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Tetrahedron Letters
journal homepage: www.elsevier.com
Catalyst- and Organic Solvent-Free Synthesis of Thioacids in Water
Mohamed Elagawany a,b,c, Lamees Hegazy , and Bahaa Elgendy a,b,d,
a,b
a
Department of Pharmaceutical and Administrative Sciences St. Louis College of Pharmacy, St. Louis, MO 63110, USA
Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA
b
c
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
d
Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt
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ARTICLE INFO
ABSTRACT
Corresponding author. Tel.: +1-314-446-8336; fax: +1-314-446-8136; e-mail: belgendy@wustl.edu
Article history:
Received
Received in revised form
Accepted
Thioacids and thioamino acids were synthesized in excellent yields from readily available acyl
benzotriazoles and sodium hydrosulfide in water at room temperature. The new methodology
features mild reaction conditions, high yields, short reaction times, and does not involve the use
of organic solvents or bases. The reaction is eco-friendly, and the workup procedure is simple
and does not require chromatographic separation.
Available online
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009 Elsevier Ltd. All rights reserved.
Keywords:
Thioacids
Water
Green chemistry
Catalyst free
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. Introduction
The most conventional way of synthesizing thioacids is to
activate the corresponding carboxylic acids using mixed
Thioacids are carboxylic acid analogues and they represent an
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anhydride method or active esters such as p-nitrophenyl esters,
important class of organic compounds. They possess higher
solubility, acidity and nucleophilicity than their corresponding
carboxylic acids. Thioacids are of considerable interest in
medicinal chemistry and have been used widely in the synthesis
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or N-hydroxysuccinimidyl esters, followed by nucleophilic
-
substitution with hydrosulfide anion ( SH). The common sources
of hydrosulfide anion are hydrogen sulfide gas (H
sulfide (Na S), lithium sulfide (Li S), or sodium hydrosulfide
NaSH). Solid-phase peptide synthesis (SPPS) over Kaiser’s
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S), sodium
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of interesting chemical scaffolds. Thioacids react with azides,
(
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-6
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isonitriles, amines, and aziridines, to facilitate the synthesis
of some of the most challenging amides and peptides. Upon trace
level of oxidative activation, thioacids can serve as excellent acyl
donors and form amide bonds quiet easily with N-terminal
peptides. In peptide chemistry, C-terminal thioacids are
important precursors in thio-formimidate carboxylate mixed
anhydride (thio-FCMA) ligation that enables the construction of
peptides that are difficult to synthesize. Recently, activation of C-
terminal thioacids using isonitriles was used in combination with
native chemical ligation in the total synthesis of all-L- and all-D-
amino acid biotinylated variants of oncogenic mutant KRas
G12V.1
oxime ester resin is the most used method for large peptide
thioacids, which can be obtained after cleavage from the resin
with hexamethyldisilathiane and tetrabutylammonium fluoride.
An important one-step method to synthesize thioacids was
developed by Danishefsky and involves the treatment of
carboxylic acids with Lawesson’s reagent in dichloromethane
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under microwave irradiation (Method A, Figure 1). Recently,
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Katritzky et al. have developed a method to synthesize
protected amino/peptide thioacids from the corresponding acyl
benzotriazoles using H S and N-methylmorpholine (NMM) in
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THF (Method B, Figure 1).
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N-Protected ɑ-amino/peptide thioacids were also synthesized
from their corresponding oxoacids via reaction with 1-ethyl-3-(3-
Thioamino acids are invaluable building blocks for
constructing complex biologics such as glycopeptides and
glycoproteins. Moreover, they hold great potential for the
treatment of cardiovascular diseases. For example, thioglycine
dimethylaminopropyl)carbodiimide (EDC) and Na
2
S in DMF
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(Method C, Figure 1). Although the reaction conditions are
mild and yields are good, the intermediates that is formed from
the reaction of the carboxylic acids with EDC is unstable and
prone to rapid hydrolysis in aqueous solution. N-Protected α-
amino thioacids can be synthesized using thioacetic acid and
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and L-thiovaline releases H S, which is a known gasotransmitter
that enhance the formation of cGMP, and consequently promote
vasorelaxation in mouse aortic rings.12
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NaSH in THF (Method D, Figure 1). However, separation of
the thioacid was problematic and requires further oxidative
dimerization to be separated from the corresponding amino acid.
Recently, Kanai and his co-workers reported a catalytic one-step
In nature, proteins containing thiocarboxylate functional group
are biosynthetic sulfide donors.13 These proteins are involved in
the biosynthesis of vitamin B1, biotin, molybdopterin, cysteine,
thioquinolobactin and S-adenosylmethionine.
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method for peptide thioacids (Method E, Figure 1). They were