Synthesis of chiral α-(tetrazol-1-yl)-substituted carboxylic acids

Article abstract of DOI:10.1016/j.mencom.2018.07.007

Optically active α-(tetrazol-1-yl)-substituted carboxylic acid OBO-esters were synthesized from the corresponding a-isocyano OBO-esters and trimethylsilyl azide in up to 92% yield. Subsequent acidic hydrolysis proceeds without epimerization and makes it p

Full text of DOI:10.1016/j.mencom.2018.07.007

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 364–365
Synthesis of chiral a-(tetrazol-1-yl)-substituted
carboxylic acids
Danil P. Zarezin, Olga I. Shmatova and Valentine G. Nenajdenko*
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow,
Russian Federation. E-mail: nenajdenko@org.chem.msu.ru
DOI: 10.1016/j.mencom.2018.07.007
Optically active a-(tetrazol-1-yl)-substituted carboxylic acid
Me
i, CF3CO2H
Me
O
O
O
OBO-esters were synthesized from the corresponding a-iso-
cyano OBO-esters and trimethylsilyl azide in up to 92% yield.
Subsequent acidic hydrolysis proceeds without epimeriza-
tion and makes it possible to prepare enantiomerically pure
a-(tetrazol-1-yl)-substituted carboxylic acids in up to 89%
yield.
O
O
R
R
R
Me3SiN3
CF3CH2OH
ii, HCl
O
OH
O
N
N
NC
N
N
N
N
N N
up to 89%
up to 92%
The development of tetrazole chemistry is related to a wide
application of tetrazoles in various fields of modern medicinal
chemistry.1 1,5-Disubstituted tetrazoles are bioisosteres of the
cis-amide group, however, they possess higher metabolic stability.2
Synthetic strategies based on the replacement of carboxylate
groups by tetrazole moiety in biologically active molecules are
of special interest in modern pharmaceutical industry. The ability
of tetrazoles to participate in the formation of stable complexes
with cations of different metals has also found broad applica-
tions.3,4
with other alcohols. In this manner, various 1-substituted tetrazoles
2a–f were prepared in high yields within reasonable reaction time
(see Scheme 1, step i) and readily isolated by flash chromatography.
Next, libertation of tetrazol acids 3 by deprotection of OBO-
esters 2 was studied. Standard removal of OBO group can be
performed in two steps (see Scheme 1, steps ii and iii): acidic
hydrolysis to obtain the corresponding diol ester followed by basic
saponification. To optimize such a transformation, isoleucine
OBO-ester derivative 2c was chosen as a model compound since
it contains additional stereo center resistant to the deprotec-
tion conditions. We found that on using the standard procedure
(trifluoroacetic acid–dioxane followed by treatment with 2 m
NaOH solution) product 3c was isolated in good yield. However,
This article describes the synthesis of chiral a-(tetrazol-1-yl)-
substituted carboxylic acids which are very attractive small
molecules.5 These compounds are interesting building blocks
to construct other tetrazole-containing molecules and can also
be used as chiral bidentate ligands for coordination chemistry.
The reaction between isocyanides and hydrazoic acid (HN3) is
a valuable method to prepare 1-substituted tetrazoles.6 We used
enantiomerically pure 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane
(OBO)-esters of a-isocyano carboxylic acids as chiral starting
materials due to their stability towards epimerization.7 Whereas
alkyl esters of these acids are prone to racemize in the presence
of even weak bases, ortho esters, in particular convenient bicyclic
OBO ones of type 1 (Scheme 1), do not contain mobile hydrogen
atom and are base-resistant,8 which made them useful in our
recent studies as well.9 Despite the apparent simplicity of chosen
approach, application of dangerous HN3 is required.10 We
decided to use trimethylsilyl azide as a safe source of hydrazoic
acid.11 To find optimal conditions for this reaction, (S)-phenyl-
alanine derived OBO-isocyanide 1e was chosen as a model
reactant. Various solvents (MeOH, EtOH, PriOH, CF3CH2OH),
acidic catalysts (ZnCl2, HCl–MeOH, HCl–H2O) were tested.
Compound 2e was not found in the reaction mixture when acidic
catalysis was tried. The influence of temperature and reagent
ratio on the yield of 2e was also investigated. The reaction in
alkanols (except for trifluoroethanol) even with a large excess of
TMSN3 proceeded very slowly, and yields of 2e did not exceed
20% within one week. Extremely low reaction rate was also
observed at room temperature. However, the reaction at 70°C in
CF3CH2OH as a solvent led to the target product 2e in high yield
(92%). Most probably high effectiveness of trifluoroethanol can
be explained by its greater acidity (pKa = 12.4) in comparison
1
its H NMR spectrum contained two sets of signals of two
diastereomers to indicate total epimerization of the sample in the
presence of sodium hydroxide. Therefore, we decided to try
acidic removal of the OBO-group. Reflux of compound 2c in
6 m HCl resulted in formation of complex reaction mixture. To
our delight, treatment of OBO-tetrazole 2c with trifluoroacetic
acid in dioxane for 1–2 h followed by heating the mixture at
90°C in 6 m HCl for 20 h gave the target compound 3c in
71% yield. Luckily, no epimerization occurred and the product
iv
Me
O
N
O
N
O
N
O
R
R
Me
OH
R
ii
iii
O
O
OH
for 2c
for 2'c
N
N
N
HO
2'c
N
N
N
N
N N
3a–f
2a–f
i
Me
a R = Me, 75% (i), 83% (iv)
b R = Pri, 82% (i), 79% (iv)
c R = Bus, 84% (i), 71% (iv)
d R = Bui, 71% (i), 75% (iv)
e R = Bn, 92% (i), 89% (iv)
O
O
R
O
NC
1a–f
f
R = Ph, 86% (i), 80% (iv)
Scheme 1 Reagents and conditions: i, Me3SiN3, CF3CH2OH, 70°C, 1–2 days;
ii, CF3CO2H, dioxane; iii, 2 m aq. NaOH, then H3O+; iv, CF3CO2H, dioxane,
H2O, 1 day, then HCl, 90°C, 1 day.
© 2018 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2018, 28, 364–365
was a single diastereomer. This procedure was extended towards
preparation of the set of enantiomerically pure tetrazolyl-substituted
carboxylic acids 3a–f (see Scheme 1, step iv).
In conclusion, the reaction of chiral OBO isocyano derivatives
1 with azidotrimethylsilane was investigated. Trifluoroethanol
was found the solvent of choice affecting the cycloaddition to
afford the target tetrazoles in up to 92% yield. Subsequent acidic
hydrolysis (TFA–HCl) leads to chiral a-(tetrazol-1-yl)-substituted
carboxylic acids in up to 89% yield.
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This study was supported by Grant for Leading Scientific Schools
(no. 4687.2018.3). The authors acknowledge M. V. Lomonosov
Moscow State University Program of Development for partial
support in measuring of NMR spectra, Thermo Fisher Scientific
Inc., MS Analytica (Moscow, Russia), and personally Professor
A. Makarov for providing mass spectrometry equipment for this
work.
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2018.07.007.
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Received: 22nd February 2018; Com. 18/5489
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