Synthesis of Pyrrolizidine Alkaloid Analogues As Potential Anti-Tumour Agents

Baxter, George (1989) Synthesis of Pyrrolizidine Alkaloid Analogues As Potential Anti-Tumour Agents. PhD thesis, University of Glasgow.

Abstract

This Thesis covers three areas of research relating to Pyrrolizidine Alkaloids: (a) Synthesis of PA analogues based on Synthanecine A [(+/-)-2,3-bis-hydroxymethyl-l-methyl-3-pyrroline]; (b) Synthesis of derivatives of supinidine, and (c) Use of 1-pyrroline aimed towards the synthesis of PA analogues. (a) Synthesis of Pyrrolizidine Alkaloid Analogues based on Synthanecine A. - The synthesis of PA analogues based on Synthanecine A has been achieved. Treatment of Synthanecine A with various acid chlorides, chloroformates and isocynates, yielded ester, carbonate and carbamate derivatives respectively. Reaction of two of these derivatives with hydrogen peroxide gave the corresponding N-oxides, both of which proved to be unstable compounds. A new monocyclic analogue [(+/-)-3-hydroxymethyl-l-methyl-3-pyrroline] of supinidine was prepared by a route analagous to that used for Synthanecine A. (b) Synthesis of supinidine derivatives. - The first synthesis of 3,3-dimethylsupinidine has been accomplished. N-Alkylation of proline using dimethyl 2-bromo-2-methylpropylidenemalonate, followed by iminium ion formation and intramolecular cyclisation gave the required pyrrolizidine skeleton. Deethoxycarbonylation, introduction of unsaturation and reduction of the ester led to 3,3-dimethylsupinidine. Extension of this approach aimed towards 8-methylsupinidine proved unsuccessful. New methods of iminium ion cyclisation were developed, using bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine (TEA). (c) Use of 1-pyrroline aimed towards the synthesis of PA analogues. 1-Pyrroline (an unstable oil) was prepared by hydrolysis of a-aminobutanal diethylacetal and found to form a stable solid complex with zinc iodide. The 1-pyrroline could be regenerated when needed by treating the complex in organic solution with a base such as triethylamine. Attempts to use this complex as a dienophile source aimed towards the synthesis of pyrrolizidine and indolizidine alkaloids proved unsuccessful. However, the complex reacted as a source of 1-pyrroline with a range of B-ketoacids to produce acylpyrrolidines in high yield. Thus, a good synthon for the construction of five-membered rings containing nitrogen is now available in a stabilised form.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1989
• Depositing User: Enlighten Team
• Unique ID: glathesis:1989-77964
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 30 Jan 2020 15:46
• Last Modified: 30 Jan 2020 15:46
• URI: https://theses.gla.ac.uk/id/eprint/77964