pot synthesis of N-alkyl purine and pyrimidine derivatives from alcohols using TsIm: a rapid
entry into carboacyclic nucleoside synthesis. Tetrahedron 2008, 64, 1778e-1785e.
32. Manoj, N.; Vijay, V.B. Selective N-alkylation of aniline with methanol over a heteropolyacid on
montmorillonite K10. Appl. Clay Sci. 2009, 44, 255-258.
33. Martínez-Asencio, A.; Ramon, D.J.; Miguel, Y. N-Alkylation of poor nucleophilic amine and
sulfonamide derivatives with alcohols by a hydrogen autotransfer process catalyzed by copper (II)
acetate. Tetrahedron Lett. 2010, 51, 325-327.
34. Shmidt, M.S.; Reverdito, A.M.; Kremenchuzky, L.; Perillo. I.A.; Blanco. M.M. Simple and
efficient microwave assisted N-alkylation of Isatin. Molecules 2008, 13, 831-840.
35. Kiuchi, F.; Nishizawa, S.; Kawanishi, H.; Kinoshita, S.; Ohsima, H.; Uchitani, A.; Sekino, N.;
Ishida, Kondo, M.K.; Tsuda, Y. Studies on crude drugs effective on visceral larva migrans. XVI.
Nematocidal activity of long alkyl chain amides, amines, and their derivatives on dog roundworm
larvae. Chem. Pharma. Bull. Jpn. 1992, 40, 3234-3244.
36. Seayad, A.M.A.; Klein, H.; Jackstell, R.; Gross, T.; Beller, M. Internal olefins to linear amines.
Science 2002, 297, 1676-1678.
37. Kim, J.W.; Yamaguchi, K.; Mizuno, N. Heterogeneously catalyzed selective N-alkylation of
aromatic and heteroaromatic amines with alcohols by a supported ruthenium hydroxide. J. Catal.
2009, 263, 205-208.
38. Reddy, C.R.; Jithender, E. Acid-catalyzed N-alkylation of tosylhydrazones using benzylic alcohols.
Tetrahedron Lett. 2009, 50, 5633-5635.
39. Ojima, I.; Delaloge, F. Asymmetric synthesis of building-blocks for peptides and peptidomimetics
by means of the β-lactam synthon method. Chem. Soc. Rev. 1997, 26, 377-386.
40. Rane, D.F.; Girijavallabhan, V.M.; Ganguly, A.K.; Pike, R.E.; Saksena, A.K.; McPhail, A.T. Total
synthesis and absolute stereochemistry of the antifungal dipeptide Sch 37137 and its 2S,3S-isomer.
Tetrahedron Lett. 1993, 34, 3201-3204.
41. Bentama, A.; El Hadrami, E.M.; El Hallaoui, A.; Elachqar, A.; et al. Synthesis of new
α-heterocyclic α-aminoesters. Amino Acids 2003, 24, 423-426.
42. Maheswaran, H.; Gopi, K.G.; Leon, P.K.; Srinivas, V.; Chaitanya, G.K.; Bhanuprakash, K.
Bis(μ-iodo)bis((−)-sparteine)dicopper(I): versatile catalyst for direct N-arylation of diverse
nitrogen heterocycles with haloarenes. Tetrahedron 2008, 64, 2471-2479.
43. Spreitzer, H.; Puschmann, C. Regioselective Alkylation of an oxonaphthalene-annelated pyrrol
system. Molbank 2009, 3, M619.
44. Won, K.J.; Yamaguchi, K.; Mizuno, N. Heterogeneously catalyzed selective N-alkylation of
aromatic and heteroaromatic amines with alcohols by a supported ruthenium hydroxide. J. Catal.
2009, 263, 205-208.
45. Raji, R.C.; Jithender, E. Acid-catalyzed N-alkylation of tosylhydrazones using benzylic alcohols.
Tetrahedron Lett. 2009, 50, 5633-5635.

Molecules 2010, 15
9363
46. Fletcher. S. Regioselective alkylation of the exocyclic nitrogen of adenine and adenosine by the
Mitsunobu reaction. Tetrahedron Lett. 2010, 51, 2948-2950.
47. Martínez-Asensio, A.; Ramón, D. J.; Yus, M. N-Alkylation of poor nucleophilic amine and
sulfonamide derivatives with alcohols by a hydrogen autotransfer process catalyzed by copper(II)
acetate. Tetrahedron Lett. 2010, 51, 325-327.
48. Zarubaev, V.V.; Golod, E.L.; Anfimov, P.M.; Shtro, A.A.; Saraev, V.V.; Gavrilov, A.S.; Logvinov,
A.V.; Kiselev. O.I. Synthesis and anti-viral activity of azolo-adamantanes against influenza A
virus. Bioorg. Med. Chem. 2010, 18, 839-848.
49. Shibinskaya, M.O.; Lyakhov, S.A.; Mazepa, A.V.; Andronati, S.A.; Turov, A.V.; Zholobak, N.M.;
Spivak, N.Y. Synthesis, cytotoxicity, antiviral activity and interferon inducing ability of
6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines. Eur. J. Med. Chem. 2010, 45, 1237-1243.
50. Boukallaba, K.; Elachqar, A.; El Hallaoui, A.; Alami, A.; El Hajji, S.; Labriti, B.; Martinez, J.;
Rolland, V. Synthesis of new α-heterocyclic α-aminophosphonates. Phosphor. Sulfur Silicon 2006,
181, 819-823.
51. Boukallaba, K.; Elachqar, A.; El Hallaoui, A.; Alami, A.; El Hajji, S.; Labriti, B.; Lachkar, M.; Bali,
B.; Bolte, M.; Martinez, J.; Rolland, V. Synthesis of α-heterocyclic α-Aminophosphonates, Part II:
morpholine, piperidine, pyrrolidine, tetrahydrofurylmethylamine, N-benzyl-N-methylamine, and
aniline derivatives. Phosphor. Sulfur Silicon 2007, 182, 1045-1052.
52. Steglich, W.; Kober, R. Untersuchungen zur Reaktion von Acylaminobrommalonestern und
Acylaminobromessigestern
mit
Trialkylphosphiten-eine
einfache
Synthese
von
2-Amino-2-(diethoxyphosphoryl)Essigsäure Ethylester. Liebigs Ann Chem. 1983, 4, 599-609.
53. Achamlale, S.; Elachqar, A.; El Hallaoui, A.; El Hajji, S.; Roumestant, M.L.; Viallefont, P.H.
Synthesis of α-triazolyl α-aminoacid derivatives. Amino Acids 1997, 12, 257-263.
54. Achamlale, S.; Elachqar, A.; El Hallaoui, A.; El Hajji, S.; Alami, A.; Roumestant, M.L.; Viallefont,
P.H. Synthesis of biheterocyclic α-aminoacid. Amino Acids 1999, 17, 149-163.
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