Year
2000
Degree Name
Doctor of Philosophy
Department
Department of Chemistry
Recommended Citation
Monteith, Alicia Anne, Ring-modified analogues of castanospermine: towards synthesis of novel glucosidase inhibitors, Doctor of Philosophy thesis, Department of Chemistry, University of Wollongong, 2000. https://ro.uow.edu.au/theses/1170
Abstract
The general aim of this work was to synthesise novel B-ring-modified analogues of castanospermine with the longer term view of creating selective glucosidase inhibitors.
A minor aspect was to begin the synthesis of casuarine 114 from castanospermine 1. Various approaches were tried to introduce a leaving group at the 1-position of castanospermine 1, with a view to elimination across the C1-C2 bond, although without success.
All B-ring-modifying studies required the synthesis of the hydroxyallyl piperidine 115. Synthesis of the TBDMS and TMS protected allylpiperidines 155 and 156 from castanospermine 1 was achieved in 6 steps and with 49% and 46% overall yields respectively. A model tetrahydroisoquinoline intermediate 116, containing the principal amine and alkene functional groups for subsequent reactions, was prepared from 1,2,3,4-tetrahydroisoquinoline in 51% over 2 steps.
Ring closing metathesis studies with the tetrahydroisoquinoline system allowed for formation of the benz-fused quinolizine 177 and the azepine-fused isoquinoline derivative 178. Attempts to cyclise related amide dienes using this reaction were unsuccessful. Application of the ring closing metathesis reaction to the castanospermine-derived system produced the novel trimethoxyhydroxy quinolizine 117 with a synthetically useful alkene moiety in the ring-expanded B-ring.
Free-radical cyclisation of allyl o-bromoamides was first investigated with the model system to produce exclusively the 5-exo-trig cyclised product as a mixture of diastereomers. Separation of these diastereomers and debenzoylation led to the benzfused tropane ring system 200, constituting a short and convenient approach to this ring system. Application of this reaction to the castanospermine derived system was carried out with both the hydroxy amide 201 and the TBDMS-protected amide 202. Cyclisation with these derivatives gave mixtures of the 5-exo 204 and 6-endo 205 products, with the 5-exo favoured for 201, although at the expense of diastereoselectivity, and 6-endo favoured for 202. Demethylation of 204 has led to isolation of a mixture of di-demethylated products, representative of a new range of poly-oxygenated tropane derivatives which could act as possible glucosidase enzyme inhibitors.
Synthesis of several 1,3-dipoles, and their attempted subsequent intramolecular cyclisation, was undertaken on the model 1-allyl-tetrahydroisoquinoline-based system. Isolation of several nitrones and oximes was successful but no cycloaddition could be observed.
A novel pyrido-fused 1,4-thiazinone 243 was also prepared from the castanosperminederived carbamate 153.
Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.