Consecutive gold[I]-catalysed cyclisation reactions leading to polyfused heterocycles of agrochemical relevance

• Main Author: Sharp, Phillip Patrick
• Format: Thesis
• Language: English
• Published: The Australian National University 2018
• Subjects: QD421.S53 2011; Alkaloids Synthesis; Organic compounds Synthesis; Sponges Antarctic Ocean; Marine natural products; Antarctic; The Antarctic; Antarctic Ocean; Antarc*
• Online Access: https://dx.doi.org/10.25911/5d4d5af5d7243; https://openresearch-repository.anu.edu.au/handle/1885/151313

Variolin B, a marine natural product isolated from the Antarctic sponge Kirkpatrickia variolosa, possesses a rare heterocyclic framework and is a potent CDK inhibitor. Such properties have prompted the industry partner associated with this project, namely the German chemical commodities company BASF, to select this compound as a lead for the development of new agrochemicals. This thesis details the development of new synthetic methods specifically designed to produce complex heterocyclic frameworks related to variolin B. The synthetic plan, which involved consecutive electrophile-promoted nucleophilic ring-closure reactions of 1-[2-(buta-1,3-diynyl)pyridyl]ureas potentially leading to pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-9(8H)-ones, is outlined in Chapter One. The first part of Chapter Two describes the synthesis of alkynylphenylureas as model cascade cyclisation precursors and the second part details the outcomes of reactions of these model compounds with various sources of iodine. The reactions delivered mono-cyclised compounds in some cases although intermolecular side-reactions prevented cascading cyclisation reactions from occurring. Details of the successful development of consecutive gold-catalysed nucleophilic ring-closure reaction of 2-(buta-1,3-diynyl)phenylureas that deliver pyrimido[1,6-a]indol-1(2H)-ones are provided in Chapter Three. The effect that substituents have on the outcome of these gold-promoted reactions were also assessed and it was found that N,N'-disubstituted cyclisation precursors give 1-methylene-1H-imidazo[1,5-a]indol-3(2H)-ones as the major products. Chapter Four outlines the preparation of pyridine-based cyclisation precursors and attempts to synthesise variolin B by applying the gold-catalysed cyclisation methodology to them. These reactions led to mono-cyclised products in some cases but side reactions were also observed. Many of the heterocycles produced during the course of this work are unprecedented and, accordingly, they are being tested for their agrochemical properties by BASF Crop-Protection Division. This aspect of the work is discussed in Appendix 1.