Synthesis and Biosynthesis of Pyrrolizidine Alkaloids and Analogues

Thomson, Glenn McLean (1990) Synthesis and Biosynthesis of Pyrrolizidine Alkaloids and Analogues. PhD thesis, University of Glasgow.

Abstract

Pyrrolizidine alkaloids are important because they have a widespread occurrence and many of the alkaloids are hepatotoxic. The work presented in this thesis is divided into three sections: (a) investigations into the synthesis of pyrrolizidine bases; (b) feeding of optically active putrescine analogues to plants which produce pyrrolizidine alkaloids; (c) structural studies on seeds which produce pyrrolizidine alkaloids. (A) Investigations into the synthesis of pyrrolizidine bases A route aimed at providing a range of necines, principally in optically active form, from the stereoisomeric forms of malic and tartaric acids was studied. A series of intermediate imides was prepared (e.g. A) from these diacids and development of the pyrrolizidine ring system was achieved (e.g. B) through condensation of the sodium salt of these imides with ethoxycarbonylcyclopropyltriphenylphosphonium tetrafluoroborate. However, attempts to convert the products of this cyclisation into the desired products (such as C and D) were unsuccessful. A brief summary of the route pursued is outlined in Scheme I for the synthesis from L-tartaric acid diethyl ester. A series of problems beset this route, including the failure of well precedented reactions in the latter stages of the reaction sequence. In addition, poor yields were encountered for certain steps together with epimerisation of key intermediates. Attempts to modify the strategy could not overcome these problems. (B) Feeding of optically active putrescine analogues to plants which produce pyrrolizidine alkaloids The feeding of putrescine analogues to Senecio pleistocephalus (family Compositae) plants was undertaken. Putrescine is known to be involved in the biosynthesis of rosmarinecine (E) , the base portion of the pyrrolizidine macrocyclic diester (rosmarinine) produced by these plants. A route was devised to enable preparation of optically active 2-methoxy- putrescines from the optically active malic acids. This is illustrated in Scheme II for synthesis of one enantiomer from L-malic acid. For feeding experiments these substituted putrescines were successfully prepared in radiolabelled form by the use of [14C] methyl iodide in the methylation step on the route from malic acid. Feeding of the [14C-Me]-2-methoxyputrescines indicated that neither of the enantiomeric forms was readily utilised in the biosynthetic pathway to rosmarinecine. No evidence of likely intermediates in the biosynthetic pathway or of the formation of rosmarinecine analogues was obtained. An intermediate trapping experiment demonstrated that the 2-methoxyputrescines do not remain intact within the plant. (C) Structural studies on seeds which produce pyrrolizidine alkaloids Seeds of Crotalaria lanceolata (family Leguminosae) were extracted and the alkaloidal mixture was separated by chromatography. Three alkaloids were present in the seeds in a ratio of 85:10:5 (F:G:H). These were identified by spectroscopic studies as the known pyrrolizidine alkaloids usaramine (F), nilgirine (G), and integerrimine (H).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1990
• Depositing User: Enlighten Team
• Unique ID: glathesis:1990-78166
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 28 Feb 2020 12:09
• Last Modified: 28 Feb 2020 12:09
• URI: https://theses.gla.ac.uk/id/eprint/78166