Doctor of Philosophy
Department of Chemistry
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
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.