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Enantioselective Approaches and Domino Sequences for the Synthesis of Compounds of Biological Interest

Pelà, Michela (2011) Enantioselective Approaches and Domino Sequences for the Synthesis of Compounds of Biological Interest. PhD Thesis , Università degli Studi di Ferrara.

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    Neuropeptide S (NPS) is the endogenous ligand of the previously orphan G-protein coupled receptor, recently named NPSR.12 NPS is a small peptide of 20 amino acids and rapresents the endogenous ligand of NPSR. In cells expressing the recombinant NPSR receptor, NPS selectively binds and activates its receptor, producing intracellular calcium mobilization and an increase of cAMP levels. The NPS-NPSR receptor system regulates important biological functions such as sleep/waking, locomotion, anxiety and food intake. (R/S) SHA-68 21 is the first non-peptide antagonist of NPSR receptor; actually only a class of molecules able to interact with NPSR are reported in the literature and they are the same oxazol-piperazine structure. Initially, in order to confirm the published data, we decided to synthesize SHA 68 in racemic form following the Okamura’s methodology21. The high selectivity of (R/S)-SHA 68 for NPSR and its good antagonist activity prompted us to synthesize the enantiomers of this non-peptide compound, starting from cheap commercially available reagents as chiral auxiliary. In order to define the conformation of the piperazine ring in this two enantiomers we performed a series of NMR experiments leading to define a chair conformation where the substituent in C9 was placed in equatorial position. To know the absolute configuration of the new chiral centre X ray analysis was performed on suitable crystals that show us the R configuration of the new stereogenic centre. From a pharmacological point of view (R)-SHA 68 was demonstrated to be the antagonist of the receptor of the Neuropeptide S. This new class of non-peptide NPSR antagonists provides additional tools for in vitro and in vivo studies required to elucidate the NPSR conformation, adding new informations to well know NPS-NPSR system. In the frame of the synthesis of biological active chiral compounds I have spend nine months at the Pierre et Marie Curie University in Paris under the supervision of Professor Giovanni Poli, focusing the attention on the synthesis of natural product (-)- Steganacin. This stage allowed me to view a different approach for the selective generation of new structures using a palladium catalysed domino reactions instead of the use of chiral auxiliaries used for the synthesis of (R) and (S)-SHA 68. Steganacin was isolated from a plant of South Africa, Steganotaenia araliacea.31 The interest of chemists for the (-)-Steganacin was initially motivated by its antitumor activity; 34 it is for this reason that in literature we found different total syntheses of this molecule. From a structural point of view the (-)-Steganacine presents a γ-lactonic skeleton condensed to an eight membered ring, a biarylic portion and three contiguous stereogenic centers with a relative stereochemistry trans, trans. Aim of this project is the synthesis of an aza-analogue of Steganacine in which the lactone structure is replaced by a γ-lactam moiety. The synthetic process starts from a commercially available propargyl alcohol to afford in seven steps the desired cyclization precursor in 19 % yield. The key step of our project was previously studied in the laboratories of Prof. Giovanni Poli and reported in literature by Kammerer et al. in 2009.41 This is an original regioand stereoselective synthesis of aryl substituted pyrrolidones by a phosphine-free Pdcatalyzed allene carbopalladation/allylic alkylation sequence. This reaction allowed us to obtain the key intermediate in 74% yield. After benzylation of this key intermediate, several strategies to remove the methoxycarbonyl group were tested, the best solution being hydrolysis in ethylene glycol at high temperatures. The next study will focus on the non-phenolic oxidative coupling between the two aromatic moieties to formed an eight membered ring. Then, an oxidative cleavage of the double bond followed by a diastereoselective reduction of the resulting ketone and final alcohol acetylation should afford the desired (-)-Steganacin aza-analogue.

    Item Type:Thesis (PhD Thesis)
    Date:8 April 2011
    Tutor:Pollini, Gian Piero - Poli, Giovanni
    Coordinator:Manfredini, Stefano
    Institution:Università degli Studi di Ferrara
    Divisions:Dipartimento > Scienze farmaceutiche
    Subjects:Area 03 - Scienze chimiche > CHIM/06 Chimica organica
    Uncontrolled Keywords:SHA-68, antagoniste NPSR, Neuropeptide S, (-)-Steganacine, séquence domino, carbopalladation d'allène, domino sequence, carbopalladazione d'allene
    Deposited on:13 Apr 2012 14:58


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