Synthesis of thromboxane A2 analogues.

The aim of the project was to synthesize novel thromboxane A2 analogues which would be potential thromboxane A2 antagonists. Three thromboxane A2 analogues were synthesized, methyl 7-[-5-(3-hydroxy-1-(E)-octenyl)-2-methylbicyclo[3.3.1]non-2-en-9-yl]-[syn]-(+/-)-5-(Z)-heptenoate, methyl 7-[-5-(hydroxy-1-(E)-octenyl)-2,2-dimethylbicyclo[3.3.1]non-9-yl]-[syn]-(-+)-5-(Z)-heptenoate and methyl 7-[-5-(3-hydroxy-l-(E)-octenyl)-2,2-dimethylbicyclo[3.2.1]oct-8-yl]-[syn]-(-)-(Z)-heptenoate from a common functionalised bicycloalkane. During the synthesis of these functionalised bicycloalkanes several unexpected products were observed. These included the formation of methyl 5-methyl-6-oxa-7-oxobicyclo[3.2.2]-nonanecarboxylate during the sulphuric acid catalysed cyclisation of methyl 2-oxo-l-(3'-oxobutyl)cyclopentane-carboxylate which was contrary to the work of W G Dauben and J W McFarland and the formation of ethyl 4-methyl-bicyclo[4.4.0]dec-4,6-dienecarboxylate from the treatment of ethyl 1-(3'-methylbut-2'-ene)-2oxocyclohexanecarboxylate with stannic chloride. Another interesting rearrangement reaction was the formation of methyl 2-methine-5-oxohexanoate as well as methyl 4-oxo-3-(3'-oxobutyl)-3-tetrahydrothio-phenecarboxylate during the Michael reaction of methyl vinyl ketone with methyl 4-oxo-3-tetrahydrothiophene-carboxylate. Methyl 2-(2-methylbut-3'-en-2-yl)-3-oxo-tetrahydrothiophenecarboxylate was also an unexpected product from the alkylation of methyl 3-oxo-tetrahydrothio-phenecarboxylate with l-bromo-3-methylbut-2-ene.