© 2013 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 86, No. 11, 1287-1294 (2013) 1287
Facile and Rapid Green Route for the Synthesis of Privileged
Peptidotriazoles Based on Oxazolonic Acids by Click Fragment Assembly
Biny Balan and Damodaran Bahulayan*
Department of Chemistry, University of Calicut, Malappuram 673635, Kerala, India
Received April 18, 2013; E-mail: bahulayan@yahoo.com
A convenient synthetic pathway to triazole-functionalized oxazolone peptidomimetics by click fragment assembly is
described. The target molecules were obtained by the ligation of oxazolone-based peptides with azidopeptides via Cu(I)-
catalyzed Huisgen cycloaddition reaction (“Click Chemistry”).
One of the most exciting and potentially rewarding chal-
lenges in modern drug discovery is the design of chemical
reaction sequences that can provide maximum structural
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complexity, diversity, and drug-like properties in a minimum
number of synthetic steps.1 Fragment-based assembly has
emerged as an efficient strategy to generate structural diversity
and complexity in drug leads for the development of small
molecule inhibitors, with multiple binding pockets in their
active sites.2a There are two major issues in fragment-based
drug discovery. One is the selection and availability of a robust,
high yielding, and low cost chemical reaction that can pro-
vide functionally diverse and structurally complex fragments.
The second one is the availability of a modular reaction that
can mimic the “nature’s creation strategy” for the assembly of
fragments. These two issues stimulated the effort toward the
search for new green chemical methods for fragment generation
and fragment assembly.2b,2c
In recent years, many new reaction methodologies have
been developed for the generation of scaffolds that can fit in
drug leads.3 Among such methods, multicomponent reactions
(MCRs) are particularly useful to produce smart molecular
fragments preferably in a one-pot and one-step manner with
high atom economy and less resource consumption.3 Among
the various MCRs, isocyanide-based MCRs like Ugi and
Passerini reactions are well known for creating small peptide
like molecules, with high degree of structural complexity and
for the incorporation of stereogenic centers in scaffolds, which
is often positively related with bioactivity.4
Among the various ligation techniques, the Cu(I)-catalyzed
Huisgen cycloaddition between two structural fragments, suit-
ably functionalized with pairing handles such as an alkyne in
one fragment and azide in the second one has greatly advanced
in the last decade.5 This cycloaddition provides a 1,2,3-triazole
linker between two scaffolds, which will ultimately change
a non-peptidic molecule to a peptide like one with enhanced
physicochemical properties such as proteolytic stability, selec-
tivity, bioavailability, etc.6-8
Oxazolones, also known as azalactones, are internal anhy-
drides of acylamino acids and can be easily prepared from N-
acylamino acids via. cyclodehydration.9 They possess important
biological activities such as antimicrobial,10 anti-inflamma-
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a
b
Figure 1. Classical examples of oxazolone-derived drugs.
tory,11 anticancer,12a,12b anti-HIV,13 antiangiogenic,14 antitumor,
antagonistic, and sedative properties.15 Interesting examples
include spirocyclopropyl oxazolone (a)13 and pancratistatin (b)
(Figure 1).12c The former represents a new class of herpes
protease inhibitor13 and the later is a phenanthrene alkaloid-
based anticancer drug16 obtained from the intramolecular Diels-
Alder reaction of phenacycloxazolone.
Moreover, the oxazolone ring resembles a cyclic ester and,
its amide like geometric parameters make it a peptide bond
isoster.17 In recent years, peptide-based drugs have emerged
as a new class of therapeutic agents and more than 60 FDA-
approved peptide based drugs are available on the market.
Most of these peptide drugs contain β-amino acids, nonnatural
amino acids or peptidomimetics as a core structural scaf-
fold.18,19 Such complex molecules are prepared by adopting
a tailoring pharmacology approach based on the combination
of heterocyclic functional parts and small peptide-like back-
bones.20 The final molecule may exert multiple agonistic func-
tions. These relatively high molecular weight peptidomimetics
can easily link with intercellular targets, a task that cannot be
addressed by small molecule approaches.
In continuation of our ongoing research for the development
of heterogenized peptidomimetics, herein we report our recent
results in the synthesis of a new series of small β-peptide-
functionalized oxazolonic acid mimics with general structure A
or B (Figure 2) based on MCR and click strategy. The overall
reaction in most cases involves two multicomponent reactions
and a “click” cycloaddition.