Synthetic Approaches to Thiatropanes and Related Homologues

The synthesis of 8-thiabicyclo[3.2.1]octanes, as structural mimics of the tropane alkaloids, was undertaken and, in particular, the feasibility of functional group modification at certain ring positions was investigated. In Chapter 1, functional group changes were effected at C(6) and C(7) of 6,7-dichloro-8-thiabicyclo[3.2.1]octane (107) which reacted with weaker nucleophiles, such as water, alcohols, catechol, 1,2-diaminobenzene, ethanoic acid and ethanoate ion, forming substitution products with stereochemical retention, replacements generally being faster in the presence of zinc metal. Substitution did not proceed at all with the stronger nucleophiles AlH4 , OR, I, or Et3N. In presence of zinc, (107) underwent elimination with CN-, 1,2-diaminoethane and glycine for- ming (114). With phenol/Zn, both substitution and elimiantion took place to yield (134). (107) underwent a novel stereospe- cific oxidation-dichlorination with NaOH forming (126). Similar reactivity was observed for the homologue, 7,8-dichloro-9-thiabicyclo[4.2.1]nonane (111), the reactivity of which is discussed in Chapter 2. (111) however, failed to react with NaOH. In Chapter 3, the addition of SCl2 to cyclohepta-3,5-dienol (108) was investigated, as a synthetic approach to C(3)-oxygenated thiatropanes. The adduct (152) was formed as a single diaste-reoisomer but only in modest yield. (152) underwent esterifi-cation with tiglic acid (or acid chloride) in low yield forming (156), as a sulphur analogue of the antiparkinson drug tropigline (14). Like (107) and (111), (152) underwent elimination with 1,2-diaminoethane/Zn forming (160) but (152) failed to react with LiAlH4 or with NaOH. Also discussed in Chapter 3, the attempts to place a methoxycarbonyl group at C(2) of the keto-thioether (110) via its enolate or enamines with pyrrolidine and morpholine were unsuccessful. (110) appears to be stereochemically hindered to reaction with these secondary amines but does form an oxine (162). The attempted methylation of the thioether bridges of (107) and (110) with CH3I in neutral conditions was also unsuccessful