Towards the biomimetic total synthesis of (±)-haloxine

Abstract

Natural products (secondary metabolites) have been the leading source of drug discoveries. Many biologically active products often exist in extremely low quantities in nature, making their extraction and isolation challenging and thus leading to low yields. Total synthesis allows chemists to produce these compounds in sufficient quantities for further studies and potential therapeutic applications. The process of total synthesis also provides educational values such as problem-solving skills and techniques that are essential for the training of new chemists.

Throughout the history of total synthesis, the field has evolved from merely determining whether molecules could be synthesized in laboratory settings to optimizing the process to achieve the shortest steps with the highest yields, adhering to green chemistry principles. By mimicking processes in nature, biomimetic synthesis has become a powerful tool to replicate chemical reactions of natural compounds based on proposed biosynthesis within a laboratory setting. This approach has enabled the successful synthesis of several complex compounds.

Despite nearly 60 years since its isolation, no synthetic studies on haloxine have been reported. This thesis aims to establish the first total synthesis of haloxine by proposing its biosynthetic origin and employing biomimetic strategies. The lack of available spectral data for haloxine added complexity to the synthesis and characterization efforts. Nevertheless, four approaches based on the key biomimetic cascade reactions were explored, leading to the syntheses of five new compounds. Due to time limits, the target natural product was not achieved. This thesis highlights the importance of biomimetic strategies in the synthesis of complex natural products and their potential to inspire innovative methodologies in synthetic chemistry.