A convergent total synthesis of the ivermectin aglycon through transition metal-mediated and anionic transformations

For decades, the avermectin class of macrolide natural products have played a critical role in the treatment of numerous infectious diseases and pests across the globe. Due to their biological activity and complex architecture, these natural products have inspired a great number of influential syntheses. Herein, we report a convergent total synthesis of the ivermectin B1a aglycon that addresses long‑standing challenges in constructing its highly functionalized macrolide framework. Systematic evaluation of multiple cyclization pathways for the southern hydrobenzofuran fragment leads to the development of a palladium‑catalyzed reductive cyclization of an alkynyl ketone, which reliably forges the benzofuran core while constructing a congested tetra-substituted stereocenter. The northern spiroacetal fragment is efficiently assembled through an epoxide ring-opening cascade using simple building blocks. A cyclization templating strategy employing a flexible succinate linker is leveraged to overcome the kinetic and thermodynamic challenges associated with macrocyclization. Ultimately, this strategy enables the selective ring-closing metathesis to forge the 21‑membered macrocycle, providing access to ivermectin B1a aglycon in 21 longest‑linear steps from p-cresol. The structural complexity and biological importance of avermectins have made them longstanding targets for chemical synthesis. Here, the authors report a convergent total synthesis of the ivermectin B1a aglycon using strategic fragment assembly and templated macrocyclization in 21 longest-linear steps.