Biomedical Engineering Reference
In-Depth Information
6.4 AMINO ACID-DERIVED SCAFFOLDS
A special interest in the development of suitable peptidomimetics for targeting
peptide-protein and protein-protein interactions has been focused on the use of
amino acids as building blocks. Side chains of natural amino acids are of great
importance for the activity of proteins, due to their functional group diversity, which
allows them to interact with other peptides or proteins; thus, amino acids and their
derivatives have been taken into account as building blocks to enable the generation of
peptidomimetic scaffolds possessing side-chain conformational restriction. Interest
in the use of easily accessible and versatile proteinogenic amino acids as a chiral pool
for synthesis of optically active heterocycles has been growing rapidly [16] because
of their versatility in the panorama of chemical transformations and for their chemical
diversity. Many reports focused on the generation of cyclic scaffolds using proline
derivatives by virtue of the conformational restriction of the pyrrolidine ring and took
advantage of the chemical and stereochemical diversity around this scaffold. Also,
a significant contribution to the generation of amino acid-derived peptidomimetic
scaffolds came out of the exploitation of the chemistry of amino aldehydes, particu-
larly as related to iminium chemistry, and the inclusion of
-amino acid derivatives
into cyclic scaffolds.
6.4.1 Scaffolds from
-Amino Acids
Nefzi et al. reported the application of
-amino acid-derived ethylenediamines on
solid phase to achieve an array of cyclic scaffolds differing by ring size and functional
groups [17]. The starting diamine deriving from N-acylated amino acid was treated
with an array of reactants such as carbonyldiimidazole, thiocarbonyldiimidazole,
and cyanogen bromide to give the corresponding five-membered ring imidazolidin-
2-one, imidazolidine-2-thione, and imidazolidin-2-imine. Six-membered heterocy-
cles consisted of diketopiperazines from the reaction with oxalyldiimidazole, and
seven-membered ring diazepinediones were achieved from the reaction with malonyl
dichloride (Scheme 6.4).
Recent applications of
-amino acids as building blocks for the diversity-oriented
synthesis of heterocyclic scaffolds were reported by Mishra and Panda. A first
report described the synthesis of benzannulated medium-ring heterocyclic scaffolds
employing inter- and intramolecular Mitsunobu reactions in enantiomerically pure
form [18].
Seven- and eight-membered rings bearing nitrogen, oxygen, and sulfur atoms
were synthesized following the Mitsunobu approach for the formation of the carbon-
heteroatom bond as a convenient route to the synthesis of benzannulated medium-
ring heterocycles in an optically pure form, containing the naturally occurring
-
amino acids (Scheme 6.5). The general synthetic strategy consisted of two Mitsunobu
reactions to install the amino acid moiety on the aromatic scaffold. The intermolecular
Mitsunobu reaction on the amino or carboxylic end was followed by functional group
interconversions enabling a second intramolecular Mitsunobu reaction to achieve the
final bicyclic scaffolds. This simple protocol is quite straightforward and may give
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