Natural product discovery: studies on the phenolic antioxidants from Smilax Glyciphylla and the synthesis and formation of Guaiane Sesquiterpenoids.

Abstract

The work within this thesis is positioned in the field of natural product (NP) chemistry and covers three main integrated studies along with some additional explorations. These studies not only included the isolation and characterisation of NP but also involved total syntheses of various NP and related derivatives and detailed mechanistic studies into potential routes of formation in nature. Given my naturally emerging zest for natural products, I have begun this thesis with a detailed discussion of the numerous syntheses of Taxol. This exemplar highlights not only why the field of natural products is so important, but also highlights the ever growing significance of total and semi-syntheses. The first major study investigated the phenolic profile and antioxidant activity of the leaves of the Australian native plant Smilax glyciphylla. Along with the sweet principle glycyphyllin A, seven phenolic compounds including two new dihydrochalcone rhamnosides, glycyphyllin B and C, and five known flavonoids were isolated from the ethanolic extract of the leaves of Smilax glyciphylla for the first time. The structures of these compounds were characterised by spectroscopic methods including UV, HRMS, 1D and 2D NMR. In vitro antioxidant capacity tests employing the FRAP and DPPH assays indicated that three of the isolated compounds exhibited potent antioxidant activity and are the key phenolics responsible for the high antioxidant activity of the leaf extract of S. glyciphylla. The second major study focused on the synthesis of guaiane type sesquiterpenoids via the diastereoselective epoxidation of guaiol and realized by manipulating the types of remote protecting groups on the isopropanoyl side chain, choice of solvent and epoxidising reagent. This stragety allowed for a concise stereoselective synthesis of a range of guaiane-type sesquiterpenoids including the natural products guaia-4(5)-en-11-ol, guaia-5(6)-en-11-ol, and aciphyllene and epimers of the recently isolated natural products, 1-epi-guaia-4(5)-en-11-ol, 1-epi-aciphyllene and 1-epi-melicodenone C and E in up to 31% yield within 11 steps. The third study explored the autoxidation of α-guaiene and the mechanisms involved. Over a dozen sesquiterpenoids including natural rotundone, corymbolone and the C7 epimers of natural chabrolidione A and several unstable hydroperoxide intermediates were isolated from the autoxidation products of α-guaiene. Their structures were elucidated on the basis of spectroscopic data along with the synthesis of authentic compounds. Detailed mechanistic studies have allowed many of the mechanisms involved in the formation of these downstream oxidation products to be elucidated. Together with the above main studies, several deuterium labelled precursors including d₇-α- guaiene, d₅-(2R/2S)-rotundols, d₅-α-bulnesone, d₇-α-bulnesene and d₅-2R-bulnesol were synthesised and used as internal standards to develop a robust analytical method (SIDA) to monitor the transformation of certain precursors to the sesquiterpneoid fragrances rotundone and 2R-bulnesol. A total of five publications support my research works herein and are included as the main research chapters of this thesis.