The functionalisation of 2-azanorbornanes and approaches to novel epidatidine analogues
thesisposted on 15.12.2014, 10:35 by Richard White
Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane) is an alkaloid found on the skin of the Ecuadorian poison-dart frog Epipedobates tricolor. It has extremely high affinity for nicotinic acetylcholine receptors and is a potent analgesic but it can not be used therapeutically as it is highly toxic. A wide range of epibatidine analogues and isomers has been produced in order to identify compounds with medicinal potential and to help elucidate the nicotinic pharmacophore. This thesis describes synthetic routes to novel epibatidine analogues, in particular, derivatives based on the 2-azabicyclo[2.2.1]heptane (2-azanorbornane) molecular framework. A general method for the synthesis of 7-functionalised 2-azanorbornanes has been devised. Bromination of N-benzyl-2-azanorborn-5-ene and treatment of the resulting tricyclic salt with hydride occurs with skeletal rearrangement to give N-benzyl-7-bromo-2-azanorbornane. Nucleophilic substitution reactions of this compound were found to occur with retention of configuration, consistent with neighbouring group participation of the bicyclic nitrogen lone pair. Heterocycles have been introduced at the 7-position of 2-azanorbornanes and manipulation of the stereochemistry at this position gave the novel epibatidine analogues isoepiboxidine and isoepibatidine. Both have very high affinity for nicotinic receptors; isoepidatidine is equipotent with epibatidine. The synthesis of fluorinated 2-azanorbornanes was investigated leading to the synthesis of a fluorinated isoepibatidine molecule ( syn-7-(6-chloro-pyridin-3-yl)-exo-6-fluoro-2-azabicyclo-[2.2.1]heptane). In addition, a novel rearrangement was discovered which results in functionalisation of the bridgehead position (Cl) of 2-azanorbornanes.