Studies on the Rearrangement in the Biosynthesis of Some Bislactone Antibiotics

Khelifi, Djamel Eddine (1993) Studies on the Rearrangement in the Biosynthesis of Some Bislactone Antibiotics. PhD thesis, University of Glasgow.

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Part I of this work is concerned with detailed studies on the biosynthesis of the bislactone antibiotics ethisolide 1 and avenaciolide 2 produced by the fungi Penicillium decumbens and Aspergillus avenaceus respectively. The alkyl-?-methyleneglutaric acid skeleton of these is thought to arise from an alkylcitric acid via an alkylitaconic acid, since the latter have previously been shown to act as efficient precursors of the antibiotics. Direct evidence that their skeletons are assembled by condensation of a preformed fatty acid with oxaloacetate has been provided by intact incorporation of deuterium labelled fatty acids. These results depended on their being clearly different from the pattern found upon feeding d3-acetate, where enrichment was mainly in the fatty acid derived part of the molecule. In other feedings with d4-succinate and d2-fumarate ethisolide 1 was obtained with enrichment mainly in the two terminal methylene positions. In several experiments with d2-fumarate no enrichment of avenaciolide 2 was observed, possibly due to inhibition of growth since [14C]-fumarate has previously shown good incorporation. However d4-succinate gave avenaciolide again showing enrichment mainly in both terminal methylene positions. This is surprising since succinate and fumarate would be incorporated via [3S, 3d1]-oxaloacetate and hence via a [d1]-alkylitaconic acid. In order to establish whether the loss of integrity of the deuterium label occurs during formation of the alkylitaconic acid or in the subsequent rearrangement, it was hoped to examine d4-succinate incorporation into relevant alkylitaconic acid derivatives if these could be produced in sufficient quantity by the fungi under study. Extensive studies based on analytical HPLC led to the detection of n-butylitaconic acid in P. decumbens but the quantity produced did not allow analysis of its deuterium content when d4-succinate had been fed. Feeding/trapping experiments also indicated that n-decylitaconic acid was not produced in detectable quantities by A. avenaceus when fed with d4-succinate. A plausible mechanism for the rearrangement of the alkylitaconic acids to beta-alkyl-alpha-methyleneglutaric acids involves a cyclopropylmethyl radical e.g. 79 with consequent loss of integrity of the two hydrogens of the methylene radical grouping. Part II of this work deals with the synthesis of bromomethylcyclopropane dicarboxylic acid derivatives which could act as precursors to such radicals. One approach aimed at 1,3-dehydrohalogenation of the dibromo derivative 113 prepared from the dimethyl ester of alpha-methylene-beta-propylglutaric acid. A number of nucleophilic bases simply debrominated the ester and treatment with DBU resulted in 1,2-dehydrohalogenation to give a vinyl bromide 114. Treatment with NaOMe however afforded three products, the vinyl methyl ether 115 corresponding to the above vinyl bromide (52 %) together with an inseparable mixture (48%) containing roughly equal amounts of the vinyl bromide 114 and the desired bromomethylcyclopropane 107. In a different approach cyclopropane derivatives were prepared via addition of diazoalkanes to appropriate alkenes. Dimethyl bromomesaconate 118 itself appeared to be unsuitable affording complex mixtures, but the corresponding acetoxy compound 119 reacted smoothly with diazomethane or diazobutane each to give a single pyrazoline which lost N2 upon photolysis to give acetoxymethylcyclopropanes e.g. 121 and 129. It was aimed to convert these to bromomethyl compounds via the corresponding hydroxymethyl compounds. This involved selective acetate hydrolysis but facile lactonisation occurred involving a cis methoxycarbonyl grouping. With careful work up it was possible to obtain the hydroxymethyl derivative 141 from the corresponding diisopropyl ester 139 but attempted conversion of this to the corresponding bromomethylcyclopropane 143 again afforded a lactone 142. An attempt to obtain the latter bromomethyl compound via its tosyloxymethyl analogue was unsuccessful since decomposition of the appropriate tosyloxymethylpyrazoline 146 gave a complex mixture. However the bromomethylcyclopropanes 158 and 159 were obtained in excellent yield by hydrobromination of the lactone 142. In relation to the stereochemistry of the proposed cyclopropylmethyl radical, the preparation of the isomeric cyclopropanes with the ester groups cis was also studied briefly using citraconic anhydride derivatives e.g. the tosyloxymethylpyrazoline 155, but no useful results were obtained.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: N J McCorkindale
Keywords: Organic chemistry, Pharmacology
Date of Award: 1993
Depositing User: Enlighten Team
Unique ID: glathesis:1993-75355
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 20:26
Last Modified: 19 Nov 2019 20:26

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