A synthetic route for atropisomeric atorvastatin

Para, Michele (2019) A synthetic route for atropisomeric atorvastatin. [Laurea magistrale], Università di Bologna, Corso di Studio in Chimica industriale [LM-DM270], Documento ad accesso riservato.
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Abstract

The aim of the thesis is to insert a chiral axis on the atorvastatin molecule without having a quaternary carbon, but by blocking the rotation of the single Carbon-Carbon bond of the aryl in position 3, to obtain stable atropisomers. This type of molecules can interact with the HMGR enzyme differently depending on the atropisomer taken into consideration, increasing or lowering the inhibition constant of the drug. Docking calculations were made, starting from the interaction of the atorvastatin with the HMGR, comparing them with the calculations of atorvastatin differently substituted in the aryl in position 3, obtaining a library of possible products. The chiral axis was introduced in the position 3 of the pyrrole ring, because it does not affect the active sites of the atorvastatin, but could give new interactions with the enzyme, depending on the substituent. At the same time, we tried to obtain an efficient synthesis path for having different substituted aryl in the 3 position, increasing the steric hindrance to obtain stable atropisomers. DFT calculations were made to optimize the geometries of the ground and transition states of the test molecules, to forecast the activation energy to rotation. The synthetized products were characterized by NMR (1H, 13C, DEPT), and by analysing the experimental rotational energy barriers with different techniques such as variable temperature NMR (VT-NMR), Dynamic HPLC (DHPLC) and kinetic studies. The absolute configuration of stable atropisomers was assigned with the simulation of the ECD spectra.

Abstract
Tipologia del documento
Tesi di laurea (Laurea magistrale)
Autore della tesi
Para, Michele
Relatore della tesi
Correlatore della tesi
Scuola
Corso di studio
Indirizzo
CHIMICA INDUSTRIALE
Ordinamento Cds
DM270
Parole chiave
atropisomeri atorvastatina barriere rotazionali HPLC NMR studi cinetici
Data di discussione della Tesi
22 Marzo 2019
URI

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