Asymmetric synthesis of pharmaceutically important lactones and cyclic ketones
Connolly, Sophie
(2022)
Asymmetric synthesis of pharmaceutically important lactones and cyclic ketones.
Master of Science thesis, Dublin City University.
The work in this thesis is divided into three parts: (A) Investigation of the synthesis of lactones from sulfoxonium salts; (B) Investigation of the synthesis of cyclohexanones from donor-acceptor cyclobutanes and ketenes; (C) The synthesis of cyclopentanones from donor-acceptor cyclopropanes and ketenes.
A synthetic route to formation of a delta-lactone from cyclopropylamino sulfoxonium salts was initially explored. Multiple reactant partners (e.g. lithium enediolate, lithium enolates, ketene) were tested and although lactone formation was not achieved, ring-opening of the cyclopropyl salt was observed under much milder conditions than previous literature findings (0°C to RT vs >65°C).
Research into the synthesis of monocyclic gamma-lactones from vinyl sulfoxonium salts was also pursued. This work was inspired by previous work from the group and aimed to introduce new substitution patterns on the gamma-lactone ring. Both the phenyl-substituted vinyl sulfoxonium salt and the isopropyl-substituted vinyl sulfoxonium salt were investigated for this reaction. Carboxylic acids such as dichloroacetic acid, α-methoxyphenylacetic acid, methoxyacetic acid, benzyloxyacetic acid, 4-methyl-2-phenylpentanoic acid and 4-methylvaleric acid were tested as enediolate precursors. Different bases such as LDA, NaHDMS and n-Butyllithium were tested to verify their ability to deprotonate the carboxylic acid to enable gamma-lactone formation to occur.
Other significant research was carried out on the development of a synthetic route to cyclohexanones from donor-acceptor cyclobutanes and ketenes. The reactant partners for this reaction have been synthesized in good yields, the phenyl-substituted donor-acceptor cyclobutane being synthesized in 54% yield, and its precursor 1,3-dibromopropylbenzene synthesized in yields of up to 82%. A variety of Lewis acids including InBr3, AlCl3, In(OTf)3, Sc(OTf)3, Yb(OTf)3 and GaCl3 were explored for their effectiveness in promoting the [4+2]-cycloaddition reaction.
Most significantly, through the reaction of a donor-acceptor cyclopropane and a ketene generated in-situ from propionyl chloride a range of substituted cyclopentanones were also synthesized in yields ranging between 60-78%.