Development of cascade cross-coupling / Diels–Alder approaches for complex molecule synthesis

Abstract

The Diels–Alder (DA) reaction is an important and frequently used synthetic transformation in the formation of both complex building blocks and natural products. Significant attention has being invested in its utilisation within cascade events, primarily due to its ability to form six-membered rings with numerous contiguous stereocenters in a selective manner. Its combination with cross-coupling reactions has become an evolving field in accessing novel chemical space, by circumventing the need for handling potentially reactive diene intermediates. This thesis will begin with a discussion surrounding the multiple terminologies defining multi-step reactions, and provide examples focussing in the area involving cross-coupling/Diels-Alder reactions (CCDA).

The first chapter highlights the development of a cascade Suzuki–Miyaura/Diels–Alder (SM/DA) protocol, involving vinyl Bpin, a bi-functional entity (as nucleophile in the SM, and the dienophile in DA), in facilitating the overall transformation. A discussion involving its optimization is disclosed, alongside the challenges that were encountered and how these were overcome. The optimised conditions were applied to generate a range of borylated carbocylic products of varying complexity (17 examples). In this work the effect of the organoboron subtype on Diels-Alder regioselectivity was investigated and post-synthetic modifications were carried out on a model substrate. Lastly, the potential for a complementary Heck/Diels-Alder process was also assessed.

Having developed the SM/DA methodology, its application was envisaged as a key step in the divergent synthesis of Aspidosperma alkaloids in the second chapter. Despite these alkaloids being synthesized numerous times, due to their challenging structural topology and beneficial biological properties, there is a lack in Structure activity relationship (SAR) studies. The SM/DA protocol allows the rapid and efficient creation of an advanced skeletal framework in a single reaction, which can then be subjected to a series of simple chemical manipulations to furnish a common intermediate from which a natural product library can be generated. The optimization of pertinent steps in the synthesis are disclosed, along with interesting observations that were encountered.