Use of the Claisen rearrangement in natural product synthesis

Abstract

The first chapter of this thesis outlines the value of natural product synthesis before introducing the Claisen rearrangement and selected examples of its use in total synthesis from the recent literature. An introduction to the natural products (+)- perophoramidine, dehaloperophoramidine and a related family of natural products, the communesins, are discussed. Their isolation, structure and previous syntheses are described. A separate class of natural products consisting of neolignans possessing a bicyclic[3,2,1]octanoid core are also introduced as they were of interest as potential targets from a lignin-derived starting material. Finally, the aims and objectives are outlined.

Chapter 2 describes a second-generation synthesis of (±)-dehaloperophoramidine. This work shortened an existing route to (±)-dehaloperophoramidine that had previously been developed within the Westwood by 3 steps. Key transformations in this Chapter were a high yielding Claisen rearrangement and a Pinnick oxidation of a cyclic aldimine to a lactam.

Chapter 3 outlines two approaches towards the preparation of enantioenriched dehaloperophoramidine. An initial approach on a racemic system was conducted to test the suitability of the use of 1,3 chirality transfer during a Claisen rearrangement. A second approach involved the gram scale resolution of an early synthetic intermediate towards dehaloperophoramidine via a chiral sulfinamide.

Chapter 4 describes an approach towards neolignans possessing a bicyclic[3,2,1]octanoid core structure from a lignin-derived aromatic monomer. A model study involved a cyanide mediated cyclisation/coupling reaction of ethyl cinnamate, and a related derivative, for the construction of stereocongested cyclopentanone core structures. A second approach involved the construction of cyclopentenones via the Ireland-Claisen rearrangement of an allylic ester. Further progress towards one of the target neolignans was made via a 1,4-hydrocyanation and a highly diastereoselective allylation reaction.

Chapter 5 describes attempts to construct the bicyclic[3,2,1[octanoid core structures via
a samarium iodide mediated pinacol coupling.

In the final section, conclusions and future work are outlined.

Date of Award	6 Dec 2018
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Nicholas Westwood (Supervisor)