Synthesis of nucleoside analogues.

ARMSTRONG, Peter L. (1993). Synthesis of nucleoside analogues. Doctoral, Sheffield Hallam University (United Kingdom)..

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Abstract

A basic introduction to a variety of nucleoside derivatives is described along with a selection of recent syntheses of the said compounds. Initial studies on the synthesis of the key furan based intermediate N-2,5-dihydro-5-(2,2-dimethyl-1,3-dioxolan-4-yl)furanyl trichloroacetamide which when hydrolysed to the free amine would yield a simple route to a variety of nucleoside derivatives. The synthesis was performed via the use of an aza-Claisen rearrangement on 1,4-anhydro-2-deoxy-5,6-O-isopropylidene-D-arabino-hex-1-enitol employing trichloroacetonitrile. This reaction proceeded to the desired amide in a facile manner, with excellent yield without the need for thermal rearrangement of the intermediate imidate. Initial efforts to hydrolyse this compound to the free amine proved inconclusive and this reaction was still being optimised at the close of the work.The Claisen rearrangement of 1,4-anhydro-2-deoxy-5,6-o-isopropylidene-D-arabino-hex-1-enitol employing dimethylacetamide dimethylacetal proceeded successfully to produce an amide useful as an intermediate to the synthesis of furan C-nucleosides. The key carbocyclic allylic alcohol intermediate 5-methoxymethylcyclopent-2-enol was synthesized via a six step synthesis in racemic form from the ethylene-acetal of 2-methoxymethylcyclopentanone but attempts at deprotection of the methyl ether proved unsuccessful. Attempts to repeat this synthesis using protecting groups other than methyl ether failed at an early stage. The aza-Claisen rearrangement of this allylic alcohol with trichloroacetonitrile proceeded in good yield to cis-N-methoxymethylcyclopent-2-enyltrichloroacetamide. This amide was easily acid hydrolysed to the amine hydrochloride which was subsequently used to synthesize a variety of purine based nucleosides. 5-Methoxymethylcyclopent-2-enol underwent the Claisen rearrangement with both dimethylacetamide dimethylacetal and triethylorthoacetate with the latters product showing promise as a useful intermediate to carbocylic C-nucleosides.

Item Type: Thesis (Doctoral)
Additional Information: Thesis (Ph.D.)--Sheffield Hallam University (United Kingdom), 1993.
Research Institute, Centre or Group: Sheffield Hallam Doctoral Theses
Depositing User: EPrints Services
Date Deposited: 10 Apr 2018 17:18
Last Modified: 25 Apr 2018 10:57
URI: http://shura.shu.ac.uk/id/eprint/19287

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