The synthesis of compounds containing alpha-arylated quaternary stereogenic centres is a significant synthetic challenge. This thesis describes the development of an organocatalytic methodology for the direct construction of this motif through the Michael addition of carbon-centered pro-nucleophiles to highly reactive and unstable ortho-benzoquinones. Proof-of-principle for the base catalysed Michael addition to ortho-quinones was established with stable 1,2-naphthoquinone (Chapter 2), however typical orthobenzoquinones were found to be too unstable to use in this process. Accordingly an oxidative coupling strategy was developed for in-situ generation of the obenzoquinone electrophile (Chapter 3.1). The base catalysed Michael addition followed by aromatisation allows for the direct construction of arylated quaternary stereocentres. An asymmetric variant was also developed by replacing the base catalyst with a cinchona alkaloid derived organocatalyst, up to 82% ee was achieved (Chapter 3.2).The methodology was then applied to the racemic total synthesis of the amaryllidaceae alkaloids powelline and buphanidrine (Chapter 4). The oxidative coupling methodology allowed rapid construction of the sterically congested arylated quaternary stereocentre in the key step of the syntheses, which were then completed in 13 and 14 steps respectively in 6% overall yield. Employing a quinidine derived organocatalyst in the oxidative coupling step gave the arylated product in 57% yield (3 steps) and 70% ee (Chapter 5). However, the enantioselective total synthesis was thwarted by racemisation during the Dieckmann-type cyclisation for the formation of enol ether 212 and an alternative synthetic strategy will berequired to synthesise the enantiopure alkaloid.
|Date of Award||1 Aug 2011|
- The University of Manchester
An Organocatalytic Oxidative Coupling Strategy for the Synthesis of Arylated Quaternary Stereocentres and its Application in the Total Synthesis of Powelline and Buphanidrine
Bogle, K. (Author). 1 Aug 2011
Student thesis: Phd