Organocatalytic tandem reactions of polyfunctional compounds for the synthesis of enantioenriched heterocycles. Reazioni tandem organocatalitiche di composti polifunzionali per la sintesi di eterocicli enantioarricchiti.

In questo lavoro di tesi sono state sviluppate reazioni domino, tandem e procedure one-pot per ottenere eterocicli enatioarricchiti. Lo sviluppo di queste metodologie sintetiche è molto importante perché permettono di ottenere molecole complesse partendo da prodotti semplici, senza effettuare ripetuti passaggi di purificazione (stop-and-go or step-by-step synthesis). Lo scopo di questo lavoro è di ottenere derivati tetraidrofuranici modificati e derivati ossoazzolinici enantioarrichiti tramite reazioni SN2-Michael o tramite reazioni aldolica-ciclizzazione-Michael usando la catalisi asimmetrica a trasferimento di fase (PTC). Come catalizzatori PTC per imprimere enantioselezione sono stati utilizzati sali di ammonio quaternario derivati dagli alcaloidi della Cinchona. Sono state ottimizzate le condizioni di reazione (base inorganica, temperatura, solvente, tempo di reazione) per i diversi substrati presi in considerazione. I prodotti target sono stati ottenuti con buone rese, ottime diastereoselezioni ma con bassa enantioselezione. I risultati ottenuti richiedono un’ulteriore ottimizzazione e dovranno essere valutate variazioni strutturali dei nucleofili utilizzati. In this thesis were developed domino, tandem reactions and one-pot procedures to obtained enantioenriched heterocycles. The development of these methodologies is very fundamental because they allow to obtain complex molecules starting from raw materials, without carrying out repeated purification steps (stop-and-go or step-by-step synthesis). The purpose of this work is to obtain enantioenriched tetrahydrofuran and oxazoline derivatives through a SN2-Michael reaction or a aldol- cyclization-Michael reaction using the phase-transfer asymmetric catalysis (PTC). For imprint enantioselection we used Cinchona alkaloids quaternary ammonium salts derivatives. The reaction conditions (inorganic base, temperature, solvent, reaction time) were optimised for the different substrates taken into account. The target products were obtained with good yields, excellent diastereoselections but with low enantioselections. The obtained results require further optimization and structural changes in the nucleophiles used must be evaluated

Preparation and Applications of Pseudopeptide-Based Nanomaterials

This thesis describes the synthesis, the conformational analysis and the applications of pseudopetide foldamers containing the 4-carboxy-5-methyl-oxazolidin-2-one moiety or the pyroglutamic acid unit. These molecules mimic a proline group and have been applied to the formation of oligomers that in solution may easily adopt a stable secondary structure. These pseudoprolines block the peptide bond always in the trans conformation, because the nitrogen atom of the ring is adjacent to both an exocyclic and an endocyclic carbonyl group, forcing them to a strict trans conformation. This remarkable property induces a constrain in the pseudopeptide chain that may help the formation of supramolecular materials. Following a simple methodology we have efficiently prepared a variety of foldamers, whose proprieties may be changed choosing different amino acids, thus providing several secondary structures

The Treatment of Heart Failure in Patients with Chronic Kidney Disease: Doubts and New Developments from the Last ESC Guidelines

Patients with heart failure (HF) and associated chronic kidney disease (CKD) are a population less represented in clinical trials; additionally, subjects with more severe estimated glomerular filtration rate reduction are often excluded from large studies. In this setting, most of the data come from post hoc analyses and retrospective studies. Accordingly, in patients with advanced CKD, there are no specific studies evaluating the long-term effects of the traditional drugs commonly administered in HF. Current concerns may affect the practical approach to the traditional treatment, and in this setting, physicians are often reluctant to administer and titrate some agents acting on the renin angiotensin aldosterone system and the sympathetic activity. Therefore, the extensive application in different HF subtypes with wide associated conditions and different renal dysfunction etiologies remains a subject of debate. The role of novel drugs, such as angiotensin receptor blocker neprilysin inhibitors and sodium glucose linked transporters 2 inhibitors seems to offer a new perspective in patients with CKD. Due to its protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. In this review, we discussed the largest trials reporting data on subjects with HF and associated CKD, while suggesting a practical stepwise algorithm to avoid renal and cardiac complications

Hydrogelation induced by Fmoc-protected peptidomimetics

Four new low molecular weight hydrogelators (LMWGs) have been prepared in multigram scale and their attitude to form hydrogels has been tested. The gelation trigger is pH variation. The resulting gels have been characterized with several techniques: measurement of the melting points (Tgel), transparency, gelation time, and viscoelastic properties, together with ECD analysis. Among them, Fmoc-l-Tyr-d-Oxd-OH 1 is an excellent gelator that leads to the preparation of strong, transparent, and viscoelastic gels, by pH variation. UV-visible analyses have demonstrated that the gels obtained with the LMWG 1 possess high transparency, with a transmittance up to 25.6% at a wavelength of 600 nm. Results of the amplitude sweep experiments showed that the elastic response component (G′) was approximately an order of magnitude larger than the viscous component, indicating an elastic rather than viscous attitude of the gels, confirmed by the frequency independence of G′ and G″ values, in the range from 0.1 to 100 rad·s-1. The thermal behavior of gel obtained from Fmoc-l-Tyr-d-Oxd-OH 1 was characterized performing an "ad hoc" rheological temperature sweep experiment, that indicated that G′ remained almost constant from 23 °C up to about 65 °C while G″ increased in the same temperature range. At higher temperatures, both G′ and G″ values started to slightly decrease without displaying a crossover point

Factors Affecting the Stabilization of Polyproline II Helices in a Hydrophobic Environment

Several parameters have a critical importance for the stabilization of either polyproline I (PPI) or polyproline II (PPII) helices in a hydrophobic environment. Among them, it was found out that the concentration is crucial as polyprolines at 3 mM concentration stably fold in PPII helices, that are organized in aggregates stable even after several days and are detectable by dynamic light scattering analysis. In more diluted concentration the same molecules stably fold in PPI helices, and no aggregates are found. In contrast, the introduction of a (4<i>S</i>,5<i>R</i>)-4-carboxy-5-methyloxazolidin-2-one (l-Oxd) moiety always inhibits the formation of the PPI helix, regardless of the l-Oxd position and the solution concentration

Shaping calcite crystals by customized self-assembling pseudopeptide foldamers

Two pseudopeptide foldamers with similar backbones, one containing a d-4-carboxy-5-methyl-oxazolidin-2-one moiety (1) and the other a d-proline moiety (2), self-assembled in a 9:1 water-ethanol mixture. Molecule 1 formed fibres that generated a highly viscous sol or a gel by increasing its concentration; molecule 2 assembled in nanoparticles that aggregated in bigger particles by increasing its concentration. This behaviour was conserved in the presence of 10 mM CaCl2. Both foldamers, which exposed carboxylate groups, were able to modify the shape of single crystals of calcite. The presence of molecule 1 favoured the formation of rhombohedral calcite showing additional crystalline faces, while molecule 2 induced the formation of cavities and curvatures. Thus, pseudopeptide foldamers diversely act as crystal growth modifiers according to minor structural changes that mutate their self-assembly. This result is of general interest for the design of new molecules affecting the crystallization process and has implications in understanding how biological molecules control the growth of mineral phases

Pseudopeptide Foldamers designed for photoinduced intramolecular electron transfer

We have designed and prepared three pseudopeptide foldamers, called dyads 1, 2 and 3, equipped with a donor and an acceptor unit to promote intramolecular electron transfer after light excitation. All the three dyads contain the same donor and acceptor, which are a derivative of 1,5-dihydroxynaphthalene and a derivative of pyromellitic diimide, respectively. The donor and acceptor units are separated by hybrid foldamers of different length in order to vary both their distance and relative orientation. Specifically, one, two or three L-Ala-D-Oxd (Ala ¼ alanine, Oxd ¼ 4-carboxy-5-methyl-oxazolidin-2-one) units are contained in dyads 1, 2, and 3, respectively. Dyad 1 folds in a bent conformation in which the donor and acceptor units lie one close to the other, while dyads 2 and 3 preferentially assume an extended conformation. In all the three dyads both the donor and acceptor emissions are efficiently quenched via intramolecular electron transfer, as suggested by photophysical and electrochemical investigations. Because of its bent conformation dyad 1 exhibits a charge-transfer (CT) band at 410 nm in CH2Cl2 solution and a photoinduced electron transfer that occurs more efficiently than in dyads 2 and 3. Upon dissolving dyad 1 in DMSO, a competitive solvent for hydrogen bonds that establish in the pseudopeptide linker, the CT band disappears and the efficiency of electron transfer slightly decreases, in agreement with an unfolded conformation in which donor and acceptor units are no longer in close contact

Solid-state properties and vibrational circular dichroism spectroscopy in solution of hybrid foldamers stereoisomeric mixtures

Upon slow evaporation of a 1:1 diastereoisomeric mixture of Boc-(l-Phe-l-Oxd)2-OBn (1; Boc=tert-butyloxycarbonyl; l- Oxd=trans-(4S,5R)-4- carboxy 5-methyloxazolidin-2-one, Bn= benzyloxycarbonyl) and Boc-l-Phe-l-Oxd-d-Phe-l-Oxd-OBn (2) in methyl tert-butyl ether, single crystals suitable for an X-ray diffraction study were obtained. In contrast, the two pure oligomers lead to the formation of amorphous solids under any crystallization conditions. The preferential conformation of both oligomers was fully elucidated in the solid phase and compared with the known conformation of Boc-(l-Phe-d- Oxd)2-OBn (3). The preferred conformation of 1 ranges from a polyproline II (PPII) helix to b strands and we can gather that longer and more structured oligomers will form PPII helices. In contrast, compound 3 forms infinite antiparallel b-sheet structures; thus showing the strong effect of the reversal of the absolute configuration of the Oxd moieties on the secondary structure of these hybrid foldamers. The same outcome was retained in solution, as demonstrated by vibrational circular dichroism analysis. Finally, we have demonstrated that a 1:1 mixture of 1 and 2 leads to the formation of new materials with interesting properties that are missing from the two pure compounds, such as the tendency to form crystals, fibers, and globules, depending on the solvent

Form Matters: Stable Helical Foldamers Preferentially Target Human Monocytes and Granulocytes

Some hybrid foldamers of various length, all containing the (4R,5S)-4-carboxy-5-methyloxazolidin-2-one (d-Oxd) moiety alternating with an l-amino acid (l-Val, l-Lys, or l-Ala), were prepared in order to study their preferred conformations and to evaluate their biological activity. Surprisingly, only the longer oligomers containing l-Ala fold into well-established helices, whereas all the other oligomers give partially unfolded turn structures. Nevertheless, they all show good biocompatibility, with no detrimental effects up to 64 μm. After equipping some selected foldamers with the fluorescent tag rhodamine B, a quantitative analysis was performed by dose– and time–response fluorescence-activated cell sorting (FACS) assays with human HeLa cells and primary blood lymphocytes, granulocytes, and monocytes. Among the cell types analyzed, the oligomers associated with monocytes and granulocytes with greatest efficacy, still visible after 24 h incubation. This effect is even more pronounced for foldamers that are able to form stable helices

α,ε-Hybrid Foldamers with 1,2,3-Triazole Rings: Order versus Disorder

Two epimeric series of foldamers characterized by the presence of a repeating alpha-epsilon-dipeptide unit have been prepared and characterized by 1H NMR and ECD spectroscopies together with X-ray diffraction. The first series contains L-Ala and D-4-carboxy-5-methyl-oxazolidin-2-one (D-Oxd). The other series contains L-Ala and L-Oxd. The L,D series of oligomers forms ordered beta-turn foldamers, characterized by a 311 pattern. The L,L series is not ordered. Simulations show that an ordered L,L trimer lies more than 2 kcal/mol higher than the more stable non folded extended conformations. Cu2+ forms complexes with both series, but is not able to order the L,L series. Analysis of the EPR spectra shows that the L,D foldamers bear two types of complexation sites that are assigned as a nitrogen donor of the triazole ring and a carboxylate ligand. The L-Ala-D-Oxd-Tri-CO motif may be introduced in any peptide sequence requiring the presence of a stable β-turn conformations, like in the study of protein-protein interactions