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Towards the total synthesis of a potential M1 muscarinic agonist and study on regioselective cyclisations for the synthesis of highly substituted piperazinones

De Francesco, Laura. 2006. Towards the total synthesis of a potential M1 muscarinic agonist and study on regioselective cyclisations for the synthesis of highly substituted piperazinones. PhD Thesis, Cardiff University.

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Abstract

The preparation of piperazinones, which are important pharmacophores, is reviewed in the introduction. This thesis provides an elucidation of the cyclisation mechanisms involving chiral secondary 1,2-diamines both with haloacetates and with 1,2-dicarbonyl compounds. The work on selective cyclisations consists of mainly three parts: (i) Regioselective preparation of N.W-disubstituted 5- and 6-piperazinones with elucidation of the cyclisation mechanism using D2O and C label (ii) Regioselective preparation of W-dibenzyl 3,6- and 3,5-disubstituted piperazinones using methyl a-bromophenylacetate, methyl 2-bromopropionate, methylglyoxal, phenylglyoxal and benzil (iii) Selective preparation of N-acetates of 5-substituted piperazinones by hydrogenolysis and intramolecular cyclisation in the same reaction pot starting from substituted dibenzyl 1,2-diaminoacetates. Additionally, the total synthesis of a potential Mi muscarinic agonist for treatment of Alzheimer's disease was planned and almost completely carried out. The multistep sequence presented two challenging steps: regioselective preparation of a chiral piperazinone successfully achieved with the haloacetate cyclisation described above Birch reduction of a lactam to an aminol, in presence of an amide, which acts as a nucleophile and cyclises to give a 1,1-aminoamide.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
ISBN: 9781303205231
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Feb 2016 23:15
URI: http://orca-mwe.cf.ac.uk/id/eprint/56087

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