Letter
Synthesis of Trifunctional Thiazolyl Amino Acids And Their Use
for the Solid-Phase Synthesis of Small Molecule Compounds and
Cyclic Peptidomimetics
Heather A. Michaels, Diana C. Velosa, and Adel Nefzi*
Torrey Pines Institute for Molecular Studies, 11350 Southwest Village Parkway, Port St. Lucie, Florida 34986, United States
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* Supporting Information
ABSTRACT: Chiral thiazolyl amino acid building blocks for the solid-phase synthesis of small molecules, peptides, and cyclic
peptides have been designed and synthesized starting from Fmoc protected asparagine and glutamine. In efforts to demonstrate
the usefulness and validity of such building blocks, a small library of 16 new thiazole containing small molecules has been
prepared and characterized. Additionally, we report the use of the newly prepared trifunctional thiazolyl glutamine for the
on-resin, head-to-tail synthesis of cyclic peptides.
KEYWORDS: unnatural amino acid, thiazole, solid-phase synthesis, peptide, heterocycle, pharmacophore
nnatural amino acids, particularly synthetic α-amino acids,
have played a significant role in the area of peptide research
building blocks are also useful for the synthesis of branched linear
peptides.11
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and drug discovery.1−4 They have been used extensively in
peptide analogs to limit conformational flexibility, enhance
enzymatic stability, and improve pharmacodynamics and
bioavailability. Because of their structural diversity and functional
versatility, they are widely used as chiral building blocks and
molecular scaffolds in constructing combinatorial libraries.5−7
Many of these unnatural amino acids are also critical components
in pharmaceuticals and developmental drugs.
Our approach toward the synthesis of orthogonally protected
trifunctional thiazolyl amino acids is outlined in Scheme 1. The
thioamide (1) of both asparagine and glutamine was prepared by
literature procedures.12 Starting from Fmoc α-amino protected
glutamine or asparagine, the carboxylic acid was orthogonally
protected with 4-methoxybenzyl (PMB) to afford intermediate 1.
Upon sonication of 1 in the presence of phosphorus pentasulfide,
the amide was selectively converted into the corresponding
thioamide 2 with no evidence of the protected C-terminus
being affected. The thioamidation was also successfully achieved
using Lawesson’s Reagent.13,14 The generated thioamide was
treated in refluxing conditions with a small excess of bromo-
pyruvic acid to afford, following Hantzsch cyclocondensation,
the desired enantiomerically pure thiazolyl amino acids in good
yields. The orthogonal deprotection of both the amine and the
acid allows for 2 sites of diversification, which allows for the
parallel synthesis of diverse thiazole based small molecule
compounds.
Additionally, the thiazole ring is present in many natural and
synthetic products8 with a wide range of pharmacological activities
that can be well illustrated by the large number of drugs on the
market containing this functional group. Small molecules containing
a thiazole moiety have been demonstrated to possess drug like
properties against varieties of diseases9 resulting in, so far, 17 FDA-
approved drugs containing the thiazole ring. The usefulness of
thiazoles is evident by the wide scope of disease to which thiazole
derivatives are prescribed. These include asthma (cinalukast),
bacterial infections (ceftizoxime), diarrhea (nitazoxanide) myelog-
enous leukemia (dasatinib), pain (meloxicam), duodenal ulcers
(famotidine), anthelmintics (thiabendazole), CNS disorders
(riluzole), and as vitamin supplements (thiamine).10 Herein, we
report the side chain manipulation of asparagine and glutamine
for the synthesis of thiazolyl amino acids and their use as building
blocks for the parallel synthesis of small molecule libraries and for
the on resin head-to-tail synthesis of cyclic peptides. Such
A simple case study illuminating the use of the Asn scaffold to
prepare thiazole based small molecules was carried out on solid
Received: September 10, 2013
Revised: November 11, 2013
Published: December 25, 2013
© 2013 American Chemical Society
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dx.doi.org/10.1021/co400114u | ACS Comb. Sci. 2014, 16, 1−4