This thesis describes the syntheses of some polyfunctionalised cyclopentanes via intramolecular aldol condensations of sugar δ-lactone precursors. The known azido carbpcycle (1S,2R,3S,4R,5R)-methyl [5-azido-1,2,3,4- tetrahydrpxy-2,3-O-isopropylidene-cyclopentane] carboxylate was prepared from 2- deoxy-2-iodo-3,4:6,7-di-O-isopropylidene-D-glycero-D-talo-heptono-1,5-lactone in five steps. The key reaction was a base-induced intramolecular aldol cyclisation of a 5- iodo-formyl-2,6-lactone. Borohydride reduction of the methyl ester gave an azido triol. Deprotection followed by reduction of the azide functionality produced an amino pentol. The analogous tetrahydroxy β-amino acid was synthesised from the azido carbocycle in three steps. The inhibitory activity of the amino pentol against human liver glycosidases is reported. Two azido bicyclic lactones, (1R,4R,5R,6R,7R)-4-azido-5,6,7-trihydroxy-5,6-0- isopropylidene-2-oxa-bicyclo[2.2.1]heptan-3-one and (1S,4S,5R,6R,7R)-4-azido- 5,6,7-trmydroxy-5,6-O-isopropydilene-2-oxa-bicyclo[2.2.1]heptan-3-one, were prepared from 3,4:6,7-di-O<./em>-isopropylidene-D-glycero-D-talo-heptono-1,5-lactone in five steps. The (1R,4R,5R,6R,7<em.R)-compound was further elaborated to give an amino pentol via a series of borohydride reduction / deprotection / catalytic hydrogenation. A novel carbocyclic spirohydantoin was synthesised by two alternative routes. The second route also provided access to an N'-phenyl spirohydantoin. The inhibitory activities of the amino pentol and the spirohydantoin against human liver glycosidases are reported. The azido bicyclic lactone triol (1R,4S,5R,6R,7R)-4-azido-5,6,7-trihydroxy-2-oxabicyclo[ 2.2.1]heptan-3-one underwent reduction of the azide functionality with concomitant epimerisation to give the (5S)-epimeric amine. The structure of this material was confirmed by X-ray diffraction analysis of a crystalline derivative. Treatment of the azido triol with base under non-aqueous conditions resulted in a retroaldol reaction to give the (5S)-epimeric azide, the relative configuration of which was determined by single crystal X-ray analysis. A third ketal protected azido bicyclic lactone was prepared via a base-induced retro-aldol epimerisation. Five tetrahydroxycyclopentane α-amino acids, including a pair of enantiomers, were synthesised from the azido bicyclic lactones. The structures of two of the α-amino acids were established by X-ray crystallographic analysis, whilst the enantiomeric compounds were identified using circular dichroism spectrometry. The diketal protected (2R,3R,4R,5R)-tetrahydroxy-cyclopentane α-amino acid was incorporated into six oligopeptides. Peptide coupling at the C-terminus of the carbocyclic amino acid was carried out using two amino acid tert-butyl esters. Chain extension at the N-terminus was achieved by reaction with N-benzyloxycarbonyl protected amino acids in the presence of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride as the carbodiimide reagent. Complete deprotection of a tetrapeptide is described.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:296923 |
| Date | January 1995 |
| Creators | Hui, Andrew W. H. |
| Contributors | Fleet, G. W. H. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:c78234b5-92e5-4dd4-8a94-94201f1471b5 |
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