Biosynthesis and Synthesis of Pyrrolizidine Alkaloids and Analogues

Hagan, Desmond Bernard (1987) Biosynthesis and Synthesis of Pyrrolizidine Alkaloids and Analogues. PhD thesis, University of Glasgow.

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This thesis deals with three aspects of research into pyrrolizidine alkaloids: (a) the synthesis of macrocyclic pyrrolizidine alkaloid analogues incorporating (+)-heliotridine (A); (b) the study of the biosynthesis of pyrrolizidine bases using specifically labelled molecules; and (c) the investigation of the pyrrolizidine alkaloid content of plants not previously studied. (a). Synthesis of macrocyclic pyrrolizidine alkaloid analogues incorporating (+) -heliotridine The synthesis of a series of novel macrocyclic diesters of (+)-heliotridine (A) has been achieved by the use of the Corey-Nicolaou double activation method of lactonisation. The base (A) was obtained by the alkaline hydrolysis of (+)-echinatine, a natural pyrrolizidine monoester isolated by methanolic extraction of Cynoglossum officinale. An alternative method of production of (+)-heliotridine utilised a short, known conversion of the pyrrolizidine base (+)-retronecine into (+)-heliotridine which was carried out with modifications. The treatment of (+)-heliotridine (A) with glutaric anhydride derivatives selectively yielded 9-monoesters of (+)-heliotridine. Lactonisation of these monoesters was effected via the corresponding pyridine-2-thiolesters. The macrocyclic nature of these 11-membered pyrrolizidine alkaloid analogues was confirmed by spectroscopic studies. An X-ray analysis of 7,9-O,O'-(3,3-dimethylglutaryl)heliotridine (B) revealed the conformation of this bislactone in the solid state. The ester carbonyl groups of (B) are anti-parallel. Attempted synthesis of 10-membered bislactones of (+)-heliotridine was unsuccessful. (b). Study of the biosynthesis of pyrrolizidine bases The biosynthetic portion of the project was to attempt to gain insight into the various processes taking place in the biosynthesis of different base portions of pyrrolizidine alkaloids by plants. Previous work had shown that 1,4-diaminobutane (putrescine) is a good precursor of retronecine. A series of putrescines specifically labelled with 2H or 13C were synthesised by known routes. They were isolated as their dihydrochloride salts. These salts were each mixed with a known activity of a radioactive tracer and were fed to Cynoglossum officinale by the xylem pricking method. The plants were later harvested and extracted to yield samples of (+)-echinatine, i.e. esters of (+)-heliotridine (A). Scintillation counting showed the specific incorporations to be below 0.5% per C4-unit of the base portion and the 2H and 13C n.m.r. spectra of the (+)-echinatine samples, also showed evidence of the disappointingly low incorporations. An exception was noted with the use of [1-13C]-putrescine dihydrochloride. A 13C n.m.r. spectrum of (+)-echinatine was obtained in which the expected four (C-3,-5,-8 and -9) of the eight signals of the base portion, (+)-heliotridine (A), were enriched. The conditions of feeding were varied over the two subsequent summers but the same low incorporations always resulted. Only the base portion of (+)-echinatine was radioactive as shown by alkaline hydrolysis of each (+)-echinatine sample. An investigation of Cynoglossum australe revealed the presence of a mixture of (+)-cynaustraline and (+)-cynaustine. Biosynthetic interest arises because of the presence of two rare 8B-bases, (+)-isoretronecanol (C) and (+)-supinidine. (D) respectively. The specifically 2H labelled compounds previously synthesised were fed to batches of young Cynoglossum australe plants. However, again the specific incorporations were low and inconclusive 2H n.m.r. spectra were obtained. The experiments were repeated the following summer, but the same results were obtained. Alkaline hydrolysis of the alkaloid samples proved that the radioactivity present was located exclusively in the base portions, (C) and (D) , of the alkaloids. Putrescine with a radioactive 3H label was fed as the dihydrochloride to several young Cynoglossum australe plants by the wick method. A good incorporation (> 1%) into each alkaloid was obtained, and radioactive samples of the two 1-hydroxymethyl pyrrolizidines (C) and (D) were obtained after separation of the alkaloids and subsequent hydrolysis. Each 8B-necine was then fed in turn to different batches of young Cynoglossum australe plants. Isoretronecanol (C) was a precursor for both alkaloids, but supinidine (D) was only incorporated into cynaustine. This finding is consistent with conversion of isoretronecanol into supinidine in the biosynthetic pathway.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1987
Depositing User: Enlighten Team
Unique ID: glathesis:1987-77629
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53

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