Synthetic and Biosynthetic Studies on Sulphur-Containing Heterocycles

Lewis, Robert Andrew (1989) Synthetic and Biosynthetic Studies on Sulphur-Containing Heterocycles. PhD thesis, University of Glasgow.

Abstract

This thesis records an investigation into synthetic and biological aspects of sulphur chemistry. A study of thioaldehyde S-oxides (sulphines), a family of labile, dienophilic heterocumulenes, RCH=S=0, was undertaken. The feasibility of generating the reactive (Z)-and (E)-isomers of ethyl thioxoacetate S-oxide, EtO2C. CHSO, by retro-Diels-Alder reactions was successfully demonstrated for the first time. The required precursors were obtained by S-oxidation of the cycloadducts formed from the thioaldehyde, EtO2C. CHS, and anthracene, cyclopentadiene, and the alkaloid thebaine. The (E)-sulphine was released from its anthracene cycloadduct at 60 C and from its cyclopentadiene or thebaine cycloadducts at 80 C. Higher temperatures were necessary to generate the (Z)-sulphine; 80 C for the anthracene and 111 C for the cyclopentadiene cycloadduct. At the highest temperature (111C) signs of Z-E isomerism were observed. However, the (E)-sulphine, formed at 60-80 C, was trapped by conjugated dienes to give trans-sulphoxides exclusively. When the (Z)- or (E)- sulphine was trapped with cyclopentadiene, the resulting cycloadducts were exo-S-oxides. Cycloadducts of 2,3-dimethylbuta-1,3-diene were transformed via a Pummerer rearrangement to a thiapyran which, on oxidation with iodine yielded a novel thiopyrylium salt. The biological studies centred on the biosynthesis of gliotoxin, a member of the sulphur containing dioxopiperazine metabolites produced by the fungus Gliocladium virens. Later steps in the biosynthetic pathway involve ring closure between the sulphur bridged dioxopiperazine and a proposed arene oxide, which arises from the known precursor cyclo-(L-Phe-L-Ser). A series of analogues, cyclo-(L-Ala-L-Fluoro-Phe) , substituted with fluorine at the o , m, and p positions were prepared and fed to the fungus, both unlabelled and labelled with C. Their metabolism was followed by 19F n. m. r. spectroscopy and radio chromatography. The o- and p fluorinated analogues were transformed into a range of fluorinated metabolites, but the m-fluorinated analogue was not. A stepwise, mechanism for arene oxide formation is proposed to explain these results.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1989
• Depositing User: Enlighten Team
• Unique ID: glathesis:1989-78000
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 30 Jan 2020 15:44
• Last Modified: 30 Jan 2020 15:44
• URI: https://theses.gla.ac.uk/id/eprint/78000