On the stereochemistry and medicinal chemistry of 6-substituted tropanes.

  • Leung Sheh

Student thesis: Doctoral ThesisPhD


This thesis is composed of four parts, preceded by a brief, general introduction to the chemistry of some well-known tropanes. In Part 1, the structure-activity relationships of pethidine-related analgesics are reviewed. The synthesis and chemistry of a novel series of narcotic analgesics based on 6-aryltropane have been reported. The analgesic activities of these drugs are reported and discussed. The chemical and biochemical aspects of the opiate receptor are also considered. The successful resolution of (+)-6[beta]-tropanol (51) into its enantiomers in this work has encouraged the synthesis of an enantiomeric pair of acetylcholine-like analogues. In Part 2, the chemical pharmacology of acetylcholine and its mimics is reviewed. General methods of resolution and the resolution of (+)-6[beta]-tropanol are described. The pharmacology of these optically-active acetylcholine mimics, together with some racemic acetylcholine mimics based on (+)-6[alpha]-tropanol (106), are reported and discussed. A model for the muscarinic receptor is proposed. Stereochemical studies on certain reductions of 6-phenyl-6-tropene (107) are reported in Part 3. Hofmann elimination and deuterium labelling experiments are described which establish the structure of the major product of lithium aluminium hydride reduction of 6-phenyl-6-tropene. This major product (123) is considered to arise by a mechanism proposed in Scheme 36. The cis-stereospecific Hofmann elimination of 6[alpha]-phenyltropane methiodide is also reported and discussed. Part 4 describes the 1H and 13C NMR studies of a series of 6-substituted tropanes synthesized by the author. Various stereo-chemical aspects of 6-substituted tropanes have been investigated, including configurational determination of the 6-substituents, and N-substituent. The qualitative determination of enantiomeric purity of resolved 6[beta]-tropanols by 1H and 13C NMR spectroscopy using a chiral shift reagent is described. Some new observations in shift parameters induced by chiral lanthanide reagent are reported.
Date of Award1981
Original languageEnglish
Awarding Institution
  • University of Bath

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