De Novo Design of secondary structures:
Synthesis and conformational studies
Creators: name: Angelici, Gaetano <1979>
Publisher: name: Alma Mater Studiorum - Università di Bologna
Year: 2009
Subjects: CHIM/06 Chimica organica

description: Chemists have long sought to extrapolate the power of
biological catalysis and recognition to synthetic systems.
These efforts have focused largely on low molecular
weight catalysts and receptors; however, biological
systems themselves rely almost exclusively on polymers,
proteins and RNA, to perform complex chemical
functions. Proteins and RNA are unique in their ability to
adopt compact, well-ordered conformations, and specific
folding provides precise spatial orientation of the
functional groups that comprise the “active site”. These
features suggest that identification of new polymer
backbones with discrete and predictable folding
propensities (“foldamers”) will provide a basis for design
of molecular machines with unique capabilities. The
foldamer approach complements current efforts to design
unnatural properties into polypeptides and
polynucleotides.
The aim of this thesis is the synthesis and
conformational studies of new classes of foldamers, using
a peptidomimetic approach. Moreover their attitude to be
utilized as ionophores, catalysts, and nanobiomaterials
were analyzed in solution and in the solid state.
This thesis is divided in thematically chapters that are
reported below.
It begins with a very general introduction (page 4) which
is useful, but not strictly necessary, to the expert reader.
It is worth mentioning that paragraph I.3 (page 22) is the
starting point of this work and paragraph I.5 (page 32) isrequired to better understand the results of chapters 4
and 5.
In chapter 1 (page 39) is reported the synthesis and
conformational analysis of a novel class of foldamers
containing (S)-β3-homophenylglycine [(S)-β3-hPhg] and D-
4-carboxy-oxazolidin-2-one (D-Oxd) residues in alternate
order is reported. The experimental conformational
analysis performed in solution by IR, 1HNMR, and CD
spectroscopy unambiguously proved that these oligomers
fold into ordered structures with increasing sequence
length. Theoretical calculations employing ab initio MO
theory suggest a helix with 11-membered hydrogenbonded
rings as the preferred secondary structure type.
The novel structures enrich the field of peptidic foldamers
and might be useful in the mimicry of native peptides.
In chapter 2 cyclo-(L-Ala-D-Oxd)3 and cyclo-(L-Ala-DOxd)
4 were prepared in the liquid phase with good overall
yields and were utilized for bivalent ions chelation (Ca2+,
Mg2+, Cu2+, Zn2+ and Hg2+); their chelation skill was
analyzed with ESI-MS, CD and 1HNMR techniques and
the best results were obtained with cyclo-(L-Ala-D-Oxd)3
and Mg2+ or Ca2+.
Chapter 3 describes an application of oligopeptides as
catalysts for aldol reactions. Paragraph 3.1 concerns the
use of prolinamides as catalysts of the cross aldol
addition of hydroxyacetone to aromatic aldeydes, whereas
paragraphs 3.2 and 3.3 are about the catalyzed aldol
addition of acetone to isatins. By means of DFT and AIM
calculations, the steric and stereoelectronic effects that
control the enantioselectivity in the cross-aldol addition
of acetone to isatin catalysed by L-proline have been
studied, also in the presence of small quantities of water.
In chapter 4 is reported the synthesis and the analysis of
a new fiber-like material, obtained from the selfaggregation
of the dipeptide Boc-L-Phe-D-Oxd-OBn,
which spontaneously forms uniform fibers consisting of
parallel infinite linear chains arising from singleintermolecular N-H···O=C hydrogen bonds. This is the
absolute borderline case of a parallel β-sheet structure.
Longer oligomers of the same series with general formula
Boc-(L-Phe-D-Oxd)n-OBn (where n = 2-5), are described
in chapter 5. Their properties in solution and in the solid
state were analyzed, in correlation with their attitude to
form intramolecular hydrogen bond.
In chapter 6 is reported the synthesis of imidazolidin-2-
one-4-carboxylate and (tetrahydro)-pyrimidin-2-one-5-
carboxylate, via an efficient modification of the Hofmann
rearrangement. The reaction affords the desired
compounds from protected asparagine or glutamine in
good to high yield, using PhI(OAc)2 as source of iodine(III).