Synthesis of Analogues of Epibatidine based on the 2-azabicyclo[2.2.1]heptane system
thesisposted on 05.06.2018, 11:23 authored by Huda Ismail Al-Rubaye
Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane) is an alkaloid isolated from the skin of the Ecuadorian poison frog. It has been known since 1992 and has high binding affinity for nicotinic acetylcholine receptors. Many studies have reported epibatidine to possess analgesic properties, but it is also toxic even in low doses, thus, it cannot be used therapeutically. A wide range of epibatidine analogues have been studied in the hope of reducing their toxicity, and hence exploiting their therapeutic potential A general method for the synthesis of anti-7-functionalised 2-benzyl-2-azabicyclo[2.2.1]heptane has been employed. Aza Diels-Alder reaction was used successfully to construct the rigid protected amine 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene skeleton. Bromination of 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene gives a reactive tricyclic salt, which in turn undergoes skeletal rearrangement with hydrid to obtain anti-7-bromo-2-benzyl-2-azabicyclo[2.2.1]heptane. Nucleophilic substitution reaction at C-7 of this compound found to be occur with retention of configuration, consistent with neighbouring group participation of the bicyclic nitrogen lone pair. An oxidation-reduction strategy facilitated the epimerisation at the C-7 of 2-azabicyclo[2.2.1]heptane, heterocycles have been introduced at this position to give the ether linkage nicotinic receptor ligands with general structure 7-(pyridyloxy)-2-benzyl-2-azabicyclo[2.2.1]heptane. Mitsunobu chemistry has been utilised to synthesis a range of pyridyl ether compounds. Methylisoxazole heterocycle has also been synthesised and incorporated to open the way to some analogues. The synthesis of fluorinated analogues of 2-azabicyclo[2.2.1]heptane has been investigated using nucleophilic fluorinating agent, diethylaminosulphur trifluoride, DAST. Moreover, fluorination of all alcohols is consistent with SN2 attack, whilst fluorination of ketones gave geminal difluorides with the 6-oxo isomer being assisted by neighbouring group participation. A range of different 5- and 6-chloropyridyl-substituted-2-azabicyclo[2.2.1]heptane derivatives have been constructed. The 5- and 6-chloropyridyl derivatives were synthesised via nucleophilic attack of lithiated-chloropyridine onto the appropriate azabicyclic ketone. Dehydration of the adduct gave an olefin. 1H, 13C and 19F NMR spectroscopy was used to characterise these compounds.