New synthetic methods in an approach to huperzine A and B.
thesisposted on 19.11.2015 by Susan E. Booth
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The aim of the research was to develop a flexible, stereocontrolled route to huperzine A and B and other lycopodium alkaloids. One of the main objectives was to investigate whether intramolecular radical cyclisation reactions on to carbon-nitrogen double bonds might provide a new method for the synthesis of key intermediates in the total synthesis. To this end the intramolecular cyclisation reactions of vinyl and aryl radicals on to oxime ethers have been explored and these reactions have been used to prepare a number of useful bicyclic and tricyclic carbocyclic compounds and related heterocyclic compounds in good yields. This represents essentially new synthetic methodology as prior to this work there was only one reported example of the use of an oxime ether as a radical trap. The best reagent for these reactions utilising vinyl and aryl halide precursors was found to be tributyltin hydride. Preliminary attempts to carry out tandem radical cyclisation reactions incorporating oxime ethers have not, so far, been successful on the model systems investigated. This new synthetic strategy has been used to carry out one-carbon ring expansions of five-membered cyclic oxime ethers similar to those reported recently for carbonyl compounds. However, attempts to extend this ring expansion to the two-carbon system resulted only in cyclisation to give a bicyclic compound, rather than ring expansion. Attempts to cleave the N-O bonds of some of the hydroxylamines resulting from these cyclisation reactions proved to be unsuccessful using SmI2, Zn and acetic acid or aluminium amalgam. Attempted cleavage of the N-O alkyl bond of a hydroxylamine group adjacent to an aromatic ring using lithium aluminium hydride resulted in a novel ring expansion reaction, which may occur by an unusual electron transfer process to give radical intermediates.