Second-Generation Synthesis of Psymberin

A second-generation formal synthesis of psymberin was successfully developed, incorporating several notable advancements. Central to this approach is a challenging Heck reaction, which effectively unites a sterically demanding aryl moiety with a terminal alkene, showcasing the method’s robustness under these conditions. Additionally, the construction of the isocoumarin scaffold was accomplished through a Pd-mediated cyclization, underscoring the efficiency and precision of this key transformation. Notably, this improved route to De Brabander’s advanced intermediate from the 2,6-trans-tetrahydropyran fragment demonstrates significant advantages over the previous synthesis. The revised method requires seven fewer steps, reducing complexity and enhancing practicality. Moreover, the overall yield has been markedly improved, increasing from 5.9% in the earlier route to 9.3%, reflecting a considerable gain in efficiency. These optimizations highlight the method’s potential for broader applicability in the synthesis of psymberin and related compounds.