Stereochemical Aspects of the Biosynthesis of Some Bislactone Antibiotics

Khelifi, Djamel Eddine (1988) Stereochemical Aspects of the Biosynthesis of Some Bislactone Antibiotics. MSc(R) thesis, University of Glasgow.

Abstract

Part 1 is concerned with biosynthetic studies on the alkylcitric acid metabolites of the fungi P. decumbens and P. canadense using deuterium labelled acetate, succinate and fumarate, with particular regard to the terminal methylene hydrogens. In the antibiotic ethisolide obtained from P. decumbens, label from acetate appeared as expected mainly in the hexanoic acid derived derived part of the molecule i.e. mainly in the methyl group (C-6) and a smaller amount at (C-4). There was however, consistently, a much smaller amount in the oxaloacetate derived part of the molecule in both terminal methylene positions. Since acetate would be expected to give mono-deutero oxaloacetate by the Krebs Cycle via succinate and fumarate, one explanation would be operation of the glyoxylate cycle to afford a dideutero-oxaloacetate. However, this was ruled out by feedings with d4-succinate and d2-fumarate which gave ethisolide and the minor metabolite ethisic acid, with deuterium enrichment in both terminal methylene hydrogens. Another significant result was that label from d4 succinate appeared in only one of the two terminal methylene positions of canadensic acid. Since the latter has an unrearranged skeleton, these results seem to reflect the mechanism of the rearrangement involved in the biosynthesis of ethisolide and ethisic acid. The discovery in the present work of a method of selective esterification of the minor acidic broth metabolite in the presence of large amounts of citric acid has led to the isolation of the key intermediate butylitaconic acid as its methyl ester for the first time and opens the way to its biosynthetic investigation. Part II deals with the attempted development of a shorter and cheaper synthesis of deuterated alkylitaconic acids. A number of potentially useful Meldrum's acid derivatives were obtained using dry catalysed condensation methods. The alkylidene compound obtained from ethyl pyruvate, rather than deuterium exchange or alkylation reactions underwent undesired Michael addition reactions (with Meldrum's acid or iteself). An attempt to block these side reactions using PhSH gave a vinyl sulphide byproduct, whose formation and possible uses were studied. The key biosynthetic intermediate butylitaconic acid has been prepared and converted to its dimethyl ester under a variety of conditions. Hydrolysis was achieved but attempts to convert the ester to its alpha-hydroxy analogue (isolated from some fermentations) using several conditions have been unsuccessful. On the other hand bromination-dehydrobromination of the same ester afforded a potentially useful unsaturated compound together with the allylic bromides which could open the way to alkylaconitic acids.

• Item Type: Thesis (MSc(R))
• Qualification Level: Masters
• Keywords: Pharmacology
• Date of Award: 1988
• Depositing User: Enlighten Team
• Unique ID: glathesis:1988-77813
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jan 2020 11:53
• Last Modified: 14 Jan 2020 11:53
• URI: https://theses.gla.ac.uk/id/eprint/77813