α-Funzionalizzazione organocatalitica enantioselettiva di aldeidi con eterocicli aromatici azotati

In this work, two enantioselective syntheses catalyzed by diphenyl prolinol silyl ethers to alfa-functionalized aldehydes are presented. In the first project, N-benzylpyridinium bromides activated at the C3 position by an electron-withdrawing group (nitro or cyano) are used. The pyridine portion added to the aldehyde losing aromaticity and forming a dihydropyridine derivative. The optimization of the reaction parameters as solvent, base, catalyst, acid co-catalyst and temperature has been reported. Moreover, the generality of the reaction has been proved varying both the pyridiuum salts and the aldehydes. Finally, the relative and absolute configuration of the products were determined and explained assuming a reaction mechanism through the syncline transition state. In the second project, the enantioselective alfa-arylation of aldehydes with isquinoline N-oxides, catalyzed by diphenyl prolinol silyl ethers, has been studied. The activation of the isquinoline N-oxide has been achieved with the use of bromotripyrolidinodiphosphonium hexafluorophosphate (PyBroP). A preliminary study of the optimal reaction conditions has been carried out, which is still underway. Currently, good enantiomeric excesses and moderate to good conversions of reagents have been obtained

Novel developments of atropisomeric organic molecules. Design of atropisomeric drugs, fluorescent compounds and investigation of reaction mechanisms.

In recent years, the study of restricted rotation bonds in organic compounds has aroused increasing interest. The reason is that this characteristic can lead to obtaining new properties in organic compounds. In this research thesis, an intense investigation was carried out using DFT calculations and experimental evaluation of the barriers to rotational energies, in order to discover new properties deriving from the restricted rotation bonds. Research has been developed in various fields of organic chemistry, ranging from drugs (the atropisomeric atorvastatin in Chapter 3) to luminescent compounds (aryls amino borane in Chapter 4). Furthermore, an organocatalytic central to axial conversion mechanism was investigated through DFT calculations, finding out interesting outcomes (Chapter 5). Finally, a project in collaboration with Dr. Farran and Prof. Vanthuyne of the Aix-Marseille University was done to investigate the interactions in transition states of rotational barriers

Atropostatin: Design and Total Synthesis of an Atropisomeric Lactone–Atorvastatin Prodrug

Atorvastatins play an important role in the inhibition of HMG-CoA reductase, an enzyme present in the liver that takes part in the biosynthesis of cholesterol. In this article, we report the total synthesis of a lactone–atorvastatin prodrug with additional atropisomeric features. Conformational and experimental studies of model compounds were designed to test the stability of the chiral axis. Docking calculations were performed to evaluate the constant inhibition of a library of atorvastatins. Full synthesis of the best candidate was achieved and thermally stable atropisomeric lactone–atorvastatin was obtained. The absolute configuration of the chiral axis of the atropisomers was assigned by means of chiroptical ECD spectroscopy coupled with TD-DFT calculations

An organocatalytic enantioselective direct alpha-heteroarylation of aldehydes with isoquinoline N-oxides

A new protocol for the enantioselective direct alpha-heteroarylation of aldehydes with isoquinoline N-oxides, via chiral enamine catalysis, has been successfully developed. High enantiomeric excesses and moderate to good yields were achieved for a variety of alpha-heteroarylated aldehydes

Electrochemical Synthesis of Unnatural Amino Acids Embedding 5- and 6-Membered Heteroaromatics

Using a commercially available potentiostat, the electrochemical synthesis of unnatural amino acids bearing heteroaromatics on the lateral chain has been accomplished. This strategy exploits the side-chain decarboxylative arylation of aspartic/glutamic acid, a reaction that becomes challenging with electron-rich coupling partners such as 5- and 6-membered heteroaromatics. These rings are underrepresented in unnatural amino acids, therefore it allowed a wider exploration of the chemical space, also given the abundance of the aryl bromides employable in this reactio

Engineering of a phosphorylatable tag for specific protein binding on zirconium phosphonate based microarrays

A phosphorylatable tag was designed and fused at the C-terminal end of proteins, which allowed efficient and oriented immobilization of capture proteins on glass substrates coated with a zirconium phosphonate monolayer. The concept is demonstrated using Nanofitin directed against lysozyme. This peptide tag (DSDSSSEDE) contains four serines in an acidic environment, which favored its in vitro phosphorylation by casein kinase II. The resulting phosphate cluster at the C-terminal end of the protein provided a specific, irreversible, and multipoint attachment to the zirconium surface. In a microarray format, the high surface coverage led to high fluorescence signal after incubation with Alexa Fluor 647 labeled lysozyme. The detection sensitivity of the microarray for the labeled target was below 50 pM, owing to the exceptionally low background staining, which resulted in high fluorescence similar to signal to noise ratios. The performance of this new anchoring strategy using a zirconium phosphonate modified surface compares favorably with that of other types of microarray substrates, such as nitrocellulose-based or epoxide slides, which bind proteins in a nonoriented way

Highly twisted carbazole-borane derivatives: B\u2013N stereodynamic analysis and consequences on their emission properties

The stereodynamic properties of amino bis-mesityl-boranes bearing carbazole and benzocarbazole as donor heterocycles have been investigated by dynamic NMR analysis and simulated by DFT calculations. The \u3c0-contribution to the B\u2013N bond has been estimated to be 24 kcal mol 121 when carbazole is the donor heterocycle, while a value of 21.7 kcal mol 121 has been found for the benzocarbazole series. Two rotational barriers were determined for the B\u2013N bond, the lower one (11.1\u201316.9 kcal mol 121) leading to conformational enantiomers, and the higher one (21.0\u201324.0 kcal mol 121) likely being responsible for the E-Z isomerization in compounds bearing different aryl rings bound to the boron atom. It has been shown that both kinds of dynamic rearrangements involve a correlated motion of all the three rings. The difference in the ground state geometries and the different \u3c0-contributions led to pronounced variations in the fluorescence spectra, due to different geometric rearrangements in the TICT excited state. Stokes shifts larger than 10\u2006000 cm 121 were observed in the carbazole series, with quantum yields up to 50%. It has been found that the \u3c0-contribution to the B\u2013N bond in the excited state is still significant, with B\u2013N isomerism likely not taking place on the ns scale

NHC-catalyzed external oxidative desymmetrization of pharmaceutically relevant dihydropyridines

The synthesis of 1,4-dihydropyridines (DHPs) was first published by A. Hantzsch in 1882 via a multicomponent approach. About 60 years later compounds of this class were found to exhibit pharmacological activities as analgesic, morphine agonist and antispasmodic and in 1975 they became the most important drugs used in the treatment of cardiovascular diseases when nifedipine (Adalat®) appeared on the market for the first time. More recently, NHC (N-Heterocyclic Carbene) catalysis has emerged as powerful tool in desymmetrization and resolution of alcohols via external and internal oxidation of Breslow intermediate. Thus, we envisioned the possibility to extend this approach directly to symmetric dialdehydes. Herein, we present a strategy for the synthesis of biologically relevant DHPs with high optical purity via NHC-catalyzed desymmetrization of 1,4- dihydropyridine-3,5-dicarbaldehyde. The Kharasch oxidant (DPQ) was found to be the best external oxidant in the process and a small library (18 entries) of DHPs was prepared. The reaction is robust and proceeds with good yield (up to 75%) and excellent enantioselectivity (up to 98%). Some synthetic elaboration of the compounds are presented as well