Synthesis and Biological Activity of Macrocyclic Diesters of Synthanecine A

Barbour, Robert Howie (1986) Synthesis and Biological Activity of Macrocyclic Diesters of Synthanecine A. PhD thesis, University of Glasgow.

Abstract

This thesis covers three areas of research relating to pyrrolizidine alkaloids, (a) Synthesis of macrocyclic pyrrolizidine alkaloid analogues based on synthanecine A; (b) Biological activity of these pyrrolizidine alkaloid analogues, and (c) Structural studies. (a) Synthesis of macrocyclic pyrrolizidine alkaloid analogues based on synthanecine A. The synthesis of macrocyclic pyrrolizidine alkaloid analogues based on synthanecine A [(+-)-2,3-bishydroxymethyl-l-methyl-3-pyrroline] has been achieved by three routes. In the first, treatment of synthanecine A with various succinic and glutaric derivatives selectively yielded 6-monoester hydroxy acids which were lactonised via their corresponding pyridine-2-thiol esters (Corey-Nicolaou lactonisation). The macrocyclic nature of these 10- and 11-membered pyrrolizidine alkaloid analogues was established by spectroscopic studies. In the second route, (+-)-3-chloromethyl-2-hydroxymethyl-l-methyl-3-pyrrolinium chloride, prepared by the reaction of synthanecine A and thionyl chloride, was treated with a series of aliphatic, olefinic and aromatic 5- and 6-membered anhydrides, in the presence of base, to yield macrocyclic diesters. Lactonisation was effected by the intramolecular nucleophilic substitution of the allylic chloride by carboxylate anion. This simple and efficient procedure resulted in higher yields of the 10- and 11-membered pyrrolizidine alkaloid analogues than by the first procedure. In the final route, macrocyclic diesters of synthanecine A with 12- to 16-membered rings were prepared by a combination of the above two methods. Treatment of (+-)-3-chloromethyl-2-hydroxymethyl-1-methyl-3-pyrrolinium chloride with the appropriate diacid, in the presence of base, gave a monoester hydroxy acid which was lactonised by the Corey-Nicolaou method. Attempts to prepare these analogues via the non-hydrolytic conversion of an intermediate monoester phenyl ester into a monoester N-acylimidazolide failed; oligomeric products were probably formed. (b) Biological activity of pyrrolizidine alkaloid analogues. The biological activity of a series of these analogues based on synthanecine A was examined. Dilactones of synthanecine A are metabolised in a similar manner to pyrrolizidine alkaloids and thus are hepatotoxic if they are resistant to esterase hydrolysis. The structure of the diacid moiety was seen to have a significant influence on the metabolic rate of these macrocyclic diesters. (c) Structural analysis. The structure of emiline, a macrocyclic pyrrolizidine alkaloid, has been revised. The original structure proposed, containing an 11-membered ring, was inconsistent with 1H and 13C n.m.r. spectroscopic data. The use of advanced n.m.r. spectroscopic techniques was invaluable in this structural revision, which showed that emiline contains a 12-membered ring.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1986
• Depositing User: Enlighten Team
• Unique ID: glathesis:1986-77412
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jan 2020 09:09
• Last Modified: 14 Jan 2020 09:09
• URI: https://theses.gla.ac.uk/id/eprint/77412