Polynuclear tetrazole-containing amino acid analogs

Article abstract of DOI:10.1007/s11178-005-0056-7

New analogs of (D,L)-phenylalanine containing tetrazole rings were synthesized. The acidity constants of (D, L)-phenylalanine and (D,L)-tryptophane derivatives containing a tetrazole ring with no substituent on N¹ (pK _a = 3.0-3.1) an

Full text of DOI:10.1007/s11178-005-0056-7

Russian Journal of Organic Chemistry, Vol. 40, No. 10, 2004, pp. 1528–1531. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004,
pp. 1576–1579.
Original Russian Text Copyright © 2004 by Morozova, Esikov, Zubarev, Malin, Ostrovskii.
Polynuclear Tetrazole-Containing Amino Acid Analogs
S. E. Morozova, K. A. Esikov, V. Yu. Zubarev, A. A. Malin, and V. A. Ostrovskii
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: ostrovskii@mail.convey.ru
Received March 29, 2004
Abstract—New analogs of (D,L)-phenylalanine containing tetrazole rings were synthesized. The acidity con-
stants of (D,L)-phenylalanine and (D,L)-tryptophane derivatives containing a tetrazole ring with no substituent
on N1 (pKa = 3.0–3.1) and of the corresponding carboxylic acids (pKa = 2.9–3.3) in aqueous methanol were
determined by potentiometric titration.
Tetrazole-containing analogs of amino acids and
peptides are important for the development of modern
therapeutic agents due to their resistance to enzymatic
cleavage and hydrolysis and the possibility for im-
proving bioavailability and bioselectivity. A combina-
tion of such properties is favorable from the viewpoint
of pharmacology, thus making these compounds
attractive targets of organic synthesis. For example,
Zabrocki et al. [1] proposed to modify peptides or
particular amino acids with tetrazole fragments to
obtain some peptidomimetics with a cis-blocked
peptide bond. For this purpose, a secondary amine is
generally treated with PCl5 in the presence of quino-
line, and intermediate imidoyl chloride is brought
into reaction with a solution of hydrazoic acid [1, 2].
An alternative way of peptide bond modification with
a tetrazole fragment involves the system PPh3–DEAD–
TMSN3 [3]. It was also shown [4] that reactions of
N-substituted carboxylic acid amides with trifluoro-
methanesulfonic anhydride (Tf2O) and sodium azide
give the corresponding 1,5-disubstituted tetrazoles [4].
El-Ahl et al. [5] recently proposed a procedure for
the synthesis of tetrazoles from carboxamides using
the system tetrachlorosilane–sodium azide. A probable
mechanism of this process is shown in Scheme 1. The
system SiCl4–NaN3 ensures preparation of both 1,5-di-
substituted [6] and 1-unsubstituted tetrazoles [5, 6],
and it can be applied to various substrates, amino acids
among these. Following this procedure, tetrazole-con-
taining analogs of (D,L)-phenylalanine, (D,L)-leucine
[7], and (D,L)-tryptophane [8] were synthesized.
We have extended the above approach to the syn-
thesis of structures containing both two and three tetra-
zole rings. As starting compound we used previously
synthesized ditetrazole I [7]. It was treated with
chloroacetamide in the presence of triethylamine to
obtain tetrazolylacetamide II, and reaction of the latter
with the system tetrachlorosilane–sodium azide gave
compound III containing three differently substituted
tetrazole rings. By alkaline hydrolysis of II we ob-
tained tetrazolylacetic acid IV (Scheme 2). The syn-
theses were performed according to the procedures
Scheme 1.
NH
NSiX3
NSiX3
N3
SiCl4, NaN3
SiCl4, NaN3
HN3
RCONH2
R
C
R
C
R
C
–X3SiOH
OSiX3
OSiX3
R
R
SiX3
N
H2O
NH
N
N
N
N
N
N
R
R'
NR'
NR'
N3
SiCl4, NaN3
SiCl4, NaN3
–X3SiOSiX3
N
RCONHR'
R
C
R
C
N
N
OSiX3
N
SiX3 = SiCln(N3)3–n, n = 0–3.
1070-4280/04/4010-1528 © 2004 MAIK “Nauka/Interperiodica”

POLYNUCLEAR TETRAZOLE-CONTAINING AMINO ACID ANALOGS
1529
Scheme 2.
N
N
N
SiCl4, NaN3
Me
NH
N
N
N
N
N
N
N
N
ClCH2CONH2, Et3N
Me
Me
III
H
CONH2
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
(1) NaOH
(2) HCl
I
II
Me
COOH
N
N
N
N
N
N
N
N
IV
1
The H and 13C NMR spectra were recorded on
a Bruker DPX-300 spectrometer at 300 and 75 MHz,
respectively, using DMSO-d6 as solvent and reference.
The progress of reactions and the purity of products
were monitored by TLC on Kieselgel 60 F254 plates
(Merck) using CHCl3–MeOH (9:1 or 95:5) as eluent;
spots were visualized with UV light.
described in [7, 8]. The alkylation of ditetrazole I
afforded a mixture of isomers, N2-isomer II prevailing.
Pure compound II was isolated by recrystallization
from ethanol.
Low toxicity and high resistance to biochemical
decomposition are the main factors responsible for
successful application of tetrazole derivatives as iso-
steric analogs of carboxy group in molecular design of
medical agents [9]. Furthermore, pKa values of car-
boxylic acids and the corresponding NH-tetrazoles
differ only slightly [10]. In the present work we deter-
mined by potentiometric titration acidity constants of
some previously synthesized compounds V–VII [7, 8],
as well as of the new polynuclear tetrazole-containing
analogs of (D,L)-phenylalanine (compounds III and
IV) (see below). It is seen that the pKa values of the
examined NH-tetrazoles and the corresponding car-
boxylic acids are very similar, in keeping with the
known relation. On the other hand, the NH and COOH
acidities of compounds I and III–VII are relatively
high, presumably due to electron-acceptor effect of the
tetrazole rings.
(R,S)-5-[1-(5-Methyl-1-tetrazolyl)-2-phenyl-
ethyl]-2-tetrazolylacetamide (II). Chloroacetamide,
4.77 g (0.051 mol), was added with stirring to a mix-
ture of 10.9 g (0.043 mol) of compound I, 90 ml of
acetonitrile, and 5.16 g (0.051 mol) of triethylamine.
The mixture was heated for 6–7 h under reflux (TLC),
the solvent was removed under reduced pressure, and
the residue was treated with a 1:1 ethyl acetate–water
mixture. The organic phase was separated, the solvent
was removed under reduced pressure, and the residue
was recrystallized from a minimal amount of ethanol.
Yield 8.91 g (67%), light yellow crystals. An analytical
sample was obtained by repeated recrystallization from
1
ethanol, mp 133–135°C. H NMR spectrum, δ, ppm:
2.25 s (3H, CH3), 3.65–3.80 m (1H, CH2Ph), 3.92 d.d
(1H, CH2Ph, J = 5.1, 13.8 Hz), 5.48 s (2H, CH2CO),
6.59 d.d (1H, CH, J = 5.1, 10.9 Hz), 7.10–7.25 m
(5H, Harom), 7.24 br.s and 7.56 br.s (1H each, CONH2).
13C NMR spectrum, δC, ppm: 8.1 (CH3); 37.8 (CH2Ph);
54.4 (CH2CO); 54.8 (CH); 127.2, 128.4, 129.1, 135.4
(Carom); 152.5 (CCH3); 163.0 (CCH), 165.7 (CONH2).
Found, %: C 50.10; H 5.25; N 40.38. C13H15N9O. Cal-
culated, %: C 49.83; H 4.83; N 40.24.
EXPERIMENTAL
Potentiometric measurements were performed
using a pH-121 potentiometer equipped with an ESL-
43-07 glass electrode, an EVL-1M3 silver chloride
electrode, and a temperature-controlled cell (25°C).
The titration was carried out in 50% aqueous methanol
which was freed from carbon dioxide; a 0.1 N solution
of sodium hydroxide was used as titrant, and a 0.1 N
solution of sodium nitrate, as supporting electrolyte.
The pKa values were calculated as described in [11].
(R,S)-5-[1-(5-Methyl-1-tetrazolyl)-2-phenyl-
ethyl]-2-(5-tetrazolylmethyl)tetrazole (III). A reactor
equipped with a reflux condenser (capped with a dry-
ing tube) and a magnetic stirrer was charged with 5.0 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

MOROZOVA et al.
1530
NH
NH
N
N
N
Me
Me
Me
NH
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
I
III
VI
pKa
2.99±0.06
3.06±0.05
3.13±0.05
NH
Me
Me
Me
COOH
N
N
N
COOH
N
N
COOH
N
N
N
N
N
N
N
N
N
N
N
V
IV
VII
pKa
3.03±0.06
2.90±0.06
3.27±0.06
(0.016 mol) of amide II, 3.11 g (0.048 mol) of sodium
azide, and 70 ml of acetonitrile, and a solution of
5.42 g (0.032 mol) of tetrachlorosilane in 20 ml of
acetonitrile was added with stirring. The mixture was
heated for 6 h under reflux and analyzed by TLC for
initial amide II. If necessary, additional amounts of the
reactants were added. This procedure was repeated
every 6 h until initial amide II disappeared completely.
The overall reaction time was 33 h. The mixture was
then poured in small portions into a solution of sodium
carbonate, maintaining the pH value greater than 7.
The precipitate of silicic acid was filtered off, charcoal
was added to the filtrate, and the mixture was stirred
for 0.5 h and filtered. A solution of sodium nitrite
was added to the filtrate, and the mixture was slowly
acidified to pH 2 by adding dilute hydrochloric acid.
The solution was cooled, and the precipitate was
filtered off. Yield 2.63 g (49%), colorless crystalline
(0.008 mol), was dissolved in a solution of 0.96 g
(0.024 mol) of sodium hydroxide in 50 ml of water on
heating to the boiling point, and the solution was kept
for 1 h at room temperature. It was diluted with 50 ml
of water, acidified to pH 2 with hydrochloric acid, and
cooled. The precipitate was filtered off and recrystal-
lized from 50% ethanol. Yield 1.95 g (78%), colorless
1
crystalline substance, mp 184–185°C. H NMR spec-
trum, δ, ppm: 2.25 s (3H, CH3), 3.70–3.80 m (1H,
CH2Ph), 3.90–4.00 m (1H, CH2Ph), 5.76 s (2H,
CH2CO), 6.55–6.70 m (1H, CH), 7.15–7.30 m (5H,
H
arom), 13.80 br.s (1H, COOH). 13C NMR spectrum,
δC, ppm: 8.1 (CH3); 37.9 (CH2Ph); 53.9 (CH2CO);
54.4 (CH); 127.3, 128.5, 129.2, 135.4 (Carom); 152.5
(CH3C); 163.3 (CHC); 167.2 (COOH). Found, %:
C 49.30; H 4.78; N 35.67. C13H14N8O2. Calculated, %:
C 49.68; H 4.49; N 35.65.
1
substance, mp 70–73°C. H NMR spectrum, δ, ppm:
This study was performed under financial support
by the Ministry of Education of the Russian Federation
(project no. T02-09.3-3222) and by the Integratsiya
Federal Program for State Support and Integration
of Education and Fundamental Science (project
no. I0667).
2.25 s (3H, CH3), 3.65–3.75 m (1H, CH2Ph), 3.90 d.d
(1H, CH2Ph, J = 5.1, 13.8 Hz), 6.48 s (2H, NCH2C),
6.58 d.d (1H, CH, J = 5.8, 10.2 Hz), 7.15–7.25 m (5H,
Ph), 12.28 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
8.1 (CH3); 37.9 (CH2Ph); 46.5 (NCH2C); 54.3 (CH);
127.3, 128.5, 129.2, 135.3 (Carom); 152.6 (CH3C);
152.9 (NCH2C), 163.7 (CH). Found, %: C 45.77;
H 5.34; N 49.85. C13H14N12. Calculated, %: C 46.15;
H 4.17; N 49.68.
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