Biosynthesis of the Pyrrolizidine Alkaloid Rosmarinine

Kelly, Henry Anderson (1987) Biosynthesis of the Pyrrolizidine Alkaloid Rosmarinine. PhD thesis, University of Glasgow.

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Abstract

The work presented in this thesis is divided into three sections: (a) Biosynthesis of rosmarinecine; (b) Synthesis of macro-cyclic pyrrolizidine diester analogues; and (c) Structural studies. (a) Biosynthesis of Rosmarinecine The biosynthesis of rosmarinecine, the base portion of the pyrrolizidine alkaloid rosmarinine (A), has been studied in Senecio pleistocephalus (family Compositae) plants. Samples of [1-13C]- and [2,3-13C2]putrescine dihydrochloride were incorporated with very high specific incorporations (up to 25% per unit) into rosmarinine. 13C N.m.r. spectroscopy established complete labelling patterns and showed that two molecules of putrescine were incorporated to about the same extent into rosmarinine. The incorporation of [1-amino-15N, 1-13C]- putrescine dihydrochloride into rosmarinine produced a labelling pattern which was indicative of the conversion of two putrescine molecules into a C4-N-C4 symmetrical intermediate. Intact incorporation of [1,9-13C2]- homospermidine trihydrochloride into rosmarinecine, was consistent with this intermediate being homospermidine. The stereochemistry of the enzymic processes in the pathway was investigated by feeding (R)-[1-2H]- and (S)-[1-2H] putrescine dihydrochloride to S. pleistocephalus. The labelling patterns obtained in rosmarinine, as determined by 2H n.m.r. spectroscopy, were consistent with the following. The oxidation of putrescine to 4-aminobutanal occurs with the loss of the pro-S hydrogen. The aldehyde and another molecule of putrescine condense to give the corresponding imine, which after reduction (on the C-si face) affords homospermidine. Two further oxidations each take place with loss of the pro-S hydrogens generating the dialdehyde, which after Mannich cyclisation produces 1B -formyl-8a-pyrrolizidine. Reduction to isoretronecanol proceeds by the delivery of a hydride equivalent on the C-re face of the carbonyl group. Feeding experiments with (R)-[2-2H]- and (S)-[2-2H]putrescine dihydrochloride established that the two hydroxylations in rosmarinecine occur with retention of configuration and that formation of the pyrrolizidine ring involves the stereospecific removal of the pro-R hydrogen on the carbon which becomes C-1 of rosmarinecine. The proposed product from the first oxidation of homospermidine, N-(4-aminobutyl)-1,2-didehydropyrrolidinium, was shown to be an intermediate in the biosynthetic pathways to several pyrrolizidine alkaloids, by 14C-labelling experiments and an intermediate trapping experiment. Platynecine was shown to be an efficient precursor for rosmarinecine biosynthesis using 3H-labelling experiments. Similarly, rosmarinecine was found to be an efficient precursor for rosmarinine biosynthesis. (b) Synthesis of Macrocyclic Pyrrolizidine Diester Analogues A number of optically active 12-membered macrocyclic dilactones containing (+)-6alpha-hydroxy-1alpha-hydroxymethyl-8beta-pyrrolizidine were prepared by lactonisation via the pyridine-2-thiolesters with different anhydrides. These are the first synthetic macrocyclic pyrrolizidine diester analogues which contain a saturated pyrrolizidine base. (c) Structural Studies The plant Lindelofia longiflora (family Boraginaceae) was shown, by spectroscopic studies, to contain one pyrrolizidine alkaloid, echinatine. Similarly, Cynoglossum macrostylum (family Boraginaceae) was found to contain two major alkaloidal components. Echinatine and heliosupine were identified in the ratio 3:1.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1987
Depositing User: Enlighten Team
Unique ID: glathesis:1987-77568
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 09:05
Last Modified: 14 Jan 2020 09:05
URI: http://theses.gla.ac.uk/id/eprint/77568

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