School of Chemistry - Theses

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    Towards the synthesis of the emestrin family of natural products
    Fisher, Brendan ( 2018)
    A Cope rearrangement of a vinyl pyrrole epoxide (397) was utilised to form the dihydrooxepino[4,3-b]pyrrole core (398) of the emestrin family of natural products which involved the first examples of the dearomatisation of pyrrole in this type of rearrangement. It was found that an electron withdrawing ester substituent on the C2 position of the epoxide was essential for the [3,3]-rearrangement to occur. The vinyl pyrrole epoxides were synthesised in an efficient manner by a vinylogous Darzens reaction. Density functional calculations showed lower transition state energies for Cope rearrangements of epoxides with C2 esters when compared to the unsubstituted substrates which agreed with the observed experimental results. Silyl substituted vinyl bromide esters also participated in the Darzens reactions to give the desired vinyl pyrrole epoxides in good to excellent yields. Only the triethoxysilyl vinyl epoxide 313c underwent Cope rearrangement to provide the fully substituted emestrin core dihydrooxepine. The anion derived from an aryl bromosulfone did not give the Darzens product but underwent a previously unobserved stereoselective trimerization to afford the cyclohexene 343 as a single diastereoisomer. A mechanistic rationale involving SN2’ additions, [3,3]-Cope rearrangements and a stereoselective intramolecular conjugate addition was proposed and this was supported by density functional theory (DFT) calculations. A four-step total synthesis of biaryl ether natural product violaceic acid (11) is described. The steps include an SNAr reaction to afford the biaryl ether 136, tin chloride-mediated chemoselective reduction of the nitro group to amine 135. A Cu-mediated Sandmeyer reaction of 135 gave violaceic acid methyl ester 374 which is hydrolysed to give pure violaceic acid 11. An improved synthesis of the known biaryl iodide 119 is also described via a Sandmeyer reaction of amine 135.