Synthesis of new triazole substituted pyroaminoadipic and pipecolic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.09.166

Racemic 5-(4,5-substituted-1H-1,2,3-triazol-1yl)-pyroaminoadipic and pipecolic acid derivatives were synthesized from meso dimethyl-α, α′-dibromoadipate 1 in good yields using mild reaction conditions. The key step of this reaction sequence was the 1,3-di

Full text of DOI:10.1016/j.tetlet.2004.09.166

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8905–8907
Synthesis of new triazole substituted pyroaminoadipic and
pipecolic acid derivatives
Fatimazohra Lenda,a Farhate Guenoun,a Bouchra Tazi,b Najib Ben larbi,c
d
´ ´
Jean Martinez and Frederic Lamaty
d,
*
a
´
`
Faculte des Sciences B.P 4010, Beni M’hamed, Meknes, Morocco
´
b
`
Ecole Nationale d’Agriculture, Departement des Sciences de Base, Meknes, Morocco
c
´
`
Faculte des Sciences Dhar El Mehraz, Fes, Morocco
´
`
Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
d
´
Laboratoire des Aminoacides, Peptides et Proteines (LAPP), UMR 5810—CNRS—Universites Montpellier 1 et 2,
Received 28May 2004; revised 24 September 2004; accepted 28September 2004
Abstract—Racemic 5-(4,5-substituted-1H-1,2,3-triazol-1yl)-pyroaminoadipic and pipecolic acid derivatives were synthesized from
meso dimethyl-a,a0-dibromoadipate 1 in good yields using mild reaction conditions. The key step of this reaction sequence was
the 1,3-dipolar cycloaddition of an acetylenic compound on a-azido-a0-bromoadipate 2. A reactive a-(substituted-1H-1,2,3-tri-
azol-1-yl)-a0- bromoadipate derivative 3a–d was generated and reacted with sodium azide followed by Pd/C-catalyzed hydrogena-
tion to provide lactams 5a–d. The chemoselective reduction of the amide carbonyl group of 5a–d with BH3 followed by acid
hydrolysis provided 5-(4,5-substituted-1H-1,2,3-triazol-1-yl) pipecolic acids in racemic form.
Ó 2004 Elsevier Ltd. All rights reserved.
N
1. Introduction
N
HO2C
NH
O
N
N
N
O
NH2
(H2 C)n
N
S
a-Amino acids with heterocyclic side chains have a par-
ticular importance in various fields, especially in bio-
chemistry, enzymology and pharmacology.1–3 Among
the heterocyclic substituents which are currently being
studied, the 1H-1,2,3-triazole heterocyclic entity is an
interesting moiety in terms of biological activity. It is
found in bioactive compounds such as anti-HIV4,5 and
anti-microbial6 agents as well as b3 selective adrenergic
receptor agonist.7 Indeed, the 1,2,3-triazole moiety is
present in a number of drugs such as the b lactam anti-
biotic Tazobactam or the cephalosporine Cefatrizine.
Furthermore, only tetrazole substituted pipecolic acids
such as LY 233053 (Fig. 1), known for their selective
and potent antagonist activity at the NMDA receptor
have been prepared.8 To our knowledge, triazole substi-
tuted pipecolic acid derivatives have not been synthe-
sized so far. Few examples in the literature describe
1H-1,2,3-triazole-a-amino acids. Also, since the selective
discovery of D,L-a-aminoadipic acid as an antagonist of
the NMDA receptor,8 several modified structures were
N
CH3
CO2H
O
N
CO2Me
CO2H
D, L-aminoadipic acid
H
Tazobactam
n=1 LY233053
Figure 1.
prepared in order to study the structure–activity rela-
tionships.2,9–11
In order to study the effects of the substituents on a-amino-
adipic acid in the neuroexcitatory activity of the acid, we
decided to prepare different pyroaminoadipates 5a–d,
precursors of d-substituted aminoadipic acids and also
the 5-substituted derivatives of pipecolic acid 6a–d.
The substituents we considered were 4,5-substituted-
1H-1,2,3-triazoles. The synthetic strategy relied on the
double substitution of meso dimethyl-a,a0-dibromoadi-
pate 1 successively by sodium azide (followed by a 1,3-
dipolar cycloaddition with an acetylenic compound)
and again by sodium azide (Scheme 1).
*
Corresponding author. Tel.: +33 04 67 14 3847; fax: +33 04 67 14 48
66; e-mail: frederic@univ-montp2.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.166

8906
F. Lenda et al. / Tetrahedron Letters 45 (2004) 8905–8907
R1
R2
R2
N
N
N
N
R1
N
O
N
N3
MeO2C
Br
CO2Me
O
ii
i
O
O
+
O
O
O
H
H
Br
62%
O
Br
O
O
O
O
Br
Br
iii
1
2
3 a-d
3' a-d
95%
R2
N
N
N
N
N
N
N
N
R1
N
R2
R2
v
65-70%
iv
90-95%
O
R1
R1
O
HO
O
N
H
N
O
O
H
O
O
O
N3
4 a-d
6 a-d
5 a-d
Scheme 1. Reagents: (i) NaN3, acetone, RT; (ii) acetylene (see Table 1); (iii) NaN3, acetone, RT; (iv) 5% Pd/C, MeOH, H2 (1atm), RT; (v)
(a) BH3 Æ THF, THF, ꢀ10°C, (b) 6N HCl, propylene oxide, CH2Cl2.
Table 1.
Products 3, 30
R1
R2
Reaction time (h)/Temperature
Isolated yield of 3 + 30 (%)
Ratio of 3/30
a
b
c
CO2Me
CO2Me
CO2Et
Ph
24/RTa
100
90
–
H
H
H
48/RTa
90/10
70/30
85/15
48/80°Cb
80
90
d
(CH)OHCH3
48/80°Cb
a The reaction was carried out in the absence of solvent.
b Benzene used as solvent.
2. Results and discussion
The 1,4- and 1,5-regioisomers of a-(4,5-substituted-1H-
1,2,3-triazol-1-yl)-a0-bromoadipate derivatives 3b–d
and 30b–d were separated by column chromatography
and were isolated in good yields. When benzene was re-
placed by toluene as the reaction solvent, the acetylenic
reactant was inert towards the a-azido-a0-bromoadipate
derivative.
According to the synthetic approach described in
Scheme 1, we initially studied the reaction of an equimo-
lar quantity of sodium azide with meso dimethyl-a,a0-
dibromoadipate, easily obtained from adipic acid.12
This reaction, carried out in acetone in the presence of
1.1equiv of sodium azide, led mainly to the product of
monosubstitution. Formation of the products of disub-
stitution was also observed, and experimental results
showed that the ratio between mono- and di-substituted
products depended on the number of equivalents of
sodium azide. While successive substitutions of 1 with
one nucleophile to make cyclic compounds have been
reported,13–20 we present herein the first examples, to
our knowledge, of two successive intermolecular
substitutions.
The triazole derivatives 3a–d were then substituted by
reaction of three equivalents of sodium azide in ace-
tone.26 4a–d were obtained in high yields (90–95%).
Reduction of 4a–d by catalytic hydrogenation over Pd/
C in methanol,26 led quantitatively to the corresponding
substituted pyroaminoadipic acids 5a–d via an intramo-
lecular aminolysis. Lactams 5a–d were selectively
reduced with BH3 in THF at ꢀ10°C27 and acid hydro-
lysis (6N HCl, 60°C, 12h) followed by neutralization
with propylene oxide yielded the fully deprotected ( )-
5(4,5-substituted-1H-1,2,3-triazol-1-yl) pipecolic acid
derivatives. 1H NMR showed that in all cases a 1/1 mix-
ture of the two possible diastereoisomers was obtained.
As it was reported by Huisgen et al.21 the 1,3-dipolar
cycloaddition reaction is a well-established and general
method for the construction of five-membered ring
heterocycles.22 Particularly, addition of azides to acetyl-
enes has been a method of choice for the synthesis of
1,2,3-triazoles.23–25 The triazole ring is a system of the
aza-pyrrole type and two regioisomers can form at the
cycloaddition step. In all cases, we obtained both N-
regioisomers, as detected by 1H NMR spectroscopy.
The experimental results showed that the ratio between
the 1,4-regioisomer and the 1,5-regioisomer depended
upon the acetylene derivative. Table 1 summarizes these
results.
3. Conclusion
The present study describes an efficient synthesis of race-
mic 5-(4,5-substituted-1H-1,2,3-triazol-1-yl) pipecolic
acids starting from meso dimethyl-a,a0-dibromoadipate.
The 4,5-substituted-1H-1,2,3-triazol-1-yl were selec-
tively synthesized in position 5 of the piperidine ring
by 1,3-dipolar cycloaddition of acetylenic compounds
on dimethyl-a-azido-a0-bromoadipate followed by

F. Lenda et al. / Tetrahedron Letters 45 (2004) 8905–8907
8907
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