Nucleoside and nucleotide analogues containing fluorine

Abstract

The work contained in this thesis is divided into four sections detailing the formation of (diethoxyphosphinyl)difluoromethylene substituted cycloalkanes and alkenes and their chemistry, as well as the syntheses of purine and pyrimidine substituted polyfluoroethers:(i) The methodology for the introduction of the (diethoxyphosphinyl)difluoromethylene group was studied and extended, with specific reference to cyclic systems. The group was successfully introduced into cyclic alkenes with (diethoxyphosphinyl)difluoro- methylene zinc bromide and saturated systems with (diethoxyphosphinyl)difluoromethyl lithium. The organolithium reagent was also shown to be capable of ring opening epoxides to yield alcohols ;(ii) The (diethoxyphosphinyl)difluoromethylene substituted cyclohexene derivative was further functionalised in a four step process to a new class of adenine and guanine based nucleotide analogues. Model studies were carried out on the (diethoxyphosphinyl)- difluoromethylene substituted cyclohexene derivative with a variety of reagents to introduce functionality at the double bond;(iii) The radical addition of (diethoxyphosphinyl)bromodifluoromethane and (diethoxyphosphinyl)difluoroiodomethane to cycloalkenes using ultraviolet photolysis and gamma-ray initiation were successfully carried out, thus opening up a new route into (diethoxyphosphinyl)difluoromethylene substituted cycloalkanes;(iv) The synthesis of purine and pyrimidine nucleoside analogues is described via the coupling of 2-amino-6-chloropurine, 6-chloropurine, silylated 5-fluorouracil and silylated uracil to various α-haloethers. The α-haloethers having previously been synthesised by radical chlorination of both cyclic and acyclic polyfluoroethers.