Biosynthetic Studies of Natural Plant Products: The Biosynthesis of Petasin in Petasites hybridus (L) Compositae

Keates, Robert Anthony Butler (1970) Biosynthetic Studies of Natural Plant Products: The Biosynthesis of Petasin in Petasites hybridus (L) Compositae. PhD thesis, University of Glasgow.

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In recent years, the study of natural products has undergone a shift in emphasis from the classical, purely structural type of chemical investigation to consideration of the relationship of such compounds with the organism of origin. The widespread application of modern chromatographic and spectroscopic techniques has considerably simplified the isolation and characterisation of these compounds, permitting increasing attention to turn to wider biological issues as well as purely chemical aspects. Among these are the examination of biosynthetic processes and pathways, and the solution of mechanistic 1,2) problems. The investigation of biosynthesis has led to a greater understanding of the metabolic significance of many natural products, and to consideration of their biological function (3). In addition, the application of chemical characters to taxonomic (4) and phylogenetic (5) systematic has provided a valuable new source of evidence for the relationships between taxa. This thesis describes an investigation into the biosynthesis of the sesquiterpenoid, petasin (1), isolated from the plant Fetasites hybridus (L) Compositae. the structure of which was originally determined by Aebi and Waaler 6). The work was initiated as part of a long-term project by Dr. G. H. Draffan and Dr. J. A. Zabkiewicz, formerly of this department. Their preliminary findings have already been described (7). Petasin has been chosen for this study because it possesses the eremophilane (2) carbon skeleton, which cannot be directly derived by the Biogenetic Isoprene Rule proposed by Ruzicka 8). It has been suggested 9), 10) that eremophilanes are derived from the eudesmane (3) skeleton by a methyl shift across the ring Junction (3A). Another factor influencing the choice of petasin has been the easy availability of P. hybridus in the wild state. Finally, the chemotaxonomic studies of the Czech group of Sorm 11, 12) into various Petasites species have provided valuable background information on the chemistry of the sesquiterpenoids of this genus. Chemical studies of P. hybridus leaves from a number of sources thoughout Britain have demonstrated the consistent nature of the sesquiterpenoid constituents, the petasin esters being the principal components in each case. A more detailed examination, using the highly sensitive techniques of gas-liquid chromatography (GLC) and gas chromatography coupled to mass spectrometry (GC-MS), has revealed a number of other, non-esterified sescuiteruenoids, in particular, the hydrocarbon eremophilene (4) 13, 14). Many of these compounds may be significant as intermediates in the biosynthetic pathway. Using the available evidence of the sesouiterpenoid constituents, coupled with chemotaxonomic information, a rationalisation has been made of the probable biosynthetic pathway leading to petasin. This places eremophilene as the first fully cyclised component of the sequence. Stereoelectronic considerations of the cyclisation of trans,trans-farnesyl pyrophosphate (5) to eremophilene have led to a detailed proposition for the mechanism of these reactions, and for the mode of action of the enzymes responsible. This approach may also be applied to the biosynthesis of other classes of terpenoids, and is consistent with currently available experimental results. A series of conventional biochemical reactions is then postulated to derive the oxidised products, including petasin. Radioactive tracer methods have been employed in this investigation of petasin biosynthesis. (2-14C)Mevalonic acid (6k) was fed to growing leaves of P. hybridus via a cotton wick inserted through the petiole. Radioactive petasin was isolated, and selective chemical degradation was carried out to determine the location of the labelled carbon atoms. Radioactivity was found in petasin as shown in structure (1A) confirming the origin of the eremophilane skeleton from mevalonic acid in the manner originally proposed by Robinson However, 14C-labelling on its own gives no information as to the mechanism of cyclisation, and the crucial point concerning the origin of the methyl group at C-15 of eremophilane remains unanswered. The main difficulty encountered in this work concerns the ineffective penetration of externally fed mevalonic acid to the site of synthesis in the plant. The level of incorporation (0.003-0.03% of total radioactivity) might appear to imply that mevalonic acid was not directly involved in the biosynthesis, but for the specific location of the label in the molecule of petasin. This type of result is consistent with work covering other isoprenoid classes from higher plants.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1970
Depositing User: Enlighten Team
Unique ID: glathesis:1970-78542
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 15:11
Last Modified: 30 Jan 2020 15:11

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