Total synthesis and SAR of Alternaric acid towards the development of a new herbicidal lead

Abstract

Crop protection is essential in agricultural chemistry to help farmers maintain a healthy and productive cropland. However, agrochemical research faces a constant need for innovation in crop protection to be able to meet the global requirement for food supplies. Over the years, fighting resistance against crop protection products has become one of the biggest challenges in the development of effective agrochemicals. As a result, there is a requirement for new agrochemicals exhibiting novel Modes of Action (MoA). Natural products are privileged scaffolds in agrochemistry, owing to their molecular complexity and rich bioactivity, which can leads to the discovery of novel MoA.

The natural product Alternaric acid, isolated from the phytopathogenic fungus Alternaria solani, has been identified as possessing herbicidal activity. As such, it represents an attractive herbicidal lead for the agrochemical industry. However, exploration of the potential of this target has remained undeveloped due to low accessibility and lack of Structure-Activity Relationship (SAR) data.

The research described in this thesis was conducted in collaboration with Syngenta. Herein, we report the development of a scalable and flexible synthetic route, which enabled the synthesis of significant quantities of Alternaric acid as well as a variety of analogues. Through biological evaluation of these compounds, SAR profiling of focused libraries identified a new class of small molecule leads, with enhanced herbicidal activity and developability. Additionally, MoA investigations have been conducted, suggesting that this new class of lead compounds is likely to exhibit a novel MoA, highlighting their potential for herbicidal discovery.