Synthesis of prenylated natural products utilising pericyclic processes

• Main Author: Lucas, Catherine Louise
• Published: University of Nottingham 2011
• Subjects: 541.39
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555739

This Thesis describes the synthesis of prenylated phenolic natural products using pericyclic reactions, including the aromatic Claisen rearrangement and 67t- electrocyclisations. Chapter 1 presents an overview of the biological processes responsible for the generation of prenylating agents in Nature and the construction of prenylated phenolic compounds by the convergence of biosynthetic pathways. This is followed by a synopsis of established methods to access prenylated phenols in the laboratory. Chapter 2 focuses on the use of the aromatic Claisen rearrangement to construct prenylated phenols. The Chapter begins with a review of the Claisen rearrangement including mechanistic aspects and the use of this methodology to construct prenylated natural products. The synthesis of two novel prenylated natural products is presented in Section 2.3; the key features of the routes being consecutive chemo- and regio-selective Claisen rearrangements to install the prenyl side-chains and chromene ring. Section 2.4 describes the synthesis of (±)-pestalotheol D, employing a novel modification of the Claisen rearrangement precursor in order to reverse the regioselectivity of the rearrangement. An asymmetric approach is also presented, using a Sharpless asymmetric dihydroxylation to introduce the requisite stereochemistry. (- )-Pestalotheol D was successfully synthesised, confirming the absolute stereochemistry of the natural product. Section 2.4.4 explores this new methodology by means of experimental and theoretical studies of the effect of the modification on regioselectivity in the Claisen rearrangement of meta-allyloxy aryl ketone substrates. Chapter 3 is directed towards the assembly of prenylated phenollc compounds using 67t-electrocyclisations. The Chapter begins with a brief summary of electrocyclisations, followed by highlights from the literature of the syntheses of related natural products. Section 3.3 introduces l,4-thiazine natural products, with exploration of the syntheses of naturally occurring 1,1-dioxo-l,4-thiazines. Studies towards the synthesis of thiaplidiaquinone A are presented in Section 3.4; the initial approach via a bis-phenol is described, utilising a Suzuki-Miyaura cross-coupling to access the key biaryl intermediate. Oxidation of the bis-phenol could not be performed, and this route was subsequently revised in order to incorporate the required hydroxyls; this is examined in Section 3.4.2. The attempted synthesis of aplidinone A is detailed in the next Section, with the conclusion being the synthesis of its thiazine regioisomer. Analysis of the resulting thiazine regiochemistry is discussed using calculations and 2D NMR experiments. Suggestions for related future work on these two projects are outlined at the end of their respective Sections. Chapter 4 details experimental procedures for the chemistry performed throughout the projects.