Synthesis of new tetrazole and triazole substituted pyroglutamic acid and proline derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.11.163

Racemic 4-(substituted-1H-1,2,3-triazol-1-yl), 4-aryl and 4-(arylmethyl)tetrazolyl-pyroglutamic and proline derivatives were synthesized from dimethyl-2,4-dibromoglutaryle 1 in good yield using mild reaction conditions. The key step for the preparation of the triazole substituted molecule was the 1,3-dipolar cycloaddition of an acetylenic compound with an azido derivative. The tetrazole derivatives were prepared by the selective N2-alkylation of 5-substituted tetrazoles with 1.

Full text of DOI:10.1016/j.tetlet.2006.11.163

Tetrahedron Letters 48 (2007) 805–808
Synthesis of new tetrazole and triazole substituted
pyroglutamic acid and proline derivatives
a
b
a
a,
*
´ ´
Fatimazohra Lenda, Farhate Guenoun, Jean Martinez and Frederic Lamaty
aLaboratoire des Aminoacides, Peptides et Prote´ines (LAPP), UMR 5810 CNRS-Universite´s Montpellier 1 et 2,
`
Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
`
Faculte´ des Sciences BP 4010, Beni M’hamed, Meknes, Morocco
b
Received 28 September 2006; revised 20 November 2006; accepted 28 November 2006
Available online 19 December 2006
Abstract—Racemic 4-(substituted-1H-1,2,3-triazol-1-yl), 4-aryl and 4-(arylmethyl)tetrazolyl-pyroglutamic and proline derivatives
were synthesized from dimethyl-2,4-dibromoglutaryle 1 in good yield using mild reaction conditions. The key step for the prepara-
tion of the triazole substituted molecule was the 1,3-dipolar cycloaddition of an acetylenic compound with an azido derivative. The
tetrazole derivatives were prepared by the selective N2-alkylation of 5-substituted tetrazoles with 1.
Ó 2006 Elsevier Ltd. All rights reserved.
Unnatural, non-proteinogenic a-amino acids are impor-
tant derivatives in different areas of chemistry, biology
and material sciences.1 They have a wide range of bio-
logical activities and hence are significant in medicinal
chemistry. The replacement of natural amino acids by
non-proteinogenic derivatives in peptides has become
an important goal in medicinal chemistry because this
substitution may influence their biological properties.2
The synthesis of proline peptidomimetics that mimic
natural dipeptides is very attractive.3 The proline residue
plays an important role in protein secondary structure,
and in many biological processes such as protein folding
and protein recognition.4 The development of new
methodologies directed towards the preparation of cyc-
lic a-amino acids is a very attractive field in organic
synthesis.5
Cefatrizine. The tetrazole substituted proline such
as LY300020 (Fig. 1), known for its relatively potent,
highly selective systemically-active AMPA receptor ago-
nist has been reported.10 To our knowledge, triazole
substituted prolines have not been synthesized so far.
Few examples in the literature describe 1H-1,2,3-tri-
azole-a-amino acids.11 Furthermore, since the discovery
of L-glutamate as a major excitatory amino acid (EAA)
neurotransmitter in the central nervous system,12 several
modified structures were prepared.13
In order to study the effects of the substituents on glu-
tamic acid in the neuroexcitatory activity, we decided
to prepare triazole or tetrazole substituted pyroglutamic
acid and proline derivatives (Fig. 2).
The general strategy relied on the successive alkylation14
of a dibromo diester derivative of glutaric acid.
Among the heterocyclic substituents which are currently
studied, the 1H-tetrazoles and 1H-1,2,3-triazoles ring
systems are important structural features found in natu-
ral products and drugs. The 1H-1,2,3-triazole hetero-
cyclic entity is an interesting moiety in terms of biological
properties such as antibacterial,6 anti-HIV7 and antial-
lergic agents.8 Triazoles are also found in herbicides.9
Indeed, the 1,2,3-triazole moiety is present in a number
of drugs such as the b-lactam antibiotic cephalosporine
The substituents we considered were 4,5-substituted-1H-
1,2,3-triazoles. The synthetic strategy relied on the
Keywords: Proline; Heterocycles; Triazole; Tetrazole; Alkylation.
*
Corresponding author. Tel.: +33 467143847; fax: +33 467144866;
e-mail: frederic.lamaty@univ-montp2.fr
Figure 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.163

806
F. Lenda et al. / Tetrahedron Letters 48 (2007) 805–808
The triazole derivative 3 was then reacted with 3 equiv
of sodium azide in acetone to give 4 in 95% yield.
Reduction of 4 by catalytic hydrogenation over Pd/C
in methanol,25 led to the corresponding substituted
pyroglutamic acid 5 via an intramolecular aminolysis.
Lactam 5 was selectively reduced with BH3 in THF at
À10 °C26 and acid hydrolysis (6 N HCl, 60 °C, 12 h) fol-
lowed by neutralization with propylene oxide yielded the
fully deprotected ( )-4-(4,5-substituted-1H-1,2,3-triazol-
Figure 2.
1
double substitution of dimethyl-2,4-dibromoglutarate
115 successively with sodium azide, followed by a 1,3-
dipolar cycloaddition with an acetylenic compound,
and again with sodium azide (Scheme 1).
1-yl)proline derivative 6. H NMR showed that in all
cases a 1/1 mixture of the two possible diastereoisomers
was obtained.
In another set of reactions, tetrazole proline derivatives
were obtained by double substitution of dimethyl-2,4-
dibromoglutarate successively by substituted tetrazoles
and sodium azide (Scheme 2).
According to the synthetic approach described in
Scheme 1, we initially studied the reaction of an equimo-
lar quantity of sodium azide with dimethyl-2,4-dibromo-
glutarate 1, easily obtained from glutaryl dichloride.
This reaction, carried out in acetone in the presence of
1.1 equiv of sodium azide, led to a 3/1 ratio of a mixture
of the monosubstituted product 2 and the disubstituted
product. Compound 2 was separated from the disusbsti-
tuted product by column chromatography.
According to the synthetic approach described in
Scheme 2, we initially studied the reaction of an equimo-
lar quantity of tetrazole with dimethyl-2,4-dibromo-
glutarate 1. This reaction, carried out in acetone in the
presence of 1.5 equiv of triethylamine, led to the forma-
tion of the monosubstituted compound 7 as the sole
product.27
Huisgen’s 1,3-dipolar cycloaddition reaction between
alkynes and azides is the earliest known method for
the synthesis of 1,2,3-triazoles,16 and is one of the proto-
type reactions in click chemistry.17 Click chemistry is a
modular approach that uses the most practical and reli-
able chemical transformations and has found several
applications in organic chemistry,18 drug discovery,19
bioconjugations,20 material sciences21 and polymer
synthesis.22 The traditional method for synthesis of
triazoles requires elevated temperatures and this non-
catalyzed reaction is generally poorly regioselective,
and gives a mixture of 1,4- and 1,5-disubstituted tri-
azoles. Recently, Sharpless and co-workers have reported
a high yielding synthesis of triazoles using a Cu(I) cata-
lyst with an excellent 1,4-regioselectivity.23 The reaction
tolerates a wide variety of functional groups and is
insensitive to water and oxygen. In our case, since the
cycloaddition leading to 3 was performed with a sym-
metrical alkyne, uncatalyzed thermal conditions were
used.24 Only one product was obtained and isolated in
a quantitative yield.
For the preparation of 5-substituted tetrazoles, we
extended the method described by Koguro28 based on
the reaction of variously substituted nitriles with sodium
azide in the presence of an amine salt in toluene. The
tetrazole ring is a system of the azapyrrole type and
therefore two tautomeric forms can exist. During our
synthesis, we obtained in all cases only one of the two
1
N-regioisomers, as detected by H NMR spectroscopy.
All the 5-aryltetrazoles and the 5-(arylmethyl)tetrazoles
obtained were N2-isomers.29 The 2-bromo-5-tetrazolyl-
glutarate derivatives 7a–c were purified by column chro-
matography and isolated in good yields. In the absence
of triethylamine, the 5-aryl- and 5-(arylmethyl)tetrazoles
were inert towards the dibromo derivative.
The bromo derivatives 7a–c were treated with 3 equiv of
sodium azide in acetone to give 8a–c as a mixture of dia-
stereoisomers rising from successive non-stereocon-
trolled SN2 reactions. Reduction of 8a–c by catalytic
Scheme 1. Reagents and conditions: (a) NaN3, acetone, rt; (b) acetylene; (c) NaN3, acetone, rt; (d) 5% Pd/C, MeOH, H2 (1 atm), rt; (e) (i) BH3ÆTHF,
THF, À10 °C, (ii) 6 N HCl, propylene oxide, CH2Cl2.

F. Lenda et al. / Tetrahedron Letters 48 (2007) 805–808
807
Scheme 2. Reagents and conditions: (a) substituted tetrazole, NEt3, acetone, rt; (b) NaN3, acetone, rt; (c) 5% Pd/C, MeOH, H2 (1 atm), rt; (d) (i)
BH3ÆTHF, THF, À10 °C, (ii) 6 N HCl, propylene oxide, CH2Cl2.
hydrogenation over Pd/C in methanol25 led to the corre-
sponding substituted pyroglutamic acids 9a–c by an
intramolecular aminolysis.
2. (a) Williams, M.; Kowaluk, E. A.; Arneric, S. P. J. Med.
Chem. 1999, 42, 1481–1500; (b) Roy, R. S.; Balarm, P. J.
Pept. Res. 2004, 63, 279–289.
3. (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.
G.; Lubell, W. D. Tetrahedron 1997, 53, 12789–12854; (b)
Zouikri, M.; Vicherat, A.; Aubry, A.; Marraud, M.;
Boussard, G. J. Pept. Res. 1998, 52, 19–26; (c) Vivet, B.;
Cavelier, F.; Martinez, J. Eur. J. Org. Chem. 2000, 807–
Lactams 9a–c were reduced with BH3 in THF at
À10 °C.26 Subsequent acid hydrolysis (6 N HCl, 60 °C,
12 h) and neutralization with propylene oxide yielded
the ( )-4-(5-aryltetrazolyl)- and ( )-4-[5-(arylmethyl)-
tetrazolyl]proline.
811.
4. Voet, D.; Voet, J.; Pratt, C. Fundamentals of Biochemistry;
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M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.;
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The present study describes an efficient synthesis of race-
mic 4-(4,5-dicarboxy-1H-1,2,3-triazol-1-yl)proline and
4-(5-aryltetrazolyl)- and 4-[5-(arylmethyl)tetrazolyl]pro-
line starting from dimethyl-2,4-dibromoglutarate. The
4,5-substituted-1H-1,2,3-triazol-1-yl were selectively
synthesized in position 4 of the proline by 1,3-dipolar
cycloaddition of acetylenic compounds on dimethyl-2-
azido-4-bromoglutarate followed by hydride reduction.
The 5-aryltetrazoles and the 5-(arylmethyl)tetrazoles
were selectively introduced in the 4-position of the pyr-
rolidine ring in good chemical yields. While double
substitutions of 1 with one nucleophile to give cyclic
compounds have been reported,15 to the best of our
knowledge these are the first examples of successive sub-
stitutions with two different nucleophiles on a dibromo-
glutaric acid derivative. Generalization of this method is
currently under investigation in our laboratory.
9. Fan, W. Q.; Katritzky, A. R. In Comprehensive Hetero-
cyclic Chemistry II; Katritzky, A. R., Rees, C. W., Seriven,
E. F. V., Eds.; Elsevier Science: Oxford, 1996; Vol. 4, pp
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Acknowledgments
11. Lenda, F.; Guenoun, F.; Tazi, B.; Ben larbi, N.;
Martinez, J.; Lamaty, F. Tetrahedron Lett. 2004, 45,
8905–8907.
We thank the CNRS, the MENRT and the Agence
Universitaire de la Francophonie for financial support.
12. For a review, see: Ma, D. Bioorg. Med. Chem. 1999, 27,
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Refs. 11 and 28.

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