a-Hydroxy-β-amino acids are a subgroup of β-amino acids present in molecules of great biological interest such as ornicorrugatin, a new lipopeptidic siderophore; KRI-1314, a potent human renin inhibitor polypeptide; amastatin, a tetrapeptide with immunoregulatory, antitumor, and antibacterial activity; microginin; threo- β-benzyloxyaspartate (TBOA), the first nontransportable blocker for all subtypes of excitatory amino acid transporters (EAATs); and most of all, taxane derivatives. In this last case, since the α-hydroxy-β-amino propanoic acid plays an important role in the interaction with the bioreceptor as well as in increasing the bioavailability of the molecule, several SAR studies were performed including modifications of the skeleton and of the functional groups linked to the heteroatoms. Phenylisoserine, whose backbone is present in taxane derivatives, is an important synthetic target. This molecule possesses in its structure both a hydrophobic phenyl ring at C3, and a polar hydroxyl group at C2. The main target of the researches related to this PhD thesis is the preparation of two classes of α-hydroxy-β-amino acids, bis-α-hydroxy-β-amino acids and α-hydroxy-α-aziridyl carboxylic acids. Our synthetic approach was addressed to the preparation of dual α-hydroxy-β-amino acids substituted at C-β with an aryl group. The protocol for their preparation is straightforward and consists in two steps. As shown in the Retro-synthetic scheme A below, the “Ley’s lactone” strategy was used to include the glycolic acid moiety into the target molecule. Through a Mannich-like reaction between a silyl ketene acetal derived from this lactone and a hydroarylamide, a condensation product was first isolated and then transformed into the target dual α-hydroxyl-β-amino acids. α-Hydroxy-β-amino acids derived from an aziridine unit have been studied in a very limited number of cases. Due to the novelty of this topic and the limited number of compounds known until now, we became interested in the study of a new stereoselective synthesis approach to these new β-amino acids. The key nucleophilic agent is the BDA lactone (see Retro-synthetic scheme) that, in its optically pure form, can be also used as chiral auxiliary.
|Titolo:||SYNTHESIS OF NEW Α-HYDROXY-Β-AMINO ACID UNITS BY STEREOSELECTIVE MANNICH-LIKE CONDENSATION|
|Supervisori e coordinatori interni:||ROBERTO, DOMINIQUE MARIE|
|Data di pubblicazione:||5-dic-2014|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||SYNTHESIS OF NEW Α-HYDROXY-Β-AMINO ACID UNITS BY STEREOSELECTIVE MANNICH-LIKE CONDENSATION / I. Pecnikaj ; tutor: F. Cozzi, M. Penso; coordinatore: D. Roberto. - Milano : Università degli studi di Milano. Università degli Studi di Milano, 2014 Dec 05. ((27. ciclo, Anno Accademico 2014.|
|Digital Object Identifier (DOI):||10.13130/pecnikaj-ilir_phd2014-12-05|
|Appare nelle tipologie:||Tesi di dottorato|