Synthesis and Biological Activity of Pyrrolizidine Alkaloids and Analogues

Chisholm, Greig (1996) Synthesis and Biological Activity of Pyrrolizidine Alkaloids and Analogues. PhD thesis, University of Glasgow.

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The work presented in this thesis is concerned with the synthesis and biological activity of pyrrolizidine alkaloids and analogues and has been divided into seven main areas: (a) the isolation and preparation of simple derivatives of pyrrolizidine alkaloids isolated from plants and root cultures available within the University; (b) the synthesis of synthanecine A, and derivatives of this compound for investigation of their anti-tumour activity; (c) approaches to the synthesis of one enantiomer of synthanecine A; (d) approaches to the synthesis of a novel synthanecine; (e) attempted synthesis of novel necic acids for esterification with synthanecine A; (f) the synthesis of novel pyrrolizidine alkaloid analogues via a 1,3-dipolar cycloaddition; (g) investigation of the biological activity of some of the compounds isolated and synthesised during the project. Those topics of greatest significance in the thesis are summarised more fully below. Isolation and Derivatisation of Pyrrolizidine Alkaloids. A number of pyrrolizidine alkaloids are available in the Chemistry Department, either from plant sources or from root cultures. Samples of these compounds were requested by Dr. Bryan Hanley, MAFF, Norwich, for metabolic studies. These compounds were also required to be radiolabelled with 14C. This was achieved by feeding [1,4-14C]putrescine (A) to the plants and root cultures. The N- oxides of the pyrrolizidine alkaloids isolated were synthesised. N-Oxides of the radiolabelled alkaloids were also synthesised. The quaternary methiodide derivatives were also prepared for biological testing. Rosmarinine (B) can be readily isolated in gram quantities from Senecio pleistocephalus. This compound can be converted into the toxic alkaloid senecionine (C) by elimination of the hydroxyl group to give a double bond in the 1,2-position. This elimination was carried out with limited success. Approaches to the Synthesis of One Enantiomer of Synthanecine A In order to prepare a closer pyrrolizidine alkaloid analogue, the synthesis of one enantiomer of synthanecine A (H, R=H) was undertaken. Several approaches were tried in this synthesis. In all approaches the key intermediate methyl (R)-3-(N-methylamino)-4-hydroxybutanoate was identified (D). Syntheses starting from (S)- malic acid (E) and from D-aspartic acid (F) were attempted. L-Aspartic acid was also used because it is cheaper and more readily available. The synthesis from L-aspartic acid proved most successful, and this route was advanced beyond the key intermediate to the diester (G). Approaches to the Synthesis of a Novel Optically Active Synthanecine Synthanecine A differs from a pyrrolizidine alkaloid in the number of carbon atoms in the molecule. Thus it was decided to attempt a synthesis of the novel synthanecine (H, R=Me). The substituted pentanoic acid derivative (I) was identified as the key intermediate. This compound could be derived from L-threonine. Synthesis of Novel Pyrrolizidine Alkaloids Analogues via a 1,3-Dipolar Cycloaddition The 1,3-dipolar cycloaddition reaction of the azomethine ylide (J) derived from N-benzyl-N-(trimethylsilylmethyl)aminomethyl methyl ether (K) with a variety of dipolarophiles was used to prepare a range of pyrrolidines of the general structure (L) and the 3-pyrroline (M). Simple derivatives of the pyrrolidines were prepared by removal of the benzyl groups and by reduction and further reaction of the ester functions.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: D J Robins
Keywords: Organic chemistry
Date of Award: 1996
Depositing User: Enlighten Team
Unique ID: glathesis:1996-74885
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 15:41
Last Modified: 27 Sep 2019 15:41

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