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Title: A synthetic study of the tropane and homotropane ring systems
Author: Justice, David E.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1995
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1,4-Functionalisation of cyclohepta-l,3-diene using a nitroso-cycloaddition strategy provided precursors which were converted into the N-methyl-8-azabicyclo- [3.2.1]octane (tropane) ring system. Cycloocta-1,3-diene was used as the starting material to prepare precursors to the N-methyl-9-azabicyclo[4.2.1]nonane (homo-tropane) ring system. Homotropane has been constructed, either with or without a bridgehead substituent, using mercury-mediated cyclisation of nitrogen onto an sp2 carbon centre. The versatile N-alkoxycarbonyl protecting group was employed to synthesise the corresponding norhomotropanes. This strategy was also used to prepare the 1-methyl-homotrop-7-ene analogue which could be epoxidised stereoselectively to yield the exo-epoxy derivative. An efficient synthesis of homotropan-l-ol and norhomotropan-l-ol is described. Using variable-temperature and NMR spectroscopy these bicyclic hemi- aminals were shown to exist in tautomeric equilibria with monocyclic amino-ketones. A range of derivatives were made; it was found that the incorporation of a double bond or an epoxide group into the 2-carbon bridge of the homotropan-l-ol structure altered the position of equilibrium. Difficulties were encountered in making quantitative measurements for some tautomer ratios and in these cases qualitative estimates were made. An identical synthetic strategy was used to make the homologous tropan-1-ols. This work includes a five-step synthesis of the tropane alkaloid physoperuvine (N-methyl-8-azabicyclo[3.2.1]octan-1-ol) in racemic form and in an overall yield of 79%. Norphysoperuvine (8-azabicyclo[3.2.1]octan-1-ol), unsaturated, and epoxide derivatives were also prepared and a study of their tautomerism with amino-ketones was investigated. A steroselective method of introducing an epoxide group into the 2-carbon bridge of homotropane was devised. Homotrop-7-ene, protected with an N-alkoxycarbonyl group, was prepared by intramolecular displacement at an sp3 carbon centre by nitrogen. Epoxidation then gave the exo-epoxide but the overall yield was low because of difficulties associated with the cyclisation step. A more attractive procedure was developed which involved epoxidation of an allylic alcohol prior to cyclisation and provided access to both exo- and endo-epoxides in improved yields. Final removal of the N-alkoxycarbonyl protecting group at the end of the synthesis showed a substantial difference in epoxide stablity. The epoxide group of the endo-isomer was ring-opened by both hydride and hydrogenolysis reduction, whereas the exo-epoxide was suprisingly more resistant to attack. The homologous epoxides of the tropane series were prepared using a similar methodology. Again, the exo-epoxide was substantially more stable to reduction than the endo-epoxide. Introduction of oxygen functionality at the C3 position of the tropane ring system was developed using cyclohepta-3,5-dienol in the initial nitroso-cycloaddition reaction. Combining this with the established approach to epoxy-tropanes led to the synthesis of the alkaloid scopine. The versatility of this procedure is demonstrated with the preparation of pseudoscopine and novel nor-derivatives.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available