Synthesis and Biosynthesis of Pyrrolizidine Alkaloids and Their Analogues

Rodgers, Michael (1990) Synthesis and Biosynthesis of Pyrrolizidine Alkaloids and Their Analogues. PhD thesis, University of Glasgow.

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Abstract

The work presented in this thesis is divided into three sections: (a) Biosynthesis of otonecine; (b) Synthesis of macrocyclic pyrrolizidine diesters; and (c) Synthetic analogue studies. (a) Biosynthesis of Otonecine The biosynthesis of otonecine, the base portion of the pyrrolizidine alkaloid emiline (A) , has been studied in Emilia flammea (family Compositae) plants and hairy root cultures. It was observed that [1,4-14C] putrescine dihydrochloride was incorporated into emiline with specific activities of >4% for hairy root cultures and 1% for plants. The incorporation of [1,9-14C] homospermidine trihydrochloride with comparable specific incorporation to [1,4-3H] putrescine indicates the conversion of putrescine via the symmetrical C4-N-C4 intermediate, homospermidine. Incorporation of 3H-labelled retronecine into emiline in E. flammea hairy root cultures is indicative of the intermediacy of retronecine in the emiline biosynthesis. The stereochemistry of the enzymic processes on the pathway was investigated by feeding (R)-[1-2H]-, (R)-[2-2h]- and (S)-[2-2H] putrescine dihydrochloride to E. flammea hairy root cultures. The labelling patterns obtained in emiline, as determined by 2H n. m. r. spectroscopy, were consistent with the following. The oxidation of putrescine to 4-aminobutanal occurs with the loss of the pro-S hydrogen. The aldehyde and another molecule of putrescine condense to give the corresponding imine, which after reduction (on the C-si face) affords homospermidine. Two further oxidations each take place with loss of the pro-5 hydrogens generating the dialdehyde, which after Mannich-type cyclisation produces 1alpha-formyl-8alpha-pyrrolizidine. Reduction to trachelanthamidine proceeds by the delivery of a hydride equivalent on the C-re face of the carbonyl group. The hydroxylation at C-7 in otonecine occurs with retention of configuration. Retronecine was shown to be an efficient precursor for otonecine biosynthesis using 3H-labelling experiments. The plant Adenocarpus decorticans was shown, by spectroscopic and comparative studies, to contain the quinolizidine alkaloid, sparteine (B). (b) Synthesis of Macrocyclic Pyrrolizidine Diesters A number of optically active 10- and 11-membered dilactones containing (-)-platynecine were prepared by lactonisation via the pyridine-2-thiolesters with different anhydrides. These are the first synthetic macrocyclic pyrrolizidine diester analogues which contain (-)-platynecine. (c) Synthetic Analogue Studies The diamines cis and (+)-trans-1,2-Bis (aminomethyl)-cyclopropane were made from acyclic precursors. Along with cis- and trans-buten-2-ene-1,4-diamines, these will be tested for anti-fungal and enzyme inhibitory activity.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1990
Depositing User: Enlighten Team
Unique ID: glathesis:1990-78017
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 15:43
Last Modified: 30 Jan 2020 15:43
URI: http://theses.gla.ac.uk/id/eprint/78017

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