Go for Gold: Development of a Scalable Synthesis of [1‐(Ethoxycarbonyl)cyclopropyl] Triphenylphosphonium Tetrafluoroborate, a Key Reagent to Explore Covalent Monopolar Spindle 1 Inhibitors

Covalent approaches have resurged in drug discovery and chemical biology during the last decade. So-called targeted covalent inhibitors typically show a strong and persistent drug-target interaction as well as a high degree of selectivity. In our research group, RMS-07 (8), a First-in-Class covalent inhibitor of the protein kinase threonine tyrosine kinase (TTK)/monopolar spindle 1, which shows promising results in a variety of different solid cancer cell types and will be further optimized in terms of covalent binding kinetics, has recently been developed. However, synthetic accessibility is restricted by a high price and limited availability of [1-(ethoxycarbonyl)cyclopropyl] triphenylphosphonium tetrafluoroborate (10), a key reagent required to assemble the tricyclic core scaffold in a Wittig-type cyclization reaction. This reagent is also described as a valuable synthon for the synthesis of a range of ring systems with interesting applications in medicinal chemistry. However, reliable procedures for its large-scale synthesis are scarce. Only one prior report describes the synthesis of reagent 10, and it contains limited experimental details, making it challenging to reproduce and scale up. Herein, a concise and reproducible decigram-scale synthetic protocol for accessing key reagent 10 is described.